Indian Patents
Title of Invention

NOVEL PHOSPHONIC ACID COMPOUNDS AS INHIBITORS OF SERINE PROTEASES
Abstract The present invention is directed to phosphonic acid compounds useful as serine protease inhibitors, compositions thereof and methods for treating inflammatory and serine protease mediated disorders.
Full Text NOVEL PHOSPHONIC ACID COMPOUNDS AS INHIBITORS OF SERINE
PROTEASES
CROSS REFERENCE TO RELATED APPLICATIONS [31 M
This application claims benefit of provisional application Serial Number
60/330,343, filed 19 October 2001 and US Serial No. 10/273,208 filed October
17, 2002, which are hereby incorporated by reference.
FIELD OF THE INVENTION
The present invention relates to certain novel compounds, methods for
preparing the compounds, compositions, intermediates and derivatives thereof
and for treating inflammatory and serine protease mediated disorders. More
particularly, the phosphonic acid compounds of the present invention are serine
protease inhibitors .useful for treating inflammatory and serine protease
mediated disorders.
BACKGROUND OF THE INVENTION
Serine proteases represent a broad class of endopeptidases that are
involved in physiological processes such as blood coagulation, complement
activation, phagocytosis and turnover of damaged cell tissue. For example,
cathepsin G (cat G) is a chymotrypsin-like serine protease found in the
azurophilic granules of polymorphonuclear leukocytes. Along with other serine
proteases such as human neutrophil elastase and protease 3, cat G functions
to degrade proteins during inflammatory responses. Cat G is thought to
degrade human elastin during chronic lung inflammation, a process which may
in part be responsible for asthma, pulmonary emphysema, chronic obstructive
pulmonary diseases (COPD) as well as other pulmonary inflammatory
conditions. Similarly, human chymase (HC) is a chymotrypsin-like serine

protease synthesized in mast cells. HC has a variety of functions, including
degradation of extracellular matrix proteins, cleavage of angiotensin I to
angiotensin n and activation of matrix proteases and cytokines. Inadequate
control by their natural inhibitors can cause these enzymes to degrade healthy
constituents of the extracellular matrix, and thereby contribute to inflammatory
disorders such as asthma, emphysema, bronchitis, psoriasis, allergic rhinitis,
viral rhinitis, ischemia, arthritis and reperfusion injury. Thus, small molecule
inhibitors of cat G and HC are likely to represent useful therapeutic agents.
US Patent 5,508,273 to Beers, et al. and Bioorganic & Med. Chem. Lett.,
1995, 5, (16), 1801-1806 describe phosphonic acid compounds useful in
treating bone wasting diseases. In particular, 1-napthylmethylphosphonic acid
derivatives have been described as osteoclastic acid phosphatase inhibitors of
the formula:

Accordingly, it is an object of the present invention to provide
phosphonic acid compounds that are serine protease inhibitors (in particular,
inhibitors of cathepsin G and chymase) useful for treating inflammatory and
serine protease mediated disorders. It is another object of the invention to
provide a process for preparing phosphonic or phosphinic acid compounds,
compositions, intermediates and derivatives thereof. It is a further object of the
invention to provide methods for treating inflammatory and serine protease
mediated disorders.


wherein
Ri is selected from the group consisting of a heterocyclyl ring (wherein the
point of attachment for the heterocydyl ring at Ri Is a nitrogen ring atom)
and -N(RrRe); wherein the heterocyclyl ring is optionally substituted with one
to two substituents independently selected from the group consisting of:
a). Ci.fi alkyl optionally substituted on a terminal carbon atom with a substltuent
selected from the group consisting of aryl, heteroaryl, (halo)^ and hydroxy;
b). Ci.8 alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of carboxyl, (halo)i.3 and
hydroxy;
c). aryl;
d). heteroaryl;
e). cyano;
f). halogen;
g). hydroxy;
h). nitro; and,
i). heterocyclyl optionally substituted with one to two substituents
independently selected from the group consisting of oxo and aryl; and,
optionally fused with the carbon of attachment to form a spiro heterocyclyl

moiety;
and, wherein the aryl portion of the a), and i). substituent, the heteroaryl
portion of the a), substituent and the c). aryl and d). heteroaryl substituents
are optionally substituted with one to four substituents independently
selected from the group consisting of CM alkyl, C2-A alkenyl, C^ alkoxy,
cycloalkyl, heterocyclyl, aryl, aryl(Ci^)alkyl, aryloxy, heteroaryl,
heteroaryl(Ci^)alkyl, halogen, hydroxy, nitro, (halo)i-3(CM)alkyl and
(halo)i.3(Ci-4)alkoxy;
R7 is selected from the group consisting of hydrogen, C1.8 alkyl and C2-s
alkenyl;
R8 is selected from the group consisting of:
aa). C1.8 alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of cycloalkyl, heterocyclyl,
aryl, heteroaryl, amino (with two substituents independently selected from
the group consisting of hydrogen and C1-8 alkyl), (halo)i.3 and hydroxy;
ab). cycloalkyl;
ac). cycloalkenyl; and,
ad), heterocyclyl (wherein the point of attachment at Rs is a carbon ring atom);
wherein the ab). cycloalkyl, ac). cycloalkenyl and ad), heterocyclyl (wherein the
ad), heterocyclyl contains at least one nitrogen ring atom) substituents and
the cycloalkyl, heterocyclyl, aryl and heteroaryl portions of the aa).
substituent are optionally substituted with one to four substituents
independently selected from the group consisting of:
ba). C1-8 alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of amino (with two
substituents independently selected from the group consisting of hydrogen
and Ci^ alkyl), (halo)i-3 and hydroxy;
bb). C1-8 alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of carboxyl, (halo)^ and

hydroxy;
be), carbonyl substituted with a substituent selected from the group consisting
of C1-8 alkyl, aryl, aryl(Ci^)alkyl, aryl(C2-8)alkenyl, heteroaryl,
heteroary^C^Bjalkyl and heteroaryl(C2-8)alkenyl;
bd). aryl;
be), heteroaryl;
bf). amino substituted with two substituents independently selected from the
group consisting of hydrogen and Ci-e alkyl;
bg). cyano;
bh). halogen;
bi). hydroxy;
bj). nitro;
bk). heterocydyl optionally substituted with one to two oxo substituents; and,
bl). sulfonyl substituted with a substituent selected from the group consisting
of C1.8 alkyl, aryl, aryl(Ci^)alkyl, aryl(C2^)alkenyl, heteroaryl,
heteroaryl(Ci.8)alkyl and heteroaryl(C2_s)alkenyl;
wherein the bd). aryl, be), heteroaryl and bk). heterocydyl substituents and the
aryl and heteroaryl portions of the be), substituent are optionally substituted
with one to four substituents independently selected from the group
consisting of CM alkyl (optionally substituted on a terminal carbon atom with
a substituent selected from the group consisting of amino (substituted with
two substituents independently selected from the group consisting of
hydrogen and Ci-8 alkyl), (halo)i^ and hydroxy), C-M alkoxy (optionally
substituted on a terminal carbon atom with a substituent selected from the '
group consisting of (halo)^), amino (substituted with two substituents
independently selected from the group consisting of hydrogen and C-M
alkyl), halogen, hydroxy and nitro;
and, provided that the optional substituent attached to the ad), heterocydyl
nitrogen ring atom is not selected from the group consisting of bf). amino
(substituted with two substituents independently selected from the group
consisting of hydrogen and Ci-a alkyl), bh). halogen, bi). hydroxy and bj).

nitro;
R4 is selected from the group consisting of C-M alkyl (optionally substituted on a
terminal carbon atom with a substituent selected from the group consisting
of aryl and heteroaryl), aryl and heteroaryl; wherein aryl and heteroaryl and
the aryl and heteroaryl portions of the substituted alkyl are optionally
substituted with one to four substituents independently selected from the
group consisting of CM alkyl, amino (substituted with two substituents
independently selected from the group consisting of hydrogen and CM
alkyl), cyano, halogen, hydroxy and (halo)i-3(Ci^)alkyl;
R2 and R3 are attached to a benzene ring and independently selected from the
group consisting of
ca). hydrogen;
cb). CM alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of amino (substituted with
two substituents independently selected from the group consisting of
hydrogen and CM alkyl), (halo)i.3 and hydroxy;
cc). CM alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of (halo)i_3 and hydroxy;
cd). C2.4alkenyl;
ce). amino substituted with two substituents independently selected from the
group consisting of hydrogen and CM alkyl;
cf). halogen; and,
eg), hydroxy;
optionally, R2 and R3 together form at least one ring fused to the benzene ring;
thereby providing a multiple ring system; wherein the multiple ring system is
selected from the group consisting of C9-C14 benzo fused cycloalkyl, C9-C14
benzo fused cycloalkenyl, C9-C14 benzo fused aryl, benzo fused
heterocyclyl and benzo fused heteroaryl; and, wherein the multiple ring
system can optionally be substituted with one to four substituents

independently selected from the group consisting of
da). ClJt alky! optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of amino (substituted with
two substituents independently selected from the group consisting of
hydrogen and CM alkyl), (halo)i-3 and hydroxy;
db). C1-4 alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of (halo)i-3 and hydroxy;
dc). amino substituted with two substituents independently selected from the
group consisting of hydrogen and C1-4 alkyl;
dd). halogen;
de). hydroxy; and,
df). nitro;
Rs is selected from the group consisting of hydrogen and Ci-a alkyl (optionally
substituted on a terminal carbon atom with a substituent selected from the
group consisting of amino (substituted with two substituents independently
selected from the group consisting of hydrogen and C1.4 alkyl), (halo)i-3 and
hydroxy) and aryl (optionally substituted with one to four substituents
independently selected from the group consisting of C^ alkyl and halogen);
R6 is selected from the group consisting of C1-8 alkyl, ary\(Ci^)a\ky\, C^ alkoxy,
aryl(Ci.a)alkoxy, d* alkenyl, C2-8 alkenyloxy, aryl(C2^)alkenyl,
aryl(C2-8)alkenyloxy, aryl, aryloxy and hydroxy;
X and Y are independently selected from the group consisting of hydrogen, C1-8
alkyl (optionally substituted on a terminal carbon atom with a substituent
selected from the group consisting of cycloalkyl, heterocyclyl, aryl,
heteroaryl, amino (substituted with two substituents independently selected
from the group consisting of hydrogen and Ci-a alkyl), (halo)^ and
hydroxy), C-i^ alkoxy (optionally substituted on a terminal carbon atom with
a substituent selected from the group consisting of aryl, (halo)^ and

hydroxy), C2-8 alkenyloxy, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl
and hydroxy; optionally, X and Y are fused together with the carbon of
attachment to form a spiro cycloalkyl or heterocyclyl moiety; and, optionally,
Y is not present; wherein X is one substituent attached by a double-bond
selected from the group consisting of O, S, imino, (C-Mjalkylimino and
hydroxyimino; and,
Z is selected from the group consisting of a bond, hydrogen and Ci.a alkyl; if Z
is a bond (wherein Z forms a double bond with the carbon of attachment for
X), then Y is not present and X is one substituent attached by a single-bond
selected from the group consisting of hydrogen, Ci„B alkoxy, C2-8 alkenyloxy,
aryloxy, ary^C^Jalkoxy and hydroxy,
and isomers, racemates, enantiomers, diastereomers and salts thereof.
Embodiments of the present invention include a process for preparing a
compound of Formula (I) comprising coupling under suitable conditions a first
compound of Formula (A):

with a second compound selected from ,the group consisting of Formula (B) and
Formula (C):


R7 is selected from the group consisting of hydrogen, C^ alkyl and C2^
alkenyl;
Rs is selected from the group consisting of:
aa). Ci-a alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of cycloalkyl, heterocyclyl,
aryl, heteroaryl, amino (substituted with two substituents independently
selected from the group consisting of hydrogen and C-is alkyl), (halo)i_3
and hydroxy;
ab). cycloalkyl;
ac). cycloalkenyl; and,
ad), heterocyclyl (wherein the point of attachment at Ra is a carbon ring atom);

wherein the ab). cycloalkyl, ac). cycloalkenyl and ad), heterocyclyl (wherein the
ad), heterocyclyl contains at least one nitrogen ring atom) substituents and
the cycloalkyl, heterocyclyl, aryl and heteroaryl portions of the aa).
substituent are optionally substituted with one to four substituents
independently selected from the group consisting of:
ba). Ci-8 alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of amino (with two
substituents independently selected from the group consisting of hydrogen
and Ci-a alkyl), (halo)i^ and hydroxy;
bb). C^e alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of carboxyl, (halo)i-3 and
hydroxy;
be), carbonyl substituted with a substituent selected from the group consisting
of C^a alkyl, aryl, aryl(Ci^)alkyl, aryl(C2-8)alkenyl, heteroaryl,
heteroaryl(Ci^)alkyl and heteroaryl(C2-e)alkenyl;
bd). aryl;
be), heteroaryl;
bf). amino substituted with two substituents independently selected from the
group consisting of hydrogen and C^ alkyl;
bg). cyano;
bh). halogen;
bi). hydroxy;
bj). nitro;
bk). heterocyclyl optionally substituted with one to two oxo substituents; and,
bl). sulfonyl substituted with a substituent selected from the group consisting
of Ci-a alkyl, aryl, aryl(Ci^)alkyl, aryl(C2-s)alkenyl, heteroaryl,
heteroaryl(Ci-8)alkyl and heteroaryl(C2-8)alkenyl;
wherein the bd). aryl, be), heteroaryl and bk). heterocyclyl substituents and the
aryl and heteroaryl portions of the be), substituent are optionally substituted
with one to four substituents independently selected from the group
consisting of C-M alkyl (optionally substituted on a terminal carbon atom with

a substituent selected from the group consisting of amino (substituted with
two substituents independently selected from the group consisting of
hydrogen and d.8 alkyl), (halo)i.3 and hydroxy), ClJt alkoxy (optionally
substituted on a terminal carbon atom with a substituent selected from the
group consisting of (halo)i.3), amino (substituted with two substituents
independently selected from the group consisting of hydrogen and CM
alkyl), halogen, hydroxy and nitra;
and, provided that the optional substituent attached to the ad), heterocyclyl
nitrogen ring atom is not selected from the group consisting of bf). amino
(substituted with two substituents independently selected from the group
consisting of hydrogen and C^ alkyl), bh). halogen, bi). hydroxy and bj).
nitro;
R4 is selected from the group consisting of C1.4 alkyl (optionally substituted on a
terminal carbon atom with a substituent selected from the group consisting
of aryl and heteroaryl), aryl and heteroaryl; wherein aryl and heteroaryl and
the aryl and heteroaryl portions of the substituted alkyl are optionally
substituted with one to four substituents independently selected from the
group consisting of CM alkyl, amino (substituted with two substituents
independently selected from the group consisting of hydrogen and CM
alkyl), cyano, halogen, hydroxy and (halo)i^(Ci^)alkyi;
R2 and R3 are attached to a benzene ring and independently selected from the
group consisting of
ca). hydrogen;
cb). CM alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of amino (substituted with
two substituents independently selected from the group consisting of
hydrogen and C-M alkyl), (halo)i-3 and hydroxy;
cc). C1-4 alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of (halo)i-3 and hydroxy;

cd). C2.4alkenyl;
ce). amino substituted with two substituents independently selected from the
group consisting of hydrogen and CM alkyl;
cf). halogen; and,
eg), hydroxy;
optionally, R2 and R3 together form at least one ring fused to the benzene ring;
thereby providing a multiple ring system; wherein the multiple ring system is
selected from the group consisting of Cg-C14 benzo fused cycloalkyl, Cg-C™
benzo fused cycloalkenyl, C9-C14 benzo fused aryl, benzo fused
heterocyclyl and benzo fused heteroaryl; and, wherein the multiple ring
system can optionally be substituted with one to four substituents
independently selected from the group consisting of:
da). CM alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of amino (substituted with
two substituents independently selected from the group consisting of
hydrogen and C1-4 alkyl), (halo)i_3 and hydroxy;
db). C1-4 alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of (halo)i^ and hydroxy;
dc). amino substituted with two substituents independently selected from the
group consisting of hydrogen and C-M alkyl;
dd). halogen;
de). hydroxy; and,
df). nitro;
R5 is selected from the group consisting of hydrogen and C1-8 alkyl (optionally
substituted on a terminal carbon atom with a substituent selected from the
group consisting of amino (substituted with two substituents independently
selected from the group consisting of hydrogen and C1.4 alkyl), (halo)i-3 and
hydroxy) and aryl (optionally substituted with one to four substituents
independently selected from the group consisting of C-i-a alkyl and halogen);

Re is selected from the group consisting of C-i-a alkyl, aryl(Ci^)alkyl, C^ alkoxy,
aryKC^alkoxy, C2.a alkenyl, C2^ alkenyloxy, aryl(C2-s)alkenyl,
aryl(C2-8)alkenyloxy, aryl, aryloxy and hydroxy;
X is selected from the group consisting of O, S, imino, (C^alkylimino and
hydroxyimino; and,
Z is selected from the group consisting of a bond, hydrogen and Ci-8 alkyl; if Z
is a bond (wherein Z forms a double bond with the carbon of attachment for
X), then X is selected from the group consisting of hydrogen, Ci-8 alkoxy,
C2_8 alkenyloxy, aryloxy, aryl(Cn)alkoxy and hydroxy,
and isomers, racemates, enantiomers, diastereomers and salts thereof.
Embodiments of the present invention include a compound of Formula
(C):
wherein
R2 and R3 are attached to a benzene ring and independently selected from the
group consisting of
ca). hydrogen;
cb). CM alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of amino (substituted with
two substituents independently selected from the group consisting of
hydrogen and C1-4 alkyl), (halo)i-3 and hydroxy;

cc). C1-4 alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of (halo)i.3 and hydroxy;
cd). C2-4 alkenyl;
ce). amino substituted with two substituents independently selected from the
group consisting of hydrogen and C1-4 alkyl;
cf). halogen; and,
eg), hydroxy;
optionally, R2 and R3 together form at least one ring fused to the benzene ring;
thereby providing a multiple ring system; wherein the multiple ring system is
selected from the group consisting of Cg-C-14 benzo fused cycloalkyl, C9-C14
benzo fused cycloalkenyl, Cg-C14 benzo fused aryl, benzo fused
heterocyclyl and benzo fused heteroaryl; and, wherein the multiple ring
system can optionally be substituted with one to four substituents
independently selected from the group consisting of
da). C1-4 alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of amino (substituted with
two substituents independently selected from the group consisting of
hydrogen and C-M alkyl), (halo)^ and hydroxy;
db). C-u alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of (halo)i.3 and hydroxy;
dc). amino substituted with two substituents independently selected from the
group consisting of hydrogen and C1.4 alkyl;
dd). halogen;
de). hydroxy; and,
df). nitro;
R4 is selected from the group consisting of C1-4 alkyl (optionally substituted on a
terminal carbon atom with a substituent selected from the group consisting
of aryl and heteroaryl), aryl and heteroaryl; wherein aryl and heteroaryl and
the aryl and heteroaryl portions of the substituted alkyl are optionally
substituted with one to four substituents independently selected from the

group consisting of C« alkyl, amino (substituted with two substituents
independently selected from the group consisting of hydrogen and C1-4
alkyl), cyano, halogen, hydroxy and (halo)i.3(Ci.e)alkyl;
R5 is selected from the group consisting of hydrogen and C^ alkyl (optionally
substituted on a terminal carbon atom with a substituent selected from the
group consisting of amino (substituted with two substituents independently
selected from the group consisting of hydrogen and CM alkyl), (halo)i-3 and
hydroxy) and aryl (optionally substituted with one to four substituents
independently selected from the group consisting of C^ alkyl and halogen);
and,
R6 is selected from the group consisting of C1.8 alkyl, aryl(C-i_8)alkyl, C-i-s alkoxy,
aryl(Ci.8)alkoxy, C2^ alkenyl, C2-8 alkenyloxy, aryl(C2^)alkenyl,
aryl(C2-8)alkenyloxy, aryl, aryloxy and hydroxy.
Embodiments of the present invention include a process for making a
benzolactone of Formula (C) comprising
a) reacting an anhydride of Formula (F):

with a compound of Formula (G):


under suitable conditions in the presence of an alkali metal (M) to provide a
compound of Formula (H):

b) and, reacting the compound of Formula (H) under conditions suitable to
form the benzolactone of Formula (C):
wherein
R2 and R3 are attached to a benzene ring and independently selected from the
group consisting of
ca). hydrogen;
cb). C-i_4 alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of amino {substituted with
two substituents independently selected from the group consisting of
hydrogen and C-M alkyl), (halo)i^ and hydroxy;
cc). CM alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of (halo)i_3 and hydroxy;
cd). C2-4 alkenyl;
ce). amino substituted with two substituents independently selected from the

under suitable conditions in the presence of an alkali metal (M) to provide a
compound of Formula (H):

b) and, reacting the compound of Formula (H) under conditions suitable to
form the benzolactone of Formula (C):
wherein
R2 and R3 are attached to a benzene ring and independently selected from the
group consisting of
ca). hydrogen;
cb). C-u alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of amino {substituted with
two substituents independently selected from the group consisting of
hydrogen and C1J} alkyl), (halo)^ and hydroxy;
cc). C1.4 alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of (halo)i-3 and hydroxy;
cd). C2-4alkenyl;
ce). amino substituted with two substituents independently selected from the

group consisting of hydrogen and C^ alkyl;
cf). halogen; and,
eg), hydroxy;
optionally, R2 and R3 together form at least one ring fused to the benzene ring;
thereby providing a multiple ring system; wherein the multiple ring system is
selected from the group consisting of C9-C14 benzo fused cycloalkyl, C9-C14
benzo fused cycloalkenyl, C9-C14 benzo fused aryl, benzo fused
heterocyclyl and benzo fused heteroaryl; and, wherein the multiple ring
system can optionally be substituted with one to four substituents
independently selected from the group consisting of
da). CM alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of amino (substituted with
two substituents independently selected from the group consisting of
hydrogen and C« alkyl), (halo)i.3 and hydroxy;
db). C1-4 alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of (halo)^ and hydroxy;
dc). amino substituted with two substituents independently selected from the
group consisting of hydrogen and C1.4 alkyl;
dd). halogen;
de). hydroxy; and,
df). nitro;
R4 is selected from the group consisting of C^ alkyl (optionally substituted on a
terminal carbon atom with a substituent selected from the group consisting
of aryl and heteroaryl), aryl and heteroaryl; wherein aryl and heteroaryl and
the aryl and heteroaryl portions of the substituted alkyl are optionally
substituted with one to four substituents independently selected from the
group consisting of C1.4 alkyl, amino (substituted with two substituents
independently selected from the group consisting of hydrogen and C1.4
alkyl), cyano, halogen, hydroxy and (halo)i-3(Ci^)alkyl;

R5 is selected from the group consisting of hydrogen and Ci-8 alkyl (optionally
substituted on a terminal carbon atom with a substituent selected from the
group consisting of amino (substituted with two substituents independently
selected from the group consisting of hydrogen and C^ alkyl), (halo)i^ and
hydroxy) and aryl (optionally substituted with one to four substituents
independently selected from the group consisting of Ci^ alkyl and halogen);
and
Re is selected from the group consisting of Ci^ alkyl, aryl(Ci.8)alkyl, C1-8 alkoxy,
aryl(C1^)alkoxy, C2-8 alkenyl, C2-8 alkenyloxy, aryl(C2-8)alkenyl,
aryl(C2^)alkenyloxy, aryl, aryloxy and hydroxy.
Embodiments of the present invention include compounds of Formula (II):

wherein
R10 is selected from the group consisting of:
a), sulfonyl substituted with a substituent selected from the group consisting
of C1-8 alkyl, aryl, aryl(Ci^)alkyl, aryl(C2-8)alkenyl, cycloalkyl, cycloalkenyl,
heterocycl, heteroaryl, heteroaryl(Ci^)alkyl and heteroaryl(C2^)alkenyl;
b). carbonyl substituted with a substituent selected from the group consisting
of C1-8 alkyl, aryl, aryl(Ci-8)alkyl, aryl(C2-8)alkenyl, cycloalkyl, cycloalkenyl,

heterocycl heteroaryl, heteroaryl(Ci-8)a!kyl, heteroaryl(C2-8)alkenyl, -ORn
and amino (with two substituents independently selected from the group
consisting of hydrogen, d-e alkyl, aryl, arylC^s alkyl, arylcarbonyl, arylC-,.
8 alkyl carbonyl and heteroaryl Ci-a alkyl);
c). C^s alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of aryl, cycloalkyl,
cycloalkenyl, heterocycl, heteroaryl, (halo)i_3, hydroxy, -C(0)Ri2 and
amino (with two substituents independently selected from the group
consisting of hydrogen, Ci-a alkyl, arylC-i-g alkyl, arylcarbonyl, arylCi_8
alkyl carbonyl and heteroaryl Ci^ alkyl);
d). aryl;
e). heteroaryl;
f). cycloalkyl
g). cycloalkenyl; and,
h). heterocyclyl
wherein the heterocycl, cycloalkyl, cycloalkenyl portion of a)., b)., and c)., the
cylcoalkyl f)., cylcoalkenyl g)., and heterocyclyl h). are optionally substituted
with one to two substituents independently selected from the group
consisting of:
ea). oxo
eb). carbonyl substituted with a substituent selected from the group
consisting of d-s alkyl, aryl, aryl(Ci^)alkyl, aryl(C2-8)alkenyl, cycloalkyl,
cycloalkenyl, heterocycl heteroaryl, heteroaryl(Ci^)alkyl,
heteroaryl(C2-8)alkenyl and amino (with two substituents independently
selected from the group consisting of hydrogen, d-a alkyl, arylCi-s alkyl,
arylcarbonyl, arylCi-a alkyl carbonyl and heteroaryl Ci.8 alkyl);
ec). Ci_8 alkyl optinally substituted with a substituent selected from the
group consisting of amino (with two substituents independently
selected from the group consisting of hydrogen, Ci-a alkyl, arylCi-8 alkyl,
arylcarbonyl, ary!Ci.8 alkyl carbonyl and heteroaryl Ci-8 alkyl), aryl,

cycloalkyl, cycloalkenyl, heterocycl, heteroaryl, (halo^.3, and hydroxy;
ed). aryl; and
ef). (halo)^
wherein the aryl portion of the a)., b)., c)., ec). and ed). substituents , the
heteroaryl portion of the a)., b)., c). and ec). substituents and the d). aryl
and e). heteroaryl substituents are optionally substituted with one to four
substituents independently selected from the group consisting of
fa). C-M alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of aryl, cycloalkyl,
cycloalkenyl, heterocycl, heteroaryl, (halo)M, hydroxy, -C(0)Ri2 and
amino (with two substituents independently selected from the group
consisting of hydrogen, C1-8 alkyl, arylCi-a alkyl, arylcarbonyl, arylCi.8 alkyl
carbonyl and heteroaryl Ci-a alkyl);
fb). C2.4 alkenyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of amino (with two
substituents independently selected from the group consisting of hydrogen
and Ci-a alkyl), (halo)i-3 and hydroxy;
fc). CM alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of (halo)i-3 and hydroxy;
fd). cycloalkyl,
fe). heterocyclyl,
ff). aryl optionally substituted with one to four substituents independently
selected from the group consisting of C^ alkyl and halogen;
fg). heteroaryl,
fh). hydroxy;
fi). hydroxy;
fj). nitro; and
fk). (halo)^;
wherein the aryl portion of the arylCi-a alkyl, arylcarbonyl, arylC^ alkyl carbonyl

of fa), are optionally substituted with one to four substituents independently
selected from the group consisting of C1-4 alkyl (optionally substituted on a
terminal carbon atom with a substituent selected from the group consisting
of amino (substituted with two substituents independently selected from the
group consisting of hydrogen and Ci^ alkyl), (halo)i-3 and hydroxy), C1.4
alkoxy (optionally substituted on a terminal carbon atom with a substituent
selected from the group consisting of (halo)^), amino (substituted with two
substituents independently selected from the group consisting of hydrogen
and C^ alkyl), halogen, hydroxy and nitro.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the percent change in specific lung resistance (SRL) from
baseline for Compound 2 compared to control in a spontaneous ascaris suum
antigen-induced model of asthma in sheep over an 8 hour period.
Figure 2 shows the change in the cumulative carbachol dose required to
increase SRL 400% (PC 400) from a baseline value (BSL) measured at 24
hours post-dosing of Compound 2 in the spontaneous ascaris suum antigen-
induced model of asthma in sheep compared to a 24 hour post-dosing
challenge with carbachol (Post Antigen).
DETAILED DESCRIPTION OF THE INVENTION
Embodiments of the present invention include those compounds wherein
R1 is selected from the group consisting of a heterocyclyl ring (wherein the
point of attachment for the heterocyclyl ring at R1 is a nitrogen ring atom) and
-N(R7R8); wherein the heterocyclyl ring is optionally substituted with a
substituent selected from the group consisting of a). aryl(Ci^)alkyl, c). aryl, d).

heteroaryl and i). heterocyclyl (optionally substituted with one to two
substituents independently selected from the group consisting of oxo and aryl;
and, optionally fused with the carbon of attachment to form a spiro heterocyclyl
moiety); and, wherein the aryl portion of the a), and i). substituent and the c).
aryl substituent are optionally substituted with one to two substituents
independently selected from the group consisting of d^ alkyl, CM alkoxy, aryl,
heteroaryl, halogen, hydroxy, (halo)i^(Ci^)alkyl and (halo)i.3(Ci^)aikoxy; and,
all other variables are as previously defined.
Preferably, R-i is selected from the group consisting of a heterocyclyl ring
(wherein the point of attachment for the heterocyclyl ring at R-i is a nitrogen ring
atom) and -N^Rs); wherein the heterocyclyl ring is optionally substituted with
a substituent selected from the group consisting of a). aryl(Ci-4)alkyl, c). aryl,
d). heteroaryl and i). heterocyclyl (optionally substituted with two substituents
independently selected from the group consisting of oxo and aryl; and,
optionally fused with the carbon of attachment to form a spiro heterocyclyl
moiety); and, wherein the aryl portion of the a), and i). substituent and the c).
aryl substituent are optionally substituted with one to two substituents
independently selected from the group consisting of C^ alkoxy and aryl; and,
all other variables are as previously defined.
More preferably, Ri is selected from the group consisting of pyrrolidinyl,
piperidinyl and -N(R7Re); wherein the point of attachment for pyrrolidinyl and
piperidinyl is a nitrogen ring atom; and, wherein pyrrolidinyl and piperidinyl are
optionally substituted with a substituent selected from the group consisting of
a), phenylethyl, c). phenyl (optionally substituted with methoxy), d).
benzothiazolyl and i). imidazolidinyl (optionally substituted with two substituents
independently selected from the group consisting of oxo and phenyl; and,
optionally fused with the carbon of attachment to form a spiro moiety); and, all
other variables are as previously defined.

Most preferably, Ri is selected from the group consisting of pyrrolidinyl,
piperidinyl and -N(R7R8); wherein the point of attachment for pyrrolidinyl and
piperidinyl is a nitrogen ring atom in the one position; and, wherein pyrrolidinyl
and piperidinyl are optionally substituted with a substituent selected from the
group consisting of a), phenylethyl, c). phenyl (optionally substituted with
methoxy), d). benzothiazolyl and i). imidazolidinyl (optionally substituted with
two substituents independently selected from the group consisting of oxo and
phenyl; and, optionally fused with the carbon of attachment to form a spiro
moiety); and, all other variables are as previously defined.
Preferred embodiments of the present invention include those
compounds wherein R7 is selected from the group consisting of hydrogen, C-M
alkyl and C2-4 alkenyl.
More preferably, R7 is selected from the group consisting of hydrogen
and C1.4 alkyl.
Most preferably, R7 is selected from the group consisting of hydrogen
and methyl.
Embodiments of the present invention include those compounds wherein
Re is selected from the group consisting of:
aa). C1.8 alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of cycloalkyl, heterocyclyl,
(halo)i_3 and hydroxy;
ab). cycloalkyl;
ac). cycloalkenyl; and,
ad), heterocyclyl (wherein the point of attachment at RB is a carbon ring atom);
wherein the ab). cycloalkyl, ac). cycloalkenyl and ad), heterocyclyl substituents
(wherein the ad), heterocyclyl contains at least one nitrogen ring atom) and
the cycloalkyl portion of the aa). substituent are optionally substituted with

one to four substituents independently selected from the group consisting
of:
ba). C1-8 alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of amino (with two
substituents independently selected from the group consisting of hydrogen
and C1-8 alkyl), (halo)i^ and hydroxy;
bb). Ci_e alkoxy;
be), carbonyl substituted with a substituent selected from the group consisting
of C-|.8 alkyl, aryl, aryl(Ci^)alkyl, aryl(C2^)alkenyl, heteroaryl,
heteroaryl(Ci-a)alkyl and heteroaryl(C2^)alkenyl;
bd). aryl;
be), heteroaryl;
bf). amino substituted with two substituents independently selected from the
group consisting of hydrogen and Ci^ alkyl;
bh). halogen;
bi). hydroxy;
bk). heterocyclyl; and,
bl). sulfonyl substituted with a substituent selected from the group consisting
of Ci-e alkyl, aryl, aryl(Ci^)alkyl, aryl(C2-8)alkenyl, heteroaryl,
heteroaryl(Ci^)alkyl and heteroaryl(C2^)alkenyl;
wherein the bd). aryl, be), heteroaryl and bk). heterocyclyl substituents and the
aryl and heteroaryl portions of the be), substituent are optionally substituted
with one to four substituents independently selected from the group
consisting of C^ alkyl (optionally substituted on a terminal carbon atom with
a substituent selected from the group consisting of (halo)i-3), C1.4 alkoxy,
amino (substituted with two substituents independently selected from the
group consisting of hydrogen and C^ alkyl), halogen and hydroxy;
and, provided that the optional substituent attached to the ad), heterocyclyl
nitrogen ring atom is not selected from the group consisting of bf), amino
(substituted with two substituents independently selected from the group
consisting of hydrogen and Ci.8 alkyl), bh). halogen, bi). hydroxy and bj).

nitro.
Preferably, Rg is selected from the group consisting of aa).
, cycloalkyl(C-i-4)alkyl, ab). cycloalkyl, ac). cycloalkenyl and ad), heterocyclyl
(wherein the point of attachment for the ad), heterocyclyl at Rs is a carbon ring
atom; and, the ad), heterocyclyl contains a single nitrogen ring atom); wherein
the ab). cycloalkyl, ac). cycloalkenyl and ad), heterocyclyl substituents and the
cycloalkyl portion of the aa). substituent are optionally substituted with one to
two substituents independently selected from the group consisting of ba). C1-4
alkyl, be), carbonyl (substituted with a substituent selected from the group
consisting of C1-4 alkyl, aryl, aryl(Ci-4)alkyl and aryl(C2^)alkenyl) and bd). aryl;
wherein the bd). aryl substituent and the aryl portions of the be), substituent are
optionally substituted with one to two substituents independently selected from
the group consisting of C-M alkyl, C-M alkoxy, di(Ci^ alkyl)amino, halogen,
hydroxy and (halo)i.3(Ci-»)alkyl.
More preferably, R8 is selected from the group consisting of aa).
adamant-1-ylmethyl, ab). cyclopentyl, ab). cyclohexyl, ac). cyclohexenyl, ad),
pyrrolidinyl and ad), piperidinyl (wherein the point of attachment for pyrrolidinyl
and piperidinyl at R8 is a carbon ring atom); wherein ab). cyclohexyl, ac).
cyclohexenyl, ad), pyrrolidinyl and ad), piperidinyl are optionally substituted with
one to two substituents independently selected from the group consisting of
ba). Ci_4 alkyl, be), carbonyl (substituted with a substituent selected from the
group consisting of C1.4 alkyl, aryl, aryl(Ci-4)alkyl and aryl(C2^t)alkenyl) and bd).
aryl; wherein the bd). aryl substituent and the aryl portions of the be),
substituent are optionally substituted with one to two substituents
independently selected from the group consisting of C1-4 alkyl, CM alkoxy,
di(C-i^ alkyl)amino, halogen, hydroxy and (halo)i^(Ci^)alkyl.
Most preferably, Rs is selected from the group consisting of aa).
adamant-1-ylmethyl, ab). cyclopentyl, ab). cyclohexyl, ac). cyclohexenyl, ad).

pyrrolidinyl and ad), piperidinyl (wherein the point of attachment for pyrrolidinyl
and piperidinyl at R8 is a carbon ring atom); wherein ab). cyclohexyl, ac).
cyclohexenyl, ad), pyrrolidinyl and ad), piperidinyl are optionally substituted with
one to two substituents independently selected from the group consisting of
ba). methyl, ba). /-butyl, be), methylcarbonyl, be), /-propylcarbonyl, be),
phenylcarbonyl, be), naphthalenylcarbonyl, be), phenethylcarbonyl, be),
phenethenylcarbonyl and bd). phenyl; and, wherein the bd). phenyl substituent
and the phenyl and naphthalenyl portions of the be), substituent are optionally
substituted with one to two substituents independently selected from the group
consisting of methyl, methoxy, /V,/V-dimethylamino, fluorine, bromine, hydroxy
and trifluoromethyl.
Embodiments of the present invention include those compounds wherein
R2 and R3 are attached to the benzene ring (shown in Formula I) on adjacent
carbon atoms. Preferred embodiments of the present invention include those
compounds wherein R2 and R3 are independently selected from the group
consisting of ca). hydrogen, cb). C-M alkyl, cc). C-M alkoxy, cd). C2-4 alkenyl,
ce). amino (substituted with two substituents independently selected from the
group consisting of hydrogen and CM alkyl), cf). halogen and eg), hydroxy;
optionally R2 and R3 together form at least one ring fused to the benzene ring;
thereby providing a multiple ring system; wherein the multiple ring system is
selected from the group consisting of naphthalene and anthracene; and,
wherein the multiple ring system can optionally be substituted with one to four
substituents independently selected from the group consisting of da). CM alkyl,
db). C-M alkoxy, dc). amino (substituted with two substituents independently
selected from the group consisting of hydrogen and CM alkyl), dd). halogen
and de). hydroxy.
More preferably, R2 and R3 are attached to the benzene ring on adjacent
carbon atoms and independently selected from the group consisting of ca).
hydrogen, cb). CM alkyl, cd). C2.4 alkenyl, cf). halogen and eg), hydroxy;

optionally, R2 and R3 together form at least one ring fused to the benzene ring;
thereby providing a multiple ring system; wherein the multiple ring system is
naphthalene; and, wherein the multiple ring system can optionally be
substituted with one to four substituents independently selected from the group
consisting of da). C^ alkyl, db). C-i^ alkoxy, dc). amino (substituted with two
substituents independently selected from the group consisting of hydrogen and
C-M alkyl), dd). halogen and de). hydroxy.
Most preferably, the multiple ring system is a non-substituted
naphthalene.
Embodiments of the present invention include those compounds wherein
R4 is selected from the group consisting of aryl and heteroaryl optionally
substituted with one to two substituents independently selected from the group
consisting of CM alkyl, amino (substituted with two substituents independently
selected from the group consisting of hydrogen and C1-4 alkyl), cyano, halogen,
hydroxy and (halo)i.3(Ci^)alkyl.
Preferably, R4 is selected from the group consisting of aryl and
heteroaryl (wherein heteroaryl is optionally substituted with one to two
substituents independently selected from the group consisting of C\^ alkyl,
amino (substituted with two substituents independently selected from the group
consisting of hydrogen and C-M alkyl), cyano, halogen, hydroxy and
(halo)1.3(C1.8)alkyl).
More preferably, R4 is selected from the group consisting of phenyl,
naphthalenyl and benzothienyl (wherein benzothienyl is optionally substituted
with one to two halogen substituents).
Most preferably, R4 is selected from the group consisting of phenyl,
naphthalenyl and benzothienyl (wherein benzothienyl is optionally substituted

with a chloro substituent).
Embodiments of the present invention include those compounds wherein
R5 is selected from the group consisting of hydrogen and C1.4 alkyl (optionally
substituted on a terminal carbon atom with a substituent selected from the
group consisting of amino (substituted with two substituents independently
selected from the group consisting of hydrogen and C1.4 alkyl), (halo)i-3 and
hydroxy).
Preferably, R5 is selected from the group consisting of hydrogen and C1.4
alkyl.
More preferably, R5 is selected from the group consisting of hydrogen
and methyl.
Most preferably, R5 is hydrogen.
Preferred embodiments of the present invention include those
compounds wherein R6 is selected from the group consisting of CM alkyl,
aryl(Ci-4)alkyl, C-M alkoxy, aryl(C1^)alkoxy, C2-4 alkenyl, C2.4 alkenyloxy,
aryl(C2-4)alkenyl, aryl(C2-4)alkenyloxy, aryl, aryloxy and hydroxy.
More preferably, R6 is selected from the group consisting of methyl,
methoxy, phenyloxy and hydroxy.
Most preferably, R6 is selected from the group consisting of methyl and
hydroxy.
Preferred embodiments of the present invention include those
compounds wherein Y is not present and X is one substituent attached by a
double-bond selected from the group consisting of O, S, imino, (Ci_4)alkylimino

and hydroxyimino.
More preferably, Y is not present and X is one substituent attached by a
double-bond selected from the group consisting of O, imino and hydroxyimino.
Most preferably, Y is not present and X is O attached by a double-bond.
Preferred embodiments of the present invention include those
compounds wherein Z is selected from the group consisting of hydrogen and
CM alkyl.
More preferably, Z is hydrogen.
Embodiments of the present invention include those compounds of
Formula (la) shown in Table 1.







In embodiments for Formula (II) the preferred embodiments of R2, R3, R4, R5
and Re are as previously described.
Preferably, R10 is selected from the group consisting of
a), sulfonyl substituted with a substituent selected from the group consisting
of Ci-8alkyl, aryl, aryl(C^)alkyl, aryl(C2-8)alkenyl, cycloalkyl, cycloalkenyl,
heterocycl, heteroaryl, heteroaryl(Ci^)alkyl and heteroaryl(C2-8)alkenyl;
b). carbonyl substituted with a substituent selected from the group consisting
of C1.8 alkyi, aryl, aryl(Ci.8)alkyl, aryl(C2-8)alkenyl, cycloalkyl, cycloalkenyl,
heterocycl heteroaryl, heteroaryl(Ci-8)alkyl, heteroaryl(C2^)alkenyl, -ORn
and amino (with two substituents independently selected from the group
consisting of hydrogen, C1.8 alkyl, aryl, arylCi.8 alkyl, arylcarbonyl, arylCi.
s alkyl carbonyl and heteroaryl C1-8 alkyl);
c). C^ alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of aryl, cycloalkyl,
cycloalkenyl, heterocycl, heteroaryl, (halo)i.3, hydroxy, -C(0)Ri2 and
amino (with two substituents independently selected from the group
consisting of hydrogen, Ci^ alkyl, aryld^ alkyl, arylcarbonyl, arylCi-s
alkyl carbonyl and heteroaryl C1.8 alkyl);
d). aryl; and
e). heteroaryl;
wherein the heterocycl, cycloalkyl, cycloalkenyl portion of a)., b)., and c). are
optionally substituted with one to two substituents independently selected
from the group consisting of:
ea). oxo
eb). carbonyl substituted with a substituent selected from the group

consisting of C-I_B alkyl, aryl, aryl(Ci-8)alkyl, aryl(C2^)alkenyl, cycloalkyl,
cycloalkenyl, heterocycl heteroaryl, heteroaryl(Ci^)alkyl,
heteroaryl(C2-8)alkenyl and amino (with two substituents independently
selected from the group consisting of hydrogen, Ci-e alkyl, arylCi-e alkyl,
arylcarbonyl, arylC-i-a alkyl carbonyl and heteroaryl C^ alkyl);
ec). C1-8 alkyl optinally substituted with a substituent selected from the
group consisting of amino (with two substituents independently selected
from the group consisting of hydrogen, C^ alkyl, arylC^ alkyl, arylcarbonyl,
arylCi-8 alkyl carbonyl and heteroaryl C1-8 alkyl), aryl, cycloalkyl,
cycloalkenyl, heterocycl, heteroaryl, (halo)i-3, and hydroxy;
ed). aryl; and
ef). (halo)^
wherein the aryl portion of the a)., b)., c)., ec). and ed). substituents , the
heteroaryl portion of the a)., b)., c). and ec). substituents and the d). aryl
and e). heteroaryl substituents are optionally substituted with one to four
substituents independently selected from the group consisting of
fa). C^ alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of aryl, cycloalkyl,
cycloalkenyl, heterocycl, heteroaryl, (halo)i-3, hydroxy, -C(0)R-i2 and
amino (with two substituents independently selected from the group
consisting of hydrogen, Ci-e alkyl, arylCi-8 alkyl, arylcarbonyl, arylCi_a alkyl
carbonyl and heteroaryl Ci_8 alkyl);
fb). C2.4 alkenyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of amino (with two
substituents independently selected from the group consisting of hydrogen
and C1-8 alkyl), (halo)i_3 and hydroxy;
fc). CM alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of (halo)i-3 and hydroxy;
fd). cycloalkyl,
fe). heterocyclyl,
ff). aryl optionally substituted with one to four substituents independently

selected from the group consisting of Ci-g alkyl and halogen;
fg). heteroaryl,
fh). hydroxy;
fi). hydroxy;
fj). nitro; and
fk). (halo)^;
wherein the aryl portion of the arylCi^ alkyl, arylcarbonyl, arylCi^ alkyl carbonyl
of fa), are optionally substituted with one to four substituents independently
selected from the group consisting of CM alkyl (optionally substituted on a
terminal carbon atom with a substituent selected from the group consisting
of amino (substituted with two substituents independently selected from the
group consisting of hydrogen and Ci^ alkyl), (halo)^ and hydroxy), CM
alkoxy (optionally substituted on a terminal carbon atom with a substituent
selected from the group consisting of (halo)i_3), amino (substituted with two
substituents independently selected from the group consisting of hydrogen
and CM alkyl), halogen, hydroxy and nitro.
Preferably, Rn is selected from the group consisting of:
aa). CM alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of cycloalkyl, heterocyclyl,
aryl, heteroaryl, amino (with two substituents independently selected from
the group consisting of hydrogen and CM alkyl), (halo)i-3 and hydroxy;
wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl portions of the aa).
substituent are optionally substituted with one to four substituents
independently selected from the group consisting of:
ba). CM alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of amino (with two
substituents independently selected from the group consisting of hydrogen
and CM alkyl), (halo)i^ and hydroxy;
bb). CM alkoxy optionally substituted on a terminal carbon atom with a

substituent selected from the group consisting of carboxyl, (halo)i-3 and
hydroxy;
be), carbonyl substituted with a substituent selected from the group consisting
of CM alkyl, aryl, aryl(Ci^)alkyl, aryl(C2-4)alkenyl, heteroaryl,
heteroaryl(Ci-4)alkyl and heteroaryl(C2-4)alkenyl;
bd). aryl;
be), heteroaryl;
bf). amino substituted with two substituents independently selected from the
group consisting of hydrogen and C-M alkyl;
bh). (halo)^;
bi). hydroxy; and
bk). heterocyclyl optionally substituted with one to two oxo substituents; and,
wherein the bd). aryl, be), heteroaryl and bk). heterocyclyl substituents and the
aryl and heteroaryl portions of the be), substituent are optionally substituted
with one to four substituents independently selected from the group
consisting of C-M alkyl (optionally substituted on a terminal carbon atom with
a substituent selected from the group consisting of amino (substituted with
two substituents independently selected from the group consisting of
hydrogen and CM alkyl), (halo)u and hydroxy), C^ alkoxy (optionally
substituted on a terminal carbon atom with a substituent selected from the
group consisting of (halo)^), amino (substituted with two substituents
independently selected from the group consisting of hydrogen and C-,.4
alkyl), halogen, hydroxy and nitro;
Preferably , R12 is selected from the group consisting of C-M alkyl, aryl,
aryl(ClJ()alkyl, aryl(C2-4)alkenyl, cycloalkyl, cycioalkenyl, heterocycl heteroaryl,
heteroaryl(Ci-4)alkyl, heteroaryl(C2^)alkenyl, -ORn and amino (with two
substituents independently selected from the group consisting of hydrogen, C1-4
alkyl, aryICi.4 alkyl, arylcarbonyl, arylCi^ alkyl carbonyl and heteroaryl Ci^
alkyl); wherein the aryl, the heteroaryl portion of R12 are optionally substituted
with one to four substituents independently selected from the group consisting

of:
fa). C1-4 alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of aryl, cycloalkyl,
cycloalkenyl, heterocycl, heteroaryl, (halo)i.3l hydroxy, -C(0)Rn and
amino (with two substituents independently selected from the group
consisting of hydrogen, Ci^ alkyl, arylCi-4 alkyl, arylcarbonyl, arylCi^ alkyl
carbonyl and heteroaryl CM alkyl);
fb). C2^t alkenyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of amino (with two
substituents independently selected from the group consisting of hydrogen
and C1-4 alkyl), (halo)i-3 and hydroxy;
fc). Ci^j alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of (halo)-)-3 and hydroxy;
fd). cycloalkyl,
fe). heterocyclyl,
ff). aryl optionally substituted with one to four substituents independently
selected from the group consisting of C1-4 alkyl and halogen;
fg). heteroaryl,
fh). (halo)i.3;
fi). hydroxy; and
fj). nitro;
wherein the aryl portion of the arylCi-e alkyl, arylcarbonyl, arylC-i-8 alkyl carbonyl
of fa), are optionally substituted with one to four substituents independently
selected from the group consisting of CM alkyl (optionally substituted on a
terminal carbon atom with a substituent selected from the group consisting
of amino (substituted with two substituents independently selected from the
group consisting of hydrogen and C1-8 alkyl), (halo)i-3 and hydroxy), C1.4
alkoxy (optionally substituted on a terminal carbon atom with a substituent
selected from the group consisting of (halo)i^), amino (substituted with two
substituents independently selected from the group consisting of hydrogen

and C1.4 alkyl), halogen, hydroxy and nitro;
Embodiments of the present invention include those compounds of Formula
(Ila) shown in Table 4.


The compounds of the present invention may also be present in the form
of pharmaceutically acceptable salts. For use in medicine, the salts of the
compounds of this invention refer to non-toxic "pharmaceutically acceptable
salts." FDA approved pharmaceutically acceptable salt forms (Ref.
International J. Pharm. 1986, 33, 201-217; J. Pharm. Sci., 1977, Jan, 66(1), p1)
include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
Pharmaceutically acceptable acidic/anionic salts include, and are not

limited to acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate,
bromide, calcium edetate, camsylate, carbonate, chloride, citrate,
dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate,
gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,
hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,
lactobionate, malate, maleate, mandelate, mesylate, methylbromide,
methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate,
pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate,
subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate and
triethiodide. Organic or inorganic acids also include, and are not limited to,
hydriodic, perchloric, sulfuric, phosphoric, propionic, glycolic, methanesulfonic,
hydroxyethanesulfonic, oxalic, 2-naphthalenesulfonic, p-toluenesulfonic,
cyclohexanesulfamic, saccharinic or trifluoroacetic acid.
Pharmaceutically acceptable basic/cationic salts include, and are not
limited to aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (also known as
tris(hydroxymethyl)aminomethane, tromethane or TRIS"), ammonia,
benzathine, f-butylamine, calcium, calcium gluconate, calcium hydroxide,
chloroprocaine, choline, choline bicarbonate, choline chloride, cyclohexylamine,
diethanolamine, ethylenediamine, lithium, LiOMe, L-lysine, magnesium,
meglumine, NH3, NHtOH, N-methyl-D-glucamine, piperidine, potassium,
potassium-f-butoxide, potassium hydroxide (aqueous), procaine, quinine, SEH,
sodium, sodium carbonate, sodium-2-ethylhexanoate, sodium hydroxide,
triethanolamine (TEA) or zinc.
Compounds of the present invention may be contacted with a
pharmaceutically acceptable cation selected from the group consisting of
aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (also known as
tris(hydroxymethyl)aminomethane, tromethane or 'TRIS"), ammonia,
benzathine, f-butylamine, calcium, calcium gluconate, calcium hydroxide,
chloroprocaine, choline, choline bicarbonate, choline chloride, cyclohexylamine,

diethanolamine, ethylenediamine, lithium, LiOMe, L-lysine, magnesium,
meglumine, NH3, NH4OH, N-methyl-D-glucamine, piperidine, potassium,
potassium-f-butoxide, potassium hydroxide (aqueous), procaine, quinine, SEH,
sodium, sodium carbonate, sodium-2-ethylhexanoate, sodium hydroxide,
triethanolamine (TEA) and zinc to form a salt.
Preferred cations for use with the instant compounds are selected from
the group consisting of benzathine, f-butylamine, calcium gluconate, calcium
hydroxide, choline bicarbonate, choline chloride, cyclohexylamine,
diethanolamine, ethylenediamine, LiOMe, L-lysine, NH3, NH4OH, N-methyl-D-
glucamine, piperidine, potassium-f-butoxide, potassium hydroxide (aqueous),
procaine, quinine, sodium carbonate, sodium-2-ethylhexanoate, sodium
hydroxide, triethanolamine and tromethane.
More preferably, cations for use with the instant compounds are selected
from the group consisting of f-butylamine, NH4OH and tromethane.
Most preferably, the cation for use with the instant compounds is
tromethane.
The present invention includes within its scope prodrugs of the
compounds of this invention. In general, such prodrugs will be functional
derivatives of the compounds, which are readily convertible in vivo into an
active compound. Thus, in the methods of treatment of the present invention,
the term "administering" shall encompass the treatment of the various disorders
described with the compound specifically disclosed or a prodrug compound
which would be obviously included within the scope of the invention although
not specifically disclosed including, but not limited to diphenylphosphonate or
diphenylphosphinate esters of certain of the instant compounds. Conventional
procedures for the selection and preparation of suitable prodrug derivatives are
described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier,

1985. Phosphonic acid prodrugs (as described in De Lombaert S., et al, Non-
Peptidic Inhibitors of Neutral Endopeptidase 24.11; Design and Pharmacology
of Orally Active Phosphonate Prodrugs, Bioorganic and Medicinal Chemistry
Letters, 1995, 5(2), 151-154; and, De Lombaert S., et al, /V-Phosphonomethyl
Dipeptides and Their Phosphonate Prodrugs, a New Generatrion Neutral
Endopeptidase (NEP, EC 3.424.11) Inhibitors, J. Med. Chem., 1994, 37,498-
511) and phosphinic acid prodrugs are intended to be included within the scope
of the present invention.
The compounds according to this invention may have at least one chiral
center and thus may exist as enantiomers. In addition, the compounds of the
present invention may also possess two or more chiral centers and thus may
also exist as diastereomers. Where the processes for the preparation of the
present compounds give rise to a mixture of stereoisomers, these isomers may
be separated by conventional techniques such as preparative chromatography.
Accordingly, the compounds may be prepared as a racemic mixture or, by
either enantiospecific synthesis or resolution, as individual enantiomers. The
compounds may, for example, be resolved from a racemic mixture into their
component racemates by standard techniques, such as the formation of
diastereomeric pairs by salt formation with an optically active base, followed by
fractional crystallization and regeneration of the compounds of this invention.
The racemic mixture may also be resolved by formation of diastereomeric
esters or amides, followed by chromatographic separation and removal of the
chiral auxiliary. Alternatively, the compounds may be resolved using a chiral
HPLC column. It is to be understood that all such isomers and mixtures thereof
are encompassed within the scope of the present invention.
The compounds according to this invention wherein Z forms a double
bond with the carbon of attachment for X, Y is not present and X is hydroxy
may have at least one keto-enol tautomeric form and thus may exist in
equilibirum as geometric isomers. It is to be understood that all such isomers

and mixtures thereof are encompassed within the scope of the present
invention.
During any of the processes for preparation of the compounds of the
present invention, it may be necessary and/or desirable to protect sensitive or
reactive groups on any of the molecules concerned. This may be achieved by
means of conventional protecting groups, such as those described in Protective
Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and
T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John
Wiley & Sons, 1991. The protecting groups may be removed at a convenient
subsequent stage using methods known in the art.
Furthermore, some of the crystalline forms for the compounds may exist
as polymorphs and as such are intended to be included in the present
invention. In addition, some of the compounds may form solvates with water
(i.e., hydrates) or common organic solvents, and such solvates are also
intended to be encompassed within the scope of this invention.
As used herein, unless otherwise noted, "alkyl" whether used alone or as
part of a substituent group refers to straight and branched carbon chains
having 1 to 8 carbon atoms or any number within this range. The term "alkoxy"
refers to an -O-alkyl substituent group, wherein alkyl is as defined supra.
Similarly, the terms "alkenyl" and "alkynyl" refer to straight and branched
carbon chains having 2 to 8 carbon atoms or any number within this range,
wherein an alkenyl chain has at least one double bond in the chain and an
alkynyl chain has at least one triple bond in the chain. An alkyl and alkoxy
chain may be substituted on a terminal carbon atom or, when acting as a
linking group, within the carbon chain.
The term "cycloalkyl" refers to saturated, moncyclic or polycyclic
hydrocarbon rings of from 3 to 20 carbon atom members (preferably from 3 to 12

2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl,
thiomorpholinyl and piperazinyl. In the present invention, when Ri is selected
from heterocyclyl, the term "heterocyclyl" refers to a nonaromatic cyclic ring of 5 to
8 members in which 1 to 4 members are nitrogen; wherein, the point of
attachment for the heterocyclyl ring at Ri is a nitrogen ring member; and, wherein
optionally the ring contains zero, one (for 5 and 6 member rings) or two (for 6, 7
and 8 member rings) unsaturated bonds.
The term "aryl" refers to an unsaturated, aromatic monocyclic ring of 6
carbon members or to an unsaturated, aromatic polycyclic ring of from 10 to 20
carbon members. Further, an aryl ring may optionally be fused to one or more
benzene rings (benzo fused aryl), cycloalkyl rings (e.g. benzo fused cycloalkyl) or
cycloalkenyl rings (e.g. benzo fused cycloalkenyl) wherein, for the purpose of
these definitions, the cycloalkyl rings and cycloalkenyl rings may be fused to an
additional benzene ring (to provide fused multiple ring systems such as fluorene).
Examples of such aryl rings include, and are not limited to, phenyl, naphthalenyl,
fluorenyl, indenyl or anthracenyl.
The term "heteroaryl" refers to an aromatic ring of 5 or 6 members
wherein the ring consists of carbon atoms and has at least one heteroatom
member. Suitable heteroatoms include nitrogen, oxygen or sutfur. In the case
of 5 membered rings, the heteroaryl ring contains one member of nitrogen,
oxygen or sulfur and, in addition, may contain up to two additional nitrogens. In
the case of 6 membered rings, the heteroaryl ring may contain from one to
three nitrogen atoms. For the case wherein the 6 member ring has three
nitrogens, at most two nitrogen atoms are adjacent. Optionally, the heteroaryl
ring is fused to a benzene ring (benzo fused heteroaryl), a 5 or 6 membered
heteroaryl ring (containing one of O, Sor N and, optionally, one additional
nitrogen), a 5 to 7 membered alicyclic ring or a 5 to 7 membered heterocyclo ring
(as defined supra but absent the option of a further fused ring). Examples of
heteroaryl groups include, and are not limited to, furyl, thienyl, pyrrolyl, oxazolyl,

thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl; fused heteroaryl groups
include indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl, indazolyl,
benzimidazolyl, benzthiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl,
benzotriazolyl, quinolizinyl, quinolinyl, isoquinolinyl or quinazolinyl.
The term "arylalkyl" means an alkyl group substituted with an aryl group
(e.g., benzyl, phenethyl). Similarly, the term "arylalkoxy" indicates an alkoxy
group substituted with an aryl group (e.g., benzyloxy).
As used herein, the term "carboxyl" refers to the linking group -C(0)0- or
(when used accordingly) to the substituent-COOH; the term "imino" refers to the
substituent HN=.
Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a
name of a substituent (e.g., arylalkyl, alkylamino) it shall be interpreted as
including those limitations given above for "alkyl" and "aryl." Designated numbers
of carbon atoms (e.g., C1-C6) shall refer independently to the number of carbon
atoms in an alkyl moiety or to the alkyl portion of a larger substituent in which alkyl
appears as its prefix root. However, for clarity in the terms "Cg-C-u benzo fused
cycloalkyT, "C9-C14 benzo fused cycloalkenyl", "C9-C14 benzo fused aryl"; C9-C14
refers to the number of carbon atoms both in the benzene ring (6) and the
number of atoms in the ring fused to the benzene ring, but does not include
carbon atoms that may be pendent from these multiple ring systems. The
amount of substituents attached to a moiety "optionally substituted with one to five
substituents" is limited to that amount of open valences on the moiety available
for substitution.
In general, under standard nomenclature rules used throughout this
disclosure, the terminal portion of the designated side chain is described first
followed by the adjacent functionality toward the point of attachment. Thus, for

example, a "phenylCi-C6 alkylamidoCi-Cealkyl" substituent refers to a group of
the formula:
It is Intended that the definition of any substituent or variable at a
particular location in a molecule be independent of its definitions elsewhere in
that molecule. It is understood that substituents and substitution patterns on
the compounds of this invention can be selected by one of ordinary skill in the
art to provide compounds that are chemically stable and that can be readily
synthesized by techniques known in the art as well as those methods set forth
herein.
Illustrative of the invention is a composition comprising a pharmaceutically
acceptable earner and any of the compounds described above. Also illustrative of
the invention is a composition made by mixing any of the compounds described
above and a pharmaceutically acceptable earner. A further illustration of the
invention is a process for making a composition comprising mixing any of the
compounds described above and a pharmaceutically acceptable carrier. The
present invention also provides compositions comprising one or more compounds
of this invention in association with a pharmaceutically acceptable carrier.
The compounds of the present invention are useful serine protease
inhibitors (in particular, inhibitors of cathepsin G and chymase) useful for treating
inflammatory and serine protease mediated disorders. Some of these disorders
include, inflammatory and serine protease mediated disorders include, and are
not limited to, pulmonary inflammatory conditions, chronic obstructive pulmonary
diseases, asthma, pulmonary emphysema, bronchitis, psoriasis, allergic rhinitis,
viral rhinitis, ischemia, arthritis, glomerulonephritis, postoperative adhesion
formation and reperfusion injury. These compounds would be useful in treating

disease states caused by angiotensin II including but not limited to hypertension,
hypercardia myocardial infarction, arteriosclerosis, diabetic and non-diabetic
retinopathy, vascular restenosis and the like. Additionally, these compounds can
be used for immune modulation. The utility of the compounds to treat
inflammatory and serine protease mediated disorders can be determined
according to the procedures described herein. '
An embodiment of the invention is a method for treating inflammatory
and serine protease mediated disorders in a subject in need thereof which
comprises administering to the subject a therapeutically effective amount of any
of the compounds or compositions described above. Also included in the
invention is the use of a compound of Formula (I) for the preparation of a
medicament for treating an inflammatory or serine protease mediated disorder
in a subject in need thereof. The term "treating" as used herein refers to a
method for improving, halting, retarding or palliating an inflammatory or serine
protease mediated disorder in the subject in need thereof. All such methods of
treatment are intended to be within the scope of the present invention.
In accordance with the methods of the present invention, the individual
components of the compositions described herein can also be administered
separately at different times during the course of therapy or concurrently in
divided or single combination forms. The instant invention is therefore to be
understood as embracing all such regimes of simultaneous or alternating
treatment and the term "administering" is to be interpreted accordingly.
The term "subject" as used herein, refers to an animal (preferably, a
mammal; most preferably, a human) who has been the object of treatment,
observation or experiment.
The term "therapeutically effective amount" as used herein, means that
amount of active compound or pharmaceutical agent that elicits the biological or

medicinal response in a tissue system, animal or human, that is being sought by
a researcher, veterinarian, medical doctor, or other clinician, which includes
alleviation of the symptoms of the disease or disorder being treated.
As used herein, the term "composition" is intended to encompass a
product comprising the specified ingredients in the specified amounts, as well
as any product which results, directly or indirectly, from combinations of the
specified ingredients in the specified amounts.
To prepare the compositions of this invention, one or more compounds
of Formula (I) or salt thereof as the active ingredient, is intimately admixed with
a pharmaceutical carrier according to conventional pharmaceutical
compounding techniques, which earner may take a wide variety of forms
depending of the form of preparation desired for administration (e.g. oral or
parenteral). Suitable pharmaceutically acceptable carriers are well known in
the art. Descriptions of some of these pharmaceutically acceptable carriers
may be found in The Handbook of Pharmaceutical Excipients, published by the
American Pharmaceutical Association and the Pharmaceutical Society of Great
Britain.
Methods of formulating compositions have been described in numerous
publications such as Pharmaceutical Dosage Forms: Tablets. Second Edition.
Revised and Expanded. Volumes 1-3, edited by Lieberman et al;
Pharmaceutical Dosage Forms: Parenteral Medications. Volumes 1-2, edited
by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems. Volumes
1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.
In preparing a composition of the present invention in liquid dosage form
for oral, topical, inhalation/insufflation and parenteral administration, any of the
usual pharmaceutical media or excipients may be employed. Thus, for liquid
dosage forms, such as suspensions (i.e. colloids, emulsions and dispersions)

and solutions, suitable carriers and additives include but are not limited to
pharmaceutical^ acceptable wetting agents, dispersants, flocculation agents,
thickeners, pH control agents (i.e. buffers), osmotic agents, coloring agents,
flavors, fragrances, preservatives (i.e. to control microbial growth, etc.) and a
liquid vehicle may be employed. Not all of the components listed above will be
required for each liquid dosage form.
In solid oral preparations such as, for example, powders, granules,
capsules, caplets, gelcaps, pills and tablets (each including immediate release,
timed release and sustained release formulations), suitable carriers and
additives include but are not limited to diluents, granulating agents, lubricants,
binders, glidants, disintegrating agents and the like. Because of their ease of
administration, tablets and capsules represent the most advantageous oral
dosage unit form, in which case solid pharmaceutical carriers are obviously
employed. If desired, tablets may be sugar coated, gelatin coated, film coated
or enteric coated by standard techniques.
Preferably these compositions are in unit dosage forms from such as
tablets, pills, capsules, powders, granules, lozenges, sterile parenteral
solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules,
autoinjector devices or suppositories for administration by oral, intranasal,
sublingual, intraocular, transdermal, parenteral, rectal, vaginal, inhalation or
insufflation means. Alternatively, the composition may be presented in a form
suitable for once-weekly or once-monthly administration; for example, an
insoluble salt of the active compound, such as the decanoate salt, may be
adapted to provide a depot preparation for intramuscular injection.
For preparing solid compositions such as tablets, the principal active
ingredient is mixed with a pharmaceutical carrier, e.g. conventional tabletting
ingredients such as diluents, binders, adhesives, disintegrants, lubricants,
antiadherents and glidants. Suitable diluents include, but are not limited to,

starch (i.e. corn, wheat, or potato starch, which may be hydrolized), lactose
(granulated, spray dried or anhydrous), sucrose, sucrose-based diluents
(confectioner's sugar; sucrose plus about 7 to 10 weight percent invert sugar;
sucrose plus about 3 weight percent modified dextrins; sucrose plus invert
sugar, about 4 weight percent invert sugar, about 0.1 to 0.2 weight percent
cornstarch and magnesium stearate), dextrose, inositol, mannitol, sorbitol,
microcrystalline cellulose (i.e. AVICEL ™ microcrystalline cellulose available
from FMC Corp.), dicalcium phosphate, calcium sulfate dihydrate, calcium
lactate trihydrate and the like. Suitable binders and adhesives include, but are
not limited to accacia gum, guar gum, tragacanth gum, sucrose, gelatin,
glucose, starch, and cellulosics (i.e. methylcellulose, sodium
carboxymethycellulose, ethylcellulose, hydroxypropylmethylcellulose,
hydroxypropylcellulose, and the like), water soluble or dispersible binders (i.e.
alginic acid and salts thereof, magnesium aluminum silicate,
hydroxyethylcellulose [i.e. TYLOSE ™ available from Hoechst Celanese],
polyethylene glycol, polysaccharide acids, bentonites, polyvinylpyrrolidone,
polymethacrylates and pregelatinized starch) and the like. Suitable
disintegrants include, but are not limited to, starches (corn, potato, etc.),
sodium starch glycolates, pregelatinized starches, clays (magnesium aluminum
silicate), celluloses (such as crosslinked sodium carboxymethylcellulose and
microcrystalline cellulose), alginates, pregelatinized starches (i.e. com starch,
etc.), gums (i.e. agar, guar, locust bean, karaya, pectin, and tragacanth gum),
cross-linked polyvinylpyrrolidone and the like. Suitable lubricants and
antiadherents include, but are not limited to, stearates (magnesium, calcium
and sodium), stearic acid, talc waxes, stearowet, boric acid, sodium chloride,
DL-leucine, carbowax 4000, carbowax 6000, sodium oleate, sodium benzoate,
sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate and the like.
Suitable gildants include, but are not limited to, talc, cornstarch, silica (i.e. CAB-
O-SIL ™ silica available from Cabot, SYLOID ™ silica available from W.R.
Grace/Davison, and AEROSIL ™ silica available from Degussa) and the like.
Sweeteners and flavorants may be added to chewable solid dosage forms to

improve the payability of the oral dosage form. Additionally, colorants and
coatings may be added or applied to the solid dosage form for ease of
identification of the drug or for aesthetic purposes. These carriers are
formulated with the pharmaceutical active to provide an accurate, appropriate
dose of the pharmaceutical active with a therapeutic release profile.
Generally these carriers are mixed with the pharmaceutical active to
form a solid preformulation composition containing a homogeneous mixture of
the pharmaceutical active of the present invention, or a pharmaceutically
acceptable salt thereof. Generally the preformulation will be formed by one of
three common methods: (a) wet granulation, (b) dry granulation and (c) dry
blending. When referring to these preformulation compositions as
homogeneous, it is meant that the active ingredient is dispersed evenly
throughout the composition so that the composition may be readily subdivided
into equally effective dosage forms such as tablets, pills and capsules. This
solid preformulation composition is then subdivided into unit dosage forms of
the type described above containing from about 0.01 mg to about 500 mg of
the active ingredient of the present invention. The tablets or pills containing the
novel compositions may also be formulated in multilayer tablets or pills to
provide a sustained or provide dual-release products. For example, a dual
release tablet or pill can comprise an inner dosage and an outer dosage
component, the latter being in the form of an envelope over the former. The
two components can be separated by an enteric layer, which serves to resist
disintegration in the stomach and permits the inner component to pass intact
into the duodenum or to be delayed in release. A variety of materials can be
used for such enteric layers or coatings, such materials including a number of
polymeric materials such as shellac, cellulose acetate, cellulose acetate
phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate,
hydroxypropyl methylcellulose acetate succinate, methacrylate and
ethylacrylate copolymers and the like. Sustained release tablets may also be
made by film coating or wet granulation using slightly soluble or insoluble

substances in solution (which for a wet granulation acts as the binding agents)
or low melting solids a molten form (which in a wet granulation may incorporate
the active ingredient). These materials include natural and synthetic polymers
waxes, hydrogenated oils, fatty acids and alcohols (i.e. beeswax, carnauba
wax, cetyl alcohol, cetylstearyl alcohol, and the like), esters of fatty acids
metallic soaps, and other acceptable materials that can be used to granulate,
coat, entrap or otherwise limit the solubility of an active ingredient to achieve a
prolonged or sustained release product.
The liquid forms in which the novel compositions of the present invention
may be incorporated for administration orally or by injection include, but are not
limited to aqueous solutions, suitably flavored syrups, aqueous or oil
suspensions, and flavored emulsions with edible oils such as cottonseed oil,
sesame oil, coconut oil or peanut oil, as well as elixirs and similar
pharmaceutical vehicles. Suitable suspending agents for aqueous
suspensions, include synthetic and natural gums such as, acacia, agar,
alginate (i.e. propylene alginate, sodium alginate and the like), guar, karaya,
locust bean, pectin, tragacanth, and xanthan gum, cellulosics such as sodium
carboxymethylcellulose, methylcellulose, hydroxymethylcellulose,
hydroxyethylcellulose, hydroxypropyl cellulose and hydroxypropyl
methylcellulose, and combinations thereof, synthetic polymers such as
polyvinyl pyrrolidone, carbomer (i.e. carboxypolymethylene), and polyethylene
glycol; clays such as bentonite, hectorite, attapulgite or sepiolite; and other
pharmaceutically acceptable suspending agents such as lecithin, gelatin or the
like. Suitable surfactants include but are not limited to sodium docusate,
sodium lauryl sulfate, polysorbate, octoxynol-9, nonoxynol-10, polysorbate 20,
polysorbate 40, polysorbate 60, polysorbate 80, polyoxamer 188, polyoxamer
235 and combinations thereof. Suitable deflocculating or dispersing agent
include pharmaceutical grade lecithins. Suitable flocculating agent include but
are not limited to simple neutral electrolytes (i.e. sodium chloride, potassium,
chloride, and the like), highly charged insoluble polymers and polyelectrolyte

species, water soluble divalent or trivalent ions (i.e. calcium salts, alums or
sulfates, citrates and phosphates (which can be used jointly in formulations as
pH buffers and flocculating agents). Suitable preservatives include but are not
limited to parabens (i.e. methyl, ethyl, /7-propyl and n-butyl), sorbicacid,
thimerosal, quaternary ammonium salts, benzyl alcohol, benzoic acid,
chlorhexidine gluconate, phenylethanol and the like. There are many liquid
vehicles that may be used in liquid pharmaceutical dosage forms, however, the
liquid vehicle that is used in a particular dosage form must be compatible with
the suspending agent(s). For example, nonpolar liquid vehicles such as fatty
esters and oils liquid vehicles are best used with suspending agents such as
low HLB (Hydrophile-Lipophile Balance) surfactants, stearalkonium hectorite,
water insoluble resins, water insoluble film forming polymers and the like.
Conversely, polar liquids such as water, alcohols, polyols and glycols are best
used with suspending agents such as higher HLB surfactants, clays silicates,
gums, water soluble cellulosics, water soluble polymers and the like. For
parenteral administration, sterile suspensions and solutions are desired. Liquid
forms useful for parenteral administration include sterile solutions, emulsions and
suspensions. Isotonic preparations which generally contain suitable
preservatives are employed when intravenous administration is desired.
Furthermore, compounds of the present invention can be administered in
an intranasal dosage form via topical use of suitable intranasal vehicles or via
transdermal skin patches, the composition of which are well known to those of
ordinary skill in that art. To be administered in the form of a transdermal delivery
system, the administration of a therapeutic dose will, of course, be continuous
rather than intermittent throughout the dosage regimen.
Compounds of the present invention can also be administered in a form
suitable for intranasal or inhalation therapy. For such therapy, compounds of
the present invention are conveniently delivered in the form of a solution or
suspension from a pump spray container that is squeezed or pumped or as an

aerosol spray from a pressurized container or a nebulizer (such as, a metered
dose inhaler, a dry powder inhaler or other conventional or non-conventional
modes or devices for inhalation delivery) using a suitable propellant (such as,
dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane,
carbon dioxide or other suitable gas). In the case of a pressurized aerosol, the
dosage unit may be determined by providing a valve to deliver a metered
amount. The pressurized container or nebulizer may contain a solution or
suspension of the active compound. Capsules and cartridges (such as, those
made from gelatin) for use in an inhaler or insufflator may be formulated
containing a powder mix of a compound of the invention and a suitable powder
base such as lactose or starch.
Compounds of the present invention can also be administered in the form
of liposome delivery systems, such as small unilamellar vesicles, large unilamellar
vesicles, multilamellar vesicles and the like. Liposomes can be formed from a
variety of phospholipids, such as cholesterol, stearylamine, phosphatidylcholines
and the like.
Compounds of the present invention may also be delivered by the use of
monoclonal antibodies as individual carriers to which the compound molecules
are coupled. The compounds of the present invention may also be coupled with
soluble polymers as targetable drug carriers. Such polymers can include, but are
not limited to polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamidephenol, polyhydroxy-ethylaspartamidephenol,
or polyethyl eneoxidepolylysine substituted with palmitoyl residue. Furthermore,
the compounds of the present invention may be coupled to a class of
biodegradable polymers useful in achieving controlled release of a drug, for
example, to homopolymers and copolymers (which means polymers containing
two or more chemically distinguishable repeating units) of lactide (which
includes lactic acid d-, I- and meso lactide), glycolide (including glycolic acid), e-
caprolactone, p-dioxanone (1,4-dioxan-2-one), trimethylene carbonate (1,3-

dioxan-2-one), alkyl derivatives of trimethylene carbonate, 5-valeroiactone, p-
butyrolactone, ^butyrolactone, e-decalactone, hydroxybutyrate,
hydroxyvalerate, 1,4-dioxepan-2-one (including its dimer 1,5,8,12-
tetraoxacyclotetradecane-7,14-dione), 1,5-dioxepan-2-one, 6,6-dimethyH ,4-
dioxan-2-one, polyorthoesters, poiyacetals, polydihydropyrans,
polycyanoacrylates and cross-linked or amphipathic block copolymers of
hydrogels and blends thereof.
The therapeutically effective amount of a compound or composition
thereof may be from about 0.001 mg/Kg/dose to about 300 mg/Kg/dose.
Preferably, the therapeutically effective amount may be from about 0.001
mg/Kg/dose to about 100 mg/Kg/dose. More preferably, the therapeutically
effective amount may be from about 0.001 mg/Kg/dose to about 50
mg/Kg/dose. Most preferably, the therapeutically effective amount may be from
about 0.001 mg/Kg/dose to about 30 mg/Kg/dose. Therefore, the
therapeutically effective amount of the active ingredient contained per dosage
unit (e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the
like) as described herein will be in the range of from about 1 mg/day to about
21,000 mg/day for a subject, for example, having an average weight of 70 Kg.
For oral administration, the compositions are preferably provided in the form of
tablets containing, 0.01, 0.05,0.1, 0.5,1.0, 2.5, 5.0, 10.0,15.0, 25.0,50.0,100,
150,200,250 and 500 milligrams of the active ingredient for the symptomatic
adjustment of the dosage to the subject to be treated.
Optimal dosages to be administered may be readily determined by those
skilled in the art, and will vary with the particular compound used, the mode of
administration, the strength of the preparation, and the advancement of the
disease condition. In addition, factors associated with the particular subject
being treated, including subject age, weight, diet and time of administration, will
result in the need to adjust the dose to an appropriate therapeutic level.
Advantageously, compounds of the present invention may be administered in a

single daily dose or the total daily dosage may be administered in divided
doses of two, three or four times daily.
Representative IUPAC names for the compounds of the present invention
were derived using the ACD/LABS SOFTWARE™ Index Name Pro Version 4.5
nomenclature software program provided by Advanced Chemistry Development,
Inc., Toronto, Ontario, Canada.
Abbreviations used in the instant specification, particularly the Schemes
and Examples, are as follows:
Boc = tert-butoxycarbonyl
BuLi = n-butyllithium
Cpd = compound
DCC = dicyclohexylcarbodiimide
h = hour/hours
HOBT = hydroxybenzotriazole
KH = potassium hydride
Mel = methyliodide
NT = not tested
rt/RT = room temperature
TFA = trifluoroacetic acid
TMSBr = bromotrimethylsilane
General Synthetic Methods
Representative compounds of the present invention can be synthesized in
accordance with the general synthetic methods described below and are
illustrated more particularly in the scheme that follows. Since the scheme is an
illustration, the invention should not be construed as being limited by the
chemical reactions and conditions expressed. The preparation of the various
starting materials used in the schemes is well within the skill of persons versed
in the art.
Scheme A
Scheme A is illustrative of a general method for the preparation of compounds

of the invention by addition of a phosphonate or phosphinate anion, prepared
from a phosphonate or phosphinate Compound A2, and an organometallic
base such as /7-butyllithium, to an anhydride Compound A1 in a solvent such
as THF to afford a ketophosphonate or ketophosphinate Compound A3,
wherein Z is hydrogen, Y is not present and X is one oxygen substituent
attached by a double-bond to the carbon in the position p to R4.
Other compounds of the present invention may be obtained from Compound
A3 using standard ketone manipulations wherein the p position carbon may be
reduced from the ketone to a compound of Formula (I) wherein X and Y are
both present or wherein Z is a bond. Examples of ketone manipulations
include, but are not limited to, the use of 1) organometallic reagents to form
alkoxy groups; 2) hydroxyl amines to form imino groups; and, 3) Lawesson's
reagent to substitute a thio group in place of the ketone (with appropriate
protecting groups added to the COOH group shown).
Compound A2, wherein R6 is as previously defined, can be made according to
known methods, such as those described in Katritsky, et. al., Org. Prep.
Proced. Int., 1990, 22(2), 209-213; J. Am. Chem. Soc, 2002, 124, 9386-9387;
and, Chem. Ber., 1963, 96, 3184-3194. In an embodiment of a general
synthetic method, the Rs substitutent of Compound A4 is hydrogen and the R6
substituted is ethoxy.
Compound A2, wherein R4 is heteroaryl, can be prepared from commercially
available or known haloalkyl substituted heteroaryl starting materials (such as
3-bromomethyl-5-CI-benzothiophene used to prepare Cpd 33) using techniques
known to those skilled in the art.
Compound A3 may be coupled to the R1 portion of Formula (I) using standard
coupling reactions. For example, when Rn is a secondary amine in a
heterocyclyl ring, the nitrogen on the ring may be coupled to Compound A3

(similar to the reaction shown in Scheme A, e.g. the ring nitrogen in Compound
A4 would be coupled with Compound A8). Appropriate blocking groups can be
employed to minimize undesirable side reactions. Analogous coupling
reactions with Compound A3 can be performed when Ri is N(R7RB) to couple
the substituted amine to the carboxylic acid of Compound A3. In one
embodiment of the present invention the coupling reaction of Compound A3
with Ri when Ri is N(R7R8) and Rg is a heterocycle is provided to further
illustrate the present invention.
In Scheme A, the reaction of a suitably protected amino substituted heterocycle
Compound A4 (wherein the protected amino is substituted with a hydrogen
atom for R7 and an unsubstituted ad), heterocycle for R8) with a Q-substituted
Raa Compound A5 (wherein Q is a suitable leaving group (such as , but not
limited to, a halogen atom) and Rsa is a substituent as previously defined in the
Ra ba).-bl) list) in a solvent such as DMF containing a base (such as, but not
limited to, triethylamine) provided an Rab substituted Compound A6.
In an embodiment of a general synthetic method, the heterocyclyl portion of
Compound A4 was further substituted on a nitrogen ring atom by reaction with
an acid chloride Compound A5, wherein the Q portion was chlorine and
wherein the Raa portion was be), carbonyl substituted with an R8b substituent
selected from Ci.8alkyl, aryl, aryl(Ci^)alkyl, aryl(C2^)alkenyl, heteroaryl,
heteroaryl(Ci^)alkyl or heteroaryl(C2-8)alkenyl. In an alternate embodiment, the
reaction may performed by reaction with an acid chloride Compound A5,
wherein the Q portion is chlorine and wherein the Reaportion is bl). sulfonyl
substituted with an R8b substituent; wherein R«b is as previously defined.
Treatment of Compound A6 with a base such as potassium hydride followed by
treatment with an R7X alkylating agent such as iodomethane in a solvent such
as THF yielded Compound A7. The amine Compound A8 can be obtained
from Compound A7 by removal of the Boc protecting group upon treatment

with an acid such as TFA in a solvent such as CHfeCfe. The free base of
Compound A8 is obtained upon treatment with a base such as aqueous
Na2C03.
Compound A9 can be prepared by a standard coupling procedure between
Compound A3 and Compound A8 using routine reagents such as DCC and
HOBT in a solvent such as CH3CN. Dealkylation of Compound A9 with reagent
such as bromotrimethylsilane in a solvent such as pyridine, followed by
treatment with dilute HCI afforded Compound A10 (wherein, in an embodiment
of a general synthetic method, the R5 ethyl group and the F^ ethoxy group were
replaced with hydrogen). A salt of Compound A10 such as target Compound
A11 can be prepared by treating Compound A10 with a monobasic or dibasic
amine such as tris(hydroxymethyl)aminomethane in a solvent system such as
i-PrOH and water.



Scheme B
Scheme B is illustrative of an alternative general synthetic method for the
preparation of compounds of the invention by addition of a Compound A2 (in
an embodiment of an alternative general method, the R5 substituted of
Compound A2 is ethyl and the R6 substituted is ethoxy) and R"M (wherein R"M
represents an organometallic reagent such as LiHMDS (lithium

hexamethyldisilylazide), lithium tetramethylpiperidide or NaHMDS (sodium PS -,
hexamethyldisilazide)) to an anhydride Compound A1.
The reaction is subsequently quenched with 6N HCI to a pH between 4 and 6
to afford an enol Compound B1, wherein for a compound of Formula (I), 2 is a
bond, Y is not present and X is one oxygen substituent attached by a single-
bond to the carbon in the position p to R4. Other compounds of the present
invention may be obtained from Compound B1 using standard ketone
manipulation wherein the enol double bond may be reduced to the ketone;
wherein for a compound of Formula (I), Y is not present and X is one oxygen
substituent attached by a double-bond on the p position carbon. A coupling
reagent (such as, but not limited to, chloroformates (such as, but not limited to,
isobutyl chloroformate), cyanuric chloride, methanesulfonyl chloride, or diethyl
chlorophosphate) may then be employed for ring closure to form a substituted
lactone intermediate Compound B2 in the presence of a base such as, but not
limited to, Et^N.
Reaction of a dihydroxy substituted heterocycle Compound B3 (or other
ketones and other protected ketones) with a Q-substituted R8a Compound A5 in
a solvent (such as, but not limited to, CH2CI2, THF or mixtures thereof)
containing a base (such as, but not limited to, sodium bicarbonate, potassium
carbonate) provided an Rsb substituted Compound B4.
Compound B4 was treated with R7NH2 in a solvent (such as, but not limited to,
CH2CI2, THF or mixtures thereof) then subjected to reductive amination or
hydrogenation using a hydride reducing agent (such as, but not limited to,
NaBH(OAc)3, or hydrogenation with Pd, Pt or Ni catalyst). The free base of
Compound A8 was obtained upon quenching the reaction with a base such as
aqueous Na2C03.
Compound A9 (in tautomeric equilibrium with Compound B6) was prepared by

opening the 5-membered lactone ring intermediate Compound B2 with
Compound A8 (or Compound B5, a salt of Compound A8) in the presence of
DIEA (diisopropylethylamine) in a solvent (such as, but not limited to, acetone
or MEK (methylethyl ketone)).
Dealkylation of the equilibrium mixture of Compound A9-Compound B6 with a
reagent (such as, but not limited to, TMSBr (bromotrimethylsilane) or TMSI) in
a solvent (such as, but not limited to, CH3CN or pyridine), followed by
recrystallization afforded Compound A10 (wherein the R5 ethyl group is
replaced with hydrogen and the R6 ethoxy group is replaced with hydroxy). A
salt of Compound A10 such as Compound A11 (and tautomers thereof) was
prepared by treating Compound A10 with a diamine such as
tris(hydroxyrnethyl)aminomethane in a solvent system such as a mixture of
EtOH and water.



Scheme C
Scheme C is illustrative of an alternative method for the preparation of the
intermediate Compound B2, wherein the enol Compound B1 is protonated to
the free acid ketone Compound A3 by adjusting the pH to about pH 1, followed
by intramolecular dehydration to provide the target lactone intermediate
Compound B2.
Scheme D is illustrative of a method for the preparation of an acid addition
compound B5, wherein Compound A8 is reacted with an acid HA (such as, but
not limited to, HCI, HBr or p-toluenesulfonic acid) to provide the target
Compound B5 which may be carried forward in place of Compound A8 in the
reaction with Compound B2.




Compound E1 can be prepared from commercially available or known starting
materials using techniques known to those of skill in the art.
Specific Synthetic Examples
Specific compounds which are representative of this invention were prepared
as per the following examples and reaction sequences; the examples and the
diagrams depicting the reaction sequences are offered by way of illustration, to
aid in the understanding of the invention and should not be construed to limit in
any way the invention set forth in the claims which follow thereafter. The
depicted intermediates may also be used in subsequent examples to produce
additional compounds of the present invention.. These reactions can be further
optimized to increase the yields. One skilled in the art would know how to
increase such yields through routine variations in reaction times, temperatures,
solvents and/or reagents.
All chemicals were obtained from commercial suppliers and used without
further purification. 1H and 13C NMR spectra were recorded on a Bruker AC
300B (300 MHz proton) or a Bruker AM-400 (400 MHz proton) spectrometer
with Me4Si as an internal standard (s = singlet, d = doublet, t = triplet, br =
broad). APCI-MS and ES-MS were recorded on a VG Platform II mass

spectrometer.
Example 1
[2-[3-[[methyl[1-(2-naphthalenylcarbonyl)-
4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-
1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (Compound 2)
To a solution of 2.5M n-BuLi in hexanes (40 ml_, 0.1 mol) in 70 mL of THF at -
78°C was added dropwise a solution of 1-naphthyldiethylphosphonate
(Compound 1A, 28 g, 0.1 mol) in 60 mL THF over 30 min. After stirring for an
additional 30 min, 2,3-naphthalenedicarboxylic anhydride (Compound 1B, 20 g,
0.1 mol) was added portionwise via solid-addition funnel to the mixture over 20
min. After the addition was complete, the slurry was allowed to reach 0°C
gradually where it was held for another 1.5 h. Excess NH4CI (sat'd., aq.) was
added, and the mixture was filtered through a pad of Celite 545. The filtrate
was extracted with 200 mL of EtOAc and the layers were separated. The
organic phase was concentrated (without drying) under reduced pressure at rt
and the residue was triturated 4X with boiling ether. The residue was treated
with 200 mL of EtOAc and adjusted to pH 3 with 2N HCI (aq.) with vigorous
stirring. The layers were separated, and the organic phase was washed once
with H20, dried (Na2S04) and concentrated to afford 24 g of Compound 1C as
a white powder: MS (ES) MH+ = 477; HPLC: 3.68 min.
To a solution of Compound 1D (4 g, 20 mmol) containing 3.1 mL of
triethylamine (22 mmol) in 45 mL of DMF was added Compound 1E (3.8 g, 20
mmol). After stirring overnight, the mixture was filtered and concentrated under
reduced pressure. The residue was taken up in CH2CI2 and washed
sequentially with H20, Na2C03 (10%, aq.), H20, KHSO4 (1N aq.) and H20. The
organic phase was dried (Na2S04), and concentrated to afford 6.0 g of
Compound 1F as a foam: MS (ES) MH+ = 355.
Potassium hydride (2.3 g of a 35% oil dispersion; 20 mmol) was washed with

hexanes, then treated with 30 ml_ of THF and cooled to 0 °C. To the
suspension was added dropwise a solution of Compound 1F (5.9 g, 16.8 mmol)
in 15 mL of THF. The mixture was stirred at 0°C for 0.5 h, then stirred an
additional 0.5 h at rt. The mixture was cooled to 0°C and iodomethane (15.7 g,
100 mmol) was added dropwise. The mixture was stirred at 0°C for 0.5 h then
warmed to rt and stirred an additional 1.5 h. Excess 10% Na2C03 (aq) was
added slowly at 0°C, and the volatiles were removed under reduced pressure.
The aqueous layer was extracted 3 times with EtOAc and the combined
extracts were dried (Na2S04) and concentrated to yield 6.1 g of Compound 1G
as foam. HPLC Rt = 3.76 min, 100%; MS (ES) MH+ = 369.
i
A solution of Compound 1G (6.1 g, 16.5 mmol) was dissolved in 15 mL of a 1:1
solution of TFA:CH2Cl2 and stirred for 1 h at rt. Volatiles were removed under
reduced pressure, and the residue was dissolved in CH2CI2 and treated with
excess 10% Na2C03 (aq). The layers were separated, and the aqueous phase
was extracted 3 times with CH2CI2. The organic extracts were combined, dried
(Na2SC"4) and concentrated to afford 4.3 g of Compound 1H as a viscous oil.
HPLC Rt = 1.5 min, 100%; MS (ES) MH+ = 269.
A, solution of Compound 1C (4.9 g, 10.3 mmol), Compound 1H (3.3 g, 12.3
mmol) and HOBT (2.1 g, 15.4 mmol) in 100 mL CH3CN was treated with a
solution of DCC (2.5 g, 12.3 mmol) in 7 mL of CH3CN. After stirring for 12 h, 5
mL of DIPEA was added and the reaction was stirred for an additional 48 h.
The mixture was filtered and concentrated. The residue was purified by flash
column chromatography (silica: C^CfeMeOH ramped from 98:1 to 95:5) to
yield 6.9 g of Compound 11. HPLC Rt = 4.3 min; MS (ES) MH+ = 727.
To a solution of Compound 11 in 15 mL of pyridine was added 5 mL of
bromotrimethylsilane. The mixture was stirred for 15 min, then concentrated
under reduced pressure. The residue was treated with excess 3N HCI(aq),
then stirred for 3h. The white precipitate was collected and rinsed with water,

then triturated with CH3CN to afford 5.1g of Compound 1J. HPLC Rt = 3.6 min;
MS (ES) MH+ = 671. To a solution of Compound 1J in 50 mL of CH3CN was
added a solution of tris(hydroxymethyl)aminomethane (0.9 g, 7.7 mmol) in 7
mL of H2O. The solution was filtered and the filtrate lyophilized after partial
concentration to remove most of the CH3CN. The resulting white solid was
recrystallized from /-PrOH to yield 5.5 g of Compound 2 as an off-white solid.
HPLC: Rt = 3.6 min; 100%; MS (ES) MH+ = 671; Anal. Calc'd for
C4oH35N206P-1.0 C4HuN03-1 .0 /-PrOH* 1.5 H20: C, 64.23; H, 6.54; N, 4.79;
H20, 3.08. Found: C, 63.93; H, 6.40; N, 4.85; H20, 2.74.
For Examplel, TLC was performed using Whatman 250-nm silica gel plates.
Preparative TLC was performed with Analtech 1000-u.m silica gel GF plates.
Flash column chromatography was conducted with flash column silica gel (40-
63 urn) and column chromatography was conducted with standard silica gel.
HPLC separations were carried out on three Waters PrepPak® Cartridges (25 x
100 mm, Bondapak® C18, 15-20 urn, 125 A) connected in series; detection was
at 254 nm on a Waters 486 UV detector. Analytical HPLC was carried out on a
Supelcosil ABZ+PLUS column (5 cm x 2.1 mm), with detection at 254 nm on a
Hewlett Packard 1100 UV detector. Microanalysis was performed by
Robertson Microlit Laboratories, Inc.










about -20 °C using a dry ice-methanol cooling bath. A solution of 1M UHMDS
(1597.0 mL, 1.597 mol) in THF was added to the cooled mixture while keeping
the temperature at about -20 °C to form a fine slurry which was stirred for an
additional 30 minutes. A 2,3-naphthalinedicarboxytic anhydride Compound 2A
(158.80 gm, 0.7612 mol) was added portionwise over about a 1 h period while
keeping the temperature of the mixture at about -20 CC. The addition funnel and
flask walls were rinsed with THF (100.0 mL), the cooling bath was removed and
the mixture temperature raised to about 5 °C for about 1.5 h. Once the reaction
was complete (as shown by HPLC), the final pH of the mixture was adjusted to
about pH 5 by slowly adding 6N HCI (422 mL, 2.34 mol) while the temperature of
the mixture was maintained at about 5 °C. The mixture was stirred for about 30
min more at about 5 °C to provide a crude product as a fine white solid. The
crude product was filtered using a porcelain filter. The wet solid was then
washed with water (1000.0 mL), left to filter overnight, then dried at 70 °C to
provide a dilithium salt Compound 2C (365.1 gms; mass yield: 100.6%).
Compound 2C was used in the next step without further purification.
Methanol (2500.0 mL) and water (360.0 mL) were added to a flask and stirred.
Compound 2C (365.1 gm, 0.7612 mol) was added to the stirring solution and
the flask was rinsed with methanol (100.0 mL) to form a slurry. The slurry was
stirred at RT for 30 minutes and then 12 N HCI (80.0 mL, 0.960 mol) was added
over a 2 min period as the slurry turned into a hazy solution. The solution was
stirred at RT until crystallization began, then was cooled to about 5 °C for 1 h to
provide a crude product as a white granular solid. The product was filtered and
washed with water (500.0 mL), then dried in vacuo overnight at a temperature
of about 50 °C to provide Compound 2D (280 gms; mass yield: 77.3%).
Compound 2D (199.8 gm) and THF (2 L) were combined in a flask, then
agitated and cooled to a temperature of from about 0 °C to about 5 °C. NMM
(4-methylmorpholine) (51.5 mL) was added to the flask while the mixture

temperature was maintained at a temperature of from about 0 °C to about 5 °C.
The mixture was then agitated for an additional 15 min or until a solution was
obtained. IBCF (isobutylchloroformate) (56 mL) was added portionwise while
the mixture temperature was maintained at a temperature of from about 0 °C to
about 15 °C. When the addition was complete, the mixture temperature was
warmed to a temperature of from about 20 °C to about 25 °C, then agitated for
1 h. Once the reaction was complete, the NMM salts were filtered, washed
with THF (150 mL) and allowed to dry. The filtrate was then combined with
n-heptane (2.5 L) over a period of about 10 min and then agitated at a
temperature of from about 20 °C to about 25 °C for about 30-45 min. Additional
n-heptane (1.5 L) was added over a period of about 10 min. The mixture was
then cooled to a temperature of from about 0 °C to about 5 °C and aged for
about 1.5 h. The resulting suspension was filtered and washed with n-heptane
(250 mL), allowed to air dry over a period of about 30 min and then dried in
vacuo overnight at a temperature of from about 45 to about 50 °C to provide
Compound 2E (165 gms; mass yield: 88.4%).
DCM (dichloromethane) (600 mL) and a 2-naphthoyl chloride Compound 2F
(189.0 gm) were combined in a flask and agitated until solubilized.
4-Piperidone hydrate hydrochloride Compound 2G (150 g) and NaHC03
(sodium hydrogen carbonate) (260.0 gms) were then added via addition funnel.
DCM (300 mL) was used to rinse the funnel and the resulting mixture was
agitated for 18 h. Once the reaction was complete (as shown by HPLC), water
(2.6 L) was added to the flask and the mixture was stirred vigorously to dissolve
the NaHC03. After a period of about 5 to about 10 minutes, the layers were
allowed to separate over a period of about 30 minutes. The aqueous layer was
removed. Saturated aqueous NaHC03 (300 mL) was again added and the
mixture agitated for a period of about 5 to about 10 min. The layers were
allowed to separate over a period of about 30 min and the aqueous layer was
removed. Water (300 mL) was added and the mixture stirred gently for a
period of from about 5 to about 10 min. The layers were allowed to separate

over a period of about 30 min and the organic layer (-960 mL) containing
Compound 2H was removed (concentration of Compound 2H in DCM: 235.98
mg/ mL; calculated mass of Compound 2H in DCM: 226.54 gms; calculated
mass yield: 93.46%).
Compound 2H (~50 gms, -265 mg/mL in DCM) and acetic acid (4.9 mL) were
combined in a flask and the mixture was cooled to a temperature of from about
0 °C to about 5 °C. 2.0M MeNH2 (methylamine) (296 mL) in THF was added
portionwise while maintaining the mixture at a temperature of from about 0 °C
to about 19 °C. The mixture was allowed to warm to ambient temperature and
was agitated for a period of about 30 min. NaBH(OAc)3 (sodium
triacetoxyborohydride) (51.4 gms) was then added portionwise while
maintaining the solution at a temperature of from about 19 °C to about 27 °C.
The mixture was aged for about 40 min at a temperature of from about ambient
to about 27°C. Once the reaction was complete (as shown by HPLC), water
(500 mL) was added while maintaining the solution at a temperature of below
about 30 °C. Sodium hydroxide (115 mL; 5% w/v in water) was then added to
the mixture to raise the pH to from about pH 10 to about pH 11. The mixture
was agitated vigorously for a period of from about 3 to about 10 min. The
layers were separated and the aqueous layer was removed. Water (143 mL)
was added and the mixture agitated for a period of from about 3 to about 10
min. The layers were again separated and the organic layer containing
Compound 21 was removed (concentration of Compound 21 in DCM: 0.229 mg/
mL; calculated mass of Compound 21 in DCM: 45.18 gms; mass yield: 85.3%).
Compound 21 (150 mL, 0.069 mol) was placed in solution with CH2CI2:THF (150
mL; 1:8) and concentrated to a thick oil in vacuo while maintaining the mixture
at a temperature of about or below 40°C using a cooling bath. 2-Butanone
(320 mL) was added portionwise to the thick oil to transfer the oil to another
flask. The mixture was agitated and EtN(/-Pr)2 (diisopropylethylamine) (11.0
mL, 0.063 mol) and Compound 2E (27.3 gms, 0.057 mol) were added. The

mixture was heated to a temperature of about 65 °C for a period of from about
6 to about 7 h. Once the reaction was complete (as shown by HPLC), the
mixture was cooled to ambient temperature and crystallized over a period of
from about 72 to about 96 h (the product can take up to 48 h to start to
crystallizing, having a cloud point time around 28 h). The product was filtered
and washed with acetone (2X 10 mL) (each wash), then dried in vacuo
overnight at a temperature of about 75 °C to provide Compound 2J (31.4 gms;
yield: 75.1%) as a white powder.
Compound 2J (10.0 g) and acetonitrile (40 mL) under nitrogen were added to a
flask to form a suspension. The suspension was agitated for a period of from
about 5 to about 10 min, then bromotrimethylsilane (10 mL) was added via
additional funnel over a period of from about 10 to about 15 min at RT. The
solution was stirred for at least a time period of about 1 h at rt. Once the
reaction was complete (as shown by HPLC), the mixture was transferred to an
addition funnel and then added to water (250 mL). The resulting slurry was
stirred vigorously during the addition and the temperature maintained at from
about 20 °C to about 25 °C. The slurry was further agitated over a period of
from about 1 to about 1.5 h, then filtered and washed with water (2X15 mL).
The resulting wet cake was then dried in vacuo overnight at a temperature of
about 40 °C to provide a crude product Compound 2K (10.2 gms) as a white
solid.
Compound 2K (110.0 gms, 0.127 mol) and methanol (550 mL) were added to a
flask to form a slurry. The slurry was stirred at RT over a period of from about
55 to about 60 min (the recrystallization mixture gave a hazy solution within
about 5 minutes after adding MeOH and gradually afforded a white suspension
after about 30 minutes). An acetone:water (1100 mL; 4:1) solution was added
and the suspension was stirred at RT for a period of from about 180 to about
190 min to afford a white solid. The solid was filtered and washed with water (3
X 350 mL), forming a wet cake was then dried in vacuo overnight at a

temperature of from about 30 to about 35 °C to provide a recrystallized
Compound 2K (82.3 gms; yield: 96.1 %) as a fine white solid.
Recrystallized Compound 2K (30.0 g, 0.0431 mol) and
tris(hydroxymethyl)aminomethane (13.07 g, 0.107 mol; a clear white crystalline
solid) were combined in a flask and ethanol (300 mL) and water (30 mL) were
added. The solution was agitated to provide a clear solution after a period of
about 15 min. A thin suspension was formed after a period of from about 2 to
about 3 h and a thick white suspension was formed after a period of from about
3 to about 5 h (the mixture may need to be seeded to enhance crystallization if
a thin suspension is not formed after a period of about 3 h). The suspension
was stirred at RT for an additional period of about 4 h. The thick suspension
was thinned by adding ethanol (180 mL), then filtered and washed with ethanol
(120 mL), allowed to air dry over a period of about 30 min and then dried in
vacuo for a time period of from about 24 to about 67 h at a temperature of
about 40 °C to provide Compound 2E (38.6 gms; yield: 91.8%) as a bis-
tromethane salt (ratio of tris(hydroxymethyl)aminomethane:Compound 2E:
1.99:1).
For Example2, analytical HPLC was carried out using Phenomenex Luna (15
cm x 4.6 mm; 5 |x; detection was at 220 nm), Phenomenex Luna 5|i C18(2) (4.6
mm x 250; detection was at 225 nm) and Synergi 4u, MAX-RP 80A (15 cm x 4.6
mm; detection was at 225 nm) columns. Microanalysis was performed by
Quantitative Technologies, Inc.




A solution of 4A (1.0 g, 2.1 mmol), 4-yV-Boc-aminopiperidine (0.42 g, 2.2 mmol;
Astatech Inc.) and HOBt (0.28 g, 2.1 mmol) in 5 mL of DMF was treated with a
solution of DCC (0.43 g, 2.1 mmol) in 1 mL of DMF dropwise. After stirring for
24 h, the mixture was filtered through dicalite and the filtrate concentrated
under reduced pressure. The residue was purified by flash column
chromatography (silica; 5% CH3OH-CH2CI2) to afford 1 g of 4B as a white
foam, 72%. MS (ES) m/z 731 (MH+ adduct ion with MeOH and CH3CN).
A solution of 20% TFA in CH2CI2 and 4B (1 g, 1.5 mmol) was stirred for 45 min,

then concentrated under a stream of N2. The residue was triturated with ether
to give 0.80 g of C as a white powder (TFA salt): MS (ES) m/z = 530 (M-CZH5)+.
To a mixture of 0.40 g (0.59 mmol) of 4C and 0.17 mL (1.2 mmol) of EfeN in 30
mL of CH2CI2 was added a solution of 2-naphthoyl chloride (0.11 g, 0.60 mmol)
in 1 mL of CH2CI2. The reaction was stirred for 2 h, then diluted with water and
the layers were separated. The organic layer was washed sequentially with
H20, NaHC03 (satd, aq.), 1N KHS04 (aq), and H20, then dried over Na2S04,
filtered and concentrated. The residue was purified by flash column
chromatography (silica, 5% CH3OH-CH2CI2) to afford 0.29 g (70%) of 4D as a
white powder: MS (ES) m/z 713 (MH+).
A solution of 0.29 g (0.40 mmol) of 4D in 2.5 mL of pyridine was treated with
0.4 rriL (3.3 mmol) of bromotrimethylsilane and the mixture was stirred for 2 h.
Volatiles were removed under reduced pressure, and the white solid residue
was treated with 15 mL of 1N HCI (aq). The slurry was stirred for 2.5 h and the
white solid was collected and rinsed with H20. The solid was triturated with
CH3CN to yield 0.12 g of the title compound (46%) as a white powder: MS (ES)
m/z 657 (MH+).



To a stirred solution of 5A (0.55 g, 1.16 mmol), the trifluoroacetate salt of 5B
(0.5 g, 1.16 mmol), triethylamine (1.28 mmol, 0.18 mL), and HOBt (0.24 g, 1.75
mmol) in 5 mL of acetonitrile was added a solution of DCC in 2 mL of
acetonitrile. (0.26 g, 1.28 mmol). The reaction was stirred for 24 h, then treated
with 1 mL of DIPEA, and stirred an additional 5 h. The mixture was filtered,
and the filtrate was concentrated under reduced pressure. The residue was
purified by flash column chromatography (silica; 100% CH2CI2 -> 98% CH2CI2-
MeOH) to afford 0.66 g of 5C as a foam: MS (ES+) MH+ = 735.
To a stirred solution of 5C (0.11 g, 0.75 mmol) in 1 mL of pyridine was added
0.15 mL of bromotrimethylsilane. The reaction was stirred for 1.5 h, then
concentrated under reduced pressure. The residue was stirred with excess 3N
HCI for 1 h, and the product collected and washed sequentially with water and
ether. The product was suspended in acetonitrile and stirred for 0.5 h at 0°C
then collected to afford 0.067 g of the title compound as a white solid: MS
(ES+) MH+ = 679.




Biological Experimental Examples
The utility of the compounds of the present invention as a serine protease
inhibitor and, particularly, as a cathepsin G or chymase inhibitor useful for the
treatment of inflammatory or serine protease mediated disorders can be
determined according to the procedures described herein.
Example 1
Enzyme-Catalyzed Hydrolysis Assays - Cathepsin G
Enzyme-catalyzed hydrolysis rates were measured spectrophotometrically
using human neutrophil"cathepsin G (Athens Research and Technology) or
human skin chymase (Cortex Biochem), a chromogenic substrate (Suc-Ala-Ala-
Pro-Phe-pNa) (Bachem) in aqueous buffer (100 mM Hepes, 500 mM NaCI, pH
7.4 for catG; 450 mM Tris, 1800 mM NaCI, pH 8.0 for chymase), and a
microplate reader (Molecular Devices). IC50 experiments were conducted by
fixing the enzyme and substrate concentrations (70 nM enzyme, 5 mM
substrate for cat G, 10 nM enzyme, 0.7 mM substrate for chymase) and varying
the inhibitor concentration. Changes in absorbance at 405 nM were monitored
using the software program Softmax (Molecular Devices), upon addition of
enzyme, with and without inhibitor present at 37CC for 30 minutes. Percent
inhibition was calculated by comparing the initial reaction slopes of the samples
without inhibitor to those with inhibitor. IC50 values were determined using a




Example 2
Anti-Asthmatic Effects in a Sheep Model of Asthma
The efficacy of Compound 2 for the treatment of asthma was evaluated in a
validated model of Ascaris suum antigen-induced asthmatic response in
conscious sheep (Abraham, W.M., Pharmacology of allergen-induced early and
late airway responses and antigen-induced airway hyperresponsiveness in
allergic sheep, Pulmonary Pharmacology, 1989, 2, 33-40).
Experimental Protocol
Baseline dose response curves to aerosol carbachol were obtained 1-3 days
prior to antigen challenge. Baseline values of specific lung resistance (SRL)
were obtained and the sheep were then given a specified amount (mg) of the
test compound as an inhaled aerosol at a specified time before antigen
challenge. Post drug measurements of SRL were obtained and the sheep were

then challenged with Ascan's suum antigen. Measurements of SRL were
obtained immediately after challenge, hourly from 1-6 h after challenge and on
the half-hour from 6!4-8 h after challenge. Measurements of SRL were
obtained 24 h after challenge followed by a 24 h post-challenge with carbachol
to measure airway hyperreactivity.
Compound 2 was administered as an aerosol at 0.1 mg/Kg/dose, twice-a-day
(BID) for three consecutive days, followed by a dose on day 4, 0.5 h prior to
antigen challenge. Ascaris suum antigen challenge was given at the zero time
point.
Figure 1 shows that the early airway response (0-2 h after antigen challenge)
was dramatically reduced and that the late airway response (6-8 h after antigen
challenge) was completely blocked (n = 4 sheep/group).
Figure 2 shows that the delayed airway hyperreactivity measured at 24 h post
antigen challenge as measured using carbachol challenge was also completely
blocked.
In addtion to blocking the increase in airway resistance, as shown in Table 5,
Compound 2 also blocked the rise in inflammatory cell numbers in the broncho-
alveolar lavage (BAL) fluid sampled from these sheep.




WE CLAIM:
1. A compound of Formula (Ha)

wherein
R10 is selected from the group consisting of:
2-naphthalene-sulfonyl,
naphthalene-2-yl-acetyl,
2-naphthoyt.
1- (4-hydroxyphenyl),
1- (4-methoxyphenyl),
N- [5- (suffonylHhiophene-2-ylmethyQ-benzamide,
6-chloro-5-sulfonyt-imklazo{2,1-bJthiazole,
Naphthyl-2-aminocarbonyt, and
1-{4-fluorophenyl).

2. A composition comprising the compound as claimed in claim 1 and a
pharmaceutical acceptable carrier.
3. A process for preparing a composition comprising mixing the compound
as claimed in claim 1 and a pharmaceutically acceptable carrier.



The present invention is directed to phosphonic acid compounds useful as serine
protease inhibitors, compositions thereof and methods for treating inflammatory
and serine protease mediated disorders.

Documents:

02027-kolnp-2005-abstract.pdf

02027-kolnp-2005-claims.pdf

02027-kolnp-2005-description complete.pdf

02027-kolnp-2005-drawings.pdf

02027-kolnp-2005-form 1.pdf

02027-kolnp-2005-form 2.pdf

02027-kolnp-2005-form 3.pdf

02027-kolnp-2005-form 5.pdf

02027-kolnp-2005-international publication.pdf

2027-KOLNP-2005-ABSTRACT 1.1.pdf

2027-KOLNP-2005-AMANDEDCLAIMS.pdf

2027-KOLNP-2005-ASSIGNMENT.1.2.pdf

2027-kolnp-2005-assignment.pdf

2027-KOLNP-2005-CORRESPONDENCE.1.2.pdf

2027-kolnp-2005-correspondence.pdf

2027-KOLNP-2005-DESCRIPTION (COMPLETE) 1.1.pdf

2027-KOLNP-2005-DRAWINGS 1.1.pdf

2027-KOLNP-2005-EXAMINATION REPORT REPLY RECIEVED.pdf

2027-KOLNP-2005-EXAMINATION REPORT.1.2.pdf

2027-KOLNP-2005-FORM 1-1.1.pdf

2027-KOLNP-2005-FORM 18.1.2.pdf

2027-kolnp-2005-form 18.pdf

2027-KOLNP-2005-FORM 2-1.1.pdf

2027-KOLNP-2005-FORM 26.1.2.pdf

2027-kolnp-2005-form 26.pdf

2027-KOLNP-2005-FORM 3-1.1.pdf

2027-KOLNP-2005-FORM 3.1.2.pdf

2027-KOLNP-2005-FORM 5-1.1.pdf

2027-KOLNP-2005-FORM 5.1.2.pdf

2027-KOLNP-2005-FORM-27.pdf

2027-KOLNP-2005-GRANTED-ABSTRACT.pdf

2027-KOLNP-2005-GRANTED-CLAIMS.pdf

2027-KOLNP-2005-GRANTED-DESCRIPTION (COMPLETE).pdf

2027-KOLNP-2005-GRANTED-DRAWINGS.pdf

2027-KOLNP-2005-GRANTED-FORM 1.pdf

2027-KOLNP-2005-GRANTED-FORM 2.pdf

2027-KOLNP-2005-GRANTED-SPECIFICATION.pdf

2027-kolnp-2005-intenational publication.pdf

2027-kolnp-2005-international preliminary examination report.pdf

2027-KOLNP-2005-OTHERS.1.2.pdf

2027-KOLNP-2005-OTHERS.pdf

2027-kolnp-2005-pct request form.pdf

2027-KOLNP-2005-PCT SEARCH REPORT.pdf

2027-KOLNP-2005-PETITION UNDER RULE 137.pdf

2027-KOLNP-2005-REPLY TO EXAMINATION REPORT.1.2.pdf

abstract-02027-kolnp-2005.jpg


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Patent Number 250551
Indian Patent Application Number 2027/KOLNP/2005
PG Journal Number 02/2012
Publication Date 13-Jan-2012
Grant Date 10-Jan-2012
Date of Filing 17-Oct-2005
Name of Patentee ORTHO-MCNEIL PHARMACEUTICAL, INC.
Applicant Address U.S. ROUTE NO. 202, PO BOX 300, RARITAN, NJ 08869-0602, UNITED STATES OF AMERICA
Inventors:
# Inventor's Name Inventor's Address
1 MICHAEL N. GRECO 1634 CLEARBROOK ROAD, LANSDALE, PA 19446 U.S.A.
2 LAWRENCE DE GARAVILLA 909 NOBLE DRIVE, DOWNINGTOWN, PA 19335 U.S.A.
3 MICHAEL J. HAWKINS 318 HECKLER STREET, AMBLER, PA 19002 U.S.A.
4 MICHAEL J. HUMORA 125 PLAINSBORO ROAD, CRANBURY, NJ 08512 U.S.A.
5 YUN QIAN 271 FOX CHASE LANE, DOYLESTOWN, PA 18901 U.S.A.
6 DONALD GILMORE WALKER 6127 HEARTHSTONE DRIVE, PIPERSVILLE, PA 18947 U.S.A.
7 SERGIO CESCO-CANCIAN 4108 SHANNON AVENUE, BETHLEHEM, PA 18020 ITALIAN
8 CHRISTOPHER NORMAN NILSEN 1315 MAGNOLIA LANE, SOMERVILLE, NJ 08876-6103 U.S.A.
9 MITUL N. PATEL 35 MANOR DRIVE, APT. 4-F, NEWARK, NJ 07106 U.S.A.
10 KIRK LEONARD SORGI 2543 RED GATE DRIVE, DOYLESTOWN, PA 18901 U.S.A.
11 EUGENE POWELL 4801 WOODSPRING DRIVE, PIPERSVILLE, FA 18947 U.S.A.
12 HAROLD R. ALMOND 1330 HANOVER PLACE, MAPLE GLEN, PA 19002 U.S.A.
PCT International Classification Number C07F 9/6509, 9/6558
PCT International Application Number PCT/US2004/011490
PCT International Filing date 2004-04-14
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 10/414, 782 2003-04-16 U.S.A.