Indian Patents
Title of Invention

NOVEL INHIBITORS OF CHYMASE
Abstract The present invention is directed to a compound of formula (I). methods for preparing these compounds, compositions, intermediates and derivatives thereof, and methods for treating inflammatory and serine protease mediated disorders.
Full Text NOVEL INHIBITORS OF CHYMASE
FIELD OF THE INVENTION
The present invention relates to certain novel compounds, methods for preparing
compounds, compositions, intermediates and derivatives thereof and methods for treating
inflammatory and serine protease mediated disorders. More particularly, the 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 proteolytic enzymes that are involved
in physiological processes such as blood coagulation, complement activation, phagocytosis
and turnover of damaged cell tissue. Human chymase (EC.3.4.21.39) is a glycosylated
monomeric chymotrypsin-like serine protease (MW = 30 kDa) localized mainly in mast cell
secretory granules. Chymase is thought to have a variety of functions, including
degradation of extracellular matrix proteins, cleavage of angiotensin I to angiotensin II.
(except in the rat), and activation of matrix proteases and cytokines. Endogenously,
chymase is regulated by the serpins ccl-antichymotrypsin and a 1-proteinase.
Although the precise patho-physiological roles of chymase have yet to be
determined, chymase has been implicated in microvascular leakage, neutrophil
accumulation, the stimulation of mucus secretion, and the modulation of cytokines. A
potent, chymase-selective inhibitor may be indicated in mast cell-mediated diseases such
as asthma, pulmonary inflammation, and chronic obstructive pulmonary diseases (COPD).
Because chymase can play a role in the generation of cardiac and vascular wall
angiotensin II, an inhibitor may have potential use as an antihypertensive treatment for
vascular wall injury and inflammation (atherosclerosis/restenosis), as well as cardiac
hypertrophy. Thus, small molecule inhibitors of chymase 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 and
phosphinic acid compounds that are serine protease inhibitors, in particular, inhibitors of
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.
SUMMARY OF THE INVENTION
The present invention is directed to a compound of Formula (I)
wherein
R1 is selected from the group consisting of hydrogen and C^alkyl;
is selected from the group consisting of aryl, heteroaryl, benzo fused heterocyclyl,
cyclopropyl when n is 0 and one of R2 or R3 is phenyl, and benzo fused cycloalkyl,
and ring A is optionally substituted with R2 and R3;
R2 is one to two substituents independently selected from the group consisting of Ci.6alkyl,
C2.6alkenyl, C2.6alkynyl, methoxy, C2.6alkoxy, CvBalkylthio, -OCF3, -NH2, -NH(d.
6)alkyl, -N(C1.6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy,
and nitro; furthermore, R2 is optionally oxo when ring A is heteroaryl or benzo fused
heterocyclyl; and, wherein any aryl-containing substituent of R2is optionally
substituted with a substituent independently selected from the group consisting of
Chalky!, d-6alkoxy, C2.6 alkenyl, d.6alkylthio, -NH2j -NH(d.6)alkyl, -N(Ci.E)dialkyl,
aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, and nitro;
and, wherein any of the foregoing Ci.6alkyl or C2.6alkoxy containing substituents of
R2 are optionally substituted with a substituent independently selected from the
group consisting of -NR11R12, aryl, heteroaryl, one to three halogens and hydroxy;
wherein R11 and R12are independently hydrogen; Ci.6 alkyi optionally substituted
with hydroxy, aryl, -C(=0)Ci-4alkoxy, or -NR15R16; or aryl;
R15 and R16 are substituents independently selected from the group
consisting of hydrogen, Ci-6 alkyl, and aryl, and said R15 and R16 are
optionally taken together with the atoms to which they are attached to form a
ring of five to seven members;
R3 is one to three substituents independently selected from the group consisting of d-
6alkyl, C2-6alkenyl, C2.6alkynyl, Ci.6alkoxy, d-ealkylthio, -OCF3, -OCH2(C2.
6)alkenyl, -NH2, -NH(d.6)alkyl, -N(d.6)dialkyl, -NHC(=0)Cy, -N(d-
6alkyl)C(=0)Cy, -(NC(=0))2NH2, -C(=0)d.4alkoxy, -C(=0)NR17R18,
-C(=0)NHcycloalkyl, -C(=0)N(Ci^alkyl)cycloalkyl, -C(=0)NHCy, -C(=0)N(d.
6alkyl)Cy, -C(=0)Cy, -OC(=0)d-6alkyl, -OC(=0)NR19R20, -C(=0)6aryl,
-C(=0)Oheteroaryl, -C02H, ureido, halogen, hydroxy, nitro, cyanol aryl,
heteroaryl, heteroaryloxy, and aryloxy;
wherein any of the foregoing d.6alkyl or d.6alkoxy containing substituents of of R3
are optionally substituted with one to three substituents independently selected
from the group consisting of -NR^R22, -NH(cycloalkyl), -N(d.6alkyl)(cycloalkyl), -
NHCy, -N(d.6alkyl)Cy, aryl, heteroaryl, hydroxy, halogen, -C(=0)NR23R24, -
OC(=0)NR25R26, -C(=0)d.4alkoxy, and -C(=0)Cy;
wherein said R17, R18, R19, R20, R21, R22, R23, R24, R25, R26are substituents
independently selected from the group consisting of hydrogen, d-e alkyl,
and aryl, wherein d-e alkyl is optionally substituted with hydroxy, aryl, -
C(=0)d.4alkoxy, NH2, NH(d-6alkyl), or -N(d-6)dialkyl; and R17and R18, R19
and R20, R21 and R22 R23and R24 and R25and R26are optionally taken
together with the atoms to which they are attached to form a ring of five to
seven members;
Cyis a heterocyclyl optionally substituted with a substituent selected from the group
consisting of d.6alkyl, C1.6alkylC(=0)C1.6alkyl, -d.«alkylC(=0)d-6alkoxy, d-
6alkylC(=0)aryl,-C(=0)(d.6)alkyl, -C(==0)(d-6)alkoxy, -C(=0)aryl, -S02aryl, aryl,
heteroaryl, and heterocyclyl; wherein the aryl portion of any aryl-containing
substituent of Cy is optionally substituted with one to three substituents
independently selected from the group consisting of Chalky], Ci.6alkoxy,
C^alkylthio, halogen, hydroxy, NH2, NH(Ci.6alkyl), and-NCC^dialkyl; and
wherein heterocyclyl is optionally substituted with aryl, one to three halogen atoms,
or one to three oxo substituents; and heterocyclyl is optionally spiro-fused to said
Cy,
and wherein the d.6alkenyl and Ci.6alkynyl substituents of R3 are optionally
substituted with aryl or -C(=0)NR27R28; wherein said R27 and R28 are independently
hydrogen; d-e alkyl optionally substituted with hydroxy, aryl, -C(=0)d-4alkoxy, NH2,
NH(C1.6alkyl), or -N(Ci^)dialkyl; or aryl; and R27and R28are optionally taken
together,with the atoms to which they are attached to form a ring of five to seven
members;
wherein the aryl, heteroaryl, and cycloalkyl substituents of R3 are optionally
substituted with oneto three substituents independently selected from R14;
wherein R14 is independently hydrogen, Chalky!, C^alkoxy, C2.6alkenyl,
d-ealkylthio, -NH2, -NH(Ci.6)alkyl, -N(C1.6)diaIkyl, aryl, heteroaryl, aryloxy,
heteroaryloxy, halogen, hydroxy, or nitro;
and any one of the foregoing Ci.6alkyl- or Ci.6alkoxy-containing substituents of R14 is
optionally substituted on a terminal carbon atom with a substituent selected from -NR29R30,
aryl, heteroaryl, one to three halogen atoms, or hydroxy; wherein R29 and R30 are
independently hydrogen; d-e alkyl optionally substituted with hydroxy, aryl, -C(=0)d-
4alkoxy, NH2, NH(d-6alkyl), or -N(Ci.6)dialkyl; or aryl; and R29and R30are optionally taken
together with the atoms to which they are attached to form a ring of five to seven members;
nisOorl;
W is O or S;
X is hydrogen or C-,.3alkyl;
Y is independently selected from the group consisting of Ci.6alkyl substituted with
-OSO2NH2 or hydroxy; S03H, C02H, heteroaryl, -OC(=0)NH2, and P(=0)OR5R6
provided that when Y is C02H, A and Z must both be bicyciic ring systems;
R5 is selected from the group consisting of hydrogen; Ci.6alkyl optionally substituted with
NH2, -NH(C1.6)alkyl, -N(Ci.6)dialkyl, 1,3-dioxolah-2-yl, C1.6alkylcarbonyloxy, d-
6alkoxycarbonyloxy, Ci.6alkylcarbonylthio, (Ci.6)alkylaminocarbonyl, di(Ci.
6)alkylaminocarbonyl, one to three halogens, or hydroxy; and aryl optionally
substituted with d-ealkyl, d^alkoxy, d-ealkylthio, C2.6 alkenyl, -NH2, -NH(C1.6)alkyl,
-N(C1.6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, or nitro;
alternatively, when.R6 is Ci.8alkoxy, R5 and R6 are taken together with the atoms to
which they are attached to form a 5-8 membered monocyclic ring;
provided that Rs is other than Chalky! substituted with di(C1.6)alkylamino-carbonyl
when ring system A is 3,4-difluoro-phenyl, n is 1, R6 is OH, and Z-R4 is 5-chloro-'
benzothiophen-3-yl; and provided that R5 is other than Ci.6alkyl substituted with d-
6alkylcarbonylthio when ring system A is 3,4-difluoro-phenyl, n is 1, R6 is CH3, and
Z-R4 is 5-chloro-benzothiophen-3-yl;
R6 is selected from the group consisting of Ci.8alkyl, d-salkoxy, C2.aalkenyl, heteroaryl,
aryl, and hydroxy; wherein Ci.8alkyl, Ci-8alkoxy, and C2.Balkenyl are optionally
substituted with a substituent selected from the group consisting of d-ealkoxy, aryl,
heterocyclyl, heteroaryl, NH2, -NH(C1.6)alkyl, -N(d-6)dialkyl, .Ci.
6alkylcarbonyloxy, d-6alkylcarbonylthio, Ci-6alkoxycarbonyloxy, (d-
6)alkylaminocarbonyl, di(Ci.6)alkylaminocarbonyl, one to three halogen atoms,
i
and hydroxy; and when R6 is d.8alkyl, said d.8alkyl 's optionally substituted with
one to four additional halogen atoms such that one to three halogen atoms are
optionally chlorine and one to seven of the halogen atoms are optionally fluorine;
wherein the heteroaryl and aryl substituents of R6are optionally substituted with a
substituent independently selected from the group consisting of d^alkyl,
d.6alkoxy, C2.6 alkenyl, d.6alkylthio, -NH2, -NH(d-e)alkyl, -N(d-6)dialkyl, aryl,
heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, and nitro;
Z is a seven to fifteen membered monocyclic or polycyclic ring system selected from the
group consisting aryl, heteroaryl, benzo fused heterocyclyl, or benzo fused
cycloalkyl, optionally substituted with R4;
R4is one to three substituents selected from the group consisting of d.6alkyl, d-
6alkenyl, d.6alkoxy, d.6alkylthio, aryl(d.6)alkyl, aryl(C2.6)alkenyl, halogen, -
C(=0)Cy, -C(=0)NR31R32, aryl, -C02H, oxo, and cyano; wherein C1.6alkyl, d-
6alkenyl and d-ealkoxy are optionally substituted with -NR33R34, aryl, heteroaryl,
cycloalkyl, one to three halogen atoms, or hydroxy; and aryl and heteroaryl are
each optionally substituted with a substituent independently selected from the group
consisting of d-ealkyl, Ci.6alkoxy, C2-6 alkenyl, Ci.6alkylthio, -NH2> -NH(Ci.
6)alkyl, -N(d-6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, one to three
halogen atoms, hydroxy, and nitro;
wherein said R31, R32, R33, and R34 are substituents independently selected
from the group consisting of hydrogen, d-e alkyl, and aryl, wherein alkyl is
optionally substituted with hydroxy, aryl, -C(=0)ClJ(alkoxy, NH2, NH(Ci.
6alkyl), or -N(Ci.6)dialkyl; and R31 with R32, and R33 with R34 are optionally
1
taken together with the atoms to which they are attached to form a ring of
five to seven members;
and pharmaceutical^ acceptable salts thereof.
Illustrative of the invention is a pharmaceutical composition comprising a
pharmaceutical^ acceptable carrier and any of the compounds described above. An
illustration of the invention is a pharmaceutical composition made by mixing any of the
compounds described above and a pharmaceutically acceptable carrier. Illustrating the
invention is a process for making a pharmaceutical composition comprising mixing any of
the compounds described above and a pharmaceutically acceptable carrier.
The present invention is also directed to methods for producing the instant
compounds and pharmaceutical compositions and medicaments thereof.
The present invention is further directed to methods for treating or ameliorating a
serine protease-mediated disorder. In particular, the method of the present invention is
directed to treating or ameliorating a chymase mediated disorder such as, but not limited
to, allergic rhinitis, viral rhinitis, asthma, chronic obstructive pulmonary diseases, bronchitis,
pulmonary emphysema, acute lung injury, psoriasis, arthritis, reperfusion injury, ischemia,
hypertension, hypercardia myocardial infarction, heart failure damage associated with
myocardial infarction, cardiac hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or
restenosis (e.g., associated with vascular injury, angioplasty, vascular stents or vascular
grafts), pulmonary fibrosis, kidney fibrosis (e.g., associated with glomerulonephritis), liver
fibrosis, post surgical adhesion formation, systemic sclerosis, keloid scars, rheumatoid
arthritis, bullous pemphigiod, and atherosclerosis. Additionally, these compounds can be
used for modulating wound healing and remodeling (e.g., cardiac hypertrophy) as well as
immune modulation.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the percent change in specific lung resistance (SRL) from baseline for
Compound 17 when administered via aerosol inhalation 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 17 via aerosol inhalation delivery in the spontaneous Ascaris suum antigen-
induced model of asthma in sheep compared to a 24 hour post-dosing challenge with
carbachol (Post Antigen).,
Figure 3 shows the percent change in specific lung resistance (SRL) from baseline for
Compound 17 when administered via oral administration compared to control in a
spontaneous Ascaris suum antigen-induced model of asthma in sheep over an 8 hour
period.
Figure 4 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 17 via oral administration 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
Preferred embodiments of the present invention include compounds of Formula (I)
wherein:
R1 is selected from the group consisting of hydrogen and C^alkyl.
More preferably, R1 is hydrogen.
Preferred embodiments of the present invention include compounds of Formula (I)
wherein:
is selected from the group consisting of aryl, heteroaryl, benzo fused heterocyclyl
and benzo fused cycloalkyl optionally substituted with R2and R3.
Preferably, ring system A is selected from the group consisting of heteroaryl, benzc
fused heterocyclyl, or aryl.
Preferably when A is a bicyclic ring system of the formula:
wherein the a1 portion of said a1a2 is optionally substituted with R2; and the a2 portion is
optionally substituted with R3.
Preferably a2 is an aromatic ring.
Preferably, ring system A is selected from the group consisting of naphthyl,
benzothiazolyl, benzothiophenyl, quinolinyl, isoquinolinyl, dihydronaphthyl, indanyl,
tetralinyl, and benzodioxdlyl when n is equal to zero; and A is phenyl, pyridin-2-yl, or
pyridin-3-yl when n is equal to one. In embodiments of the present invention wherein a
bicyclic ring system is used for A, the a2 ring will be aromatic. More preferably, ring system
A is selected from the group consisting of naphthyl, benzothiazolyl, and benzothiophenyl,
when n is equal to zero, and A is selected from phenyl, pyridin-2-yl, and pyridin-3-yl when n
is equal to one.
A preferred embodiment of the present invention includes compounds of Formula
(I) wherein n is equal to one.
Preferred embodiments of the present invention include compounds of Formula (I)
wherein R2 is one to three substituents independently selected from the group consisting of
CVealkyl, methoxy, C2.6alkoxy, -NH2, NH(C1.6alkyl), -N(d-e)dialkyl, aryl, heteroaryl, halogen,
hydroxy, and nitro; wherein Ci.6alkyl and C2.6alkoxy are optionally substituted with a
substituent selected from -NR11R12, aryl, heteroaryl, one to three halogens, and hydroxy.
More preferably, R2 is a substituent independently selected from the group
consisting of C,.4alkyl, methoxy, C2.4alkoxy, hydroxy, halogen, and -NH2.
Most preferably, R2 is Chalky!, halogen, or -NH2.
Preferred embodiments of the present invention include compounds of Formula (I)
wherein R3 is one to three substituents independently selected from the group consisting of
d.galkyl, C2.6alkenyl, Ci.6alkoxy, -OCH2(C2.6)alkenyl, NH2, -NH(C,.6aIkyl), -N(d-
6)dialkyl, -NHC(=0)Cy, -N(C1.6alkyl)C(=0)Cy, -C(=0)Ci.4alkoxy, -C(=0)NR17R18, -
C(=0)NHcycloalkyl, -C(=0)N(d-6alkyl)cycloalkyl, -C(=0)NHCy, -C(=0)N(d*alkyl)Cy,
-C(=0)Cy, -OC(=0)NR19R20, halogen, hydroxy, nitro, cyano, aryl, and aryloxy; wherein
alkyl and alkoxy are optionally substituted with one to three substituents independently
selected from the group consisting of -NR21R22, -NHcycloalkyl, -N(d-6alkyl)cycloalkyl,
-NHCy, -N(d.6alkyl)Cy, aryl, heteroaryl, halogen, -C(=0)NR23R24, -OC(=0)NRa5R26,
-C(=0)(d-4)alkoxy, and -C(=0)Cy; wherein alkenyl is optionally substituted on a terminal
carbon with aryl and -C(=0)NR27R28; and wherein aryl and cycloalkyl are optionally
substituted with one to three substituents independently selected from R14.
More preferably, R3 is one to three substituents independently selected from the
group consisting of d-ealkyl, C14alkoxy, -NR19R*°, -NHC(=0)Cy, -C(=0)NR17R18,
-C(=0)NHcycloalkyl, -C(=0)N(d.6alkyl)cycloalkyl, halogen, andaryl; wherein alkyl and
alkoxy are optionally substituted on a terminal carbon atom with one to three fluorine
atoms, -NH2,' -NHCy, or-N(C1.4alkyl)Cy; and wherein aryl and cycloalkyl are optionally,
substituted with a group independently selected from R14.
Even more preferably, R3 is one to two substituents independently selected from
trifluoromethyl, Ci_4alkoxy optionally substituted with one to three fluorine atoms, -NH2,
-NHC(=0)Cy, or halogen.
Preferably when R3 is NHC(=0)Cy then Cy is preferably piperadinyl, and
substituted with a substituent selected from the group consisting of Ci^alkyl,'
C1.4alkylC(=0)C1.4alkyl, -Ci.4alkylC(=0)C1.4alkoxy, C1.4alkylC(=0)aryl, -C(==0)(Ci-4)alkyl,
-C(=0)(C1^)alkoxy, -C(=0)aryl, -S02aryl, aryl, heteroaryl, and heterocyclyl; wherein aryl
and the aryl portion of the Ci-4alkylC(=0)aryl, -C(=0)aryl, and -S02aryl is optionally
substituted with one to three substituents independently selected from the group consisting
of Ci^alkyl, C^alkoxy, halogen, hydroxy, NH2, NH(Ci.6alkyl), and -N(d-4)dialkyl; and
wherein heterocyclyl is optionally substituted with aryl, one to three halogen atoms, or, one
oxo substituents. "
Most preferably, R3 is trifluoromethyl, one to two fluorine atoms, chloro, methoxy,
i
trifluoromethoxy, or NH2; furthermore, when A is naphthyl arid n is equal to zero, R3 is (4-
{[1-(naphthalene-2-carbonyl)-piperadine-4-carbonyl]-amino}-naphthalene-2-yl.
Preferred embodiments of the present invention include compounds of Formula (I)
wherein X is hydrogen or Ci.3alkyl.
More preferably, X is hydrogen.
Preferred embodiments of the present invention include compounds of Formula (I)
wherein Y is independently selected from a group consisting of C^alkyl, S03H, C02H,
heteroaryl, -OC(=0)NH2, and P(=0)OR5R6; wherein alkyl is substituted with a substituent
selected from the group consisting of -OS02NH2 and hydroxy.
More preferably, Y is independently S03H or P(=0)OR5R6.
Most preferably, Y is P(=0)OR5R6.
Preferred embodiments of the present invention include compounds of Formula (I)
wherein R5 is selected from the group consisting of hydrogen; d^alkyl optionally
substituted with NH2, -NH(Ci.6)alkyl, -N(Ci.6)dialkyl, d-ealkylcarbonyloxy, d-«a!koxy-
carbonyloxy, d-ealkylcarbonylthio, (d.6)alkylaminocarbonyl, di(d.6)alkylamino-carbonyl,
one to three halogens, or hydroxy; and aryl optionally substituted with d-ealkyl, d.6alkoxy,
d.6alkylthio, C2.6 alkenyl, -NH2, -NH(d-e)alkyl, -N(d-6)dialkyl, aryl, heteroaryl, aryloxy,
heteroaryloxy, halogen, hydroxy, or nitro; alternatively, when R6 is d.8alkoxy, R5 and R6
are taken together with the atoms to which they are attached to form a 5-8 membered
monocyclic ring;
provided that R5 is other than d-eaikyl substituted with di(Ci.6)alkylaminocarbonyl when
ring system A is 3,4-difluoro-phenyl, n is 1, Ft6 is OH, and Z-R4 is 5-chloro-benzothiophen-
3-yl; and provided that R5 is other than C^alkyl substituted with C^alkylcarbonylthio when
ring system A is 3,4-difluoro-phenyl, n is 1, R6 is CH3, and Z-R4 is 5-chloro-benzothiophen-
3-yl.
More preferably, R5 is selected from the group consisting of hydrogen, Ci.3alkyl
optionally substituted with d.6alkylcarbonyloxy, C1.6alkoxycarbonyloxy, d-ealkyl-
carbonylthio, (d.6)alkylaminocarbonyl, di(d-6)alkylaminocarbonyl, one to three halogens, ,
or hydroxyl; and aryl; alternatively, when R6 is Ci.8alkoxy, R5 and R6 are taken together with
the atoms to which they are attached to form a 6-7 membered monocyclic ring;
provided that Rs is other than C^alkyl substituted with di(C1.6)alkylaminocarbonyl when
ring system A is 3,4-difluoro-phenyl, n is 1, R6 is OH, and Z-R4 is 5-chloro-benzothiophen-
3-yl; and provided that R5 is other than d-3alkyl substituted with C^alkylcarbonylthio when
ring system A is 3,4-difluoro-phenyl, n is 1, R6 is CH3, and Z-R4 is 5-chloro-benzothiophen-
3-yl.
Most preferably, R5 is hydrogen or Ci.3alkyl optionally substituted with d_
6alkylcarbonyloxy, C1.6alkoxycarbonyloxy, Ci.Balkylcarbonylthio, (Ct^alkylamino-carbonyl,
or di(C1.6)alkylaminocarbonyl; and alternatively, when R6 is Ci.8alkoxy, R6 and R6 are taken
together with the atoms to which they are attached to form a 6-membered monocyclic ring;
provided that R5 is other than Chalky! substituted with di(d.6)alkylaminocarbonyl when
ring system A is 3,4-difluoro-phenyl, n is 1, R6 is OH, and Z-R4 is 5-chloro-benzothiophen-
3-yl; and provided that R5 is other than d.3alkyl substituted with d.6alkylcarbonylthio when
ring system A is 3,4-difluoro-phenyl, n is 1, R6 is CH3, and Z-R4 is 5-chloro-benzothiophen-
3-yl.
Preferred embodiments of the present invention include compounds of Formula (I)
wherein R6 is selected from the group consisting of Chalky!, Cvsalkoxy, C2.8alkenyl,
heteroaryl, aryl, and hydroxy; wherein alkyl, alkoxy, and alkenyl are optionally substituted
on a terminal carbon atom with a substituent independently selected from the group
consisting of C1.4alkoxy, aryl, heteroaryl, heterocyclyl, d.6alkylcarbonyloxy, d-
6alkylcarbonylthio, d.6alkoxycarbonyloxy, (d-6)alkylaminocarbonyl, di(C1.6)alkyl-
aminocarbonyl, and hydroxy; and wherein heteroaryl and aryl are optionally substituted
with one to three substituents independently selected from the group consisting of aryl,
hydroxy, C1.salkoxy, and halogen.
More preferably, R6 is selected from the group consisting of Chalky!, d.8alkoxy,
heteroaryl, aryl, and hydroxy; wherein alkyl and is optionally substituted on a terminal
carbon atom with a substituent selected from Ci.3alkoxy, aryl, or hydroxy; and alkoxy is
optionally substituted on a terminal carbon with a substituent independently selected from
^e group consisting of d-ejalkylcarbonyloxy, and di(C)-6)alkyl-aminocarbonyf; and wherein
heteroaryl and aryl are optionally substituted with one to three substituents independently
selected from the group consisting1 of aryl, hydroxy, Ci-6alkoxy, and halogen.
Most preferably, R6 is selected from the group consisting of methyl, ethyl
methoxypropyl, phenethyl„benzo[1,3]dioxol-5-yl-propyl, hydroxy, and C^alkoxy optionally
t
substituted with C^alkylcarbonyloxy, and di(Ci.6)alkylaminocarbonyI.
Preferred embodiments of the present invention include compounds of Formula (I)
wherein Z is a bicyclic aryl or bicyclic heteroaryl; wherein aryl and heteroaryl are optionally
substituted with the group R4; provided that when Y is C02H, A must be a bicycle.
More preferably, Z is selected from the group consisting of indolyl, benzothiophenyl,
naphthalenyl, quinolinyl, isoquinolinyl and benzothiazolone.
Most preferably, Z is selected from the group consisting of indolyl, benzothiophenyl,
and naphthalenyl.
Embodiments of the present invention include compounds of Formula (I) wherein
R4 is one to three substituents selected from the group consisting of hydrogen, C^alkyl, Ci.
6alkenyl, d.6alkoxy, aryl(C2.6)alkenyl, halogen, -C(=0)Cy, ~C(=0)NR31R32, aryl, -C02H, oxo,
and cyano; wherein alkyl and alkoxy are optionally substituted on a terminal carbon atom
with a substituent selected from aryl, -NR^R34, one to three'halogens, or hydroxy; wherein
aryl is optionally substitututed with one to three substituents independently selected from
from the group consisting of hydrogen, Ci.6alkyl, Ci.6alkoxy, C2.6 alkenyl, -NH2, -NH{Ci_
6)alkyl, -N(Ci.6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, and nitro.
Preferably, R4 is one to three substituents selected from the group consisting of d.
6alkyl, Ci.6alkenyl, d-ealkoxy, aryl(C2.6)alkenyl, halogen, -C(=0)Cy, -C(=0)NR31R32, aryl,
-C02H, oxo, and cyano; wherein alkyl and alkoxy are optionally substituted with a
substituent independently selected from -NR^R34, aryl, one to three halogen atoms, or
hydroxy; wherein aryl is optionally substitututed with a substituent independently selected
from the group consisting of hydrogen, d^alkyl, Ci-6alkoxy, aryl, halogen, hydroxy, and
nitro.
More preferably, R4 is one to three substituents selected from the group consisting
of Ci.6alkyl, d-ealkenyl, aryl(C2.6)alkenyi, halogen, and -C(=0)Cy; wherein aryl is optionally
substituted with a substituent selected from halogen and C^alkoxy.
Most preferably, R4 is one to two substituents selected from the group consisting of
fluorine, chlorine, bromine, methyl, phenyl(C2.6)alkenyl, and -C(=0)(2-(4-phenyl-piperidin-1-
ylcarbonyl)).
Embodiments of the phosphonic and phosphinic acids of the present invention
include those compounds of Formula (la) wherein the substituents are as previously
defined (including the previously, listed preferred substitutions in any combination).
Examples of embodiments of the present, invention are shown in Table I:
Embodiments of the present invention include those compounds of Formula (II)
shown in Table II:
Preferred embodiments of the phosphonic and phosphinic acids of the present
invention include those compounds of Formula (lb) wherein the substituents are as
previously defined (including any combinations of the preferred embodiments). Examples
of some of these embodiments are shown in Table III:

Preferred embodiments of the phosphonic arid phosphinic acids Of the present
invention include those compounds of Formula (Ic) shown in Table IV:
Table IV
A preferred embodiment of the present invention includes the representative
compounds presented in Table V.
Table V
The compounds of the present invention may also be present in the form of
pharmaceutical^ acceptable salts. For use in medicine, the salts of the compounds of this
invention refer to non-toxic "pharmaceutically acceptable salts." FDA approved
pharmaceutical^ 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, and trifluoroacetic acid.
Pharmaceutically acceptable basic/cationic salts includes and are not limited to
aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (also known as tris(hydroxyr
methyl)aminomethane, tris(hydroxymethyl)methylamine, tromethamine), ammonia,
benzathine, f-butylamine, calcium, chloroprocaine, choline, cyclohexylamine,
diethanolamine, ethylenediamine, lithium, L-lysine, magnesium, meglumine, NH3, NH4OH,
N-methyl-D-glucamine, piperidine, potassium, procaine, quinine, SEH, sodium,
triethanolamine (TEA), imidazole, and 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,
tris(hydroxymethyl)methylamine, tromethamine), ammonia, benzathine, f-butylamine,
calcium, chloroprocaine, choline, cyclohexylamine, diethanolamine, ethylenediamine,
lithium, L-lysine, magnesium, meglumine, NH3, NH4OH, N-methyl-D-g|ucamine, piperidine,
potassium, procaine, quinine, SEH, sodium, triethanolamine (TEA), imidazole, 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, choline, cyclohexylamine, diethanolamine,
ethylenediamine, L-lysine, NH3, NH4OH, N-methyl-D-glucamine, piperidine, potassium,
procaine, quinine, sodium, triethanolamine, imidazole, and tris(hydroxymethyl)methylamine
(tromethamine).
More preferably, cations for use with the instant compounds are selected from the
group consisting of f-butylamine, NH4OH, imidazole, sodium, and
tris(hydroxymethyl)methylamine (tromethamine).
Most preferably, the cations for use with the instant compounds are tromethamine
and sodium.
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. 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 technique's 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.
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 -Oalkyl 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 or partially unsaturated, moncyclic or
polycyclic hydrocarbon rings of from 3 to 20 carbon atom members (preferably from 3 to 14
carbon atom members). Further, a cycloalkyl ring may optionally be fused to one or more
cycloalkyl rings. Examples of such rings include, and are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.
The term "heterocyclyl" refers to a nonaromatic cyclic ring of 5 to 10 members in which
1 to 4 members are nitrogen or a nonaromatic cyclic ring of 5 to 10 members in which zero,
one or two members are nitrogen and up to two members is oxygen or sulfur; wherein,
optionally, the ring contains zero, one or two unsaturated bonds. Alternatively, the
heterocyclyl ring may be fused to a benzene ring (benzo fused heterocyclyl), a 5 or 6
membered heteroaryl ring (containing one of O, S or N and, optionally, one additional
nitrogen), a 5 to 7 membered cycloalkyl or cycloalkenyl ring, a 5 to 7 membered heterocyclyl
ring (of the same definition as above but absent the option of a further fused ring) or fused
with the carbon of attachment of a cycloalkyl, cycloalkenyl or neterocyclyl ring to form a spiro
moiety. For instant compounds of the invention, the carbon atom ring members that form the
heterocyclyl ring are fully saturated. Other compounds of the invention may have a partially
saturated heterocyclyl ring. Additionally, the heterocyclyl can be bridged to form bicyclic rings.
Preferred partially saturated heterocyclyl rings may have from one to two double bonds. Such
compounds are not considered to be fully aromatic and are not referred to as heteroaryl
compounds. Examples of heterocyclyl groups include, and are not limited to, pyrrolinyl
(including 2H-pyrrole, 2-pyrroJinyl or 3-pyrrolinyl), pyrrolidinyl, 2-imidazolinyl, imidazolidinyl,
2-pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl.
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.
Examples of such aryl rings include, and are not limited to, phenyl, naphthalenyl and
anthracenyl. Preferred aryl groups for the practice of this invention are phenyl and
naphthalenyl.
The term "benzo fused cycloalkyl" refers to a bicyclic or tricyclic ring structure wherein
at least one of the ring substituents is phenyl or naphthalenyl and at least one of the other
substituents is a cycloalkyl ring (as cycloalkyl was previously defined). For the purpose of
these definitions, the cycloalkyl rings may be fused to an additional benzene ring (to provide
fused multiple ring systems such as fluorene). Example of such benzo fused cycloalkyls
include, but are not limited to, indanyl, 1,2,3,4-tetrahydronaphthalenyl and fluorenyl.
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 sulfur. 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 three
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 membered 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, S or N and, optionally, one additional nitrogen), a 5 to 7 membered cycloalkyl 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,a nd quinazolinyl.
The term "arylalkyl" means an alkyl group substituted with an aryl group (e.g., benzyl
and phenethyl). Similarly, the term "arylalkoxy" indicates an alkoxy group substituted with an
aryl group (e.g., benzyloxy).
The term "halogen" refers to fluorine, chlorine, bromine, and iodine. Substituents that
are substituted with multiple halogens are substituted in a manner that provides compounds
which are stable.
Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a
substituent (e.g., arylalkyl and alkylamino), it shall be interpreted as including those limitations
given above for "alkyl" and "aryl." Designated numbers of carbon atoms (e.g., Ci-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. For alkyl, and alkoxy substituents
the designated number of carbon atoms includes all of the independent member included in
the range specified individually and all the combination of ranges within in the range specified.
For example C^ alkyl would include methyl, ethyl, propyl, butyl, pentyl and hexyl individually
as well as sub-combinations thereof (e.g., C^.2, C^3, Cm, Ci-5,C2.6, C3.6, C^, C5^, C2.5,etc.).
However, for clarity in the terms "C9-C14 benzo fused cycloalkyl", "C9-C14 benzo fused
cycloalkenyl", "C9-Cu benzo fused aryl"; Cg-Cu 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 "phenylCrC6 alkylamidoCr
C6alkyl" 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
carrier 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 carrier. A further illustration of the invention is a process for making a composition
comprising mixing any of the compounds described above anfcl 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 chymase) useful for treating inflammatory, and serine protease
mediated disorders. Serine proteases such as chymase produced by mast cells have been
recognized to be involved in a variety of inflammatory and wound healing events (e.g.,
angiogenesis, collagen deposition and cell proliferation). Chymase plays these roles by
activating a variety of pre-existing factors present in the microenvironment surrounding the
mast cells. For examplejust to name a few of these interactions chymase activates SCF,
angiotensin I to angiotensin II, endothelin 1, type 1 procollagen, metalloprotienases, IL-1B,
TGF-p, as well as, degrades the extracellular matrix (de Paulis etal. Int Arch Allerg
Immunol 118 (1999) 422-425; Longley etal. Proc Natl Acad Sci USA 94 (1997) 9017-
9021). Consequently, the release of chymase plays significant role in a variety of
pathological conditions associated with vascular proliferation, fibrosis, tissue remodeling,
inflammation, and the like.
Some of these, inflammatory and serine protease mediated disorders include, and are
not limited to, allergic rhinitis, viral rhinitis, asthma, chronic obstructive pulmonary diseases,
bronchitis, pulmonary emphysema, acute lung injury (e.g. adult (acute) respiratory distress
syndrome) psoriasis, arthritis, reperfusion injury, ischemia, hypertension, hypercardia
myocardial infarction, heart failure damage associated with myocardial infarction, cardiac
hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or restenosis (e.g., associated with
vascular injury, angioplasty, vascular stents or vascular grafts), pulmonary fibrosis, kidney
fibrosis (e.g., associated with glomerulonephritis), liver fibrosis, post surgical adhesion
formation, systemic sclerosis, keloid scars rheumatoid arthritis, bullous pemphigiod and
atherosclerosis. Additionally, these compounds can be used for modulating wound healing
and remodeling (e.g., cardiac hypertrophy) as well as immune modulation. The utility of the
compounds to treat inflammatory and serine protease mediated disorders is illustrated by the .
following non-limiting discussions of the proposed mechanisms of actions of chymase. Other
disorders that can be treated with chymase inhibitors can be determined according to the
procedures described herein and the use of animal knock-out models and the like.
As mentioned above, chymase coverts angiotensin I into angiotensin II, and this
activity has been associated with vascular proliferation. In human vascular extracts only
about 8% of angiotensin II activity is inhibited with an angiotensin converting enzyme
inhibitor (lisinopril) while 95% is inhibited by a chymase inhibitor. In vein grafts, vascular
injury associated with catheter or balloon injury, chymase induces vascular hyperplasia and
restenosis in dogs (Takai and Miyazaki, 21 (2003) 185-189). This same mechanism of
action would also be expected to apply to restenosis associated with the use of vascular
stents. Pathological serine protease mediated disorders associated with angiotensin II,
including but not limited to hypertension, hypercardia myocardial infarction, arteriosclerosis,
saroidosis, vascular stenosis or restenosis (e.g., associated with vascular injury,
angioplasty, vascular stents or vascular grafts), and the like.
Pathological fibrosis can be associated with the degeneration of organs (e.g., skin,
heart, kidneys or liver) or as an undesirable outcome of surgery. Preventing the formation
of pathological fibrosis would be beneficial in a variety of diseases. For example mast cell
chymase has been implicated in pulmonary fibrosis, kidney fibrosis, liver fibrosis, post
surgical adhesion formation, systemic sclerosis, keloid scars, and the like.
In the heart mast cells have been implicated in cardiac hypertrophy, which involves
both fibrosis and remodeling. Cardiac hypertrophy develops to preserve its function by
normalizing chamber wall stress. Mast cells have been implicated as being involved in the
development of myocardial fibrosis and systolic pressure over load induced hypertrophy
(Hara era/., J. Exp. Med. 195 (2002) 375-381). The remodeling of the heart associated
under these conditions is believed to involve mast cell chymase, which activates endothelin
1, matrix metalloproteinases and TGF-(3. Chymase inhibitors have been shown to exert
favorable cardioprotective action in a dog model of hypertrophy (Matsumoto etal.,
Circulation 107 (2003) 2555-2558). '
In the kidneys mast cell chymase has also been implicated in pathological firbrosis.
For example, glomerulonephritis has also been reported to involve mast cells (Ehara and
Shigematsu, Kidney Inter. 54 (1998) 1675-1683). The results of this found that mast cells
were one of the constitutive cell types in the interstitium of IgA nephritis patients and
contributed to interstitial fibrosis resulting in deterioration of renal function. Similarly, liver
fibrosis has been associated with mast cells (Yamashiro etal., Virchows Arch. 433 (1998)
471-479). Although, the mechanisms for fibrosis in the kidney and liver have not been as
well defined as for coronary fibrosis, it is very likely that chymase is operating through
similar signaling pathways to cause fibrosis (especially in liver fibrosis where fibrosis seem
to be occurring more frequently where mast cells stained positive for chymase).
Chymase is also involved in the formation of fibrous adhesions associated with
surgery. Chymase inhibitors have been tested in two different animals models and found
to reduce the number of adhesions (Okamoto etal., J. Surg. Res. 107 (2002) 219-222 and
Lucas et al., J. Surg. Res. 65 (1999) 135). It has been suggested that the prevention of
adhesions is associated with blocking the activation of latent TGF-B by chymase (Yoa.ef
al., J. Surg. Res. 92 (2000) 40-44). " ••
Collagen induced arthritic mice show increased numbers of mast cells and
expression of chymase in fibroproliferative inflammation (Kakizoe etal., Inflamm. Res. 48
(1999) 318-324). In human rheumatoid arthritis increased mast cell density in the
superficial synovium is associated with the severity of the disease (Grotis-Graham and
McNeil, Arthritis & Rheumatism 40 (1997) 479-489). It was theorized by these authors that
chymase and its ability to activate metalloprotinases plays a significant role in the rapid
functional deterioration observed in rheumatoid arthritis.
Mast ceil chymase has been implicated in artherosclerosis via its ability to cleave
apolipoprotein B-100 of LDL which facilitates lipoprotein aggregation and uptake by
macrophages (Paananen et al., J. Biol. Chem. 269 (1994) 2023-2031). Chymase also
degrades apolipoprotein A of HDL, which would reduce cholesterol efflux and increases
lipid deposition (Lindstedt etal., J. Clin. Invest. 97 (1996) 2174-2182). Thus chymase is
involved in two different pathways to atherosclerosis.
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 carrier
may take a wide variety of forms depending of the form of preparation desired for
administration (e.g. oral or parenteral). Suitable pharmaceutical^ acceptable carriers are
well known in the art. Descriptions of some of these pharmaceutical^ 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 carboxymethy-
cellulose, 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., corn 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 palatability 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 pharmaceutical^ 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 preformufation 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, hydroxy-
propyl 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 pharmaceutical^
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
n-propyl and n-butyl), sorbic acid, 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, polyhydroxypropylmeth'acrylamidephenol, polyhydroxy-ethylaspartamidephenol,
and 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, 8-valerolactone,
p-butyrolactone, y-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-dimethyl-1,4-dioxan-2-one, polyorthoesters, polyacetals,.
polydihydropyrans, polycyanoacrylat.es, 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/close. 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 or AutoNom Version 2.1 provided by Beilstein Informationssysteme.
Abbreviations used in the instant specification, particularly the Schemes and
Examples, are as follows:
Boc =i tert-butoxycarbonyl
BOC-ON = 2-(fert-butoxycarbonyloxyimino)-2-phenylacetonitrile
BuLi = n-butyllithium
f-BuOH = fert-butanol
Cpd or Cpd = compound
d = day/days
DCC = dicyclohexylcarbodiimide
DIPEA = diisopropylethylamine
EtOH = ethanol
h = hour/hours
HOBt = hydroxybenzotriazole
KH - potassium hydride
LDA = lithium diisopropyamide
M = molar
Mel = methyliodide
MeOH = methanol
min = . minutes
NT = not tested
PPA = polyphosphoric acid
rt/RT = room temperature
THF = tetrahydrofuran
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 schemes that follow. Since the schemes are 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.
The following schemes describe general synthetic methods whereby intermediate
and target compounds of the present invention may be prepared. Additional representative
compounds and stereoisomers, racemic mixtures, diasteromers and enantiomers thereof
can be synthesized using the intermediates prepared in accordance to the general
schemes and other materials, compounds and reagents known to those skilled in the art.
All such compounds, stereoisomers, racemic mixtures, diasteromers and enantiomers
thereof are intended to be encompassed within the scope of the present invention. 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 scheme is well within the skill of persons versed in the art.
Scheme A illustrates the general method for the preparation of compounds of the
present invention by the reaction of a phosphonate or phosphinate anion (prepared from its
corresponding phosphonate or phosphinate Compound A2 and an organometallic base
such as n-butyllithium) to isocyanate A1 in a solvent such as THF to afford an
amidophosphonate or amidophosphinate compound A3. One versed in the art will
recognize that conventional chemical transformations may be utilized to prepare certain R2
and R3 substituents of the present invention. For example, for the preparation of a
compound wherein R3 is amino, a nitro group may be reduced with hydrazine hydrate in the
presence of a palladium catalyst; or, for the preparation of a compound wherein R3is
ureido, a compound in which R3 is an amino group may be reacted with a cyanate salt or
the like.
Compound A2, wherein R5 and R6 are as previously defined, may be made
according to known methods (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).
Fluorinated R6 compounds can be made following methods known in the art such as the
methods similar those set forth in Garabadzhia et al., Journal General Chemistry USSR,
English translation, 1981, pages 1905-1910. Compound A3 may be dealkylated with
bromotrimethyisilane in a solvent such as pyridine, followed by treatment with dilute HCI to
afford Compound A4.
Scheme A

Compound A2, wherein Z is a heteroaryl or aryl ring, may be prepared from a
commercially available or known haloalkyl substituted heteroaryl ring. Another method for
preparing Compound A2 uses a quaternary ammonium salt rather than an alky! halide:
Scheme B shows a method for preparing Compound A2 wherein R6 is an alkyl or
alkehyl substituent using methods described in the literature (J. Organomei. Chem. 2002,
643-644,154-163; J. Amer. Chem. Soc. 2002, 124, 9386-9387). An alternate method for
preparing such compounds is described in the literature (Med. Chem. 1995, 3S(17), 3297-
3312; Bioorg. Med. Chem. 1999, 7,2697-2704).
Scheme C

Scheme C illustrates a general method for the preparation of compounds of the
present invention wherein ring system A of Formula (I) is an aryl substituent and n of
Formula (I) is equal to 1. Reaction of an a/p-unsaturated carboxylic acid, Compound C3,
with phosphorazidic acid dialkyl ester Compound C4 provides Compound C5. Compound
C5 may subsequently undergo a Curtius rearrangement to afford an isocyanate
intermediate, Compound C6. Compound C6 may be treated with a phosphonate or
phosphinate anion (as previously described in Scheme A) in an aprotic solvent such as
THF to yield amidophosphonate or amidophosphinate Compound C7. Compound C7 may
be dealkylated with bromotrimethylsilane, followed by treatment with dilute HCI to afford
Compound C8.
Scheme D
Scheme D further illustrates the preparation of compounds of the present invention
wherein Y of Formula (I) is a heteroaryl substituent. Compound D1 may be dissolved in an
aprotic solvent, treated with an organometallic base such as n-BuLi, and subsequently
reacted with isocyanate Compound A1 to afford Compound D2. Compound' D2 may
undergo a cycloaddition reaction with sodium azide to provide Compound D3.
Scheme E

Scheme E shows the preparation of compounds of the present invention wherein Y
of Formula (I) is a sulfonic acid. Compound B2 may be treated with sodium sulfite to afford
i - •
Compound E2. Compound E2 may then be treated with an organometallic base such as
isopropylmagnesium bromide and reacted with isocyanate Compound A1 to yield
Compound E3.
Scheme F
Scheme F illustrates the preparation of compounds of the present invention wherein
Y of Formula (I) is a carboxylic acid. Compound F1 may be reacted with isobutylene under
acidic conditions to provide ester Compound F3. Compound F3 may then be treated with a
strong base such as lithium diethylamide and further reacted with isocyanate Compound
A1 to give Compound F4. Compound F4 is converted into its corresponding carboxylic
acid Compound F5 by treatment with TFA.
Scheme G
Scheme G illustrates the preparation of compounds of the present invention
wherein Y of Formula (I) is a carbamate. Compound G1 may be prepared by the methods
described in the literature (J. Med. Chem. 1989, 32(12), 2548-2554, J.HetChem. 1998, 25,
1271). Compound G1 may be converted to Compound G2 by the method described in the
literature (Eur.J.Med.Chem. 2001, 36(1), 55-62). Compound G2 may be oxidized using
selenium dioxide to yield resultant carboxylic acid Compound G3. Compound G3 may be
coupled with amine Compound G4 in the presence of an appropriate coupling agent, base,
activating agent, and solvent to afford amide Compound G5. In the present invention,
Compound G3 is coupled to Compound G4 in the presence of DCC and HOBt to form
Compound G5. Compound G5 may be reduced in the presence of a hydride source such
as sodium borohydride to give alcohol Compound G6, which may be treated with
isocyanate Compound G7 to form Compound G8. Compound G8 may be deprotected in
the presence of f-butyl alcohol and potassium carbonate to yield carbamate Compound G9.
Scheme H illustrates the preparation of compounds of the present invention
wherein Y of Formula (I) is hydroxymethyl. Nitrile Compound D2 may be converted to an
irmdate in the presence of HCI gas, followed by hydrolysis to yield Compound H1.
Compound H1 may be reduced to a primary alcohol in the presence of hydride source,
such as sodium borohydride, to give methyl alcohol Compound H2.
Scheme I
Scheme I illustrates the preparation of compounds of the present invention wherein
Y of Formula (I) is a sulfamic acid methyl group. Compound H2 may be treated with a
base such as sodium hydride, followed by the addition of sulfamoyl chloride to yield
Compound 11.
Scheme* J illustrates the general method for the preparation of compounds of the
present invention wherein R3 is an amide substituent on ring A as defined by the invention.
Dinitro-substituted Compound J1 may be reduced by hydrogenation in the presence of a
palladium catalyst to give Compound J2 which then may be acylated with BOC-ON to
provide Compound J3.
Compound J4 may be acylated with acid chloride Compound J5 to yield Compound
J6, followed by saponification of Compound J6 to provide carboxylic acid Compound J7.
Compound J8 may be prepared by coupling Compound J3 to Compound J7 using an
appropriate coupling agent, activating agent, and solvent.
The Boc protecting group of Compound J8 was removed under acidic conditions to
afford the free amine, Compound J9. Treatment of Compound A2 with an organometallic
base such as n-butyllithium, followed by reaction with carbon dioxide afforded the
carboxylated phosphonic ester, Compound J10. Compound J10 was converted to its acid
chloride by treatment with thionyl chloride followed'by condensation with amine Compound
J9 to afford amide Compound J11. Compound J11 was dealkylated using
bromotrimethylsilane and treated with HCI to provide Compound J12.
Scheme K
Scheme K illustrates a general method for the preparation of compounds of the
present invention wherein Z is an N-substituted indole as previously defined. Compound
K1 may be reacted with an alkylating agent such as methyl iodide or an arylating agent
such as bromobenzene with copper oxide, Compound K2. Compound K2 may be treated
with N,N-dimethylmethyleneammonium iodide to afford Compound K3. Compound K3
may be converted to Compound K4 using methyl iodide, and then reacted with a phosphite
or phosphonite to provide Compound K5. Compound K5 may be reacted with Compound
A1 and dealkylated as previously described to yield Compound K6.
Optionally, the phenyl portion of Compound K2 may be substituted with an
alkoxycarbonyl. In this instance, the ester may be reduced to its corresponding methyl
alcohol, and converted to a methyl halide using techniques and reagents known to those
skilled in the art. The halide may then be converted to Compound A2 wherein Z is an
indole as previously defined in the present invention. Compound A2 may be subsequently
reacted according to Scheme A to form a compound of Formula (I) wherein the phosphonic
attached through the aryl portion of indole Z.
Scheme L
Scheme L illustrates the general method for the preparation of compounds of the
present invention wherein R4 is a heterocyclylcarbonyl substituent. Compound L1 may be
made by the procedures described in JACS1963, 6, 711 - 716 and JACS1971, 93(12),
2897-2904.
Compound L1 may be reacted with an organometallic base, such as butyllithium,
followed by treatment with di-terf-butyldicarbonate to give Compound L2. Compound L2
may be converted to Compound L4 using the methods described previously. Compound
L4 may be deprotected under acidic conditions to afford Compound L5. The carboxylic
acid group of Compound L5 may be treated with an amine, such as 4-phenylpiperidine, in
the presence of an appropriate coupling agent, base, activating agent, and solvent,
to afford Compound L6. Dealkylation of Compound L6 as described supra yields
Compound L7.
Scheme M illustrates a general method for the preparation of compounds of the
present invention. A Compound M1, wherein R3 is an alkoxycarbonyl substituent, may be
reduced in the presence of a hydride source to the corresponding alcohol, Compound M2.
Compound M2 may be oxidized to aldehyde Compound M3. Reaction of Compound M3
with a Wittig reagent affords alkene Compound M4. Saponification of Compound M4
provides carboxylic acid Compound M5, which may be coupled with an amine, such as
benzyl amine, in the presence of an appropriate coupling agent as described supra, to give
amide Compound M6. Compound M6 may be dealkylated using the procedure previously
described in Scheme A to yield Compound M7.
Alternatively, other compounds of the present invention wherein R3 is alkoxy or -
C(=0)NR11R12 may be derived from Compound M2. The hydroxy group of Compound M2
may be alkylated using reagents and methods known to one skilled in the art to afford
compounds wherein R3 is alkoxy. Alternatively, the hydroxy group of Compound M2 may
be reacted with' a variety of acylating agents known to one skilled in the art, such as
isocyanates, to arrive at compounds of the present invention wherein R3 is a carbamate.
As shown in Scheme N, Compound M3 may be reacted with a variety of amines in
the presence of a hydride source under acidic conditions to yield Compound N1.
Dealkylation of Compound N1 by the method described in Scheme A affords Compound
N2.

The preparation of compounds of the present invention wherein R3 is -C(=0)Cy as
previously defined, and said Cy is attached through a nitrogen atom, is shown in Scheme
P. Compound M1 may be saponified under basic conditions to provide Compound P1,
which may be treated with thionyl chloride to give Compound P2. Compound P2 may be
reacted with a heterocyclic amine to provide Compound P3. Dealkylation of Compound P3
using methods previously described affords Compound P4.

Scheme Q illustrates a method for the preparation of compounds of the present
invention wherein R5 and R6 are appropriately substituted alkoxy substituents as defined •'
herein. A compound of formula Q1 wherein R5 is hydrogen and R6 is hydroxyl may be-
coupled with an appropriately substituted alcohol in the presence of MSNT (1-(mesitylene-
2-sulfonyl)-3-nitro-1,2,4-triazole) to afford a compound of formula Q2 wherein R5 is a
substituted alkyl and R6is a substituted alkoxy as defined herein.
Alternatively, compounds of formula Q1 may be elaborated using an appropriately
substituted alkylating agent to provide compounds of the present invention where either
one or both hydroxyl groups of the phosphonic acid are alkylated. An alkylating agent in
this instance is an alkyl substituent that is optionally substituted as defined for R5 or R6, and,
said alkyl substituent is substituted with a leaving group. A leaving group is defined as a
substituent that is activated toward nucleophilic displacement, including halides, tosylates,
and the like.
Scheme R
Scheme R illustrates the preparation of compounds of the present invention
wherein R5and R6 (when R6 is alkoxy) are taken together with the atoms to which they are
both attached to form a monocyclic ring. A diol of formula R1 may be treated with a
benzyl- or lower aikyl-dichlorophosphite to form a cyclic phosphonate of formula R2. A
compound of formula R2 may be condensed under refluXing conditions with a compound of
formula B2 to form a compound of formula R3. The elaboration of a compound of formula
R3 to a compound of formula R4 may be achieved using the methods described for
Scheme A.
SPECIFIC SYNTHETIC EXAMPLES
The following Examples are set forth to aid in the understanding of the invention,
and are not intended 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. No
attempt has been made to optimize the yields obtained in any of the reactions. 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, m= multiplet, t = triplet, br = broad). ES-MS were
recorded on a Micromass® mass spectrometer or on an Agilent® HPLC mass spectrometer.
TLC was performed with Whatman® 250-jim silica gel plates. Preparative TLC was
performed with Analtech® tapered silica gel GF plates. Preparative HPLC separations
were carried out on a Gilson®HPLC using a Phenomenex® Kromasil 100A C18 column (25,
cm x 50 mm, or 10 cm x 21.2 mm) using gradients of CH3CN/ water/ 0.2% TFA; Analytical
HPLC separations were carried out on a Supelco® ABZ+Plus column (5 cm x 2.1 mm) or a
YMC® J'Sphere H80 S4 column (5 cm x 2 mm) with detection at 220 nm and 254 nm on a
Hewlett Packard® 1100 UV detector. The gradient used was 10% to 90%
CH3CN/water/0.1% TFA in 6 min. Reported percent purity data is based on the 220 nm
data. Microanalysis was performed by Robertson Microlit Laboratories, Inc.
Representative Chemical Abstracts Service (CAS) Index-like names for the
compounds of the present invention were derived using the Autonom Version 2.1
nomenclature software.
EXAMPLE 1
[(5-Chloro-benzo[b]thiophen-3-yl)- (naphthalen-2-ylcarbamoyl)-methyl]-phosphonicacid,
Cpd 9
A solution of Compound 1a (5.01 g, 19.2 mmol) and Compound 1b (10 mL) was
refluxed for 105 min. The solution was concentrated under high vacuum at 90 °C to yield
6.01 g of Compound 1c as a pale yellow viscous oil; HPLC: 3.51 min; MS (ES) m/z 319
(MH+).
To a solution of 2.5 M n-BuLi in hexanes (4.73 mL, 12 mmol) in THF (30 mL) at -
78°C was added dropwise a solution of Compound 1c (3.77 g, 12 mmol) in THF (30 mL)
over 15 min. After stirring for an additional 30 min, Compound 1d (naphthalen-2-yl
isocyanate) (2.0 g, 12 mmol) in THF (30 mL) was added dropwise to the mixture over 5
min. After the addition was complete, the solution was allowed to reach rt and stirred
overnight. Excess saturated NH4CI (aq) was added, and the layers were separated. The
aqueous portion was extracted with EtOAc (3 x 20 mL). The combined organic extracts
were dried (Na2S04), filtered, and concentrated under reduced pressure at rt. The residue
was taken up in CH3CN (10 ml_), the solid was collected and dried under N2/vacuum to >
afford Compound 1e (4.3 g) as a white powder: HPLC: 4.25 min; MS (ES) m/z 488 (MH+).
Procedure A: General Method for Deethvlation of Phosphonates and Phosphinates
To a solution of the phosphonate or phospinate (x mmol) in pyridine (5 mL/ mmol of
phosphonate or phosphinate) is added excess bromotrimethylsilane (5x to 8x mmol) in
three portions at 15 min intervals. The mixture is stirred for 60 min after the last addition,
then concentrated under reduced pressure. The residue is stirred with excess 1N HCI (aq)
for 60 min. The white precipitate is collected and rinsed sequentially with 1N HCI (aq) and
water, then dried under N2/vacuum. The crude product may be purified by trituration with
appropriate solvents, salt formation, recrystallization, or reverse phase chromatography.
Compound 1e (4.3 g, 8.8 mmol) was deethylated according to Procedure A. The
crude product was further purified: the white solid was stirred with CH3CN for 60 min,
collected, rinsed with CH3CN, and dried under N2/vacuum to afford 3.2 g of Cpd 9 as a
white powder: HPLC 4.47 min; MS (ES) m/z 432 (MH+).
To a solution of Cpd 9 (2.68 g, 6.2 mmol) in CH3OH (10 mL) was added a solution
of tris(hydroxymethyl)aminomethane (1.5 g, 12.4 mmol) in CH3OH (10 mL). The solution
was concentrated, and the resulting white solid was recrystallized from /-PrOH to yield 4.0
g of the tromethamine salt of Cpd 9 as an off-white solid. HPLC: 4.4 min, 94%; MS (ES)
m/z (MH+) = 432; 1H NMR (DMSO-d6) 5 3.32 (s, 1QH), 4.59 (d, 1H), 7.30 - 7.42
(overlapping m, 3H), 7.56 (d, 1H), 7.71 -7.80 (overlapping m, 3H), 7.94-7.05
(overlapping m, 3H), 8.28 (s, 1H), 11.40 (s, 1H); Anal. Calc'd for C20H15NO4PSCI -1.6
C4HHNO3 -1.0 /-PrOH ¦ 0.25 H20: C, 51.16; H, 6.01; N, 5.28; H20, 0.66. Found: C, 51.21;
H, 5.92; N, 5.22; H20, 0.74.
Other compounds of the present invention may be prepared by those skilled in the
art by varying the starting materials, reagent(s) and conditions used. Using the procedure
. for Example 1, the following compounds were prepared without further purification:
EXAMPLE 2
[(Benzo[b]thiophen-2-yl)- (naphthalen-2-ylcarbamoyl)-methyl]-
phosphonic acid, Cpd 140
To a solution of Compound 2a (3.5 g, 26.1 mmol) in 25 ml_ of THF at -78 °C was
added a solution of 2.5 M n-BuLi in hexanes (13 ml_, 32.6 mmol). The reaction was
warmed to 0 °C and stirred for 25 min, then 4 mL of DMF was added slowly. The solution
was heated to reflux for 1 h. The reaction was cooled to rt, poured into water and extracted
three times with Et20. The combined organic extracts were washed with brine, dried
(Na2S04), filtered, and concentrated under reduced pressure at rt. The crude oil was
dissolved in 25 mL of MeOH, cooled to 0°C, and NaBH4 (1.6 g, 42 mmol) was added and
stirred for 2 h. After quenching with excess acetone, the mixture was concentrated, and
the residue was partitioned between EtOAc and brine. The brine was extracted twice with
EtOAc, and the combined organic extracts were washed twice with brine, dried (Na2S04),
filtered and concentrated under reduced pressure at rt. The crude solid was stirred with
6:1 CH2CI2/hexane, then collected to afford Compound 2b (2.52 g) as an off-white powder:
HPLC: 2.85 min.
To Compound 2b (2.52 g, 16.8 mmol) was added 10 mL of thionyl chloride and
refluxed for 1.5 h. The reaction was concentrated under reduced pressure at rt, and the
residue was treated with hexanes. After concentration, the residue was treated with
excess triethylphosphite Compound 1b and refluxed for 1.5 h. The reaction was
concentrated under reduced pressure at 90 °C and purified by flash column
chromatography (silica, 0 to 40% EtOAc/Hexane) to yield Compound 2c (2.5 g) as an oil:.'
HPLC: 3.32 min; MS (ES) m/z 285 (MH+).
From Compound 2c (0.64 g, 2.25 mmol) was prepared Compound 140 according to
Procedure A: HPLC: 3.87 min; MS (ES) m/z 398 (MH+).

EXAMPLE 3
[(5-Chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylthiocarbamoyl)-
methyl]-phosphonic acid, Cpd 45
Using the procedure described in Example 1 and substituting 2-
napthylthioisocyanate for 2-naphthylisocyanate, Compound 45 was synthesized as a pale
yellow powder: HPLC: 4.89 min; MS (ES) m/z 448 (MH+).
EXAMPLE 4
[1-(5-Chloro-benzo[6]thiophen-3-yl)- 1-(naphthalen-2-ylcarbamoyl)-
ethyl]-phosphonic acid, Cpd 125
To a solution of 2.5 M /7-BuLi in hexanes (0.44 mL, 12 mmol) in THF (7 mL) at -78
°C was added dropwise a solution of Compound 1c (3.77 g, 1-1 mmol) in THF (7 mL).
After stirring for 30 min, methyl iodide (0.068 mL, 1.1 mmol) was added dropwise by
syringe. The reaction was warmed to 0 °C and then to rt. The solution was returned to
-78°C and a solution of 2.5 M /7-BuLi in hexanes (0.44 mL, 12 mmol) was added dropwise.
After stirring for 30 min, Compound 1d (0.19,1.1mmol) in THF (7 mL) was added dropwise
to the mixture. After the addition was complete, the solution was allowed to reach rt and
stirred overnight. Excess saturated NH4CI (aq) was added, and the layers were separated.
The aqueous portion was extracted with EtOAc (3x5 mL). The combined organic extracts
were dried (NazS04), filtered, and concentrated under reduced pressure at rt. The residue
was dissolved in CH3CN (5 mL), and filtered. The filtrate was purified by flash column
chromatography (silica, CH2CI2) to yield Compound 4a (0.036 g) HPLC: 4.62 min; MS (ES)
m/z502(MH+).
Compound 4a was converted to Compound 125 using Procedure A: HPLC: 4.34
min (94%); MS (ES) m/z 444 (MH).
EXAMPLE 5
[(5-Chloro-1,1-dioxo-1 HA A,6-benzo[b]thiophen-3-yl)-
(naphthalen-2-ylcarbamoyl)-methyl]-phosphonic acid, Cpd 86
Compound 1e (0.20 g, 0.41 mmol) was suspended in acetic acid (5 mL) and heated
to 47.5 °C and sodium perborate tetrahydrate Compound 5a (0.31 g, 2.0 mmol) was added
portionwise over 15 min, and the reaction was stirred at 47.5 °C overnight. The reaction
was partitioned between water and EtOAc, and the layers were separated. The aqueous
phase was extracted with EtOAc, and the combined organic phases were washed
sequentially with saturated NaHC03 (aq), brine, and then dried (Na2S04), filtered, and
concentrated under reduced pressure at rt. The residue was purified by flash column
i
chromatography (silica, 0 - 40% EtOAc/ hexane) to yield Compound 5b (0.052 g): HPLC:
3.87 min; MS (ES) m/z 520 (MH+).
Compound 5b (0.052 g, 0.10 mmol) was converted Compound 86 (0.0185 g) by
Procedure A: HPLC:3.25 min, 95%; MS (ES) m/z 462 (MH-).
EXAMPLE 6
{[(5-Chloro-benzo[£>]thiophen-3-yl)-
[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinic acid, Cpd 17
A solution of Compound 1a (1.96 g, 7.48 mmol) in excess diethylmethylphosphonite
was refluxed for 3 h. The solution was concentrated under high vacuum at 90 °C, and the
residue was purified by flash column chromatography (silica, 0-100% EtOAc/ hexanes) to
yield 1.88 g of Compound 6a as a slightly cloudy pale yellow viscous oil: HPLC: 3.19 min;
MS (ES) m/z 290 (MH+).
To a suspension of Compound 6b (5.0 g, 27.2 mmol) in dry benzene (20 mL) Was
added triethylamine (3.74 mL, 27.2 mmol). The solution cooled to 0°C, and Compound 6c
(5.86 mL, 27.2 mmol) was added rapidly dropwise, and the cooling was removed. The
reaction was stirred 18 h, then poured into H20. The mixture was extracted three times
with EtOAc, and the combined organic extracts were washed once with brine, dried
(Na2S04), filtered, and concentrated under reduced pressure at rt. The residue was
purified by flasfvcolumn chromatography (silica, 0-100% EtOAc/hexanes) to yield 4.88 g of
Compound 6d as a white solid: HPLC: 3.65 min.
Compound 6d (3.4 g, 16.3 mmol) was dissolved in benzene (30 mL) and refluxed.
for 3 h. The solution was concentrated under reduced pressure at rt and the resulting
crude Compound 6e was used without purification in the next reaction.
To a solution of 2.5M n-BuLi in hexanes (8.9 mL, 22.3 mmol) in THF (30 mL) at
-78°C was added dropwise a solution of Compound 6a (4.7 g, 16.3 mmol) in THF (30 mL)
over 15 min. After stirring for an additional .30 min, a solution of Compound 6d (3.4 g, 16.3
mmol) in THF (30 mL) was added dropwise to the mixture over 5 min. After the addition
was complete, the solution was stirred at -78CC for 30 min, then quenched cold with excess
NH4CI (saturated, aq.), and stirred overnight at rt. The layers were separated, and the
aqueous portion was extracted with EtOAc (2 x 20 mL). The combined organic extracts
were washed once with brine, dried (Na2S04), filtered, and concentrated under reduced
pressure at rt. The residue was purified by flash column chromatography (silica, 0-50%
EtOAc/hexanes) to yield 4.1 g of a pale yellow solid, which was stirred with 15 mL CH3CN,
collected, and dried under N2/vacuum to afford 3.5 g of Compound 6f as a white powder:
HPLC: 4.04 min., 97%, broad; MS (ES) m/z 470 (MH+).
Compound 6f (3.5 g, 7.46 mmol) was deethylated following Procedure A. The solid
was further purified by taking it up in MeOH, followd by collection of the precipitate to afford
Compound 17 (2.93 g) as a white powder: HPLC 4.0 min.
To a mixture of Compound 17 (2.93 g, 6.2 mmol) in CH3QH (10 mL) was added a
solution of tris(hydroxymethyl)aminomethane (0.75 g, 6.2 mmol) in CH3OH (10 mL). The
solution was filtered and concentrated under reduced pressure at rt, and the resulting white
solid was recrystallized from CH3CN/EtOAc to yield the tromethamine salt of Compound 17
(3.35 g) as a white solid. HPLC: 4.02 min, 100%; MS (ES) 442 (MH+); 1H NMR (DMSO-d6)
8 1.07 (d, 3H), 3.45 (s, 6H), 4.48 (d, 1H), 6.12 (d, 1H), 7.12-7.18 (br m, 1H), 7.24-7.45
(overlapping m, 4H), 7.92 - 8.00 (overlapping m, 3H), 10.92 (d, 1H); Anal. Caic'd for
C19H15N03PSCI F2 -1.0 C4HHNO3 ¦ 0.15 H20: C, 48.84; H, 4.69; N, 4.96; HzO, 0.48.
Found: C, 48.99; H, 4.62; N, 4.97; H20, 0.42.

Other compounds of the present invention may be prepared by those skilled in the
art by varying the starting materials, reagent(s) and conditions used. Using the procedure
of Example 6, the following compounds were prepared without further purification:
The following compounds can be made by those skilled in the art by using Example
6 and varying the starting materials, reagent(s) and conditions used: compounds 300, 301,
302, 303, 304, 305, 306, and 30.7.
EXAMPLE 7
[(5-Chloro-benzo[bjthiophen-3-yl)- (2-amino-4-benzothioazol-6~ylcarbamoyl)-methyl]-
phosphonic acid, Cpd 69
Using the procedure described in Example 6 for the conversion of Compound 6b to
Compound 17, Compound 7a was converted to Compound 7b. Compound 7b was
suspended in a small volume of 1,4-dioxane and gaseous HCI was bubbled in to yield a
clear yellow solution and the solution was stirred for 1 h. The reaction was concentrated
under reduced pressure at rt, the residue stirred with 1N HCI (aq) for 45 min, and the solid
was collected to yield Compound 69 as a yellow powder: HPLC: 2.58 min; MS (ES) m/z
454(MH+).
EXAMPLE 8
2-(5-Chloro-benzo[i>]thiophen-3-yl)-/7-naphthalen-2-yl-2-(1ft-tetrazol-5-yl)-acetamide,
Cpd 88
A solution of Compound 8a (1.15 g, 5.53 mmol) in THF (10 mL) was added
dropwise to a solution of 2.5M n-BuLi in hexanes (2.40 mL, 6.08 mmol) in THF (10 mL) at
-78°C. After stirring for 30 min at -78°C, a solution of Compound 1d (0.94 g, 5.60 mmol) in
THF (10 mL) was added dropwise. After 1 h, the reaction was quenched at -78°C with
excess NH4CI (aq). After warming to rt gradually, the layers were separated, and the
aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic extracts
were dried (Na2S04), filtered, and concentrated under reduced pressure at rt. The residue
was stirred with MeOH, and the precipitate was collected to yield Compound 8b (1.5 g) as
an off-white powder: HPLC: 4.39 min.
A suspension of Compound 8b (0.28 g, 0.75 mmol), sodium azide (0.15 g, 2.24
mmol), and triethylamine hydrochloride (0.31 g, 2.24 rrimol) in toluene (7 mL) was refluxed
overnight., Upon cooling to rt, EtOAc (10 mL) and 1 N HCI (10 mL) were added and the
mixture was stirred vigorously. The biphasic mixture was filtered and a tan solid was
collected. The layers were separated, and the organic layer was concentrated under
reduced pressure at rt. The residue was treated with CH3CN, and a tan solid was,
collected. The combined solids were treated with hot CH3CN (100 mL), cooled, and the
solid was collected to afford Compound 88: HPLC: 4.11 min; MS (ES) m/z 420 (MH+) =
420; 1H NMR (DMSO-d6) 5 6.15 (s, 1H), 7.41-7.62 (overlapping m, 4H), 7.82-7.93
(overlapping m, 5H), 8.10 (d, 1H, J= 8.6 Hz), 8.32 (s, 1H), 10.92 (s, 1H).
EXAMPLE 9
[(5-Chloro-benzo[/?]thiophen-3-yl)-
(naphthalen-2-ylcarbamoyl)-methyl]-su!fonic acid, Cpd 50
To a solution of Compound 1a (1.0 g, 3.85 mmol) in acetone (5 mL) was added a
solution of sodium sulfite (0.49 g, 3.85 mmol) and Kl (potassium iodide) (0.13 g, 0.77
mmol) in water (10 mL). The solution was refluxed for 3.5 h, then cooled to rt and
concentrated under reduced pressure. The residue was treated with 1N HCI (15 mL),
filtered, and the filtrate was extracted with EtOAc (3x10 mL). The combined organic
extracts were filtered, and concentrated under reduced pressure at rt to yield 0.60 g of
Compound 9a as a white powder: HPLC: 3.38 min; MS (ES) m/z 261 (MH").
To a suspension of Compound 9a (0.29 g, 1.11 mmol) in THF (7 mL)at -5°C was
added a solution of 2 M /-PrMgBr in Et20 (1.39 mL, 2.77 mmol). The mixture was stirred
for 2 h at rt, then cooled to -10°C before treatment with a solution of Compound 1d (0.20 g,
1.17 mmol) in THF (7 mL). After stirring overnight at rt, the reaction was quenched with 3
mL of 1N HCI (aq), and extracted with EtOAc (3x10 mL). The combined organic layers
were washed with brine (10 mL), dried (Na2S04), filtered, and concentrated under reduced
pressure at rt. The resulting tan foam was dissolved in a minimum volume of CH3CN and
allowed to stand overnight. The solution was filtered, and the filtrate was concentrated
under reduced pressure and the residue was purified by reverse phase HPLC (20-90%
CH3CN/H20). The resulting white powder was dissolved in CH3CN, filtered, and
concentrated under reduced pressure at rt to yield Compound 50 (0.14 g) as a white solid:
HPLC: 3.14 min; MS (ES) m/z 430 (MH"); 1H NMR (DMSO-d6) 8 5.35 (s, 1H), 7.28-7.51
(overlapping m, 4H), 7.72-7.80 (m, 3H), 7.92-8.05 (overlapping m, 3H), 8.24 (s, 1H), 10.40
EXAMPLE 10
{[(5-Chloro-benzo[£]thiophen-3-yl)-[2-(4-amino-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphonic acid, Cpd 12
Using the procedure described in Example 6, substituting p-nitro-cinnamic acid for
3,4-difluorocinnamic acid and substituting Compound 1c for Compound 6a, Compound 10a
was prepared. To a solution of Compound 10a (0.115 g, 0.226 mmol) in 6 mL of 1:1 EtOH
/CH2CI2was added 10% Pd/C (0.060 g) and hydrazine hydrate (0.173 mL, 3.35 mmol).
After 2 h, the reaction mixture was filtered, concentrated under reduced pressure at rt, and
the resulting yellow solid was taken up in hot acetonitrile and filtered. The filtrate was
concentrated under reduced pressure at rt, and the residue was purified by flash column
chromatography (silica, 1% CH3OH/CH2CI2) to yield Compound 10b (0.064 g) as a bright
yellow solid: HPLC: 2.94 min; MS (ES) m/z 479 (MH+).
Compound 10b (0.064 g, 0.134 mmol) wasdeethylated by Procedure A to yield
Compound 12 (0.036 g) as an orange solid: HPLC: 2.41 min; MS (ES) m/z 423 (MH+).
Cpd 12
EXAMPLE 11
{[(5-Chloro-benzo[t)]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphonic acid, Cpd 2
Using the procedure described in Example 6, substituting phosphonate Compound
Compound 2 (0.116 g) was prepared as a white solid: HPLC: 3.98 min; MS (ES) m/z 444
(MH+); Anal. Calc'd for C18H13N03PSCI F2«1.0 C4HnN03 • 0.10 H20 C4HHNO3 • 0.33
C2HeO: C, 46.34; H, 4.43; N, 4.87; H20, 1.04. Found: C, 46.47; H, 4.09; N, 4.65; H20,
1.34.

Other compounds of the present invention may be prepared by those skilled in the
art by varying the starting materials, reagent(s) and conditions used. Using the procedure
of Example 11, the following compounds were prepared without further purification:
The following compounds can be made by those skilled in the art by'using Example
11 and varying the starting materials, reagent(s) and conditions used: compounds 192,
193, 194, 195, 196, 197, 198, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 308, 309,
310, 311, 312, 313, 314, and 315.
EXAMPLE 12
[(5-Chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-
methyl]-phenyl-phosphinic acid, Cpd 89Compound 12a (0.35 g, 1.17 mmol) was prepared
by the method described in Aust.J.Chem. 1983, 36,2517-2536. Using the procedure
described in Example 1 and Procedure A, substituting Compound 12a for Compound 1c,
Compound 89 was prepared as a white solid: HPLC: 4.19 min; MS (ES) m/z 490 (MH').
EXAMPLE 13
[(5-Chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-
methyi]-carboxylic acid, Cpd 84
A stream of isobutylene (g) Compound 13b was introduced into a suspension of
Compound 13a (1.07 g, 4.71 mmol) in acetone (15 mL) containing H2S04 (0.026 mL, 0.94
mmol). After 40 min, the cloudy solution was stoppered and stirred overnight. The
reaction was poured into 1N NaOH (aq), and the layers were separated. The aqueous
portion was extracted with CH2CI2(2 x 10 mL). The combined organic extracts were
washed with brine (10 mL), dried (Na2S04), filtered, and concentrated under reduced,
pressure at rt to yield Compound 13c (1.20 g): HPLC: 4.37 min.
To a solution of diisopropylamine (0.26 mL, 1.84 mmol) in THF (7 mL) at -40°C was
added a 2.5M solution of n-BuLi in hexanes (0.74 mL, 1.84 mmol). The temperature
lowered to -70°C, and a solution of Compound 13c (0.38 g, 1.34 mmol) in THF (7 mL) was
added slowly dropwise. The mixture was stirred for 30 min, at which time a solution of
Compound 1d (0.24 g, 1.41 mmol) in THF (7 mL) was added dropwise. After 45 min the
reaction was quenched with 3 mL of NH4CI (aq), then extracted with EtOAc (2x10 mL).
The combined organic extracts were washed with brine (10 mL), dried (Na2S04), filtered,
and concentrated under reduced pressure at rt. The residue was purified by flash column
chromatography (silica, 0-10% EtOAc/hexanes) to afford Compound 13d (0.18 g): HPLC:
4.73 min; MS (ES) m/z 452 (MH+).
A solution of Compound 13d (0.10 g, 0.22 mmol) in 1 mL of 1:1 CH2CI2/TFA was
allowed to stand for 65 min. The solution was concentrated under reduced pressure at rt
and the residue was held under vacuum at rt overnight. The residue was dissolved in
CH3CN, filtered and concentrated under reduced pressure at rt. The residue was triturated
from diethyl ether at rt, and the white solid was collected to yield Compound 84 (0.023 g)
as a tan solid: HPLC: 4.16 min; MS (ES) m/z 396 (MH+); 1H NMR (DMSO-d6) .8 5.33 (s,
1H), 7.39-7.59 (overlapping m, 4H), 7.82-7.91 (overlapping m, 4H), 8.02-8.08 (overlapping
m,2H), 8.31 (s,1H), 10.63

EXAMPLE 14
[(5-Chloro-benzo[£>]thiophen-3-yl)-
(naphthalen-2-ylcarbamoyl)-methyl]-carbamate, Cpd 80
Compound 14d was prepared from Compound 14a by the methods described in t
J.Med.Chem. 1989, 32(12), 2548-2554 and J.HetChem. 1998, 25,1271: HPLC: 3.95 min.
Compound 14d was converted to Compound 14e using the method described in
Eur.J.Med.Chem. 2001, 36(1), 55-62). Compound 14e was oxidized with selenium dioxide,
to yield Compound 14f using the method described in British patent 1399089 (1971):
HPLC: 3.78 min; MS (ES) m/z 239 (MH").
To a solution of Compound 14f (2.0 g, 8.22 mmol), Compound 14g (1.18 g, 8.22
mmol), and HOBT (1.11 g, 8.22 mmol) in DMF (15 mL) was added DCC (1.69 g, 8.22
mmol) and the reaction was stirred for 48 h. The slurry was filtered, and the filtrate
concentrated under high vacuum at rt.. The residue was purified by trituration from boiling
CH3CN to yield Compound 14h (1.41 g) as a bright yellow powder: HPLC: 4.91 min; MS
(ES) m/z 364 (MH").
To a suspension of Compound 14h (1.02 g, 2.79 mmol) in 20 mL of 1:1 THF/
MeOH was added NaBH4 (0.32 g, 8.42 mmol). The reaction was stirred for 1 h, then
quenched with 1N HCI (5 mL). The volume was reduced approximately 50% under
reduced pressure at rt and the solution was extracted with EtOAc (2x10 mL). The
combined organic extracts were washed with brine (10 mL), dried (Na2S04), filtered, and
concentrated under reduced pressure at rt. The residue was purified by recrystallization
from CH3CN, to yield Compound 14i (0.70 g): HPLC: 4.18 min; MS (ES) m/z 368 (MH+).
To a suspension of Compound 14i (0.25 g, 0.68 mmol) in CH2CI2 (10 mL) at 0°C,
was added Compound 14j (0.11 mL, 0.88 mmol). After stirring for 3 h at rt, a white solid
was collected and rinsed with a minimal volume of CH2CI2, then dried under N2/vacuum to
yield 0.36 g of Compound 14k: HPLC: 4.56 min; MS (ES) m/z 554 (MH).
A suspension of Compound 14k (0.36 g, 0.65 mmol) in saturated aqueous K2C03
(6 mL) and f-BuOH (3 mL) was refluxed for 2 h, then stirred at rt for 24 h. The reaction was
concentrated under reduced pressure at rt, treated with aqueous 1N HCI (10 mL), and
extracted with EtOAc (3x10 mL). The combined organic extracts were washed with brine
(10 mL), dried (Na2S04), filtered, and concentrated under reduced pressure at rt to yield
Compound 80 (0.105 g): HPLC: 4.29 min; MS (ES) m/z 410 (MH"); 1H NMR (DMSOd6) 5
6.16 (s, 1H), 7.38-7.49 (overlapping m, 3H), 7.57-7.61 (m, 1H), 7.77-7.86 (overlapping m,;
3H), 7.97 (s, 1H), 8.07 (d, 1H, J= 8.7 Hz), 8.13 (s, 1H), 8.22 (d, 1H, J= 2 Hz), 10.02 (S,
1H).
EXAMPLE 15
2-(5-Chloro-benzo[b]thiophen-3-yl)-3-hydroxy~N-naphthalen-2-yl-propionamide, Cpd 136
A suspension of Compound 8b (1.23 g, 3.27 mmol) in 1,4-dioxane/methanol (1:1,
50 mL) at -78°C was saturated with HCI (g). The mixture was maintained at -20°C
overnight, then concentrated under vacuum, such that the temperature remained below
20°C. The residue was partitioned between EtOAc (10 mL) and water (10 mL). The
organic layer was dried (Na2S04), filtered, and concentrated under reduced pressure at rt,
and the resulting residue was recrystallized from CH3CN to afford Compound 15a (1.47 g)
as a white powder: HPLC: 4.31 min.
To a solution of Compound 15a (0.23 g, 0.56 mmol) in THF (5 mL) was added
NaBH4 (0.043 g, 1.12 mmol), LiCI (0.048 g, 1.12 mmol), and EtOH (10 mL). The reaction
was stirred for 90 min, then quenched with several drops of 1N HCI (aq). The mixture was
cooled to -10°C and treated with 10 mL of 1N HCI. The mixture was extracted with EtOAc
(4x) and the combined organic extracts were washed with brine (4x), dried (Na2S04),
filtered, and concentrated under reduced pressure at rt to yield a white solid. The solid was
triturated with CH3CN to yield Compound 136 (0.14 g) as a snow-white solid: HPLC: 4.11
min; MS (ES) m/z 382 (MH+); 1H NMR (DMSO-d6) 5 3.69-3.75 (m, 1H), 4.11-4.19 (m, 1H),
4.33-4.37 (m, 1H), 5.17 (t, 1H, J= 5 Hz), 7.37-7.49 (m, 3H), 7.59-7.63 (m, 1H), 7.76 (s,
1H), 7.80-7.88 (m, 3H), 8.05 (d, 1H, J=8Hz), 8.18 (d, 1H, J=2Hz), 8.35 (s, 1H), 10.46
(s,1H).

EXAMPLE 16
Sulfamic acid 2-(5-chloro-benzo[b]thiophen-3-yl)-2-(naphthalen-2-ylcarbamoyl)-ethyl ester,
Cpd 120
To a suspension of 95% NaH (0.017 g, 0.68 mmol) in DMF (2 mL) at 0°C was
added a solution of Compound 136 (0.10 g, 0.26 mmol) in DMF (2 mL) dropwise. The
suspension was stirred at 0°C for 1 h, then sulfamoyl chloride (0.067 g, 0.58 mmol) was
added as a solid. After stirring for 1 h at 0°C, the mixture was treated with e'xcess
sulfamoyl chloride. After stirring overnight, the reaction was quenched with water and
extracted with EtOAc (3x5 mL). The combined organic phases were washed with brine,
dried (Na2S04), filtered and concentrated under reduced pressure at rt. The residue was
purified by flash column chromatography (silica, 0-40% EtOAc/hexanes) to yield
Compound 120 (0.1.0 g) as a white foam: HPLC: 4.12 min; MS (ES) m/z 461 (MH+); 1H
NMR (DMSO-d6) 8 4.29 - 4.34 (m, 1H), 4.65 - 4.75 (m, 2H), 7.39 - 7.50 (m, 3H), 7.57 -
7.64 (m, 1H), 7.81 - 7.90 (m, 4H), 8.09 (d, 1H, J= 8.5 Hz), 8.215 (d, 1H, J= 2 Hz), 8.34 (S,
1H), 10.55 (s,1H).

EXAMPLE 17
[(4-{[1-(Naphthalene-2-carbonyl)-piperidine-4-carbonyl]-amino}-
naphthalen-2-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic acid, Cpd 8
A solution of Compound 17a (10 g, 45.9 mmol) in MeOH (200 mL) was added to
10% Pd/C and hydrogenated for 3.5 h at 40-50 psi. The mixture was filtered (Celite) and
concentrated under reduced pressure at rt, and the resulting material was triturated with
EtOAc to yield Compound 17b as a crude black solid. Compound 17b (1.36 g, approx.
8.61 mmol) was dissolved in DMF (20 mL) and TEA (1.32 mL, 9.46 mmol). To this solution
was added 2-(terf-butoxycarbonyloxyimino)-2-phenylacetonitrile, (BOC-ON) (2.33 g, 9.46
mmol), and the reaction was heated at 55 °C overnight. The solution was concentrated
under reduced pressure at rt and filtered through a plug of silica gel. The crude product
was stirred with.CH2CI2 and filtered to yield 0.18 g of Compound 17c: HPLC: 2.68 min; MS
(ES) m/z 259 (MH+). , ,
A solution of ethyl isonipecotamate, Compound 17d (2.04 g, 13.0 mmol), and
DIPEA (2.3 mL, 13.0 mmol) in 10 mL of CH2CI2 was treated with 2-naphthoyl chloride,
Compound 17e (2.48 g, 13.0 mmol). After stirring for 1.5 h, the mixture was sequentially
washed with 1N HCI (2 x 10 mL), saturated Na2C03 (aq) (2x10 mL), and brine (10 mL).
The organic phase was dried (Na2S04), filtered, and concentrated under reduced pressure
at rt. The residue was dissolved in 1,4-dioxane (41 mL) and treated with a solution of
LiOH-H20 (1.63 g, 39 mmol) in 5 mL of water. After 2 h, the reaction was concentrated
under reduced pressure at rt, and the residue was acidified with 1N HCI (aq), and extracted
with CH2CI2 (3x10 mL). The combined organic extracts were washed with brine (10 mL),
dried (Na2S04), filtered, and concentrated under reduced pressure at rt to yield 3.57 g of
Compound 17g: HPLC: 2.77 min; MS (ES) m/z 284 (MH+).
To a solution of Compound 17c (0.18 g, 0.70 mmol), Compound 17g (0.20 g, 0.70
mmol), and HOBT (0.094 g, 0.70 mmol) in DMF (8 mL) was added DCC (0.14 g, 0.70
mmol) and the reaction was stirred for 6 d. The mixture was filtered, concentrated under
reduced pressure at rt, and the residue suspended in a minimal volume of CH2CI2, and
filtered again. The clear solution was washed with 1N KHS04 (aq) and the organic phase
was filtered and washed sequentially with saturated Na2C03 (aq) and brine. The organic
phase was then dried (Na2S04), filtered, and concentrated under reduced pressure at rt.
The residue was purified by flash column chromatography (silica, 0-3% MeOH/ CH2CI2) to
afford Compound 17h (0.20 g, 0.382 mmol). A solution of 17h in TFA (3 mL) was stirred
for 50 min. The mixture was concentrated under reduced pressure at rt and the residue
was suspended in CH2CI2, washed with saturated Na2C03 (2x5 mL), dried (Na2S04),
filtered, and concentrated under reduced pressure at rt to yield 0.17 g of Compound 17i.
To 100 mL of THF and 2.5 M n-BuLi (79.2 mL, 0.198 mol) at -78 PC was added
dropwise a solution of Compound 17j (50 g, 0.18 mol). After 30 min, C02 was bubbled
through the reaction for 1 h, after which point the mixture was warmed to rt. The ice bath-
cooled mixture was quenched with excess saturated Na2C03 (aq), and the volatile solvents
were removed under reduced pressure at rt. The resulting solution was washed with Et20
(3x), acidified with 3N HC1 (aq), and extracted with EtOAc (4x). The combined organic
extracts were washed once with water, dried (Na2S04), filtered (Celite), and concentrated
under reduced pressure at rt to yield 32.59 g of Compound 17k: HPLC: 3.06 min, MS (ES)
m/z 323 (MH+).
Compound 17k (0.13 g, 0.40 mmol) was stirred with 1 ml_ of thionyl chloride for 30
min and the mixture was concentrated under reduced pressure at rt. The residue was
treated with hexanes and concentrated under reduced pressure at rt again. The residue
was dissolved in THF (5 ml_), at -78 °C, treated with a solution of Compound 17i (0.17 g,
0.40 mmol) in pyridine (3.5 ml_). The solution was stirred at rt overnight, then concentrated
under reduced pressure at rt. The residue was taken up in CH2CI2 (5 mL) and washed
sequentially with 1N KHS04 (aq), saturated Na2C03 (aq) (3x5 mL), and brine (5 mL),
dried (Na2S04), filtered, and concentrated under reduced pressure at rt. The residue was
purified by prep-plate chromatography (75% EtOAc/hexanes) to yield 0.11 g of Compound
171: HPLC: 4.02 min; MS (ES) m/z 728 (MH+).
Compound 171 was deethylated by Procedure A to yield Compound 8 (0.063 g):
HPLC: 3.91 min; MS (ES) m/z 424 {M -[COCH(1-Naph)P(=0)(OH)2}; 1H NMR (DMSO-d6)
81.6-2.2 (br overlapping ms 4H), 2.7-3.3 (br overlapping m, 3H), 3.6-4.0 (br m, 1H),
4.45-4.75 (br m, 1H), 5.32 (d, 1H, J= 24 Hz), 7.39-7.60 (overlapping m, 8l-j), 7.79-8.0
(overlapping m, 9H), 8.24 (s, 1H), 8.31 (d, 1H, J= 7 Hz), 8.38 (d, 1HyJ= 10 Hz), 9.95 (s,
1H), 10.6 (s, 1H).
EXAMPLE 18
[(4-Chloro-1 -methyl-1 W-indol-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-phosphonic acid,
Cpd 63
To a stirred mixture of 95% sodium hydride (0.35 g, 13.85 mmol) in THF (3 mL) at 0°C
was added a solution of 4-chloroindole Compound 18a (0.35 g, 6.59 mmol) in THF (3 mL),
and the mixture was stirred for 15 min. Methyl iodide (1.03 g, 7.26 mmol) was added and the
reaction was stirred overnight. The reaction was quenched with saturated NaHC03 (aq), the
volatiles were removed under reduced pressure at rt, and the resulting mixture was extracted
with EtOAc (3x). The combined organic extracts were washed with brine, dried (Na2S04),
filtered (Celite), and concentrated under reduced pressure at rt to yield 1.11 g of Compound
18b as an oil: HPLC: 3.37 min, 77%.
To a stirred suspension of Compound 18b (1.09 g, 6.59 mmol) in CH2CI2 (10 mL)
was added Compound 18c (1.58 g, 8.57 mmol). After stirring overnight, the solid was
collected and rinsed sequentially with CH2CI2 and Et20. The solid was dissolved in 1N
NaOH (aq) and extracted with CH2CI2 (3x). The combined organic extracts were washed
with brine, dried (Na2S04), filtered (Celite), and concentrated under reduced pressure at rt to
yield 0.95 g Compound 18d as a clear oil: HPLC: 1.18 min, 97%; MS (ES) m/z 223 (MH+).
To a stirred solution of Compound 18b (0.944 g, 4.24 mmol) in EtOH (10 mL) at 0°C
was added methyl iodide (0.66 g, 4.66 mmol). After stirring at room temperature overnight,
a solid was collected by filtration and rinsed sequentially with EtOH and Et20 to yield 1.46 g
of Compound 18e as a white solid: HPLC: 1.93 min, 68%.
A mixture of Compound 18e (1.0 g, 2.74 mmol) in triethyl phosphite (8 mL) was
refluxed overnight and concentrated under high vacuum at 90 "C. The residue was
dissolved in EtOAc, washed with H20, dried (Na2S04), filtered (Celite), and concentrated
under reduced pressure at rt. The residue was purified by flash column chromatography
(silica, 0-1% MeOH/ CH2CI2) to yield 0.82 g of Compound 18f as an oil: HPLC: 3.39 min;
MS (ES) m/z 316 (MH+).
Using the procedure described in Example 1 for the conversion of Compound 1c to
Compound 9; including deethylatibn by Procedure A, Compound 18f was converted to •
Compound 63.

Other compounds of the present invention may be prepared by those skilled in the
art by varying the starting materials, reagent(s) and conditions used. Using the procedure
of Example 18, the following compounds were prepared without further purification:
EXAMPLE 19
{(5-Chloro-1 -methyl-1 /+indol-3-yl)-f_2-(4-f luoro-phenyl)-
vinylcarbamoyl]-methyl}-phosphonic acid, Cpd 4
Using the procedure described in Example 18, substituting 5-chloroindole for 4-
chloroindole, Compound 19a was prepared.
Using the procedure described in Example 11, Compound 4 was prepared: HPLC:
3.60 min; MS (ES) m/z 423 (MH+).
EXAMPLE 20
[(5-Chloro-1-methyl-1H-indol-3-yl)-(naphthalen-2-ylcarbamoyl)-
methyl]-methyl-phosphinic acid, Cpd 1
Using the procedure described in Example 18, substituting 5-chloroindole for 4-
chloroindole, Compound 20a was prepared.
Using the procedure described in Example 18, substituting Compound 20a for
Compound 18b, Compound 20b was prepared.
Using the procedure described in Example 1 followed by deethylation by Procedure A,
Compound 20b was converted to Compound 1: HPLC: 3.77 min, 97%; MS (ES) m/z 427
(MH+).
Other compounds of the present invention may be prepared by those skilled in the
art by varying the starting materials, reagent(s) and conditions used. Using the procedure
of Example 20, the following compounds were prepared without further purification:
EXAMPLE 21
1-Methyl-3-[(naphthalen-2-ylcarbamoyl)-phosphono-methyl]-
1 H-indole-5-carboxylic acid, Cpd 56
Using the procedure described in Example 18, Compound 21a was prepared. To a
solution of 2.5 M n-BuLi in hexanes (0.56 mL, 1.40 mmol) in THF (2 mL) at -78°C was
added dropwise a solution of Compound 21a (0.27 g, 0.79 mmol) in THF (1 mL). After
stirring for an additional 45 min, Compound 1d (0.15 g, 0.87 mmol) in THF (1.5 mL) was
added dropwise to the mixture. After the addition was complete, the solution was stirred at
-78°C for 2 h. The mixture was warmed to rt, excess saturated NaHC03 (aq) was added,
and the solid was collected by filtration. The solid was rinsed (THF), and air dried to yield
Compound 21b (0.12 g): HPLC: 3.77 min.
Compound 21b (0.060 g, 0.12 mmol) was deethylated by Procedure A to yield
Compound 56 (0.042 g): HPLC: 3.19 min; MS (ES) m/z 420 (M - H20).
EXAMPLE 22
[[5-(4-Fluoro-phenyl)-1 -methyl-1 H-indol-3-yl]-(naphthalen-
2-ylcarbamoyl)-methyl]-phosphonic acid, Cpd 98
Compound 22a (0.27 g, 0.75 mmol), prepared by the method of Syn/eff Jan. 1994,93,
was methylated as described in Example 18 to yield 0.27 g of Compound 22b: HPLC: 3.65
min, 96.5%; MS (ES) m/z 362 (MH+).
Using the procedure described in Example 1, followed by deethylation Procedure A,
Compound 22b converted to Compound 98: HPLC: 4.46 min; MS (ES) m/z487 (MH).
EXAMPLE 23
[(Naphthalen-2-ylcarbamoyl)-(1-phenyl-1H-indol-3-yl)-methyI]-phosphonic acid, Cpd 128
A mixture of Compound 23a (5.0 g, 29 mmol), copper(ll) oxide (4.9 g, 63 mmol),
potassium carbonate (5.0 g, 36 mmol), and bromobenzene (30 mL) was refluxed for 13 h.
After cooling to rt, the mixture was filtered (dicalite) and concentrated under reduced pressure
at rt. The residue was triturated with hexanes to yield 5.2 g of Compound 23b as a brown
solid: HPLC: 4.44 min, 93%; MS (ES) m/z 252 (MH+).
To a suspension of lithium aluminum hydride (1.0 g, 26 mmol) in THF (30 ml) was
added Compound 23b (5.2 g, 20 mmol) in THF (25 ml_) at 0°C. The reaction was stirred for
1 h, then quenched at 0°C with moist Na2S04. The mixture was diluted with THF and
filtered (dicalite). The filtrate was concentrated under reduced pressure at rt, and the
residue was purified by flash column chromatography (silica, 25% EtOAc/hexanes) to yield
2.7 g of Compound 23c as a white solid: HPLC: 3.62 min, 99%; MS (ES) m/z 224 (MH+).
To a solution of Compound 23c in DMF (15 ml_) and CCI4 (4 mL) at 0°C was added .
triphenylphosphine (3.4 g, 13 mmol) and the mixture was stirred at rt overnight. The
reaction was concentrated under reduced pressure at rt, dissolved in EtOAc and passed
through a short plug of silica gel (30% EtOAc/hexanes) to yield 1.3 g of Compound 23d:
HPLC: 4.19 min, 91%; MS (ES) m/z 513 (MH+).
Using the procedure described in Example 1, substituting Compound 23d for
Compound 1a, Compound 128 was prepared: HPLC: 4.23 min, 83%; MS (ES) m/z 479 (M
+ Na).
EXAMPLE 24
Methyl-{(naphthalen-2-ylcarbamoyl)-[2-(4-phenyl-piperidine-1-carbonyl)-benzotb]thiophen-
3-yl]-methyl}-phosphinic acid, Cpd 32
Compound 24a was prepared according to the procedures described in JACS
1963, 6, 711 - 716 and JACS 1971, 93(12), 2897-2904.
To a solution of 2.5 M n-BuLi in hexanes (8.5 mL, 21.2 mmol) and THF (33 mL) at
-78°C was added droowise a solution of Compound 24a (3.52 a, 18.4 mmol) in THF (33
mL). After stirring the resulting yellow slurry for 45 min, di-tert-butyldicarbonate (4.14 g,
19.0 mmol) in THF (33 mL) was added dropwise to the mixture. After the addition was
complete, the solution was allowed to reach rt then quenched with 50 mL of saturated
NH4CI (aq). The layers were separated, and the aqueous portion was extracted with
EtOAc (2 x 20 mL). The combined organic phases were dried (Na2S04), filtered, and
concentrated under reduced pressure at rt. The residue was purifjed by flash column
chromatography (silica, 0 to 75% EtOAc/ hexanes) to yield 3.68 g of Compound 24b:
HPLC: 2.74 min, 90%; MS (ES) M/Z (MH+) = 292.
Ljsing the procedure described in Example 18, substituting Compound 24b (3.68 g,
12.65 mmol) for Compound 18d, and diethylmethylphosphonite for triethylphosphite,
Compound 24c (3.36 g) was prepared: HPLC: 3.67 min.
Using the procedure described in Example 1, followed by deethylation Procedure A,
Compound 24c (3.36 g, 9.5 mmol) was converted to Compound 24d (2.18 g): HPLC: 4.24
min; MS (ES) m/z 524 (MH+).
To Compound 24d (2.18 g, 4.17 mmol) was added 5 mL of TFA. After 50 min, the
mixture was concentrated under reduced pressure at rt and the residue was purified by
flash column chromatography (silica, 0 to 20% MeOH/EtOAc) to yield 0.30 g of Compound
24e: HPLC: 3.63 min, 91%; MS (ES) m/z 468 (MH+).
To a solution of Compound 24e (0.20 g, 0.43 mmol), Compound 24f (0.07 g, 0.45
mmol), and HOBT (0.061 g, 0.45 mmol) in DMF (2 mL) was'added DCC (0.093 g, 0.45
mmol). After 1 h, the reaction mixture was filtered, the residue was suspended in a
minimal volume of CH2CI2 and filtered. The filitrate was washed sequentially with 1N HCI
(2X), 10% aqueous NazC03, and brine, then dried (Na2S04), filtered, and concentrated
under reduced pressure at rt. The residue was purified by flash column chromatography
(silica, 0 - 60% EtOAc/heptane) to yield 0.12 g of Compound 24g: HPLC: 4.44 min; MS
(ES) m/z 611 (MH+).
Compound 24g (0.12 g, 0.197 mmol) was deethylated by Procedure A to afford
Compound 32 (0.086 g): HPLC: 4.49 min, 92%; MS (ES) m/z 583 (MH+).
Other compounds of the present invention may be prepared by those skilled in the
art by varying the starting materials, reagent(s) and conditions used. Using the procedure
of Example 24, the following compounds were prepared without further purification:
EXAMPLE 25
[(5-Chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-
methyl]-(3-phenyl-propyl)-phosphinicacid, Cpd 36
Compound 25a was prepared according to the procedures described in. JACS 2002,
124,9386-9387 and J.Organomet.Chem 2002, 643-644,154-163.
To a solution of Compound 25a (0.51 g, 2.58 mmol) in THF (10 mL) at -78°C was
added a solution of 2.5 M n-BuLi in hexanes (1.29 mL, 3.22 mmol). After stirring for 30
min, a solution of Compound 1a (0.225 g, 0.86 mmol) in THF (7mL) was added dropwise.
After 35 min, the reaction was quenched with excess saturated NH4Cl (aq), and the layers
were separated. The aqueous layer was extracted with EtOAc (3x) and the combined
organic extracts were washed with brine, dried (Na2S04), filtered and concentrated under
reduced pressure at rt. The residue was purified by flash column chromatography (silica, 0
- 30% EtOAc/hexanes) to yield 0.070 g of Compound 25b: HPLC: 3.93 min, 88%; MS (ES)
m/z 379 (MH+).
Using the procedure described in Example 1 with deethylation Procedure A,
Compound 25b was converted to Compound 36: HPLC: 4.70 min, 90%; MS (ES) m/z 520
(MH+).
Other compounds of the present invention may be prepared by those skilled in the
art by varying the starting materials, reagent(s) and conditions used. Using the procedure
of Example 25, the following compounds were prepared without further purification:
EXAMPLE 26
3-(2-Naphthalen-1-yl-2-phosphono-acetylamino)-naphtha!ene-
2-carboxylic acid methyl ester, Cpd 75
Using the procedure described in Example 17, Compound 17k was converted to
Compound 75: HPLC: 4.13 min; MS (ES) m/z 450 (MH+).
Other compounds of the present invention may be prepared by those skilied in the
art by varying the starting materials, reagent(s) and conditions used. Using the procedure
of Example 26, the following compounds were prepared without further purification:
EXAMPLE 27
[(3-Benzylcarbamoyloxymethyl-naphthalen-2-ylcarbamoyl)-
riaphthalen-1-yl-methyl]-phosphonic acid, Cpd 72
To a suspension of Compound 75 (7.6 g, 15.03 mmol) in THF (150 ml_) at 0°C was
added dropwise'a 1M solution of diisobutyl aluminum hydride in toluene (90 mL) and stirred at
rt overnight. The reaction was cooled to 0°C, quenched with saturated NH4CI (aq), and.
extracted with EtOAc (2x). The combined organic extracts were filtered (Celite), washed with
brine, dried (Na2S04), filtered, and concentrated under reduced pressure at rt. The residue
was purified by flash column chromatography (0 - 3% MeOH/CH2Ci2). The product was
recrystallized from MeOH to yield Compound 27a (1.85 g) as a crystalline solid: HPLC: 3.66
min; MS (ES) m/z 478 (MH+).
To a solution of Compound 27a (0.30 g, 0.63 mmol) in THF (4 mL) was added
triethylamine (28 jxl, 0.20 mmol) followed by benzylisocyanate (0.084 g, 0.63 mmol) in THF
(2 mL) dropwise. The flask was wrapped with foil and stirred at rt for 96 h. Additional
benzylisocyanate (0.042 g, 0.032 mmol) and triethylamine (60 uJ, 0.43 mmol) were added
and the reaction was stirred for an additional 48 h. The mixture was concentrated under
reduced pressure at rt and the residue was taken up in CH2CI2 and washed sequentially with
1N KHS04 (aq) (2x), brine, dried (Na2S04), then filtered, and concentrated under reduced
pressure at rt. The residue was purified by flash column chromatography (silica, 0 - 3%
MeOH/CH2CI2) to yield 0.22 g of Compound 27b: HPLC: 4.19 min, 95%; MS (ES) m/z 611
(MH+).
Compound 27b (0.22 g, 0.36 mmol) was deethylated by Procedure A to yield
Compound 72 (0.16 g): HPLC: 3.80 min; MS (ES) m/z 555 (MH+).
Other compounds of the present invention may be prepared by those skilled in the
art by varying the starting materials, reagent(s) and conditions used. Using the procedure
of Example 27, the following compounds were prepared without further purification:
EXAMPLE 28
{[3-(2-Benzylcarbamoyl-vinyl)-naphthalen-2-ylcarbamoyl]-
naphthalen-1-yl-methyl}-phosphonicacid, Cpd 109
A solution of Compound 27a (3.9 g ,8.1 mmol) in CHCI3 (50 mL) was treated with
activated Mn02 (7.0 g ,80 mmol) and stirred for 48 h. The mixture was filtered (Celite), and
concentrated under reduced pressure at rt. The residue was triturated with Et20 to obtain
3 g of Compound 28a as a yellow powder: HPLC: 4.35 min; MS (ES) m/z 476 (MH+).
A solution of Compound 28a (1.0 g, 2.0 mmol), methyl-triphenylphosphoranylidene
acetate (1.5 g ,4.5 mmol), and THF (25 mL) was refluxed for 7 h, then concentrated under
reduced pressure at rt. The residue was purified by flash column chromatography (silica,
5% MeOH/ CH2CI2) to obtain 1.4 g of Compound 28b: HPLC: 4.33 min; MS (ES) m/z 531
(MH+).
To a solution of Compound 28b (1.0 g, 1.89 mmol) in 3:1 dioxane-H20 (20 mL) was
added LiOH (0.18 g, 7.50 mmol) and the mixture was stirred for 3 h. The layers were
separated, and the aqueous layer was acidified with 3N HCI and extracted repeatedly with
EtOAc. The combined organic extracts were dried (Na2S04), and filtered. The filtrate was
concentrated under reduced pressure at rt to afford 0.52 g of Compound 28c as a white
foam: HPLC: 3.89 min, 70%; MS (ES) m/z 518 (MH+).
A solution of Compound 28c (0.40 g), benzylamine (0.10 g, 0.93 mmol) and HOBt
(0.104 g, 0.77 mmol) in DMF (5 mL) was treated DCC (0.16 g, 0.77 mmol) in DMF (1 ml_>.
The mixture was stirred for 24 h, then filtered (Celite) and concentrated under reduced
pressure at rt. The residue was taken up in CH2CI2 and washed sequentially with saturated
NaHC03 (aq), H20,1 N KHS04 (aq) and H20, then dried (Na2S04) and filtered. The
residue was purified by flash column chromatography (silica, 5% MeOH/ CH2CI2) to yield
0.22 g of Compound 28d: MS (ES) m/z 607 (MH+).
Compound 28d was deethylated by Procedure A to afford Compound 109: HPLC:
3.64 min; MS (ES) m/z (MH+) = 551.
EXAMPLE 29
t(3-Cyclohexylaminomethyl-naphthalen-2-ylcarbamoyl)-
naphthalen-1-yl-methyl]-phosphonic acid, Cpd 70
To a stirred solution of Compound 28a (0.125 g, 0.263 mmol) and cyclohexyl amine
(0.031 g, 0.316 mmol) in DCE (4 mL) was added NaB(OAc)3H (0.111 g, 0.526 mmol) and
glacial acetic acid (0.017 g, 0.316 mmol) and the mixture was stirred for 48 h. The reaction
was treated with 3N NaOH, and the layers were separated. The aqueous layer was extracted
with CH2CI2 (3x) and the combined organic extracts'were washed with water, dried (Na2S04),
filtered (Celite), and concentrated under reduced pressure at rt. The residue was treated with
1N HCI (aq), and the solid was collected, rinsed with water, and air-dried. The product was
dissolved in CH3CN, precipitated with Et20, and the solid was collected and rinsed with Et20
to yield 0.084 g of Compound 29a: HPLC: 3.27 min; MS (ES) m/z 559 (MH+).
From Compound 29a (0.079 g) was prepared Compound 70 by deethylation
Procedure A. The crude product was dissolved in 1:1 CH2CI2 /TFA and concentrated. The
residue was stirred with Et20, and the solid was collected and rinsed with Et20 to yield
Compound 70 (0.046 g): HPLC: 2.91 min; MS (ES) m/z 503 (MH+).
Other compounds of the present invention may be prepared by those skilled in the
art by varying the starting materials, reagent(s) and conditions used. Using the procedure
of Example 29, the following compounds were prepared without further purification:

EXAMPLE 30
{[3-({Methyl-[1-(naphthalene-2-carbonyl)-piperidin-4-yl]-amino}-methyl)-naphthalen-2-
ylcarbamoyl]-naphthalen-1-yl-methyl}-phosphonicacid, Cpd 102
Using the procedure of Example 29, substituting (4-methylamino-piperidin-1-yl)-
naphthalen-2-yl-methanone for cyclohexylamine, Compound 102 was prepared: HPLC: 3.12
min; MS (ES) m/z 672 (MH+).
EXAMPLE 31
({3-[(1-Benzoyl-piperidin-4-ylamino)-methyl]-naphthalen-2-ylcarbamoyl}-naphthalen-1-yl-
methyO-phosphonic acid, Cpd 44
Using the procedure of Example 29, substituting (4-amino-piperidin-1-yI)-phenyl-
methanone for cyclohexylamine, Compound 44 was prepared: HPLC: 2.84 min; MS (ES) m/z
608 (MH+).
EXAMPLE 32
({3-[4-(6-Chloro-2-oxo-2,3-dihydro-benzoimidazoM-yl)-piperidine-1-carbonyl]-
naphthaien-2-ylcarbamoyl}-naphthalen-1 -yl-methyl)-phosphonic acid, Cpd 60
Using the procedure of Example 17, Compound 17k was converted to Compound
32a.
To a suspension of Compound 32a (9.02 g, 17.9 mmol) in 1,4-dioxane (200 mL)
was added a mixture of LiOH-H20 (2.25 g, 53.6 mmol) in water (25 mL). The mixture was
stirred for 4.5 h, then concentrated under reduced pressure at rt. The residue was
partitioned between 1N HCI and EtOAc, and the aqueous portion was extracted with EtOAc
(5x). The combined organic extracts were washed'with brine, dried (Na2S04), filtered and
concentrated under reduced pressure at rt. The solid was suspended in MeOH, collected,
washed with MeOH, and dried under N2/vacuum to yield 6.87 g of Compound 32b as a
white powder: HPLC: 3.99 min.
A mixture of Compound 32b (2.85 g, 9.79 mmol) and excess thionyl chloride was
stirred until the solution became clear. The solution was concentrated under reduced
pressure at rt, and the residue was taken up in hexanes and concentrated under reduced
pressure at rt. The residue was stirred with CH3CN, and the solid was collected and dried
under N2/vacuum to yield 2.45 g of Compound 32c: HPLC: 4.10 min, 87%.
A mixture of Compound 32c (0.31 g, 0.66 mmol) Compound 32d (0.33 g, 1.311
mmol; J.Med.Chem. 1987, 30(5), 814-819) in CH3CN (15 mL) was refluxed for 1 h. The
mixture was cooled to rt, filtered, and concentrated under reduced pressure at rt. The
residue was purified by flash column chromatography (silica, 0-3% MeOH/CH2CI2) to
yield 0.38 g of Compound 32e: HPLC: 3.98 min.
Compound 32e (0.18 g, 0.25 mmol) was deethylated by Procedure A to yield
Compound 60 (0.14 g): HPLC: 3.65 min; MS (ES) m/z 669 (MH+).
326 k^ V '
Other compounds of the present invention may be prepared by those skilled in the
art by varying the starting materials, reagent(s) and conditions used. Using the procedure
of Example 32, the following compounds were prepared without further purification:
. EXAMPLE 33
({3-[Methyl-(4-phenyl-cyclohex-3-enyl)-carbamoyl]-naphthalen-2-ylcarbamoyl}-naphthalen-1-
yl-methyl)-phosphonic acid, Cpd 46
To a stirred solution of Compound 33a (0.68 g, 3.96 mmol; Syn.Comm. 1994,24(6),
799-808) and a 2 mL of a 2M solution of methyl amine in THF (6 mL) was added sodium
triacetoxyborohydride (1.30 g, 5.94 mmol) followed by glacial acetic acid (0.24 g, 3.96 mmol).
After stirring for 2.5 h, the mixture was treated with water and extracted with CH2Cl2 (3x). The
combined organic extracts were dried (Na2S04), filtered (Celite) and concentrated under
reduced pressure at rt. The residue was purified by flash column chromatography (silica, 0 -
10% MeOH/ CH2CI2) to yield 0.25 g of Compound 33b as a light brown tacky solid: HPLC:
1.91 min; MS (ES) m/z 188 (MH+).
Using the procedure described in Example 32, Compound 33b was converted to
Compound 46: HPLC: 3.97 min; MS.(ES) m/z 605 (MH+).
EXAMPLE 34
[(3-Benzylcarbamoyl-naphthalen-2-ylcarbamoyl)-naphthalen-
1-yl-methyrj-phosphonic acid, Cpd 119
Compound 119 was prepared from Compound 32b via a standard BOP-CI/TEA
coupling and deethylation by Procedure A: HPLC: 3.81 min, 90%; MS (ES) m/z 525 (MH+).
EXAMPLE 35
[(5-Bromo-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-
methyrj-phosphonic acid, Cpd 23
Compound 35a (6-bromobenzothiophene) was prepared by the method described in
J.Med.Chem 1998, 41,4486-4491. Compound 35a (3.45 g, 16.2 mmol) was converted to
3.68 g of crude Compound 35b by the method described in the reference cited supra: HPLC:
4.14 min, 53%.
Following the procedure of Example 1 for the conversion of Compound 1c to
Compound 9, Compound 35b was converted to Compound 23: HPLC: 4.53 min; MS (ES)
m/z 475 (MK).
Other compounds of the present invention may be prepared by those skilled in the
art by varying the starting materials, reagent(s) and conditions used. Using the procedure
of Example 35, the following compounds were prepared without further purification:
EXAMPLE 36 ;
[(5-phenyl-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-
methyl]-phosphonic acid, Cpd 71
To a heat-gun dried flask under Ar was sequentially added toluene (15 mL),
Compound 35a (0.33 g, 0.91 mmol) and then tetrakis triphenylphosphine Pd(0) (0.053 g,
0.046 mmol). After stirring for 30 min, the mixture was treated with a solution of phenyl
boronic acid, Compound 36a (0.17 g, 1.36 mmol) in EtOH (5 mL) followed by saturated
NaHC03 (aq) (7.5 mL). After 4 h at reflux, the mixture was cooled to rt and treated with brine
(15 mL). The layers were separated, and the aqueous portion was extracted with EtOAc (3x)
and the combined organic extracts were washed sequentially with 0.1 N NaOH (aq) (3x),
brine, dried (Na2S04), filtered and concentrated under reduced pressure at rt. The residue
was purified by flash column chromatography (silica, 0 -3% MeOH/CH2CI2) to yield 0.27 g of
Compound 36b: HPLC: 3.91 min, 95%; MS (ES) m/z 361 (MH+).
Following the procedure of Example 35 for the conversion of Compound 35a to
Compound 35b, Compound 36b was converted to Compound 36c.
Following the procedure of Example 1 with Procedure A for the conversion of
Compound 1c to Compound 9, Compound 36c was converted to Compound 71: HPLC: 4.84
min; MS (ES) m/z 572 (MH").
Cpd 71
Other compounds of the present invention may be prepared by those skilled in the
art by varying the starting materials, reagent(s) and conditions used. Using the procedure
of Example 36, the following compounds were prepared without further purification:
EXAMPLE 37
[(Naphthalen-2-ylcarbamoyl)-(1-phenyl-1H-indol-3-yl)-methyl]-phosphonic acid, Cpd 82
A/-phenyl indole Compound 37a was prepared by the procedure described in JOC
2001, 66(23), 7729-7737.
Using the procedure described in Example 18, substituting Compound 37a for
Compound 18b, Compound 82 was prepared: HPLC: 4.04 min; MS (ES) m/z 457 (MH+).
EXAMPLE 38
[(3-Benzyloxy-naphthalen-2-ylcarbamoyl)-naphthalen-
1-yl-methyl]-phosphonic acid, Cpd 122
Using the procedure described in Example 17, substituting Compound 38a (0.30 g,
1.89 mmol) for Compound 17i, Compound 38b (0:38 g) was prepared: HPLC: 3.85 min,
95%; MS (ES) m/z 464 (MH+).
Using the method described in J>ACS1998, 110(14), 4789, Compound 38b (0.22 g,
0.48 mmol) was converted to Compound 38c (0.16 g): HPLC: 4.43 min, 98%.
Compound 38c (0.14 g, 0.25 mmol) was deethylated by Procedure A to give
Compound 122 (0.114 g):, HPLC: 4.08 min; MS (ES) m/z 498 (MH+).
Other compounds of the present invention may be prepared by those skilled in the
art by varying the starting materials, reagent(s) and conditions used. Using ttie procedure
of Example 38, the following compounds were prepared without further purification:
EXAMPLE 39
[Naphthalen-1-yl-(3-phenylcarbamoyloxy-naphthalen-2-yl-carbamoyl)-methyl]-
phosphonic acid, Cpd 95
Using the procedure described in Example 27, substituting Compound 38b (0.19 g,
0.41 mmol) for Compound 27a and phenylisocyanate for benzylisocyanate, Compound 39a
(0.18 g) was prepared: HPLC: 4.30 min, 95%; MS (ES) m/z 583 (MH+).
Compound 39a (0.18 g, 0.31 mmol) was deethylated by Procedure A to give
Compound 95 (0.12 g): HPLC: 4.16 min; MS (ES) m/z 527 (MH+).
EXAMPLE 40
[(3-{[1-(Naphthalene-2-carbonyl)-piperidine-4-carbonyl]-amino}-naphthalen-2-ylcarbamoyl)-
naphthalen-1-yl-methyl]-phosphonic acid, Cpd 141
Compound 40a was synthesized by the method described in lMCS1993, 115(4),
1321-1329.
Using the procedure described in Example 17, substituting Compound 40a (0.80 g,
3.11 mmol) for Compound 17c, Compound 40b (0.53 g) was prepared: HPLC: 4.20 min.
Compound 40b (0.28 g, 0.50 mmol) was dissolved in TFA (1 mL) and allowed to
stand for 30 min. The solution was concentrated under reduced pressure at rt to yield 0.47
g of Compound 40c as a 4.2 TFA solvate: HPLC: 3.40 min; MS (ES) m/z 463 (MH+).
To a solution of Compound 40c (0.47 g), diisopropylamine (0.37 mL, 2.1 mmol),
HOBt (0.068 g, 0.50 mmol), and Boc-isonipecotic acid (0.115 g, 0.50 mmol) in CH2CI2 (5
mL) was added DCC (0.103 g, 0.50 mmol). After stirring for 72 h, the mixture was diluted
with CH2CI2 and filtered. The filtrate was washed sequentially with 1N KHS04, saturated
NaHC03 (aq), and brine, then dried (Na2S04), filtered and concentrated under reduced
pressure at rt. The residue was crystallized from CH3CN to yield 0.14 g of Compound 40d
as a white solid: HPLC: 4.08 min; MS (ES) m/z 674 (MH+).
Compound 40d (0.14 g, 0.21 mmol) was stirred with TFA (1 mL) for 45 min, then
concentrated. The residue was dissolved in CH2CI2 (5 mL) containing DIPEA (0.21 mL, 1.2
mmol). To the mixture was added 2-naphthoyl chloride (0.04 g, 0.21 mmol) and the
reaction stirred for 20 min. The mixture was washed sequentially with 1N KHS04 (aq),
saturated NaHC03 (aq), and brine, then dried (Na2S04), filtered and concentrated under
reduced pressure at rt to yield 0.15 g of Compound 40e as a white solid: HPLC: 4.01 min.
Compound 40e was deethylated by Procedure A to yield Compound 141: HPLC:
3.75 min; MS (ES) m/z 672 (MH+).
Other compounds of the present invention may be prepared by those skilled in the
art by varying the starting materials, reagent(s) and conditions used. Using the procedure
of Example 40, the following compounds were prepared without further purification:
EXAMPLE 41
[2-(2-Naphthalen-1-yl-2-phosphono-acetylamino)-naphthalen-
1-yloxy]-acetic acid methyl ester, Cpd 134
Using the procedure described in Example 38 for the conversion of Compound 38a to
38c, substituting methyl bromoacetate for benzyl bromide, Compound 41a was reacted to
give Compound 41 b.
Compound 41b was deethylated by Procedure A to yield Compound 134: HPLC:
4.23 min; MS (ES) m/z 498 (MH+).
EXAMPLE 42
(Naphthalen-1 -yl-{1 -[2-oxo-2-(4-phenyl-piperidin-1 -yl)-ethoxy]-naphthalen-2-ylcarbamoyl}-
methyl)-phosphonic acid, Cpd 114
Using the procedure of Example 32 for the saponification of Compound 32a to 32b,
Compound 41b (1.01 g, 1.89 mmol) was converted to Compound 42a (1.12 g): HPLC: 3.78
min; MS (ES) m/z 522 (MH+).
Using the procedure described in Example 24, substituting Compound 42a (0.25 g,
0.48 mmol) for Compound 24e, Compound 42b (0.27 g) was prepared: HPLC: 4.54 min,
97%; MS (ES) m/z 665 (MH+).
Compound 42b (0.15 g, 0.23 mmol) was deethylated by Procedure A to give of
Compound 114 (0.096 g): HPLC: 4.19 min; MS (ES) m/z 609 (MH+).
Other compounds of the present invention may be prepared by those skilled in the
art by varying the starting materials, reagent(s) and conditions used. Using the procedure
of Example 40, the following compounds were prepared without further purification:
EXAMPLE 43
([(5-Chloro-benzo[jb]thiophen-3-yl)-[2-(4-hydroxyl-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphonic acid, Cpd 66
Compound 43a (0.100 g, 0.192 mmol), prepared as in Example 11, was
deethylated by Procedure A and the crude product was dissolved in 5 ml_ of methanol and
treated with 0.210 g of KOH. The mixture was stirred for 7.5 h, then acidified with 1N HCI
(aq), concentrated under reduced pressure at rt and rJurified by reverse phase HPLC (12-
90% MeCN/HaO) to yield 0.014 g of Compound 66 as a grey powder: HPLC: 3.04 min;
77%; MS (ES) m/z 422 (MH").
EXAMPLE 44
{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(2-hydroxy-phenyl)- .
vinylcarbamoyl]-methyl}-methyl-phosphinic acid, Cpd 149
A solution of Compound 44a (0.29 g, 0.63 mmol; prepared according to Example 6)
in 15 mL of methanol containing 5 mL of 1N NaOH (aq) was stirred for 25 min. The
solution was concentrated under reduced pressure, and the residue was suspended in 1N
HCI (aq) and stirred for 1 h. The solid was collected, rinsed sequentially with 1N HCI and
water, then dried under a stream of N2 to yield 0.23 g of Compound 149 as a pale yellow
powder: HPLC: 3.71 min; MS (ES) m/z 422 (MH+).
EXAMPLE 45
[[2-(2-Amino-phenyl)-vinylcarbamoyl]-(5-chloro-benzo[b]thiophen-
3-yl)-methyl]-methyl-phosphinic acid, Cpd 151
Compound 45a (prepared according to Example 6) was converted to compound
45b by the method of Example 10. Compound 45b was deethylated according to
Procedure A and purified by trituration with 1N HCI (aq) to yield Compound 151: HPLC:
2.78 min; MS (ES) m/z 421 (MH+).

Other compounds of the present invention may be prepared by those skilled in the
art by varying the starting materials, reagent(s) and conditions used. Using the procedure
of Example 45, the following compounds were prepared without further purification:
EXAMPLE 46
{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(2-ureido-phenyl)-
vinylcarbamoyl]-methyl}-methyl-phosphinicacid, Cpd 158
To a suspension of Compound 45b (0.14 g, 0.31 mmol), acetic acid (0.4 mL) and
water (1.6 mL) was added a five-fold excess of sodium cyanate. The reaction was stirred
at 60°C for 1 h, and the crude product was collected, washed with water, dried under a stream
of N2 and deethylated by Procedure A. The product was subjected to reverse phase HPLC
(25-90% MeCN/H20) to yield 0.026 g of Compound 158 as a white powder: HPLC: 3.22 min;
MS (ES) m/z 464 (MH+), and 0.037 g of Compound 159 as a white powder: HPLC: 3.46
min; MS (ES) m/z 507 (MH+).
EXAMPLE 47
(Naphthalen-l-yl-styrylcarbamoyl-methyl)-phosphonic acid didiethylcarbamoylmethyl ester,
Cpd 180
To a solution of Compound 37 (0.21 g, 0.53 mmol) and W,A/-diethyl-2-
hydroxyacetamide (0.15 g, 1.17 mmol) in pyridine (5 mL) was added 1-(mesitylene-2-
sulfonyl)-3-nitro-1,2,4-triazole (MSNT; 0.47 g, 1.59 mmol) and the mixture was stirred at rt
for 3.5 h. The reaction was concentrated under reduced pressure, and the residue taken
up in EtOAc. The solution was washed sequentially with 1N KHS04 (aq), saturated
NaHC03(aq), and brine, then dried (Na2S04), and concentrated under reduced pressure.
The crude product was purified by flash column chromatography (silica, 0 - 30%
acetone/heptane) to yield 0.07 g of Compound 180 as a yellow solid: HPLC: 3.88 min; MS
(ES) m/z 594 (MH+).

Other compounds of the present invention may be prepared by those skilled in the
art by varying the starting materials, reagent(s) and conditions used. Using the procedure
of Example 47, the following compounds were prepared:
EXAMPLE 48
2-Naphtha!en-i-yl-2-(2-oxo-2l5-[1,3,2]dioxaphosphinan-2-yl)-
N-styryl-acetamide, Cpd 178
Using the procedure described in Example 47, Compound 37 (0.10 g, 0.27 mmol),
1,3-propanediol (0.02 g, 0.27 mmol), and MSNT (0.48 g, 1.62 mmol) in pyridine (5 ml)
afforded 0.01 g of Compound 178, as a white powder: HPLC: 3.52 min; MS (ES) m/z 408
(MH+).
Other compounds of the present invention may be prepared by those skilled in the ¦
art by varying the starting materials, reagent(s) and conditions used. Using the procedure
of Example 48, the following compound was prepared:
EXAMPLE 49
{(5-Chloro-benEo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-methyl}-methyl-
phosphinic acid diethylcarbamoylmethyl ester, Cpd 185
Using the procedure described in Example 47, Compound 17 (0.25 g, 0.57 mmol),
A/,A/-diethyl-2-hydroxyacetamide (0.37 g, 2.86 mmol), and MSNT (0.25 g, 0.86 mmol) in
pyridine (5 ml) yielded 0.14 g of Compound 185, as a white powder (-3:1 mixture of
diastereomers). HPLC: 4.03 min (24%), 4.11 min (76%); MS (ES) m/z 555 (MH+).
Other compounds of the present invention may be prepared by those skilled in the
art by varying the starting materials, reagent(s) and conditions used. Using the procedure
of Example 49, the following compound was prepared:
EXAMPLE 50
{(5-Chloro-benzo[b]thiophen-3-yl)-t2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-methyl}-methyl-
phosphinic acid 2-amino-ethyl ester, Cpd 184
Using the procedure described in Example 47, Compound 17 (0.27 g, 0.61 mmol),
N-Boc-ethanolamine (0.11 g, 0.67 mmol), and MSNT (0.54 g, 1.83 mmol) in pyridine (5 mL)
yielded 0.27 g of Compound 50a, as a white powder: (-2:1 mixture of diastereomers).
HPLC: 4.17 min (22%), 4.20 min (46%); MS (ES)' m/z 585 (MH+).
A solution of Compound 50a (0.27 g, 0.46 mmol) in 3 mL of TFA was stirred for 30
min, then concentrated under reduced pressure. The residue was purified by reverse
phase HPLC (30-90% MeCN/H20) to afford 0.12 g of Compound 184 as a white powder
(TFA salt; -1:1 mixture of diastereomers by 1H NMR); HPLC: 3.17 min; MS (ES) m/z 485
(MH+).
EXAMPLE 51
2,2-Dimethyl-propionicacid{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-(2,2-dimethyl-propionyloxymethoxy)-phosphinoyloxymethyl ester,
Cpd 186
and
2,2-Dimethyl-propionicacid{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-
vinylcarbamoyl]-methyl}-hydroxy-phosphinoyloxymethyl ester, Cpd 187
A solution of Compound 2 (0.25 g, 0.56 mmol), triethylamine (0.31 mL, 2.24 mmol),
and chloromethylpivaloate (0.32 ml, 2.24 g) in DMF (2 ml) was heated at 60°C for 2.5 h.
The mixture was cooled to rt and concentrated under reduced pressure. The crude
product mixture was subjected to reverse phase HPLC (37.5 - 90% MeCN/H20) to yield
0.035 g of Compound 186 as a white powder; HPLC: 4.77 min; MS (ES) m/z 672 (MH+),
and 0.16 g of Compound 187 which was converted to its tromethamine salt by treatment of
a methanol solution of Compound 186 with 1 eq of tris-(hydroxymethyl) methylamine. The
mixture was concentrated under reduced pressure to afford the tromethamine salt of
Compound 187 as a white powder: HPLC: 5.13 min; MS (ES) m/z 558 (MH+).

Other compounds of the present invention may be prepared by those skilled in the
art by varying the starting materials, reagent(s) and conditions used. Using the procedure
of Example 51, the following compounds were prepared:

Using the procedure of Example 51, and substituting Compound 37 for Compound
2, the following compounds were prepared:

Using the procedure of Example 51, and substituting Compound 17 for Compound
2, the following compound was prepared:

The following compounds can be made by those skilled in the art by using Example
6 followed by Example 51, and varying the starting materials, reagent(s) and conditions
used: compounds 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223,
224, 225, 226, 227, 316, 317, 318, 319, 320, 321, 322, and 323.
The following compounds can be made by those skilled in the art by using Example
11 followed by Example 51, and varying the starting materials, re^gen^s) and conditions
used: compounds 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241,
242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259,
260, 261,, 262, 263, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295,
296, 297, 298, 299, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337,
338, 339, 348, 349, 350, 351, 352, 353, 354, and 355.
EXAMPLE 52
2-(5-Chloro-benzo[b]thiophen-3-yl)-N-[2-(3,4-difluoro-phenyl)-vinyl]-
2-(2-oxo-2^5-[1,3,2]dioxaphosphinan-2-yl)-acetamide, Cpd 189
A solution of Compound 1a (1.75 g, 6.69 mmol) and Compound 52a (prepared
according to JACS1969, 91(24), 6838-6841; 1.36 g, 10.04 mmol) in toluene (15 mL) was
refluxed for 24 h. After cooling to rt, the mixture was concentrated under reduced pressure
and the residue was purified by flash column chromatography (silica; 0-30% '
acetone/heptane) to afford 1.0 g of Compound 52b as a viscous oil: HPLC:' 3.03 min; MS
(ES) m/z 303 (MH+).
From Compound 52b (0.51 g, 1.69 mmol) was prepared 0.28 g of Compound 189
by the procedure of Example 1: HPLC: 3.96 min; MS (ES) m/z 484 (MH+).

The following compounds can be made by those skilled in the art by using Example
52 and varying the starting materials, reagent(s) and conditions used: compounds 264,
265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 340,
341, 342, 343, 344, 345, 346, and 347.
Biological Experimental Examples
The utility of the compounds of the present invention as a serine protease inhibitor
and, particularly^, as a 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
Enzyme-catalyzed hydrolysis rates were measured spectro-photometrically using
human skin chymase (Cortex Biochem), a chromogenic substrate (Suc-Ala-Ala-Pro-Phe-
pNa) (Bachem) in aqueous buffer (450 mM Tris, 1800 mM NaCI, pH 8.0), and a microplate
reader (Molecular Devices). IC50 experiments were conducted by fixing the enzyme and
substrate concentrations (10 nM enzyme, 0.7 mM substrate) 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 37QC for 30 minutes. Percent inhibition was calculated by comparing the initial
reaction slopes of the samples without inhibitor to those with inhibitor. ICS0 vafues were
determined using a four parameter fit logistics model. The term "NT' indicates a compounc
that was not tested.
Table VI summarizes the assay results for chymase inhibition for compounds of the
present invention:
Table VI
Example 2
Anti-Asthmatic Effects in a Sheep Model of Asthma
The efficacy of Compound 17 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 (BSL) dose response curves to aerosol carbachol were obtained from
historical control responses 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 or as a oral dose at a specified time before
antigen challenge. Post-drug measurements of SRL were obtained and the sheep were
then challenged with Ascaris suum antigen. Measurements of SRL were obtained
immediately after challenge, hourly from 1-6 h after challenge and on the half-hour from
61/2-8 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 17 was administered as an aerosol at 4.5 mg/dose (ca. 0.1 mg/Kg/dose,
based on a 45 Kg sheep), 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.
Compound 17 was administered as an oral solution at 15 mg/Kg/dose, twice-a-day
{BID) for three consecutive days, followed by a dose on day 4,2 h prior to antigen
challenge. Ascaris suum antigen challenge was given at the zero time point.
Figure 1 shows that after aerosol administration the early airway response (0-2 h
after antigen challenge) was unchanged and that the late airway response (6-8 h after
antigen challenge) was completely blocked (n = 2 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 by
compound following aerosol administration.
Figure 3 shows that after oral administration the early airway response (0-2 h after
antigen challenge) was unchanged and that the late airway response (6-8 h after antigen
challenge) was completely blocked (n = 2 sheep/group).
Figure 4 shows that the delayed airway hyperreactivity measured at 24 h post
antigen challenge as measured using carbachol challenge was also completely blocked by
compound,following oral administration.
Example 3
Pharmacokinetic Assay for Evaluation of Oral Absorppon Potential
Procedural Overview
Male Sprague Dawley rats, weighing 250-300 g, were fasted overnight then dosed
by oral gavage at a level of 15 mg/kg with a compound. Compounds were formulated in
20% hydroxy-beta-cyclo dextran.
Blood samples (0.5 mL) were collected into lithium heparinized tubes at 0.5,1.0 and
2.0 h post dose via orbital sinus puncture. Blood samples were centrifuged at 2000 rpm for
~3 min for cell removal, approximately 200 uL of plasma supernatant was then transferred
to a clean vial, frozen then placed on dry ice and delivered to SFBC Analytical Labs, Inc. for
analysis.
Plasma samples were prepared as follows. Two hundred microliters of acetonitrile
containing 1 (iM internal standard was added to 100 uL of plasma to precipitate proteins.
Samples were centrifuged at 5000 g for 5 min and supernatant removed for'analysis by
LC-MS. Two hundred microliters of water was added to adjust sample solvent strength
and prevent peak splitting. Calibration standards were prepared by adding appropriate
volumes of stock solution directly into plasma and treated identically to collected plasma
samples. Calibration standards were prepared in the range of 0.1 to 10 m-M for
quantitation. LC-MS analysis was performed using MRM (Multiple Reaction Monitoring)
detection of characteristic ions for each drug candidate and internal standard.
PKData(N = 2)
While the foregoing specification teaches the principles of the present invention, with
examples provided for the purpose of illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations and/or modifications as come
within the scope of the following claims and their equivalents.
1. A compound of Formula (I)

Formula (I)
wherein
R1 is selected from the group consisting of hydrogen and Cwalkyl;
is selected from the group consisting of aryl, heteroaryl, benzo fused heterocyclyl,
cyclopropyl when n is 0 and one of R" or R' is phenyl, and benzo fused cycloaikyl, and
ring A is optionally substituted with R" and RJ;
R" is one to two substituents independently selected from the group consisting of Cj^alkyl,
C2-6alkenyl, C2-6alkynyl, methoxy, C2-6alkoxy, C^alkylthio, -OCF3, -NH2, -NH(C].
e)alkyl, -N(Ci.6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, and
nitro; furthermore, R2 is optionally oxo when ring A is heteroaryl or benzo fused
heterocyclyl; and, wherein any aryl-containing substituent of R2 is optionally substituted
with a substituent independently selected from the group consisting of Chalky!,
C,.6alkoxy, C2.6 alkenyl, C,.6alkylthio, -NH2, -NH(C,.6)alkyl, -N(C,.6)dialkyl, aryl,
heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, and nitro;
and, wherein any of the foregoing Cj-eaJkyl or C2-6alkoxy containing substituents of R~
are optionally substituted with a substituent independently selected from the group
consisting of-NR1!R12, aryl, heteroaryl, one to three halogens and hydroxy; wherein RH
and R12are independently hydrogen; C,_6 alkyl optionally substituted with hydroxy, aryl,
-C(=0)CMalkoxy, or-NR15R16; or aryl;
R15 and R16 are substituents independently selected from the group consisting of
hydrogen, Ci_6 alkyl, and aryl, and said R15 and R16 are optionally taken together
with the atoms to which they are attached to form a ring of five to seven
members;
is one to three substituents independently selected from the group consisting of Q^alkyl,
C2.6alkenyl, C2-6alkynyl, C,.6alkoxy, C,.6alkylthio, -OCF3, -OCH2(C2_6)alkenyl, -NH2,
-NH(Ci.6)alkyl, -N(C,.6)dialkyl, -NHC(=0)Cy, -N(C,.6alkyl)C(=0)Cy, -
(NC(=0))2NH2, -C(=0)CMalkoxy> -C(=0)NR17R18, -C(=0)NHcycloalkyl, -
C(=0)N(C,.6alkyl)cycloalkyl, -C(=0)NHCy, -C(=0)N(C,.6alkyl)Cy, -C(==0)Cy, -
OC(=0)C,.6alkyl, -OC(=0)NR19R20, -C(=0)Oaryl, -C(=0)Oheteroaryl, -C02H,
ureido, halogen, hydroxy, nitro, cyano, aryl, heteroaryl, heteroaryloxy, and aryloxy;
wherein any of the foregoing Ci^alkyl or Cue alkoxy containing substituents of of R3 are
optionally substituted with one to three substituents independently selected from the
group consisting of -NR21R22, -NH(cycIoalkyl), -N(C,.6alkyl)(cycIoalkyl), -NHCy, -
N(C!.6alkyl)Cy, aryl, heteroaryl, hydroxy, halogen, -C(=0)NR23R24, -
OC(=0)NR25R26, -C(=0)CMalkoxy, and -C(=0)Cy;
wherein said R'7, R18, R19, R20, R21, R22, R23, R24, R25, R26 are substituents
independently selected from the group consisting of hydrogen, Ci_6 alky], and
aryl, wherein Ci-6 alkyl is optionally substituted with hydroxy, aryl, -C(=0)Ci.
4alkoxy, NH2, NH(Ci.6alkyl), or -N(C,.6)dialkyl; and R17 and R18, R19 and R20, R2'
and R22 R23 and R24 and R25 and R26 are optionally taken together with the atoms
to which they are attached to form a ring of five to seven members;
is a heterocyclyl optionally substituted with a substituent selected from the group consisting of
Ci.6alkyl, CI.6alkylC(=0)Ci.6alkyl, -C1.6alkylC(=0)C,.6alkoxy, C,.6alkylC(==0)aryl, -
C(=0)(Ci„6)alkyl, -C(=0)(C,.6)alkoxy, -C(=0)aryl, -S02aryl, aryl, heteroaryl, and
heterocyclyl; wherein the aryl portion of any aryl-containing substituent of Cy is
optionally substituted with one to three substituents independently selected from the
group consisting of Ci.6alkyl, C^alkoxy, Ci_6alkylthio, halogen, hydroxy, NH?,
NH(Ci_6alkyl), and -N(C!.6)dialkyl; and wherein heterocyclyl is optionally substituted
with aryl, one to three halogen atoms, or one to three oxo substituents; and heterocyclyl is
optionally spiro-fused to said Cy;
and wherein the C].6alkenyl and C^alkynyl substituents of R3 are optionally substituted
with aryl or -C(=0)NR27R28; wherein said R27 and R28 are independently hydrogen; Ci.6
alkyl optionally substituted with hydroxy, aryl, -C(=0)C1.4alkoxy, NH2, NH(Ct„6alkyI), or
-N(Ci.6)dialkyl; or aryl; and R27and R28 are optionally taken together with the atoms to
which they are attached to form a ring of five to seven members;
wherein the aryl, heteroaryl, and cycloalkyl substituents of R3 are optionally substituted
with one to three substituents independently selected from R14;
wherein R14 is independently hydrogen, Ci_6alkyl, Ci.6alkoxy, C2.6alkenyl,
Ci_6alkylthio, -NH2, -NH(C].6)alkyl, -N(Ci.6)dialkyl, aryl, heteroaryl, aryloxy,
heteroaryloxy, halogen, hydroxy, or nitro;
and any one of the foregoing Ci^alkyl- or C].6alkoxy-containing substituents of R14 is optionally
substituted on a terminal carbon atom with a substituent selected from -NR29R30, aryl, heteroaryl,
one to three halogen atoms, or hydroxy; wherein R29 and R30 are independently hydrogen; C^
alkyl optionally substituted with hydroxy, aryl, -C(=0)C,.4alkoxy, NH2, NH(Ci.6alkyl), or -N(C}.
6)dialkyl; or aryl; and R29and R30 are optionally taken together with the atoms to which they are
attached to form a ring of five to seven members;
n is 0 or 1;
W is O or S;
X is hydrogen or Ci.3alkyl;
Y is independently selected from the group consisting of S03H and P(=0)OR5R6;
R5 is selected from the group consisting of hydrogen; Ci^alkyl optionally substituted with NH2, -
NH(Ci_6)alkyl, -N(Ci.6)dialkyl, l,3-dioxolan-2-y], Ci.6alkylcarbonyloxy, C(.
6alkoxycarbonyloxy, C^alkylcarbonylthio, (Ci.6)alkylaminocarbonyl, di(Ci_
6)alkylaminocarbonyl, one to three halogens, or hydroxy; and aryl optionally substituted
with C,.6alkyl, C,_6alkoxy, C,.6alkylthio, C2.6 alkenyl, -NH2, -NH(C,.6)alkyl, -N(C,.
6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, or nitro;
alternatively, when R is Ci_galkoxy, R and R are taken together with the atoms to which
they are attached to form a 5-8 membered monocyclic ring;
provided that R5 is other than Ci^alkyl substituted with di(Ci_6)alkylamino-carbonyl
when ring system A is 3,4-difluoro-phenyl, n is 1, R6 is OH, and Z-R4 is 5-chloro-
benzothiophen-3-yl; and provided that R5 is other than Ci.6alkyl substituted with Ct.
6alkylcarbonylthio when ring system A is 3,4-difluoro-phenyl, n is 1, Rb is CH3, and Z-R4
is 5-chloro-benzothiophen-3-yl;
6 is selected from the group consisting of Ci_8alkyl, C^alkoxy, C2.8alkenyl, heteroaryl, aryl,
and hydroxy; wherein C^galkyl, C^alkoxy, and C2-galkenyl are optionally substituted
with a substituent selected from the group consisting of C^alkoxy, aryl, heterocyclyl,
heteroaryl, NH2, -NH(Ci^)alkyl, -N(Ci^)dialkyl, C^alkyl-carbonyloxy, Cj.
6alkylcarbonylthio, Ci.6alkoxycarbonyloxy, (Ci.6)alkylamino-carbonyl, di(C].
6)alkylaminocarbonyl, one to three halogen atoms, and hydroxy; and when R6 is Ci.
galkyl, said Ci.8alkyl is optionally substituted with one to four additional halogen atoms
such that one to three halogen atoms are optionally chlorine and one to seven of the
halogen atoms are optionally fluorine;
wherein the heteroaryl and aryl substituents of R6 are optionally substituted with a
substituent independently selected from the group consisting of Ci_6alkyl, C^alkoxy, C2-6
alkenyl, Chalkylthio, -NH2, -NH(C]^)alkyl, -N(Ci^)dialkyl, aryl, heteroaryl, aryloxy,
heteroaryloxy, halogen, hydroxy, and nitro;
is a seven to fifteen membered monocyclic or polycyclic ring system selected from the group
consisting aryl, heteroaryl, benzo fused heterocyclyl, or benzo fused cycloalkyl;
R4 is one to three substituents selected from the group consisting of: H, Chalky!, Q.
6alkenyl, C^alkoxy, Ci_6aIkylthio, aryl(C|.6)alkyl, aryl(C2-6)alkenyl, halogen,
-C(=0)Cy, -C(=0)NR3lR32, aryl, -C02H, oxo, and cyano; wherein C,.6alkyl, C,.
6alkenyl and Cj^alkoxy are optionally substituted with -NR33R34, aryl, heteroaryl,
cycloalkyl, one to three halogen atoms, or hydroxy; and aryl and heteroaryl are each
optionally substituted with a substituent independently selected from the group consisting
of C,.6alkyl, C,.6alkoxy, C2.6 alkenyl, C,.6alkyIthio, -NH2, -NH(C,.6)alkyl, -N(C,.
6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, one to three halogen atoms,
hydroxy, and nitro;
wherein said R31, R32, R33, and R34 are substituents independently selected from
the group consisting of hydrogen, Ci.6 alkyl, and aryl, wherein alkyl is optionally-
substituted with hydroxy, aryl, -C(=0)CMalkoxy, NH2, NH(Ci_6alkyl), or -N(C,.
6)dialkyl; and R31 with R32 _ and R33 with R34 are optionally taken together with
the atoms to which they are attached to form a ring of five to seven members;
and pharmaceutical ly acceptable salts thereof.
2. The compound of claim 1 wherein R1 is hydrogen.
3. The compound of claim 1 wherein is independently selected from the group
consisting of aryl, heteroaryl, and benzo fused heterocyclyl, optionally substituted with
R2andR3.
4. The compound of claim 1 wherein is a bicyclic ring system of the formula:

wherein the a1 portion of said a'a2 is optionally substituted with R2; and the a2 portion is
optionally substituted with R3.
5. The compound of claim 4 wherein a2 is aromatic.
6. The compound of claim 1 wherein is selected from group consisting of naphthyl,
benzothiazolyl, benzothiophenyl, quinolinyl, isoquinolinyl, dihydronaphthyl, indanyl,
tetralinyl, and benzodioxolyl when n is equal to zero; and A is selected from phenyl,
pyridin-2-yl, and pyridin-3-yl when n is equal to one.
7. The compound of claim 1 wherein is selected from naphthyl and benzothiazolyl
when n is equal to zero; and A is selected from phenyl, pyridin-2-yl, and pyridin-3-yl
when n is equal to one.
8. The compound of claim 1 wherein R2 is one to three substituents independently selected
from the group consisting of Chalky!, methoxy, C2.6alkoxy, -NH2, -NH(Ci_6alkyl), -
N(C!.6)dialkyl, aryl, heteroaryl, halogen, hydroxy, and nitro; wherein Ci^alkyl and
C2-6alkoxy are optionally substituted with a substituent selected from the group consisting
of-NRnR12, aryl, heteroaryl, one to three halogens, and hydroxy.
9. The compound of claim 1 wherein R2 is a substituent independently selected from the
group consisting of Ci^alkyl, methoxy, C2.4alkoxy, hydroxy, halogen, and -NH2.
10. The compound of claim 1 wherein R2 is Cj_4alkyl, halogen, or -NH2.
11. The compound of claim 1 wherein RJ is one to three substituents independently selected
from the group consisting of Ci.6alkyl, C2.6alkenyl, C^alkoxy, -OCH2(C2-6)alkenyl, NH2,
-NH(Ci.6alkyl), -N(C,.6)dialkyl, -NHC(=0)Cy, -N(C,.6alkyl)C(=0)Cy, -C(=0)C,.4alkoxy,
-C(=0)NR17R18, -C(=0)NHcycloalkyl, -C(=0)N(C1.6alkyl)cycloalkyl, -C(=0)NHCy, -
C(=0)N(C,.6alkyl)Cy, -C(=0)Cy, -OC(=0)NR19R20, halogen, hydroxy, nitro, cyano, aryl,
and aryloxy; wherein alkyl and alkoxy are optionally substituted with one to three
substituents independently selected from the group consisting of-NR21R22, -
NHcycloalkyl, -N(C|.6alkyl)cycloalkyl, -NHCy, -N(C!.6alkyl)Cy, aryl, heteroaryl,
halogen, ~C(=0)NR23R24, -OC(=0)NR25R26, -C(=0)(CM)alkoxy, and -C(=0)Cy;
wherein alkenyl is optionally substituted on a terminal carbon with aryl and -
C(=0)NR27R28; and, wherein aryl and cycloalkyl are optionally substituted with one to
three substituents independently selected from R14.
12. The compound of claim 1 wherein R3 is one to three substituents independently selected
from the group consisting of C,.6alkyl, C^alkoxy, -NRl9R20, -NHC(=0)Cy,
-C(=0)NR17R18, -C(=0)NHcycloalkyl, -C(=0)N(C,.6alkyl)cycloalkyl, halogen, and
aryl; wherein alkyl and alkoxy are optionally substituted on a terminal carbon atom with
one to three fluorine atoms, -NH2, -NHCy, or -NXQ^alkyOCy; and wherein aryl and
cycloalkyl are optionally substituted with a group independently selected from R14.
13. The compound of claim 1 wherein R3 is one to two substituents independently selected
from trifluoromethyl; C^alkoxy optionally substituted with one to three fluorine atoms; -
NH2; -NHC(=0)Cy; or halogen.
14. The compound of claim 1 wherein R is NHC(=0)Cy, and Cy is piperadinyl; wherein
said piperadinyl is substituted with a substituent selected from the group consisting of
CM alkyl, CMalkylC(=0)CMalkyl, -€MaIkylC(=0)CMalkoxy, C,.4alkylC(=0)aryl, -
C(=0)(Ci.4)alkyl, -C(=0)(CM)alkoxy, -C(=0)aryl, -S02aryl, aryl, heteroaryl, and
heterocyclyl; wherein aryl and the aryl portion of the Ci_4alkylC(=0)aryl, -C(=0)aryl and
-S02aryl is optionally substituted with one to three substituents independently selected
from the group consisting of Ci_4alkyl, CMalkoxy, halogen, hydroxy, NH2, NH(Ci.
6alkyl), or -N(Ci.4)dialkyl; and wherein heterocyclyl is optionally substituted with aryl,
one to three halogen atoms, or one oxo substituents.
15. The compound of claim 1 wherein R3 is trifluoromethyl, one to two fluorine atoms,
chloro, methoxy, trifluoromethoxy, or NH2; furthermore, when A is naphthyl and n is
equal to zero, R3 is (4-{[l-(naphthalen-2-yl-carbonyl)-piperadin-4-yl-carbonyl]-
amino}naphthalen-2-yl.
16. The compound of claim 1 wherein X is C|.3alkyl.
17. The compound of claim 1 wherein X is hydrogen.
18. The compound of claim 1 wherein Y is P(=0)OR5R6.
19. The compound of claim 1 wherein R5 is selected from the group consisting of hydrogen;
C^alkyl optionally substituted with NH2, -NH(C,.6)alkyl, -N(Ci.6)dialkyl, Cu
6alkylcarbonyloxy, C^alkoxycarbonyloxy, Ci^alkylcarbonylthio, (Q.
6)alkylaminocarbonyl, di(Ci.6)alkyIaminocarbonyl, one to three halogens, or hydroxy;
and aryl optionally substituted with C^alkyl, d^alkoxy, Ci_6alkylthio, C2.6 alkenyl, -
NH2, -NH(C].6)alkyl, -N(C].6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen,
hydroxy, or nitro; alternatively, when R6 is Ci.8alkoxy, R5 and R6 are taken together with
the atoms to which they are attached to form a 5-8 membered monocyclic ring;
and provided that R5 is other than C^alkyl substituted with di(Ci.6)alkylaminocarbonyl
when ring system A is 3,4-difiuoro-phenyl, n is 1, R6 is OH, and Z-R4 is 5-chloro-
benzothiophen-3-yl; and provided that R5 is other than Cualkyl substituted with C\.
6alkylcarbonylthio when ring system A is 3,4-difluoro-phenyl, n is l,R6isCH3, andZ-R4
is 5-chloro-benzothiophen-3-yl.
20. The compound of claim 1 wherein R5 is selected from the group consisting of hydrogen,
Ci.3alkyl optionally substituted with Ci.6alkylcarbonyloxy, Ci_6alkoxycarbonyloxy, C].
6alkylcarbonylthio, (Ci.6)alkylaminocarbonyl, di(Ci_6)alkylaminocarbonyl, one to three
halogens, or hydroxyl; and aryl; alternatively, when R6 is C^galkoxy, R5 and R6 are taken
together with the atoms to which they are attached to form a 6-7 membered monocyclic
ring;
and provided that when R5 is C].3alkyl substituted with either di(Ci_6)alkylaminocarbonyl
or Ci.6alkylcarbonylthio, ring system A is other than 3,4-difluoro-phenyl when n is 1 and
Z-R45-chloro-benzothiophen-3-yl.
21. The compound of claim 1 wherein R5 is hydrogen or C^alkyl optionally substituted with
Cj^alkylcarbonyloxy, Ci^alkoxycarbonyloxy, Ci^alkylcarbonylthio, (Cj.
8alkoxy, R5 and R6 are taken together with the atoms to which they are attached to form a
6-membered monocyclic ring;
and provided that R5 is other than d^alkyl substituted with di(Ci_6)alkylaminocarbonyl
when ring system A is 3,4-difluoro-phenyl, n is 1, R6 is OH, and Z-R4 is 5-chloro-
benzothiophen-3-yl; and provided that R5 is other than C].3alkyl substituted with Ci_
6alkylcarbonylthio when ring system A is 3,4-difluoro-phenyl, n is 1, R6 is CH3, and Z-R4
is 5-chloro-benzothiophen-3-yl.
22. The compound of claim 1 wherein R5 is selected from the group consisting of Ci^alkyl,
Ci_8alkoxy, C2.salkenyl, heteroaryl, aryl, and hydroxy; wherein alkyl, alkoxy, and alkenyl
are optionally substituted on a terminal carbon atom with a substituent independently
selected from the group consisting of Cj^alkoxy, aryl, heteroaryl, heterocyclyl, C).
6alkylcarbonyloxy, Ci^alkylcarbonylthio, Ci^alkoxycarbonyloxy, (Ci_
6)alkylaminocarbonyl, di(Ci.6)alkylaminocarbonyl, and hydroxy; and wherein heteroaryl
and aryl are optionally substituted with one to three substituents independently selected
from the group consisting of aryl, hydroxy, Ci.6alkoxy, and halogen.
23. The compound of claim 1 wherein R6 is selected from the group consisting of Ci^alkyl,
Ci_8alkoxy, heteroaryl, aryl, and hydroxy; wherein alkyl and alkoxy is are optionally
substituted on a terminal carbon atom with a substituent selected from Ci.3alkoxy, aryl, or
hydroxy; and alkoxy is optionally substituted on a terminal carbon with a substituent
independently selected from the group consisting of Ci_6alkylcarbonyloxy, and di(C[.
6)alkylaminocarbonyl; and wherein heteroaryl and aryl are optionally substituted with one
to three substituents independently selected from the group consisting of aryl, hydroxy,
C^alkoxy, and halogen.
24. The compound of claim 1 wherein R6 is selected from the group consisting of methyl,
ethyl, methoxypropyl, phenethyl, benzo[l,3]dioxol-5-yl-propyl, hydroxy, and C^alkoxy
optionally substituted with C].6alkylcarbonyloxy, and di(Ci.6)alkylaminocarbonyl.
25. The compound of claim 1 wherein Z is a bicyclic aryl or bicyclic heteroaryl.
26. The compound of claim 1 wherein Z is independently selected from the group consisting of
indolyl, benzothiophenyl, naphthalenyl, quinolinyl, isoquinolinyl and benzothiazolone.
27. The compound of claim 1 wherein Z is indolyl, benzothiophenyl, or naphthalenyl.
28. The compound of claim 1 wherein R4 is one to three substituents selected from the group
consisting of C^alkyl, C^alkenyl, C^alkoxy, aryl(C2.6)alkenyl, halogen, -C(=0)Cy, -
C(=0)NR31R 2, aryl, -C02H, oxo, and cyano; wherein the alkyl and alkoxy are optionally
substituted with a substituent independently selected from the group consisting of
-NR 3R 4, aryl, one to three halogen atoms, and hydroxy; wherein the aryl is optionally
substitututed with a substituent independently selected from the group consisting of
hydrogen, C|.6alkyl, C].6alkoxy, aryl, halogen, hydroxy, and nitro.
29. The compound of claim 1 wherein R4 is one to two substituents selected from the group
consisting of fluorine, chlorine, bromine, methyl, phenyl(C2-6)alkenyl, and -C(=0)(2-(4-
phenyl-piperidin-1 -carbonyl)).
30. A compound of Formula (la)
s independently selected from the group consisting of aryl, heteroaryl, and benzo fused
heterocyclyl, optionally substituted with R2 and R3;
R2 is one to three substituents independently selected from the group consisting of Ci„4alkyl,
methoxy, C2.6alkoxy, NH2, NH(C].6alkyl), -N(Ci_6)dialkyl, aryl, heteroaryl, halogen,
hydroxy, and nitro; wherein Chalky! and C2.6alkoxy are optionally substituted with a
substituent selected from the group consisting of-NRHR12, aryl, heteroaryl, one to three
halogens and hydroxy!;
wherein Ci^alkyl and C^alkoxy substituents of R2 are optionally substituted with a
substituent independently selected from the group consisting of-NRnR12, aryl,
heteroaryl, one to three halogens and hydroxy; wherein Ru and R12are substituents
independently selected from the group consisting of hydrogen, C]_6 alkyl, and aryl;
wherein Ci.6alkyl substituent of Rn or R12 is optionally substituted with substituent
selected from the group consisting of hydroxy, aryl, -C(=0)C].4alkoxy, and -NR15R16;
wherein said R15 and R16 are substituents independently selected from the group
consisting of hydrogen, Ci.6 alkyl, and aryl, and said R15 and R16 are optionally
taken together with the atoms to which they are attached to form a ring of five to
seven members;
R is one to three substituents independently selected from the group consisting of Ci^alkyl,
C2.6alkenyl, Ci.6alkoxy, -OCH2(C2_6)alkenyl, NH2, -NH(d.6alkyl), -N(Ci.6)dialkyl, -
NHC(=0)Cy, -N(C,.6alkyl)C(=0)Cy, -C(=0)CMalkoxy, -C(=0)NR17R1S,
-C(=0)NHcycloalkyI, -C(=0)N(C,.6alkyl)cycloalkyl, -C(=0)NHCy, -C(=0)N(C,.
6alkyl)Cy, -C(=0)Cy, -OC(=0)NRiyR , halogen, hydroxy, nitro, cyano, aiyl, and
aryloxy; wherein alkyl and alkoxy are optionally substituted with one to three
substituents independently selected from the group consisting of -NR21R22,
-NHcycloalkyl, -NCCLealkyOcycioalkyl, -NHCy, -N(d.6alkyl)Cy, aryl, heteroaryl,
halogen, -C(=0)NR23R24, -OC(=0)NR25R26, -C(=0)(CM)alkoxy, and -C(=0)Cy;
wherein alkenyl is optionally substituted on a terminal carbon with aryl and
-C(=0)NR27R28; and, wherein aryl and cycloalkyl are optionally substituted with one to
three substituents independently selected from R14.
Cy is a heterocyclyl optionally substituted with a substituent selected from the group
consisting of Ci.6 alkyl, Ci.6alkylC(=0)Ci_6alkyl,-Ci_6alkylC(=0)Ci.6alkoxy, Ci.
6alkylC(=0)aryI, -C(=0)(C1.6)alkyl, -C(=0)(Ci.6)alkoxy, -C(=0)aryl, -S02aryl, aryl,
heteroaryl, and heterocyclyl; wherein aryl and the aryl portion of the Ci^alkylC(=0)aryl,
-C(=0)aryl and -S02aryl are optionally substituted with one to three substituents
independently selected from the group consisting of Q^alkyl, Ci^alkoxy, halogen,
hydroxy, NH2, NH(Ci.6alkyl), or-N(Ci_6)dia!kyl; and wherein heterocyclyl is optionally
substituted with aryl, one to three halogen atoms, or one to three oxo substituents; and,
wherein heterocyclyl is optionally spiro-fused to said Cy;
R5 is selected from the group consisting of hydrogen; C^alkyl optionally substituted with NH2, -
NH(Ci.6)alkyl, -N(Ci_6)dialkyl, Ci_6alkylcarbonyloxy, Ci^alkoxycarbonyloxy, Ci_
6alkylcarbonylthio, (Cu)alkylaminocarbonyl, di(Ci.6)alkylaminocarbonyl, one to three
halogens, or hydroxy; and aryl optionally substituted with Ci_6alkyl, C^alkoxy,
Ci.6alkylthio, C2.6 alkenyl, -NH2, -NH(Ci.6)alkyl, -N(Ci_6)dialkyl, aryl, heteroaryl,
aryloxy, heteroaryloxy, halogen, hydroxy, or nitro; alternatively, when R6 is C].galkoxy,
R5 and R6 are taken together with the atoms to which they are attached to form a 5-8
membered monocyclic ring;
and provided that R5 is other than Ci.3alkyl substituted with di(Ci„6)alkylamino-carbonyl
when ring system A is 3,4-difluoro-phenyl, n is 1, R6 is OH, and Z-R4 is 5-chloro-
benzothiophen-3-yl; and provided that R5 is other than Cualkyl substituted with Ci_
6alkylcarbonylthio when ring system A is 3,4-difluoro-phenyl, nisl,R6isCH3,andZ-R4
is 5-chloro-benzothiophen-3-yl.
R6 is selected from the group consisting of Ci„6alkyl, Ci.8alkoxy, heteroaryl, aryl, and hydroxy;
wherein alkyl and Ci_galkoxy are optionally substituted on a terminal carbon atom with a
substituent selected from Cualkoxy, aryl, or hydroxy; and alkoxy is optionally
substituted on a terminal carbon with a substituent independently selected from the group
consisting of Ci.6alkylcarbonyloxy, and di(Ci.6)alkylaminocarbonyl; and wherein
heteroaryl and aryl are optionally substituted with one to three substituents independently
selected from the group consisting of aryl, hydroxy, Ci^alkoxy, and halogen.
Z is a bicyclic aryl or bicyclic heteroaryl;
R4 is one to three substituents selected from the group consisting of H, C^alkyl, Ci^alkenyl, Cj.
6alkoxy, aryl(C2.6)alkenyl, halogen, -C(=0)Cy, -C(=0)NR3lR32, aryl, -C02H, oxo, and
cyano; wherein the alkyl and alkoxy are optionally substituted with a substituent
independently selected from the group consisting of-NR33R34, aryl, one to three halogen
atoms, and hydroxy; wherein the aryl is optionally substituted with a substituent
independently selected from the group consisting of hydrogen, Cj^alkyl, Ci^alkoxy, aryl,
halogen, hydroxy, and nitro;
wherein said R31, R32, R33, and R34 are substituents independently selected from
the group consisting of hydrogen, Q.6 alkyl, and aryl, wherein alkyl is optionally
substituted with hydroxy, aryl, -C(=0)CMalkoxy, NH2, NH(C,.6alkyl), or -N(C,_
6)dialkyl; and R31 with R32, and R33 with R34 are optionally taken together with
the atoms to which they are attached to form a ring of five to seven members;
and pharmaceutical ly acceptable salts thereof.
31. The compound of claim 30 wherein is selected from group consisting of naphthyl,
benzothiazolyl, benzothiophenyl, quinolinyl, isoquinolinyl, dihydronaphthyl, indanyl,
tetralinyl and benzodioxolyl when n is equal to zero; and A is selected from phenyl,
pyridin-2-yl, or pyridin-3-yl when n is equal to one.
32. The compound of claim 31 wherein is selected from phenyl, pyridin-2-yl, or
pyridin-3-yl when n is equal to one.
33. The compound of claim 32 wherein R2 is a substituent independently selected from the
group consisting of Ci.4alkyl, methoxy, C2-4alkoxy, hydroxy, halogen, and -NH2.
34. The compound of claim 33 wherein R3 is one to three substituents independently selected
from the group consisting of C,.6alkyl, C,.6alkoxy, -NR19R20, -NHC(=0)Cy,
-C(=0)NR17R18, -C(=0)NHcycloalkyl, -C(=0)N(C,.6alkyl)cycloalkyl, halogen, and aryl;
wherein alkyl and alkoxy are optionally substituted on a terminal carbon atom with one to
three fluorine atoms, -NH2, -NHCy, or-N(Ci„4alkyl)Cy; and wherein aryl and cycloalkyl
are optionally substituted with a group independently selected from R14.
35. The compound of claim 34 wherein R is hydrogen or C^alkyl optionally substituted
with C).6alkylcarbonyloxy, Ci^alkoxycarbonyloxy, C|.6alkylcarbonylthio, (C\.
6)alkylaminocarbonyl, or di(C].6)alkylaminocarbonyl; and alternatively, when R6 is Ci.
galkoxy, R5 and R6 are taken together with the atoms to which they are attached to form a
6-membered monocyclic ring;
and provided that R5 is other than Ci_3alkyl substituted with di(Ct_6)alkylamino-carbonyl
when ring system A is 3,4-difluoro-phenyl, n is 1, R6 is OH, and Z-R4 is 5-chloro-
benzothiophen-3-yl; and provided that R5 is other than C^alkyl substituted with Q.
6alkylcarbonylthio when ring system A is 3,4-difluoro-phenyl, n is l,R6isCH3,andZ-R4
is 5-chloro-benzothiophen-3-yl.
36. The compound of claim 35 wherein R6 is selected from the group consisting of methyl,
ethyl, methoxypropyl, phenethyl, benzo[l,3]dioxol-5-yl-propyl, hydroxy, and Ci.3alkoxy
optionally substituted with Ci_6alkylcarbonyloxy, and di(C].6)alkylamino-carbonyl.
37. The compound of claim 36 wherein Z is independently selected from the group
consisting of indolyl, benzothiophenyl, naphthalenyl, quinolinyl, isoquinolinyl and
benzothiazolonyl.
38. The compound of claim 37 wherein R4 is one to three substituents selected from the
group consisting of Ci„6alkyl, Ci_6alkenyl, aryl(C2_6)alkenyl, halogen, and -C(=0)Cy;
wherein aryl is optionally substituted with a substituent selected from halogen or Ci_
4alkoxy.
(
39. The compound of claim 30 wherein is a ring system of the formula:

wherein the a' portion of said a'a2 is optionally substituted with R2; and the a2 portion is
optionally substituted with R3 and n is 0.
40. The compound of claim 39 wherein a2 portion is aromatic and

is selected from group consisting of naphthyl, benzothiazolyl, benzothiophenyl,
quinolinyl, isoquinolinyl, dihydronaphthyl, indanyl, tetralinyl and benzodioxolyi.
41. The compound of claim 40 wherein R2 is a substituent independently selected from the
group consisting of Ci^alkyl, methoxy, C2.4alkoxy, hydroxy, halogen, and -NH2.
42. The compound of claim 41 wherein R3 is one to three substituents independently selected
from the group consisting of C,.6alkyl, C,.6alkoxy, -NR19R20, -NHC(=0)Cy,
-C(=0)NR,7R18, -C(=0)NHcycloalkyl, -C(=0)N(C,.6alkyl)cycloalkyl, halogen, and aryl;
wherein alkyl and alkoxy are optionally substituted on a terminal carbon atom with one to
three fluorine atoms, -NH2, -NHCy, or -N(Ci4alkyl)Cy; and wherein aryl and cycloalkyl
are optionally substituted with a group independently selected from R14.
43. The compound of claim 42 wherein R5 is hydrogen or C^alkyl optionally substituted
with Chalkylcarbonyloxy, Ci^alkoxycarbonyloxy, Ci^alkylcarbonylthio, (Cj.
6)alkylaminocarbonyl, or di(Ci_6)alkylaminocarbonyl; and alternatively, when R6 is Ci.
galkoxy, R5 and R6 are taken together with the atoms to which they are attached to form a
6-membered monocyclic ring;
provided that R3 is other than Chalky! substituted with di(Ci_6)alkyIaminocarbonyl when
ring system A is 3,4-difluoro-phenyl, n is 1, R5 is OH, and Z-R4 is 5-chloro-
benzothiophen-3-yl; and provided that R5 is other than Ci.3alkyl substituted with Ci.
6alkylcarbonylthio when ring system A is 3,4-difluoro-phenyl, n is 1, R6 is CH3, and Z-R'
is 5-chloro-benzothiophen-3-yl.
44. The compound of claim 43 wherein R6 is selected from the group consisting of methyl,
ethyl, methoxypropyl, phenethyl, benzo[l,3]dioxol-5-yl-propyI, hydroxy, and C^alkoxy
optionally substituted with C^alkylcarbonyloxy, and di(Ci_6)alkylamino-carbonyl.
45. The compound of claim 44 wherein Z is independently selected from the group
consisting of indolyl, benzothiophenyl, naphthalenyl, quinolinyl, isoquinolinyl, and
benzothiazolone.
46. The compound of claim 45 wherein R4 is one to three substituents selected from the
group consisting of Chalky!, Ci^alkenyl, aryl(C2-6)alkenyl, halogen, and -C(=0)Cy;
wherein aryl is optionally substituted with a substituent selected from halogen or Ci_
4alkoxy.
47. The compound of claim 30 wherein R1, ring A, R2, R3, R5, R6, Z, and R4 are dependently
selected from the group consisting of
48. The compounds of claim 30 wherein the compounds have a formula selected from the
group consisting of:
50. A compound of Formula la selected from the group consisting of:
51. A compound of claim 50 that is

52. A compound of claim 50 that is:

53. A compound of claim 1 of Formula II

wherein Y is -S03H.
54. A compound of claim 50 that is:


The present invention is directed to a compound of formula
(I).

methods for preparing these compounds, compositions,
intermediates and derivatives thereof, and methods for
treating inflammatory and serine protease mediated
disorders.

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Patent Number 259293
Indian Patent Application Number 2383/KOLNP/2006
PG Journal Number 11/2014
Publication Date 14-Mar-2014
Grant Date 06-Mar-2014
Date of Filing 23-Aug-2006
Name of Patentee JANSSEN PHARMACEUTICA N.V.
Applicant Address TURNHOUTSEWEG 30, B-2340, BEERSE
Inventors:
# Inventor's Name Inventor's Address
1 MICHAEL J. HAWKINS 318 HECKLER STREET, AMBLER, PA 19002
2 EUGENE POWELL 4801 WOODSPRING DRIVE, PIPERSVILLE, PA 18947
3 LAWRENCE DE GARAVILLA 909 NOBLE DRIVE, DOWNINGTOWN, PA 19335
4 BRUCE E, MARYANOFF 4029 DEVONSHIRE DRIVE, FOREST GROVE, PA 18922
5 MICHAEL N, GRECO 1634 CLEARBROOK ROAD, LANSDALE, PA 19446
PCT International Classification Number C07D 333/00
PCT International Application Number PCT/US2005/001659
PCT International Filing date 2005-01-18
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/538,663 2004-01-23 U.S.A.