Note: Descriptions are shown in the official language in which they were submitted.
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ALPHA SUBSTITUTED CARBOXYLIC ACIDS AS PPAR MODULATORS
Background of The Invention
This invention relates to alpha substituted carboxylic acids that modulate
the activities of peroxisome proliferator-activated receptor (PPAR),
preferably two
or more of PPAR-a, PPAR-8, or PPAR-y, enabling them to be useful in modulation
of blood glucose and the increase of insulin sensitivity in mammals. This
invention
also relates to treatment of PPAR related disorders, such as diabetes,
dyslipidemia, obesity and inflammatory disorders.
Peroxisome proliferators are a structurally diverse group of compounds
which, when administered to rodents, elicit dramatic increases in the size and
number of hepatic and renal peroxisomes, as well as concomitant increases in
the
capacity of peroxisomes to metabolize fatty acids via increased expression of
the
enzymes required for the (3-oxidation cycle. Chemicals included in this group
are
the fibrate class of hypolipidermic drugs, herbicides, and phthalate
plasticizers
(Reddy and Lalwani, Crit. Rev. Toxicol., 12:1-58 (1983)). Peroxisome
proliferation
can also be elicited by dietary or physiological factors such as a high-fat
diet and
cold acclimatization
Insight into the mechanism whereby peroxisome proliferators exert their
pleiotropic effects was provided by the identification of a member of the
nuclear
hormone receptor superfamily activated by these chemicals (Isseman and Green,
Nature, 347-645-650 (1990)). This receptor, termed PPAR-a, was subsequently
shown to be activated by a variety' of medium and long-chain fatty acids and
to
stimulate expression of the genes encoding rat acyl-CoA oxidase and hydratase-
dehydrogenase (enzymes required for peroxisomal [3-oxidation), as well as
rabbit
cytochrome P450 4A6, a fatty acid Q-hydroxylase.
PPAR-oc activates transcription by binding to DNA sequence elements,
termed peroxisome prol'~ferator response elements (PPRE), as a heterodimer
with
the retinoid X receptor. The retinoid X receptor is activated by 9-cis
retinoic acid
(see Kliewer, et al., Nature, 358:771-774 (1992), Gearing, et al., Proc. NatL
Acad.
Sci. USA, 90:1440-1444 (1993), Keller, et al., Prow Natl. Acad. Sci. USA,
90:2160-
2164 (1993), Heyman, et al., Cell, 68:397-406 (1992), and Levin, et al.,
Nature,
355:359-361 (1992)). Since the PPAR-a-RXR complex can be activated by
peroxisome proliferators and/or 9-cis retinoic acid, the retinoid and fatty
acid
signaling pathways are seen to converge in modulating lipid metabolism.
Since the discovery of PPAR-a, additional isoforms of PPAR have been
identified, e.g., PPAR-b, or PPAR-y, which are spatially differentially
expressed.
Each PPAR receptor shows a different pattern of tissue expression, and
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differences in activation by structurally diverse compounds. PPAR~y, for
instance,
is expressed most abundantly in adipose tissue and at lower levels in skeletal
muscle, heart, liver, intestine, kidney, vascular endothelial and smooth
muscle cells
as well as macrophages. Two isoforms of PPAR~y exist, identified as y, and y2,
respectively. PPAR-,ymediates adipocyte signalling, lipid storage, and fat
metabolism. Evidence gathered to date support the contusion that PPAR-y is the
primary, and pefiaps the only, molecular target mediating the insulin
sensitizing
action of one class of antidiabetic agents, the thiazolidine 2,4 diones.
In a monotherapeutic or combination therapy context, new and established
oral antidiabetic agents are still considered to have non-uniform and even
limited
effectiveness. The effectiveness of oral antidiabetic therapies may be
limited, in
part, because of poor or limited glycemic control, or poor patient compliance
due to
unacceptable side effects. These side effects include edema, weight gain, or
even
more serious complications. For instance, hypoglycemia is observed in some
patients taking sulfonylureas. Metformin, a substituted biguanide, can cause
diarrhea and gastrointestinal discomfort. Finally, edema, weight gain, and in
some
cases, hepatoxicity, have been linked to the administration of some
thiazolidine 2,4
dione antidiabetic agents. Combination therapy using two or more of the above
agents is common, but generally only leads to incremental improvements in
glycemic control.
As a result, there is a need for antidiabetic agents that display combined
PPAR-a and PPAR-Y activation which should lead to the discovery of efficacious
glucose and triglyceride lowering drugs that have great potential in the
treatment of
type 2 diabetes and the metabolic syndrome (i.e., impaired glucose tolerance,
insulin resistancem hyoertrigfyceridemia and/or obesity).
Summary of The Invention
The present invention provides novel compounds of Formula (I):
R'
Q R3
RZ (I)
or a pharmaceutically acceptable salt or solvate thereof, wherein:
Ring Q is (C6-C~o)aryl or (4-10)-membered heterocyclyl;
R' is H, halo, (C~-Ce)alkyl, (C,-Ca)alkoxy, CN, CF3, -O-CF3,
-O-S02-(C,-Ce)alkyl, -O-SOZ-(CR" R'2)t(C~-C,o)aryl,
-(CR"R'2),{C3-C~o)cycloalk I- CR"R'Z " '2 " '2
y ( ),, -(CR R ),(C3-C~o)cycloalkyl-(CR R ),-O-
-(CR'~R~2)~(Cs-C~o)arYl-(CR'~R~2)u -(CR~~R~2)c{Cs-C~o)aryl-{CR"R~z)t-O_.
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-(CR"R'z),-(4-10)-membered heterocyclyl-(CR"R'z)t, or -(CR"R'z),-(4-10)-
membered heterocyclyl-(CR"R'z),-O-; wherein the ring carbon atoms of R' are
optionally substituted by 1 to 3 R'3 groups; and the ring nitrogen atoms of R'
are
optionally substituted by 1 to 3 (C,-CB)alkyl;
Rz is H, (C,-C8)alkyl, -(CR"R'z),-(C3-C~°)cycloalkyl, -(CR"R'z),-
(Cs-C~°)aryl, or -(CR"R'z),(4-10)-membered heterocyclyl; and wherein
the carbon
atoms of Rz are optionally substituted by 1 to 3 R'3 groups; and the ring
nitrogen
atoms of Rz are optionally substituted by 1 to 3 (C~-CB)alkyl;
R3 is selected from the group consisting of:
A) ~ R4 Are-A~ Rs Rs
R~ .Re
R4-y-Y~~ Ar3-Rs Rs
~C~
R ~ R~2 R' \Rs
-Ra Ara Rs Rs
C)
A and
D)
Y is -(C=O)- or -SOz-;
Y" is NR'° or-0-;
p is 0, 1, or 2;
each q, r, and t are independently 0, 1, 2, 3, 4, or 5;
each n is independently 0, 1, 2, 3, or 4;
each k is independently 1, 2, or 3;
each m and s are independently 0, 1, 2, or 3;
each j is 0, 1, or 2;
Each R° IS -(CR"R~z)~_~ -(CR"R,z)~ S_(CR"R~z)~-~ -(CR,~R~z)~
NR~°_~
_(CR"R,Z)~ NR~o-(CR"R~z)~ O-, -(CR"R~z)~ O-(CR"R~z)k-NR'°
-(CR"R,z)~ O-(CR"R~z)~- -(CR~,R,z)~ O-(CR"R,z)k-O_(CR"R,z)r;
-(CR"R'Z-)~ CR"=CR'z-(CR"R'z),; , or-CH=CH-(CR"R'z)-O-(CHz)~ ;
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Each RS is a bond or-(CR"R'2)m Z-(CR"R'2)S; wherein Z is -CR"R'2-, -O-
-NR~oa- or-S(~)~ ;
Each Re is -(C=O)-OH, -(C=O)-OM', -(C=O)-(C~-C8)alkyl,
-(C=O)-O-(C~-Ce)atkyl, -(C=O)-NR'°R", -(C=O)-NR'°-SOz-R", -S02-
NH-R'°,
-NH-SOrR'°, -(C=O)-NH-C---N, or Rs has a formula:
O
__
NH ~~ ' \N
_N/
O ; or H
M' is an alkali metal ration or an alkaline earth metal ration;
Each R' and Re is independently H, (C~-C8)alkyl, (C,-CB)alkoxy,
-(CR"R,x)c(Ca-C~o)cYcloalkyl, -(CR"R,z)c(Cs-C,o)a~'Yl~ -(CR"R,2)~(Cs-C,o)a~'YI-
O-~
-(CR"R'2),(4-10)-membered heterocyclyl or -(CR"R'2),(4-10)-membered
heterocyclyl-O-;
Or R' and R8 may optionally be taken together with the carbon to which
they are attached to form a (C3-C~o)cycloalkyl or a (3-10)-membered
heterocycfyl;
Each of Ar', Arz, Ar3, and Ar4 represents (C6-C~°)aryl or (5-10)-
membered
heterocyclyl; wherein the ring carbon atoms of each of Ar', Arz, Ar3, and Ar4
are
optionally substituted by 1 to 3 R'3 groups;
Ring A represents a 3, 4, 5, 6 or 7-membered ring optionally containing 1
to 4 heteroatoms which may be the same or different and which are selected
from -
N(R'°e)-, O, and S(O);, wherein j is 0, 1, ar 2, with the proviso that
the ring does not
contain two adjacent O or S(O); atoms, and wherein the carbon atoms of the
ring A
moiety are optionally substituted by 1 to 3 R'3 groups;
Re is (C~-C8)alkyl, -(CR"R'2),(Cs-C,°)aryl or -(CR"R'2),(4-10)-
membered
heterocyclyl, wherein t is independently 0, 1, 2, 3, 4, or 5, wherein said R9
groups
are substituted with 1 to 3 groups independently selected from -
(CR"R'2)qNR'°R",
-(CR"R'2)qNR'°(C,-Cs)alkanoyl, -(CR"R'Z)q0(CR"R'2)~R'°, and -
(CR"R'2)qR'°; and
wherein the heterocyclyl, aryl and alkyl moieties of the foregoing groups are
optionally substituted with 1 to 3 R'3 groups;
R98 and R'° are independently H or (C,-C8)alkyl;
R" and R'2 are independently H, (C,-Ce)alkyl, hydroxy, or (C~-C6)alkoxy;
R'°~ is selected from H, (C~-Ce)alkyl, -(C=O)-R'°, -
SO2NR'SR'6, or
-S(O);(C~-C6)alkyl;
Each R'3 and R'38 are independently selected from the group consisting of
halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, (C~-
C6)alkoxy,
(C,-C,o)alkyl, (CZ-C6)alkenyl, (CZ-Cs)alkynyl, -O-(CR"R'2)k-O-(CR"R'2)", -
(C=O)-
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Rta -(C=O)-aR,s~ -O-(C=OrR~s~ -NR~s(C=O)-R~s~ -NR~s(C=O)-O-R~s
-(C=O)-NR'SR's, -NR'SR's, -NR'SOR's, -S02NR'SR's, -S(O)i(CrCs)alkyl, -O-S02_
R", -NR'S-S02-R's, R'S-(CR"R'2),(Cs-Coo aryl), -(CR"R'z),(4-10)-membered
heterocyclyl, -(CR" R'2)q(C=O)(CR" R'2),(Cs-C,o)aryl,
-(CR"R'2)q(C=O)(CR"R'2),(4-10)-membered heterocyclyl,
-(CR"R'2),O(CR"R'2)q(Cs-C,o)aryl, -(CR"R'Z),O(CR"R'2)q(4-10)-membered
heterocyclyl, -(CR" R'2)qS02(CR" R'Z),(Cs-C~o)aryl, and
-(CR"R'2)qS02(CR"R'Z),(4-10)-membered heterocyclyl; 1 or 2 ring carbon atoms
of the heterocyclic moieties of the foregoing R'3 and R'~ groups are
optionally
substituted with an oxo (=O) moiety, and the alkyl, alkenyl, alkynyl, aryl and
heterocyclic moieties of the foregoing R'3 and R'38 groups are optionally
substituted
with 1 to 3 substituents independently selected from halo, cyano, vitro,
trifluoromethyl, trifluoromethoxy, azido, -OR'S, -(C=O)-R'S, -(C=O)-O-R'S,
-O-(C=O)-R~s -NR~s(C=O)-R~s~ -(C=O)-NR~sR~s -NR~sR~s~ -NR~sOR,s~ (C
Cs)alkyl, (CZ-Cs)alkenyl, (CZ-Cs)alkynyl, -(CR"R'2),(Cs-C~o)aryl, and
-(CR"R'2),(4-10)-membered heterocyclyl;
each R'4, R'S, and R's is independently selected from H, (C,-Cs)alkyl,
-(CR"R'2),(Cs-C,o)aryl, and -(CR"R'Z),(4-10)-membered heterocyclyl; 1 or 2
ring
carbon atoms of the heterocyclic group are optionally substituted with an oxo
(=O)
moiety, and the alkyl, aryl and heterocyclic moieties of the foregoing R'4,
R'S and
R's groups are optionally substituted with 1 to 3 substituents independently
selected from halo, cyano, vitro, -NR"R'2, trifluoromethyl, trifluoromethoxy,
(C,-
Cs)alkyl, (CZ-Cs)alkenyl, (CZ-Cs)alkynyl, hydroxy, and (C~-Cs) alkoxy;
R" is H, (C~-Ce)alkyl, -O-(C~-Ce)alkyl, halo, CN, OH, CF3, or-0-CF3;
and wherein any of the above-mentioned substituents comprising a CH3
(methyl), CHZ (methylene), or CH (methane) group which is not attached to a
halo,
SO or SOZ group or to a N, O or S atom optionally bears on said group a
substituent selected from hydroxy, halo, (C~-C4)alkyl, (C~-C4)alkoxy, -NH2, -
NH(C,-
C8)alkyl, and -N((C,-C8)afkyl)2.
In one embodiment, the invention relates to compounds of the Formula I
wherein R3 is
R4 Are-A~ R5 Rs
A)
R~ Ra
In another embodiment, the invention relates to compounds of the Formula
I wherein R3 is
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g) ~ R4-Y-y~~ Ar3 RS s
R
~C~
R i Rt2 R~ ~R$
Within this embodiment, preferred -R4-Y-Y°- are
-(CR'~R,2),; O-(CR"Rt2)"-(C°O)-NR'°- or-(CR"R,2)"-NR'°-
(C=O)-O-.
In another embodiment, the invention relates to compounds of the Formula
I wherein R3 is
6
C) ;---R4 Ar4 R5 R
A
In another embodiment, the invention relates to compounds of the Formula
I wherein R3 is
D)
In another embodiment, the invention relates to compounds of the Formula
I wherein ring Q is selected from the group consisting of
O O~ /O-N O~ O-N S N~ N-N
N.NI ~N~ DN.N N ~ \ ~~~ ~N.N N ~ \
N ~N N ~ N ~ ~N
, , , , and ~ O .
In another embodiment, the invention relates to compounds of the Formula
I wherein R' is H, halo, (C,-C8)alkyl, (C~-Ce)alkoxy, CF3, -O-CF3, -O-SOZ-(C~
C8)alkyl, -O-S02-(CR"R'2),(Cs-C,o)aryl, or -(CR"R'2),(Ce-C,o)aryl-O-, wherein
the
ring carbon atoms of R' are optionally substituted by 1 to 3 R'3 groups.
In another embodiment, the invention relates to compounds of the Formula
I \ / ~ O-N
v
I wherein R2 is H, phenyl, ~ , CH~N~ ,
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~CH3
O
CH3-S02-NH ~ ~ F
, , ,
~CF3
O
O
HsC-O ~ ~ \
and
CH3 ~
N=N
In another embodiment, the invention relates to compounds of the Formula
R~
Q R3
I wherein said ~ is selected from the group consisting of:
CF3 O-CF3 O-(C~-C8)alkyl
CF3 \ ( \ I \
\ R3 \ R3 R3 R3 R3
, , , , ,
O-S02-(C~-C8)alkyl O-(C6-C ~ o)aryl O-SOZ-(C6-C 1 o)aryl
~I ~i ~I
R3 R3 R3
,
CH3 CH3
\ 3 ~ ~ ~~ 3 ~ Ca ~ 3
~N R ~N R ~ ~ N R
,
CH3
O
\~~ NR3~-N _
i CHs N ~ / R3
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CH3-S02-NH ~ ~ ~ ~ R3
/ Hs
O
F ~ ~ ~- ~ Rs ~ ~ ~ ~ Rs
, ,
r Rs
H3C-O ~ ~ ~ ~ R3
v
, ,
/CF3
O
Rs CH3 ~ ~ N~Rs
N=N ,
Rs
and
In another embodiment, the invention relates to compounds of the Formula
wherein R" is -CHrO-, -CH2-O-CHZ-, -CHrCHz-O-, -CH=CH-CH2-O-, or
-CHz-CH2-CHZ-O-.
In another embodiment, the invention relates to compounds of the Formula
I wherein R4 is -(CHZ)"-; wherein n is independently 0, 1, 2, or 3.
Iri another embodiment, the invention relates to compounds of the Formula
I wherein RS is a bond or -(CR"R'2)m Z-(CR"R'Z)g; wherein Z is -O-, -
NR'°~-, or
-S(O)S ; wherein each m and s are independently 0, 1, 2, or 3; and wherein j
is 0, 1,
or 2.
In another embodiment, the invention relates to compounds of the Formula
I wherein R5 is a bond, -O-, -CHZ-, -C(CH3)H-, -C(OH)H-, or -C(O-(C~-
C8)alkyl)H-.
In another embodiment, the invention relates to compounds of the Formula
I wherein Rs is -(C=O)-OH.
In another embodiment, the invention relates to compounds of the Formula
I wherein R6 is -(C=O)-OM', wherein M' is selected from the group consisting
of
Ca", Li', Na+ and K'.
In another embodiment, the invention relates to compounds of the Formula
I wherein each R' and R8 is independently H, (C~-Ce)alkyl, or (C~-C8)alkoxy.
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In another embodiment, the invention relates to compounds of the Formula
1 wherein each R' and R8 are taken together with the carbon to which they are
attached to form a (3-7)-membered heterocyclyl.
In another embodiment, the invention relates to compounds having a
formula:
R2
O
R,-~ I
N
Ra-Are-Arz-R5 Rs
7"RB
R
Within this embodiment, the invention relates to compounds wherein said
-Ar'-Arz- is selected from the group consisting of:
N - N
/ \ / / \ \ /N.
/ \ -N
N ;
/ \ ~ ~ ~ ~ / / ~ -N
\
N N-
/ \ N N~ \ N=~N N~N N-
\ /. \ / . - \
N
N~ / \ / O / \ ~ -NR~o
\ /.~J. J
N~ N , N , and N ;
wherein the ring carbon atoms of each of Ar' and Arz are optionally
substituted by 1 to 3 R'3 groups selected from the group consisting of halo,
(C~-
C$)alkyl, and (C,-Ce)alkoxy.
Preferably, said -Ar'-Arz- is selected from the group consisting of:
\ \ /
\ / ; N- ~ ; and
/ \ ~ /
Within this embodiment, specific compounds of the present invention are
selected from the group consisting of
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2-Methyl-2-({3'-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1'-biphenyl-
3-yl}oxy)propanoic acid;
2-Methyl-2-[(3'-{[4-(trifluoromethyl)benzyl]oxy}-1,1'-biphenyl-3-
yl)oxy]propanoic acid;
2-Methyl-2-[(3'-{2-[1-(6-methylpyridazin-3-yl)piperidin-4-yl]ethoxy}-1,1'-
biphenyl-3-yl)oxy]propanoic acid;
1-({3'-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1'-biphenyl-3-
yl}oxy)cyclobutanecarboxylic acid; ---
2-({3'-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1'-biphenyl-3-
yI}oxy)butanoic acid;
2-(3-{&[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-
yl}phenoxy)butanoic acid;
1-(3-{6-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-
yl}phenoxy)cyclobutanecarboxylic acid;
2-Methyl-2-(3-{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-
yl}phenoxy)propanoic acid;
2-Methyl-2-(3-{ti-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyrazin-2-
yl}phenoxy)propanoic acid; and
and pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 1-
({3'-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1'-biphenyl-3-
yl}oxy)cyclobutanecarboxylic acid or the pharmaceutically acceptable salts
thereof.
Within this embodiment, a speck compound of the present invention is 2-
({3'-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1'-biphenyl-3-
yl}oxy)butanoic
acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
(3-{6-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-
yl}phenoxy)butanoic
acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 1-
(3-{6-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-
yl}phenoxy)cyclobutanecarboxylic acid or the pharmaceutically acceptable salts
thereof.
Within this embodiment, a specific compound of the present invention is 1-
[(3'-{[2-(3-fluorophenyl)-5-methyl-1, 3-oxazol-4-yl]methoxy}biphenyl-3-
yl)oxy]cyclobutanecarboxylic acid or the pharmaceutically acceptable salts
thereof.
Within this embodiment, a specific compound of the present invention is 1-
({3'-[3-(5-methyl-2-phenyl-1, 3-oxazol-4-yl)propoxy]biphenyl-3-
yl}oxy)cyclobutanecarboxylic acid or the pharmaceutically acceptable salts
thereof.
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Within this embodiment, a specific compound of the present invention is 1-
[(3'-{[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy}biphenyl-3-
yl)oxy]cyclobutanecarboxylic acid or the pharmaceutically acceptable salts
thereof.
Within this embodiment, a specific compound of the present invention is 2-
[(3'-{2-[2-(3-Fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}biphenyl-3-yl)oxy]-
2-
methylpropanoic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
methyl-2-({3'-[(5-methyl-2-phenyl-1, 3-oxazol-4-yl)meth oxy]biphenyl-3-
yl}oxy)propanoic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a speck compound of the present invention is 2-
ethoxy-3-{3'-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]biphenyl-3-
yl}propanoic
acid or the pharmaceutically acceptable salts thereof.
In another embodiment, the invention relates to compounds having a
formula:
R'
Ar3-R5 RB
R~ ~Re
'
wherein Y is -(C=O)- or -SOY, Y" is NR'°, and p is 1.
Preferably, each of R" and R'Z are independently H.
Preferably, Are is phenyl.
Within this embodiment, specific compounds of the present invention are
selected from the group consisting of
1-(3-{[({2-[3
(Trifluoromethyl)phenyl]ethoxy}carbonyl)amino]methyl}phenoxy)
cyclobutanecarboxylic acid;
2-(3-{[({2-[3
(T~~fluoromethyl)phenyl)ethoxy}carbonyl)amino]methyl}phenoxy)butanoic acid;
2-Methyl-2-(3-{[({2-[3-
(trifluoromethyl)phenyl]ethoxy}carbonyl)amino)methyl}phenoxy)
propanoic acid;
2-Methyl-2-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-
yl)ethoxy]carbonyl}amino)methyl]
phenoxy}propanoic acid;
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2-Methyl-2-(3-{[({[4-(5-methyl-1,2,4-oxadiazol-3-
yl)benzyl]oxy}carbonyl)amino]methyl}
phenoxy)propanoic acid;
2-{3-[({(2-(5-Methyl-2-phenyl-1,3-oxazol-4-
yl)ethoxy]carbonyl}amino)methyl]phenoxy}
butanoic acid;
1-{3-[({[2-(5-Methyl-2-phenyl-1,3-oxazol-4-
yl)ethoxy]carbonyl}amino)methyl]phenoxy} cyclobutanecarboxylic acid;
1-{3-[({[3-(5-Methyl-2-phenyl-1,3-oxazol-4-
yl)propoxy]carbonyl}amino)methyl]phenoxy} cyclobutanecarboxylic acid;
2-{3-j({[3-(5-Methyl-2-phenyl-1, 3-oxazol-4-
yl)propoxy]carbonyl}amino)methyl]
phenoxy}butanoic acid;
2-Methyl-2-{3-[({[3-(5-methyl-2-phenyl-1, 3-oxazol-4-
yl)propoxy]carbonyl}amino)methyl]
phenoxy}propanoic acid;
and pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
Methyl-2-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-
yl)ethoxy]carbonyl}amino)methyl]phenoxy}propanoic acid or the pharmaceutically
acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
methyl-2-{3-[({[(5-methyl-2-phenyl-1,3-oxazol-4-
yl)methoxy]carbonyl}amino)methyl]phenoxy}propanoic acid or the
pharmaceutically
acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
methyl-2-{4-[({(3-(5-methyl-2-phenyl-1, 3-oxazol-4-
yl)propoxy]carbonyl}amino)methyljphenoxy}propanoic acid or the
pharmaceutically
acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
{3-fluoro-4-[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-
yl)ethoxy]carbonyl}amino)methyl]phenoxy}-2-methylpropanoic acid or the
pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
{3-[({[2-(5-Methyl-2-phenyl-1,3-oxazol-4-
yl)ethoxy]carbonyl}amino)methyl]phenoxy}butanoic acid or the pharmaceutically
acceptable salts thereof.
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Within this embodiment, a specific compound of the present invention is 2-
{3-(({[(5-methyl-2-phenyl-1,3-oxazol-4-
yl)methoxy]carbonyl}amino)methyl]phenoxy}butanoic acid or the pharmaceutically
acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 1-
{3-[({[2-(5-Methyl-2-phenyl-1,3-oxazo(-4-
yl)ethoxy]carbonyl}amino)methyl]phenoxy}cyclobutanecarboxylic acid or the
pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
methyl-2-(3-{[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-
yl)ethyl]amino}carbonyl)oxy]methyt}phenoxy)propanoic acid or the
pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
ethoxy-3-{3-[({[3-(5-methyl-2-phenyl-1,3-oxazol-4-
yI)propoxy]carbonyl}amino)methyl]phenyl}propanoic acid or the pharmaceutically
acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
ethoxy-3-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-
yl)ethoxy]carbonyl}amino)methyl]phenyl}propanoic acid or the pharmaceutically
acceptable salts thereof.
In another embodiment, the invention relates to compounds having a
formula:
R2
O
R'
Rs
R° Ar4 RS
A
In another embodiment, ring A is selected from the group consisting of
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In another embodiment, ring A is selected from the group consisting of
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O ..rr O O
O ~ ', ',
.._...~, , O ' , N
' O Rtoa
NRt°a NRt°a Rtoa
' ' NRtoa - ~ N
',
' NRt°a
O , , ~N
Rte Rtoe
S
N ,
,
N
S , Rtoa ;
wherein - is an optional double bond.
In another embodiment, ring A is selected from the group consisting of
Rtoa
O S N O
I , . O
I ,
I I ;
I I ._J
S NRt°a
' ' ' 2~ NRtoa
RtoaN , RtoaN RtoaN , RtoaN-NRtoa
' ' ~ ,
,
IN IN
RtoaN." ,
O O-NRtoa; S-NRt°a ; O 'N ; RtoaN~N .
,,
wherein --- is an optional double bond.
In another embodiment, ring A is selected from the group consisting of
O ~ and NRtoa
wherein - is an optional double bond.
Within this embodiment, Ar' is phenyl, naphthyl, pyridinyl, pyrimidinyl, or
pyrazinyl.
Within this embodiment, specific compounds of the present invention are
selected from the group consisting of
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1-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-
yl)ethoxy]benzyl}cyclohexanecarboxylic acid;
1-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-
yl)ethoxy]benzyl}cyclopentanecarboxylic acid;
1-{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-
yl)propoxy]benzyl}cyclopentanecarboxylic acid;
4-{4-[(5-methyl-2-phenyl-9 , 3-oxazol-4-yl)methoxy]benzyl}tetrahydro-2H-
pyran-4-carboxylic acid;
4-{4-[2-(5-methyl-2-phenyl-1,3-oxazoM-yl)ethoxy]benzyl}tetrahydro-2H-
pyran-4-carboxylic acid;
1-{4-[2-(4'-methoxy-1,1'-biphenyl-4-yl)ethoxy]benzyl}cyclobutanecarboxytic
acid;
1-{4-[2-(4'-fluoro-1,1'-biphenyl-4-yl)ethoxy]benzyl}cyclobutanecarboxylic
acid;
1-{4-[2-(2'-methoxy-1,1'-biphenyl-4-yl)ethoxy]benzyl}cyclobutanecarboxylic
acid;
1-(4-{2-[3'-(trifluoromethoxy)-1,1'-biphenyl-4-
yl]ethoxy}benzyl)cyclobutanecarboxylic acid;
1-(4-{2-[4-(6-methoxypyridin-3-
yl)phenyl]ethoxy}benzyl)cyclobutanecarboxylic acid;
1-(4-{2-[4'-(methylsulfonyl)-1,1'-biphenyl-4-
yl]ethoxy}benzyl)cyclobutanecarboxylic acid;
1-(4-{2-[4-(2,3-dihydro-1-benzofuran-6-
yl)phenyl]ethoxy}benzyl)cyclobutanecarboxylic acid;
1-[4-(2-{4'-[(methylsulfonyl)amino]-1,1'-biphenyl-4-
yl}ethoxy)benzyl]cyclobutanecarboxylic acid;
1-{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-
yl)propoxy]benzyl}cyclobutanecarboxylic acid;
1-{4-[(5-methyl-2-phenyl-1, 3-oxazol-4
yl)methoxy]benzyl}cyclobutanecarboxylic acid;
1-{3-[2-(5-methyl-2-phenyl-1,3-oxazol-4
yl)ethoxy]benzyl}cyclobutanecarboxylic acid;
1-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-
yl)ethoxy]benzyl}cyclobutanecarboxylic acid;
1-{4-[(2,5-Biphenyl-1,3-oxazol-4-yl)methoxy]benzyl}cyclobutanecarboxylic
acid;
1-{4-[3-(2,5-Biphenyl-1,3-oxazol-4-yl)propoxy]benzyl}cyclobutanecarboxylic
acid;
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1-{4-[(2,5-Biphenyl-1,3-oxazol-4
yl)methoxy]phenoxy}cyclobutanecarboxylic acid;
1-{4-[3-(2,5-Biphenyl-1,3-oxazol-4-
yl)propoxy]phenoxy}cyclobutanecarboxylic acid;
1-(4-{2-[2-(1,1'-biphenyl-4-yl)-5-methyl-1,3-oxazol-4-
yl]ethoxy}phenoxy)cyclobutanecafioxylic acid;
1-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-
yl)ethoxy]phenoxy}cyclobutanecarboxylic acid; -
1-{4-[3-(5-methyl-2-phenyl-1,3-oxazo!-4-
yl)propoxy]phenoxy}cyclobutanecarboxylic aciB;
1-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-
yl)methoxy]phenoxy}cyclobutanecarboxylic acid;
1-({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-
yl}methyl)cyclobutanecarboxylic acid;
1-(hydroxy{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-
yl}methyl)cyclobutanecarboxylic acid;
1-({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-
yl}methyl)cyclopentanecarboxylic acid;
1-({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-
yl}methyl)cyclohexanecarboxylic acid;
2-({6-[2-(5-methyl-2-phenyl-1, 3-oxazol-4-yl)ethoxy]pyridin-3-
yl}methyl)tetrahydrofuran-2-carboxylic acid;
2-({5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-
yl}methyl)tetrahydrofuran-2-carboxylic acid;
and the pharmaceutically acceptable salts thereof.
W~hin this embodiment, a specific compound of the present invention is 1-
{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]benzyl}cyclobutanecarboxylic
acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 1-
{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl}cyclobutanecarboxyiic
acid
or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-
yl}methyl)tetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptable
salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
({5-[2-(5-methyl-2-phenyl-1, 3-oxazol-4-yl)ethoxy]pyridin-2-
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yl}methyl)tetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptable
salts thereof.
Within this embodiment, a speck compound of the present invention is 2-
({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-
yl}methyl)tetrahydro-2H
pyran-2-carboxylic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
[(6-{2-[2-(3-chlorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}pyridin-3-
yl)methyl]tetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptable
salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
[(6-{2-[2-(3-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}pyridin-3-
yl)methyl]tetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptable
salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
{5-j2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyrazin-2-ylmethyl}-tetrahydro-
furan-
2-carboxylic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is -
{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl}tetrahydrofuran-2-
carboxylic
acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
{6-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-2-ylmethyl}-
tetrahydro-
furan-2-carboxylic acid or the pharmaceutically acceptable salts thereof.
In another embodiment, the invention relates to compounds having a
formula:
R2
0 ,.,
R~
N
-R9.
Within this embodiment, preferably the invention relates to compounds
having a formula:
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Rz
O
Rm
R
N Ra ~ -,_! CH2 Rs
N
s
Rs O R
Within this embodiment, preferably the invention relates to compounds
having a formula:
Rz
O
R~ R»
a Rs
R ~ /~CHz
N
Rsa \O Re
Within this embodiment, preferably R9 is methyl, ethyl, or benzyl. Preferably
R" is H.
Within this embodiment, a specific compound of the present invention is 2-
ethoxy-3-{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-
yl}propanoic
acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a speck compound of the present invention is 2-
methoxy-3-(6-{2-[5-methyl-2-(3-methylphenyl)-1,3-oxazol-4-yl]ethoxy}pyridin-3-
yl)propanoic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
methoxy-3-{6-[2-(4-phenoxyphenyl)ethoxy]pyridin-3-yl}propanoic acid or the
pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
ethoxy-3-[6-(2-{4-[(phenylsulfonyl)oxy]phenyl}ethoxy)pyridin-3-yl]propanoic
acid or
the pharmaceutically acceptable salts thereof.
Within this embodiment, a speck compound of the present invention is 2-
Ethoxy-3-{5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-2-yl}-propionic
acid
or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
Methoxy-2-methyl-3-{6-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propoxy]-pyridin-3-
yl}-
propionic acid or the pharmaceutically acceptable salts thereof.
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Within this embodiment, a specific compound of the present invention is 2-
Methoxy-2-methyl-3-{5-[2-(5-riiethyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-2-
yl}-
propionic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a spec'fiic compound of the present invention is 3
(6-{2-[2-(4-Chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-pyridin-3-yl)-2-
methoxy-2
methyl-propionic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
Methoxy-2-methyl-3-{6-[2-(5-methyl-2-phenyl oxazol-4-yl)-ethoxy}-pyridin-3-yl}-
propionic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
Methoxy-3-(6-{2-[2-(3-methoxy phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-pyridin-3-
yl)-
2-methyl-propionic acid or the pharmaceutically acceptable salts thereof.
The present invention also provides a method of treating non-insulin
dependent diabetes mellitus in a mammal comprising administering to the mammal
in need thereof a therapeutically effective amount of a compound of Formula
(I). In
one embodiment, said mammal has an impaired glucose tolerance.
The present invention also provides a method of treating polycystic ovarian
syndrome in a mammal comprising administering to the mammal in need thereof a
therapeutically effective amount of a compound of Formula (I).
The present invention also provides a method of treating obesity in a
mammal comprising administering to the mammal in need thereof a
therapeutically
effective amount of a compound of Formula (I).
The present invention also provides a method of reducing body weight in
an obese mammal comprising administering to the mammal in need thereof a
therapeutically effective amount of a compound of Formula (I).
The present invention also provides a method of treating hyperglycemia in
a mammal comprising administering to the mammal in need thereof a
therapeutically effective amount of a compound of Formula (I).
The present invention also provides a method of treating hyperlipidemia in
a mammal comprising administering to the mammal in need thereof a
therapeutically effective amount of a compound of Formula (I).
The present invention also provides a method of treating
hypercholesteremia in a mammal comprising administering to the mammal in need
thereof a therapeutically effective amount of a compound of Formula (I).
The present invention also provides a method of treating atherosclerosis in
a mammal comprising administering to the mammal in need thereof a
therapeutically effective amount of a compound of Formula (1).
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The present invention also provides a method of treating
hypertriglyceridemia in a mammal comprising administering to the mammal in
need
thereof a therapeutically effective amount of a compound of Formula (I).
The present invention also provides a method of treating hyperinsulinemia
in a mammal comprising administering to the mammal in need thereof a
therapeutically effective amount of a compound of Formula (I).
The present invention also provides a method of treating a patient suffering
from abnormal insulin and/or evidence of glucose disorders associated with
circulating glucocorticoids, growth hormone, catecholamines, glucagon, or
parathyroid hormone, comprising administering to said patient a
therapeutically
effective amount of a compound of Formula (I).
The present invention also provides a method of treating insulin resistance
syndrome in humans comprising administering to a patient in need of treatment
a
therapeutically effective amount of a compound of Formula (I).
The present invention also provides a method of treating PPAR-related
disorders in humans comprising administering to a patient in need of treatment
a
therapeutically effective amount of a compound of Formula (I).
The present invention also provides a method of modulating PPAR activity
in a mammal, comprising administering to a mammal a therapeutically effective
amount of a compound of Formula (I).
The present invention also provides a method of lowering blood glucose in
a mammal, comprising administering to a mammal an amount of a compound of
Formula (I) effective to lower blood glucose levels.
The present invention also provides a method of modulating fat cell
differentiation in a mammal, comprising administering to a mammal a
therapeutically effective amount of a compound of Formula (1).
The present invention also provides a method of modulating processes
mediated by PPAR in a mammal, comprising administering to a mammal a
therapeutically effective amount of a compound of Formula (I).
The present invention also provides a method of increasing insulin
sensitivity in mammals, comprising administering to a mammal a therapeutically
effective amount of a compound of Formula (I).
The present invention also provides a method of treating metabolic
syndromes selected from the group consisting of galactosemia, maple syrup
urine
disease, phenylketonuria, hypersarcosinemia, thymine uraciluria, sulfinuria,
isovaleric acidemia, saccharopinuria, 4-hydroxybutyric aciduria, glucose-6-
phosphate dehydrogenase deficiency, and pyruvate dehydrogenase deficiency.
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The present invention also provides a composition comprising at least one
modulator of PPAR of Formula (I) and a pharmaceutically acceptable carrier
thereof. Exemplary pharmaceutically acceptable carriers include carriers
suitable
for oral, intravenous, subcutaneous, intramuscular, intracutaneous, and the
like
administration. Administration in the form of creams, lotions, tablets,
dispersible
powders, granules, syrups, elixirs, sterile aqueous or non-aqueous solutions,
suspensions or emulsions, and the like, is contemplated.
The PPAR agonists of the present invention may be administered in
combination with other agents such as a-glucosidase inhibitors, aldose
reductase
inhibitors, biguanide preparations, statin base compounds, squalene synthesis
inhibitors, fibrate base compounds, LDL catabolism promoters and angiotensin-
converting enzyme inhibitors.
In the above description, an a-glucosidase inhibitor is a medicament
having action in inhibiting a digestive enzyme such as amylase, maltase, a-
dextrinase or sucrase, thereby retarding the digestion of starch or sucrose.
Examples of a-glucosidase inhibitors include acarbose, N-(1,3-dihydroxy-2-
propyl)variolamine (common name: voglibose) and miglitol.
In the above description, an aldose reductase inhibitor is a medicament
which inhibits a rate-limiting enzyme of the first step of the polyol pathway,
thereby
inhibiting diabetic complications. Examples include tolrestat, epalrestat, 2,7
difluoro-spiro(9H-fluoren-9,4'-imidazolidine)-2',5'-dione (common name:
imirestat),
3-[(4-bromo-2-fluorophenyl)methyl]-7-chloro-3,4-dihydro-2,4-dioxo-1 (2H)-qu
inozolineacetic acid (common name: zenarestat), 6-fluoro-2,3-dihydro-2,5'-
dioxo-
spiro[4H-1-benzopyran-4,4'-imidazolidine]- 2-carboxamide (SNK-860),
zopolrestat,
sorbinil and 1-[(3-bromo-2-benzofuranyl)sulfonyl]-2,4-imidazolidinedione (M-
16209).
In the above description, a biguanide preparation is a medicament having
effects in anaerobic glycolysis promotion, insulin action reinforcement at the
periphery, intestinal glucose absorption inhibition, hepatic gluconeogenesis
inhibition and fatty-acid oxidation inhibition and examples include
phenformin,
metformin and buformin.
In the above description, a statin base.compound is a medicament which
inhibits hydroxymethylglutaryl CoA (HMG-CoA) reductase, thereby lowering the
blood cholesterol level and examples include pravastatin and the sodium salt
thereof, simvastatin, lovastatin, atorvastatin and fluvastatin.
In the above description, a squalene synthesis inhibitor is a medicament
for inhibiting squalene synthesis, thereby lowering the blood cholesterol
level and
examples include monopotassium (S)-a-[bis(2,2-dimethyl-1-
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oxopropoxy)methoxy]phosphinyl-3-phenoxybenzene-butanesulfonate (BMS-
188494).
In the above description, a fibrate base compound is a medicament for
inhibiting synthesis and secretion of tr7glycerides in the liver and
activating
lipoprotein lipase, thereby lowering the triglyceride level in the blood.
Examples
include bezaflbrate, beclobrate, binifibrate, ciprofibrate, clinoflbrate,
clofibrate,
clofibric acid, ethofibrate, fenofibrate, gemfibrozil, nicofibrate,
pirifibrate, ronifibrate,
simfibrate and theofibrate.
In the above description, a LDL catabolism promoter is a medicament for
increasing LDL (low-density lipoprotein) receptors, thereby lowering the blood
cholesterol level and examples include compounds described in Japanese Patent
Application Kokai Hei 7-316144 or salts thereof, more specifically, N-[2-[4-
bis(4
fluorophenyl)methyl-1-piperazinyl]ethyl]-7,7-Biphenyl-2,4,6- heptatrienoic
amide.
The above-described statin base compounds, squalene synthesis
inhibitors, fibrate base compounds and LDL catabolism promoters can be
replaced
with another chemical effective for lowering the blood cholesterol or
triglyceride
level. Examples of such a medicament include nicotinic acid derivative
preparations such as nicomol and niceritrol; antioxidants such as probucol;
and ion
exchange resin preparations such as cholestyramine.
In the above description, an angiotensin-converting enzyme inhibitor is a
medicament for inhibiting angiotensin-converting enzyme, thereby lowering the
blood pressure and at the same time, partially lowering the blood sugar level
of a
patient suffering from diabetes. Examples include captopril, enalapril,
alacepril,
delapril, ramipril, lisinopril, imidapril, benazepril, ceronaprill cilazapril,
enalaprilat,
fosinopril, movettipril, perindopril, quinapril, spirapril, temocapril and
trandolapril.
For the preparation of oral liquids, suitable carriers include emulsions,
solutions, suspensions, syrups, and the like, optionally containing additives
such as
wetting agents, emulsifying and suspending agents, sweetening, flavoring and
perfuming agents, and the like.
For the preparation of fluids for parenteral administration, suitable carriers
inGude sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
Examples of non-aqueous solvents or vehicles are propylene glycol,
polyethylene
glycol, vegetable oils, such as olive oil and corn oil, gelatin, and
injectable organic
esters such as ethyl oleate. Such dosage forms may also contain adjuvants such
as preserving, wetting, emulsifying, and dispersing agents. They may be
sterilized,
for example, by filtration through a bacteria-retaining filter, by
incorporating
sterilizing agents into the compositions, by irradiating the compositions, or
by
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heating the compositions. They can also be manufactured in the form of sterile
water, or some other sterile injectable medium immediately before use.
Definitions
For purposes of the present invention, as described and claimed herein,
the following terms are defined as follows:
The term "halo", as used herein, unless otherwise indicated, means fluoro,
chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term "alkyl', as used herein, unless otherwise indicated, inGudes
saturated monovalent hydrocarbon radicals having straight or branched
moieties.
The term "alkenyl", as used herein, unless otherwise indicated, includes alkyl
moieties having at least one carbon-carbon double bond wherein alkyl is as
defined
above and including E and Z isomers of said alkenyl moiety.
The term "alkynyl", as used herein, unless otherwise indicated, includes alkyl
moieties having at least one carbon-carbon triple bond wherein alkyl is as
defined
above.
The term "alkoxy", as used herein, unless otherwise indicated, includes O-
alkyl groups wherein alkyl is as defined above.
The term "Me" means methyl, "Et" means ethyl, and "Ac" means acetyl.
The term "cycloalkyl", as used herein, unless otherwise indicated refers to a
non-aromatic, saturated or partially saturated, monocyclic or fused, spiro or
unfused bicyclic or tricyclic hydrocarbon referred to herein containing a
total of from
3 to 10 carbon atoms, preferably 5-8 ring carbon atoms. Exemplary cycloalkyls
include monocyclic r7ngs having from 3-7, preferably 3-6, carbon atoms, such
as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
Illustrative
examples of cycloalky) are derived from, but not limited to, the following:
i .
/~ \
. and
The term "aryl", as used herein, unless otherwise indicated, includes an
organic radical derived from an aromatic hydrocarbon by removal of one
hydrogen,
such as phenyl or naphthyl.
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The term "4-10 membered heterocyclic", as used herein, unless otherwise
indicated, includes aromatic and non-aromatic heterocyclic groups containing
one to
four heteroatoms each selected from O, S and N, wherein each heterocyclic
group
has from 4-10 atoms in its ring system, and with the proviso that the ring of
said
group does not contain two adjacent O or S atoms. Non-aromatic heterocyclic
groups include groups having only 4 atoms in their ring system, but aromatic
heterocyclic groups must have at least 5 atoms in their ring system. The
heterocyclic
groups include benzo-fused ring systems. An example of a 4 membered
heterocyclic group is azetidinyl (derived from azetidine). An example of a 5
membered heterocyclic group is thiazolyl and an example of a 10 membered
heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups
are
pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,
tetrahydropyranyl,
dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,
thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl,
oxepanyl,
thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-
pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-
dioxolanyl,
pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,
dihydrofuranyl,
pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-
azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic
heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,
triazolyl,
pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,
isothiazolyl,
pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,
cinnolinyl,
indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,
pteridinyl, purinyl,
oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,
benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and
furopyridinyl. The foregoing groups, as derived from the groups listed above,
may
be C-attached or N-attached where such is possible. For instance, a group
derived
from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
Further, a
group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-
yl (C-
attached). The 4-10 membered heterocyclic may be optionally substituted on any
ring carbon, sulfur, or nitrogen atoms) by one to two oxo, per ring. An
example of a
heterocyclic group wherein 2 ring carbon atoms are substituted with oxo
moieties is
1,1-dioxo-thiomorpholinyl. Other Illustrative examples of 4-10 membered
heterocyclic are derived from, but not limited to, the following:
O H
O N
NH
N N N N
H O ~ H ' H ' H
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O NH
'N ~ CJ~ ~~
N ~~ N N
g . , G J . O ~ H ~ H ,
O
N O N' J , N N
H ' H ' H '
\ ° \ o , \
0
N
\ H H ~ \ .
O
O~~O
~NH
and
Unless otherwise indicated, the term "oxo" refers to =O.
The term'=Ar'-Are-", as used herein, unless otherwise indicated include two
rings without any limitation of the order of attachments to R° and R5.
For example, if
-Ar'-Are- is defined as
\ /
--~ ; then the -Ar'-Are- groups can be
Rs Rs
/ \ N=~~
Ra /- \ ~ °r Ra /- \ / ,
N-O
/ \ /
and if -Ar'-A~- is defined as N~ ; then the -Ar'-A~- groups can
~/ \ / ~' R5 R4 ~~ \ / \
be Ra / - N~ or L"N " 'R5.
The phrase "pharmaceutically acceptable salts)", as used herein, unless
otherwise indicated, includes salts of acidic or basic groups which may be
present in
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the compounds of formula (I). The compounds of formula (I) that are basic in
nature
are capable of forming a wide variety of salts with various inorganic and
organic
acids. The acids that may be used to prepare pharmaceutically acceptable acid
addition salts of such basic compounds of formula (I) are those that form non-
toxic
acid addition salts, i.e., salts containing pharmacologically acceptable
anions, such
as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,
bitartrate, borate,
bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate,
citrate,
dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate,
fumarate,
gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,
hydrabamine,
hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate,
laurate,
malate, maleate, mandelate, mesylate, methylsulfate, mutate, napsylate,
nitrate,
oleate, oxalate, pamoate (embonate), palmitate, pantothenate,
phospate/diphosphate, polygalacturonate, salicylate, stearate, subacetate,
succinate,
tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts.
In the compounds of formula (I), where terms such as (CR"R'2)q or
(CR"R'2), are used, R" and R'2 may vary with each iteration of q or t above 1.
For
instance, where q or t is 2 the terms (CR"R'Z)q or (CR"R'2), may equal -CHZCHZ-
,
or -CH(CH3)C(CH2CH3)(CHzCH2CH3)-, or any number of similar moieties falling
within the scope of the definitions of R" and R'2. Further, as noted above,
any
substituents comprising a CH3 (methyl), CHZ (methylene), or CH (methine) group
which is not attached to a halogeno, SO or SOZ group or to a N, O or S atom
optionally bears on said group a substituent selected from hydroxy, C,-C4
alkoxy
and amines.
The term "treating", as used herein, unless otherwise indicated, means
reversing, alleviating, inhibiting the progress of, or preventing the disorder
or
condition to which such term applies, or one or more symptoms of such disorder
or
condition. The term "treatment', as used herein, unless otherwise indicated,
refers to
the act of treating as "treating" is defined immediately above.
The term "modulate" or "modulating", as used herein, refers to the ability of
a modulator for a member of the steroid/thyroid superfamily to either directly
(by
binding to the receptor as a ligand) or indirectly (as a precursor for a
ligand or an
inducer which promotes production of ligand from a precursor) induce
expression
of genes) maintained under hormone expression control, or to repress
expression
of genes) maintained under such control.
The term "obesity" or "obese", as used herein, refers generally to
individuals who are at least about 20-30% over the average weight for his/her
age,
sex and height. Technically, "obese" is defined, for males, as individuals
whose
body mass index is greater than 27.8 kg/m, and for females, as individuals
whose
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body mass index is greater than 27.3 kg/m2. Those of skill in the art readily
recognize that the invention method is not limited to those who fall within
the above
criteria. Indeed, the method of the invention can also be advantageously
practiced
by individuals who fall outside of these traditional criteria, for example, by
those
who may be prone to obesity.
The term "Inflammatory disorders", as used herein, refers to disorders such
as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis,
psoriasis,
chondrocalcinosis, gout, inflammatory bowel disease, ulcerative colitis,
Crohn's
disease, fibromyalgia, and cachexia.
The phrase "therapeutically effective amount", as used herein, refers to
that amount of drug or pharmaceutical agent that will elicit the biological or
medical
response of a tissue, system, animal, or human that is being sought by a
researcher, veterinarian, medical doctor or other.
The phrase "amount . . . effective to lower blood glucose levels," as used
herein, refers to levels of compound sufficient to provide circulating
concentrations
high enough to accomplish the desired effect. Such a concentration typically
falls in
the range of about 10 nM up to 2 NM; with concentrations in the range of about
100
nM up to 500 nM being preferred. As noted previously, since the activity of
different
compounds which fall within the definition of Formula (I) as set forth above
may
vary considerably, and since individual subjects may present a wide variation
in
severity of symptoms, it is up to the practitioner to determine a subject's
response
to treatment and vary the dosages accordingly.
The phrase "insulin resistance", as used herein, refers to the reduced
sensitivity to the actions of insulin in the whole body or individual tissues,
such as
skeletal muscle tissue, myocardial tissue, fat tissue or liver tissue. Insulin
resistance occurs in many individuals with or without diabetes mellitus.
The phrase "insulin resistance syndrome", as used herein, refers to the
cluster of manifestations that include insulin resistance, hyperinsulinemia,
non
insulin dependent diabetes mellitus (NIDDM), arterial hypertension, central
(visceral) obesity, and dyslipidemia.
The phrase "in combination with", as used herein, means that the alpha
substituted carboxylic acids compound of Formula (I) may be administered
shortly
before, shortly after, concurrently, or any combination of before, after, or
concurrently, with such other agents as described in the previous paragraphs.
Thus, the alpha substituted carboxylic acids compound of Formula (I) and the
other
agents may be administered simultaneously as either as a single composition or
as
two separate compositions or sequentially as two separate compositions.
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Certain compounds of formula (I) may have asymmetric centers and
therefore exist in different enantiomeric forms. All optical isomers and
stereoisomers
of the compounds of formula (I), and mixtures thereof, are considered to be
within
the scope of the invention. With respect to the compounds of formula (I), the
invention includes the use of a racemate, one or more enantiomeric forms, one
or
more diastereomeric forms, or mixtures thereof. The compounds of formula (I)
may
also exist as tautomers. This invention relates to the use of all such
tautomers and
mixtures thereof. --
Certain functional groups contained within the compounds of the present
invention can be substituted for bioisosteric groups, that is, groups which
have similar
spatial or electronic requirements to the parent group, but exhibit differing
or
improved physicochemical or other properties. Suitable examples are well known
to
those of skill in the art, and include, but are not limited to moieties
described in Patini,
et al., Chem. Rev, 1996, 96, 3147-3176 and references cited therein.
The subject invention also includes isotopically-labelled compounds, which
are identical to those recited in Formula (1), but for the fact that one or
more atoms
are replaced by an atom having an atomic mass or mass number different from
the
atomic mass or mass number usually found in nature. Examples of isotopes that
can be incorporated into compounds of the invention include isotopes of
hydrogen,
carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H,
'3C,
,aC, ,sN, ,e0, ,~~, s,P~ szP, 355, ,aF, and 36CI, respectively. Compounds of
the
present invention, prodrugs thereof, and pharmaceutically acceptable salts of
said
compounds or of said prodrugs which contain the aforementioned isotopes and/or
other isotopes of other atoms are within the scope of this invention. Certain
isotopically-labelled compounds of the present invention, for example those
into
which radioactive isotopes such as 3H and'4C are incorporated, are useful in
drug
and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-
14, i.e.,
'4C, isotopes are particularly preferred for their ease of preparation and
detectability. Further, substitution with heavier isotopes such as deuterium,
i.e., ZH,
can afford certain therapeutic advantages resulting from greater metabolic
stability,
for example increased in vivo half life or reduced dosage requirements and,
hence,
may be preferred in some circumstances. Isotopically labelled compounds of
Formula (I) of this invention and prodrugs thereof can generally be prepared
by
carrying out the procedures disclosed in the Schemes and/or in the Examples
and
Preparations below, by substituting a readily available isotopically labelled
reagent
for a non-isotopically labelled reagent.
This invention also encompasses pharmaceutical compositions containing
and methods of treating bacterial infections through administering prodrugs of
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compounds of the formula 1. Compounds of formula 1 having free amino, amido,
hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include
compounds wherein an amino acid residue, or a polypeptide chain of two or more
(e.g., two, three or four) amino acid residues is covalently joined through an
amide or
ester bond to a free amino, hydroxy or carboxylic acid group of compounds of
formula 1. The amino acid residues include but are not limited to the 20
naturally
occurring amino acids commonly designated by three letter symbols and also
includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-
methylhistidine,
norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine,
homoserine, omithine and methionine sulfone. Additional types of prodrugs are
also
encompassed. For instance, free carboxyl groups can be derivatized as amides
or
alkyl esters. Free hydroxy groups may be derivatized using groups including
but not
limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and
phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery
Reviews,
1996, 19, 115. Carbamate prodrugs of hydroxy and amino groups are also
included,
as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy
groups.
Derivatization of hydroxy groups as (acyloxy)methyl and (acylaxy)ethyl ethers
wherein the acyl group may be an alkyl ester, optionally substituted with
groups
including but not limited to ether, amine and carboxylic acid functionalities,
or where
the acyl group is an amino acid ester as described above, are also
encompassed.
Prodrugs of this type are described in J. Med. Chem., 1996, 39, 10. Free
amines
can also be derivatized as amides, sulfonamides or phosphonamides. Alf of
these
prodrug moieties may incorporate groups including but not limited to ether,
amine
and carboxylic acid functionalities.
Other aspects, advantages, and preferred features of the invention will
become apparent from the detailed description below.
Detailed Description And Preferred Embodiments of The Invention
The following reaction Scheme illustrates the preparation of the
compounds of the present invention. Unless otherwise indicated, R - R", Q, Y,
Ar'-Ar', and Ring A, in the reaction scheme and discussion that follow are as
defined
above.
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Scheme 1
R~
Lv2
Ra
Q
R2 Vla
R1 HO~Ar~'Lv1
Va
Ra-Are-Lv~
R2
IVa
R~ Rs
M t A~\RS~CO R Illa
2
R'
R~ Rs
4
R ~Ar1' A~\ R5~C02R
R
Ila
R'
R~ Rs
4
Q R~Ar~.Ar~\Rs Rs
R2
la
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Scheme 2
Lv3 R~ Rs
~A~2.OH Lv~C02R
Vllla IXa
R7 Rs
~Ar~
Lv3 ~R5~C02R
Vlla
R~ Rs
Are
Me ~R5~CO2R
Illa
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Scheme 3
i
R~ Re
O'p,r~~A~~ s~
C02R
Xla
R7 Ra
HO .A
\Ar~ '\R
C02R
R'
Q R4lLvz
RZ '"
Vla
R'
R'
R4 .Ar2~ s~R
R2 ~Ar~ R C02R
Ila
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Scheme 4
R1
Ra
~H
Q
R2
Vb
R'
a iN~
Q
R2
IVb
COOR
Y ~~Ar3 R5
P
12 ~~~R$
R11 R R
1 Illb
Ilb ~~P
n11 Q12 R
1
Ib R~1 R1z R
R5 is -(CR"R'2)m Z-(CR"R'Z)g; wherein Z is -O-, -NR'°a-, or -S(O)S ;
wherein
m and s are independently 0, 1, 2, or 3; and wherein j is 0, 1, or 2
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Scheme 5
Ar3p-R5H
R» R 2
Vlib
Ar3 RS COOR
P ~
Rv~Rs
R R
Illb
R5 is -(CR"R'Z)m Z-(CR"R'Z)S; wherein Z is -O-, -NR'°e-, or -S(O)S
;
wherein each m and s are independently 0, 1, 2, or 3; and wherein j is 0, 1,
or 2
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Scheme 6
R'
Q R°-Ar°--Lv$
Rz Vllc
R1
O
Q -R°-.-Ar°-R) s
~H
Rz Vlc
R'
Q ---R°-Ar°-RSOH
Rz Vc
Rt
Q R°-Ar°-RsLv~
Rz IVc
Lvs COOR
R Ills
Q -R°-Ar°-R6 COOR
Rz
Ilc A
R'
Q R°-Ar°----Rs COOH
Rz
Ic
Rsis-(CR~~Rt2)m-Z-(CR~~R~2)s;whereirl2is -CHi.
wherein each m and s are independently 0, 1, 2, or 3.
t0 Scheme T
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R'
Q R4 Ar4-Lv~
R2 ~ Vllc
R1
O
Q R4 Ar4 I I 5.
H
Rz Vlc
Lv5 COOR
Ills
R~ A
OH
Q R4 Ar4 ~ 5 COOR
R2 Viltc q
R'
Q R4 Ar4 R5 COOK
Rz
Ilc
RS is -(CR~~R~2)m Z-(CR~~R~2)g; wherein Z is -CH2-;
wherein each m and s are independently 0, 1, 2, or 3.
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Scheme 8
PO-Ara-Lv9
Xilic
0
I
PO-Ara-C-H
Xlic Lv5 COOR
A nI~
OH
PO-Ara-RS COOR
Xlc A
i
PO-Ara-R5 COOR
Xc
A
HO-Ara-R5 COOR
IXc
A
R'
VIa
R' Q
Ra-Lv~o
R2
Q Ra Ara RS COOR
RZ Ilc A
RS is-(CR~~R~2)m-Z-(CR~~R~2)s; wherein Z is -CHZ-;
wherein each m and s are independently 0, 1, 2, or 3.
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Scheme 9
PO-Ar4-Lv9
Xlllc
O
PO-Ar4
Xllc \H
PO-Ar4 R50H
XVc
PO-Ar4 R5Lv~o
XIVc Lv5 COOR
IIIc A
PO-Ar4 R5 COOR
Xc A
RS is -(CR~~R~2)m-Z-(CR~1R~2)s; wherein Z is -CH2-;
wherein each m and s are independently 0, 1, 2, or 3.
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Scheme 10
PO Ar° OH
XIVc
ws COOR
\ Illc
A
PO Ar'° R5 COOR
Xic t~A
HO Ar4 R5 COOR
!Xc R~
R~ R2 O Via
Q R4-Ar4 RS COOR
2
R , Ilc A
R'
Q R4-Ar4 RS COOH
R2
is A
RS is -(CR"R'2)m Z-(CR"R'2)S; wherein Z is -O-, -NR'°e-, or -S(O)S
;
wherein each m and s are independently 0, 1, 2, or 3; and wherein j is 0, 1,
or 2.
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Scheme 11
i halide
N
halide
XVIc ~~s
COOR
\ Illc
A
\ COOR
JA
'N
halide
XVc
R'
\ COOR
A
R4 N
Ic
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Scheme i2
Ri Ri~
Q R4-OH LV12%~~ 11
N--~~ Lv
R2 VIId VId
R17
R1
i
4-~' '~ 11
Q R N--~~ Lv
RZ
Vd
1 R17
i
R
Q 4 N~
CN
R2 IVd
O
Rtt
R1
COOR
R4 N"i\CH
Rz IIId ~O-Rs
r Ri
R1
~i
Q R4 NCH COOR
2
R2
IId H~O-R9
R1'
R1
Q R4 N~r\CHZ COOH
R2
Id H~O-R9
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Scheme 13
O
~Br
OCHZCH3
IXd
Br N Xlid
O R, 1 O
~O.CH3 I I ~ / 'OCH2CH3
Br I N -H3C~(OCH3
VIIId XId
R, I O R, i
I ~ .CH3 I
~ i O i I
Q .[ R4 I N H3C OCH3 RZ~.Ra I N
ud Xd
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Referring to Scheme 1 above, the compound of formula la may be prepared
by hydrolysis of compounds Ila, wherein the group C02R is a hydrolyzable ester
group such as methyl ester (COZ-CH3) or ethyl ester (COZ-CHzCH3), by alkali
metal
hydroxides (e.g. NaOH, LiOH, KOH) in a suitable solvent (e.g. aqueous THF,
aqueous methanol or combinations thereof) at a temperature between 0 and 100
degrees or by heating in a microwave synthesizer. Compounds of formula Ila may
be prepared by a coupling reaction of compound IVa, wherein Lv' is CI, Br, I,
or
triflate, and an organometallic compound Illa, wherein Met = boronic acid or
ester,
stannane etc, and the group COZR is as described above, mediated by a
palladium(0) or other transition metal catalyst. Compound IVa can be obtained
by
alkylation of compound Va, wherein Lv' is as described above, with compound
Vla,
wherein Lvz is CI, Br, I, or triflate.
Referring to Scheme 2 above, the compound of formula Ills, which is used in
Scheme 1, may be obtained from compounds Vlla, wherein Lv3 is CI, Br, t, or
triflate, by palladium(O) mediated coupling reactions with a reagent such as
pinacolatodiborane. Compounds Vlla, wherein Lv3 is as described above, can be
obtained by alkylation of compounds Vllla, wherein Lv3 is as described above,
with
compound IXa, wherein Lv4 is CI, Br, 1, or triflate.
Referring to Scheme 3 above, esters Ila, which is used in Scheme 1,
wherein the group COZR is as described above, may also be prepared by
alkylation
of compound Xa, wherein the group COZR is as described above, with compound
Vla, wherein LvZ is as described above in the description of Scheme 1.
Compounds Xa may be obtained from compound Xla, wherein the group C02R is
as described above, by reacting compound Xla with a deprotecting agent, such
as
with hydrogen gas over a metal catalyst (e.g. palladium on carbon) in a
suitable
solvent (e.g. THF, methanol, ethanol) at a temperature between 0 degrees
Celcius
and 100 degrees Celcius.
Compounds Xla are commercially available or can be made by those
skilled in the art.
Referring to Scheme 4 above, compounds of formula Ib; wherein RS is -
(CR"R'2)m Z-(CR"R'2)s; wherein Z is -O-, -NH'°a-, or -S(O)S-; wherein
each m
and s are independently 0, 1, 2, or 3; and wherein j is 0, 1, or 2; may be
prepared
by hydrolysis of compounds Ilb, wherein R5 is as described in the compounds of
formula Ib and the group C02R is as described above, by an alkali metal
hydroxide
(e.g. Na OH, LiOH, KOH) in a suitable solvent (e.g. aqueous THF, aqueous
methanol or combinations thereof) at a temperature 0 degrees Celcius and 100
degrees Celcius. Compounds of formula tlb, wherein RS is as described in the
compounds of formula Ib, may be prepared by reaction of compounds Illb,
wherein
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RS is as described in the compounds of formula Ilb and the group C02R is as
described above, with an activated acylating agent such as Vlb in a suitable
solvent (e.g. THF, acetonitrile, dioxane, toluene) at a temperature between 0
degrees Celcius and 100 degrees Celcius. Compounds IVb may be obtained from
compound Vb by reacting compound Vb with compound Vlb, wherein Lvs is a
leaving group. Suitable compound Vlb includes N,N'-carbonyl diimidazole.
Compounds Vb and Vlb are commercially available or can be made by
those skilled in the art.
Referring to Scheme 5 above, compounds of formula Illb, which is used in
Scheme 4, wherein R5 is as described in the description of Scheme 4 and the
group COZR is as described above, may be prepared by reacting compound Vllb
wherein R5 is as described in the previous paragraph, with an appropriate
electrophile of formula Lvs-C(R'RB)-COOR, wherein Lvs is a leaving group such
as
halo, in the presence of a base (e.g. cesium carbonate, potassium carbonate)
in a
suitable solvent (e.g. THF, DMF, acetonitrile, or DMSO) at a temperature
between
0 degrees Celcius and 100 degrees Celsius. Suitable electrophiles of formula
Lvs-
C(R'R8)-COOR include methyl 2-bromo-2-methyl propanoate. Compounds Vllb are
commercially available or can be made by those skilled in the art.
Compounds of formula Ib, Ilb, Illb, and Vllb; wherein R5 is -(CR"R'2),"-Z
(CR"R'2)8; wherein Z is -CHZ-, and wherein each m and s are as described
above;
can be prepared by methods known to those skilled in the art.
Referring to Scheme 6 above, compounds of formula Ic, wherein RS is -
(CR"R'z)m Z-(CR"R'2)s; wherein Z is -CHI-, may be prepared by hydrolysis of
compounds Ilc, wherein the group COZR is as described above, by alkali metal
hydroxides (e.g. NaOH, LiOH, KOH) in a suitable solvent (e.g. aqueous THF,
aqueous methanol or combinations thereof) at a temperature between 0 degrees
Celsius and 100 degrees Celsius or by heating in a microwave synthesizer.
Compounds Ilc may be prepared by alkylation of compound Ills, wherein Lv5 is a
leaving group, with compound IVs (when Lv' is iodide, bromide, chloride or
other
leaving group). Various methods can be used to effect this reaction, such as
deprotonation of compound Ills (Lv5 - H) with a base e.g. sodium
bis(trimethylsilyl)amide. Compounds IVs may be prepared from compounds Vc by
reaction with a halogenation agent or halogenation system e.g, oxalyl chloride
and
dimethyl formamide or from another halide (e.g. reaction of compound IVs, Lv'
= CI
with sodium iodide). Compounds Vc may be prepared from compounds Vlc by
reacting compounds Vlllc with a reducing agent, such as sodium borohydride.
Compounds Vlc may be obtained from compound Vllc (LvB = Br or other halogen)
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by metal-halogen exchange (e.g. with butyllithium) followed by reaction with
dimethyl formamide.
Alternatively, referring to Scheme 7 above, compounds of formula Ilc,
wherein RS is -(CR"R'2)m Z-(CR"R'z)e; wherein Z is -CHZ-, may be prepared by
the reductive deoxygenation of compound Vlllc using a silane and an acid
source,
typically triethylsilane and trifluoroacetic acid. Compounds Vlllc may be
obtained
by addition of compound Illc to compound Vlc. Various methods can be used to
effect this reaction, such as deprotonation of Illc (Lv5 = H) with a base e.g.
lithium
diisopropylamide, or Reformatsky type activation of Illc (Lv5 = Br) with a
metal or
metal salt (e.g. chromium(II) chloride). Compounds Vlc may be obtained from
compound Vllc (Lv8 = Br or other halo) by metal-halogen exchange (e.g. with
butyllithium) followed by reaction with dimethyl formamide.
Alternatively, referring to Scheme 8 above, compound Ilc, wherein R5 is
-(CR"R'2)m Z-(CR"R'z)e; wherein Z is -CHZ-, may be obtained by reaction of
compounds IXc with suitable coupling partners of formula Vla. These reactions
may be effected using electrophiles Vla (e.g. Lv2 = halides, sulphonate
esters) in
the presence of a base (e.g. cesium carbonate) or with alcohols (Lv2 = OH)
under
Mitsunobu-type conditions (e.g. triphenyl phosphine and
diethylazodicarboxylate).
Compounds IXc can be prepared by deprotection of protected compounds Xc.
Suitable protecting groups can include allyl, benzyl etc. Deprotection of Xc
(P =
allyl) can be achieved by exposure to a soluble transition metal (e.g.
tetrakis(triphenylphosphine)palladium(0)) in the presence of a base e.g.
morpholine.
Intermediates Xc-Xlllc may be prepared by the methods described in
Scheme 6.
Alternatively, referring to Scheme 9 above, compound Xc can be prepared
by reacting compound XIVc (e.g. Lv'° = halides, sulphonate esters) with
compound
Illc, wherein Lvs is as described above. Compound XIVc can be prepared by
reacting compound XVc with (C=O)CIZ in a polar aprotic solvents such as
dimethylformamide. Compound XVc can be prepared by reacting compound Xllc
with a reducing agent, such as sodium borohydride. Compounds Xlllc may be
prepared by the method described in Scheme 6.
Alternatively, referring to Scheme 10 above, the compound of formula Ic,
wherein R5 is - CR"R'2 -Z- CR"R'2
( )m ( )S; wherein Z is -O-, -NR , or -S(O)S ;
wherein each m and s are independently 0, 1, 2, or 3; and wherein j is 0, 1,
or 2;
may be prepared by hydrolysis of compounds Ilc by alkali metal hydroxides
(e.g.
NaOH, LiOH, KOH) in a suitable solvent (e.g. aqueous THF, aqueous methanol or
combinations thereof) at a temperature between 0 degrees Celcius and 100
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degrees Celcius or by heating in a microwave synthesizer. Compounds of formula
Ilc may be obtained by reaction of compounds IXc with suitable coupling
partners.
These reactions may be effected using electrophiles (e.g. Vla; Lv2 = halides,
sulphonate esters) in the presence of a base (e.g. cesium carbonate, potassium
carbonate or potassium t-butoxide) or with alcohols (Vla; Lvz = OH) under
Mitsunobu-type conditions (e.g. triphenyl phosphine and
diethylazodicarboxylate).
Compounds IXc may be prepared by deprotection of compounds Xlc wherein P is
a protecting group. Suitable P protecting groups can include allyl, benzyl
etc.
Deprotection of Xlc (P = ally!) can be achieved by exposure to a soluble
transition
metal (e.g. tetrakis(triphenylphosphine)palladium(0)) in the presence of a
base e.g.
morpholine or by reduction (Xlc; P = benzy!) with hydrogen gas over a metal
catalyst (e.g. palladium on carbon) in a suitable solvent (e.g. THF, methanol,
ethanol) at a temperature between 0 degrees Celcius and 100 degrees Celcius.
Compounds Xlc can be obtained by alkylation of compounds XtVc with compound
II(c (Lv5= CI, Br, 1, triflate, as described above).
Referring to Scheme 11 above, in certain cases alkylation of an enolate
anion of compound Illc with a benzylhalide having a formula XVIc affords
compounds XVc. Compounds XVc can be converted into compounds Ic by e.g.
palladium mediated coupling reaction in a solvent known by those skilled in
the art
(e.g., March, Advanced organic Chemistry, Fourth Edition).
Referring to Scheme 12 above, compounds of formula Id may be prepared
by hydrolysis of compounds Ild by alkali metal hydroxides (e.g. NaOH, LiOH,
KOH)
in a suitable solvent (e.g. aqueous THF, aqueous methanol or . combinations
thereof) at a temperature between 0 degrees Celcius and 100 degrees Celcius.
Compounds of formula Ild may be prepared by reaction of compounds Illd with an
appropriate hydrogenation agent such as hydrogen gas over a metal catalyst
(e.g.,
palladium on carbon) in a suitable solvent (e.g. THF, methanol, ethanol) at a
temperature between 0 degrees Celcius and 100 degrees Celcius. Compounds of
formula Illd may be prepared by reaction of compounds IVd with an appropriate
triphenyl phosphine reagent having a formula: (CsHS)3P+-CH(OR9)(COOR) Cf in a
Wittig reaction. Suitable triphenyl phosphine reagents include 1,2-diethoxy-2-
oxoethyl)(triphenyl) phosphonium chloride. Compounds of formula tVd may be
prepared by reaction of compounds Vd as described in Scheme 9. Compounds of
formula Vd may be prepared by reaction of compounds Vld and Vlld as described
in Scheme 9.
Alternatively, compounds of formula Ild may be prepared by the methods
of Scheme 13. Referring to Scheme 13, alkylation of enolate anion of methyl 2-
methoxy propanoate with a benzyl halide IXd affords compounds Vllld.
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Compounds Vllld can be elaborated to compounds Ild by e.g. palladium mediated
coupling reaction. Compounds Ild may also be prepared from compounds Xd.
Compounds Xd can be prepared from compounds Xlld by a sequence of reactions
such as (i) palladium mediated coupling reaction to form compounds Xld, and
(ii)
reduction of the ester to alcohol, and (iii) halide formation to form
compounds Ild.
Any of the above compounds of formula 1 and any of the compounds in the
schemes 1-13 above can be converted into another analogous compound by
standard chemical manipulations. These chemical manipulations are known to
those
skilled in the art and include a) removal of a protecting group by methods
outlined in
T. W. Greene and P.G.M. Wuts, °Protective Groups in Organic Synthesis",
Second
Edition, John Wiley and Sons, New York, 1991; b) displacement of a leaving
group
(halide, mesylate, tosylate, etc) with a primary or secondary amine, thiol or
alcohol to
form a secondary or tertiary amine, thioether or ether, respectively; c)
treatment of
phenyl (or substituted phenyl) carbamates with primary of secondary amines to
form
the corresponding ureas as in Thavonekham, B et. al. Synthesis (1997), 10,
p1189;
d) reduction of propargyl or homopropargyl alcohols or N-BOC protected primary
amines to the corresponding E-allylic or E-homoallylic derivatives by
treatment with
sodium bis(2-methoxyethoxy)aluminum hydride (Red-AI) as in Denmark, S. E.;
Jones, T. K. J. Org. Chem. (1982) 47, 4595-4597 or van Benthem, R. A. T. M.;
Michels, J. J.; Speckamp, W. N. Synlett (1994), 368-370; e) reduction of
alkynes to
the corresponding 2-alkene derivatives by treatment hydrogen gas and a Pd
catalyst
as in Tomassy, B. et. al. Synth. Commun. (1998), 28, p120t f) treatment of
primary
and secondary amines with an isocyanate, acid chloride (or other activated
carboxylic acid derivative), alkyl/aryl chloroformate or sulfonyl chloride to
provide the
corresponding urea, amide, carbamate or sulfonamide; g) reductive amination of
a
primary or secondary amine using R'CH(O); and h) treatment of alcohols with an
isocyanate, acid chloride (or other activated carboxylic acid derivative),
alkyl/aryl
chloroformate or sulfonyl chloride to provide the corresponding carbamate,
ester,
carbonate or sulfonic acid ester.
The compounds of the present invention may have asymmetric carbon
atoms. Diasteromeric mixtures can be separated into their individual
diastereomers
on the basis of their physical chemical differences by methods known to those
skilled
in the art, for example, by chromatography or fractional crystallization.
Enantiomers
can be separated by converting the enantiomeric mixtures into a diastereomric
mixture by reaction with an appropriate optically active compound (e.g.,
alcohol),
separating the diastereomers and converting (e.g., hydrolyzing) the individual
diastereomers to the corresponding pure enantiomers; or by chromatographic
separation using chiral stationary or mobile phase. All such isomers,
including
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diastereomeric mixtures and pure enantiomers are considered as part of the
invention.
The compounds of formulas (I) that are basic in nature are capable of
forming a wide variety of different salts with various inorganic and organic
acids.
Although such salts must be pharmaceutically acceptable for administration to
animals, it is often desirable in practice to initially isolate the compound
of formula (I)
from the reaction mixture as a pharmaceutically unacceptable salt and then
simply
convert the latter back to the free base compound by treatment with an
alkaline
reagent and subsequently convert the latter free base to a pharmaceutically
acceptable acid addition salt. The acid addition salts of the base compounds
of this
invention are readily prepared by treating the base compound with a
substantially
equivalent amount of the chosen mineral or organic acid in an aqueous solvent
medium or in a suitable organic solvent, such as methanol or ethanol. Upon
careful
evaporation of the solvent, the desired solid salt is readily obtained. The
desired acid
salt can also be precipitated from a solution of the free base in an organic
solvent by
adding to the solution an appropriate mineral or organic acid.
Those compounds of formula (1) that are acidic in nature are capable of
forming base salts with various pharmacologically acceptable cations. Examples
of
such salts include the alkali metal or alkaline-earth metal salts and
particularly, the
sodium and potassium salts. These salts are all prepared by conventional
techniques. The chemical bases which are used as reagents to prepare the
pharmaceutically acceptable base salts of this invention are those which form
non-
toxic base salts with the acidic compounds of formula (I). Such non-toxic base
salts
include those derived from such pharmacologically acceptable cations as
sodium,
potassium calcium and magnesium, etc. These salts can easily be prepared by
treating the corresponding acidic compounds with an aqueous solution
containing the
desired pharmacologically acceptable rations, and then evaporating the
resulting
solution to dryness, preferably under reduced pressure. Aftematively, they may
also
be prepared by mixing lower alkanolic solutions of the acidic compounds and
the
desired alkali metal alkoxide together, and then evaporating the resulting
solution to
dryness in the same manner as before. In either case, stoichiometric
quantities of
reagents are preferably employed in order to ensure completeness of reaction
and
maximum yields of the desired final product.
The compounds of the present invention are modulators of PPAR, preferably
PPAR r and a. The compounds of the present invention can modulate processes
mediated by PPAR-y, which refers to biological, physiological,
endocrinological,
and other bodily processes which are mediated by receptor or receptor
combinations which are responsive to the PPAR agonists described herein (e.g.,
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diabetes, hyperlipidemia, obesity, impaired glucose tolerance, hypertension,
fatty
liver, diabetic complications (e.g. retinopathy, nephropathy, neurosis,
cataracts and
coronary artery diseases and the like), arteriosclerosis, pregnancy diabetes,
polycystic ovary syndrome, cardiovascular diseases (e.g. ischemic heart
disease
and the like), cell injury (e.g. brain injury induced by strokes and the like)
induced
by atherosclerosis or ischemic heart disease, gout, inflammatory diseases
(e.g.
arthrosteitis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis,
acne,
sunburn, psoriasis, eczema, allergosis, asthma, GI ulcer, cachexia, autoimmune
diseases, pancreatitis and the like), cancer, osteoporosis and cataracts.
Modulation
of such processes can be accomplished in vitro or in vivo. In vivo modulation
can
be carried out in a wide range of subjects, such as, for example, humans,
rodents,
sheep, pigs, cows, and the like.
The compounds of the present invention may also be useful in the treatment
of other metabolic syndromes associated with impaired glucose utilization and
insulin resistance include major late-stage complications of NIDDM, such as
diabetic angiopathy, atherosGerosis, diabetic nephropathy, diabetic
neuropathy,
and diabetic ocular complications such as retinopathy, cataract formation and
glaucoma, and many other conditions linked to NIDDM, inGuding dyslipidemia
glucocorticoid induced insulin resistance, dyslipidemia, polycysitic ovarian
syndrome, obesity, hyperglycemia, hyperlipidemia, hypercholesteremia,
hypertriglyceridemia, hyperinsulinemia, and hypertension. Brief definitions of
these
conditions are available in any medical dictionary, for instance, Stedman's
Medical
Dictionary (Xth Ed.).
The in vitro activity of the compounds of formula (I) may be determined by
the following procedure.
Scintillatian Proximity Assav~SPA) assaXs
In the SPA assay, 3H labeled darglitazone (for PPAR-y) or GW2331 (for
PPAR-a) is bound to the PPAR protein captured on SPA polylysine beads and
generates radioactive count signal that can be detected by TopCounts
(Packard).
The PPAR-bound 3H labeled ligand can be displaced by an unlabeled compound.
The Ki of the compound can be then determined by the extent of displacement at
various compound concentrations.
Reagents:
SPA polylysine beads, which can be purchased from Amersham
Bioscience.
3H labeled Darglitazone for PPAR-y.
3H labeled GW2331 for PPAR-a.
PPAR proteins.
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Buffer- PBS, 10% glycerol, 14 mM beta-mercaptoethanol.
The compounds of the present invention that were tested all have Kis in at
least one of the above SPA assays of between 0.3 nM to 30 ~M. Certain
preferred
groups of compounds possess differential selectivity toward the various PPARs.
One group of preferred compounds possesses selective activity towards PPAR-a
over PPAR~y. Another preferred group of compounds possesses selective activity
towards towards PPAR-y over PPAR-a. Another preferred group of compounds
possesses selective activity towards both PPAR-a and PPAR-y over PPAR-8.
Another preferred group of compounds possesses selective activity towards PPAR
S over both PPAR-a and PPAR-y.
The alpha substituted carboxylic acids compounds of Formula (I) may be
provided in suitable topical, oral and parenteral pharmaceutical formulations
for use
in the treatment of PPAR mediated diseases. The compounds of the present
invention may be administered orally as tablets or capsules, as oily or
aqueous
suspensions, lozenges, troches, powders, granules, emulsions, syrups or
elixars.
The compositions for oral use may inGude one or more agents for flavoring,
sweetening, coloring and preserving in order to produce pharmaceutically
elegant
and palatable preparations. Tablets may contain pharmaceutically acceptable
excipients as an aid in the manufacture of such tablets. As is conventional in
the art
these tablets may be coated with a pharmaceutically acceptable enteric
coating,
such as glyceryl monostearate or glyceryl distearate, to delay disintegration
and
absorption in the gastrointestinal tract to provide a sustained action over a
longer
period.
Formulations for oral use may be in the form of hard gelatin capsules
wherein the active ingredient is mixed with an inert solid diluent, for
example,
calcium carbonate, calcium phosphate or kaolin. They may also be in the form
of
soft gelatin capsules wherein the active ingredient is mixed with water or an
oil
medium, such as peanut oil, liquid paraffin or olive oil.
Aqueous suspensions normally contain active ingredients in admixture w'tth
excipients suitable for the manufacture of an aqueous suspension. Such
excipients
may be a suspending agent, such as sodium carboxymethyl cellulose, methyl
cellulose, hydroxypropylmethyl cellulose, sodium alginate,
polyvinylpyrrolidone,
gum tragacanth and gum acacia; a dispersing or wetting agent that may be a
naturally occuring phosphatide such as lecithin, a condensation product of
ethylene
oxide and a long chain fatty acid, for example polyoxyethylene stearate, a
condensation product of ethylene oxide and a long chain aliphatic alcohol such
as
heptadecaethylenoxycetanol, a condensation product of ethylene oxide and a
partial ester derived from a fatty acid and hexitol such as polyoxyethylene
sorbitol
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monooleate or a fatty acid hex'ttol anhydrides such as polyoxyethylene
sorbitan
monooleate.
The pharmaceutical compositions may be in the form of a sterile injectable
aqueous or oleagenous suspension. This suspension may be formulated according
to know methods using those suitable dispersing or wetting agents and
suspending
agents that have been mentioned above. The sterile injectable preparation may
also be formulated as a suspension in a non toxic perenterally-acceptable
diluent
or solvent, for example as a solution in 1,3-butanediol. Among the accetable
vehicles and solvents that may be employed are water, Ringers solution and
isotonic sodium chloride solution. For this purpose any bland fixed oil may be
employed including synthetic mono- or diglycerides. In addition fatty acids
such as
oleic acid find use in the preparation of injectables.
The alpha substituted carboxylic acids compounds of Formula (I) may also
be administered in the form of suppositories for rectal administration of the
drug.
These compositions can be prepared by mixing the drug with a suitable non
irritating excipient that is solid at about room temperature but liquid at
rectal
temperature and will therefore melt in the rectum to release the drug. Such
materials include cocoa butter and other glycerides.
For topical use preparations, for example, creams, ointments, jellies
solutions, or suspensions, containing the compounds of the present invention
are
employed.
The alpha substituted carboxylic acids compounds of Formula (I) may also
be administered in the form of liposome delivery systems such as small
unilamellar
vesicles, large unilamellar vesicles and multimellar vesicles. Liposomes can
be
formed from a variety of phospholipides, such as cholesterol, stearylamine or
phosphatidylcholines.
Dosage levels of the compounds of the present invention are of the order
of about 0.5 mg/kg body weight to about 100 mglkg body weight. A preferred
dosage rate is between about 30 mglkg body weight to about 100 mg/kg body
weight. It will be understood, however, that the specific dose level for any
particular
patient will depend upon a number of factors including the activity of the
particular
compound being administered, the age, body weight, general health, sex, diet,
time
of administration, route of administration, rate of excretion, drug
combination and
the severity of the particular disease undergoing therapy. To enhance the
therapeutic activity of the present compounds they may be administered
concomitantly with other orally active an6diabetic compounds such as the
sulfonylureas, for example, tolbutamide and the like.
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Methods of preparing various pharmaceutical compositions with a specific
amount of active compound are known, or will be apparent, to those skilled in
this art.
For examples, see Remington's Pharmaceutical Sciences, Mack Publishing
Company, Easter, Pa., 15th Edition (1975).
The examples and preparations provided below further illustrate and
exemplify the compounds of the present invention and methods of preparing such
compounds. tt is to be understood that the scope of the present invention is
not
limited in any way by the scope of the following examples and preparations. In
the
following examples molecules with a single chiral center, unless otherwise
noted,
exist as a racemic mixture. Those molecules with two or more chiral centers,
unless otherwise noted, exist as a racemic mixture of diastereomers. Single
enantiomers/diastereomers may be obtained by methods known to those skilled in
the art.
Where HPLC chromatography is referred to in the preparations and
examples below, the general conditions used, unless otherwise indicated, are
as
follows. The column used is a ZORBAX'''" RXC18 column (manufactured by
Hewlett Packard) of 150 mm distance and 4.6 mm interior diameter. The samples
are run on a Hewlett Packard- 1100 systemA gradient solvent method is used
running 100 percent ammonium acetate / acetic acid buffer (0.2 M) to 100
percent
acetonitrile over 10 minutes. The system then proceeds on a wash cycle with
100
percent acetonitrile for 1.5 minutes and then 100 percent buffer solution for
3
minutes. The flow rate over this period is a constant 3 ml / minute.
In the following examples and preparations, "Et" means ethyl, °AC"
means
acetyl, °Me" means methyl, °ETOAC" or °ETOAc" means ethyl
acetate, °THF" means
tetrahydrofuran, and "Bu" means butyl.
Chiral supercritical fluid chromatography (SFC) conditions.
Single enantiomers of certain racemic compounds were obtained by SFC
using a chiralpak AD-H column at 140 bar and 2.5 mUmin, chiralpak AS-H column
at 140 bar and 2.5 mUmin, chiralpak OJ-H column at 140 bar and 2.5 mL/min.
Throughout the following sections, compounds of the general formula
below were prepared by procedures analogous to those described in Heterocycles
2001, 55(4), 689-703.
OH
Ar--('
O
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Example A-1
2-Methyl-2~[3'-f2-(5-methyl-2-phenyl-1 3-oxazol-4-vl)ethoxvl-1 1'-biphenyl-3
Y)oxy)propanoic acid
/ \ N O ~ ~ I ~OMe O w I OH
0~ I ~ O O / \ N~ ~ O
0
To a solution of methyl 2-methyl-2-({3'-[2-(5-methyl-2-phenyl-1,3-oxazol-4-
yl)ethoxy]-1,1'-biphenyl-3-yl}oxy)propanoate (0.89 g, 1.76 mmol) in methanol
(20
mL) was added water (2.6 mL) and potassium carbonate (0.73 g, 2.0 equiv). The
mixture was then heated at reflux for 5 hours and allowed to cool to ambient
temperature. The solution was poured into water, acidified to pH 2 with 1 N
hydrochloric acid and extracted with ethyl acetate (3x30 mL). The combined
organics were washed with saturated aqueous sodium chloride, dried (anhydrous
sodium sulfate), filtered and concentrated to dryness to give the title
compound as
a white crystalline solid (0.6 g, 70%).
Elemental Analysis: Calcd for C28HZTN05 C 73.51, H 5.95, N 3.06. Found:C
73.26,
H 6.08, N 3.06.
LRMS: 458 (M+H)+.
' H NMR (CDCI3, 400 MHz): 7.97 (2H, dd, J = 3.0, 6.6 Hz), 7.43 (2H, d, J = 2.8
Hz),
7.41 (1 H, s), 7.31 (2H, t, J = 8.0 Hz), 7.23 (2H, d, J = 8.6 Hz), 7.17 (1 H,
d, J = 7.6
Hz), 7.12 (1 H, bs), 6.93 (1 H, dd, J = 1.4, 8.2 . Hz), 6.87 (1 H, dd, J =
2.0, 8.1 Hz),
4.29 (2H, t, J = 7.7 Hz), 3.07 (2H, t, J = 7.7 Hz), 2.40 (3H, s), 1.63 (6H,
s).
Examale A-2
2-Methyl-2-fl3'-df4-(trifluorometh I)~yl]oxy>~1.1'-biphenyl-3-yl)oxvlpr~anoic
acid
CF3 i i CFs i i
w ~ O ( ~ w ~ O~OMe _---.. w ~ O I ~ w ~ OOH
i fOI i tlO
Following the procedure described in Example A-1, starting from methyl 2-
methyl-
2-[(3'-{[4-(trifluoromethyl)benzyl]oxy}-1,1'-biphenyl-3-yl)oxy]propanoate, the
title
compound was produced.
LRMS: 431 (M+H)+.
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Example A-3
2-Methyl-2-f(3'-(2-f 1-(6-methylpyridazin-3-yl)piperidin-4-yllethoxy ~-1 1'-
biphen
vl)oxv)propanoic acid
N~O I i w I O~OMe ~O I ~ w I OOH
IOI ~ INJ lI
H3C~ H3C.LN.,N
Following the procedure described in Example A-1, starting from methyl 2-
methyl-
2-[(3'-{2-[1-(6-methylpyridazin-3-yl)piperidin-4-yl]ethoxy}-1,1'-biphenyl-3-
yl)oxy]propanoate, the title compound was produced as a pale yellow
crystalline
solid.
LRMS: 477 (M+H)'.
'H NMR (CDCI3, 400 MHz): 7.27 (2H, q, J = 8.1 Hz), 7.20-7.18 (2H, m), 7.12 (1
H,
bd, J = 7.8 Hz), 7.08-7.06 (2H, m), 6.94-6.93 (1 H, m), 6.91-6.90 (1 H, m),
6.84 (1 H,
dd, J= 2.0, 7.8 Hz), 4.25 (2H, bd, J= 13.1 Hz), 4.04 (2H, t, J= 6.1 Hz), 2.88
(2H, t,
J = 13.4 Hz), 2.48 (3H, s), 1.80-1.70 (5H, m), 1.65 (6H, s), 1.33-1.27 (2H,
m).
Example A-4
1-(13'-f2-(5-Methvl-2-phenyl-1.3-oxazol-4-yl)ethoxv]-1.1'-biphenyl-3-
}oxv)cvclobutanecarboxylic acid
I ~
/ \ N O ~ ~ O~OEt ~ N O ~ ~ I OX'OH
~ i O ~ \ ~~ I i llffO
To a solution of ethyl 1-({3'-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-
1,1'
biphenyl-3-yl}oxy)cyclobutanecarboxylate (0.138 g, 0.278 mmol) in
tetrahydrofuran
(3 mL) and methanol (1 mL) was added 2M aqueous lithium hydroxide (0.28 mL).
The resulting mixture was stirred at ambient temperature for 16 hours. Water
(5
mL) and diethyl ether (10 mL) were added and the resulting solution stirred
for 10
min. The ethereal layer was removed and the aqueous layer acidified to pH 2
with
1 N hydrochloric acid at 0 °C and stirred for 20 min. The white
precipitate was
collected by filtration and washed with ice-cold water. After drying at 40
°C under
high vacuum the title compound was afforded as a white crystalline solid
(0.091 g,
70%).
Elemental Analysis: Calcd for CZ9H2~N05,0.15LiCl C 73.18, H 5.72, N 2.94.
Found:C 73.08, H 5.67, N 2.93.
LRMS: 471 (M+H)'.
'H NMR (CDCI3, 400 MHz): 8.03-8.00 (2H, m), 7.43 (3H, t, J= 3.3 Hz), 7.30 (2H,
t,
J = 7.8 Hz), 7.16 (2H, d, J = 6.8 Hz), 7.09 (1 H, t, J = 2.3 Hz), 6.91-6.85
(3H, m),
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4.27 (2H, t, J = 7.8 Hz), 3.06 (3H, t, J = 8.1 Hz), 2.83-2.76 (2H, m), 2.53-
2.46 (2H,
m), 2.40 (3H, s), 2.06-1.97 (2H, m).
Examples A-5 to A-28
Examples A-5 to A-28 were prepared using procedures analogous to those
described for Example A-4.
Ex. Structure 'H NMR MS (m~Z)Analysis
# (LR
or
HR)
(CDCI3, 400 MHz)
7.95 (2H, dd,
J = 2.9, 6.7 Hz),
7.38-7.35 (3H,
), 7.29-7.22 (2H, Calcd for
m), 7.13-7.10
(3H m), 7.07 (1 CzBHz~NOs,0.41
H t J = 2.3 Hz), Hz
A-5 0 \ I / off 6.91-6.88 (1 H, for O C 72.34,
~ m), 6.81 (1 H, LR H
dd, '
~ ~ "~ I J = 1.8, 8.3 Hz), 458 6.03, N
4.57 (1 H, t, J (M+H) 3.01.
~ =
0 0,~ 6.2 Hz), 4.23 (2H, Found:C
t, J = 7.7 Hz), 72.33,
H
3.05-2.92 (2H, m), 6.01, N
2.34 (3H, s), 2.95.
2.03-1.96 (2H, m),
1.06 (3H, t, J
= 7.5 Hz .
(DMSO-ds, 400 MHz)
7.91 (2H,
dd, J = 1.8, 7.6
Hz), 7.73 (1 H,
t,
J = 7.8 Hz), 7.52-7.44 Calcd for
(6H, m),
7.25 (1H, t, J= Cz~HzsLiN20s,2.32
8.0 Hz), 6.83
A-6 a ~ I r off (1 H, dd, J = 2.0, for H20 C 64.82
8.1 Hz), 6.72 LR H
+
o (1 H, d, J = 8.1 459 6.17, N
=l Hz), 4.61 (2H, (M+H) 5.60.
~ ~ t,
o J = 6.7 Hz), 4.11 Found:C
~", (1 H, t, J = 6.3 64.83,
H
Hz), 2.98 (2H, t, 5.89, N
J = 6.7 Hz), 5.52.
2.32 (3H, s), 1.84-1.69
(2H, m),
0.95 3H t,J=7.3
Hz.
(CDCI3, 400 MHz)
8.02-8.00
" \ i ~" (2H, m), 7.65-7.64
(1 H, m), 7.61
r ~ "~ ~ ; (1H, m), 7.45-7.42 Calcd for
(3H, m),
" 7.40-7.30 (3H, m), 0.09Li
7.05 (1H, CzaHzsNZOs
A-7 ddd, J = 1.0, 2.5, for ,
7.8 Hz), 6.65 LR CI C 70.89,
H
(1 H, d, J = 8.1 471 5.52, N
Hz), 4.74-4.69 (M+H)+ 5.90.
(2H, m), 3.10-3.07 Found:C
(2H, m), 70.94,
H
2.83-2.76 (2H, m), 5.65, N
2.47-2.38 . 5.93.
(2H, m), 2.40 (3H,
s), 2.09-1.95
2H,m.
(CDCI3, 400 MHz)
8.11 (1H, dd,
i ", ", J = 1.5, 2.5 Hz),
" 8.00-7.97 (2H,
"
"
~ m), 7.62 (1 H, t,
i J = 7.6 Hz),
; ~
H 7.46-7.41 (4H, m),
7.35 (1H, d,
A-8 J = 7.3 Hz), 7.31 for
( 1 H, t, J = 7.8 LR
Hz), 7.00 (1 H, 459
ddd, J = 1.0, 2.8, (M+H)+
8.1 Hz), 6.65 (1
H, d, J = 8.3
Hz), 4.74-4.69 (2H,
m), 3.16-
3.12 (2H, m), 2.41
(3H, s), 1.63
6H, s .
(CDCI3, 400 MHz) Calcd for
8.63 (1H, bs),
8.13 (1 H bs) 8.06 0
N~ (1 H, dd, J = 47H
X .O" CzsHzsNaOs
" ~ 1.3 2.5 Hz), 7.99-7.96 ,
(2H, m), for .
~o~ Il" ~( LR 0 C 66
73
H
A-9 ~~, 7.52 (1 H, d, J 460 z
= 7.8 Hz), 7.46- (M+H)+ .
,
5.59
N 8.98.
7.42 (3H, m), 7.35 ,
(1 H, t, J = Found:C
66
69
H
7.8 Hz), 7.04 (1 .
H, dd, J = 2.3, ,
5
48
N 8
96
.
8.1 Hz), 4.72-4.68 ,
2H, m , .
.
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3.16-3.12 (2H, m),
2.43 (3H, s),
1.63 (6H, s).
'H NMR (400 MHz,
CDCI3)
1.91 - 2.02 (m,
2 H), 2.24 - 2.31
(m, 3 H), 2.38 - LRMS
A-10i ~ 2.49 (m, 2 H),
' 2.75 (td, 2 H),
~" 2.86 (t, 2 H) 4.04
r v Nx J" f ~ (t, 2 H), 6.58 (dd,(m/z):
~ 1 H), 6.75 - 470
(M+H)*.
6.86 (m, 3 H), 7.04
(d, 1 H),
7.16 - 7.22 (m,
2 H), 7.30 - 7.38
m,3H,7.90 dd,2H.
'H NMR (400 MHz,
CDCI3)
1.83-2.05(m, 2H),
1 " 2.51 (s 3H),
~ 2.50-2.2.58(m 2H),
~ 2.75-
A- i 2.83(m, 2H), 5.02(s,
1 ~ ~ 2H), 6.52
(m, 1 H), 6.96-7.
56(m, 9H),
7.73-7.86 m, 2H
.
'H NMR (400 MHz,
CDCI3)
1.97 - 2.07 (m,
2 H), 2.13 - 2.23
(m 2 H), 2.29 (s, LRMS
~ ~ 3 H), 2.45 -
54 (m
2 H)
2
70 - 2
81 (m
4
2
A-12i ~ ~~ , (m/z):
, 484.5
.
.
.
,
H 4
21
2 H)
)
(
6
63-6
65 (m
, (M+H)*.
.
,
,
q
.
.
,
1 H), 7.07 - 7.18
(m, 2 H) 7.24 -
7.34 (m, 4 H) 7.37
- 7.45 (m, 4
H 7.98 dd, 2 H .
'H NMR (400 MHz,
CDCI3)
1.61 (s, 6 H), 2.35LRMS
A-13v , i (s, 3 H), 2.78
~ 2.89 (m, 4 H), 4.235
~ - 4.31 (m, (m/z):
473
~ H) .
~ ~ ~ N 6
77 (d
2 H)
4 H)
7
15 (d
~ , (M+H)
.
,
,
,
.
,
7.36 - 7.45 (m,
4 H), 7.97 (dd,
2
H.
'H NMR (400 MHz,
CDC13)
1.99 - 2.11 (m,
2 H), 2.51 (dq,
2
H) 2.77 - 2.85 (m, LRMS
2 H), 5.25 (s,
A-14N% v ~ i ~~, 2 H), 6.65 - 6.72 (m/z):
(m, 2 H), 6.94 443.0
-
i ~ 6.99 (m, 2 H), 7.15(M+H)+.
- 7.22 (m, 2
H), 7.35 (t, 2 H),
7.42 - 7.51 (m,
2H,7.80 dd,4H
'H NMR (400 MHz,
CDCI3)
1.98 - 2.08 (m,
2 H), 2.45 - 2.55
(m, 2 H), 2.74 - LRMS
A-15~ I ~ ~ ~ ~" 2.83 (m, 2 H), (m/z):
5.18 (s, 2 H) 6.91 423
- 6.98 (m 1
H) 7.13 - 7.21 (m, (M+H)'.
2 H) 7.26 -
7.37 (m, 5 H), 7.56
- 7.63 (m, 2
H,7.69 d,2H.
'H NMR (400 MHz,
CDCI3)
1.96 - 2.07 (m,
2 H), 2.48-
2.51 (m 2H), 2.73 LRMS
~ ~ - 2.82 (m, 2
~ ~
~'
A-16w H), 4.31 - 4.40 (m/z):
(m, 4 H), 6.63 423
' (dd, 1 H), 6.92 (M+H)'.
- 7.00 (m, 5 H),
7.13 - 7.21 (m,
3 H), 7.25 - 7.36
m,4H
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H NMR (400 MHz,
CDCI3)
1.96 - 2.07 (m,
2 H), 2.44 - 2.55
A-17' ~~ (m, 2 H), 2.74 - LRMS
~" 2.82 (m 2 H), (mh):
3.89 (s, 1 H), 5.25473.5
- 5.31 (s 2
' ' ' H), 6.63-6.65 (m, (M+H)'.
1 H), 7.00 -
7.10 (m, 4 H), 7.17
(t, 2 H), 7.23
-7.31 m,4H,8.12
d,2H.
'H NMR (400 MHz,
CDCI3)
2.02 - 2.14 (m,
2 H) 2.44 - 2.54
(m, 5H) 2.75 - 2.86LRMS
' (m, 2 H)
A-18~ N N I 5.26 (s, 2 H) 6.95 (m/z):
- 7.05 (m, 1 456.5
' H) 7.16 - 7.23 (m, (M+H)a.
2 H) 7.25 -
7.36 (m, 6 H) 7.46
(t, 2H) 8.02
d,2H.
'H NMR (400 MHz,
CDCI3)
1.96 - 2.07 (m,
2 H), 2.44 - 2.54
N N ' I (m, 5 H), 2.74 - LRMS
~ 2.82 (m, 2 H),
~'
~
~
"
A-19~ 5.25 (s,
" 2 H), 6.96 - 7.04 (m/z):
I ~ (m, 1 456.1
(
' H), 7.16 (d, 2 H), (M+H)+.
7.22 - 7.28 (m,
2 H), 7.32 (td,
4 H), 7.42 - 7.49
m,2H,7.99-8.05 m,2H
'H NMR (400 MHz,
CDCI3)
1.97 - 2.07 (m,
2 H), 2.52 (s,
3
I H), 2.64 - 2.65
A-20 (m, 2 H), 2.74 LRMS
I ' - 2
~ 2.82 (m, 2 H) 4.89 456
~" (s, 2H), /
~ 6 .
I ~ 68 (m
6
70
1 H
6
3
6
8
N , M+
o - ( H)
.
),
(m,
.8
-
.
5 (m,
2H), 7.24 - 7.30
(m, 3 H) 7.41 -
7.47 (m, 3 H), 7.58-7.62(m,
2H),
7.66-7.68 m, 2H
.
'H NMR (400 MHz,
CDCf3)
1.56 - 1.65 (m,
6 H), 2.43 (s,
3
;~ ~ H), 3.09 (t, 2 H), LRMS
A-21~N~o ~ I ~ ~o" 4.33 (t, 2 H), (m/z):
F I 6.86 - 6.96 (m, 476
2 H), 7.11 - 7.19
(m, 2 H), 7.20 - (M+H)+.
7.26 (m, 4 H),
7.32 (t, 2 H), 7.41
(td, 1 H), 7.70
ddd, 1 H 7.81 d,
1 H .
'H NMR (400 MHz,
CDCI3)
F 1.64 (s, 6 H), 2.41
~ (s, 3 H), 3.06 M
A-22I \ H (t, 2 H) 4.31 (t (AR
~N~ 2 H), 6.88 (dd, 94
~ 3
H)
04
7
7
13
1 H
7
14
F I ~ , (M+H)..
.
-
.
),
(m,
.
-
7.23 (m, 2 H), 7.23
- 7.34 (m, 3
H,7.52 dd,2H.
'H NMR (400 MHz,
CDCI3)
1.71 (s, 6 H), 2.10
- 2.22 (m, 2
H), 2.35 (s, 3 H),
A-23~ ~ ' I ~ 2.67 - 2.77 (m, LRMS
~ 2 H) 3.99 - 4.09 472
(m, 2 H), 6.67- 5
/
~ 6 z):
t 69 .
4 (m
2H
7
7
3
, (M+H)+
(m,
-
),
.0
.1
(m, 2
H) 7.20 - 7.32 (m,
4 H) 7.37 -
7.44 (m, 2 H) 7.92
- 8.02 (m,
3H .
'H NMR (400 MHz,
CDCI3)
1.76 (s 6 H), 2.49
A-24I ~ (s 3 H), LRMS
N 5.16(s 2H), 7.07 5
~ - 7.19 (m, 2 (~Z)r
444
I % H), 7.23 (t, 1 H), .
I ~ 7.32 (td, 4 H), (M+H)
7.
36 - 7.47 (m, 4
H), 7.98 (dd, 2
H
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'H NMR (400 MHz,
CDCI3)
1.58 (s, 6 H), 3.35
(t, 2 H), 3.99
"!~ I o o (s, 3 H), 4.40 (t LRMS
A-25N o I ~ ~or, 2 H) 6.80 (d, 1 (m/z):
H), 6.81 (dd, 1 458
H), 7.00 (d, 1
H),
7.11 - 7.20 (m, (M+H)'.
3 H), 7.25 (m,
2
H), 7.33 - 7.38
(m, 3 H), 7.92
-
8.00 m,2H.
'H NMR (400 MHz,
CDCI3)
0 1.56 (s, 6 H), 2.31LRMS
A (s, 3 H), 3.11
26 ~ I (t 2 H) 4.25 (t
~ \ N~N~ 2 H) 6.81 (m, 2
- off (m/z):
~ 458
H) 6.96 (s 1 H) (M+H)
7.06 (m, 2 H), .
7.20 (m, 4 H), 7.30
(t, 2 H), 7.82
d,2H.
'H NMR (400 MHz,
CDCI3)
1.62 (s, 6 H), 2.07
- 2.15 (m, 2
H), 3.60 - 3.71 LRMS
A-27oMO ~ I (m, 2 H), 4.13 (m/z):
~or, (q, 421
93
2 H) 4
53 (s 2 H)
6
83 - 6
I ~ .
I ~ ,
.
.
(m, 2 H), 7.01 - (M+H)
7.09 (m, 1 H), .
7.12 (d, 1 H), 7.14
- 7.20 (m, 1
H,7.30 ddd,8H.
'H NMR (400 MHz,
CDCI3)
1.18(t,3H),2.43(s,3H),2.96
- 3.08 (m, 4 H),
~ 3.32-3.35(m, LRMS
I
A-28~ ~, 2H), 3.62-3.65(m (m/z):
_ 1H) 4.24 - 472.5
~ 3
N I 2 H
7
7
7
1
2
I ~ (m, (M+H)
~ 1 ), .
.0
-
9 (m,
4.3
.
H), 7.23 (t, 1 H),
7.32 (td, 4 H),
7.36 - 7.47 (m,
4 H), 7.98 (dd,
2
H.
Preparations of Starting Materials for Examples A-1 to A-28 (Preparations a-1
to a-
Preparation a-1
Methyl 2-(3-iodoohenoxy)-2-methylpropanoate
i OMe
I O
O
To a solution of 3-iodophenol (1.08 g, 4.9 mmol) in N,N-dimethylformamide (10
mL)
was added methyl 2-bromo-2-methyl-propionate (0.76 mL, 1.2 equiv) and cesium
carbonate (3.45 g, 2 equiv). The resulting mixture was heated at 90 °C
for 24
hours and then allowed to cool to ambient temperature. Water was introduced
and
the mixture extracted with diethyl ether (3x20 mL). The combined organics were
washed with water and saturated aqueous sodium chloride, dried (anhydrous
sodium sulfate), filtered and concentrated. The residue was purified by silica
gel
chromatography using 0-30% ethyl acetate in hexanes to provide the title
compound (0.83 g, 53%).
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LRMS: 321 (M+H)+.
'H NMR (CDCI3, 400 MHz): 7.22 (1H, dt, J= 1.3, 7.8 Hz), 7.12 (1H, dd, J= 1.6,
2.4 Hz), 6.84 (1 H, t, J = 8.1 Hz), 6.66 (1 H, ddd, J = 0.8, 2.5, 8.3 Hz),
3.66 (3H, s),
1.47 (6H, s).
Preparation a-2
Methyl 2-l3-iodo~~henoxv)butanoate
OMe
I O
O
Following the procedure described in Preparation a-1, using ethyl 2-
bromopropionate in place of methyl 2-bromo-2-methyl-propionate at ambient
temperature, the title compound was obtained in 93% yield.
LRMS: 321 (M+H)'.
'H NMR (CDCI3, 400 MHz): 7.30 (1H, ddd, J= 1.0, 1.5, 7.8 Hz), 7.24 (1H, dd, J=
1.6, 2.4 Hz), 6.97 ( 1 H, dd, J = 7.8, 8.3 Hz), 6.82 ( 1 H, ddd, J = 1.0, 2.5,
8.6 Hz),
4.53 (1 H, dd, J = 5.8, 6.6 Hz), 3.75 (3H, s), 2.00-1.93 (2H, m), 1.05 (3H, t,
J = 7.5
Hz).
Preparation a-3
Ethyl 1-(3-bromophenoxv)cvclobutanecarboxylate
i OEt
I O
O
Following the procedure described in Preparation a-1, using 3-bromophenol and
ethyl 1-bromocyclobutanecarboxylate as starting materials and heating in a
solution of acetonitrile, the title compound was obtained in 56% yield.
LRMS: 300 (M+H)'.
Preparation a-4
~2-(3-IodophenoxvLethyll-5-methyl-2-phenyl-1.3-oxazole
/ \ N I O I I
O
Following the procedure described in Preparation a-1, starting from 3-
iodophenol
and 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethyl-4-methylbenzenesulfonate at
ambient temperature, the title compound was produced in 77% yield as a
colorless
oil.
LRMS: 406 (M+H)''.
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'H NMR (CDCI3, 400 MHz): 7.87 (2H, dd, J= 1.9, 7.7 Hz), 7.34-7.29 (3H, m),
7.15-
7.13 (2H, m), 6.86 (1 H, t, J = 8.1 Hz), 6.76-6.73 (1 H, m), 4.10 (2H, t, J =
6.6 Hz),
2.85 (2H, t, J = 6.6 Hz), 2.26 (3H, s).
Preparation a-5
2-Bromo-6-f2-(5-meth I-~ 2-phenyl-1.3-oxazol-4-yl)ethoxvlpvridine
N O N~ Br
/ \
O
To a solution of 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethanol (1.04 g, 5.1
mmol)
and 2,6-dibromopyridine (1.21 g, 5.1 mmol) in anhydrous dioxane (20 mL} at 0
°C
was added sodium hydride (60% in oil, 0.368 g, 3 equiv). The resulting mixture
was stirred at ambient temperature for 16 hours. The mixture was poured into
ice-
cold water and extracted with ethyl acetate (3x50 mL). The combined organics
were washed with saturated aqueous sodium bicarbonate and saturated aqueous
sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated.
The
residue was purified by silica gel chromatography using 0-50% ethyl acetate in
hexanes to afford the title compound as a white crystalline solid (1.19 g,
65%).
LRMS: 359 (M+H)'.
'H NMR (CDCI3, 400 MHz): 7.97 (2H, dd, J= 1.8, 7.8 Hz), 7.44-7.35 (4H, m),
7.03
(1 H, d, J = 7.3 Hz), 6.65 (1 H, d, J = 8.1 Hz), 4.55 (2H, t, J = 6.8 Hz),
2.97 (2H, t, J =
6.8 Hz), 2.34 (3H, s).
Preparation a-6
2-Chloro-6-(2-(5-meth)rl-2-phenyl-1.3-oxazol-4-vl)ethoxy]Ipvrazine
N O~N~CI
/ \ . II
O N
Following the procedure described in Preparation a-5, starting from 2-(5-
methyl-2
phenyl-1,3-oxazol-4.-yt)-ethanol and 2,6 dichloropyrazine, the title compound
was
obtained in 64% yield.
LRMS: 316 (M+H)+.
'H NMR (CDCI3, 400 MHz): 8.11 (2W, d, J= 10.4 Hz), 7.97 (2H, dd, J= 1.9, 7.7
Hz), 7.44-7.39 (3H, m), 4.60 (2H, t, J = 6.7 Hz), 2.99 (2H, t, J = 6.7 Hz),
2.35 (3H,
s).
Preparation a-7
Methyl 2-(3-(4,4,5.5-tetramethvl-1 3 2-dioxaborolan-2-yl)phenoxy]butanoate
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O.B ~ i O OMe
~O O
To a solution of methyl 2-(3-iodophenoxy)-2-methylpropanoate (Preparation a-2)
(1.49 g, 4.65 mmol) in dimethylsulfoxide (40 mL) was added potassium acetate
(1.37 g, 3 equiv), bis(pinacolato)diboron (1.3 g, 1.1 equiv) and a solution of
[1,1'-
bis(diphenylphosphino)-ferrocene]dichloropalladium (11) complex (0.152 g, 0.04
equiv) in dichloromethane. The resulting mixture was heated at 80 °C
for 16 hours
and allowed to cool to ambient temperature. Water was introduced and the
mixture
extracted with diethyl ether (3x30 mL). The combined organics were washed with
5% aqueous sodium bicarbonate (2x50 mL) and saturated aqueous sodium
chloride, dried (anhydrous sodium sulfate), filtered and concentrated. The
residue
was purified by silica gel chromatography using 0-25% ethyl acetate in hexanes
to
provide the title compound (0.92 g, 62%)
LRMS: 321 (M+H)''.
'H NMR (CDCI3, 400 MHz): 7.40 (1H, d, J= 7.3 Hz), 7.32 (1H, d, J= 2.8 Hz),
7.28
(1 H, d, J = 8.1 Hz), 6.97 (1 H, ddd, J = 1.0, 2.8, 8.1 Hz), 4.64 (1 H, t, J =
6.3 Hz),
3.73 (3H, s), 2.01-1.94 (2H, m), 1.32 (12H, s), 1.06 (3H, t, J = 7.5 Hz).
Preparation a-8
Methyl 2-meth~2_[,3 54,4.5,5-tetramethy(-1,3,2-dioxaborolan-2
yl)phenoxX]proaanoate
O.B ~ i O OMe
~O O
Following the procedure described in Preparation a-7, using methyl 2-(3-
iodophenoxy)-2-methylpropanoate (Preparation 1) as starting material, the
title
compound was produced in 75% yield.
LRMS: 321 (M+H)~.
'H NMR (CDCI3, 400 MHz): 7.42 (1H, d, J= 7.1 Hz), 7.29 (1H, d, J= 2.8 Hz),
7.22
(1 H, t, J = 7.8 Hz), 6.90 (1 H, ddd, J = 0.8, 2.8, 8.1 Hz), 3.75 (3H, s),
1.56 (6H, s),
1.30 (12H, s).
Preparation a-9
Ethvl 1-[3-(4.4.5,5-tetramethyl-1.3.2-dioxaborolan-2-
yl ohenoxylcvclobutanecarboxylate
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O~ ~ / O-CHZ-CH3
B O
I
O O
Following the procedure described in Preparation a-7, using ethyl 1-(3-
bromophenoxy)cyclobutanecarboxylate (Preparation 3) as starting material, the
title
compound was produced in 80% yield.
LRMS: 347 (M+H)'.
Preparation a-10
Methyl 2-(i3'-(benzyloxy~-1.1'-biphenyl-3-ylloxy)-2-methyloropanoate
O ~ ~ ~ O O-CHa
/ O
To a solution of methyl 2-(3-iodophenoxy)-2-methylpropanoate (Preparation a-1
)
(1.14 g, 3.56 mmol) in benzene (20 mL) was added 3-benzyloxyphenylboronic acid
(0.89 g, 1.1 equiv), 2M aqueous sodium carbonate (3.56 mL) and
tetrakis(triphenylphosphine)
palladium (0) (0.2 g, 0.05 equiv). The resulting mixture heated at reflux for
2 hours
and allowed to cool to ambient temperature. Water was added and the mixture
extracted with diethyl ether (3x20 mL). The combined organics were washed with
5% aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried
(anhydrous sodium sulfate) and concentrated. The residue was purified by
silica
gel chromatography using 0-15% ethyl acetate in hexanes to give the title
compound as a colorless oil (1.08 g, 81%).
LRMS: 377 (M+H)+.
'H NMR (CDCI3, 400 MHz): 7.47-7.45 (2H, m), 7.39 (2H, t, J= 7.3 Hz), 7.33 (2H,
t,
J = 7.8 Hz), 7.28 (1 H, t, J = 8.0 Hz), 7.21 (1 H, ddd, J = 1.0, 1.5, 8.1 Hz),
7.17 (1 H,
dd, J = 1.8, 2.3 Hz), 7.14 (1 H, dm, J = 7.6 Hz), 7.08 (1 H, dd, J = 1.8, 2.3
Hz), 6.96
( 1 H, ddd, J = 0.8, 2.5, 8.3 Hz), 6.79 (1 H, ddd, J = 1.0, 2.5, 8.1 Hz), 5.11
(2H, s),
3.78 (3H, s), 1.62 (6H, s).
Preparation a-11
Meths 2-methyl-2~{3'-f2-(5-methyl-2-phenyl-2H 1.2.3-triazol-4-
yl)ethoxylbiohenyl
3-vl)oxv)prooanoate
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-63-
~ NN~ ~ I O
N O ~ W O/ \ Oi
2-(5-Methyl-2-phenyl-2H-1,2,3-triazol-4-yl)ethanol (51 mg, 0.25 mmol), methyl
2-
[(3'-hydroxybiphenyl-3-yl)oxy]-2-methylpropanoate (86 mg, 0.30 mmol), and Ph3P
(98 mg, 0.375 mmol) were dissolved in anhydrous THF (1 mL) and followed by the
dropwise addition of diethyl azodicarboxylate (65 mg, 0.375 mmol) in anhydrous
THF (1 mL) at room temperature via a syringe. The resulting reaction solution
was
stirred at room temperature for 18 hours and concentrated. Purification by
silica
gel column with 20 - 40% EtOAc in hexane afforded 69 mg (59%) of light yellow
oil.
'H NMR (400 MHz, CDCI3) 1.55 (s, 6 H), 2.31 (s, 3 H), 3.10 (t, 2 H), 3.68 (s,
3 H),
4.25 (t, 2 H), 6.70 (m, 1 H), 6.82 (m, 1 H), 7.00 (s, 1 H), 7.05 (d, 1 H),
7.20 (m, 4
H), 7.32 (t, 2 H), 7.90 (d, 2 H)
LRMS (m/z): 472 (M+H)+.
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Example B-1
1-(3-{I( 2-(3-
Trifluoromethyl)phenyllethoxy)carbonvllaminolmethyl)phenoxyZcyclobutane
carboxylic acid
CF3 ~ O N ~ i OH
O
i O O
To a solution of ethyl 1-(3-{[({2-[3-
(trifluoromethyl)phenyl]ethoxy}carbonyl)amino]
methyl}phenoxy)cyclobutanecarboxylate (0.150 g, 0.32 mmol) in tetrahydrofuran
(3
mL) and methanol (0.6 mL) at 0 °C was added 2M aqueous lithium
hydroxide (0.32
mL, 2 equiv). The resulting mixture was stirred at ambient temperature for 24
hours. Water (10 mL) was added and the mixture was extracted with diethyl
ether
(1x15 mL, discarded). The aqueous phase was adjusted to pH 2 with 1N
hydrochloric acid and extracted with ethyl acetate (3x20 mL). The combined
organics were washed with saturated aqueous sodium chloride, dried (anhydrous
sodium sulfate), filtered and concentrated to dryness to produce the title
compound
(85%).
LRMS: 438 (M+H)'.
' H NMR (CDCI3, 400 MHz): 7.62 (1 H, d, J = 7.8 Hz), 7.46 (1 H, t, J = 7.3
Hz), 7.36
(1H, d, J = 7.3 Hz), 7.31 (1H, dd, J = 6.1, 7.6 Hz), 7.18 (1H, t, J = 8.0 Hz),
6.84
(1 H, d, J = 7.6 Hz), 6.65 (1 H, s), 6.56 (1 H, d, J = 7.8 Hz), 4.32-4.27 (4H,
m), 3.11
(2H, t, J = 6.8 Hz), 2.79-2.72 (2H, m), 2.49-2.41 (2H, m), 2.09-1.93 (2H, m).
Examples B-2 to B-29
Examales B-2 to B-29 were prepared by procedures analoQOUS to that used for
Example B-1.
ExampleStructure 'H NMR MS (m/z)
# (LR or HR)
(CDCI3, 400 MHz)
7.62 (1H,
d, J = 7.8 Hz),
7.46 (1 H, t,
J =
7.3Hz),7.36(1H,d,J=7.6
Hz), 7.31 (1 H,
t, J = 7.6 Hz),
7.22 (1 H, t J For LR
= 7.8 Hz), 6.88
B-2 F, \ a N ~ i o j (1 H, d, J = 7.3 426 M+H
o" Hz), 6.83 (1 ( )
~ H,
o ~ 1 6
78 (1 H
dd
J = 1
s)
9
8
2
.
,
,
,
.
,
.
Hz), 4.60 (1 H,
t, J = 5.8 Hz),
4.36-4.29 (4H,
m), 3.11 (2H,
t,
J=6.8 Hz), 2.03-1.97
(2H,
m,1.08 3H t,J=7.5
Hz.
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(CDCI3, 400 MHz)
7.62 {1 H,
d,J=7.8Hz),7.46(lH,t,J=
7.5 Hz), 7.36
( 1 H, d, J =
7.6
Hz), 7.31 (1 H,
" ~ t, J = 7.6 Hz), for LR
B-3 I ~ 7.21 (1 H, t, 426 (M+H)f
~3 \ J = 7.6 Hz) 6.94
0 o N ~ o (1H
" 3 Hz)
d
J= 7
6
86 (1H
o .
,
,
.
,
,
s), 6.81 (1 H,
d, J = 7.8 Hz),
4.36-4.29 (4H,
m), 3.11 (2H,
t,
J=7.OHz,1.58 6H,s.
'H NMR (400 MHz,
CDC13)
1.69 (s, 6 H),
4.34 (d, 2 H),
5.05 - 5.17 (m,
~ 1 H) 5.23 {s,
B-4 I y~, 2 H) 6.71 (dd, LRMS (mlz):
~ 1 H), 6.78 (s 426.4
1
~F,~ o H), 6.90 (d, 1 (M+H)~'.
H), 7.18 - 7.23
(m, 1 H), 7.26
- 7.33 (m, 1
H),
7.69 (d, 1 H),
7.89 (d, 1 H),
8.73 s,lH.
H I X
~
'
D~D O N (CDC13, 400 MHz)
O~OH 7.98-7.92
'"' (2H, m), 7.44-7.38
(3H, m),
7.15 (1 H, t, for LR
J = 7.7 Hz),
6.87
B-5 (1H s), 6.84-6.79439 (M+H)+
(2H, m),
4.33-4.28 (4H,
m), 2.89 (2H,
t,
J = 6.8 Hz), 2.32
(3H, s), 1.60
(6H, s).
'H NMR (400 MHz,
CDCI3)
1.58 (d, 6 H),
2.46 (s, 3 H),
~ 4.32 (d, 2 H),
5.06 (s, 2 H) LRMS (m/z):
~ ' 423.5
~
6 (M+H)'
2
H
6.9
lH)
(m,
7.23
7 28 (m, 2
H), 7.39 - 7.48
(m, 2 H), 7.96
-8.05 m,2H.
'H NMR (400 MHz,
CDCI3)
1.63 (m, 6 H),
1.95-2.01 (m,
~ 2H), 2.34 (s,
~'- 3 H), 2.56-2.58 LRMS (m/z):
4 453
(m 2 H) 5
11-4
13(m 2H)
B-7 p.~ . .
,
.
,
4.32-4.35(d, 2H),(M+H)+.
4.89-4.92(b,
1 H), 6.82-6.83(m,
2H), 7.21 -
7.27 (m, 3 H)
7.36 - 7.44 (m,
2H,7.93-7.96m,2H.
'H NMR (400 MHz,
CDC13)
1.59 (s, 6 H),
2.47 (s, 3 H),
4.24 - 4.32 (m,
~ 2 H), 4.99 - 425.5
~ LRMS (m/z
B-8 ~ 5.09 (m, 3 H), j+
6.73 - 6.80 (m, (M+H
2 W), 7.15 (d,
2 H), 7.21 -
7.27 (m, 1 H),
7.37 - 7.46 (m,
2H,7.96-8.04 m,2H.
'H NMR (400 MHz,
CDC13)
1.64 (m, 6 H),
~ ~ 2.35 (s, 3 H), LRMS (m/z):
~ .82 (t, 2 H), 457.5
4.28 - 4.38 (m,
4
B-9 " H), 6.55 (d, 2 (M+H)+.
H), 7.17 - 7.28
~ ~
I I ~~
(m, 2 H), 7.36
- 7.45 (m, 2
H),
7.92 - 8.00 m,
2 H
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'H NMR (400 MHz,
CDCIa)
1.67 (s, 6 H),
4.33 (d, 2 H),
5.03 - 5.14 (m, LRMS (m/z):
B-10 ~.o~~~. 3 H), 6.69 (dd, 435.5
6.78 (s
1 H)
6.92 (dd
1 H)
2
, (M+H) .
,
,
,
H), 7.01 (d, 3
H), 7.06 - 7.14
(m, 2 H), 7.18
(t, 1 H), 7.25
-
7.36 m,3H.
'H NMR (400 MHz,
CDCI3)
1.05 -1.16 (m,
3 H), 2.02-
.04(m, 2H), 4.11
- 4.13 (m, 1
H), 4.48 - 4.58 LRMS (m/z):
B-11 ~'~"~~'~ (m, 2 H) 4.95- 451
1 H)
11 (s
2 H)
5
96(m
5
~ p , (M+H).
.
,
.
,
,
5.21 (s, 2H),
6.75 (d, 1 H),
6.83 - 6.93 (m,
2 H), 7.10 -
7.21 (m, 1 H),
7.30 - 7.41 (m,
6H,8.44 s,2H.
(CDCI3, 400 MHz)
8.06-8.00
(1H, m), 8.01
(1H, d, J=7.6
_" Hz), 7.47-7.42
(1 H, m) 7.43
'~'~"' ~ i (1 H, d, J= 7.8
~ Hz), 7.19 (1
~~ H,
o t, J = 7.8 Hz) for LR
~" 6.87 (1 H, d,
J =
B-12 7.1 Hz), 6.68
(1 H, s), 6.57 426 (M+H)'
(1 H, dd, J =
2.3, 8.1 Hz),
5.17
(2H, s), 4.32
(2H, d, J = 6.1
Hz), 2.80-2.75
(2H, m), 2.65
(3H, s), 2.49-2.41
(2H, m),
2.03-1.97 2H,
m .
'H NMR (400 MHz,
CDCI3)
0.85 - 0.95 (m,
'" 3 H), 1.82 (s,
, 2 H), 2.13 (s,
11~ ~" 3 H), 2.62 -
2.73 (m, 2 H), LRMS (m/z):
3.85 (d 1 H), 439
B-13 3.91 (s, 1 H), (M+H)+.
4.30 - 4.41 (m,
2 H), 4.99 (s,
1 H), 6.58 (d,
1
H), 6.66 (s, 2
H), 6.94 - 7.06
(m, 2 H), 7.22
(s, 3 H), 7.70
-
7.81 m, 2 H .
'H NMR (400 MHz,
CDCI3)
1.93 - 2.01 (m,
2 H), 2.46 (s,
3 H), 4.34 (d,
2 H), 4.56-
4.57(m, 1 H),
B-14 ~ a ~ ~ ~ 5.06 (s, 3 H), LRMS (m/z):
425.5
1 H)
6
74-6
76(m
6
82-
~" . (M+H)'
.
.
,
,
6.84(m, 1 H),
6.89-6.91 (m,
1 H), 7.19 - 7.28
(m, 2 H),
7.41 - 7.46 (m,
2 H), 7.98 -
8.04 m, 2 H
" o a~~o"
B-15 ~ ~ llff for LR
451 (M+H)+
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(CDCI3, 400 MHz)
7.96-7.94
(2H, m), 7.42-7.40
(3H, m),
7.19 (1 H, t J
~ = 7.7 Hz), 6.79
(2H, d, J = 7.6
Hz), 6.60 (1
H,
B-16 s), 4.32 (1 H, for LR
d, J = 6.1 Hz),
4.20 (2H, s), 465 (M+H)+
2.81-2.75 (2H,
m), 2.62-2.59
(1 H, m), 2.49-
2.41 (3H, m),
2.32-2.28 (2H,
m), 2.08 (3H,
s), 2.00-1.92
3H,m.
'H NMR (400 MHz,
CDCI3)
1.94 - 2.05 (m,
2 H), 2.38 -
2.48 (m, 5 H),
2.68 - 2.76 (m,
2 H) 4.31 (d, LRMS (m/z):
B-17 ~ ~ ~ ~ ~ 2 H), 5.06 (s 411.4
3
H)
6
52-6
65-
53(m
1 H)
6
~ ~ , (M+H).
.
.
,
,
.
6.67(m, 1 H),
6.83-6.85(m,
1 H), 7.16-7.17(m,
1 H), 7.41 -
7.46 (m, 3 H)
,7.99 - 8.03
(m,
2H.
v o ~~
off for LR
N . ~
~ "~'~'~
B-18 o
~
453 (M+H)'
~\ N~~XN ~ ~ o~H for LR
B-19 453 (M+H)'
'H NMR (400 MHz,
CDCI3)
1.51 (s, 6 H),
4.02 (d, 2 H),
0 5.12 (s, 1 H),
B-20 I ~ ~ ~ 6.72 - 6.80 (m, LRMS (m/z):
I ~ 2 H) 442
~~H 6
89 - 6
96 (m 2 H)
~ , (M+H)
o ,
.
.
6.96 - 7.02 (m, .
2 H), 7.09 (t,
1
H), 7.29 (s, 2
H), 7.31 - 7.39
m,2H,7.64-7.73
m,2H.
'H NMR (400 MHz,
CDCI3)
1.62 (s, 6 H),
2.30 (s, 3 H),
2.69-2.71 (m,
~ 2H), 3.49 - 3.58 ~
~ (
~ '
B-21 ~ - 5 439 5(M+
" 3g~m~ 1 H) 6573-6H)'.
~ )75(m6
"
I
I
, 1 H), 6.97-6.99(m,
1 H), 7.19 -
7.28 (m, 3 H),
7.38 - 7.48 (m,
1 H , 7.96-7.98
m, 2H
'H NMR (400 MHz,
CDCI3)
1.19 - 1.26 (m,
3 H), 2.46 (s,
3 H), 2.93 - 3.02LRMS (m/z):
~ (m 2 H), 439.5
B-22 \ _ 3.26-3.29 (m, (M+H)'.
~N ~ ~ 2H), 3.99-
4.01 (m, 1 H),
4.36 (d, 2 H),
5.06 (s, 3 H),
7.15 (m, 3 H),
7.40 - 7.47 (m,
3 H), 7.98 -
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8.04 (m, 2 H).
'H NMR (400 MHz,
CDC13)
1.21 - 1.27 (m,
3 H), 1.97 -
2.06 (m, 2 H),
2.34 (s, 3 H),
.57 (t, 2 H),
J 2.95 - 3.03 (m,
2
B-23 ~ H) 3.34-3.59(m, LRMS (m/z):
2H) 4.11 - 467.5
4.20 (m, 4 H), (M+H)'
4.35 (d, 2 H),
4.96-4.98(m, 1
H), 7.11 - 7.18
(m, 3 H), 7.21
- 7.27 (m, 3
H),
7.37 - 7.45 (m,
2 H), 7.93 -
7.99 m,2H.
'H NMR (400 MHz,
CDCI3)
1.26 - 1.28 (m,
3 H), 2.35 (s,
3 H), 2.86-2.88(m,
2H), 2.95
3.06 (m, 1 H),
B-24 ' 3.47-3.52(m, LRMS (m/z):
~ '~~~ I ~ 2H), 4.18 - 4.20 453.5
(m, 2 H),
4.29 - 4.40 (m, (M+H)+.
I 4 H), 4.96-
.99(m, 1 H), 7.10
- 7.18 (m, 2
H), 7.19 - 7.28
(m, 3 H), 7.35
- 7.46 (m, 2 H),
7.92 - 7.99
m,2H.
'H NMR (400 MHz,
CDCI3)
1.07 (t, 3 H),
1.94 - 2.05 (m,
3
H), 2.17 (s, 3
H), 2.57 (t,
2 H),
B ~ a ~ ~ ~. 4.15 (t, 1 H),
25 4.17(d, 2H), LRMS (m/z):
4.33 453.5
4
d
2 H
5
1 H
- ~" , (M ).
1r ), +H
.
(
8(m,
), 6.83(m,
1 H), 6.89(m,
1 H), 6.95(m,
1 H), 7.21 - 7.27
(m, 3 H),
7.37 - 7.44 (m,
2 H), 7.94 -
7.99 m, 1 H .
'H NMR (400 MHz,
CDCIs)
1.65 (s, 6 H),
2.88 (d, 2 H), LRMS (m/z):
3.46 (s, 2 H), 426.4
5.03 (d, 3 H),
B-26 F F ~ ~ ~ ~" 6.73 (s, 1 H), (M+H)'.
6.83 (d, 1 H),
6.89 - 7.00 (m,
1 H), 7.19 -
7.31 (m, 3 H),
7.55 (t, 2 H)
CI3) : 1.07 (t,
3H), 1.98 (dq,
2
(s, 2 H) 4.57-4.59(m,LRMS (m/z):
B-27 -f' ~ ~ ~ ~~ ~ ~ 1H), 426.5
~~ (s, 2 H), 6.83(m,'
1 H), 6.89(m,
(M+H)
~N (t, 1 H), 7.48 .
(d, 2 H), 8.06
(d,
2 H).
'H NMR (400 MHz,
CDCI3)
1.21 (m, 3 H),
1.57 (s, 6 H),
2.63-2.84 (m, LRMS (m/z):
2H), 4.22 (d, 372.4
2
B-28 ~ H), 4.83-4.85(b, (M+H)~.
1H), 5.23-
5.25(m, 1 H),
6.84-6.87(m,
3H), 7.13 (dt,
2 H) 7.18 7.23
m,4H.
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'H NMR (400 MHz,
CDCI3)
1.78 (s, 6 H),
2.66 (s, 3H),
4.34 (d, 2 H),
4.85-4.87(b,
_ ' 1 N), 5.05-5.06(s,LRMS (m/z):
B ~' ~ ~ 2H), 6.53- 426.5
29 G~~ '
lf 6.54(m, 1 H), (M+H)
6.67-6.69(m, .
1 H), 6.83-6.85(m,
1 H), 7.13
(dt, 1 H) 7.18
- 7.23 (m, 2
H),
7.95-7.97 m, 2H
.
Preparations of starting materials for Examples B-1 to B-29 (Preparations b-1
to b
Preaaration b-1
Methyl 2-(3-cyanoohenoxy~ 2-methyl~ropanoate
NC I ~ O OMe
O
To a solution of 3-cyanophenol (5 mmol) in acetonitrile (20 mL) or any polar,
aprotic solvent such as dimethyl sulfoxide, N,N-dimethylformamide, etc) was
added
methyl 2-bromo-2-methyl-propanoate (1.2 equiv) and cesium carbonate (2 equiv).
The resulting was mixture heated at 60 °C for 6 hours and then cooled
to ambient
temperature. Water (20 mL) was introduced and the mixture extracted with ethyl
acetate (3x20 mL). The combined organics were washed with saturated aqueous
sodium bicarbonate and saturated aqueous sodium chloride, dried (anhydrous
sodium sulfate), filtered, and evaporated to dryness to provide the title
compound
in 75% yield.
LRMS: 220 (M+H)+.
'H NMR (CDCI3, 400 MHz): 7.30 (1H, t, J= 8.0 Hz), 7.23 (1H, dt, J= 1.3, 7.6
Hz),
7.05 (1H, dd, J = 1.3, 2.3 Hz), 7.01 (1H, ddd, J = 2.3, 2.8, 8.3 Hz), 3.73
(3H, s),
1.57 (6H, s).
Preparations b-2 to b-3
Preparations b-2 to b-3 were prepared using procedures analo4ous to those
described for pre~oaration b-1
PreparationStructure 'H NMR MS (m/z)
# (LR or HR)
CH3 (CDCI3, 400 MHz) 7.33
(1 H, dd, J =
I 7.6, 8.8 Hz), 7.22
( 1 H, dt, J = 1.3,
2
~ p OMe 7,6 Hz), 7.09-7.06 For LR
NC (2H, m), 4.56
(1 H, dd, J = 5.6, 220 (M+H)"
6.6 Hz), 3.73 (3H,
s), 2.01-1.93 (2H,
m), 1.03 (3H, t,
J
= 7.5 Hz).
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(CDCI3, 400 MHz) 7.31
(1H, dd, J=
7.6, 9.1 Hz), 7.22
( 1 H, dt, J = 1.0,
7.8 Hz), 6.91-6.88 For LR
3 ~ (2H, m), 4.20 '
N~ (2H, q, J= 7.2 Hz), 246 (M+H)
i O OEt 2.78-2.71 (2H,
p m), 2.48-2.40 (2H,
m) 2.08-1.96
(2H, m), 1.18 (3H,
t, J = 7.2 Hz).
Preparation b-4
Meth~rl 2 j3-(aminometh,~rl)phenoxy-2-methvlpropanoate
HZN ~ i O OMe
O
To a solution of methyl 2-(3-cyanophenoxy)-2-methylpropanoate (Preparation b-1
)
(4 mmol) in methanol (20 mL) was added 10% palladium on carbon (20% by
weight). The resulting mixture was stirred under an atmosphere of hydrogen for
24
hours and filtered through Celite. The filtrate was concentrated and the
residue
taken up in ethyl acetate and washed with 1 N hydrochloric acid (2x20 mL). The
combined aqueous washes were adjusted to pH >10 with 4N aqueous sodium
hydroxide and extracted with dichloromethane (3x20 mL). The combined organic
extracts were washed with saturated aqueous sodium chloride, dried (potassium
carbonate), filtered and concentrated to dryness to provide the title compound
in
65% yield.
LRMS: 224 (M+H)'.
Preparations b-5 to b-6
Preparations b-5 to b-6 were prepared using procedures analogous to those
described for preparation b-4
Preparation , MS (m/z)
Structure H NMR (LR or HR)
CH3 (CDCI3, 400 MHz) 7.22
(1H, t J=
~ 7.8 Hz), 6.91 (1 H,
d, J = 7.6 Hz),
b-5 O ~e 6.86 (1 H, s), 6.72 For LR
~N (1 H, dd, J = 2.5,
0 8.1 Hz), 4.58 (1 H, 224 (M+H)
t, J = 6.2 Hz),
3.82 (2H, s), 3.74
(3H, s), 2.01-1.94
(2H, m), 1.06 (3H,
t, J = 7.6 Hz).
for LR
b-6 HZN ~ , O OEt 250 (M+H)+
O
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Preparation b-7
~5-Methvl-2-phenyl-1 3-oxazol-4-vl)ethyl 1H imidazole-1-carboxylate
N
/ \ N O~N
O
O
To a solution of 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethanol (1.015 g, 5
mmol) in
toluene (25 mL) was added potassium carbonate (1.38 g, 2 equiv) and N,N=
carbonyldiimidazole (0.97 g, 1.2 equiv). The resulting mixture was stirred at
ambient temperature for 24 hours before water (20 mL) was introduced.
Extraction
with ethyl acetate and washing the combined organic extracts with saturated
aqueous sodium chloride, drying (anhydrous sodium sulfate), filtration, and
concentration to dryness afforded the title compound (100%).
LRMS: 298 (M+H)'.
'H NMR (CDCI3, 400 MHz): 8.10 (1H, s), 7.97-7.93 (2H, m), 7.44-7.39 (5H, m),
4.68 (2H, t, J = 6.7 Hz), 2.98 (2H, t, J = 6.7 Hz), 2.34 (3H, s).
Preparations b-8 to b-10
Preparations b-8 to b-10 were prepared usin4 procedures analogous to those
described for preparation b-7
Prep Structure 'H NMR MS (m/z)
#
(LR or
HR)
rN (CDCI3, 400 MHz) 8.10
cF (1 H, s), 7.68 1 H,
o N J
, ~ d, J = 7.6 Hz), 7.52 For LR
(1 H, t, J = 7.6 Hz),
b-8 ~ ~ 0 7.40 (1 H, s), 7.38 (1 285 (M+H)'
H, s), 7.24 (1 H, t,
J =
7.3 Hz), 7.17-7.13 (1
H, m), 4.63 (2H, t,
J
= 6.8 Hz), 3.29 (2H,
t, J = 6.8 Hz).
"3c"'~N N ~ rN (CDCI3, 400 MHz) 8.49
J (1 H, bs), 8.13
(2H
3 H
d
J= 8
7
57
1H
7
5
o~.N , for LR
. +
,
z),
.
(
, s),
.
4
o (2H, s), 7.26-7.24 (1 285 (M+H)
H, m), 5.52 (2H, s),
2.66 (3H, s).
b-10
for LR
312 (M+H)~
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O~ rN
v , ~~NJ
N
O
Predaration b-11
Meth~2-methyl-2-~3-f((f2l5-metal-2 ~~henyl-1,3-oxazol-4
~)ethoxy]carbon~}amino)methy,
phenoxyjrdroQanoate
i
O N w ( O OMe
/ \
O O
O
To a solution of 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethyl 1H imidazole-1-
carboxylate (Preparation 7) (0.48 g, 1.6 mmol) in tetrahydrofuran (3 mL) was
added
methyl 2-[3-(aminomethyl)phenoxy]-2-methylpropanoate (Preparation b-4) (0.39
g,
1.1 equiv). The resulting mixture was heated at retlux for 16 hours and then
cooled
to ambient temperature. Concentration and purification by silica gel
chromatography using 0-50% ethyl acetate in hexanes gave the title compound
(0.39 g, 53%).
LRMS: 453 (M+H)'.
'H NMR (CDCI3, 400 MHz): 7.96 (2H, dd, J= 1.9, 7.7 Hz), 7.44-7.38 (3H, m),
7.16
(1 H, t, J = 8.0 Hz), 6.89 (1 H, d, J = 7.3 Hz), 6.77 (1 H, s), 6.67 (1 H, dd,
J = 2.3, 8.3
Hz), 4.36 (2H, t, J = 6.7 Hz), 4.30 (2H, d, J = 5.8 Hz), 3.75 (3H, s), 2.83
(2H, t, J =
6.7 Hz), 2.32 (3H, s), 1.57 (6H, s).
Predarations b-12 to b-20
Preparations b-12 to b-20 were prepared usinct procedures analogious to those
used for Pre~~aration b-11
PreparationStructure 'H NMR MS (m/z)
# (LR or
HR)
/ I GN
~~
~~~
cF~
b-12 o for LR
~ ~
440 (M+H)r
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(CDCI3, 400 MHz) 7.63
(1 H, d, J = 7.8
~ Hz), 7.47 (1H, t J= 7.5
Hz), 7.38 (1H, d,
~ = 6.3 Hz), 7.34-7.28 (1
~ H, m), 7.18 (1 H,
b-13 dd, J = 7.6, 8.1 Hz), 440 (M
6.89 (1 H, d, J = 7.3 H)'
Hz), 6.77 (1 H, s), 6.69
(1 H, dd, J = 2.3,
8.3 Hz), 4.33-4.30 (4H,
m), 3.75 (3H, s),
3.13 2H, t, J = 7.0 Hz
, 1.58 6H, s .
(CDCI3, 400 MHz) 7.99
(2H, d, J= 8.1
Hz), 7.41 (2H, m), 7.11
(1 H, t, J = 8.1 Hz),
6.79 (1 H, d, J = 7.6
Hz), 6.60 ( 1 H, s),
6.46
b-14 "~-~ N (1H, dd, J= 2.3 8.1 Hz) For LR
" ~ ~ ~N ~ ~ 5.12 (2H, s), 440 (M+H)+
~~, 4.27 (2H d J = 6.1 Hz),
4.12 (2H q, J =
7.1 Hz), 2.71-2.60 (2H,
m), 2.59 (3H, s),
.42-2.32 (2H, m), 1.98-1.88
(2H, m), 1.09
3H, t,J=7.1 Hz.
"~
~
"~- for LR
b-15
~
~ ~ a~
453 (M+H)'
(CDCI3, 400 MHz) 7.96
(2H, dd, J= 1.9,
i 7.7 Hz), 7.44-7.36 (3H
~ m), 7.18-7.13 (1 H,
~o~ o " m), 6.85 (1 H, d, J =
~~' 7.6 Hz), 6.66 (1 H, s),
", 6.50 (1 H, dt, J = 1.3, For LR
8.1 Hz), 4.35 (2H, t,
b-16 J = 7.1 Hz), 4.29 (2H,
d, J = 6.1 Hz), 4.11 479 (M+H)+
(2H, q, J = 7.1 Hz), 2.83
(2H, t, J = 6.8
Hz), 2.77-2.69 (2H, m),
2.48-2..38 (2H,
m), 2.32 (3H, s), 2.01-1.94
(2H, m), 1.16
3H, t,J=7.2 Hz.
(CDC13, 400 MHz) 7.96
(2H, dd, J = 1.8,
7.8 Hz) 7.43-7.38 (3H,
m), 7.17 (1 H t J =
7.8 Hz), 6.85 (1 H, d,
J = 7.6 Hz), 6.66
(1 H, s), 6.50 (1 H, dd, For LR
J = 2.3, 8.1 Hz),
b-17 4.30 (2H, d, J = 5.8 Hz),4g3 (M+H)+
4.19 (2H, q, J =
7.3 Hz), 4.18-4.08 (2H,
t, J = 7.5 Hz),
.77-2.69 (2H, m), 2.56
(2H, t, J = 7.5 Hz),
2.48-2.39 (2H, m), 2.30
(3H, s), 2.02-1.94
4H, m , 1.16 3H, t, J
= 7.1 Hz .
(CDCI3, 400 MHz) 7.96
(2H, dd, J= 1.8,
~ " .8 Hz), 7.43-7.38 (3H,
~. m), 7.22 (1 H, t J =
~ 8.1 Hz), 6.89 (1 H,
d J = 7.8 Hz), 6.82
X18 (1H, s), 6.74 (1H, dd, For LR
J= 2.2, 8.2 Hz),
4.56 (1 H, t, J = 6.2 467 (M+H)'
Hz), 4.32 (2H, d, J =
5.8 Hz), 4.14 (2H, t,
J = 6.3 Hz), 3.74 (3H,
s), 2.56 (2H, t, J = 7.3
Hz), 2.30 (3H, s),
2.03-1.93 4H, m , 1.06
3H, t, J = 7.3 Hz .
(CDCI3, 400 MHz) 7.96
(2H, dd, J = 1.8,
7.8 Hz), 7.43-7.38 (3H,
m), 7.18 (1 H, t, J =
". ",~,", 8.0 Hz), 6.90 (1 H, d
"~ J = 7.6 Hz) 6.78
p'~
A"
o (1 H, s), 6.68 (1 H, dd, for LR
b-19 D J = 2.2, 8.0 Hz), +
4.31 (2H, d, J = 6.1 Hz),467 (M+H)
4.13 (2H, t, J =
6.1 Hz), 3.75 (3H, s),
2.56 (2H, t, J = 7.3
Hz), 2.30 (3H, s), 2.00
(2H, t, J= 7.1 Hz),
1.58 6H, s .
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(CDCI3, 400 MHz) 7.63
(1H, d, J= 7.8
Hz), 7.47 (1 H, t, J =
7.6 Hz), 7.38 (1 H, d, For LR
b-20 = 7.6 Hz), 7.32 ( 1 H
t J = 7.7 Hz), 7.16 412 (M+H)'
(1 H, t, J = 8.0 Hz),
6.83 (1 H, d, J = 7.3
Hz), 6.65 ( 1 H, s), 6.51
( 1 H, dd, J = 2.3,
8.1 Hz), 4.33-4.29 (4H,
m), 4.18 (2H, q, J
= 7.1 Hz), 3.13 (2H, t,
J= 7.0 Hz), 2.76-
2.69 (2H, m), 2.47-2.39
(2H, m), 2.01-1.94
2H, m , 1.16 3H, t, J
= 7.1 Hz .
Preparation b-21
HO \ Ohi HO ~ O COOMe
b-21a b-216
O
O' /COOMe
b-21c
Preparation of imidazole b-21c
To a solution of the alcohol b-21b (1 mmol) in toluene (5 ml) were added N, N"-
carbonyldiimidazole (1.05 mmol) and potassium carbonate (1 mmol). The
resulting
solution heated at reflux for 3 hr. After cooling to room temperature, water
(20 ml)
was added and the mixture extracted with ethyl acetate (3x20 ml). The combined
extracts were washed with brine, dried over sodium sulfate and concentrated in
vacuo to provide the acyl imidazole b-21c in quatitative yield.
Preparation of alcohol b-21 b
To a solution of 3-hydroxybenzyl alcohol b-21a (1 mmol) and cesium carbonate
(1
mmol) in acetonitrile (10 ml) was added methyl 2-bromo-2-methyl propionate (2
mmol). The mixture was heated under reflux for 6 hours. After cooling to room
temperature, water (50 ml) was introduced and the mixture extracted with ethyl
acetate (3x20 ml). Combined organics were washed with brine, dried over sodium
sulfate and evaporated in vacuo. Silica gel chromatography (SGC) using 10-30%
ethyl acetate-hexane gave alcohol b-21b. Yields ranged betuveen 40-85%.
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O ~ OTs O ~ N3
I \ N \ N O ~ NH2
/ I / ~ \ ~N
b-21d b-21e I / b-21f
b-Zlc
O
O
O COOMe
I \ 'N H O I /
b-Zlg
Preparation of methyl ester b-21g
Following the procedures described in b-11, methyl ester b-21g was prepared by
reacting compound b-21f with compound b-21c in yields ranging from 60 to 90%.
Preparation of amine b-21f
A solution of the azide b-21e (2 mmol) in ethyl acetate (20 ml) and palladium
on
carbon (10% by weight, 50 mg) was treated with hydrogen gas at room
temperature for 4 hours. Removal of palladium by filtration through a pad of
Celite
and concentration produced the amine b-21f in quantitative yield.
Preparation of azideb-21e
To a solution of the tosylate b-21d (1 mmol) in DMF (5 ml) was added sodium
azide (3 mmol). The resulting mixture stirred at room temperature for 14 hours
before water (50 ml) was added. Extraction with ethyl acetate (3x20 ml),
washing of
the combined organics with water, saturated sodium bicarbonate and brine,
drying
over sodium sulfate and concentration gave rise to the azide b-21e in 85%
yield.
Example C-1
1-f4-f2-(5-methyl-2-phenyl-1.3-oxazol-4,r1)ethoxylbenzy~c~hexanecarboxvlic
acid
O
/ ~ N~ ~ ~ OH
O
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Triethylsilane (1.03 g, 8.86 mmol) was added to a solution of methyl 1-
(hydroxyl{4-
[2-(5-methyl-2-phenyl-1, 3-oxazol-4-
yl)ethoxy]phenyl}methyl)cyclohexanecarboxylate (0.797 g, 1.77 mmol) in
dichloromethane (5 mL) and trifluoroacetic acid (1 mL) at room temperature.
The
resulting mixture was stirred for 1 hour then evaporated in vacuo and
azeotroped
with heptane. The residue was dissolved in tetrahydrofuran (3 mL) and water (3
mL) and lithium hydroxide monohydrate (0.223 g, 5.31 mmol) was added. The
resulting mixture was stirred at room temperature for 18 hours, acidified to
pH 2
with 4N hydrochloric acid and extracted with ethyl acetate. The organic phase
was
dried (anhydrous magnesium sulfate), filtered and evaporated to afford the
title
compound (0.332 g, 45%).
Elemental Analysis: Calcd for C~HZ9NOa C 74.44, H 6.97, N 3.34. Found:C 74.22,
H 6.89, N 3.34.
LRMS: 420 (M+H)+.
'H NMR (DMSO-ds, 400 MHz): 7.90 (2H, dd, J= 1.8, 7.8 Hz), 7.51-7.46 (3H, m),
6.98 (2H, d, J = 8.6 Hz), 6.80 (2H, d, J = 8.6 Hz), 4.16 (2H, t, J = 6.6 Hz),
2.90 (2H,
t, J = 6.6 Hz), 2.64 (2H, s), 2.34 (3H, s), 1.85 (2H, d, J = 12.6 Hz), 1.53-
1.46 (3H,
m), 1.29-1.11 (5H, m).
Examples C-2 to C-5
Examples C-2 to C-5 were prepared by procedures analogous to those used for
Example C-1 with the exception that the final hvdrolysis step was carried out
by
dissolving the crude residue in dimethyl sulfoxide (75 mg/mL) and 6N sodium
ydroxide (1 mL) and heatin4 at 150 °C for 10 minutes in a microwave
synthesizer.
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Ex Structure 'H NMR MS (m/z)analysis
#
(LR
or
HR)
(DMSO-ds, 400 MHz)
7.90
(2H, dd, J= 1.9,
H 7.7 Hz), 7.51- for Calcd for
04 (2H d LR C
J= H
7 N
44 (3H
m) 7
, z5 a
C-2 ~H' . 406 2~
. C 74.OS,
, H 6.71,
8.6 Hz), 6.80 (2H,
d, J = 8.6
Hz), 4.15 (2H, (M+H)+ 3.45. Found:3,
t, J = 6.7 Hz), C 73.
2.90 (2H, t, J H 6.69,
= 6.6 Hz), 2.79 N 3.36.
(2H, s), 2.34 (3H,
s), 2.05-2.00
2H, m , 1.75-1.60
6H, m .
(DMSO-dfi, 400
MHz) 7.89
i ~ ~ ~~o (2H, dd, J = 1.8, Calcd for
7.8 Hz), 7.51-
i ~ m, 7.46 (3H, m), 7.04 C~HZ9N04
(2H, d, J = C
0 8.6 Hz) 6.81 (2H, for 74.44
d J = 8.6 LR H 6.97
~ N
C-3 Hz), 3.93 (2H, 20 (M+H},
t, J= ,
6.2 Hz), 3.34. Found:
C
2.79 (2H, s), 2.60 74.30
(2H, t, J = H 6.95
N
7.3 Hz), 2.27 (3H, ,
s), 2.04- ,
26
3
.
1.97 (2H, m), 1.92-1.85 .
(2H,
m , 1.61-1.46 6H,
m .
(DMSO-ds, 400 MHz)
7.94-
0 7.92 (2H, m), 7.54-7.48 Calcd for
(3H,
I ~ off m), 7.04 (2H, d, C24H25NO5
J= 8.6 Hz), C
0 6.92 (2H, d, J for 70.75
= 8.6 Hz), 4.95 LR H 6.18
408 N
C-4 (2H, s) 3.75-3.70 (M+H}+ ,
(2H, m) ,
3.44. Found:
C
3.28 (2H, dd, J 70.60
= 10.0, 11.2 H 6.33
N
Hz), 2.73 (2H, ,
s), 2.43 (3H, ,
s), 3
31
.
1.81 (2H, d, J .
= 13.1 Hz), 1.49-
1.42 2H m .
(DMSO-d6, 400 MHz)
7.90
o ~ (2H, dd J = 1.9,
off 7.7 Hz), 7.51- Calcd for
7
44 (3H
99 (2H
d
m)
6
J=
"' 0 . CZSH2~N05
. C
,
,
,
,
8.6 Hz), 6.81 (2H,
d, J= 8.6
C-5 Hz), 4.16 (2H, for 71.24, H
t, J = 6.6 Hz), LR 6.46, N
i
3.74-3.69 (2H, 22 (M+H)3.32. Found:
m), 3.27 (2H, C
t,
J = 10.6 Hz), 2.90 71.01, H
(2H, t, J = 6.47, N
6.4 Hz), 2.71 (2H, 3.32.
s), 2.34 (3H,
s), 1.79 (2H, d,
J = 13.1 Hz},
1.47-1.39 2H, m
.
Example C-6
1-{4-f2-L'-methox~1.1'-b~hen~ylethoxy]benzy~~cvclobutanecarbo~lic acid
HsC.O ~ ~ O
OH
O
To a solution of ethyl 1-{4-[2-(4'-methoxy-1,1'-biphenyl-4-yl)ethoxyJbenzyl}
cyclobutanecarboxylate (Preparation 14) (0.3921 mmol, 1 equiv.) in
acetonitrile (2
mL) was added 1N aqueous sodium hydroxide (7.2 mL, 8 equiv.). The resulting
mixture was subjected to microwave heating (100 °C) in a Personal
Chemistry
Smith Synthesizer for 40 minutes. Following cooling of the reaction mixture,
1M
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aqueous hydrochloric acid was added until pH 9 was achieved. The mixture was
extracted with ethyl acetate (3x50 mL). The combined organic extracts were
then
washed with saturated aqueous sodium chloride (100 mL), dried (anhydrous
magnesium sulfate), filtered and concentrated in vacuo to afford the crude
product.
The residue was purified by trituration from diethyl ether to afford the title
compound as a white crystalline solid (0.1321 g, 81%).
Elemental Analysis: Calcd for CZ~H280a C 77.86, H 6.78. Found:C 77.65, H 6.85.
LRMS (m/z): 416 (M)'.
'H NMR (Acetone-ds, 300 MHz): 7.53 (2H, d, J = 6.1 Hz), 7.66 (2H, d, J = 5.1
Hz),
7.46 (2H, d, J = 8.5 Hz), 7.13 (2H, d, J = 8.7 Hz), 7.07 (2H, d, J = 8.7 Hz),
6.85
(2H, d, J = 8.5 Hz), 4.20 (1 H, t, J = 6.1 Hz), 3.86 (3H, s), 3.10 (2H, t, J =
7.0 Hz),
3.00 (2H, s), 2.40-2.30 (2H, m), 2.07-1.98 (2H, m), 1.92-1.80 (2H, m).
Examules C-7 to C-93
Examples C-7 to C-93 were ureoared by procedures analogous to those used for
Example C-6 or by stirring a solution of the ester with sodium or lithium h
dry oxide
in aaueous methanol. aaueous ethanol, aqueous tetrahvdrofuran or mixtures
thereof at temperatures between 20 °C and 75°C.
MS
(m/z)
Ex Structure 'H NMR (LR Analysis
# or
HR)
(Acetone-ds, 300 MHz) 7.48 Calcd
(2H, d, J = 8.9 for
Hz), 7.58 (2H, d, J = 8.7 C2sHzsF
Hz), 7.41 (2H, d, J
= 8.5 Hz), 7.13 (2H, t 03
F J = 8.9 Hz) 7.07 (2H for C
LR 77.21
H
C-7" d, J = 8.7 Hz), 6.78 (2H, 404 ,
d, J = 8.7 Hz), 4.14 (M)- 6
23
(2H, t, J= 7.0 Hz), 3.03 .
(2H, t, J= 7.0 Hz), .
Found:
C
2.97 (2H, s), 2.40-2.30 77.13
(2H, m), 2.01-1.92 H
(2H, m), 1.85-1.72 (2H, ,
m). 6.28.
(Acetone-dfi, 300 MHz) Calcd
7.58 (2H d J= 8.3 for
Hz), 7.41 (2H, d, J = 8.3 CZ~H2804
Hz), 7.34 ( 1 H, t, J
=
, 7.9 Hz), 7.21-7.15 (2H,
"' m), 7.12 (2H, d, J = C 77.86
_ I 8.7 Hz), 6.90 (1 H, ddd, for ,
C ~ J = 0.94, 2.64, 8.3 LR H 6.78.
8 " Hz) 416
6.83 (2H (M)'
J = 8.7 Hz)
4.19 (2H
d
t
J =
,
,
,
,
,
,
6.9 Hz), 3.85 (3H, s), 77
3.09 (2H, t, J = 6.8 67
H
Hz), 3.02 (2H, s), 2.39-2.30 ,
(2H, m), 2.07- 67
6
.
1.98 2H, m , 1.89-1.81 .
2H, m
(Acetone-ds, 300 MHz) 7.69 Calcd
(1 H, dt, J = 0.9, for
8.3 Hz), 7.65 (2H, d, J C27H25F3
= 8.3 Hz), 7.58 (2H, t,
J = 8.1 Hz), 7.47 (2H, 04
d, J = 8.3 Hz), 7.31 C
C-9F (1 H, dt, J = 1.1, 8.1 for 68.93,
Hz), 7.13 (2H, d, J = LR H
8.7
Hz), 6.83 (2H, d, J= 8.7 470 5.36.
Hz), 4.21 (2H, t, J= (M)'
~ 6.8 Hz), 3.12 (2H, t, J Found:
= 6.8 Hz), 3.03 (2H, C
s), 2.40-2.30 (2H, m), 69.04,
2.08-1.98 (2H, m), H
1.92-1.79 2H, m 5.47.
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Calcd
for
(Acetone-ds, 300 MHz) 8:42 CzsHz~N
(1 H, d, J = 2.6
Hz), 7.93 (1 H, dd, J = 04
2.6, 8.7 Hz), 7.57 (2H, C
d, J = 8.3 Hz), 7.44 (2H, 74.80,
d, J = 8.3 Hz), 7.13 H
C-10~ d, J = 8.7 Hz), for 6.52
(2H, d, J = 8.9 Hz), 6.84 LR H
(2H
~ ~ 417 3.35.
~~ 6.85-6.81 (1 H, m), 4.20 (M)-
(2H, t, J = 6.8 Hz),
3.91 (3H, s), 3.10 (2H, Found:
t, J - 7.0 Hz), 3.03 C
(2H, s), 2.40-2.30 (2H, 74.67,
m), 2.07-1.99 (2H, H
m), 1.90-1.82 (2H, m). 6.46,
N
3.31.
(Acetone-dfi, 300 MHz) Calcd
8.01 (2H, d, J= 8.5 for
Hz), 7.92 (2H, d Cz7HzeOs
J= 8.5 Hz), 7.70 (2H, d,
J
, S C
", = 8.5 Hz), 7.50 (2H, d, for 69.80
J= 8.1 Hz), 7.13 (2H, LR H
C-11~ d, J = 8.7 Hz), 6.84 (2H,
d, J = 8.7 Hz), 4.22 482 6.07.
(M)'
" (2H, t J = 6.8 Hz) 3.15 Found:
(3H, s) 3.13 (2H, t, C
J=6.8 Hz), 3.03 (2H, s), 68.41
2.40-2.30 (2H, m), H
2.07-1.98 (2H, m), 1.92-1.79 ,
(2H, m). 6.12.
(Acetone-ds, 300 MHz) 7.53-7.48
(1 H, m),
7.52 (2H, d, J = 8.3 Hz), Calcd
7.38-7.34 (1 H, m), for
7.37 (2H, d, J = 8.3 Hz), CzeHz804
7.13 (2H, d, J = 8.7
Hz), 6.83 (2H, d, J = 8.7 for C 78.48,
Hz), 6.78 (1 H, d, J LR
C-12 = 8.3 Hz), 4.57 (2H, t, 428 H 6.59.
J = 8.7 Hz), 4.18 (2H, (M)'
t, J = 6.8 Hz), 3.25 (2H, Found:
t, J = 8.7 Hz), 3.08 C
(2H, t, J = 7.0 Hz), 3.03 78.30,
(2H, s), 2.40-2.30 H
(2H, m), 2.07-1.99 (2H, 6.62.
m), 1.92-1.79 (2H,
m.
Calcd
for
(Acetone-d6, 300 MHz) 7.65 Cz~HzsN
(2H, d, J = 8.7 OsS
C
Hz), 7.59 (2H, d, J = 8.1 H
Hz), 7.42 (4H, dd, 67.62
N~O " = 1.5, 8.1 Hz) 7.13 (2H, for ,
" d J= 8.5 Hz), 6.84 LR 6.09
N
C-13 (2H, d, J = 8.9 Hz), 4.20 '
~ (2H, t, J = 6.8 Hz), 479 2.92.
(M)~
~" 3.10 (2H t, J = 6.8 Hz), Found:
3.03 (2H, s) 3.01 C
(3H, s), 2.40-2.30 (2H, 67.36
m), 2.07-1.99 (2H, H
m), 1.92-1.81 (2H, m). ,
6.11,
N
2.85.
'H NMR (400 MHz, CDCI3) LRMS
2.29 (s, 3 H),
2.39 (m, 2 H), 2.75 (m, (~z):
2 H), 3.00 (q, 2 H),
C-14r v ~ ' ~ 3.30 (d, 2 H), 6.00 (td, 3g0
~~ 1 H), 6.25 (d, 1 H),
6.56 (d, 2 H), 7.08 (d, (M+H)+.
2 H), 7.35 (m, 3 H),
7.90 (m, 2 H).
'H NMR (400 MHz, CDCI3) LRMS
1.77 1.89 (m, 2
o H), 1.93 2.05 (m, 2 H), (m~z):
2.27 (s, 3 H), 2.40
C-15r ~ ~' 2.51 (m 6 H) 2.71 2.80
~~ (m, 2 H) 6.63 (d, 2
H), 6.97 (d, 2 H), 7.40 (M
(dd, 3 H), 7.92 (m, 2 H)..
H).
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
-80-
Calcd
for
CzsHz~N
(DMSO-ds 400 MHz) 12.13 Calcd04
(1H s), 7.86 for C
(2H, m), 7.49-7.40 {3H, CzsHzsNO74.05,
~ m), 7.01 (2H, d, J = H
~
C-16 8.8Hz) 6.78 (2H, t, J = 4 6.71,
~ 8.6Hz), 3.90 (2H, t, J N
= 6.3Hz), 2.89 (2H, s), 06.2013.3.45.
2.56 (2H, t, J =
.3Hz), 2.24 (3H, s), 2.24-2.15Found:Found:
(2H, m) 2.00- C
1.67 (6H, m). 06.2002.73.75,
H
6.64,
N
3.44.
Calcd
for
CzsHzsN
Calcd04
i (DMSO-ds 400 MHz) 12 for C
off 04 (1H s)
7
79
~ .
, CzsHzaNO73.19,
~ . H
\ (2H, m), 7.40-7.34 (3H, 6
0 m) 6.95 (2H d J =
C-17 8.6Hz), 6.78 (2H, t, J= 378 71
0~ 8.6Hz), 4..80 (2H, s) 1700 N
3
2.80 (2H, s), 2.28 (3H, . .
s), 2.12-2.06 (2H, m) .
Found:Found:
1.83-1.57 (4H, m). C
378.1692.73.15,
H
6.26,
N
3.75.
Calcd
for
CzaHzsN
o" (CDCI3 400 MHz) 8.00-7.97 Calcd
(2H m), 7.49- for On0.2Hz
r ~ "~'~~~ ~ 7.40 (3H, m), 7.17 (1 H, Cz4H2sN0O C
t, J = 7.8Hz), 7.03 96
72
H
_ ~ (1 H, s), 6.78 (2H, t, 4 .
C J = 7.1 Hz), 4.24 (2H, ,
18 t, 48
N
6
= 8.1 Hz), 3.14 (2H, s), 92.1857..
2.90 (2H, t, J = ,
7.8Hz), 2.51-2.40 (2H, Found:3-55.
m), 2.36 (3H, s), 2 Found:
2 C
07
1
83
4H
. 39 72.66,
- .1859.H
.
(
, m).
6.65,
N
3.47.
Calcd
for
CzaHzsN
(DMSO-ds 400 MHz) 7.90 Oa
(2H, dd, J= 1.9, C
i ~ o" 7.7 Hz), 7.51-7.44 (3H, 73.64,
m), 7.05 (2H d J= f H
C-19~~ 0 8.6 Hz), 6.81 (2H, d, J= 392 6.44
8.6 Hz), 4.15 (2H t, N
J = 6.7 Hz), 2.92 (2H, (M+H)'3.58.
s), 2.90 (2H, t, J = 6.8
Hz), 2.34 (3H, s), 2.25-2.18 Found:
(2H, m), 1.95- C
1.88 (2H, m), 1.86-1.71 73.49,
(2H, m). H
6.46,
N
3.54.
'H NMR (DMSO-ds, 400 MHz) Calcd
: 7.83 (2H, for
d, J = 9.1 Hz), 7.06-7.02 C2sHzsNO
p~~ (4H, m), 6.82 (2H,
~"~
wo_u d J = 8.6 Hz), 4.17 (2H, s
C ~~1, t, J = 6.3 Hz) 3.80
2 0
- o 3H, s), 3.10 (2H, t, J 22.1962.
( = 6.3 Hz), 2.92 (2H, s),
2.25-2.17 (2H, m), 2.08 Found:
(3H, s), 1.95-1.69
(4H, m). 422.1961
(DMSO-d6, 400 MHz) 7.25-7.24HR
(1 H, m), Calcd
7.19-7.17 (2H, m), 7.00-6.97for
(2H, m), 6.76- CzsHsoNz
6
75
1 H
6
70
10
72
6
2H
4
2H
C-21~ ~ , t,
.
(
, m),
.
.
-
.
(
, m),
(
, N\ J = 6.5 Hz), 2.90 (6H, (M+H)'
s), 2.85 (2H, t, J = 6.5
Hz), 2.25 (3H, s), 2.24-2.2135
(2H, m), 1.95- 2279
.
or, 1.92 (2H, m), 1.78-1.74 .
(2H, m). Found
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
-81-
35.2270.
For
LR
435
(M+H).
HR
Calcd
for
o (CDC13, 400 MHz) 8.13-8.11C25HzaN-
(1 H, m) 7.77-
~ 7.75 (1H, m), 7.66-7.62 204
(1H, m), 7.49-7.45
I ~ ~ (1H, m), 7.09-7.07 (2H, (M+H)'
m), 6.81-6.79 (2H,
C-22N ~ ~ m), 4.23 (2H, t, J= 6.3 17.1809.
Hz), 3.03 (2H, s),
2.99 (2H, t, J = 6.3 Hz), Found
2.46-2.38 (2H, m),
2.40 (3H, s), 2.09-2.02 17.1813.
(2H, m), 1.90-1.86
a " (2H, m). For
LR
418
M+H
HR
Calcd
for
(DMSO-d6, 400 MHz) 12.04 CzsH2sN-
(1H, s), 7.89-
7.84 (4H, m), 6.96-6.94
I (2H, m), 6.72-6.70 (M+H),
C-23~ , ~ (2H, m), 4.06 (2H, t, J; 1915
~" 6.5 Hz), 3.06-3.05 35
(1 H, m), 2.82-2.80 (4H, .
m), 2.26 (3H, s), .
Found
2.15-2.08 (2H, m), 1.83-1.7935
(2H, m), 1.69- 1922
.
" 1.65 (2H, m). .
For
LR
435
M+hi
''
HR
Calcd
for
(CDC13, 300 MHz) 7.84-7.76CzsH2aN-
(2H, m), 7.66- 04F4
61
1H
7
7
7
0
H
( +
~ .
, m)
.
9-
.06 (2
, m), 6.80-6.77
C-24' , ~ (2H, m), 4.19 (2H, t, J 7$
F = 6.5 Hz), 3.03 (2H, 1636
F .
s), 2.96 (2H, t, J = 6.4 Found
Hz), 2.47-2.40 (2H,
" m), 2.37 (3H, s), 2.10-2.0178
(2H, m), 1.95- 1624
,
1.81 (2H, m). .
For
LR
478
M+H
HR
Calcd
for
(CDC13, 300 MHz) 8.06-8.05C24H23N-
(1 H, d), 7.80- OaCl2
7
77
1 H
7
50
7
47
1 H
.
~ (
, m),
.
-
.
(
, d), 7.09-7.06
C-25r ~ (2H, m), 6.80-6.77 (2H, gp
~ m), 4.19 (2H, t, J= 1077
.
6.5 Hz), 3.03 (2H, s), Found
2.94 (2H, t, J = 6.5
" Hz), 2.44-2.38 (2H, m), 80
2.35 (3H, s), 2.08- 1089
.
2.01 (2H, m), 1.92-1.84 .
(2H, m). For
LR
461
M+H
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
- 82 -
HR Calcd
for
(CDC13 300 MHz) 7.87-7.85 (2H,m) 7.24- Cz5H2'N-
I ~ '~~ 7.21 (2H, m) 7.09-7.07 (2H m), 6.81-6.78
C-26 ~ r ~ (2H, m), 4.20-4.17 (2H, m), 3.04 (2H, s), (M+H).
2.98-2.94 (2H, m), 2.48-2.41 (2H, m), 2.38 06.2013.
Found
(3H, s), 2.35 (3H, s), 2.10-2.02 (2H, m), 406.2014
°H 1.90-1.83 (2H, m). For LR
°
406
M+H
HR Calcd
for
(CDC13, 300 MHz) 7.91-7.88 (2H, m), 7.40- CzaHzaN-
,~ 7.37 (2H, m), 7.09-7.06 (2H, m), 6.80-6.77 O4CI
I ~ " ° (2H, m), 4.18 (2H, t, J= 6.5 Hz), 3.03 (2H, (M+H)~
C-27 ~ r ~ s), 2.95 (2H, t, J = 6.5 Hz), 2.44-2.41 (2H, 26.1467.
m), 2.35 (3H, s), 2.08-2.01 (2H, m), 1.90- Found
°" 1.87 (2H, m). 26.1471.
° For LR
426
M+H
HR Calcd
for
°~ (CDC13, 300 MHz) 7.92-7.89 (2H, m), 7.10- CzsOz~N-
7.07 (2H, m), 6.95-6.92 (2H, m), 6.80-6.77 ( 5 )t
C-28 ~° I ~ r ~ (2H, m) 4.17 (2H, t, J = 6.5 Hz), 3.85 (3H, M+H
s), 3.04 (2H, s), 2.95 (2H, t, J = 6.5 Hz), 22.1962.
2.48-2.38 (2H, m), 2.34 (3H, s), 2.10-2.02 Found
°" (2H, m),.1.94-1.83 (2H, m). 22.1948.
° For LR
423
M+H
HR Calcd
for
(CDC13, 300 MHz) 7.57-7.55 (1H, m), 7.51- CzSHz~N-
0 7.49 (1 H m), 7.35-7.30 (1 H, m), 7.10-7.07
(2H, m), 6.97-6.93 (1 H, m), 6.81-6.78 (2H, (M+H)'
C-29 ,o ~ ~ m), 4.19 (2H, t, J= 6.5 Hz), 3.87 (3H,s), 22.1962.
3.04 (2H, s), 2.96 (2H, t, J = 6.5 Hz), 2.48- Found
off 2.38 (2H, m), 2.36 (3H, s), 2.11-2.02 (2H, 22.1947.
o m), 1.94-1.85 (2H, m). For LR
22
M+H
HR Cafcd
for
\ CzsHzaN_
o (CDCI3, 400 MHz) 8.23 (1 H, s), 8.15-8.13 04F3
I
(1H, m), 7.64-7.63 (1H, m), 7.54-7.50 (1H, (M+H)'
C-30 F F ~ \ m), 7.07-7.05 (2H, m), 6.99-6.96 (1 H, m), 60.1730.
6.77-6.75 (2H, m), 6.70-6.68 (1 H, m), 4.19 Found
off (2H, t, J = 6.5 Hz), 60.1728.
o For LR
460
M+hi '
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
-83-
HR Calcd
for
(CDC13, 300 MHz) 7.96 (1H, s), 7.86-7.83 CZ4H2aN-
I ~ N o (1H, m), 7.36-7.33 (2H, m), 7.09-7.06 (2H, (M+
C-31 ~ ~ ~ m), 6.79-6.76 (2H, m), 4.18 (2H, t, J = 6.5 26.1467.
Hz), 3.03 (2H, s), 2.95 (2H, t, J= 6.5 Hz), Found
2.47-2.38 (2H, m), 2.35 (3H, s), 2.08-2.01
(2H, m), 1.91-1.84 (2H, m). 26.1465.
o" For LR
0 426
M+H ''
HR Calcd
for
(CDC13, 400 MHz) 7.81 1H, s), 7.77-7.75 CZSHz~N-
o (1 H, m), 7.33-7.29 (1 H, m), 7.22-7.20 (1 H, 0
i ~ m), 7.09-7.07 (2H, m), 6.81-6.78 (2H, m), (M+H)
C-32 i ~ 4.19 (2H, t, J = 6.5 Hz), 3.04 (2H, s), 2.96 06.2013.
(2H, t, J= 6.5 Hz), 2.44-2.42 (2H, m), 2.39 Found
(3H, s), 2.35 (3H, s), 2.08-2.03 (2H, m), 06.2026.
off 1.89-1.87 (2H, m). For LR
0 407
M+H
HR Calcd
for
(CDC13, 400 MHz) 8.08-8.06 (2H, d), 7.68- CzsH2aN
7.66 (2H, d), 7.09-7.07 (2H, m), 6.80-6.78 (M+H).
C-33 F ~ ~ ~ (2H, m), 4.91 (2h, t, J = 6.5 Hz), 3.03 (2H, 60.1730.
s), 2.97 (2H, t, J= 6.5 Hz), 2.46-2.38 (2H, Found
m), 2.37 (3H, s), 2.09-2.02 (2H, m), 1.92- 80.1723.
1.82 (2H, m). For LR
0
461
M+H '
(DMSO-ds, 300 MHz) 12.19 (1H, s), 8.12- Calcd for
8.11 (2H, m), 7.82-7.79 (2H, m), 7.59-7.44 CZBHzsNO
C-34 \ \N o _ (6H, m), 7.13-6.98 (4H, m), 5.17 (2H, s),
0 2.97 (2H, s), 2.30-2.21 (2H, m), 2.01-1.73 Found?~
off (4H, m). 40.1846.
i~
o (CDC13 300 MHz) 8.09-8.07 (2H, m), 7.68- Calcd for
3
7.66 (2H, m), 7.46-7.26 (6H, m), 7.10-6.78 C oH3oN0
J = 5.8 Hz), 3.04-3.00
C-35 ~ ~ ° ~ o (4H, m), 2.49 2?39 (2H, m), 2.30-2.21 (2H, Found7~
o" m), 2.11-2.02 (2H, m), 1.94-1.81 (2H, m). 68.2165.
(DMSO-ds, 300 MHz) 12.92 (1 H s), 8.12- Calcd for
8.09 (2H, m) 7.82-7.79 (2H m) 7.60-7.44 C2'H24N0
C-36 ~ ~ 'N ° ~ , o (6H, m), 7.02-6.99 (2H m) 6.64-6.60 (2H, 5
m), 5.13 (2H, s), 2.68-2.59 (2H, m), 2.37- 2.1649.
or, 2.26 (2H, m), 1.95-1.84 (2H, m). 42.1639.
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
_g4_
Calcd
for
CzsHz7N
v (CDCl3, 300 MHz) 8.10-8.06Calcd 05
~ ~ ~" (2H, m), 7.69- for C
32 (6H C 18
m) H 74
79-6 NO H
7
66 (2H
m)
7
46-7
6
66
. zs .
. ze ,
,
,
.
,
,
.
.
C-37~ ~ (4H, m), 3.91 (2H, t, J 4 5.80,
= 6.0 Hz), 2.98 (2H, t, N
o~ J= 7.3 Hz), 2.80-2.71 (2H,70.1962.2.98.
m), 2.50-2.40
" (2H, m), 2.24-2.15 (2H, Found:Found:
m), 2.06-1.93 (2H, C
m). 70.1952.73.07,
H
6.81,
N
2.43.
HR
Calcd
for
CaoHzsNO
(CDCI3, 300 MHz) 8.09-8.07).
(2H, m), 7.68- M
v 7.66 (2H, m), 7.46-7.26 6
C-38I ~ 'N (6H, m), 7.10-6.78 2 07.
(4H, m), 4.01 (2H, t
J = 5.8 Hz)
3.04-3.00
_ , Found
,
~ , (4H, m), 2.49-2.39 (2H, 2165
m), 2.30-2.21 (2H, 68
m), 2.11-2.02 (2H, m), .
1.94-1.81 (2H, m) .
For
LR
H 468
M+H
Calcd
for
CzsH2~N
(CDCI3, 400 MHz) 8.03 (2H,Calcd Os
d, J = 8.3 Hz), for
7.66 (2H, d, J = 8.3 Hz), CzsHzsNOC
7.65-7.60 (2H, m), 74.18,
C-39v v N~ ~ OH 7'49-7.32 (3H, m), 6.74-6.63s H
~ (4H, m) 4.03 5.80,
N
(2H, t, J = 6.6 Hz), 2.96 70.1962.2.98.
(2H, t, J = 6.6 Hz),
2.81-2.70 (2H, m), 2.49-2.35Found:Found:
(2H, m), 2.38 C
(3H, s), 2.10-1.90 (2H, 70.1948.74.07,
m). H
5.83,
N
2.89.
Calcd
for
Cz3HzsN
(CDCI3, 400 MHz) 8.00-7.93Calcd Os
(2H m), 7.46- for C
O
H
C
"' o 7.40 (3H, m), 6.73-6.62 zaN 75
(4H, m), 4.02 (2H, t za 89
'
N
C-40"~~ ~ J = 6.6Hz), 2.94 (2H, t, s
J = 6.6Hz), 2.80-2.69 3
394 56
1649
. .
(2H, m), 2.47-2.33 (2H, . .
m), 2.36 (3H, s), Found:Found:
C
2.10-1.88 (2H, m). 84.1639.69.87,
H
6.05,
N
3.47.
Calcd
for
CzaHzsN
(CDCI3, 400 MHz) 8.01-7.94
(2H, m), 7.47-
70.74,
i for H
.39 (3H, m), 6.82-6.65 LR
(4H, m), 3.87 (2H, d,
C-41" J = 6.OHz), 2.82-2.71 (2H,408 6
~ ~ m), 2.67-2.60 N
~ (2H, m), 2.50-2.38 (2H, (M+H)~3.44
o ,~ m), 2.29 (3H, s), Found:
C
2.10-1.90 (4H, m). 70.52,
H
6.19,
N
3.41.
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
-85-
Calcd
for
CzzHz,
N
O5
C
(CDCI3, 400 MHz) 8.04-7.97 69.64,
~o I (2H, m), 7.47- for H
7.40 (3H, m) 6.86-6.63 LR 5
(4H 58
m) 4.90 (2H N
C-42o-~-o~ , ,
" , ,
s), 2.78-2.70 (2H, m), (M 6.69.
2.47-2.35 (2H, m), 8H)+
2.41 (3H, s),.2.10-1.90(2H, Found:
m). C
69.49,
H
5.68,
N
3.62.
(MeOH-d4, 400 MHz) 7.87-7.84Calcd
(3H, m), for
7.46 (1 H, dd, J = 2.3, Cz3HzaNz
8.6 Hz), 7.39-7.35
C-43"~O N (3H, m), 6.57 (1H, d, J= 04
o " 8.6 Hz), 4.38 (2H, 93.1809.
~.~~ t, J= 6.7 Hz), 2.88 (4H,
m), 2.25 (3H, s),
~ 2.29-2.20 (2H, m), 1.88-1.81Found:
(2H, m), 1.75-
1.68 (2H, m). 93.1815.
Calcd
for
(DMSO-ds, 300 MHz) 8.02 CzaHzaNz
(1H, d, J= 2.1
Hz), 7.91-7.88 (2H, m), OS
7.60 (1H, dd, J= C
2.3, 8.5 Hz), 7.52-7.47 67.63,
(3H, m), 6.72 (1 H, d, H
C-44~"~'o " J = 8.7 Hz), 5.66 (1 H, for 5.92,
~~o" bs), 4.73 (1 H, s), 4.45 LR N
(2H, t J = 6.8 Hz), 2.90 408 6.86.
(2H, t, J = 6.7 Hz), (M)'
or, 0 2.40-2.16 (2H, m), 2.30 Found:C
(3H, s), 2.14-2.02
(2H, m), 1.75-1.63 (1H, 67.51,
m), 1.56-1.42 (1H, H
m). 6.08,
N
6.75.
(Methyl sulfoxide-ds, 400
MHz): 8.02 (1 H, d,
J = 2.1 Hz), 7.91-7.88
(2H, m), 7.60 (1 H, dd,
J = 2.3, 8.5 Hz), 7.52-7.47
(3H, m), 6.72
(1 H, d, J = 8.7 Hz), 4.68for
~ (1 H, s), 4.45 (2H, t, LR
C-450 J = 6.8 Hz), 4.01 (2H, 437
o q, J = 7.1 Hz), 2.90 +
(2H, t, J = 6.7 Hz), 2.40-2.16(M+H)
(2H, m), 2.30
(3H, s), 2.14-2.02 (2H,
m), 1.75-1.63 (1 H,
m), 1.56-1.42 (1 H, m),
1.29 (3H, t, J = 7.2
Hz
(CDC13, 400 MHz) 8.00-7.93
(3H, m), 7.42-
7.37 (4H, m), 6.63 (1 H,
" d, J = 8.5 Hz), 4.48 for
~''o " LR
C-46~ (2H, t, J = 6.6 Hz), 2.96 406
~ (2H, t, J = 6.7 Hz), (M)'
0"
~~~
3 2.86 (2H, s), 2.31 (3H,
s), 2.10-2.02 (2H, m),
1.66-1.50 (6H, m).
(CDCI3, 400 MHz) 7.97-7.93
(3H, m), 7.43-
7.33 (4H, m), 6.63 (1 H,
~ ~~o" d, J = 8.5 Hz), 4.48 for
t LR
J = 6
8 Hz)
2
95 (2H
t
J = 6
8 Hz)
(2H
C-47 ,
,
.
,
.
,
,
.
,
0 2.73 (2H, s), 2.30 (3H, 420
s), 2.01 (2H, d, J = (M)'
12.6 Hz), 1.59-1.50 (3H,
m), 1.40-1.15 (5H,
m).
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
- 86 -
(CDCI3, 400 MHz) 7.99-7.94
(3H, m), 7.49
(1 H, dd, J = 2.4, 8.6
Hz), 7.44-7.36 (3H, m),
6.63 (1 H, d, J = 8.5 Hz),
N 4.50 (2H, t, J = 6.7
'o
C-48~ Hz), 4.00-3.93 (1H, m), 409
~ 3.89-3.81 (1H m), (M)'
~H
"9 3.14 ( 1 H, d, J = 14.1
Hz), 2.95 (2H
t, J = 6.7
0 ,
Hz), 2.85 (1H, d, J= 14.1
Hz), 2.31 (3H, s),
1.99-1.73 (4H, m).
Calcd
for
(MeOH-d4, 300 MHz) 8.37 C23H2sN2
(1 H,. d, J = 2.6
Hz), 8.07 (1 H, dd, J = OSCI
2.6, 8.9 Hz), 7.93- C
7.90 (2H, m), 7.79 (1 H, 62.09,
d, J = 8.9 Hz), 7.47- H
7.40 (3H, m), 4.41 (2H, for 5.66,
t, J = 6.2 Hz), 3.92- LR N
3.86 (2H, m), 3.05 (2H, 408 6.30.
t, J = 6.2 Hz), 2.36 (M)-
(3H, s), 3.50 (1 H, d, Found:
J = 14.3 Hz), 3.15 (1 C
H,
d, J = 14.3 Hz), 2.31-2.23 61.96,
(1 H, m), 2.00-1.92 H
(1H, m), 1.89-1.73 (2H, 5.75,
m). N
6.18.
(MeOD, 400 MHz): 8.37 (1H,
d, J= 2.6 Hz),
8.07 (1 H, dd, J = 2.6,
8.9 Hz), 7.93-7.90
(2H, m), 7.79 (1 H d, J
= 8.9 Hz), 7.47-7.40 f
C-50~ ~ ,~ ~ ; o (2H, m), 4.41 (2H, t, J 423
or, = 6.2 Hz), 3.92-3.86
(2H
m) 3
50 (1 H
d
J = 14
3 Hz) 3
15 (1 H
, (M+H)+
.
,
,
.
.
d, J = 14.3 Hz), 3.05 (2H,
t, J = 6.2 Hz), 2.36
(3H, s), 2.34 (3H, s),
2.31-2.23 (1 H, m),
2.00-1.92 1 H, m , 1.89-1.73
2H, m
(CDCI3, 400 MHz): 8.03
(1 H, d, J = 2.5 Hz),
7.77-7.74 (2H, m), 7.36-7.31
(4H, m), 7.26
( 1 H, d, J = 8.6 Hz),
4.31 (2H, t, J = 6.6 Hz), for
LR
C-51i ~ N~ 3.81-3.69 (2H, m), 3.11 425
I N O H (2H, t, J = 6.4 Hz),
3
02
1 H
d
J = 13
9 H
2
37
2
36
3H
. (M+H)
(
,
,
.
z),
.
(
.
-
, s),
2.34 (1 H, m), 2.18-2.11
(1 H, m), 1.94-1.87
(1 H, m), 1.78-1.68 (1
H, m), 1.60-1.53 (1 H,
m
(CDCI3, 400 MHz): 8.04
(1H, d, J= 2.8 Hz),
7.85-7.83 (2H, m), 7.41-7.39
(2H, m), 7.33
(1 H dd, J = 8.6 3.0 Hz),
7.27 (1 H, d J = 8.8 for
LR
C-52 Hz), 4.23 (2H, t J= 6.3 '~3
,~ Hz), 3.82-3.70 (2H
~
~
"
N m), 3.17-3.15 (1 H, m), (M+H).
o 3.03 (1 H, d, J = 14.2
N
Hz), 2.91 (2H, t, J=6.3
Hz), 2.29 (3H, s),
2.19-2.12 (1H, m), 1.96-1.88
(1H, m), 1.78-
1.71 1 H, m , 1.61-1.54
1 H, m
(MeOD, 400 MHz): 8.01 (1H,
d, J= 1.5 Hz),
7.80-7.77 (2H, m), 7.25-7.24
(2H, m), 6.93-
6.91 (2H, m), 4.20 (2H, for
t, J = 6.3 Hz), 3.80- LR
~ 3.69 (2H m), 3.75 (3H,
53 s), 3.17-3.15 (1 H
C
- O-~N~o N O m), 3.01 (1 H, d, J = 13.9(M+H)+
Hz), 2.88 (2H, t, J
6.3 Hz), 2.26 (3H, s),
2.17-2.11 (1 H, m),
1.94-1.87 (1 H, m), 1.75-1.66
(1 H, m), 1.58-
1.49 1H, m
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
-87-
(MeOD, 400 MHz): 8.01 (1H,
d, J= 2.3 Hz),
7.44-7.40 (2H, m), 7.30-7.22
(3H, m), 6.94-
0 6.91 (1 H, m), 4.21 (2H, for
t, J = 6.4 Hz), 3.80- LR
r ~ ~~ ~~o" 3.67 (2H m), 3.75 (3H s),
C-54~ " 3.21-3.17 (1 H, 439
" m), 3.01 (1 H, d, J = 13.9(M+H)
o Hz), 2.90 (2H, t, J
= 6.4 Hz), 2.28 (3H, s),
2.17-2.11 (1 H, m),
1.94-1.87 (1 H, m), 1.77-1.67
(1 H, m), 1.60-
1.50 1 H, m
(CDCI3, 300 MHz): 8.43
(1 H, d, J= 2.6 Hz),
7.97-7.93 (1 H, m), 7.83-7.79
(1 H, m), 7.60-
7.52 (2H, m), 7.48-7.42 for
" (3H, m), 4.14 (2H, t, LR
C-55~" i ~ N J = 6.0 Hz), 4.06-3.99 4+3
(2H, m), 3.62 (1 H, d,
J - 3.9 Hz), 3.37 (1 H, (M
d, J = 13.9 Hz), 2.69 H)
(2H, t, J = 6.0 Hz), 2.32
(3H, s), 2.23-1.96
(6H, m)
(CDCI3, 300 MHz): 7.93-8.03
(3H, m), 7.83-
7.79 (1H, m), 7.37-7.54 for
(4H, m), 6.65 (1H, LR
C-56r ~ ,~ i ; o" m), 4.50 (2H, t, J= 6.0 423
Hz), 3.75 (2H, m),
" " .95 (4H, m) 2.33 (3H, s) (M+H)'
2.12 (2H, m), 1.39-
1.77 (5H, m)
(MeOD, 400 MHz): 7.98 (1H,
d, J= 2.8 Hz),
7.86-7.84 (2H, m), 7.39-7.36
(3H, m), 7.24
(1 H, d, J = 8.8, 2.8 Hz),for
7.19 (1 H, d, J = 8.6 LR
C-57r ~ ~~~o" Hz), 4.21 (2H t J = 6.6
~ Hz) 3.70-3.66 (1 H,
~ 3
N 60
3
53
1 H
2
9
2H
0
" m),
/ .
.
-
(
, m)
.
, s) 2.9
5 (
(2H, t, J = 6.4 Hz), 2.28
(3H, s), 2.07-2.01
(1H, m), 1.61-1.58 (1H,
m), 1.40-1.32 (4H,
m
Calcd
for
CsoH3oN
(DMSO-ds 400 MHz) 8.17 Calcd O'~02H2
(2H d, J = 8.3 for
Hz), 7.99 (2H, d, J = 8.3 CaoHsoNOO
Hz), 7.92 (2H, d, J
6
= 8
H
7
2H
=
H
7
5
1
z), 4 C
.3 76.47
.
, t, J
8.3
z),
.
8 (
8 (
H,
C-58~ t, J= 8.3 Hz), 7.24-7.02 H
(4H, m), 4.36 (2H, t, 2170 6.29,
68 N
J = 6.6 Hz), 3.11 (2H, . 2,g7.
s), 3.11-3.07 (2H, m), .
Found:
2.55 (3H, s), 2.44-2.37 Found:
(2H, m), 2.15-1.89 68 C
2163
(4H, m). . 76.48,
. H
6.30,
N
2.90.
'H NMR (DMSO-ds, 400 MHz)
: 8.04 (2H,
d, J = 8.3 Hz), 7.95-7.93 Calcd
(3H, m), 7.53 (1 H, for
r ~ " o dd, J = 8.6 and 2.3 Hz), Cz3H24C1
o~ N ~ 6.69 (1 H, d, J = 8.3 N
Hz) 0
4
45 (2H
t
J = 6
6 Hz) 3
75 (2H t J =
C-59 , 2
~~ . 5
,
,
.
.
6.8 Hz), 3.01 (1 H, d, 443.1368
J = 13.9 Hz), 2.93 (2H,
" t, J = 6.6 Hz), 2.82 (1 .
H, d, J = 14.2 Hz), 2.33 Found:
(3H, s), 2.13-2.07 (1 H, 443.1377
m), 1.84-1.62 (3H,
m
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
_ 88 _
'H NMR (DMSO-ds, 400 MHz) : 12.45 (1H,
s), 7.95 (1 H, d, J = 2.3 Hz), 7.83 (2H, d, J = Calcd for
8.8 Hz), 7.53 (1 H, dd, J = 8.6 and 2.3 Hz),
i ~ N~o i ~ 7.03 (2H, d, J = 8.8 Hz), 6.69 (1 H, d, J = 8.3 C24HZ~N2
C-60 ° " ~ °
Hz), 4.42 (2H, t, J= 6.8 Hz), 3.80 (3H, s), Os
°" 3.75 (2H, t, J = 6.8 Hz), 3.01 (1 H, d, J = 13.9 439.1864
Hz), 2.87 (2H, t, J=6.8 Hz), 2.82 (1H, d, J= . Found:
14.2 Hz), 2.28 (3H, s), 2.14-2.07 (1H, m), 39.1874
1.83-1.63 3H, m
'H NMR (DMSO-ds, 400 MHz): 8.04 (2H, d,
J= 8.3 Hz), 7.95-7.93 (3H, m), 7.53 (1H, dd, Calcd for
"- r ~ " ° J = 8.6 and 2.3 Hz), 6.69 (1 H, d, J = 8.3 Hz), CZaHzaNa
C-61 °~ N ~ ° 4.45 (2H, t, J= 6.6 Hz), 3.75 (2H, t, J= 6.8
OS
° °H Hz), 3.01 (1 H, d, J = 13.9 Hz), 2.93 (2H, t, J 34.1711
= 6.6 Hz), 2.82 (1 H, d, J= 14.2 Hz), 2.33 . Found:
(3H, s), 2.13-2.07 (1H, m), 1.84-1.62 (3H, 34.1705
m
'H NMR (DMSO-ds, 400 MHz) : 7.95 (1H,
d, J = 2.0 Hz), 7.53 ( 1 H, dd, J = 8.3 and 2.3 Caicd for
Hz), 7.48 (1 H, d, J = 7.8 Hz), 7.42-7.38 (2H,
m), 7.04 (1 H, dd, J = 8.3 and 2.5 Hz), 6.69 C24O2'Nz
C-62 ~ ° ( 1 H, d J = 8.3 Hz), 4.43 (2H, t J = 6.6 Hz), 439.1864
° °r, 3.81 (3H, s), 3.75 (2H t J= 6.8 Hz) 3.01 . Found:
(1 H, d, J = 13.9 Hz), 2.90 (2H, t, J = 6.6 Hz), 439.1874
2.82 (1 H, d, J = 13.9 Hz), 2.31 (3H, s), 2.13-
2.07 1 H, m , 1.83-1.58 3H, m
'H NMR (DMSO-ds, 400 MHz) : 12.51 (1H,
s), 8.10 (2H d, J = 8.1 Hz), 7.95 (1 H, d, J = Calcd for
F F 2.0 Hz) 7.85 (2H, d J = 8.3 Hz), 7.53 (1 H,
~ "~ ° ~ . dd J = 8.3 and 2.3 Hz), 6.69 (1 H, d, J = 8.6 C N 05 s
C-63 °~ " ~ o Hz), 4.45 (2H, t, J = 6.8 Hz), 3.75 (2H, t, J =
77.1632.
° °" 6.6 Hz), 3.01 (1 H, d, J = 13.9 Hz) 2.93 (2H, Found:
t, J = 6.6 Hz), 2.82 (1 H, d, J = 13.9 Hz), 2.34
(3H, s), 2.13-2.06 (1 H, m), 1.84-1.60 (3H, 477.1635
m
'H NMR (CDCI3, 400 MHz) : 8.16 (1H, s),
7.88 (2H, d, J = 8.6 Hz), 7.81 (1 H, d, J = 8.6
°, r ~ N o ~ Hz), 7.41 (2H, d, J = 8.6 Hz), 6.87 (1 H, d, J
= 8.8 Hz), 4.51 (2H, t J = 6.1 Hz), 4.03-3.90 for LR
C-64 ° o" (2H, m), 3.23 (1H, d, J= 14.2 Hz), 3.04 (2H, (M+H)
t, J = 6.1 Hz), 2.86 ( 1 H, d, J = 14.2 Hz),
2.42-2.35 (1H, m), 2.37 (3H, s), 2.01-1.87
3H, m
'H NMR (DMSO-ds, 400 MHz) : 7.95 (1H, Calcd for
d, J = 2.0 Hz), 7.73 (1 H, s), 7.69 (1 H, d, J = Calcd for C'24H26N2
" ° 7.3 Hz), 7.51 (1H, dd, J= 8.6 and 2.3 Hz), C H 050.4H20
7.37 (1 H, t, J = 7.8 Hz), 7.28 (1 H, d, J = 7.1 24 z'NZ C 64.23
C-65 ° " ~ ° Hz), 6.69 (1 H, d, 8.3 Hz) 4.43 (2H, t J = 6.8
OS H 6.01 N
~~o" Hz), 3.75 (2H, t, J = 6.6 Hz), 3.01 (1 H, d, J = 23.1915. 6.19.
Found:
14.2 Hz), 2.89 (2H, t, J = 6.8 Hz), 2.82 (1 H, 23.1927. Found:
d, J = 14.2 Hz), 2.36 (3H, s), 2.30 (3H, s), C 64.16
2.14-2.08 (1 H, m), 1.84-1.60 (3H, m) H 6.16 N
6.01
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
-89-
'H NMR (DMSO-dfi, 400 MHz) Ca~H2
: 7.95 (1H,
NZ
d, J = 2.3 Hz), 7.79 (2H, Calcd O
d, J = 8.1 Hz), 7.53 for 0
9H
0
(1H, dd, J= 8.3 and 2.5 C2qH2~N2s
~ " Hz), 7.29 (2H, d, J= O .
1 Hz) z
8
6
d
8
3 Hz) 4
68 (1 H
43 (2H t J =
C-66~ . s H
, 2 6
. 39
, N
.
.
,
7
1 H
3
J = 6
8 H
75
2H
t
3
01
~1 H
. 3.1915.
" z),
.
.
(
,
,
z),
.
(
, d,
J = 13.9 Hz), 2.88 (2H, Found:Found:
t, J = 6.8 Hz), 2.82
(1H, d, J= 13.9 Hz), 2.34 23.1929
(3H, s), 2.29 (3H, ~ 61
C
65
s), 2.14-2.07 (1 H, m), .
1.84-1.60 (3H, m) H
6.34
N
6.20
'H NMR (MeOH-d4, 400 MHz):
8.28 (1 H, s)
7.76 (2 H, dt, J=7.7, 0.2
Hz) 7.56 (1 H, d,
J=9.1 Hz) 7.34 - 7.39 (1 LRMS
H, m) 7.14 - 7.20 (2
:
C-67, ~ N~ H, m) 6.28 (1 H d J=9.2
~ Hz) 4.12 (2 H t 426
" J=8
0 H
3
70
84
2 H
3
3
14
3
o . (M+H)
N z) '
.
.
(
-
, m)
-
.20 (1
.
H, m) 3.00 - 3.06 (1 H,
m) 2.75 (2 H, t, J=8.0
Hz) 2.34 - 2.44 (1 H, m)
2.26 - 2.31 (3 H, m)
1.82 - 2.05 3 H, m
'H NMR (MeOH-d4, 400 MHz):
8.28 (1 H, s)
7.56 (1 H, d, J=9.1 Hz)
6.28 (1 H, d, J=9.2
Hz) 4.12 (2 H t, J=8.0 for
Hz) 3.70 - 3.84 (2 H LR
C-68 m) 3.14 - 3.20 (1 H, m) 364
H ~ i ", ~ ~ 2.99 - 3.06 (1 H, m) +
, 2
" 58
2 H
. (M+H)
(
, t, J=8.0 Hz) 2.48 (3
H, s) 2.31 -
2.44 (1 H, m) 2.18 (3 H,
s) 1.81 - 2.05 (3 H,
m)
'H NMR (MeOH-d4, 400 MHz):
8.19 (1 H, s)
7.45 (2 H, dd, J=9.0, 8.4
Hz) 7.33 (1 H, d,
J=7.7 Hz) 7.15 - 7.21 (1 for
H, m) 6.99 - 7.05 (1 LR
H, m) 6.24 (1 H, d J=9.2
C-69~ Hz) 4.02 (2 H t,
~~
~ J=5.2 Hz) 3.70 - 3.84 (2 (M
H, m) 3.42 (2 H t, 9H)+
J=5.2 Hz) 3.14 - 3.20 (1
H, m) 2.99 - 3.06 (1
H, m) 2.93 (3 H, s) 2.34
- 2.43 (1 H, m) 1.82
-2.05 3H,m
'H NMR (MeOH-da, 400 MHz):
8.28 (1 M, s)
7.56 (1 H, d, J=9.1 Hz)
7.08 - 7.20 (4 H, m)
6.28 (1 H, d, J=9.2 Hz) for
4.50 (2 H, t, J=6.9 LR
C-70\ ~~ Hz) 3.70 - 3.84 (2 H, m) 342
~ 3.14 - 3.20 (1 H m) '
3.00 - 3.05 (1 H, m) 2.90 (M+H)
" (2 H, t, J=6.9 Hz)
2.32 - 2.43 (1 H, m) 2.28
(3 H, s) 1.81 - 2.05
(3 H, m)
'H NMR (MeOH-dq, 400 MHz):
8.28 (1 H, s)
7.56 (1 H, d, J=9.1 Hz)
7.09 - 7.15 (4 H, m)
6.28 (1 H, d, J=9.2 Hz) for
4.57 (2 H, t, J=6.5 LR
C-71 Hz) 3.70 - 3.84 (2 H, m) 342
\ ~" 3.28 (2 H, t, J=6.5 +
~
Hz) 3.14 - 3.20 ( 1 H, (M+H)
" m) 3. 00 - 3.06 ( 1 H,
m)
2.34 - 2.44 (1 H, m) 2.27
- 2.31 (3 H, m)
1.82 - 2.05 (3 H, m)
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
-90-
'H NMR (CDCI3, 400 MHz):
8.2-8.6 (1H, br
s), 8.10 (1 H, s) 7.58
(1 H, d, J=9.1 Hz)
C-72"~c. .o ~ ~ 6.85-7.25 (4 H, m) 6.70
~" (1 H, d, J=9.2 Hz)
s~
o ~ I 3,80.05 (2H, m), 3.63 (2
o H, t, J=6.5 Hz)
o N
3.35 (3H, s), 2.85 (2 H,
t, J=6.5 Hz) 2.30
(1 H, m) 1.65-2.05 (3H,
m)
'H NMR (CDCI3, 400 MHz):
7.98 (1H, s)
"~~,c"~ 7.48 (1 H, d, J=9.1 Hz)
~ 7.15-7.30 (4 H, m)
C-73o b 6.65 (2 H, m) 4.37 (2 H,
0 ~ [ t ,~6.5 Hz) 3.80-
N OH
~ 4.03 (2H, m), 2.80-3.20
(4H, m) 2.35 (3H,
m) 1.70-2.05 (3H, m) 1.50
(9H, s)
(Acetone-ds, 300 MHz):
8.37 (1 H, d, J = 1.9
Hz), 7.96 (2H, m), 7.56
(1H, dd, J= 7.9, 2.3
C-74H Hz), 7.45 (3H, m), 7.14 4
(1H, d, J= 7.9 Hz),
05
3.89 (2H, m), 3.05 (2H, M
m), 2.77 (2H, m), (
)
2.50 (2H, t, J = 7.4 Hz),
2.30 (3H, s) 2.16
(2H, m), 1.88 (4H, m)
(MeOD, 400 MHz): 8.19 (1H,
s), 7.82-7.80
(2H, m), 7.61 (1 H, dd,
J = 7.8, 1.8 Hz), 7.35-
7.33 (3H, m), 7.15 (1 H, for
d, J = 8.1 Hz), 3.83- LR
C-75N ~ ; " 3.73 (2H, m) 3.09 (1 H, 421
d, J = 13.9 Hz) 2.82
r ~ - i N (1 H, d, J = 13.9 Hz), (M+H)+
2.69 (2H, t, J = 7.2 Hz),
2.41 (2H, t, J = 6.7 Hz),
2.23-2.13 ( 1 H, m),
2.20 (3H, s), 1.88-1.79
(1 H, m), 1.78-1.53
6H, m
(MeOD, 300 MHz): 8.34-8.32
(2H, bm),
0 7.87-7.85 (2H, bm), 7.8-7.36for
(3H, bm), 4.54 LR
C-76~ \ N~~N o off (2Hz) 2.93 2389 H1HSbm)o2.80(M+H
(1H, d X0.7
10.7 Hz), 2.24 (3H, s),
1.92-1.77 (5H, m)
(Acetone-ds, 400 MHz):
8.08 (1H, s), 7.95
C-77 H for
/ \ N~ 3 83 LR
~N~H 2H ~
(
3 10
H~2~
4H
(
6
3
O z), 408
( (M)
,
m),
(
H,
,
m
.3
(
s), 2.20 (2H, d, J= 7.0
Hz), 1.75 (2H, m)
Calcd
for
'H NMR (DMSO-ds, 400 MHz) Cz4HzsN
: 12.40 (1H,
s), 7.90 (2H, dd, J = 7.8 Calcd05
and 1.8 Hz), 7.51- for C
r ~ N r o I ~ 7.44 (3H m), 7.10 (2H, Cz4HzsN070.75
~ d J = 8.3 Hz), 6.81 H
(2H 18
d N
~J = 8 6
6)
4
16 (2H
t
J = 6
8 Hz
C-78~ , 5 .
,
.
,
.
,
,
.
),
3.73 (2H, t, J = 6.8 Hz), 08.1806.3.44.
2.99 (1 H, d, J = 13.9
" Hz), 2,90 (2H, t, J= 6.6 Found:Found:
Hz), 2.81 (1H, d, J=
13.9 Hz), 2.34 (3H, s), 08.1797.C 70.53
2.'I 1-2.04 (1 H, m),
1.82-1.57 (3H, m). H 6.18
N
3.31
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
-91 _
(DMSO-ds 400 MHz) 7.25-7.24 (1 H, m), HR Calcd for
\ 7.19-7.17 (2H, m), 7.06-7.04 (2H, m), 6.76- CzsH3oN +Os
6.75 (1 H, m), 6.72-6.70 (2H, m), 4.11 (2H, t, (M+H
_ I J = 6.5 Hz), 3.77-3.71 (2H, m), 3.00-2.96 451.2228.
/N~
C 79 ~ ~ \ (1H, m), 2.89 (6H, s), 2.87-2.85 (2H, m), Found
0 2.84-2.76 (1 H, m), 2.98 (3H, s), 2.12-2.10 451.2213.
o" (1 H, m), 1.85-1.82 (1 H, m), 1.71-1.56 (2H, For LR 451
o m M+H
HR Calcd for
(DMSO-ds, 300 MHz) 12.40 (1 H, s), 8.14- CzsHzaNzOs
8.11 (2H, m), 8.03-8.04 (2H, m), 7.19-7.16
i ' " ° (2H, m), 6.89-6.86 (2H, m), 4.24 (2H, t J = (M+H)
C-80 N' ~ ~ ~ 6.5 Hz), 3.80 (2H, t, J= 6.6 Hz), 3.09-3.04 433.1758.
(1 H m) 3.00 (2H t, J = 6.4 Hz), 2.91-2.86 Found
° 433.1741.
o °" (1 H, m~), 2.45 (3H, s), 2.19-2.13 (1 H, m), For LR 433
1.88-1.67 (3H, m) M+H
(DMSO-ds, 300 MHz) 8.10 (1 H, s), 8.03-
7.96 (4H m), 7.48 (1 H s) 7.15-7.12 (2H
"," ~ ~ " ° m), 6.85-6.83 (2H, m), 4.20 (2H, t, J = 6.5 For LR 451
C-81 ° i ~ Hz), 3.76 (2H, t, J = 6.5 Hz), 3.04-3.00 (1 H, (M+H)+
m), 2.95 (2H, t, J = 6.5 Hz), 2.86-2.82 (1 H,
°" m), 2.39 (3H, s), 2.12 (1H, m), 1.83-1.60
° (3H, m)
(CDCI3, 300 MHz) 7.85-7.77 (2H, m), 7.68- HR Calcd for
CzsHzsNOsFa
7.63 (1 H, m), 7.15-7.12 (2H, m), 6.82-6.80
C-82 , ~ ' " ~ (2H, m), 4.22 (2H, t, J = 6.5 Hz), 4.01-3.96 (M+H)
(1 H, m), 3.90-3.85 (1 H, m), 3.19-3.14 (1 H, 494.1585.
m), 2.97 (2H, t, J = 6.5 Hz), 2.90-2.85 (1 H, Found
m), 2.39 (3H s), 2.36-2.32 (1 H m), 2.06- For LR 494
1.96 (1 H, m), 1.87-1.77 (2H, m). M+H
(CDCI3, 400 MHz) 7.87-7.84 (2H, d), 7.23-
7.21 (2H, d), 7.14-7.12 (2H, d), 6.82-6.80
" ° (2H, d) 4.19 (2H, t, J= 6.5 Hz) 4.01-3.94
C-83 ~ r v (1 H, m), 3.87-3.81 (1 H, m), 3.17-3.14 (1 H, For LR 422
m), 2.95 (2H, t, J= 6.5 Hz), 2.90-2.87 (1H, (M+H)
°°" m), 2.38 (3H, s), 2.35 (3H, s), 2.33-2.30 (1 H,
° m), 2.03-1.95 (1H, m), 1.87-1.72 (2H, m).
HR Calcd for
(CDCI3, 400 MHz) 7.92-7.90 (2H, m), 7.12- Czsl"Izn'10s
7.10 (2H, m), 6.94-6.92 (2H, m), 6.80-6.78
'" ° (2H m), 4.18 (2H t, J = 6.5 Hz), 4.02-3.97 (M+H)
C-84 '° ~ r ~ (2H, m), 3.84 (3H, s), 3.17-3.13 (1H, m), 438.1911.
2.95 (2H, t, J = 6.5 Hz), 2.90-2.86 (1 H, m), Found
° °°" 2.35 (3H, s), 2.03-2.00 (2H, m), 1.87-1.81 Fort R
438
(2H, m). M+H ,
o~ (CDCI3, 400 MHz) 7.57-7.55 (1 H, m), 7.51-
1 ~ ~N 7.49 (1 H, m) 7.35-7.30 (1 H m), 7.10-7.07
° (2H, m), 6.97-6.93 (1 H, m), 6.81-6.78 (2H,
C-85 0 / \ m), 4.19 (2H, t, J = 6.5 Hz), 3.87 (3H, s),
3.04 (2H, s), 2.96 (2H, t, J = 6.5 Hz), 2.48
0 .38 (2H, m) 2.36 (2H, s), 2.11-2.02 (2H, m),
o " 1.94-1.85 (2H, m).
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(CDC13, 400 MHz) 7.97 (1 H, s), 7.86-7.84
(1H, m), 7.37-7.35 (2H, m), 7.15-7.12 (2H,
o m), 6.82-6.80 (2H, m), 4.20 (2H, t, J = 6.5
C-86 ~ ~ ~ Hz), 3.99-3.95 (1 H, m), 3.88-3.84 (1 H, m),
ci 3.18-3.14 (1 H, m), 2.96 (2H, t, J = 6.5 Hz),
2.90-2.87 (1 H, m), 2.37 (3H, s), 2.36-2.31
off (1H, m), 2.01-1.98 (1H, m), 1.88-1.73 (2H,
o m.
HR Calcd for
CDCI3, 400 MHz) 8.24 (1H, s), 8.15-8.14 CzsHzaN~sF3
(1 H, m), 7.66-7.64 (1 H, m), 7.57-7.54 (1 H,
° m), 7.15-7.13 (2H, m), 6.82-6.80 (2H, m), (M+H)
C-87 F ~F r ~ 4.21 (2H, t, J = 6.5 Hz), 3.88-3.84 (2H, m), 476.1680.
3.18-3.15 (1 H, m), 2.97 (2H, t, J = 6.5 Hz), Found
° 2.90-2.86 (1 H, m), 2.39 (3H s), 2.01-1.98 Fo 6 R 477
° °H (2H, m), 1.85-1.81 (2H, m). M+H
HR Calcd for
(CDCI3, 400 MHz) 7.91-7.89 (2H, m), 7.40- Cz"Hz4NCsCl
7.38 (2H, m), 7.14-7.13 (2H, m) 6.81-6.79 (M+H)+
C-88 ~, i ~ ~ ~ (2H, m), 4.19 (2H, t, J = 6.5 Hz), 4.02-3.93 44Fo 1nd 6~
(2H, m), 3.19-3.14 (1 H, m), 2.95 (2H, t, J = 442.1413.
° 6.5 Hz), 2.90-2.87 (1 H, m), 2.36 (3H, s), For LR 443
° off 2.01-1.94 (2H, m), 1.87-1.81 (2H, m). (M+H)+
(CDCI3, 400 MHz) 7.81-7.75 (2H, m), 7.32- HR Calcd for
7.28 (1H m), 7.22-7.20 1H, M0, 7.14-7.12 CAM+H ~s
I ~ N ° (2H, m), 6.81-6.78 (2H, m), 4.19 (2H, t, J= 422.1962.
C-89 r ~ 6.5 Hz), 3.98-3.81 (2H, m), 3.17-3.10 (1 H, Found
1 m), 2.96 (2H, t, J= 6.5 Hz), 2.91-2.86 (1H,
°°H m), 2.38 (3H, s), 2.36 (3H, s), 2.00-1.69 (4H, For LR 422
o m). M+H ,.
HR Caicd for
(CDCI3, 300 MHz) 8.09-8.06 (2H d), 7.69- CzsHzaNOsFs
° 7.66 (2H, d), 7.15-7.12 (2H, m), 6.82-6.79 (M+H)'
C-90 FF I ~ , ~ (2H, m), 4.21 (2H, t, J= 6.5 Hz), 4.00-3.81 476.1680.
(2H, m), 3.18-3.14 (1 H, m), 2.97 (2H, t, J = Found
° 6.5 Hz), 2.91-2.86 (1 H, m), 2.39 (3H, s), 476.1661.
° °H 2.36-2.30 (1H, m), 2.04-1.72 (3H, m). For LR 475
M+H
(CDCI3, 400 MHz): 7.99-7.97 (2H, m), 7.66
(1H, d, J=9.3 Hz), 7.62-7.59 (2H, m), 7.45-
7.32 (4H, m), 7.11-7.08 (2H, m), 4.31 (2H t, for LR
off J = 6.6 Hz), 3.97-3.82 (2H m), 3.34 (1 H d,
C-91 ~ N i ° ~ ~ ° J= 13.9 Hz), 3.08-3.01 (3H, m,) 2.39-
2.33 458 (M+H)
(4H, m), 2.08-2.00 (1 H, m), 1.87-1.67 (2H,
m)
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(CDCI3, 400 MHz): 7.98
(2H, d, J = 5.8 Hz),
7.68 (1 H, d, J = 9.1 Hz),
7.62-7.60 (2H, m),
7.42-7.33 (4H, m), 7.14(1
H, dd, J = 2.2, 8.8
Hz), 7.07 (1H, s), 4.06-3.96for LR
(3H, m), 3.87
C-92~ N ~ ~ J~~~ (1 H q J = 7.5 Hz), 3.36 472 (M+H)+
(1 H, d J = 13.9
Hz), 3.08 (1 H, d, J =
13.9 Hz), 2.73 (2H, t,
J
= 7.1 Hz), 2.43-2.35 (1
H, m), 2.27 (3H, s),
2.22-2.15 (2H, m), 2.10-2.01
(1 H, m), 1.88-
1.72 2H, m
(MeOD, 400 MHz): 7.93-7.90
(2H, m), 7.63-
7.56 (3H, m), 7.41-7.38
(3H, m), 7.31 (1H,
dd, J = 2.5, 8.9 Hz), 5.01for LR
C-93~ ~ (2H, s), 3.84-3.73
~ \ N~ 2H, m), 3.23-3.00 (2H, 444 (M+H)+
( m), 2.39 (3H, s),
2.23-2.16 (1 H, m), 1.96-1.88
(1 H, m), 1.76-
1.57 (2H, m)
Alternative Preparations of the enantiomers of 2-((6-f2-(5-methyl-2-phenyl-1.3-
oxazol-4- 1)ethox~lpyridin-3-yl~methyl tetrahyd~ofuran-2-carboxylic acid
(Examples
C-48a and C-48b)
Example C-48a
Enantiomer 1 of 2-(f6-f2-(5-methyl-2-phenyl-1,3-oxazol-4-vl)ethoxyjp- ridin-3
}methyl)tetrahydrofuran-2-carboxylic acid
O
O ~ OH
O
N O ~N~ U
Lithium hydroxide monohydrate (993 mg, 21.1 mmol) was added to a solution of
(4S)-4-benzyl-3-{[2-({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxyjpyridin-3-
yl}methyl)tetrahydrofuran-2-yl]carbonyl}-1,3-oxazolidin-2-one (600 mg, 1.06
mmol)
in a mixture of tetrahydrofuran:methanol:water (1:1:1, 12 mL). The mixture was
stirred at 50°C for 4.5 hours, then cooled to ambient temperature and
stirred for 2
days. The volatile components were removed by evaporation and the residue was
diluted with water (5 mL) and extracted with 1:1 hexanes:ether. The aqueous
phase was acidified to pH 5 and extracted with ethyl acetate. The organic
phase
was washed with brine, dried over magnesium sulfate, filtered and evaporated.
The
residue was purified twice by flash column chromatography (95:4:1
dichloromethane:methanol:ammonium hydroxide) to yield the title compound as a
colorless oil (72 mg)
LRMS (m/z): 409 (M+H)'.
'H NMR (CDCI3, 300 MHz) 7.99-7.94 (3H, m), 7.49 (1 H, dd, J = 2.4, 8.6 Hz),
7.44-
7.36 (3H, m), 6.63 (1 H, d, J = 8.5 Hz), 4.50 (2H, t, J = 6.7 Hz), 4.00-3.93
(1 H, m),
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3.89-3.81 ( 1 H, m), 3.14 (1 H, d, J = 14.1 Hz), 2.95 (2H, t, J = 6.7 Hz),
2.85 (1 H, d, J
= 14.1 Hz), 2.31 (3H, s), 1.99-1.73 (4H, m).
Example C-48b
Enantiomer 2 of ~~6-f~5-methylr2=phenyl-1 3-oxazol-4-yl)ethoxy]pvridin-3-
vl)methyl)tetrahydrofuran-2-carboxylic acid
Enantiomer 2 was prepared using a similar sequence of reactions to those
described for enantiomer 1, except starting from (4R)-4-benzyl-1,3-oxazolidin-
2-
one.
Example C-94
1-~6-12-(5-Methyl-2-phenyl-oxazol-4-ylLthoxyl-p ridin-3-ylmeth~}-
cyclopropanecarboxylic acid
O
O OH
N O N
To a solution of 1-{6-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-3-
ylmethyl}-
cyclopropanecarboxylic acid tertbutyl ester (0.2017 g, 0.4642 mmol) in anisole
(1.2
mL) was added trifluoroacetic acid (1.2 mL). The resulting solution was
stirred at
ambient temperature for 3 hours and then concentrated under reduced pressure.
The crude residue was diluted with ethyl acetate (25 mL) and water (10 mL) and
then basified to pH 5-6 by the addition of saturated aqueous sodium
bicarbonate.
The phases were separated and the aqueous layer extracted with ethyl acetate
(3
x 25 mL). The combined organic extracts were then dried (anhydrous magnesium
sulfate), filtered and concentrated in vacuo to afford the crude product. The
pure
acid (0.071 g, 40%) was obtained, by recrystallization from diethyl ether/
hexanes,
as a white solid.
LRMS (m/z): 379 (M+H)'.
'H NMR (MeOD, 300 MHz): 7.89-7.83 (3H, m), 7.53 (1H, dd, J = 8.5, 1.9 Hz),
7.37-7.35 (3H, m), 6.60 (1 H, d, J = 8.5 Hz), 4.39 (2H, t, J = 6.5 Hz), 2.87
(2H, t, J =
6.4 Hz), 2.73 (2H, s), 2.23 (3H, s), 1.14-1.11 (2H, m), 0.77-0.74 (2H, m).
Examale C-95
2-f2-(5-Methyl-2-phenyl-oxazol-4-yl -etho~l-5-12-(1 H-tetrazol-5,r1)-
tetrahydro-
furan-2-ylmethyll-p~idine
N-N
I N
O~ ~ ~ H.
~N O N
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A solution of 2-{6-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-3-
ylmethyl}-
tetrahydro-furan-2-carbonitrile (0.11 g, 0.27 mmol), sodium azide (0.04 g,
0.54
mmol) and zinc bromide (0.03 g, 0.14 mmol) in water and isopropanol (1:2, 1.24
mL) was refluxed for 23 hours. After cooling to ambient temperature, the
reaction
was quenched with 3N hydrochloric acid (0.14 mL) and ethyl acetate (2.8 mL),
and
the mixture stirred until completely homogeneous. The aqueous phase was
extracted with ethyl acetate (3 x 50 mL) and the combined organic extracts
washed
with water (30 mL), dried (anhydrous magnesium sulfate), filtered, and
concentrated in vacuo to give the crude product. The residue was
recrystallized
with diethyl ether/hexanes to afford the title compound (0.052 g, 44%) as a
white
solid.
Elemental Analysis: Calcd CZZHz3N~03 C 60.96, H 5.35, N 22.62. Found: C 63.50,
H 5.62, N 18.80.
'H NMR (CDCI3, 300 MHz): i5 7.93 (2H, m), 7.86 (1H, s), 7.40 (3H, m), 7.11
(1H, d,
J = 1.7 Hz), 6.49 (1H, d, J = 8.5 Hz), 4.42 (2H, t, J = 6.6 Hz), 3.88 (2H, m),
3.12
(2H, m), 2.92 (2H, t, J= 6.5 Hz), 2.62 (1H, m), 2.31 (3H, s), 2.23 (1H, m),
1.89 (2H,
m).
LRMS (m/z): 433 (M+H)+.
Preparations of starting materials for Examples C-1 to C-95 (Preparations c-1
to c-
130~
Preparation c-1
4-[2-(5-methyl-2-phenyl-1.3-oxazol-4-)rl)ethoxy]benzaldehvde
~CHO
O ~ i
To a solution of the 4-hydroxybenzaldehyde (5.05 g, 41.4 mmol), 2-(5-methyl-2-
phenyl-oxazol-4-yl)-ethan-1-of (8.39 g, 41.4 mmol), and triphenylphosphine
(10.9 g,
41.4 mmol) in anhydrous tetrahydrofuran (165 mL), under an atmosphere of
nitrogen, was added diethyl azodicarboxylate (7.21 g, 41.4 mmol) dropwise. The
resulting solution was stirred at ambient temperature for 8 hours, then
diluted with
water and extracted with ethyl acetate. The organic phase was dried (anhydrous
magnesium sulfate), filtered and evaporated in vacuo. This residue was then
purified by flash column chromatography (hexanes to ethyl acetate) to yield
the title
compound as a white crystalline solid (10.2 g, 80%).
LRMS (m/z): 308 (M+H)''.
Preparation c-2
Methyl 1-(h~droxv 4-f2-(5-methyl-2-phenyl-1.3-oxazol-4-
vl)ethoxvlohenvllmethvl)
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cvclohexane carboxylate
OH O
OMe
O
To a suspension of chromium(II) chloride (1.00 g, 8.10 mmol) and lithium
iodide
(0.087 g, 0.648 mmol} in tetrahydrofuran (20 mL) was added 4-[2-(5-methyl-2-
phenyl-1,3-oxazol-4-yl)ethoxy]benzaldehyde (Preparation 1) (1.00 g, 3.24 mmol)
and methyl 1-bromocyclohexanoate (1.07 g, 4.85 mmol). The resulting mixture
was heated at 50 °C until TLC analysis indicated the reaction was
complete. The
mixture was cooled to ambient temperature and satuarted aqueous sodium
chloride (15 mL) was added. The resulting mixture was stirred for 15 minutes,
then
partitioned between water and ethyl acetate. The organic phase was washed with
water and dried (anhydrous magnesium sulfate), filtered and evaporated. The
residue was purified by flash column chromatography (hexanes to 50% ethyl
acetate/hexanes) to yield the title compound as a colorless oil (0.797 g,
55°~).
LRMS (m/z): 450 (M+H)+.
Preparation c-3
Ethyl 1-(hvdroxy{4-j2-(5-methyl-2-phenyl-1.3-oxazol-4
yl)ethoxvlnhen I)~ meth~cyclobutane carboxylate
O
~ i OEt
O
OH O
Using analogous procedures to those described for Preparation c-2, the title
compound was obtained as a colorless oil.
LRMS (m/z): 436 (M+H)'.
Preaaration c-4
Methyl 1-ff4-(allyloxy)phenyll(hvdroxy)methyl]cvclopentanecarboxylate
~O
OMe
OH O
To a solution of methyl cyclopentanoate (3.84 g, 30.0 mmol), in
tetrahydrofuran (30
mL) at -78 °C was added a solution of lithium diisopropylamide (15.0 mL
of a 2M in
tetrahydrofuran, 30.0 mmol) dropwise. The mixture was stirred for 2 hours and
then 4-allyloxy benzaldehyde (2.12 g, 13.1 mmol) was added. The mixture was
allowed to warm to ambient temperature and stirred for 18 hours. The mixture
was
diluted with water and extracted with ethyl acetate. The organic phase was
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washed with saturated aqueous sodium chloride and dried (anhydrous magnesium
sulfate), filtered and evaporated. The residue was purified by flash column
chromatography (hexanes to 50% ethyl acetate/hexanes) to yield the title
compound as a colorless oil (3.67 g, 97%).
LRMS (m/z): 273 (M-OH)'.
Preparation c-5
Meth~~f4-lbut-3-envloxy)pheny](hydroxK)methylltetrahydro-2H-p, ry an-4_,
carbox late
O
~O
I i OMe
OH O
Using analogous procedures to those described for Preparation c-4, the title
compound was obtained as a colorless oil.
LRMS (m/z): 273 (M-OH)''.
Preparation c-6
Et~l 1-ff4-(allyloxy)phen r~11(h~roxy)meth~yclobutanecarboxylate
OH O
O~
~o I ~
,
Using analogous procedures to those described for Preparation c-4, the title
compound was obtained as a colorless oil.
LRMS (m/z): 289 (M)+.
'H NMR (CDC13, 300 MHz) 7.22 (2H, d, J= 8.5 Hz), 6.85 (2H, d, J= 8.7 Hz), 6.10
5.98 (1 H, m), 5.39 (1 H, ddd, J = 1.5, 3.2, 17.3 Hz), 5.27 (1 H, ddd, J =
1.5, 2.8, 10.4
Hz), 4.85 (1 H, d, J = 6.4 Hz), 4.51 (2H, dt, J = 1.5, 5.3 Hz), 4.13 (2H, dq,
J = 0.9,
7.2 Hz), 3.12 (1 H, d, J = 6.6 Hz), 2.84-2.78 (1 H, m), 2.64-2.58 (1 H, m),
2.35-2.29
(2H, m), 1.89-1.83 (1 H, m), 1.72-1.66 (1 H, m), 1.19 (3H, t, J = 7.0 Hz).
Preparation c-7
Methvl 1-(4-hydroxvbenzyl)c~opentanecarboxylate
HO
OMe
O
Triethylsilane (10.0 mL, 63 mmol) was added to a solution of methyl 1-[[4-
(allyloxy)phenyl](hydroxy)methyl]cyclopentanecarboxylate (Preparation c-4)
(3.66
g, 12.6 mmol) in dichloromethane (30 mL) and trifluoroacetic acid (30 mL) at
room
temperature. The resulting mixture was stirred for 1 hour then evaporated in
vacuo
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and azeotroped with toluene. The residue was dissolved in tetrahydrofuran (32
mL) and morpholine (3.62 mL, 41.6 mmol) and
tetrakis(triphenylphosphine)palladium (0) (1.46 g, 1.26 mmol) was added. The
resulting mixture was stirred at room temperature for 18 hours, filtered
through
Celite and evaporated to dryness. The residue was dissolved in ethyl acetate
and
washed with 1N hydrochloric acid then saturated sodium bicarbonate solution.
The
organic phase was dried (anhydrous magnesium sulfate), filtered and evaporated
and the residue was purified by flash column chromatography (hexanes to ethyl
acetate) to yield the title compound as a white crystalline solid (1.75 g,
59%).
LRMS (m/z): 233 (M)'.
Preaaration c-8
Meth I~ydroxyben~l)tetrahydro-2H-pyran-4-carboxylate
HO ~ O
i OMe
O
Using analogous procedures to those described for Preparation c-7, the title
compound was obtained as a white crystalline solid.
LRMS (m/z): 249 (M)'.
Preparation c-9
Ethyl 1-(4-hydroxybenzyl)cvclobutanecarboxylate
O
O~
HO
Using analogous procedures to those described for Preparation c-7, the title
compound was obtained as a white crystalline solid.
LRMS (m/z): 234 (M)-.
'H NMR (CDCI3, 300 MHz) 6.97 (2H, d, J = 8.5 Hz), 6.68 (2H, d, J = 8.5 Hz),
5.10
(1H, bs), 4.10 (2H, q, J = 7.2 Hz), 3.00 (2H, s), 2.44-2.35 (2H, m), 2.07-1.99
(2H,
m), 1.91-1.80 (2H, m), 1.20 (3H, t, J = 7.2 Hz).
Preparation c-10
Methyl 1-f4-f2-(5-methyl-2-phenyl-1.3-oxazol-4-yl)ethoxylbenzyl
cvclopentanecarboxylate
O
/ \ N~ ~ ~ OMe
O
Using analogous procedures to those described for Preparation c-1-c-7, the
title
compound was obtained as a colorless oil.
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LRMS (m/z): 249 (M)'.
Preparation c-11
Methyl 1-(4-f3-(5-methyl-2-phenyl-1.3-oxazol-4
vl)propoxylbenzyl)cvclopentanecarboxvlate
O
-OMe
/ \ O~O i
Using analogous procedures to those described for Preparation c-1-c-7, the
title
compound was obtained as a colorless oil.
LRMS (m/z): 434 (M+H)+.
Preparation c-12
Methvl4-(4-![2-(5-methyl-2-phenyl-1,3-oxazol-4-vl)ethoxylbenzylltetrahvdro-2H-
pyran-4-carboxylate
O
/ \ N~ ~ % OMe
0 O
Using analogous procedures to those described for Preparation c-1-c-7, the
title
compound was obtained as a colorless oil.
LRMS (m/z): 436 (M+H)'.
Preparation c-13
Ethyl 1-(4-f2-(4-bromophenyllethox~~benzYl, cvclobutanecarboxvlate
O
Br
O
Using analogous procedures to those described for Preparation c-1-c-7, the
title
compound was obtained as a colorless oil.
LRMS (m/z): 417 (M)+.
'H NMR (CDCI3, 300 MHz) 7.36 (2H, d, J = 8.3 Hz), 7.08 (2H, d, J = 8.3 Hz),
6.96
(2H, d, J = 8.7 Hz), 6.70 (2H, d, J = 8.7 Hz), 4.04 (2H, t, J = 6.8 Hz), 4.03
(2H, q, J
= 7.2 Hz), 2.95 (2H, t, J = 6.8 Hz), 2.94 (2H, s), 2.37-2.27 (2H, m), 2.00-
1.91 (2H,
m), 1.84-1.73 (2H, m), 1.14 (3H, t, J = 7.2 Hz).
Preparations c-14 to c-35
Preparations c-14 to c-35 were prepared usinq_analoqous procedures to those
used for Preparation c-1.
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Prep # Structure 'H NMR MS (m/z)
(LR or HR)
'" '-o
I
c-14 N ~ \ For LR 463
(M+H)
0
0
(CDC13, 300 MHz) 8.14-8.11 (1 H,
o~ ), 7.78-7.75 (1 H, m), 7.67-7.62
(1H, m) 7.51-7.45 (1H, m), 7.04-
1 ~ " ° .01 (2H, m), 6.80-6.78 (2H, m), For LR 446
c-15 I ~ \ .23 (2H, t, J = 6.5), 4.13-4.06 (2H,
" q, J = 7.1 Hz), 3.00 (2H, t, J = 3.3 (M+H)
Hz), 2.42 (3H, s), 2.40-2.36 (2H,
° ° ), 2.05-2.00 (2H, m), 1.87-1.84
2H m 1.21 3H, t, J = 7.1 Hz .
(CDCI3, 300 MHz) 8.07-8.04 (2H,
°~ m), 7.71-7.68 (2H, m), 7.03-7.01
I ~ ~" ° (2H, m) 6.78-6.75 (2H m) 4.19
N' ~ (2H, t, J = 6.5 Hz), 4.13-4.06 (3H, For LR 445
c-16 ~ \ m), 2.99 (2H, s), 2.96 (2H, t, J = (M+H)'
.SHz), 2.39 (3H, s), 2.38-2.34 (2H,
), 2.02-1.99 (2H, m), 1.87-1.82
(2H, m), 1.20 (3H, t, J = 6.9 Hz).
(CDCI3, 300 MHz) 8.08-8.05 (2H,
° \ m), 7.71-7.68 (2H m) 7.16-7.13
(2H, m) 6.80-6.77 (2H, m), 5.01-
" I ~ ° .92 (2H, m), 4.21 (2H, t, J = 6.5 For LR 461
c-17 ' i \ Hz), 3.92-3.85 (2H, m), 3.15-3.08
(1H, m), 2.97 (2H, t, J = 6.4 Hz), (M+H)'
- .95-2.88 (1 H, m), 2.40 (3H, s),
° ° .28-2.21 (1 H, m), 2.04 (3H, s),
1.91-1.86 (2H, m).
\N
O
For LR 506
c-18 F F F ~ \ (M+H)'
0 0~
(CDCI3, 300 MHz) 8.05-8.04 (1 H,
d), 7.79-7.75 (1 H, m), 7.47-7.44
~" o (1H, d), 7.03-7.00 (2H, m), 6.76-
c-19 °' ~ ~ \ .75 (2H, m), 4.18 (2H, t, J = 6.5 For LR 489
a z), 4.13-4.06 (2H, q, J= 7.1 Hz), (M+H)'
3.00 (2H, s), 2.94 (2h, t, J= 6.5
o Hz), 2.49-2.36 (2H, m), 2.35 (3H,
o ~ ), 2.04-1.97 (2H, m), 1.87-1.81
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(2H, m), 1.20 (3H, t, J = 7.1 Hz).
o ~
° For LR 435
c-20 / \ (M+H)*
0
0
\N
O
c-21 c~ ~ / ~ For LR 455
(M+H)+
0
0
~N
O
c-22 ° / \ For LR 450
(M+H)+
0
0
(CDC13, 400 MHz) 7.57-7.56 (1 H,
m), 7.51-7.50 (1H, m), 7.34-7.30
°~ (1 H, m), 7.03-7.01 (2H, m), 6.96-
~N 6.93 (1 H, m), 6.80-6.77 (2H, m),
c-23 ~ / ~ 4.20 (2H, t, J = 6.6 Hz), 4.12-4.07 For LR 450
,o (2H, q, J= 7.0 Hz), 3.86 (3H, s), (M+H)a
3.00 (2H, s), 2.95 (2H, t, J = 6.5
o hiz), 2.42-2.37 (2H, m), 2.35 (3H,
o m), 2.05-1.98 (2H, m), 1.88-1.81
2H,m.
\N
O
c-24 ~ / ~ For LR 450
(M+H).
d
0
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I
c-25 F ~F / \ For LR 488
(M+H).
F
O
O
N °
c-26 ° / \ For LR 466
(M+H).
o~
0
0
(CDC13, 400 MHz) 7.57-7.56 (1H,
/ m), 7.51-7.50 (1 H, m), 7.34-7.30
o~ (1 H, m), 7.03-7.01 (2H, m), 6.96
6.93 (1 H, m), 6.80-6.77 (2H, m)
I ~ N ° 4.20 (2H, t, J = 6.5 Hz), 4.12-4.07 For LR 450
c-27 /° / \ (2H, q, J= 7.0 Hz), 3.86 (3H, s), (M+H)+
3.00 (2H, s), 2.95 (2H, t, J = 6.5
o ~ Hz), 2.42-2.37 (2H, m), 2.35 (3H,
° ° s), 2.05-1.98 (2H, m), 1.86-1.81
(2H, m) 1.20 (3H, t, J = 7.0 Hz).
(CDC13, 400 MHz) 7.97 (1 H, s),
\ 7.86-7.83 (1 H, s), 7.35-7.33 (2H,
m), 7.03-7.01 (2H, m), 6.79-6.77
° (2H, m), 4.19 (2H t, J = 6.5 Hz),
c-28 ~ / \ 4.12-4.07 (2H, q, J = 7.0 Hz), 3.00 For LR 454
(2H, s), 2.95 (2H, t, J = 6.5 Hz), (M+H)''
2.422.38 (2H, m), 2.35 (3H, s),
o ~ 2.05-1.99 (2H, m), 1.91-1.82 (2H,
m , 1.20 3H, t, J = 7.0 Hz
(CDCI3, 400 MHz) 7.97 (1 H, s),
7.87-7.84 (1 H, m), 7.36-7.35 (2H,
m), 7.16-7.14 (2H, m), 6.81-6.78
I ~ ~" ° (2H, m), 4.21 (2H, t, J = 6.5 Hz),
c-29 ~ / \ 4.15-4.10 (q, J= 7.0 Hz), 3.91-3.87 For LR 470
(2H, m), 3.14-3.10 (1 H, m), 2.96 (M+H)'
(2H, t, J= 6.5 Hz), 2.93-2.90 (1H,
o m), 2.37 (3H, s), 2.26-2.12 (2H, m),
o ~ 1.89-1.76 (2H, m), 1.21 (3H, t, J =
7.0 Hz .
(CDCI3, 400 MHz) 8.24 (1 H, s),
\ 8.16-8.14 (1 H, m), 7.66-7.64 (1 H,
m), 7.57-7.53 (1 H, m), 7.16-7.14
I ~ ° (2H, m), 6.81-6.79 (2H, m), 4.22 For LR 504
c-30 F F ~ \ (2H, t, J= 6.5 Hz) 4.15-4.10 (2H, (M+H)+
F q, J = 7.0 Hz), 3.93-3.86 (2H, m),
3.14-3.11 (1 H, m), 2.97 (2H, t, J =
° ~ 6.5 Hz), 2.93-2.90 (1 H, m), 2.39
(3H, s), 2.26-2.20 2H, m), 1.91-
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1.78 (2H, m), 1.21 (3H, t, J = 7.0
Hz).
(CDCI3, 300 MHz) 7.81-7.75 (2H,
m), 7.32-7.27 (1 H, m), 7.21-7.19
(1 H, m), 7.03-7.00 (2H, m) 6.78-
1 ~ ~~' ° 6.76 (2H, m), 4.19 (2H, t, J = 6.5
c-31 ~ ~ \ Hz), 4.13-4.06 (2H, q, J = 7.1 Hz), For LR 434
3.00 (2H, s), 2.95 (2H, t, J = 6.5 (M+H)'
Hz), 2.43-2.40 (2H, m), 2.37 (3H,
° s), 2.35 (3H, s), 2.07-1.97 (2H, m),
o ~ 1.89-1.79 (2H, m), 1.19 (3H, t, J=
7.1 Hz
(CDCI3, 300 MHz) 8.09-8.06 (2H,
m), 7.69-7.66 (2H, m) 7.04-7.01
F I ~ ~N ° (2H, m), 6.80-6.77 (2H, m), 4.21
(2H, t, J = 6.5 Hz), 4.15-4.06 (2H, For LR 488
c-32 F F ~ \ m), 3.00 (2H, s), 2.96 (2H, t, J= (M+H)+
6.5 Hz), 2.43-2.34 (5H, m), 2.01-
1.97 (2H, m), 1.92-1.79 (2H, m),
° ~ 1.20 (3H, t, J = 7.1 Hz)
°\
'" 'o
For LR 470
c-33 ~ \ (M+H),
0
0
0
(CDCI3, 300 MHz) 7.81-7.75 (1 H,
/ m), 7.33-7.27 (2H, m), 7.22-7.19
o~ (1 H, m), 7.16-7.13 (2H, m), 6.81
-~ 6.78 (2H, m) 4.20 (2H t, J = 6.7
I ~ 'N ° Hz), 4.16-4.09 (2H, q, J= 7.1 Hz), For LR 450
c-34 ~ \ 3.94-3.82 (2H, m), 3.14-3.08 (1 H, (M+H).
1 m), 2.98-2.94 (2H, t, J = 6.5 Hz),
° 2.94-2.88 (1 H, m), 2.38 (3H, s),
° ~ 2.36 (3H, s), 2.27-2,19 (1 H, m),
1.92-1.74 (2H, m), 1.68-1.62 (1 H,
m,1.21 3H,t J=7.1 Hz.
(CDCI3, 300 MHz) 8.09-8.07 (2H,
m), 7.69-7.66 (2H, m), 7.16-7.14
\ (2H, m), 6.81-6.78 (2H, m), 4.21
(2H, t, J = 6.5 Hz), 4.16-4.09 2H,
F I
c-35 F F ~ \ 3 ~15-3 1.0 (1 H, m), 2 98 (2HHt, J)= F (NI H) ~4
0 6.5 Hz), 2.94-2.89 (1 H, m), 2.39
° (3H, s), 2.27-2.18 (1 H, m), 1.92
° ~ 1.61 (3H, m), 1.21 (3H, t, J = 7.1
Hz .
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Preparation c-36
Ethyl 1-f4-f2-(4'-methoxv-1 1'-biphenyl-4-
vl)ethoxv)benzvl)cvclobutanecarboxvlate
~O i O
i
0
To a solution of ethyl 1-{4-[2-(4-
bromophenyl)ethoxy]benzyl}cyclobutanecarboxylate (Preparation c-13) (0.25 g,
0.5990 mmol), tetrakis(triphenylphosphine)palladium(0) (0.1252 g, 0.6589
mmol),
benzene (1.6 mL), and 2M aqueous sodium carbonate (0.8 mL), under an
atmosphere of nitrogen, was added a solution of the boronic acid (0.8640 mmol,
1.1 equiv.) in ethanol (0.4 mL). The resulting mixture was degassed and then
refluxed for 16 hours followed by cooling to ambient temperature. To this was
then
added 30% aqueous hydrogen peroxide (0.04 mL) dropwise and the resulting
solution stirred at ambient temperature for 1 hour. The solution was then
extracted
with ethyl acetate (3x100 mL) and the combined organic extracts washed with
saturated aqueous sodium chloride (100 mL), dried (anhydrous magnesium
sulfate), filtered and concentrated in vacuo to afford the crude product. The
residue was purified by flash column chromatography (hexanes to 40% ethyl
acetate/hexanes) to yield the pure product as a colorless oil.
LRMS (m/z): 462 (M+HZp)+,
'H NMR (CDCI3, 300 MHz) 7.51 (2H, d, J = 5.7 Hz), 7.49 (2H, d, J = 4.7 Hz),
7.32
(2W, d, J = 8.1 Hz), 7.03 (2H, d, J = 8.5 Hz), 6.97 (2H, d, J = 8.9 Hz), 6.80
(2H, d, J
= 8.5 Hz), 4.15 (1 H, t, J = 7.2 Hz), 4.10 (2H, q, J = 7.2 Hz), 3.84 (3H, s),
3.10 (2H,
t, J = 7.1 Hz), 3.01 (2H, s), 2.43-2.34 (2H, m), 2.07-1.98 (2H, m), 1.90-1.80
(2H,
m), 1.20 (3H, t, J = 7.2 Hz).
Preparations c-37 to c-43
Preparations c-37 to c-43 were prepared usinc,Lanaloqous~~rocedures to those
used for Preparation c-36
p I IMS (m/z)I
Prena~ratio Structure 'H NMR (LR o Iir
HR)
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(CDCI3, 300 MHz) 7.46 (2H,
d, J= 8.9 Hz), 7.41
(2H d, J= 8.3 Hz), 7.27 (2H,
/' d, J= 8.1 Hz), for
0 7.03 (2H, t J = 8.9 Hz), 6.97LR
(2H d, J = 8.5 Hz),
c-37 ~ ~ o ~ ~ 6.73 (2H, d, J= 8.7 Hz), 4.09433
(2H, t, J= 7.0 Hz),
4.03 (2H, q, J = 7.0 Hz), (M+H)+
3.03 (2H, t, J = 7.0 Hz),
2.94 (2H, s), 2.37-2.27 (2H,
m), 2.00-1.91 (2H,
m), 1.83-1.72 (2H, m), 1.13
(3H, t, J = 7.1 Hz).
c-38 (CDCI3, 300 MHz) 7.48 (2H, for
d, J= 8.1 Hz), 7.34- LR
7.29 (4H, m), 7.05 (2H, d, 467
J = 8.7 Hz), 6.99 (2H,
d, J = 8.5 Hz), 6.81 (2H, (M+Na)'
d, J = 8.7 Hz), 4.18
0
(2H, t, J = 7.3 Hz) 4.11 (2H
o~~~ q J = 7.0 Hz), 3.81
(3H, s), 3.12 (2H, t, J =
7.3 Hz), 3.02 (2H, s),
i i 2.44-2.35 (2H, m), 2.08-1.99
, (2H, m), 1.91-1.80
0
(2H, m), 1.21 (3H, t, J =
7.0 Hz).
(CDCI3, 300 MHz) 7.53-7.49
(3H, m), 7.44 (2H,
o.~F t, J = 7.9 Hz), 7.38 (2H,
t, J = 7.9 Hz), 7.09 (1 H,
a dm, J = 8.0 Hz), 7.04 (2H for
c-39 ~ ~ d, J = 8.5 Hz), 6.80 LR
o-~~", (2H, d, J = 8.5 Hz), 4.17 499
(2H, t, J = 7.0 Hz), 4.10
\ i i ~ (2H, q, J = 7.0 Hz), 3.12 (M+H)'
o (2H, t, J = 7.0 Hz), 3.01
(2H, s), 2.44-2.35 (2H, m),
2.07-1.98 (2H, m),
1.90-1.83 (2H, m), 1.21 (3H,
t, J = 7.2 Hz).
(CDCI3, 300 MHz) 8.36 (1H,
s), 7.77 (1H, dd, J=
2.5 and 8.7 Hz), 7.46 (2H,
d, J = 8.1 Hz), 7.35
(2H, d, J = 8.1 Hz), 7.03 for
(2H d J = 8.3 Hz) LR
6.81 ( 1 H, d, J = 8.3 Hz),
c-40 6.79 (2 H, d, J = 8.3
Hz), 4.16 (2H, t, J = 6.8 (M
Hz), 4.09 (2H, q, J = 7.2 4H)+
Hz), 3.97 (3H, s), 3.10 (2H,
t, J= 7.0 Hz), 3.00
(2H, s), 2.43-2.33 (2H, m),
2.06-1.97 (2H, m),
1.89-1.79 (2H, m), 1.20 (3H,
t, J = 7.1 Hz).
(CDCI3, 300 MHz) 7.99 (2H,
d, J= 8.1 Hz), 7.75
(2H, d, J = 8.1 Hz), 7.56
(2H, d, J = 8.1 Hz),
0 7.40 (2H, d, J = 7.9 Hz), for
7.03 (2H d, J = 8.5 LR
Hz), 6.79 (2H, d, J = 8.5
c-41 "~ Hz), 4.17 (2H, t, J = 6.8 511
H
09
2H
J = 7
2 H
4
3
13
2H
9
=
z), (M+Na)
(
, q,
.
.
z),
.
(
, t, J
6.
Hz), 3.08 (3H, s), 3.00 (2H,
s), 2.43-2.33 (2H,
m), 2.06-1.97 (2H, m), 1.90-1.79
(2H, m), 1.20
(3H, t, J = 7.2 Hz).
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(CDCI3, 300 MHz) 7.48 (2H,
d, J= 8.3 Hz), 7.41
1 H, s), 7.34-7.31 (1 H,
m), 7.31 (2H, d, J = 8.3
z), 7.04 (2H, d J = 8.7 Hz),
6.85 (1 H d J =
.5 Hz), 6.80 (2H, d, J = or
~ 8.5 Hz), 4.61 (2H, t, J LR
~ =
c-42 8.7 H 4 16 2 2
z), . ( H, t, J = 7. Hz), 79
4.10 (2H, q, J =
.2 Hz), 3.27 (2H, t, J = (M+Na)'
8.7 Hz), 3.10 (2H, t, J
=
.0 Hz), 3.01 (2H, s), 2.44-2.35
(2H, m), 2.07-
1.99 (2H, m), 1.91-1.83 (2H,
m), 1.21 (3H, t, J=
.2 Hz).
(CDCI3, 300 MHz) 7.57 (2H,
d, J= 8.5 Hz), 7.50
(2H, d, J = 8.5 Hz), 7.35
(2H, d, J = 8.5 Hz),
7.27 (2H, d, J = 8.5 Hz),
7.03 (2H, d, J = 8.7
NN-SOyCN~ Hz), 6.79 (2H, d, J = 8.7 for
c-43 Hz), 6.37 (1 H, bs), 4.16 LR
\ ~ ~ ~~c~' (2H t, J = 7.0 Hz), 4.09 508
(2H q, J = 7.0 Hz) 3.11 (M)'
(2H, d, J= 7.0 Hz), 3.04
(3H, s), 3.00 (2H, s),
2.43-2.33 (2H, m), 2.06-1.97
(2H, m), 1.89-1.79
(2H, m), 1.20 (3H, t, J=
7.2 Hz).
Preparation c-44
Methyl 4-t4-f(5-methyl-2-phenyl-1.3-oxazol-4-vl)methoxylbenzyl~tetrahydro-2H
pvran-4-carboxvlate
OMe
/ ~ N~O ~ O
O
A solution of methyl 4-(4-hydroxybenzyl)tetrahydro-2H-pyran-4-carboxylate
(Preparation c-8) (0.500 g, 2.0 mmol), cesium carbonate (1.96 g, 6.0 mmol) and
chloride (0.458 g, 2.2 mmol) in acetonitrile was heated at 140 °C in a
microwave
synthesizer for 10 minutes. The mixture was cooled, filtered and the filtrate
evaporated. The residue purified by flash column chromatography (hexanes to
ethyl acetate) to yield the title compound as a white crystalline solid (0.827
g, 98%).
LRMS (m/z): 422 (M+H)'.
Preparation c-45
5-Bromo-2-[2-(5-methyl-2-phenyl-1.3-oxazol-4-~Lthoxylpvridine
O ~ Br
O N
To a solution of 2,5-dibromo-pyridine (5 g, 21.1060 mmol) and 2-(5-methyl-2-
phenyl-oxazol-4-yl)-ethanol (5.1472 g, 25.3271 mmol) in anhydrous
tetrahydrofuran
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(85 mL), under an atmosphere of nitrogen, was added potassium tent butoxide
(2.8422 g, 25.3271 mmol). The resulting mixture was heated at reflux for 16
hours
and then allowed to cool to ambient temperature. The mixture was evaporate to
about 20 mL and partitioned between saturated aqueous ammonium chloride (50
mL) and ethyl acetate (50 mL). The layers were separated and the aqueous layer
extracted with ethyl acetate (2x50 mL). The combined organic extracts were
then
washed with water (2x50 mL), saturated aqueous sodium chloride (50 mL), dried
(anhydrous magnesium sulfate), filtered and concentrated in vacuo to afford
the
crude product. The residue was purified by flash column chromatography
(hexanes to 20% ethyl acetatelhexanes) to yield a white crystalline solid (6.3
g,
83%).
LRMS (m/z): 359 (M)'.
'H NMR (CDCI3, 400 MHz) 8.17 (1 H, d, J = 2.0 Hz), 7.96 (2H, dd, J = 2.0, 8.1
Hz),
7.61 (1 H, dd, J = 2.7, 8.7 Hz), 7.43-7.38 (3H, m), 6.62 (1 H, d, J = 8.6 Hz),
4.52 (2H,
t, J = 6.8 Hz), 2.96 (2H, t, J = 6.8 Hz), 2.32 (3H, s).
Preparations c-46 to c-47
Preparations c-46 to c-47 were prepared by aeneralprocedure for Preioaration c-
45.
Prep Structure 'H NMR MS (m/z)
# (LR or HR)
(CDCI3, 400 MHz):
7.97 (2H,
dd, J= 8.0, 7.6
Hz), 7.49 (1H,
o ~ dd J= 8.1, 7.6 Hz),
C-46 / \ N~o I ni CI 7.43-7.38 315 (M H)'
(3H, m), 6.87 (1
H, d, J = 7.6
Hz), 6.62 ( 1 H,
d, J = 8.1 Hz),
4.55 (2H, t, J =
7.0 Hz), 2.97
(2H, t, J = 7.0
Hz), 2.34 (3H,
s)
(CDCI3, 300 MHz):
8.51 (2H,
o ~ Br s) 7.97-7.94 (2H,
c-47 / ~ ~ ~ ~~ m) 7.45-7.38 for LR
(3H, m), 4.61 (2H, 361 (M*H)T
t, J = 6.9
Hz), 3.01 (2H, t,
J = 6.9 Hz),
2.35 (3H, s)
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Preparation c-48
6-f2-(5-Methyl-2-phenyl-1 3-oxazol-4-yl)ethoxv]nicotinalde~de
0
/ \ o
N~/'O N
To a solution of butyllithium (27.4 mL of a 1.6M solution in hexanes, 43.8199
mmol)
in anhydrous tetrahydrofuran (200 mL), under an atmosphere of nitrogen, was
added a solution of 5-bromo-2-[2-(5-methyl-2-phenyl-1,3-oxazol-4-
yl)ethoxy]pyridine (Preparation c-45) (14.31 g, 39.8363 mmol) in anhydrous
tetrahydrofuran (170 mL) and anhydrous diethyl ether (170 mL) over a period of
45
minutes. To this solution was then added anhydrous N,N-dimethylformamide (5.7
mL) dropwise and the mixture stirred at 0 °C for 1 hour. The reaction
was
quenched by addition of saturated aqueous ammonium chloride (250 mL) and then
ethyl acetate (250 mL). The resulting layers were separated and the aqueous
layer
extracted with ethyl acetate (2x250 mL). The combined organic extracts were
washed with water (2x250 mL), saturated aqueous sodium chloride (250 mL),
dried
(anhydrous magnesium sulfate), filtered and concentrated in vacuo to afford
the
crude product. The residue was purified by flash column chromatography
(hexanes to 50% ethyl acetate/hexanes) to yield a pale yellow crystalline
solid
(7.17 g, 58%).
LRMS (m/z): 309 (M+H)+.
.'H NMR (CDCI3, 300 MHz) 9.93 (1 H, s), 8.61 (1 H, d, J = 2.3 Hz), 8.04 (1 H,
dd, J =
2.5, 8.7 Hz), 7.98-7.95 (2H, m), 7.43-7.39 (3H, m), 6.81 (1 H, d, J = 8.7 Hz),
4.68
(2H, t, J = 6.8 Hz), 3.00 (2H, t, J = 6.8 Hz), 2.34 (3H, s).
Preparation c-49
Ethyll-(hvdroxy{6-f2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxylpyridin-3-
y~methyl)cyclobutanecarboxylate
OH O
/ \
To a solution of 6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-
yl)ethoxy]nicotinaldehyde
(Preparation c-48) (0.65 g, 2.1081 mmol), chromium (II) chloride (1 g, 8.1367
mmol), and lithium iodide (0.0784 g, 0.5859 mmol) in anhydrous tetrahdrofuran
(15
mL), under an atmosphere of nitrogen, was added a solution of 1-bromo-
cyclobutanecarboxylic acid ethyl ester (0.79 mL, 4.8821 mmol) in anhydrous
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tetrahydrofuran (5 mL) dropwise. The resulting mixture was stirred at 50
°C for 3
hours and allowed to cool to ambient temperature. The solution was then
quenched by addition of water (50 mL) and the organic layer separated, which
was
further washed with water (2x50 mL), saturated aqueous sodium chloride (50
mL),
dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to
afford
the crude product: The residue was purified by flash column chromatography
(50%
ethyl acetate/hexanes to ethyl acetate) to yield a yellow oil (0.3422 g, 37%).
LRMS (m/z): 437 (M+H)'.
'H NMR (CDCI3, 400 MHz) 8.05 (1H, d, J= 2.3 Hz), 7.98-7.95 (2H, m), 7.56 (1H,
dd, J = 2.5, 8.7 Hz), 7.44-7.37 (3H, m), 6.67 (1 H, d, J = 8.7 Hz), 4.85 (1 H,
d, J =
6.6 Hz), 4.54 (2H, t, J = 6.6 Hz), 4.18-4.07 (2H, m), 3.31 (1 H, bs), 2.96
(2H, t, J =
6.7 Hz), 2.46-2.30 (2H, m), 2.32 (3H, s), 2.21-2.12 (1 H, m), 1.97-1.85 (1 H,
m),
1.79-1.65 (2H, m), 1.21 (3H, t, J = 7.2 Hz).
Preparation c-50
1-(Ethoxv-f6-[2-(5-methyl-2 ~ohenyl-oxazol-4-yl)-ethoxvl-pvridin-3-yl~-methyl)-
cyclobutanecarboxylic acid ethyl ester
Jo
/v
O N
To a solution of 1-(hydroxy-{6-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-
pyridin-3-
yl}-methyl)-cyclobutanecarboxylic acid ethyl ester (0.1711 g, 0.3920 mmol) in
dry
acetonitrile (2 mL) was added silver(I) oxide (1.8168 g, 7.8396 mmol) and
iodoethane (0.64 mL, 7.8396 mmol). The resulting mixture was stirred for 5
days
and concentrated under reduced pressure to afford the crude product and
recovered remaining starting material. The residue was purified by flash
column
chromatography (hexanes to ethyl acetate) to yield the pure ester (0.0474 g,
26%)
as a colorless oil.
LRMS (m/z): 465 (M+H)+.
'H NMR (CDCI3, 400 MHz): 8.05 (1H, d, J= 2.3 Hz), 7.98-7.95 (2H, m), 7.56 (1H,
dd, J = 2.5, 8.7 Hz), 7.44-7.37 (3H, m), 6.67 (1 H, d, J = 8.7 Hz), 4.65 (1 H,
m), 4.54
(2H, t, J = 6.6 Hz), 4.18-4.07 (2H, m), 4.06 (2H, q, J = 7.1 Hz), 2.96 (2H, t,
J = 6.7
Hz), 2.46-2.30 (2H, m), 2.32 (3H, s), 2.21-2.12 (1 H, m), 1.97-1.85 (1 H, m),
1.79-
1.65 (2H, m), 1.42 (3H, t, J = 7.1 Hz), 1.21 (3H, t, J = 7.2 Hz).
Preparation c-51
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!6-f2-(5-methyl-2-phenyl-1.3-oxazol-4-vllethoxvlpyridin-3-yl~methanol
/ \ ~~ ~ ~ OH
N O N
Sodium borohydride (0.480 g, 12.7 mmol) was added portionwise to a solution of
6-
[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]nicotinaldehyde (Preparation c-
48)
(1.30 g, 4.22 mmol) in methanol (40 mL) at ambient temperature. The mixture
was
stirred for 30 minutes then evaporated. The residue was partitioned between
saturated aqueous ammonium chloride and ethyl acetate. The organic phase was
washed with saturated aqueous sodium chloride and dried (anhydrous magnesium
sulfate), filtered and evaporated to give the title compound as a white
crystallinesolid (1.24 g, 100%).
LRMS (m/z): 311 (M+H)+.
'H NMR (CDCI3, 300 MHz) 8.11 (1 H, d, J = 2.6 Hz), 8.00-7.95 (2H, m), 7.60 (1
H,
dd, J= 2.5, 8.5 Hz), 7.45-7.38 (3H, m), 6.72 (1H, d, J= 8.5 Hz), 4.61 (2H,
bs), 4.56
(2H, t, J = 6.8 Hz), 2.98 (2H, t, J = 6.8 Hz), 2.33 (3H, s).
Preparation c-52
!2-12-!5-Methyl-2-phenyl-oxazol-4-yll-ethoxyl-pyrimidin-5-yl~-methanol
/ \ ~~ ~.~OH
N O N
A solution of 5-bromo-2-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyrimidine
(1.0
g, 2.7765 mmol), tert-butyl-dimethyl-tributylstannanylmethoxy-silane (1.8 g,
4.1648
mmol), and tetrakis(triphenylphosphine)palladium(0) (0.3209 g, 0.2777 mmol) in
1,4-dioxane (2.8 mL) was heated (by microwave irradiation) at 150 °C
for 2 hours.
The resulting solution was allowed to cool to ambient temperature and
saturated
aqueous potassium fluoride (10 mL) was added followed by stirring for 30
minutes.
This mixture was then extracted with ethyl acetate (3 x 25 mL) and the
combined
organic extracts dried (anhydrous magnesium sulfate), filtered and
concentrated in
vacuo to afford the crude product as a yellow oil.
To a solution of the crude residue in dry tetrahydrofuran (24 mL) was added
tetrabutylammonium fluoride (3.1 mL of a 1.OM solution in tetrahydrofuran).
The
resulting mixture was stirred at ambient temperature for 16 hours and
concentrated
under reduced pressure. The residue was purified by flash column
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chromatography (50% ethyl acetate/hexanes to 10% methanol/ethyl acetate) to
yield the pure alcohol (0.6137 g, 71 % for 2 steps) as a white solid.
LRMS (m/z): 312 (M+H)'
Preparation c-53
5-Benzyloxy-2-methyl-pyridine
I
~N
i
To a solution of 5-hydroxy-2-methylpyridine (20 g, 183.2677 mmol) and sodium
hydroxide (8.0638 g, 201.5944 mmol) in acetone (400 mL) and water (120 mL) was
added benzyl bromide (24 mL, 201.5944 mmol). The resulting mixture was
refluxed for 16 hours and allowed to cool to ambient temperature. The acetone
was removed in vacuo and the mixture extracted with ethyl acetate (3 x 150
mL).
The combined organic extracts were washed with saturated aqueous sodium
chloride (200 mL), dried (anhydrous magnesium sulfate), filtered and
concentrated
in vacuo to afford the pure product (31.35 g, 86%) as an orange oil
LRMS (m/z): 200 (M+H)+.
'H NMR (CDCI3, 300 MHz): 8.25 (1 H, d, J = 2.8 Hz), 7.43-7.31 (5H, m), 7.15 (1
H,
dd, J = 8.5, 2.8 Hz), 7.04 (1 H, d, J = 8.5 Hz), 5.06 (2H, s), 2.47 (3H, s).
Preparation c-54
5-Benzyloxy-2-methyl-pyridine 1-oxide
i
0
I
zo
To a solution of 5-benzyloxy-2-methyl-pyridine (31.35 g, 157.34 mmol) in dry
chloroform (800 mL), at ambient temperature, was added 3-chloroperoxybenzoic
acid (77% max.) (38.7888 g, 173.074 mmol). The resulting mixture was stirred
for
2 hours and then quenched with a solution of sodium thiosulfate (36.0805 g,
286.5
mmol) in water (500 mL) and stirred for 15 minutes. The phases were separated
and the organic layer washed with water (500 mL), saturated sodium chloride
(500
mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo
to
afford the crude product. The residue was recrystallized from acetonelhexanes
to
yield the pure product (33.1597 g, 97%) as a white solid.
LRMS (m/z): 216 (M+H)'.
' H NMR (CDCI3, 300 MHz): 8.10-8.09 (1 H, bm), 7.38-7.34 (5H, m), 7.10 (1 H,
d, J
= 8.7 Hz), 6.87 (1 H, dd, J = 8.7, 2.3 Hz), 5.04 (2H, s), 2.43 (3H, s).
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Preparation c-55
15-Benzyloxy-pyridin-2-yl)-methanol
OH
~N
i
A solution of 5-benzyloxy-2-methyl-pyridine 1-oxide (0.92 g, 4.2741 mmol) in
acetic
anhydride (6.5 mL) was heated at 100 °C for 30 minutes. After cooling
to ambient
temperature, the reaction mixture was poured into ethyl acetate (50 mL),
washed
with saturated aqueous sodium bicarbonate (50 mL), saturated aqueous sodium
chloride (50 mL), dried (anhydrous magnesium sulfate), filtered, and
concentrated
in vacuo to afford the crude acetate.
To the crude residue in methanol (45 mL) was added potassium carbonate (2.1784
g, 15.7719 mmol) and the solution allowed to stir at ambient temperature for
16
hours. The reaction mixture was poured into water (50 mL) and the organic
removed under reduced pressure. The resulting residue was extracted with ethyl
acetate (3 x 50 mL) and the combined organic extracts dried (anhydrous
magnesium sulfate), filtered, and concentrated in vacuo to afford the crude
product.
The residue was purified by flash column chromatography (hexanes to 20%
methanol/ethyl acetate) to yield the pure alcohol (0.5719 g, 62% for two
steps) as a
white solid.
LRMS (m/z): 216 (M+H)+.
'H NMR (CDCI3, 300 MHz): 8.31 (1H, d, J=2.8 Hz), 7.44-7.31 (5H, m), 7.27 (1H,
dd, J = 8.7, 2.8 Hz), 7.17 (1 H, d, J = 8.5 Hz), 5.11 (2H, s), 4.69 (2H, s).
Preparation c-56
2-Methyl-5-f2-!5-methyl-2-phenyl-oxazol-4-yl)-ethoxyl-pyridine 1-oxide
/ \
O O
To a solution of 2-methyl-5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-
pyridine
(6.7973 g, 23.0917 mmol) in dry chloroform (140 mL), at ambient temperature,
was
added 3-chloroperoxybenzoic acid (77% max.) (7.7629 g, 34.6376 mmol). The
resulting mixture was stirred for 2 hours and then quenched with a solution of
sodium thiosulfate (4.3621 g, 34.6376 mmol) in water (25 mL) and stirred for
15
minutes. The phases were separated and the organic layer washed with water (50
mL), saturated sodium chloride (50 mL), dried (anhydrous magnesium sulfate),
filtered and concentrated in vacuo to afford the crude product. This pale
yellow oil
(7.0689 g, 98%) was used without further purification.
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LRMS (m/z): 311 (M+H)+,
'H NMR (CDCI3, 300 MHz): 8.06 (1H, d, J= 2.3 Hz), 7.96-7.93 (2H, m), 7.41-7.39
(3H, m), 7.10 (1 H, d, J = 8.9 Hz), 6.85 (1 H, dd, J = 8.8, 2.4 Hz), 4.23 (2H,
t, J = 6.6
Hz), 2.95 (2H, t, J = 6.6 Hz), 2.43 (3H, s), 2.35 (3H, s).
Preparation c-57
(5-f2-(5-Methyl-2-phenyl-oxazol-4-y~ ethoxyl-pvridin-2-vl~-methanol
/ \ ~~ ~ ~ OH
N ~ ~N
A solution of 2-methyl-5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridine 1-
oxide
(3.5979 g, 11.5181 mmol) in acetic anhydride (17.5 mL) was heated at 100
°C for
30 minutes. After cooling to ambient temperature, the reaction mixture was
poured
into ethyl acetate (150 mL), washed with saturated aqueous sodium bicarbonate
(150 mL), saturated aqueous sodium chloride (150 mL), dried (anhydrous
magnesium sulfate), filtered, and concentrated in vacuo to afford the crude
acetate.
To the crude residue in methanol (120 mL) was added potassium carbonate
(5.8705 g, 42.617 mmol) and the solution allowed to stir at ambient
temperature for
16 hours. The reaction mixture was poured into water (150 mL) and the organic
removed under reduced pressure. The resulting residue was extracted with ethyl
acetate (3 x 150 mL) and the combined organic extracts dried (anhydrous
magnesium sulfate), filtered, and concentrated in vacuo to afford the crude
product.
The residue was purified by flash column chromatography (ethyl acetate to 10%
methanol/ethyl acetate) to yield the pure alcohol (1.52 g, 43% for two steps)
as a
pale yellow low melting solid.
LRMS (m/z): 311 (M+H)'.
'H NMR (CDCI3, 300 MHz): 8.22 (1 H, d, J = 2.5 Hz), 7.97-7.94 (2H, m), 7.42-
7.38
(3H, m), 7.20 (1 H, dd, J = 8.5, 2.6 Hz), 7.15 (1 H, d, J = 8.7 Hz), 4.67 (2H,
s), 4.28
(2H, t, J = 6.7 Hz), 2.98 (2H, t, J = 6.7 Hz), 2.37 (3H, s).
Preparation c-58
5-(chloromethyl)-2-f2-(5-methyl-2=phenyl-1 3-oxazol-4-y)ethoxylpyridine
/ \ ~~ ~ ~ CI
O N
Oxalyl chloride (0.30 mL, 3.44 mmol) was added to a solution of {6-[2-(5-
methyl-2-
phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}methanol (Preparation 26) (0.97 g,
3.13
mmol) in dichloromethane (30 mL) and N,N-dimethyl formamide (3 mL) at 0
°C.
The mixture was warmed to ambient temperature and stirred for 1 hour then
evaporated. The residue was partitioned between saturated aqueous sodium
bicarbonate and ethyl acetate. The organic phase was washed with saturated
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aqueous sodium chloride and dried (anhydrous magnesium sulfate), filtered and
evaporated to give the title compound as a white crystalline solid (1.01 g,
100%).
LRMS (m/z): 329 (M+H)'.
'H NMR (CDCI3, 300 MHz) 8.12 (1 H, d, J = 2.5 Hz), 7.98-7.95 (2H, m), 7.60 (1
H,
dd, J = 2.5, 8.5 Hz), 7.45-7.37 (3H, m), 6.72 (1 H, d, J = 8.5 Hz), 4.57 (2H,
t, J = 6.8
Hz), 4.53 (2H, s), 2.97 (2H, t, J= 6.8 Hz), 2.33 (3H, s).
Preparations c-59 to c-63
Preparations c-59 to c-63 were prepared bypeneral arocedure for Preparation c-
58
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WO 2004/092145 PCT/IB2004/001159
~m
Prep Structure 'H NMR MS (m/z)
# (LR or
HR)
c-59 / ~ ~~ NCI for LR
I
N O~N 330 (M+H)~'
for LR
c-60 I ~ p 234 (M+H)+
CI for LR
c-61 N I o I ~ N 329 (M+H).
(CDCIa, 300 MHz):_
8.16 (2H, s),
/ ~ N~O~N~CI .97 (2H, d, J = 7.7 for LR
c-62 I JI Hz), 7.40 (3H,
330 (M+H)+
), 4.61 (4H, m),
2.99 (2H, t, J =
.7 Hz), 2.35 (3H,
s)
i I w CI (CDCIa, 400 MHz):_ for LR
c-63 I ~ O ~ ~ 7.75-7.72 (3H, 282 (M+H
), 7.50-7.33 (6H, )
m), 7.24-7.22
(2H, m), 5.18 (2H,
s), 4.74 (2H, s)
Preparation c-64
5-(iodomethvl)-2-f2-(5-methyl-2-phenyl-1.3-oxazol-4-yl)ethoxylpvridine
/ \ N~O ~ N I
Sodium iodide (0.750 g) was added to a solution of 5-(chloromethyl)-2-[2-(5-
methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridine (Preparation 27) (0.690 g,
2.10
mmol) in acetone (5 mL) and the mixture was heated at reflux for 30 minutes,
cooled and evaporated. The residue was suspended in ethyl acetate and filtered
through a pad of silica gel. The filtrate was evaporated to give the title
compound
as a yellow crystalline solid that was used directly in subsequent reactions.
LRMS (m/z): 421 (M+H)+.
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116
Preparations c-65 to c-69
Preuarations c-65 to c-69 were~arenared by general arocedure for Preparation c-
64
MS (m/z)
Prep Structure H NMR
# (LR or HR)
o N ~~ ~ for LR
c-65 N oJ.NJ 422 (M+H)'
w
c-66 I for LR
~O
326 (M+H)+
o~ I i i for LR
c-67 N o N 421 (M+H)+
for LR
c-68 N o N 422 (M+H)~
(CDCI3, 400 MHz):,
7.76-
7.66 (3H, m), for LR
c-69 I ~ ~ ~ 7.49-7.32 375 (M+H)~
(6H, m), 7.24-7.18
(2H, m),
5.18 (2H, s),
4.63 (2H, s)
Preparation c-70
Ethyl1~~6-[2-(5-methyl-2-phenyl-1.3-oxazol-4-yllethoxyloyrridin-3-
y I~methylLvclobutane carboxylate
0
/ \ N~ I
O N
Sodium (bis)trimethylsilyl amide (3.0 mL of a 1 M solution in tetrahydrofuran,
3.0
mmol) was added dropwise to a solution of ethyl cyclobutanoate (0.41 mL, 3.0
mmol) in anhydrous tetrahydrofuran (5 mL) at -60 °C. The mixture was
stirred for
1 hour and then a solution of 5-(iodomethyl)-2-[2-(5-methyl-2-phenyl-1,3-
oxazol-4-
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117
yl)ethoxy]pyridine (Preparation 28) (0.271 g, 0.64 mmol) in anhydrous
tetrahydrofuran (4 mL) was added dropwise. The resulting mixture was stirred
at -
60 °C for 1 hour then quenched with saturated aqueous ammonium chloride
and
warmed to ambient temperature. The mixture was extracted with ethyl acetate
and
the organic phase dried (anhydrous magnesium sulfate), filtered and evaporated
to
afford a 1:1 mixture of the title compound and dimer (0.160 g) which was used
directly in the subsequent step.
LRMS (m/z): 421 (M+H)'.
Preparation c-71
e_thyl2-((6-f2-(5-methyl-2-phen,~l-1.3-oxazol-4-yl)ethoxvlpvridin-3-
yl~meth I)ty etrah~drofuran-2-carbox~ate
O
/ \ ~ ,~ ~ ~ o
O
0 N
Sodium (bis)trimethylsityl amide (3.18 mL of 1M solution in tetrahydrofuran,
3.18
mmol) was added dropwise to a solution of ethyl 2-tetrahydrofuranoate (0.458
g,
3.18 mmol) in anhydrous tetrahydrofuran (4 mL) at -50 °C. The mixture
was
stirred for 45 minutes and then a solution of 5-(iodomethyl)-2-(2-(5-methyl-2-
phenyl-1,3-oxazol-4-yl)ethoxy]pyridine (Preparation 28) (0.267 g, 0.64 mmol)
in
anhydrous tetrahydrofuran (2 mL) was added dropwise. The resulting mixture was
stirred at -50 °C for 1.5 hours then quenched with saturated aqueous
ammonium
chloride and warmed to ambient temperature. The mixture was extracted with
ethyl acetate and the organic phase dried (anhydrous magnesium sulfate),
filtered
and evaporated. The residue was purified by flash column chromatography (25%
to 35% ethyl acetate/hexanes) to yield the title compound as a colorless oil
(0.250
g, 90%).
LRMS (m/z): 437 (M+H)+.
'H NMR (CDCI3, 300 MHz) 7.95 (3H, m), 7.51 (1 H, dd, J = 2.5, 8.5 Hz), 7.43-
7.36
(3H, m), 6.61 (1 H, d, J = 8.5 Hz), 4.51 (2H, t, J = 6.8 Hz), 4.29-4.18 (1 H,
m), 413
(2H, q, J = 7.2 Hz), 3.95-3.82 (2H, m), 3.10 (1 H, d, J = 14.1 Hz), 2.95 (2H,
t, J = 6.8
Hz), 2.86 (1 H, d, J = 14.1 Hz), 2.31 (3H, s), 2.26-2.20 (1 H, m), 1.92-1.77
(2H, m),
1.70-1.61 (1H, m), 1.21 (3H, t, J= 7.2 Hz).
Preparations c-72 to c-79
Preparations c-72 to c-79 were pre~~ared b~general procedure for Preparation c-
71. '
MS (m/z)
Prep # Structure ~H NMR
(LR or
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11 ~3
HR)
(CDCI3, 300 MHz): 8.38 (2H,
s), 7.97-7.94 (2H,
m), 7.44-7.38 (3H, m), 4.59
(2H, t, J= 7.0 Hz),
for
LR
c-72~ ~ N~ ~ ; o o~ .15 (2H, q, J= 7.0 Hz), 3.99-3.86
(2H, m), 3.13
438
" (1 H, d, J = 14.3 Hz), 3.00
(1 H, t, J = 6.9 Hz), 2.84
(M+H)'
(1 H, d, J = 14.3 Hz), 2.35
(3H, s), 2.26-2.20 (1 H,
), 1.91-1.63 (4H, m), 1.23
(3H, t, J= 7.0 Hz)
(CDCI3, 300 MHz): 8.27 (1
H, d, J = 2.3 Hz), 7.42-
p .32 (5H, m), 7.20-7.13 (2H,
m), 5.06 (2H, s), 4.13
I N p p~ (2H, q, J = 13.9 Hz), 3.33 f
(1 H, d, J = 13.9 Hz),
-7 o 342
c I j 14 (1 H
3 J = 13
d
9 Hz)
2
64-2
55 (1 H
m)
2
27-
. (M+H)i
,
,
.
,
.
.
,
,
.
.20 (1 H, m), 1.89-1.63 (4H,
m), 1.24 (3H, t, J =
13.9 Hz)
(CDC13, 300 MHz): 8.27 (1H,
d, J= 2.6 Hz), 7.42-
for
o' .29 (5H, m), 7.16 (1 H, dd, LR
1 J = 8.7, 2.8 Hz), 7.14-
,
0
c-74I ~ -N ~ .08 (1H, m), 5.06 (2H, s), 316
3.71 (3H, s), 3.30 (3H, '
(M+H)
), 3.16 (2H, s), 1.40 (3H,
s)
O (CDCI3, 400 MHz): 8.14 (1
H, d, J = 2.3 Hz), 7.41
for
(1 H, dd, J = 8.3, 2.5 Hz), LR
7.36 (1 H, dd, J = 8.3, 0.8
289
c-75~ ~ O Hz), 3.69 (3H, s), 3.27 (3H,
s), 2.99 (1 H, d, J =
Br N ~ (M+H)
13.9 Hz), 2.87 (1H, d, J=
13.9 Hz), 1.33 (3H, s)
(CDCI3, 400 MHz): 8.17 (1
H, d, J = 2.3 Hz), 7.96
(2H, dd, J= 7.7, 1.9 Hz),
7.43-7.38 (3H, m), 7.12
(1 H, d, J = 8.1 Hz), 7.09
(1 H, dd, J = 8.6, 2.8 Hz),
for
~ ~ ~~ ~ N ~ .24 (2H, t, J = 6.7 Hz), 4.15LR
(2H, q, J = 7.2 Hz),
451
c-76
.88-3.84 (1 H, m), 3.64 (1
H, dt, J = 11.6, 3.3 Hz),
(M+H),
.07 (2H, s), 2.96 (2H, t,
J = 6.6 Hz), 2.36 (3H, s),
.22-2.18 (1 H, m), 1.52-1.36
(5H, m), 1.20 (3H, t,
= 7.1 Hz)
(CDCI3, 300 MHz); 8.09 (1
H, s), 7.91-8.01 (3H, m),
.34-7.45 (3H, m), 4.48-4.64 for
(2H, m), 3.84-4.24 LR
.
2H m 3.22 1 H, d, J = 15.0
c-77i ~ ,~ ~~~~~ Hz 438
( ~ )~ ( ), 3.11 (1 H, d,
J =
N O N
15.0 Hz), 2.91-3.03 (1 H, (M+H)'
m), 2.31-2.35 (1 H, m),
1.65-2.30 (2H, m), 1.24 (3H,
t, J = 6.6 Hz)
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119
(CDC13, 300 MHz): 7.96 (1H,
m), 7.92 (2H, d, J=
for
c-78o .1 Hz), 7.41 (4H, m), 6.63 LR
i ~ (1 H, d, J = 8.5 Hz),
~ 411
~
'
N .52 (2H, t, J = 6.8 Hz), 3.70
.o (3H, s), 3.30 (3H, m ,
rf p )
.93 (4H, m), 2.33 (3H, s), (M+H)'
1.33 (3H, s)
(CDCI3, 400 MHz): 7.69 (1
H, d, J = 9.3 Hz), 7.64-
.62 (2H, m), 7.49-7.48 (2H,
m), 7.42-7.32 (4H, for
LR
! ), 7.21-7.18 (2H, m), 5.17
(2H, s), 4.24-4.18 2H,
(
c-79o ), 3,g6-3.86 (2H, m), 3.33 391
! ~ o ~ ~ ( 1 H, d, J = 13.6 Hz), +
(M+H)
3.13 (1 H, d, J = 13.8 Hz),
2.32-2.20 (1 H, m), 2.03-
1.89 (3H, m), 1.19 (3H, t,
J = 7.1 Hz)
Preaaration c-80
2-Bromo-5-(bromomethyl)pyridine
Br
Br N
Phosphorous tribromide (100 mmol, 27.1 g, 2.0 eq.) was added carefully to 2-
chloro-5-hydroxymethyl pyridine (50.0 mmol, 7.18 g, 1.0 eq.). The pyridine
clumped together and the mixture was heated to 160 degrees C. Within 5 minutes
of stirring at > 150 degrees C the mixture was seen to go very dark in color
with
gas evolution. The mixture was stirred at this same temperature for
approximately
2.5 hours at which point it was cooled to room temperature. The mixture was
cooled further to 0 degrees C whereupon saturated sodium bicarbonate was added
very cautiously (highly exothermic!). As foaming became less vigorous, ice was
added to the mixture until foaming subsided. Solid sodium bicarbonate was then
carefully added to achieve a pH of - 8-9. The mixture was extracted with ethyl
acetate and the organic layer was washed with brine and dried over anhydrous
magnesium sulfate. Concentrated in vacuo to afford a dark solid. This material
was dissolved in a minimal amount of DCM and purified using a Biotage Sp4 65i
over a gradient of 0 - 100 % ethyl acetate in hexanes to afford the title
compound
as a pale yellow solid (5.57 g, 44%).
LRMS: 252 (M+H)'. ,
'H NMR (DMSO-ds, 400 MHz); 8.39 (1H, s) 7.59 (1H, d, J = 8.5 Hz) 7.48 (1H, d,
J
= 8.5 Hz) 4.46 (2H, s)
Preaaration c-81
ethyl 2-f(6-bromopvridin-3-,~IZmethylltetrahydrofuran-2-carboxylate
CA 02521915 2005-10-07
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120
O
O
Br N
To a solution of ethyl tetrahydrofuran-2-carboxylate (52.9 mmol, 9.10 g, 1.5
eq.)
cooled to -78 degrees C in THF (90 mL) was added dropwise a solution of 2 M
lithium diisopropylamide (52.9 mmol, 1.5 eq.) in a mixture of
heptane/THF/ethylbenzene. The enolate was allowed to form for one hour at the
same low temperature whereupon a solution of 2-bromo-5-(bromomethyl)pyridine
(35.3 mmol, 8.85 g, 1.0 eq.) in THF was added dropwise. The reaction was
allowed to warm slowly to room temperature overnight. The reaction was
quenched with saturated ammonium chloride. The mixture was extracted with
ethyl acetate and the organic extract was washed with brine. The organic layer
was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield
a
yellow oil. This crude product was purified on a Biotage Sp4 65i over a
gradient of
5% to 95 % ethyl acetate in hexanes to afford a golden oil (8.70 g, 78%).
LRMS: 315 (M+H)+.
'H NMR (DMSO-ds, 400 MHz):, 8.21 (1 H, s) 7.40 - 7.49 (2 H, m) 3.94 (2 H, q,
J=7.0 Hz) 3.71 - 3.85 (2 H, m) 3.05 - 3.11 (1 H, m) 2.91 - 2.97 (1 H, m) 2.38 -
2.47
(1 H, m) 1.83 - 2.09 (3 H, m) 1.09 (3 H, t, J=7.0 Hz)
Preparation c-82
Cycloprooanecarboxylic acid tert-butt ester
O O
Concentrated sulfuric acid (3.45 mL, 62.7832 mmol) was added to a vigorously
stirred suspension of anhydrous magnesium sulfate (30.1987 g, 251.1326 mmol)
in
dichloromethane (250 mL). The mixture was stirred for 15 minutes, after which
cyclopropanecarboxylic acid (5 mL, 62.7832 mmol) and 2-methyl-propan-2-of (30
mL, 313.9158 mmol) were added. The mixture was stoppered tightly and stirred
at
ambient temperature for 16 hours. The reaction mixture was then quenched with
saturated aqueous sodium bicarbonate (450 mL) and stirred until all the
magnesium sulfate had dissolved. The phases were separated and the organic
phase washed with water (100 mL), saturdated aqueous sodium chloride (100 mL),
dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to
afford
the pure ester (8.3921 g, 59.0162 mmol) as a colorless liquid.
'H NMR (CDCI3, 300 MHz): 1.45 (9H, s), 0.93-0.86 (3H, m), 0.79-0.73 (2H, m).
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121
Preparation c-83
1--f6-f2-(5-Methyl-2-phe~l-oxazol-4-vl)-ethoxyl-pvridin-3-vlmeth~,l?-
c~ proaanecarboxylic acid tert-butyl ester
0
o w o
/ \
N O N
To a solution of diisopropylamine (0.14 mL, 0.9518 mmol) in dry
tetrahydrofuran
(2.4 mL), at 0 °C under an atmosphere of nitrogen, was added
butyllithium (0.38
mL of a 2.5M solution in hexanes, 0.9518 mmol). The resulting solution was
stirred
for 30 minutes and then cooled to -50 °C. To this was added a solution
of
cyclopropanecarboxylic acid tert-butyl ester (0.1269 g, 0.8924 mmol) in dry
tetrahydrofuran (1 mL) and stirring was continued for 2 hours. A solution of 5-
iodomethyl-2-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridine (0.25 g,
0.5949
mmol) in dry tetrahydrofuran (1 mL) was then added dropwise and the solution
stirred for a further 3 hours. The reaction was quenched by the addition of
saturated aqueous ammonium chloride (25 mL) and extracted with ethyl acetate
(3
x 25 mL). The combined organic extracts were then dried (anhydrous magnesium
sulfate), filtered and concentrated in vacuo to afford the crude product and
remaining starting iodide. The residue was purified by flash column
chromatography (hexanes to 60% ethyl acetate/hexanes) to yield the ester
(0.0827
g, 32%), partially contaminated with started iodide, as a pale yellow solid.
LRMS (m/z): 435 (M+H)+.
Preparation c-84
etyl 2-(f6-f2-!5-meth r~l-2-phenyl-1.3-thiazol-4-yl)ethoxv)pyridin-3-
yl)methylltetrahydrofuran-2-carbox~ate
0
0
O N
To an argon-purged solution of the bromopyridine (0.636 mmol) in toluene (12
mL)
was added palladium (II) acetate (11.4 mg, 0.0508 mmol) and racemic-2-(di-t-
butylphosphino)-1,1'-binaphthyl (25.4 mg, 0.0636 mmol). The activated complex
was allowed to form over approximately ten minutes, at which point cesium
carbonate (414 mg, 1.27 mmol) and the appropriate alcohol (0.956 mmol) were
added. The mixture was heated to 115 °C and stirred at this temperature
for 12-18
hours. The mixture was cooled to room temperature and filtered through a pad
of
silica. The filter pad was washed with 2-3 aliquots of ethyl acetate and the
combined organic filtrates were combined and concentrated in vacuo. The
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
resulting residue was either purified by flash chromatography, or used without
further purification
Preparations c-85 to c-88
Preparations c-85 to c-88 were prepared by procedures analogous to those used
for Preparation c-84
MS (m/z)
PreparationStructure 'H NMR
#
(LR or HR)
c-85 (DMSO-d6, 400-MHz)for LR
" 420 (M+H)+
N O N
O
c-86 ~ I ~ o off
N NC
O N
~ O
O
C-87
o O"
O N
c-88
I I ~ OH
O N
Preparation c-89
5-fftert-butyl(diphenyl)silyl oxy}-~iodomethyllpyridine
I
--Si.O I . N
To a solution of 2-bromomethyl-5-(ten.'-butyl-diphenyl-silanyloxy)-pyridine
(Schow,
S. R.; Quinn DeJoy, S.; Wick, M. M.; Kerwar, S. S. J. Org. Chem. 1994, 59,
6850-
6852) (1.2692 g, 2.9763 mmol) in acetone (15 mL) was added sodium iodide
(0.8922 g, 5.9526 mmol) and the resulting heterogeneous mixture stirred for 3
hours at ambient temperature. The reaction mixture was concentrated in vacuo
and the resulting residue diluted with ethyl acetate (50 mL) and washed with
water
(50 mL). The organic layer was further washed with saturated aqueous sodium
bicarbonate (50 mL) and saturated aqueous sodium thiosulfate (50 mL). The
CA 02521915 2005-10-07
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123
combined aqueous layers were extracted with ethyl acetate (3x50 mL)
and the combined organic extracts dried (anhydrous magnesium sulfate),
filtered
and concentrated in vacuo to afford the crude product. The residue was
purified by
flash column chromatography (hexanes to 20% ethyl acetate/hexanes) to yield a
pale yellow oil (0.72 g, 51%). This compound was unstable to concentration and
thus was used immediately.
LRMS (m/z): 474 (M+H)'.
Preparation c-90
ethyltetra~drofuran-2-carboxylate
O
O~
To a solution of tetrahydrofuran-2-carboxylic acid (20 g, 172.2356 mmol) in
anhydrous ethanol (100 mL) was added concentrated sulfuric acid (0.46 mL). The
resulting mixture was stirred at reflux for 16 hours and then allowed to cool
to
ambient temperature. To this was added water (100 mL) and extracted with
diethyl
ether (3x100 mL). The combined organic extracts were washed with saturated
aqueous sodium bicarbonate (2x50 mL), saturated aqueous sodium chloride (100
mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo
to
afford the pure product as a colorless liquid (22.5964 g, 91 %).
LRMS (m/z): 145 (M+H)'.
'H NMR (CDCI3, 300 MHz) 4.38 (1H, dd, J= 4.9, 8.1 Hz), 4.14 (2H, q, J= 7.2
Hz),
3.99-3.92 (1 H, m), 3.88-3.81 (1 H, m), 2.24-2.12 (1 H, m), 2.00-1.79 (3H, m),
1.22
(3H, t, J = 7.2 Hz).
Preparation c-91
Tetrahydro-oyran-2-carboxylic acid ethyl ester
0
O ~
o
The above compound was prepared according to the procedure described in
Rychnovsky, S. D.; Hata, T.; Kim, A. I.; Buckmelter, A. J. Org. Lett. 2001, 3,
807-
810.
Preaaration c-92
ethvl2-ff5-fftert-butyl(diphenyllsilylloxy}pyridin-2-yilmeth~etrahydrofuran-2-
carboxylate
o
O~
-~-Si0 I ~ N O
I
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124
To a solution of ethyl tetrahydrofuran-2- carboxylate (Preparation 32) (1.0965
g,
7.604 mmol) in anhydrous tetrahydrofuran (7 mL) at -50 °C, under an
atmosphere
of nitrogen, was added sodium bis(trimethylsilyl)amide (7.6 mL of a 1.OM
solution
in tetrahydrofuran, 7.604 mmol) dropwise. The reaction mixture was stirred for
1
hour and then a solution of 5-(tent-butyl-Biphenyl-silanyloxy}-2-iodomethyl-
pyridine
(Preparation 31) (0.72 g, 1.5208 mmol) in anhydrous tetrahydrofuran (7 mL) was
added dropwise. The resulting solution was stirred at -50 °C far 2
hours and then
quenched with saturated aqueous ammonium chloride (25 mL). This was then
extracted with ethyl acetate (3x25 mL), dried (anhydrous magnesium sulfate),
filtered and concentrated in vacuo to afford the crude product. The residue
was
purified by flash column chromatography (hexanes to 40% ethyl acetatelhexanes)
to yield a colorless oil (0.2438 g, 33%).
LRMS (m/z): 490 (M+H)+.
'H NMR (CDCI3, 300 MHz) 8.07 (1 H, d, J = 2.5 Hz), 7.67-7.63 (4H, m), 7.41-
7.31
(6H, m), 6.97 (1 H, d, J = 8.5 Hz), 6.86 (1 H, dd, J = 2.8, 8.5 Hz), 4.21 (2H,
q, J = 7.2
Hz), 4.09 (2H, q, J = 7.2 Hz), 3.22 (1 H, d, J = 13.9 Hz), 3.07 (1 H, d, J =
13.9 Hz),
2.53-2.44 (1 H, m), 2.31-2.15 (1 H, m), 1.82-1.72 (1 H, m), 1.60-1.46 (1 H,
m), 1.25
(3H, t, J = 7.2 Hz), 1.09 (9H, s).
Preparation c-93
ethyl2-f(5-hydroxypVridin-~methylltetrahvdrofuran-2-carboxvlate
O
O~
HO I ~ N O
To a solution of ethyl 2-[(5-{[tert butyl(diphenyl)silyl]oxy}pyridin-2-
yl)methyl]tetrahydrofuran-2-carboxylate (Preparation c-92) (0.5118 g, 1.1677
mmol) in anhydrous tetrahydrofuran (10 mL) was added tetrabutylammonium
fluoride (1.3 mL of a 1.OM solution in tetrahydrofuran) dropwise. The
resulting
mixture was stirred at ambient temperature for 1 hour and the volatiles
removed in
vacuo.. The residue was purled by flash column chromatography (50% ethyl
acetatelhexanes to 10% methanol/ethyl acetate) to yield a colorless oil
(0.2321 g,
79%).
LRMS (m/z): 252 (M+H)+.
'H NMR (CDCI3, 300 MHz) 8.10 (1 H, d, J = 2.3 Hz), 7.20 (1 H, d, J = 8.5 Hz},
7.14
(1 H, dd, J = 2.6, 8.5 Hz), 4.14 (2H, q, J = 7.2 Hz), 3.88 (2H, q, J = 7.8
Hz}, 3.35
(1 H, d, J = 13.9 Hz), 3.12 (1 H, d, J = 13.9 Hz), 2.30-2.21 (1 H, m), 2.04-
1.94 (1 H,
m), 1.89-1.76 (1 H, m), 1.75-1.63 (1 H, m), 1.20 (3H, t, J = 7.2 Hz).
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125
Preparation c-93a
Alternative preparation of eth rLI 2-f(5-hydroxvpyridin-2-
vl)methytetrahvdrofuran-2-
carboxv)ate
To a solution of 2-(5-benzyloxy-pyridin-2-ylmethyl)-tetrahydro-furan-2-
carboxylic
acid ethyl ester (0.6065 g, 1.7765 mmol) in dry ethanol (10 mL) was added
palladium (0.0607 g, 10 wt. % on activated carbon). The resulting solution was
heated at 45 °C under an atmosphere of hydrogen for 16 hours. After
cooling to
ambient temperature the solution was filtered through a 3" bed of Celite and
washed with ethanol (100 mL). The filtrate was then concentrated in vacuo to
afford the crude product which was used without further purification.
LRMS (m/z): 252 (M+H)',
'H NMR (CDCI3, 400 MHz): 8.10 (1H, d, J= 2.3 Hz), 7.20 (iH, d, J= 8.5 Hz),
7.14
(1 H, dd, J = 2.6, 8.5 Hz), 4.14 (2H, q, J = 7.2 Hz), 3.88 (2H, q, J = 7.8
Hz), 3.35
(1H, d, J= 13.9 Hz), 3.12 (1H, d, J= 13.9 Hz), 2.30-2.21 (1H, m), 2.04-1.94
(1H,
m), 1.89-1.76 (1 H, m), 1.75-1.63 (1 H, m), 1.20 (3H, t, J = 7.2 Hz).
Pre~,arations c-94 to c-95
Preparations c-94 to c-95 were »repared bY general arocedure for Preparation c-
93
Prep ~ MS (m/z)
Structure H NMR
(LR
or
HR)
(CDCI3, 400 MHz): 8.24 (1 H,
bs), 7.37-7.30 (1 H, bm),
for
LR
c-94O .24-7.22 (1 H, bm), 3.71 (3H,
~~ ~ s), 3.28 (3H, s), 3.23
I 26 M+H
O ( )
N
p ' .18 (2H, m), 1.40 (3H, s)
/
CDCI3, 400 MHz): 7.64 (1 H,
d, J = 8.6 Hz), 7.61 (1 H,
7.53(lH,d,J=8.6Hz),7.36(lH,dd,J=1.7,8.6
Hz), 7.05-7.01 (2H, m), 5.32 for
c-95I (1 H, s), 3.99-3.88 (2H, LR
~
0 \ m) 3.34 (1 H, d, J = 13.6 Hz), 301
~ o 3.11 (1 H, d, J = 13.9 (M+H)+
Hz), 2.33-2.27 (1H, m), 2.00-1.93
(1H, m), 1.89-1.77
(1H, m), 1.73-1.65 (1H, m),
1.19 (3H, t, J= 7.3 Hz)
Preparation c-96
ethyl2-(l5-f2-(5-methyl-2-phenyl-1.3-oxazol-4-vl)ethoxy]pyridin-2-
}methyl)tetrahvdrofuran-2-carboxylate
0
/ \
N~ I ~N O
O
To a solution of ethyl 2-[(5-hydroxypyridin-2-yl)methyl]tetrahydrofuran-2-
carboxylate (Preparation c-93) (0.2321 g, 0.9237 mmol), 2-(5-methyl-2-phenyl-
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126
oxazol-4-y()-ethanol (0.2065 g, 1.0161 mmol), and triphenylphosphine (0.3634
g, 1.3856 mmol) in anhydrous tetrahydrofuran (10 mL), under an atmosphere of
nitrogen, was added a solution of diethyl azodicarboxylate (0.22 mL, 1.3856
mmol)
in anhydrous tetrahydrofuran (1 mL) dropwise. The resulting solution was
stirred at
ambient temperature for 16 hours and the volatiles removed in vacuo. This
residue
was then purified by flash column chromatography (hexanes to 50% ethyl
acetate/hexanes) to yield a pale yellow oil (0.2618 g, 65%).
LRMS (m/z): 437 (M+H)'.
' H NMR (CDCI3, 300 MHz) 8.20 (1 H, d, J = 2.8 Hz), 7.99 (1 H, d, J = 2.5 Hz),
7.96
(1 H, d, J = 1.7 Hz), 7.70-7.64 (1 H, m), 7.49-7.39 (2H, m), 7.19 (1 H, d, J=
8.5 Hz),
7.11 (1 H, dd, J = 3.0, 8.5 Hz), 4.26 (2H, t, J = 6.6 Hz), 4.17 (2H, q, J =
7.2 Hz),
3.95-3.81 (2H, m), 3.33 (1 H, d, J = 13.8 Hz), 3.16 (1 H, d, J = 13.8 Hz),
2.98 (2H, t,
J = 6.6 Hz), 2.37 (3H, s), 2.34-2.22 (1 H, m), 2.09-2.00 (1 H, m), 1.87-1.76
(1 H, m),
1.72-1.62 (1 H, m), 1.23 (3H, t, J = 7.2 Hz).
Preaarations c-97 to c-112
Preparations c-97 to c-112 were prepared b general arocedure for Preparation c
96
Prepa ( )
rationStructure 'H NMR M
(
R or HR)
(CDCI3, 300 MHz): 8.19
(1 H, d, J = 2.8
Hz), 7.97-7.93 (2H,
m), 7.42-7.39 (3H,
m), 7.18 (1 H, d, J
= 8.5 Hz), 7.10 (1
H,
d, J = 8.5, 2.8 Hz),
4.16 (2H, q, J =
c-97I N ~ .2 Hz), 3.98 (2H t, for LR
J = 6.0 Hz), 3.92-
.
.82 (2H, m), 3.33 (1 451 (M+H)
H, d, J = 13.8 Hz),
.14 (1 hi, d,J=13.9Hz),2.67(2H,t,J
- 6.0 Hz), 2.26 (3H,
s), 2.19-2.10 (2H,
), 1.91-1.63 (4H, m),
1.22 (3H, t, J=
.2 Hz
(CDCI3, 400 MHz): 8.20
(1 H, dd, J =
2.0, 1.5 Hz), 7.95 (2H,
dd, J = 7.7, 1.9
Hz), 7.43-7.36 (3H,
m), 7.10 (2H, d, J
=
1.5 Hz), 4.25 (2H, t,
o-98~ ~ J = 6.6 Hz), 4.23-
~ 13 (3H
~ 37-
~ m) 3
63-3
55 (1 H
m)
3
N . 425 M H
o , ( )
N o .
.
.
,
,
3.27 (1 H, m), 3.15-3.02
(2H, m), 2.97
(2H, t, J= 6.7 Hz),
2.35 (3H, s), 1.21
(3H, t, J = 7.2 Hz),
1.08 (3H, t, J = 7.1
Hz
(CDC13, 400 MHz): 8.19
(1H, dd, J=
.0, 1.5 Hz), 7.08-7.07
(2H, m), 4.26-
o~ .23 (3H, m), 4.16 (2H for LR
c-99-C. ~ I q, J = 7.0 Hz),
.63-3.56 (1 H
m)
3.36-3.28 (1 H
m)
, N o , 379 M+H
, ( )
,
,
1 3.15-3.02 (4H, m), 2.58
(3H, s), 2.34
(3H, s), 1.21 (3H, t,
J= 7.1 Hz), 1.08
(3H, t, J = 7.0 Hz)
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127
(CDC13, 400 MHz): 8.22
(1H, dd, J=
.4, 1.1 Hz), 7.86-7.83
(2H, m), 7.42-
7.36 (3H, m), 7.11-7.10
(2H, m), 4.35
(2H, t, J = 6.8 Hz),
4.24 (1 H, dd J =
c-100~ ~ S~ I ; ~ 8.3, 5.1 Hz), 4.18 (2H,for LR
q J = 7.1 Hz),
o N ~ .63-3.56 (1H, m), 3.36-3.28441 (M+H)'
(1H, m),
.18 (2H, t, J = 6.8
Hz), 3.14 (1 H, dd,
J
13.9, 5.1 Hz), 3.05
(1 H, dd, J = 13.9,
8.3 Hz), 2.45 (3H, s),
1.22 (3H, t, J =
.1 Hz , 1.09 3H, t,
J = 7.1 Hz
(CDCI3, 400 MHz): 8.22
(1H, dd, J=
.0, 1.5 Hz), 7.97-7.93
(2H, m), 7.43-
.37 (3H, m), 7.11-7.10
(2H, m), 4.25
(1H, dd, J= 8.6, 5.1
Hz), 4.18 (2H, q, J
.~ 7.2 Hz), 3.99 (2H, t,
I J = 6.2 Hz), for LR
c-101~ \ N o .64-3.56 (1 H, m), 3.37-3.29439 (M+H)
,N o (1 H, m),
~
.14 (1 H, dd, J = 13.9,
5.1 Hz), 3.06
(1H, dd, J= 13.9, 8.6
Hz), 2.68 (2H, t,
= 7.1 Hz), 2.26 (3H,
s), 2.18-2.12
(2H, m), 1.22 (3H, t,
J= 7.1 Hz), 1.09
3H, t, J= 7.0 Hz
(CDCI3, 400 MHz): 8.18
(1 H, dd, J =
.3, 1.3 Hz), 7.96 (2H,
dd, J = 7.6, 2.0
Hz), 7.54-7.51 (3H,
' m), 7.10-7.08 (2H, fo
LR
c-102/ ~ ~ I ~ o m), 4.25 (2H, t, J = '
'N ~ 6.7 Hz), 3.29 (3H, )+
411 M+H
o ), 3.15 (2H, s), 2.96
(2H, t, J = 6.7
Hz), 2.36 (3H, s), 2.32
(3H, s), 1.38
3H, s)
(CDCI3, 400 MHz): 8.20
(1 H, t, J = 7.8
Hz), 7.97-7.93 (2H,
m), 7.44-7.38 (3H,
m) 7.09 (2H, d J = 7.8 for LR
~ Hz), 3.99 (2H,
c-103I .rr P , J = 6.1 Hz), 3.72 ( )t
o (3H, s) 3.30 (3H, 425 M+H
~ ), 2.68 (2H, t, J
= 7.1 Hz), 2.62 (2H,
t,
= 6.7 Hz), 2.27 (3H,
s), 2.18-2.12
(2H, m), 1.40 (3H, s)
o~ ~~o-~ for LR
c-104N I 451
I N o M+I-[
+
o (
)
c-105i ~ S ~ o~ for LR
+
453
M+H
)
(
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WO 2004/092145 PCT/IB2004/001159
128
c-106r v ~ ~~'~ for LR
' +
~
~ "
" 471 (M+H)
c-107' r ~ ~ i ; '~ for LR
467
+
'
" o " _ _ (M
H)
c-108~~--C +
~
i -" ~
" 467 (M
o H)
-
(CDC13, 300 MHz): 8.16
(1H, d, J= 2.6
Hz), 7.97-7.94 (2H,
m), 7.48-7.39 (3H,
109~ ~ ~~ I ~ )~ 7.10 (1 H, dd, J for LR
= 8.7, 3.0 Hz), 7.02
c- (1 H, d, J = 8.5 Hz), 295 (M+H)
4.25 (2H, t, J = 6.7
z), 2.96 (2H, t, J =
6.7 Hz), 2.46 (3H,
), 2.36 (3H, s)
(CDCi3, 300 MHz); 8.16
(1 H, d, J = 1.3
p N er Hz), 7.96 (3H, dd, J for LR
c-110~~ I~ ~ = 7.4, 1.7 Hz),
.41 (3H, dd, J = 5.3, -
1.9 Hz), 4.58
360 (M)
(2H, t, J = 6.7 Hz),
2.98 (2H, t, J = 6.8
z), 2.34 (3H, s)
(CDCI3, 400 MHz): 7.99-7.97
(2H, m),
.66 (1 H, d, J = 8.8
Hz), 7.62-7.59 (2H,
m), 7.45-7.35 (4H, m),
7.12-7.08 (2H,
), 4.35 (2H, t, J =
6.8 Hz), 4.16-4.09
c-111 (2H, m), 3.96-3.85 (2H,for LR
m) 3.32 (1 H,
r ~
d, J = 13.6 Hz), 3.11 486 (M+H)
(1 H, d, J = 13.9
z), 3.04 (2H, t, J =
6.8 Hz), 2.40 (3H,
. ), 2.31-2.24 (1 H, m),
1.99-1.76 (1 H,
m), 1.69-1.60 (1H, m),
1.18 (3H, t, J =
.1 Hz
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1Ly
(CDC13, 400 MHz): 7.99-7.97
(2H, m),
.67 (1H, d, J= 8.8 Hz),
7.61-7.59 (2H,
), 7.45-7.35 (4H, m),
7.12 (1H, dd,
2.3 8.8 Hz) 7.08-7.07
(1 H d, J = 2.3
c-112~ ~ Hz), 4.16-4.06 (4H, for LR
m) 3.96-3.86 (2H,
N ), 3.33 (1 H, d, J = 500 (M+H)
13.6 Hz), 3.11 (1 H,
J = 13.6 Hz), 2.74 (2H,
t, J = 7.1
Hz), 2.32-2.18 (6H,
m), 1.99-1.91 (1 H,
), 1.86-1.77 (1 H, m),
1.69-1.61 (1 H,
m,1.19 3H, t,J=7.l Hz
Preaaration c-113
3-(5-Meth~2-phenyl-oxazol-4-yl)-aroaionaldehyde
O
/ ' ~ H
N
O
To a solution of 3-(5-methyl-2-phenyl-oxazol-4-yl)-propan-1-o! (1.0 g, 4.6026
mmol)
in dichloromethane (20 mL) was added pyridinium chlorochromate (9.9213 g of
-20 wt. % on Si02, 9.2051 mmol). The resulting mixture was stirred under an
atmosphere of nitrogen at ambient temperature for 16 hours and the volatiles
removed under reduced pressure. The residue was purled by flash column
chromatography (hexanes to ethyl acetate) to yield the pure aldehyde (0.4752
g,
48%) as a colorless oil.
LRMS (m/z): 216 (M+H)+.
'H NMR (CDCI3, 300 MHz): 9.84 (1H, s), 7.96-7.93 (2H, m), 7.42-7.37 (3H, m),
2.85 (2H, dd, J = 6.0, 0.9 Hz), 2.80 (2H, d, J = 6.0 Hz), 2.33 (3H, s).
Preaaration c-114
4-But-3-em,L-methyl-2-iphenyl-oxazole
O
N
To a solution of methyl triphenylphosphonium iodide (1.7848 g, 4.4154 mmol) in
dry tetrahydrofuran (95 mL), under an atmosphere of nitrogen at 0 °C,
was added
butyllithium (1.8 mL of a 2.5M solution in hexanes, 4.4154 mmol) dropwise. The
suspension dissolved and the solution turned orange. After 10 minutes a
solution
of 3-(5-methyl-2-phenyl-oxazol-4-yl)-propionaldehyde (0.4752 g, 2.2077 mmol)
in
dry tetrahydrofuran (15 mL) was added dropwise and the solution allowed to
warm
to ambient temperature. After 16 hours, hexanes (200 mL) was added and the
precipitate filtered off. The filtrate was then extracted with water (200 mL)
and the
organic phase dried (anhydrous magnesium sulfate), filtered, and concentrated
in
vacuo to afford the crude product. The residue was purified by flash column
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130
chromatography (hexanes to ethyl acetate) to yield the pure title compound
(0.291 g, 62%) as a colorless oil.
LRMS (m/z): 214 (M+H)'.
'H NMR (CDCI3, 300 MHz): 7.99-7.96 (2H, m), 7.43-7.38 (3H, m), 5.93-5.79 (1H,
m), 5.09-5.02 (1 H, m), 5.00-4.95 (1 H, m), 2.57 (2H, t, J = 7.4 Hz), 2.42
(2H, t, J =
7.4 Hz), 2.31 (3H, s).
Preparation c-115
2-d6-f4-(5-Methyl-2-ohenvl-oxazol-4-yl)-butyll-pyridin-3- Imethvl)~-tetrahydro-
furan
2-carboxylic acid ethyl ester
O
O
O
9-Borabicyclononane (5.5 mL of a 0.5M solution in tetrahydrofuran, 2.729 mmol)
was added to a yellow solution of 4-but-3-enyl-5-methyl-2-phenyl-oxazole
(0.291 g,
1.3645 mmol) in dry tetrahydrofuran (1.3 mL). The mixture was stirred at
ambient
temperature for 4 hours and then transferred to another flask containing 2-(6-
bromo-pyridin-3-ylmethyl)-tetrahydro-furan-2-carboxylic acid ethyl ester
(0.3297 g,
1.0496 mmol), palladium dichloride bis(diphenylphosphino)ferrocene (0.0857 g,
0.1050 mmol), cesium carbonate (0.9551 g, 2.9389 mmol), triphenylarsine
(0.0322
g, 0.1050 mmol) in N,N dimethylformamide (2.8 mL) and water (0.23 mL). The
dark red mixture was stirred for 16 hours at ambient temperature under a
nitrogen
atmosphere. After cooling to 0 °C, the reaction was quenched with 2M
aqueous
sodium acetate (5 mL) and 30% aqueous hydrogen peroxide (2 mL). The resulting
solution was stirred for 2 hours, diluted with water (25 mL), and extracted
with ethyl
acetate (4 x 50 mL). The combined organic extracts were washed with water (25
mL), dried (anhydrous magnesium sulfate), filtered, and concentrated in vacuo
to
give the crude product. The residue was purified by flash column
chromatography
(hexanes to ethyl acetate) to afford the title compound (0.2805 g, 60%) as
pale
yellow oil.
LRMS (m/z): 449 (M+H)r.
'H NMR (CDCI3, 300 MHz): 8.34 (1H, d, J= 1.9 Hz), 7.95 (2H, dd, J= 7.7, 1.9
Hz),
7.52 (1 H, dd, J = 8.0, 2.2 Hz), 7.42-7.36 (3H, m), 7.04 (1 H, d, J = 7.9 Hz),
4.13 (2H,
q, J = 7.2 Hz), 3.96-3.84 (2H, m), 3.16 (1 H, d, J = 13.9 Hz), 2.90 (1 H, d, J
= 13.9
Hz), 2.77 (2H, t, J = 7.3 Hz), 2.50 (2H, t, J = 6.9 Hz), 2.31-2.19 (1 H, m),
2.28 (3H,
s), 1.92-1.64 (7H, m), 1.20 (3H, t, J = 7.2 Hz).
Preparation c-116
2-~(,6-f3-(5-meth rLl-2:phenyl-oxazol-4-yl)-prop)rIl-p)rridin-3-ylmethyl?-
tetrahvdro-furan-
2-carboxylic acid ethyl ester
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131
O
~0~
~/ \- O ~ ~ ~ O.J
~N N
9-Borabicyclononane (4.2 mL of a 0.5M solution in tetrahydrofuran, 2.07 mmol)
was added to a yellow solution of 4-allyl-5-methyl-2-phenyl-oxazole (0.21 g,
1.04
mmol) in dry tetrahydrofuran (1 mL). The mixture was stirred at ambient
temperature for 4 hours and then transferred to another flask containing 2-(6-
bromo-pyridin-3-ylmethyl)-tetrahydro-furan-2-carboxylic acid ethyl ester (0.25
g,
0.80 mmol), palladium dichloride bis(diphenylphosphino)ferrocene (0.07 g, 0.1
mmol), cesium carbonate (0.72 g, 2.90 mmol), triphenylarsine (0.02 g, 0.1
mmol) in
N,N-dimethylformamide:water (4:1, 2.63 mL). The dark red mixture was stirred
for
16 hours at ambient temperature under a nitrogen atmosphere. After cooling to
0
°C, the reaction was quenched with 2M aqueous sodium acetate (4.7 mL)
and 30%
aqueous hydrogen peroxide (1.7 mL). The resulting solution was stirred for 2
hours, diluted with water (20 mL), and extracted with ethyl acetate (4 x 50
mL).
The combined organic extracts were washed with water (20 mL), dried (anhydrous
magnesium sulfate), filtered, and concentrated in vacuo to give the crude
product.
The residue was purified by flash column chromatography (40% to 90% ethyl
acetate/hexanes) to afford the title compound (0.20 g, 57%) as a colorless
oil.
LRMS (m/z): 435 (M+H)+.
'H NMR (Dimethyl sulfoxide-ds, 400 MHz): 8.35 (1 H, s), 7.96 (2H, d, J = 7.9
Hz),
7.55 (1 H, d, J = 8.3 Hz), 7.39 (3H, t, J = 5.9 Hz), 7.09 (1 H, d, J = 8.1
Hz), 3.91 (2H,
m), 3.80 (2H, t, J = 10.9 Hz), 3.17 (1 H, d, J = 14.0 Hz), 2.91 (1 H, d, J =
13.94 Hz),
2.81 (2H, t), 2.53 (2H, t, J = 7.3 Hz), 2.28 (3H, s), 2.09 (2H, d, J = 7.5
Hz), 1.87
(4H, d, J = 10.9 Hz), 1.23 (3H, m).
Preaaration c-117
Ether{4-f(1~-3-(5-methyl-2-ahenvl-1.3-oxazol-4-vl)prop-1-en-1-
yllnhenoxy~~cyclobutanecarboxylate
O
0 i ~ p
/ \
N
A mixture of Pd(OAc)2 (12 mg, 0.05 mmol) and Ph3P (26 mg, 0.05 mmol) in
toluene
(2 mL) was stirred under nitrogen at room temperature for 1 hour and followed
by
the addition of Et3N (2 mL) and a solution of 4-allyl-5-methyl-2-phenyl-1,3-
oxazole
100 mg, 0.50 mmol) and ethyl 1-(4-iodophenoxy)cyclobutanecarboxylate (173 mg,
0.50 mmol) in toluene (2 mL). The resulting reaction solution was heated at 80
°C
CA 02521915 2005-10-07
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13L
under nitrogen for 17 hours and cooled to room temperature. After solvent
removal, the residue was partitioned between EtOAc and brine. The separated
organic layer was washed with brine, dried over Na2S04, and concentrated to
give
the crude product as brown oil. Purification by silica gel column with 20%
EtOAc in
hexane gave 85 mg (41 %) of yellow oil.
'H NMR (400 MHz, CDC13) 1.19 (t, 3 H), 1.98 (m, 2 H), 2.38 (s, 3 H), 2.43 (m,
2 H),
2.72 (m, 2 H), 3.41 (d, 2 H), 4.18 (q, 2 H), 6.20 (td, 1 H), 6.40 (d, 1 H),
6.60 (d, 2
H), 7.25 (d, 2 H), 7.40 (d, 3 H), 8.00 (d, 2 H).
LRMS (m/z): 418 (M+H)'.
Preparation c-118
Ethyl 1- 4-f3-l5-methyl-2-phenyl-1.3-oxazol-4-vf)prooyllphenoxv)cyclobutane
carboxylate
O
o 0
N
Ethyl 1-{4-[( 1 ~-3-(5-methyl-2-phenyl-1, 3-oxazol-4-yl)prop-1-en-1-
yl]phenoxy)cyclobutanecarboxylate (85 mg, 0.20 mmol) was dissolved in MeOH (5
mL) and followed by the addition of 10% Pd/C (15 mg). The mixture was stirred
at
room temperature for 16 hours with a balloon, full of hydrogen gas, attached
to the
flask. The mixture was filtered through a pad of Celite and the cake was
rinsed
with MeOH. The filtrate was concentrated to give 85 mg (100%) of yellow oil.
'H NMR (400 MHz, CDCI3) 1.19 (t, 3 H), 1.92 - 2.02 (m, 4 H), 2.27 (s, 3 H),
2.39 -
2.51 (m, 4 H), 2.60 (t, 2 H), 2.66 - 2.77 (m, 2 H), 4.19 (q, 2 H), 6.60 (d, 2
H), 7.05
(d, 2 H), 7,36 - 7.47 (m, 3 H), 7.98 (dd, 2 H).
LRMS (m/z): 420 (M+H)+.
Preparation c-119
5-Bromo_pvrazin-2-vlamine
~N~Br
HzN ~ N
To a solution of pyrazin-2-ylamine (2.0 g, 21.03 mmol) in dry dichloromethane
(120
mL) at 0 °C, was added N-bromosuccinimide (3.74 g, 21.03 mmol) slowly
to
maintain the internal temperature below 0 °C. The mixture was stirred
at the same
temperature for 24 hours, and then washed with saturated aqueous sodium
bicarbonate (30 mL) and water (30 mL). The combined aqueous extracts were
extracted with dichloromethane (3 x 100 mL). The combined organic extracts
were
dried (anhydrous magnesium sulfate), filtered, and concentrated in vacuo to
afford
the crude product. The residue was purified by flash column chromatography
(10%
to 50% ethyl acetate/hexanes) to yield the title compound (2.57 g, 70%) as a
yellow
solid.
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133
LRMS (m/z): 174 (M)~.
'H NMR (CDCI3, 300 MHz): 8.08 (1H, d, J= 1.3 Hz), 7.76 (1H, d, J= 1.3 Hz).
Preparation c-120
5-Bromo-pyrazin-2-of
~N~Br
HO I JN
Sodium nitrite (1.35 g, 19.53 mmol) was added portionwise to concentrated
sulfuric
acid (9.8 mL) at 0 °C. The mixture was heated at 50 °C until all
of the sodium
nitrite had dissolved and the mixture was again cooled to 0 °C. A
solution of 5-
bromo-pyrazin-2-ylamine (2.57 g, 14.68 mmol) in concentrated sulfuric acid
(14.7
mL) was added dropwise to the nitronium solution at 0 °C. The ice bath
was
removed, the mixture warmed to ambient temperature and stirred for 15 minutes
before heating to 45 °C for seven minutes. After cooling to ambient
temperature,
the mixture was poured slowly with precaution into crushed ice water (100 mL).
The aqueous phase was neutralized to pH 4 with 20% aqueous sodium hydroxide
then extracted with ethyl acetate (3 x 100 mL). The combined organic extracts
were washed with water (50 mL), dried (anhydrous magnesium sulfate), filtered,
and evaporated to afford the title compound (1.88 g, 73%) as a yellow solid.
'H NMR (CDC13, 300 MHz); 8.07 (1 H, s), 7.62 (1 H, d, J = 3.0 Hz).
Preparation c-121
2-(tert-Butyl-dimeth I-~ silanyloxymethvl)-5~2-(5-methyl-2-phenyl-oxazol-4-yl)-
ethoxvl-,prrazine
I
~/ \- O~ ~N~~I~
U N O N
To a solution of 2-bromo-5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyrazine
(0.50 g, 1.39 mmol) and tert-butyl-dimethyl-tributylstannanylmethoxy-silane
(0.91 g,
2.09 mmol) in dry 1,4-dioxane (8 mL) was added tetrakistriphenylphosphine(0)
palladium (0.16 g, 0.14 mmol). The mixture was degassed three times and then
heated at 120 °C for 22 hours. After cooling to ambient temperature the
mixture
was diluted with diethyl ether (10 mL) and then quenched with saturated
aqueous
potassium fluoride (5 mL). The resulting mixture was stirred for 30 minutes
and
then extracted with ethyl acetate (3 x 50 mL). The organic phase was washed
with
water (30 mL), dried (anhydrous magnesium sulfate), filtered, and evaporated
to
afford the title compound without any further purification.
LRMS (m/z): 426 (M+H)'.
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134
'H NMR (CDC13, 300 MHz): 8.20 (1H, s), 8.09 (1H, s), 7.97 (2H, d, J= 7.4 Hz),
7.41 (3H, d, J = 5.3 Hz), 4.78 (2H, s), 4.58 (2H, d, J = 6.6 Hz), 2.98 (2H,
s), 2.34
(3H, s), 0.97 (2H, m), 0.14 (6H, m).
Preparation c-122-
~5-f2-(5-Methyl-2-p_henvl-oxazol-4-vll-ethoxvl-nyrazin-2-yl)-methanol
/ ~ N~ ~N~OH
O N
Tetrabutylammonium fluoride (2.8 mL of a 1M solution in tetrahydrofuran, 2.78
mmol) was added dropwise to a solution of 2-(tert-butyl-dimethyl-
silanyloxymethyl)
5-(2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy)-pyrazine (--1.39 mmol) in dry
tetrahydrofuran (20 mL). The mixture was stirred at ambient temperature for 16
hours and then quenched with water (1 mL), and acidified to pH 5 with 1M
aqueous
acetic acid solution. The organics were removed in vacuo and the aqueous phase
extracted with dichloromethane (3 x 50 mL). The combined organic extracts were
dried (anhydrous magnesium sulfate), filtered, and concentrated in vacuo to
afford
the title compound (0.0928 g, 21 %).
LRMS (m/z): 312 (M+H)'.
' H NMR (CDCI3, 300 MHz): 8.12 (2H, s), 8.05 (2H, d, J = 6.0 Hz), 7.40 (3H, d,
J =
6.0 Hz), 4.72 (2H, s), 4.59 (2H, t, J= 6.0 Hz), 2.99 (2H, t, J= 6.0 Hz), 2.33
(3H, s).
Preparation c-123
6-BenzYox~aphthalene-2-carboxylic acid benzyl ester
0
i I
i i
i
The above compound was prepared according to the procedure described in Inui,
S.; Suzuki, T.; limura, N.; (wane, H.; Nohira, H. MoL Cryst. Liq. Cryst. Sci.
TechnoL
Sect. A. 1994, 239, 1-10.
Preparation c-124
(6-Benzyloxy-naphthalen-2-yl)-methanol
OH
O W
To a solution of 6-benzyfoxy-naphthalene-2-carboxylic acid benzyl ester (7.09
g,
19.24 mmol) in dry tetrahydrofuran (60 mL), under an atmosphere of nitrogen at
0
°C, was added diisobutylaluminum hydride (58 mL of a 1.OM solution in
tetrahydrofuran, 57.73 mmol). The resulting mixture was allowed to warm to
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1:ib
ambient temperature and stirred for 16 hours. An solution of citric acid (19
g) in
water (40 mL) was added dropwise (CAUTION!: strong exotherm). The aqueous
layer was then extracted with ethyl acetate (3 x 50 mL) and the combined
organic
extracts washed with saturated aqueous sodium chloride (50 mL), dried
(anhydrous magnesium sulfate), and concentrated in vacuo to afford the crude
product. The residue was purified by flash column chromatography (hexanes to
ethyl acetate) to yield the title compound (4.37 g, 86%) as a white solid.
LRMS (m/z): 287 (M+Na)'.
'H NMR (CDCl3, 400 MHz): 7.76-7.72 (3H, m), 7.50-7.33 (6H, m), 7.25-7.23 (2H,
m), 5.18 (2H, s), 4.82 (2H, d, J= 6.1 Hz).
Preparation c-125
2-L-(5-Methyl-2-phen~-oxazol-4-ylmethoxy)-naphthalen-2-ylmethyll-tetrahydro
furan-2-carboxylic acid et~rl ester
0
0
N
'\O
A heterogeneous mixture of 2-phenyl-4.-(chloromethyl)-5-methyloxazole (0.133
g,
0.639 mmol), 2-(6-hydroxy-naphthalen-2-ylmethyl)-tetrahydro-furan-2-carboxylic
acid ethyl ester (0.192 g, 0.639 mmol), and cesium carbonate (0.521 g, 1.59
mmol)
in dry acetonitrile (2 mL) was heated (in a microwave) at 140 °C for 10
minutes. A
second portion of 2-phenyl-4-(chloromethyl)-5-methyloxazole (0.5 eq.) was
added
and the mixture heated at 200 °C for a further 20 minutes. The reaction
mixture
was filtered through Celite and washed with acetonitrile (200 mL). The
filtrate was
concentrated in vacuo and the residue purified by flash column chromatography
(hexanes to ethyl acetate) to yield the title compound (0.180 g, 60%) as a
colorless
oil.
Preparation c-126
(4S)-4-benzyl-3-(tetrahvdrofuran-2-ylcarbonvll-1.3-oxazolidin-2-one
0 0
~N~O
n-Butyllithium (22.6 mL of a 2.5M solution in hexanes, 56.4 mmol) was added
dropwise to a solution of (4S)-4-benzyl-1,3-oxazolidin-2-one (10.0 g, 56.4
mmol) in
tetrahydrofuran (200 mL) at -78°C. The mixture was stirred for 30
minutes then a
solution of tetrahydrofuran-2-carbonyl chloride (9.12 g, 67.7 mmol) in
tetrahydrofuran (25 mL) was added. The mixture was stirred at -78°C for
30
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136
minutes, warmed to 0°C over 1 hour and quenched with saturated ammonium
chloride solution. The Mixture was extracted with ethyl acetate and the
organic
phase was washed with brine, dried over magnesium sulfate, filtered and
evaporated. The residue was purified by flash column chromatography (1:3 then
1:2 ethyl acetate:hexanes) to yield the title compound as a ca. 1:1 mixture of
diastereoisomers as a colorless oil (15.0 g, 97%).
Preiparation c-127
(4S)-4-benzvl-3-ff2-(f6-f2-(5-methyl-2-phenyl-1.3-oxazoi-4-yi)ethoxytp rids
I methyl tetrahydrofuran-2-~lcarbonvl~-1,3-oxazolidin-2-one
O o
/ \ ~ ~ ~o
y I , o
N O N
Sodium (bis)trimethylsilyl amide (3.57 mL of 1 M solution in tetrahydrofuran,
3.57
mmol) was added dropwise to a solution of (4S)-4-benzyl-3-(tetrahydrofuran-2-
ylcarbonyl)-1,3-oxazolidin-2-one (0.983 g, 3.57 mmol) in anhydrous
tetrahydrofuran
(6 mL) at -50 °C. The mixture was stirred for 45 minutes and then a
solution of 5-
(iodomethyl)-2-(2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridine
(Preparation
28) (0.500 g, 1.19 mmol) in anhydrous tetrahydrofuran (6 mL) was added
dropwise.
The resulting mixture was stirred at -50 °C for 1.5 hours then
quenched with
saturated aqueous ammonium chloride and warmed to ambient temperature. The
mixture was extracted with ethyl acetate and the organic phase dried
(anhydrous
magnesium sulfate), filtered and evaporated. The residue was purified by flash
column chromatography (1:1 ethyl acetate:hexanes) to yield the title compound
as
a single diastereoisomer as a colorless oil (0.617 g, 90%).
LRMS (m/z): 568 (M+H)+.
'H NMR (CDCI3, 300 MHz) 8.01 (1 H, s), 7.96 (2H, m), 7.61 (1 H, dd, J = 2.5,
8.5
Hz), 7.40 (3H, m), 7.28 (3H, m), 7.17 (1 H, m), 6.64 (1 H, d, J = 8.6 Hz),
4.55 (3H,
m), 4.18 (2H, m), 3.90 (1 H, m), 3.79 (1 H, m), 3.27 (1 H, d, J = 14 Hz), 3.20
(1 H, m),
3.13 (1 H, d, J = 14 Hz), 2.96 (2H, t, J = 6.8 Hz), 2.79 (1 H, m), 2.32 (3H,
s), 2.34
(3H, m), 2.11 (1 H, m), 1.73 (1 H, m), 1.54 (1 H, m)
Preparation c-128
Tetrahvdro-furan-2-carboxylic acid amide
O
O
~NH2
To a solution of tetrahydro-furan-2-carboxylic acid (2.42 g, 20.82 mmol) in
anhydrous tetrahydrofuran (120 mL), under an atmosphere of nitrogen at 0
°C, was
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137
added triethylamine (8.5 mL, 61.23 mmol) and ethyl chloroformate (2.4 mL,
25.10 mmol). White precipitation formed after the addition of ethyl
chloroformate
and the resulting mixture stirred for 45 minutes at 0 °C. Ammonia gas
was bubbled
into the solution for 2 hours and the gas source removed. The reaction mixture
was then allowed to warm to ambient temperature and stirred for 16 hours. The
solution was adjusted to pH 1 by addition of 1 N hydrochloric acid, and then
extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were
dried (anhydrous magnesium sulfate), filtered, and concentrated in vacuo to
give
the crude product. The residue was purified by flash column chromatography
(hexanes to 10% ethyl acetate/hexanes) to afford the title compound (0.97 g,
41 %)
as a white solid.
LRMS (m/z): 116 (M+H)+.
'H NMR (CDCI3, 300 MHz): 4.35 (1H, dd, J= 8.5, 5.8 Hz), 3.92 (2H, m), 2.18
(2H,
m), 1.90 (2H, m).
Preparation c-129
Tetrah~dro-furan-2-carbonitrile
~N
Trifluoroacetic anhydride (1.55 g, 7.38 mmol) was added slowly, with a rate of
one
drop every 10 seconds, to an ice-cold solution (0 °C) of tetrahydro-
furan-2-
carboxylic acid amide (0.77 g, 6.71 mmol) and pyridine (1.06 g, 13.42 mmol) in
anhydrous 1,4-dioxane (10 mL). The addition of trifluoroacetic anhydride was
monitored to keep the internal temperature below 5 °C and was completed
after 20
minutes. The resulting mixture was allowed to warm to ambient temperature, and
stirred for 3 hours. Chloroform (100 mL) was added to the mixture, and then
extracted with water (30 mL) and saturated aqueous sodium chloride (20 mL).
The
organic extracts were dried (anhydrous magnesium sulfate), filtered, and
concentrated in vacuo to give the crude product. The residue was purified by
flash
column chromatography (hexanes to 25% ethyl acetateihexanes) to afford the
title
compound (0.51 g, 62%) as a colorless oil.
'H NMR (CDCI3, 300 MHz): 4.70 (1H, m), 3.96 (2H, m), 2.24 (2H, m), 2.08 (2H,
m).
Preparation c-130
2-f6-[~5-Methyl-2-phenyl-oxazol-4-vl)-ethoxvl-pyridin-3- Iy methy}-tetrah~dro
furan-2-carbonitrile
~N
/ \ N" ~ ~ O
~ ~O N
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Sodium bis(trimethylsilyl)amide (1.8 mL, 1.79 mmol) was added to a solution of
tetrahydro-furan-2-carbonitrile (0.17 g, 1.79 mmol) in anhydrous
tetrahydrofuran (6
mL) under an atmosphere of nitrogen at -78 °C. The resulting yellow
solution was
stirred for 50 minutes, and then a solution of 5-iodomethyl-2-[2-(5-methyl-2-
phenyl-
oxazol-4-yl)-ethoxy]-pyridine (0.25 g, 0.596 mmol) in anhydrous
tetrahydrofuran (3
mL) was added to the enolate solution. The mixture was stirred at -78
°C for 1.5
hours, and quenched with saturated aqueous ammonium chloride (5 mL). The
aqueous phase was extracted with ethyl acetate (3 x 50 mL), and the combined
organic extracts washed with water (30 mL), dried (anhydrous magnesium
sulfate),
filtered, and concentrated in vacuo to give the crude product. The residue was
purified by flash column chromatography (7% to 45% ethyl acetate/hexanes) to
afford the title compound (0.11 g, 46%) as a white solid.
LRMS (m/z): 390 (M+H)~.
'H NMR (CDCI3, 300 MHz); 8.03 (1 H, d, J = 2.5 Hz), 7.96 (2H, m), 7.56 (1 H,
dd, J
= 8.5, 2.5 Hz), 7.40 (3H, m), 6.68 (1H, d, J= 8.5 Hz), 4.54 (2H, m), 3.96 (2H,
m),
3.00 (4H, m), 2.33 (5H, d, J = 3.2 Hz), 1.92 (2H, m).
Example D-1
2-ethoxv-3-(6=f2-(5-methyl-2-ahenyl-1.3-oxazot-4-yl)ethoxvlpyridin-3-
yl)propanoic
acid
/ \ O~ I ~ OH
O N OI
Lithium hydroxide monohydrate (180 mg, 4.31 mmol) was added to a solution of
ethyl 2-ethoxy-3-(6-[2-(5-methyl-2-phenyl-1, 3-oxazol-4-yl)ethoxy]pyridin-3-
yl}propanoate (183 mg, 0.431 mmol) in a mixture of
tetrahydrofuran:methanol:water (1:1:1, 6 mL). The mixture was stirred 18.hours
then the volatile components were removed by evaporation. The aqueous phase
was acidified with 3M hydrochloric acid and extracted with ethyl acetate. The
organic phase was washed with brine, dried over magnesium sulfate, filtered
and
evaporated. The residue was purified twice by flash column chromatography
(98:2
dichloromethane:methanol) to yield the title compound as a colorless glass (31
mg)
LRMS (m/z): 396 (M)'.
'H NMR (CDCI3, 300 MHz) 7.99 (3H, m), 7.50 (1H, m), 7.40 (3H, m), 6.65 (1H,
m),
4.50 (2H, t, J = 7 Hz), 4.01 (1H, m), 3.64 (1 H, m), 3.42 (1 H, m), 2.98 (4H,
m), 2.34
(3H, s), 1.16 (3H, t, J = 7 Hz).
Examples D-2 to D-45
Examples D-2 to D-45 were prepared by procedures analogous to those used for
Example D-1 by stirring a solution of the ester with sodium or lithium
hydroxide in
CA 02521915 2005-10-07
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139
aqueous methanol, aqueous ethanol, aqueous tetrahydrofuran or mixtures
thereof at temperatures between 20 °C and 75°C.
Ex Structure H NMR n L nalysis
# )
R/HR
'H NMR (DMSO-ds,
400 MHz)
8.05 (2H, d, J = for
8.6 Hz), 7.96- LR
408
N o 7.94 (3H m), 7.55 (M+H)+
' i ~ (1 H, dd, J -
N / 8.3 and 2.3 Hz),
6.70 (1 H, d
D-2CHy - 8.3 Hz), 4.45
(2H, t, J = 6.6
Hz), 3.89 (1 H,
dd, J = 7.6 and
cH, off 5.1 Hz), 3.22 (3H,
s), 2.95-2.87
(3H, m), 2.80 (1
H, dd, J = 14.2
and 7.8 Hz , 2.35
3H, s
'H NMR (DMSO-ds,
400 MHz)
7.96 (1 H, d, J
= 2.3 Hz), 7.73
(1H, s), 7.69 (1H, Calcd
d, J = 7.8 for
Hz), 7.55 (1 H dd,
D-3 J = 8.6 and Calcd C H N
' for O 0.
.3 Hz), 7.37 (1
H, t, J = 7.8 Hz) 22 24
2 5
s 5H
17
H3C CH3 n
.28 (1 H, d, J = 39~ H 6 22
7.1 Hz), 6.70 1758 N
(1H, d, 8.3 Hz), . 6.91
4.44 (2H, t, J Found: Found:
cH, off .8 Hz), 3.89 (1 397.1775.
H, dd, J = 8.1 C 65
03 H
and 4.8 Hz), 3.22 .
(3H, s), 2.92 10 N
7
6
07
.88 (3H, m), 2.80 .
(1H, d, J - .
14.7 and 8.1 Hz),
2.36 (3H, s),
.31 3H, s
'H NMR (DMSO-ds,
400 MHz)
7.98 (1 H, d, J
= 1.8 Hz), 7.92 Calcd
for
Ci ~ \ N~o ~ (2H d, J = 8.6 Hz),C2,H22CIN2
- 7.58-7.55
~ ~ (3H
m)
6.72 (1 H
d J = 8
6
D-4~ , Os
N ~ ,
,
.
CH3
Hz), 4.46 (2H, t, 4
J= 6.6 Hz),
3.91 (1 H, dd, J Found
= 7.8 and 4.6 2~
cH, or, Hz), 3.24 (3H, s),
2.94-2.89 1232
417
(3H, m), 2.82 (1 .
H, dd, J = 14.4
and 7.6 Hz , 2.33
3H, s .
'H NMR (DMSO-dfi,
400 MHz)
12.71 (1 H, s),
7.96 (1 H, d, J
=
2.3 Hz), 7.90 (2H, Calcd
dd, J= 7.6 for
and 2.0), 7.55 (1 C2, H~N20s0.
D-5~ N ~ H, dd, J = 8.6 1 H20
/ \ and 2.3 Hz), 7.51-7.46 C 65.65
(3H, m),
o 6.71 ( 1 H, d, J H 5.82
c~3 = 8.6 Hz), 4.44 N
~ (2H, t, J = 6.6 7.29.
q Hz), 3.89 (1 H, Found:
cH, or, dd, J = 7.6 and C 65.45
5.1 Hz), 3.22 H
(3H, s), 2.92-2.88 5.92
(3H, m), 2.80 N 7.26.
(1H, dd, J= 14.2
and 7.6 Hz),
2.32 3H, s .
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140
'H NMR (DMSO-ds,
400 MHz)
12.81 (1 H, s),
7.96 (1 H, d, J
=
2.0 Hz), 7.90 (2H, Calcd
dd, J = 7.7 for
~r ~--~"y~ o and 1.9), 7.55 (1H CZ 5H
~ dd, J= 8.6 OzOsO.
3H
d 2
46
7
3 H
7
51
D ~ N , m),
an
.
(
.
z),
.
-
-6 ~ 6.70 (1 H, d, J 65.19
o = 8.6 Hz), 4.44 H 5.86
cH,
(2H, t, J=6.8 Hz), 4.
3.88 (1H,
Found
cH, off dd, J = 7.6 and C
4.8 Hz), 3.22
(3H, s), 2.92-2.87 65.19
(3H, m), 2.80 H 5.80
(1 H, dd, J = 14.2 N 7.03
and 7.8 Hz),
2.32 3H, s .
'H NMR (DMSO-ds,
400 MHz)
12.54 (1 H, s),
7.96 (1 H, d,-J
=
2.0 Hz), 7.83 (2H,
d, J= 9.1),
" 7.55 (1 H dd J = Calcd
H,c ~-(' ~ i ~ 8.6 and 2.3 for
Hz), 7.03 (2H, d C22HzsN20s
J = 8.8 Hz),
D-7cH3 " ~ 6.70 (1 H, d, J 413.1707.
= 8.6 Hz), 4.43
(2H, t, J = 6.8 Found:
Hz), 3.90 (1 H,
cH, off dd, J = 7.8 and 413.1717
4.8 Hz), 3.80
(3H, s), 3.22 (3H,
s), 2.92-2.86
(3H, m), 2.80 (1
H, dd, J = 14.7
and 7.6 Hz , 2.29
3H, s
'H NMR (DMSO-ds,
400 MHz)
12.77 (1H, s), 7.96
(1H, d, J=
2.3 Hz), 7.55 (1
H, dd, J = 8.3
and 2.3), 7.48 (1
H, d, J = 7.8
r " o Hz), 7.41 (1H, d, Calcd
' ~ ~ J= 8.1 Hz), for
" .39-7.37 (1 H, m), CZZH2sN20s
7.04 (1 H dd,
D-8~ J = 8.1 and 2.5 413.1707.
cr,, Hz), 6.71 (1 H,
~
cH, d, J = 8.6 Hz), Found:
4.44 (2H, t, J
=
cH, off 6.8 Hz), 3.89 (1 413.1715
H, dd, J= 7.8
and 4.8 Hz), 3.81
(3H, s), 3.22
(3H, s), 2.92-2.88
(3H, m), 2.80
(1 H, dd, J = 14.4
and 8.0 Hz),
2.31 3H, s .
'H NMR (DMSO-ds,
400 MHz)
12.70 (1 H, s),
8.04 (2H, d, J
=
8.1 Hz), 7.91 (1 Calcd
H, d, J = 2.0), for
F F 7.80 (2H, d, J =
" ~ , ~ 8.3 Hz), 7.49 C22HZZFaNz
~ (1 H dd, J = 8.3
and 2.4 Hz),
Os
" ~
D-9 6.65 (1 H, d, J 1476
= 8.3 Hz), 4.40 451
o (2H, t, J = 6.6 .
Hz), 3.84 (1 H, .
Found:
dd, J = 7.6 and 1474
4.7 Hz), 3.16 451
(3H, s), 2.90-2.82 .
(3H, m), 2.74
(1H, dd, J= 14.4
and 7.8 Hz),
2.29 3H, s .
'H NMR (DMSO-ds,
400 MHz)
12.76 (1 H, s),
7.96 (1 H, d, J
=
2.3 Hz), 7.79 (2H, Caicd
d, J = 8.1 ), for
D-10H3c i " 0 7.55 (1 H, dd, J Calcd CZZH2nNzOsO.
o N\ = 8.6 and 2.5 for 3H20 C
J Hz), 7.29 (2H, d C22HzsNzOs65.75
J= 8.1 Hz),
cr,, 6.68 ( 1 H, d, J 397.1758.H 6.17
= 8.3 Hz), 4.43 N
,o~ (2H, t, J = 6.8 Found: 6.97.
Hz), 3.89 (1 H, Found:
cr,, off dd, J = 7.8 and 397.1770C 65.74
4.8 Hz), 3.22 H
(3H, s), 2.92-2.87 6.14 N
(3H, m), 2.80 6.81
(1 H, dd, J = 14.2
and 7.8 Hz),
2.34 3H,s,2.30 3H,s.
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141
O
'H NMR (MeOH-da,
400 MHz):
I i .30 (1 H, s) 7.58
off 8 (1 H, d, J=9.2
'p z) 7.11 (2 H d
o N H C H J=8.2 Hz) 6.71
' (2 H, d, J=8.2
Hz) 6.31 (1 H,
d,
D-11 J=9.2 Hz) 4.57 LRMS:
(2 H, t, J=6.5 410
Hz) 4.18 (1 H, (M+H)+.
dd, J=13.5, 0.2
I H z) 3.98 (2 H, q,
J=7.7 Hz) 3.52
(3 H, s) 3.28 (2
H, t, J=6.5 Hz)
0 3.05 - 3.11 (1
H, m) 2.89 - 2.98
HzCvso ( 1 H, m) 1.44 (3
H, t, J=7.7 Hz)
o 'H NMR (MeOH-da,
400 MHz):
off 8 .30 (1 H s) 7.58
(1 H d, J=9.2
o H z) 7.10 (2 H, d,
J=8.2 Hz) 6.74
, (2 H, d, J=8.2
O N H3C Hz) 6.31 (1 H,
d,
D-72 J=9.2 Hz) 4.57 for
(2 H, t, J=6.5 LR
Hz) 4.18 (1 H, 396
dd, J=13.5, 0.2 (M+H)+
Hz) 3.52 (3 H,
I s) 3.34 (3 H,
s)
3.28 (2 H, t, ,J=6.5
Hz) 3.06 -
o ,0 3.11 (1 H, m) 2.89
- 2.98 (1 H,
H c'S m)
3 p
o 'H NMR (MeOH-da,
400 MHz):
off 8.30 (1 H, s) 7.58
(1 H, d, J=9.2
I N o Hz) 7.31 - 7.37
(2 H, m, J=8.0,
o 7.5, 0.2, 0.2 Hz)
cH~ 7.06 - 7.14 (3
H, m) 6.96 - 7.04 for
(4 H, m) 6.31 LR
D-13~ i (1 H, d, J=9.2 3g4
Hz) 4.57 (2 H, (M+H)+
t,
J=6.5 Hz) 4.18
(1 H, dd,
o J=13.5, 0.2 Hz)
3.52 (3 H, s)
I ~ 3.28 (2 H, t, J=6.5
Hz) 3.06 -
3.11 (1 H, m) 2.89
- 2.97 (1 H,
m
0
'H NMR (MeOH-da,
400 MHz):
0 on 8.28 - 8.34 (1
H, m) 7.59 (1
H,
o N r m)7.31-7.37(2H,m)6.96-
cH, 7.14 (7 H, m) 6.27LRMS:
- 6.34 (1 H, 409
D-14 m) 4.53 - 4.60
(2 H, m) 4.22 (M+H)+.
-
4.30 (1 H, m) 3.49
- 3.66 (2 H,
m) 3.25 - 3.31
(2 H, m) 3.05
-
3.11 (1 H m) 2.89
- 2.97 (1 H,
m) 1.19 (3 H, t,
J=7.0 Hz)
'H NMR (MeOH-da,
400 MHz):
8.31 (1 H, s) 8.02
(2 H, d, J=8.3
Hz) 7.59 (1 H,
d, J=9.1 Hz) 7.43
(2 H, d, J=8.3
Hz) 6.31 (1 H,
d,
D-15~ ; " J=9.1 Hz) 4.20 32 (M
- 4.29 (3 H, m) H)'
ci ~ ~ ~~ " ~ 3.49 - 3.66 (2
H, m) 3.05 - 3.11
" ' (1 H, m) 2.89 -
2.97 (1 H, m)
2.70 (2 H, t, J=8.0
Hz) 2.19 (3
H,s 1.19 3H, t,J=7.O
Hz
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142
o 'H NMR (MeOH-da,
400 MHz):
~oH 8 .31 (1 H, s) 7.59
(1 H, d, J=9.1
I Hz) 6.87 (2 H,
o d, J=8.2 Hz) 6.73
o (2 H, d, J=8.2
N Hz) 6.31 (1 H,
d,
J=9.2 Hz) 4.57 for
(2 H, t, J=6.5 LR
D-16~ Hz) 4.43 (2 H, 391
s) 4.26 (1 H, (M+H)+
dd,
J=13.5, 0.2 Hz)
3.76 (2 H, s)
3.49 - 3.66 (2
H, m) 3.38 (3
H,
o s) 3.28 (2 H, t,
J=6.5 Hz) 3.05
-
3.11 (1 H m) 2.89
- 2.97 (1 H,
cH m) 1.19 (3 H, t,
3 J=7.0 Hz)
'H NMR (MeOH-da,
400 MHz):
~oH 8.31 (1 H, s) 7.66
- 7.74 (5 H,
m) 7.59 (1 H, d,
J=9.1 Hz) 7.19
cH, (2 H, d, J=8.2
Hz) 6.86 (2 H,
d,
J=8.3 Hz) 6.31 for
(1 H, d, J=9.2 LR
D-17\ ~ Hz) 4.57 (2 H,
t, J=6.5 Hz) 4.26 73 (M+H)'
(1 H, dd, J=13.5,
0.2 Hz) 3.49 -
.s.o 3 .66 (2 H, m) 3.28
(2 H, t, J=6.5
Hz) 3.05 - 3.11
0 (1 H, m) 2.89
-
2 .97(1 H,m)1.19(3H,t,J=7.0
Hz)
o 'H NMR (MeOH-d4,
400 MHz):
8.31 (1 H, s) 7.59
(1 H, d, J=9.1
I ~ off Hz) 7.11 (2 H d
J=8.2 Hz) 6.71
o ni ro (2 H, d, J=8.2
Hz) 6.31 (1 H,
d,
cH, J=9.2 Hz) 4.57
(2 H, t, J=6.5
_ Hz) 4.26 (1 H, for
D dd, J=13.5, 0.2 LR
18
i Hz) 3.98 (2 H, 425
q, J=7.7 Hz) 3.49 (M+H)+
- 3.66 (2 H, m)
3.28 (2 H, t,
,o J=6.5 Hz) 3.05
H - 3.11 (1 H, m)
cvs
3 .89 - 2.97
o 1 H, m) 1.44 (3
( H, t,
J=7.7 Hz) 1.19
(3 H, t, J=7.0
Hz
o 'H NMR (MeOH-d4,
400 MHz):
~oH 8.31 (1 H, s) 7.59
(1 H, d, J=9.1
J Hz) 7.10 (2 H,
d, J=8.2 Hz) 6.74
cH, (2 H, d, J=8.2
Hz) 6.31 (1 H,
d,
D-19 J=9.2 Hz) 4.57 for
(2 H, t, J=6.5 LR
Hz) 4.26 (1 H, 11 (M+H)+
dd, J=13.5, 0.2
I Hz) 3.49 - 3.66
(2 H, m) 3.34
(3
H, s) 3.28 (2 H,
t, J=6.5 Hz)
~ .0 3.05 - 3.11 (1
S H, m) 2.89 - 2.97
H,C' (1 H, m) 1.19 (3
O H, t, J=7.0 Hz)
'H NMR (MeOH-d4,
400 MHz):
8.31 (1 H, s) 7.59
(1 H, d, J=9.1
Hz) 7.34 (2 H,
d, J=8.2 Hz) 7.24
(2 H, d, J=8.2
Hz) 6.31 (1 H,
d,
D-20 J=9.2 Hz) 4.57 for
(2 H, t, J=6.5 LR
Hz) 4.26 (1 H, 00 (M+H)+
dd, J=13.5, 0.2
Hz) 3.49 - 3.66
(2 H, m) 3.28
(2
H, t, J=6.5 Hz)
3.05 - 3.11 (1
H,
m) 2.89 - 2.97
(1 H, m) 1.19
(3
H, t, J=7.0 Hz
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143
o
off
°
CH,
F~O
F
'H NMR (MeOH-d4, 400 MHz):
0 8.31 (1 H, s) 7.59 (1 H, d, J=9.1
Hz) 6.94 (2 H, d, J=8.2 Hz) 6.66
I ~ o" (2 H, d, J=8.3 Hz) 6.31 (1 H, d,
ri r° J=9.2 Hz) 4.57 (2 H, t, J=6.5
D-21 c"3 Hz) 4.26 (1 H, dd, J=13.5, 0.2 for LR
Hz) 4.01 (2 H, q, J=6.9 Hz) 3.49360 (M+H)+
~ I - 3.66 (2 H, m) 3.28 (2 H, t,
J=6.5 Hz) 3.05 - 3.11 (1 H, m)
r° .89 - 2.97 (1 H, m) 1.40 (3 H, t,
c", J=7.0 Hz) 1.19 (3 H, t, J=7.0
Hz
'H NMR (MeOH-d4, 400 MHz):
0 8.31 (1 H, s) 7.59 (1 H, d, J=9.1
~oH Hz) 6.97 (2 H, d, J=8.2 Hz) 6.77
o I ri ~o (2 H, d, J=8.2 Hz) 6.31 (1 H, d,
D-22 c" J=9.2 Hz) 4.57 (2 H, t, J=6.5 for LR
' Hz) 4.26 (1 H, dd, J=13.5, 0.2 346 (M+H)'
i Hz) 3.78 (3 H, s) 3.49 - 3.66 (2
H, m) 3.28 (2 H, t, J=6.5 Hz)
3.05 - 3.11 (1 H, m) 2.89 - 2.97
H,c'° (1 H, m) 1.19 (3 H, t, J=7.0 Hz)
(MeOD, 400 MHz): 8.03 (1H, d,
J= 2.8 Hz), 7.84-7.82 (2H, m),
.35-7.34 (3H, m), 7.26 (1 H, dd,
J=8.6,2.5Hz),7.16(lH,d,J
= 8.6 Hz), 4.20 (2H, t, J = 6.4
D-23 ~ ~ N I~ ~ N ° OH Hz), 4.06 (1 H, dd, J = 8.6, 4.6 for LR
o ~ Hz), 3.52-3.44 (1H, m), 3.22- 397 (M H)
cH, 3.14 (1 H, m), 3.03 (1 H, dd, J =
13.9, 4.6 Hz), 2.88 (2H, t, J=
6.3 Hz), 2.92 (1 H, d, J = 9.1
Hz), 2.26 (3H, s), 0.94 (3H, t, J
= 7.0 Hz
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
(CDCI3, 400 MHz):
8.25 (1 H, d,
J = 1.5 Hz), 7.95
(2H, dd, J =
7.6, 1.8 Hz), 7.44-7.36
(3H, m),
.28-7.22 (2H, m),
4.19 (1 H, dd,
J=7.1,4.6Hz),4.02(2H,t,J=
D-24I N o 6.1 Hz), 3.80-3.72 for
(1 H m), LR
3.47-3 1 3.34 1 1 +
1 H dd
1 (M
.39 ( H m), ( H)
~
~
o J= 15.2, 7.1 Hz),
3.20 (lH,
dd,
J = 15.2, 4.3 Hz),
2.67 (2H, t, J
= 7.2 Hz), 2.27
(3H, s), 2.19-
2.12 (2H, m), 1.17
(3H, t, J=
7.0 Hz
' (CDCI3, 400 MHz):
8.16 (1 H, d,
J = 2.3 Hz), 7.24-7.19
(2H, m),
O 4.27 (2H, t, J=
6.8 Hz), 4.17
~ (1 H dd J = 7.6,
g CH3 ' 3.8 Hz), 3.79-
D ~ 3.72 (1 H m), 3.47-3.40for
25 H (1 H, LR
C~OH
C~
~
- ~ m), 3.32 (1 H, dd, 351
3 J = 15.4, 7.6 (M+H)+
N
o . N Ol
CH3 Hz), 3.18 (1 H,
dd, J = 15.4, 3.5
Hz), 3.09 (2H, t,
J = 6.7 Hz),
2.59 (3H, s), 2.34
(3H, s), 1.17
3H t, J = 7.0 Hz
(MeOD, 400 MHz):
8.01 (1 H, d,
J = 3.0 Hz), 7.74-7.71
(2H, m),
.34-7.27 (3H, m),
7.24 (1 H, dd,
J = 8.6, 2.8 Hz),
7.14 (1 H, d, J
= 8.6 Hz), 4.27
(2H, t, J = 6.6
~ ~ S I~ I ; off Hz), 4.06 (1H, dd, for
J= 8.7, 4.7 LR
D-26o N o~ Hz), 3.51-3.44 (1 413
H, m), 3.22- (M+H)'
cH3 3.14 (1 H, m), 3.08
(2H, t, J =
6.4 Hz), 3.02 (1
H, dd, J = 14.2,
4.6 Hz), 2.89 (1
H, dd, J = 13.9,
8.6 Hz), 2.34 (3H,
s), 0.93 (3H,
t,J=7.1 Hz
(MeOD, 400 MHz):
7.86-7.82
(3H, m), 7.47 (1
H, dd, J = 8.6,
.0 Hz), 7.39-7.36
(3H, m), 6.62
I ; off (1 H, d, J = 8.3 for
Hz), 4.14 (2H, LR
t,
D-27~ \ N I o N ~c o,c~J = 6.2 Hz), 3.22-3.2011 (M+H)'
(3H, m),
0 2.85 (2H, dd J =
22.5 13.9
Hz), 2.60 (2H, t,
J = 7.1 Hz),
2.19 (3H, s), 2.03
(2H, dd, J =
12.9, 6.1 Hz , 1.26
3H, s
(MeOD, 400 MHz):
8.02 (1 H, d,
J = 2.5 Hz), 7.85-7.83
(2H, m),
Q .39-7.33 (3H, m),
7.26 (1H, dd,
~
~~oH J = 8.6, 2.8 Hz),
I 7.20 (1 H, d, J for
LR
D-28~N / ' c~,~ = 8.6 Hz), 3.96 11 (M+H)'
N o (2H, t, J = 6.1
H,c dd
Hz)
20 (3H
s)
05 (2H
3
3
o CH ,
,
.
,
,
.
,
3
J = 21.0, 13.9 Hz),
2.61 (2H, t,
J = 7.2 Hz), 2.20
(3H, s), 2.07-
2.01 2H, m , 1.24
3H, s
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
-I 40
( MeOD, 400 MHz):
8.02 (1 H, d,
J= 2.8 Hz), 7.87-7.83
(2H, m),
.39-7.36 (3H, m),
7.27 (1H, dd,
J = 8.6, 2.8 Hz),
7.19 (1 H, d, LR
J f
D-29/ \ ~ ~ ~ o = 8.6 Hz), 4.22 )+
'N p (2H t J = 6.4 (
397
M+H
N p
Hz), 3.19 (3H,
s), 3.05 (2H,
dd,
J = 21.2, 13.9
Hz), 2.91 (2H,
t,
J= 6.4 Hz), 2.29
(3H, s), 1.23
3H, s
(MeOD, 400 MHz):
7.87-7.84
(3H, m), 7.48 (1
H, dd, J = 8.6,
2.3 Hz), 7.41 (2H,
d, J = 8.6
Hz) 6.61 (1 H, for
D-30of / \ N~o ~ N p d J = 8.6 Hz), LR
H 4.42 (2H, t, J 31 (M+H)+
= 6.6 Hz), 3.22
(3H, s), 2.91-2.88
(3H, m), 2.83
(1H, d, J= 13.9
Hz), 2.27 (3H,
s , 1.25 3H, s
( MeOD, 400 MHz):
8.04 (2H, d,
J = 8.1 Hz), 7.84
(1 H, d, J = 2.0
Hz), 7.70 (2H,
d, J = 8.3 Hz),
p 7.46 (1 H, dd,
J = 8.5, 2.4 Hz),
D-31F i \ ~ ~oH 6.60 (1 H, d J for
~ = 8.3 Hz) 4.43 LR
2H t 65
J = 6 '
6 H
22
3
3H
o ( (M+H)
N p .
.
,
z),
(
s),
2.91 (2H, t, J
= 6.4 Hz), 2.88
(1H, d, J = 14.2
Hz), 2.82 (1 H,
d, J = 14.2 Hz),
2.28 (3H, s),
1.25 3H, s
( MeOD, 400 MHz):
7.84 (1 H, d,
J = 2.0 Hz), 7.47
(1 H, dd, J =
8.5, 2.4 Hz), 6.59
(1 H, d, J =
8.6 Hz), 4.32 (2H,
t, J = 6.6 Hz),
3.23 (3H, s), 2.89
(1H, d, J=
14.2 Hz), 2.83 for
(1 H, d, J = 13.9 LR
D-32~N~ ~ ; o off Hz), 2.78 (2H, 03 (M+H)'
t, J = 6.7 Hz), '
o N 2.64 (1 H, tt,
J = 11.6, 3.5
Hz),
2.13 (3H, s), 1.93-1.89
(2H, m),
1.75-1.71 (2H,
m), 1.65-1.62
(1 H, m), 1.50-1.40
(2H, m),
1.37-1.27 (2H, .
m), 1.26 (3H,
s),
1.23-1.19 1 H,
m
( MeOD, 400 MHz):
7.85 (1 H, d,
J = 2.3 Hz), 7.77
(2H, dd, J =
7.6, 1.8 Hz), 7.47
(1 H, dd, J =
0 8.6, 2.3 Hz), 7.39-7.31
(3H, m),
D-33/ \ S~ ~ ; off 6.61 (1H, d, J= for
N 8.6 Hz), 4.49 LR
p ) 13 (M+H)
(
~
H
~
t
(
Z
N 11
6.7
2.89
3
(2H
Hz)
J
(1H, d, J= 13.9
Hz), 2.83 (1H,
d, J= 14.2 Hz),
2.36 (3H, s),
1.26 3H, s
(MeOD, 400 MHz):
7.84 (1 H, d,
J = 2.3 Hz), 7.43
(1 H, dd, J =
8.5, 2.4 Hz), 7.17
(2H, dd, J =
D-34N~. ~ - o off 8.1, 0.8 Hz), 7.09-7.05for
N (1H, m), LR
, 6.94 (1 H, dt, 386
/ \ o N ~ J = 7.8, 1.0 Hz), (M+H)
6.53 ( 1 H, d,
J = 8.3 Hz), 4.49
(2H, t, J = 5.3
Hz), 3.87 (2H,
t,
=5.3Hz,3.23 3H,s,3.18
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
l4n
(3H, s), 2.88 (1H,
d, J= 13.9
Hz), 2.82 (1 H,
d, J = 13.9 Hz),
1.26 (3H, s)
Calcd
(Dimethyl sulfoxide-dfi, C~H24N205
300 C
MHz): 7.91 (3H, 6.65,
m), 7.49 (4H, H 6.10,
o m), 7.40 (3H, m), N 7.07.
6.69 (1 H, d, for
J LR
D-35~~ ~ -Co~ I ; off = 8.5 Hz), 4.44 Found:
~ (2H, t, J = 6.7 395
~ (M)-
N O N Hz), 3.44 (2H, C~H24N205
m), 3.18 (3H,
s),
2.89 (2H, m), 2.31 0.06H20
(3H, s), 1.19
(3H, s) 6.16,
H 6.15,
N 6.96.
( MeOD, 400 MHz):
7.83 (1 H, d,
J = 1.8 Hz), 7.69
(1 H, s), 7.65
(1 H, d, J = 7.6
Hz), 7.46 (1 H,
o dd, J = 8.6, 2.3
Hz), 7.25 (1 H,
t,
=
7.6 Hz), 7.19 (1
D-36~ ~ ~ I ~ o off H, d, J = 7.6 for
J LR
Hz), 6.59 (1 H,
d, J = 8.3 Hz),
11 (M+H)
4.39 (2H, t, J
= 6.6 Hz), 3.19
( 3H, s), 2.87 (2H,
t, J = 6.4 Hz),
2.87 (1H, d, J=
13.9 Hz), 2.80
( 1 H, d, J = 13.9
Hz), 2.30 (3H,
s,2.24 3H,s,1.21
3H,s
( MeOD, 400 MHz):
7.83 (1 H, d,
J = 2.3 Hz), 7.79-7.76
(2H, m),
7.46 (1 H, dd,
J = 8.5, 2.4 Hz),
6.90 (2H, d, J
= 8.8 Hz), 6.59
( 1H d, J= 8.6 Hz),4.38for
(2H, t, LR
D-37I N o off = 6.7 Hz), 4.00
o i v N~ (2H q, J = 7.1 441
(M+H)
o Hz), 3.21 (3H,
s), 2.88 (1 H,
d, J
= 13.9 Hz), 2.86
(2H, t, J = 6.6
Hz), 2.81 (1 H,
d, J = 13.9 Hz),
2.22 (3H, s), 1.31
(3H, t, J = 7.0
Hz , 1.24 3H, s
( CDCI3, 400 MHz):
7.93 (1H, d,
J = 2.3 Hz), 7.45
( 1 H, dd, J =
8.5, 2.4 Hz), 6.63
(1 H, d, J =
O 8.6 Hz), 4.40 (2H,
t, J = 6.8 Hz),
D-380 ~ off 3.37 (3H, s), 3.05-2.96for
O (1 H m), LR
2.97 (1 H, d, J 363
= 14.4 Hz), 2.92 (M+H)
( 1 H, d, J = 14.4
Hz), 2.86 (2H,
t , J= 6.7 Hz), 2.20
(3H, s), 1.43
(3H, s), 1.30 (3H,
s), 1.28 (3H,
s
( MeOD, 400 MHz):
7.82 (1 H, d,
J = 2.0 Hz), 7.44
(1 H, dd, J =
8.6, 2.3 Hz), 6.57
(1 H, d, J =
~\ ~oH 8.6 Hz), 6.45 (1 for
D-39~ H, s), 4.39 (2H, LR
~ ~~ I ~ t, J= 6.4 Hz)
4.00 (3H, s), 3.20
_ , 15 (M+H)
(3H, s), 2.86 (2H,
t, J = 6.6 Hz),
2.86 (1 H, d, J
= 14.2 Hz), 2.80
(1H, d, J= 14.2
Hz), 2.22 (3H,
s , 2.14 3H, s
, 1.23 3H, s
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
147
(MeOD, 400 MHz):
7.82 (1 H, d,
J = 2. 3 Hz), 7.44
( 1 H, dd, J =
8.0, 1.9 Hz), 7.34-7.29
(2H, m),
7.22 (2H, d, J =
8.6 Hz), 7.09-
0
7.03 (1 H, m), 6.98-6.91
(4H,
D-40I ~ ' I I ; off m), 6.60 (1 H, d,
~ J = 8.6 Hz), 0
o N 4.33 (2H, t, J=
7.1 Hz), 3.2
(3H, s), 3.00 (2H,
t, J = 7.0 Hz),
2.82 (1 H, d, J
= 14.2 Hz), 2.80
(iH, d, J= 14.2
Hz), 1.23 (3H,
s
(MeOD, 400 MHz):
7.81 (1 H, d,
J = 2.3 Hz), 7.44
(1 H, dd, J =
8.6, 2.3 Hz), 7.27
(2H, d, J =
0 8.6 Hz), 7.07 (2H,
d, J = 7.8
F o ~ ~oH Hz), 6.57 (1 H, for
~1 F F d, J = 8.6 Hz), LR
I 33 (2H 00
I 7 Hz) M+H
4 +
t
J= 6
3
20
N o . (
~ , )
o .
,
.
,
(3H, s), 2.97 (2H,
t, J = 6.7 Hz),
2.84 (1 H, d, J
= 14.2 Hz), 2.82
(1 H, d, J = 14.2
Hz), 1.24 (3H,
s
(MeOD, 400 MHz):
7.83 (1 H, d,
J=1.8Hz),7.65(1H,d,J=7.6
Hz), 7.46 (1H, dd,
J= 8.6, 2.3
o Hz), 7.29 (1 H,
s), 7.25 (1 H,
t, J
=7.6Hz),7.19(1H,d,J=7.6
D-42/ \ ~~ I ; o off Hz), 6.59 (1 H, fo(
d, J = 8.3 Hz), LR
+
o N ~ )
15 M+H
4.39 (2H, t, J =
6.6 Hz), 3.19
(3H, s), 2.87 (2H,
t, J= 6.4 Hz),
2.87 (1 H, d, J
= 13.9 Hz), 2.80
(1 H, d, J = 13.9
Hz), 2.24 (3H,
s , 1.21 3H, s
(MeOD, 400 MHz):
7.81 (1 H, d,
J = 2.3 Hz), 7.45-7.38
(2H, m),
.32-7.24 (2H, m),
6.91 (1 H, dd,
J = 8.0, 2.4 Hz),
6.58 (1 H, d, J
D-43~ ~ ~~ I ; o o" = 8.3 Hz), 4.38 for
(2H, t, J= 6.7 LR
N p N I Hz), 3.74 (3H, s), 27 (M+H)
3.18 (3H, s),
-0 2.86 (2H, t, J =
6.7 Hz), 2.85
(1 H, d, J = 13.9
Hz), 2.79 (1 H,
d, J = 13.9 Hz),
2.22 (3H, s),
1.22 3H, s
Pr~arations of starting materials for Examples D-1 to D-43 (Preparations d-1
to d-
421
Preparation d-1
Ethyl 2-ethoxv-3-f6-f2-(5-methyl-2-phenyl-1.3-oxazol-4-vllethoxvlavridin-3-
I acr late
~/ \ ~I
0
~N~O N
N,N,N',N'-tetramethylguanidine (0.305 mL, 2.43 mmol) was added dropwise to a
solution of 6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]nicotinaldehyde
(250 mg,
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
l4tf
0.811 mmol) and (1,2-diethoxy-2- oxoethyl)(triphenyl)phosphonium
chloride (696 mg, 1.62 mmol) in chloroform (4 mL). The mixture was stirred for
16
hours then partitioned between saturated ammonium chloride solution and ethyl
acetate. The organic phase was washed with brine, dried over magnesium
sulfate,
filtered and evaporated* and evaporated. The residue was purified by flash
column
chromatography (1:2 ethyl acetate:hexanes) to yield the title compound as a
white
solid (330 g, 96%).
LRMS (m/z): 423 (M+H)''.
'H NMR (CDCl3, 300 MHz) 8.42 (1H, m), 8.10 (1H, m), 7.97 (1H, m), 7.40 (2H,
m),
7.28 (3H, m), 6.90 (1H, s), 6.73 (1H, m), 4.60 (2H, t, J= 7 Hz), 4.30 (2H, q,
J= 7
Hz), 4.01 (2H, q, J= 7 Hz), 2.99 (2H, t, J= 7 Hz), 2.34 (3H, s), 1.36 (6H, m)
Preaaration d-2
Ethvl 2-ethoxv-3-(6 j2-(5-methyl-2~henyl-1.3-oxazol-4-yl)ethoxvlaYridin-3
yl;yoropanoate
O
/ \ N~ I ~ O-W
° N °1
A solution of ethyl 2-ethoxy-3-{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-
yl)ethoxyJpyridin-3-yl}acrylate (328 mg, 0.776 mmol) in ethanol (t0 mL) was
hydrogenated at 50psi over 10% palladium on carbon (33 mg) for 3 hours. The
mixture was filtered through celite and the solid was washed with ethyl
acetate.
The filtrate and washings were evaporated and the residue was purified by
flash
column chromatography (1:2 ethyl acetate:hexanes) to yield the title compound
as
a colorless oil (183 mg, 56%).
LRMS (m/z): 425 (M+H)+.
'H NMR (CDCI3, 300 MHz) 7.99 (3H, m), 7.42 (4H, m), 6.65 (1H, m), 4.54 (2H, t,
J
= 7 Hz), 4.18 (2H, q, J = 7 Hz), 3.93 (1 H, m), 3.63 (1 H, m), 3.36 (1 H, m),
2.90 (4H,
m), 2.33 (3H, s), 1.25 (3H, t, J = 7 Hz), 1.16 (3H, t, J = 7 Hz).
Preparation d-3
Preparation of 2-(benzyloxy~-5-bromop ri~dine
~Br
of[~'~rv~I
I
To a solution of 5-bromopyridin-2(1f-rJ-one (100 mmol, 17.4 g, 1.0 eq.) in
benzene
(170 mL) was added silver (I) carbonate (67.0 mmol, 18.5 g, 0.67 eq.). The
flask
was wrapped with aluminum foil and then benzyl bromide (120 mmol, 20.5 g, 1.2
eq.) was added via syringe in a steady stream. The mixture was heated to 50
°C
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
149
and stirred in the dark for approximately 24 hours. LC/MS of the reaction
mixture
indicates two peaks both with M+H = 265 corresponding to the desired molecular
weight. On the basis of relative polarities, the more polar peak was thought
to be
the N-alkylated product and consisted of approximately 20 % of the total. The
reaction mixture was allowed to cool to room temperature and the silver salt
was
removed by filtration of the mixture through a pad of celite. The filter cake
was
washed with benzene and the organic layer was washed twice with 2% sodium
bicarbonate and twice with water. The organic layer was dried over magnesium
sulfate and concentrated in vacuo. The crude residue was purified on a Biotage
Sp4 65i over a gradient of 5-95% hexanes in ethyl acetate to afford the title
compound as a golden oil (25.1 g, 95%).
LRMS: 265 (M+H)+.
'H NMR (DMSO-ds, 400 MHz); 8.29 (1 H, s) 7.72 (1 H, d, J=8.5 Hz) 7.31 - 7.43
(5
H, m) 6.54 (1 H, d, J=8.5 Hz) 5.34 (2 H, s)
Preparation d-4
Preparation of 6-lbenzylox~~nicotinalde~de
H
O
O ~N
n-Butyl lithium (2.5M, 95.9 mmol, 38.4 mL, 1.05 eq.) was added dropwise via
syringe to a stirred solution of 2-(benzyloxy)-5-bromopyridine (91.3 mmol,
24.1 g,
1.0 eq.) in THF (260 mL, c = 0.35) cooled to -78 °C. Upon completion of
addition,
the solution was allowed to continue stirring at the same low temperature for
1
hour. At this point, N,IV dimethylformamide (183 mmol, 13.4 g, 2.0 eq.) was
added
dropwise as a solution in 5 mL THF. Stirring was continued at the same low
temperature for a further 30 minutes at which point the reaction was quenched
by
addition of 5% sodium bicarbonate. The mixture was transferred to a separatory
funnel and extracted with ether (3 x 250 mL). The combined organic layers were
washed with brine, dried over anhydrous magnesium sulfate and concentrated in
vacuo. The resultant yellow oil was purified on a Biotage Sp4 65i over a
gradient
of 0 - 50% hexanes in ethyl acetate to afford the title-compound (14.1 g,
73%).
LRMS: 214 (M+H)+.
'H NMR (DMSO-ds, 400 MHz); 10.02 (1 H, s) 8.86 (1 H, s) 8.03 (1 H, d, J=9.3
Hz)
7.31 - 7.43 (5 H, m) 6.50 (1 H, d, J=9.3 Hz) 5.33 (2 H, s)
Preparation d-5
Preparation of ethyl (227-3-f6-(benzyloxv)oyridin-3=yll-2-ethoxyacrvlate
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
15D
O
a ~N ~ rO
To a solution of 6-(benzyloxy)nicotinaldehyde (1.0 eq., 33.1 mmol, 7.05 g) and
(1,2-diethoxy-2-oxoethyl)(triphenyl)phosphonium chloride (2.0 eq., 66.2 mmol,
28.4
g) in chloroform (165 mL, 0.2 M) was added tetramethylguanidine (3.0 eq., 99.3
mmol, 11.4 g). The flask was capped with a hollow glass stopper and stirred at
room temperature overnight. TLC analysis after approximately 18 hours
indicated
the presence of a small amount of unreacted starting material. The reaction
mixture was heated to reflux and TLC reanalyzed after 2 hours. The reaction
was
quenched with saturated ammonium chloride. The layers were separated and the
organic layer was washed with brine, dried over magnesium sulfate and
concentrated in vacuo. A large amount of triphenylphosphine oxide
precipitated.
The residue was triturated with ether and filtered. Washed filter cake with
ether
and concentrated combined filtrates in vacuo to afford a pale yellow solid
which
was dissolved in a minimal amount of DCM and loaded onto Biotage Sp4 65i and
eluted over a gradient of 10 - 100 % hexanes to ethyl acetate. Obtained 12.3 g
of
a clear, colorless oil (37.6 mmol, quant.).
LRMS: 328 (M+H)''.
'H NMR (DMSO-ds, 400 MHz); 8.33 (1 H, s) 7.92 (1 H, d, J=8.0 Hz) 7.31 - 7.43
(5
H, m) 6.76 (1 H, d, J=8.1 Hz) 6.60 (1 H, s) 5.37 (2 H, s) 4.23 (2 H, q, J=7.1
Hz)
3.90 - 3.99 (2 H, m) 1.34 (6 H, dt, J=15.8, 7.0 Hz)
Preparation d-6
Pre~~aration of ethyl 2-ethoxy-3~6-oxo-1.6-dihydropvridin-3~1)propanoate
O
~I o~
H /O
To a Parr shaker bottle containing a solution of ethyl (2~-3-[6-
(benzyloxy)pyridin-3-
yl]-2-ethoxyacrylate in ethanol was added 10% Pd on carbon ( ~ 1.23 g). The
bottle was purged with hydrogen and degassed under reduced pressure three
times. The mixture was placed under 50 psi hydrogen and shaken at room
temperature overnight. After -- 20 hours shaking was stopped and the bottle
was
degassed in vacuo. TLC analysis indicated consumption of starting material.
The
mixture was filtered through a pad of celite to remove palladium. The filter
cake
was washed with an additional portion of ethanol. This solution was
concentrated
in vacuo to yield the reduced and debenzylated pyridone as a golden oil. This
oil
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
151
was purified on a Biotage Sp4, 65i, 80 mUmin over a gradient of 0 - 10%
MeOH in DCM to yield 2.77 g of a clear, colorless oil (11.6 mmol, 31%).
LRMS: 240 (M+H)+.
'H NMR (DMSO-ds, 400 MHz): 7.29 (1 H, d, J=9.5 Hz) 7.19 (1 H, d, J=5.2 Hz)
6.55 (1 H, d, J=9.5 Hz) 4.20 (2 H, q, J=7.0 Hz) 4.10 (1 H, dd, J=9.6, 0.3 Hz)
3.59
3.73 (2 H, m) 2.65 - 2.70 (1 H, m) 2.53 - 2.61 (1 H, m) 1.23 (6 H, td, J=7.0,
3.6 Hz)
Preparation d-7
5-Benzyloxv-pyridine-2-carbaidehYde
O
H
\ o .N
To a solution of (5-benzyloxy-pyridin-2-yl)-methanol (2.3619 g, 10.9728 mmol)
in
dichloromethane (120 mL) and pyridine (2.68 mL, 32.9184 mmol) was added 1,1,1-
triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1l-~-one (6.9812 g, 16.4592 mmol).
The
resulting solution was stirred, under an atmosphere of nitrogen at ambient
temperature, for 16 hours and then diluted with diethyl ether (100 mL)
followed by
partial concentration under reduced pressure. The residue was taken up in
diethyl
ether (150 mL), and precipitates were removed by extraction with 1:1 10%
aqueous
sodium thiosulfateaaturated aqueous sodium bicarbonate (2 x 100 mL). The
organic layer was washed with water (100 mL) and saturated aqueous sodium
chloride (100 mL), dried (anhydrous magnesium sulfate), filtered, and
concentrated
in vacuo to afford the pure title compound (9.1694 g, 50%) as a pale yellow
oil.
LRMS (m/z): 214 (M+H)+.
'H NMR (CDCI3, 300 MHz): 9.98 (1 H, d, J = 0.8 Hz), 8.49 (1 H, d, J = 2.5 Hz),
7.94
(1 H, d, J = 8.7 Hz), 7.44-7.40 (4H, m), 7.38-7.33 (2H, m), 5.19 (2H, s).
Preparation d-8
3-(5-Benzyloxy-pyridin-2-vl -2-ethox~crylic acid et~l ester
O
I w w
~N O
1
To a solution of 5-benzyloxy-pyridine-2-carbaldehyde (1.1694 g, 5.4842 mmol),
(ethoxycarbonyl-methoxy-methyl)-triphenyl-phosphonium chloride (4.7043 g,
10.9684 mmol) in chloroform (30 mL), under an atmosphere of nitrogen at
ambient
temperature, was added tetramethylguanidine (2.1 mL, 16.4526 mmol) dropwise.
The resulting solution was stirred for 16 hours and then quenched with
saturated
aqueous ammonium chloride (50 mL). The phases were separated and the
organic phase washed with saturated aqueous sodium chloride (50 mL), dried
CA 02521915 2005-10-07
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1bL
(anhydrous magnesium sulfate), filtered and concentrated in vacuo to afford
the
crude product. The residue was purified by flash column chromatography
(hexanes to ethyl acetate) to yield the pure title compound (1.8051 g, 100%)
as a
yellow oil.
LRMS (m/z): 328 (M+H);.
' H NMR (CDCI3, 300 MHz): 8.37 (1 H, d, J = 2.6 Hz), 8.18 (1 H, d, J = 8.9
Hz), 7.44-
7.33 (5H, m), 7.25 (1 H, dd, J = 8.9, 3.0 Hz), 7.13 (1 H, s), 5.13 (2H, s),
4.27 (2H, q,
J = 7.2 Hz), 4.05 (2H, q, J = 7.2 Hz), 1.35 (3H, t, J = 7.0 Hz), 1.34 (3H, t,
J = 7.0
Hz). --
Preparation d-9
2-Ethoxv-3-(5-hydroxy-pvridin-2-yl)-propionic acid ethyl ester
O~
HO ' N O\
To a solution of 3-(5-benzyloxy-pyridin-2-yl)-2-ethoxy-acrylic acid ethyl
ester
(1.8051 g, 5.5144 mmol) in dry ethanol (40 mL) was added palladium (0.1805 g,
10
wt. % on activated carbon). The resulting solution was stirred at ambient
temperature under an atmosphere of hydrogen (50psi) for 16 hours. The
resulting
solution was filtered through a 3" bed of Celite and washed with ethanol (200
mL).
The filtrate was then concentrated in vacuo to afford the pure title compound
(1.2231 g, 93%) as a pale yellow oil.
LRMS (m/z): 240 (M+H)+.
'H NMR (CDCI3, 300 MHz): 8.14 (1H, s), 7.20-7.11 (2H, m), 4.19-4.10 (3H, m),
3.71 (1 H, q, J = 7.0 Hz), 3.63-3.53 (1 H, m), 3.36-3.26 (1 H, m), 3.18-3.03
(1 H, m),
1.18 (3H, t, J = 7.2 Hz), 1.07 (3H, t, J = 7.1 Hz).
Preparation d-10
ethyl2-ethoxy-3-d6-f2-l4~uhenoxvphenyl)ethoxy]pyridin-3_yl~propanoate
0
I~ o~
'0
i 1
~'0
To an argon-purged solution of the appropriate bromopyridine (0.636
mmol) in toluene (12 mL) was added palladium (II) acetate (11.4 mg, 0.0508
mmol)
and racemic-2-(Di-t-butylphosphino)-1,1'-binaphthyl (25.4 mg, 0.0636 mmol).
The
activated complex was allowed to form over approximately ten minutes, at which
point cesium carbonate (414 mg, 1.27 mmol) and the appropriate alcohol (0.956
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mmol) were added. The mixture was heated to 115 °C and stirred at this
temperature for approximately 12-18 hours. The mixture was cooled to room
temperature and filtered through a pad of silica. The filter pad was washed
with 2-
3 aliquots of ethyl acetate and the combined organic filtrates were combined
and
concentrated in vacuo. The resulting residue was either purified by flash
chromatography, or subjected to the general hydrolysis procedure.
Preparations d-11 to d-18
Preparations d-11 to d-18 were prepared by procedures analogous to those used
for Preparation d-10
Prep # Structure 'H NMR MS (m/z)
(LR or NR)
0
I.
d-'! 1 N ~°
CI / \
~I °~
O
d-12
f°
0
o-.
° I N 'O
d-13
I
~s
I
°
~o~
-IIN~'O
d-14 [i
°. .o
mss,
b
0
Iw O~
N, 'O
d-15
I
,o
,'s.,
0
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0
I ~ o~
o N ro
d-16
~I
F~O
F
O
O~
O N r0
d-17
I
~
0
0
d-18
~ I
,o
Preparation d-19
2-Bromo-5~bromomethyl)pyridine
Br
Br N
Phosphorous tribromide (100 mmol, 27.1 g, 2.0 eq.) was added carefully to 2-
chloro-5-hydroxymethyl pyridine (50.0 mmol, 7.18 g, 1.0 eq.). The pyridine
clumped together and the mixture was heated to 160 °C. Within 5 minutes
of
stirring at >150 °C the mixture went very dark in color with gas
evolution. The
mixture was stirred at this same temperature for approximately 2.5 hours at
which
point it was cooled to room temperature. The mixture was cooled further to 0
°C
whereupon saturated sodium bicarbonate was added very cautiously (highly
exothermic!). As foaming became less vigorous, ice was added to the mixture
until
foaming subsided. Solid sodium bicarbonate was then carefully added to achieve
a pH of ~ 8-9. The mixture was extracted with ethyl acetate and the organic
layer
was washed with brine and dried over anhydrous magnesium sulfate.
Concentrated in vacuo to afford a dark solid. This material was dissolved in a
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155
minimal amount of DCM and purified using a Biotage Sp4 65i over a gradient
of 0 - 100 % ethyl acetate in hexanes to afford the title compound as a pale
yellow
solid (5.57 g, 44%).
LRMS: 252 (M+H)'.
'H NMR (DMSO-ds, 400 MHz); 8.39 (1H, s) 7.59 (1H, d, J= 8.5 Hz) 7.48 (1H, d, J
= 8.5 Hz) 4.46 (2H, s)
Preparation d-20
Preparation of dimethvl ((6-bromooyridin-3- I)y methy~methoxv)malonate
O
O~
Br , N O O
To a slurry of potassium t butoxide (46.6 mmol, 5.22 g, 1.3 eq.) in anhydrous
DMF
(250 mL) cooled to 0 °C was added methoxy dimethylmalonate (46.6 mmol,
7.55 g,
1.3 eq.) via syringe in small portions. The enolate was allowed to form over
approximately 30 minutes at which point 2-bromo-5-(bromomethyl)pyridine was
added portionwise. The reaction mixture was allowed to warm slowly to room
temperature over 3 hours. The reaction mixture was diluted with ethyl ether
and
transferred to a separatory funnel containing saturated ammonium chloride. The
layers were shaken and separated and the organic layer was Washed with water.
The organic layer was then dried over anhydrous magnesium sulfate and
concentrated in vacuo. The yellow oil obtained was purified on a Biotage Sp4
65i
over a gradient of 0 - 100 % ethyl acetate in hexanes to afford a colorless
oil that
solidified on standing (12.1 g, quant.)
LRMS: 333 (M+H)+.
'H NMR (DMSO-ds, 400 MHz); 8.27 (1 H, s) 7.45 - 7.55 (2 H, m) 3.82 (6 H, s)
3.57
(3 H, s) 3.42 (2 H, s)
Preaaration d-21
Preparation of methyl 3-(6-bromopiridin-3-vll-2-methoxy)xopanoate
O
O~
Br N ,O
To a solution of dimethyl [(6-bromopyridin-3-yl)methylJ(methoxy)malonate (3.55
mmol, 1.18 g, 1.0 eq.) in anhydrous DMF (2 mL) was added lithium bromide (3.20
mmol, 0.278 g, 0.9 eq.) followed by water (3.55 mmol, 0.064 g, 1.0 eq.). The
solution was placed in a oil bath preheated to 165 °C. Rapid gas
evolution
commenced. Bubble formation ceased within 30 minutes and LC/MS of the
reaction mixture at this time indicated reaction was complete. Cooled to room
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156
temperature and diluted with water. Extracted aqueous layer with ethyl ether
(4x 25 mL). Combined organic layers and washed with brine. Dried organic layer
over anhydrous magnesium sulfate and concentrated in vacuo to afford 536 mg of
a brown oil that was a single spot by TLC. Used in next step without further
purification.
LRMS: 275 (M+H)+.
'H NMR (DMSO-d6, 400 MHz):. 8.23 (1 H, s) 7.42 - 7.51 (2 H, m) 4.26 (1 H, d,
J=8.1 Hz) 3.79 (3 H, s) 3.51 (3 H, s) 2.97 - 3.03 (1 H, m) 2.82 - 2.88 (1 H,
m).
Preparation d-22
ethv l~ 3-f6~2-~4-f(eth i~ifon I)~henyl}ethoxy)pyridin-3-ylj-2-
methoxyproaanoate
0
I
0
°. . o
~s
0
Preparations d-23 to d-38
Preaarations d-23 to d-38 were~repared by procedures analogous to those used
for Preaaration d-22.
Prepara Structure 'H NMR MS (m/z)
tion # (LR or HR)
o N ,o
d-23
~I
°.S.o
0
0
I~ o~
N
d-24
~I
~o
I~
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~5%
(CDC13, 300 MHz): 7.90-7.99
(3H, m),
7.35-7.47 (4H, m), 6.65
(1 H, d. J = 8.5
o. Hz), 4.27 (2H, t J= 6.3 for
~ Hz) 4.17 (2H, t, LR
d-25~ \ o I o J = 7.0 Hz), 3.29 (3H, 439
N o s), 2.91 (2H, q, J = (M+H)+
14.1 Hz), 2.66 (2H, t,
J= 7.4 Hz), 2.27
(3H, s), 2.16 (3H, s),
2.13 (2H, m), 1.25
(3H, t, J = 7.2 Hz)
(CDCI3, 400 MHz): 7.91-7.88
(3H, m),
7.41 (1 H, dd, J = 8.6,
2.5 Hz), 7.39-7.36
o ~ ~ (2H m) 6.62 (1 H d J for
d-26~, i \ , ~ ~j ~o = 8.3 Hz), 4.51 LR
~
N o N (2H, t, J = 6.8 Hz), 445
3.70 (3H, s), 3.28 (M+H)
(3H, s), 2.97-2.93 (3H,
m), 2.86 (1 H, d, J
= 14.2 Hz), 2.32 (3H,
s), 1.32 (3H, s)
(CDCI3, 400 MHz): 8.07
(2H, d, J =
8.07), 7.91 (1H, d, J=
2.3 Hz), 7.66 (2H,
d, J = 8.3 Hz), 7.41
(1 H, dd, J = 8.5, 2.4
d-27F ~ ~ O Hz), 6.62 (1 H d J = for
o~ 8.3 Hz), 4.52 (2H t, LR
~ ~ ; o J = 6.7 Hz), 3.70 (3H, 479
F s), 3.28 (3H, s), (M+H)
N o N ,
2.97 (2H, t, J = 6.7
Hz), 2.95 (1 H, d, J
=
14.2 Hz), 2.86 (1 H,
d, J = 14.2 Hz), 2.34
3H s , 1.33 3H, s
(CDCI3, 400 MHz): 7.90
(1 H, d, J = 2.3
Hz), 7.41 (1 H, dd, J
= 8.5, 2.4 Hz), 6:61
(1 H, d, J = 8.3 Hz),
4.42 (2H, t, J = 6.8
Hz), 3.71 (3H s), 3.29
(3H, s), 2.95 (1H,
d-28~o~ I ; o o~ d, J = 13.9 Hz), 2.86 for
--~ ~N o N ~ (1 H d, J = 14.2 Hz), LR
2.86 (2H, t, J= 7.1 Hz),417
2.67 (1H, tt, J= (M+H)+
11.6, 3.5 Hz), 2.19 (3H,
s), 2.02-1.98
(2H, m), 1.81-1.77 (2H,
m), 1.69-1.65
(1 H, m), 1.54-1.46 (2H,
m), 1.38-1.31
2H, m , 1.33 3H, s ,
1.28-1.24 1 H, m
(CDCI3, 400 MHz): 7.92
(1H, d, J=2.3
Hz), 7.85 (2H, dd, J
= 8.0, 1.6 Hz), 7.41
(1 H, dd, J = 8.5, 2.4
Hz), 7.39-7.35 (3H,
d-29/ \ o' m), 6.63 (1 H, d, J = for
~N~ I , o 8.6 Hz), 4.59 (2H t, LR
o N J= 7.0 Hz), 3.70 (3H, r
s), 3.28 (3H, s), 427
(M+H)
3.18 (2H, t, J = 7.0
Hz), 2.95 (1 H, d, J
=
14.2 Hz), 2.87 (1 H,
d, J = 14.2 Hz), 2.42
3H, s , 1.33 3H, s
(CDC13, 400 MHz): 7.90
(1 H, d, J = 2.3
Hz), 7.41 (1 H, dd, J
= 8.5, 2.4 Hz), 7.33
o (1H, d, J= 7.6 Hz), 7.21
(1H, d, J= 7.6
I ; o o' Hz), 7.13 (1 H dt, J for
= 7.6, 1.0 Hz), 6.97 LR
d-30N, N~o N ~ (1 H, dt, J = 7.8, 1.3
p Hz), 6.60 (1 H, d, J 400
= (M+H)+
/ \ 8.6 Hz), 4.56 (2H, t,
J= 5.4 Hz), 3.92
(2H, t, J = 5.4 Hz),
3.70 (3H, s), 3.28
(6H, s), 2.95 (1H, d,
J= 13.9 Hz), 2.86
lH,d,J=14.2Hz,1.32 3H,s
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(CDC13, 400 MHz): 7.91
(1 H, d, J = 2.3
Hz), 7.81 (1 H, s), 7.75
(1 H, d, J = 7.8
Hz), 7.41 (1 H, dd, J
= 8.5, 2.4 Hz), 7.29
(lH,t J=7.7Hz),7.19(lH,d
d-31 ~ ~ N~ J=7.6 '
I N o Hz), 6.62 (1 H, d, J
= 8.3 Hz), 4.52 (2H
t
o , 425
, (M
H)
J = 6.8 Hz), 3.70 (3H,
s), 3.28 (3H, s),
2.96 (2H, t, J = 6.8
Hz), 2.95 (1 H, d, J
=
13.9 Hz), 2.86 (1 H,
d, J = 13.9 Hz), 2.38
3H, s , 2.32 3H, s ,
7.33 3H, s
(CDCI3, 400 MHz): 7.91
(1 H, d, J = 2.0
Hz), 7.89-7.86 (2H, m),
7.59 (1 H, dd, J =
8.5, 2.2 Hz), 6.92-6.90
(2H, m), 6.62 (1 H,
d, J= 8.3 Hz), 4.51 (2H,
' t, J= 6.8 Hz), for
LR
d-32 o r ~ N~o ~ N o o 4.06 (2H, q J = 7.1 Hz),455
3.70 (3H, s). (M+H)+
3.28 (3H, s), 2.95 (2H,
t, J = 6.8 Hz),
2.96 (1 H, d, J = 13.9
Hz), 2.87 (1 H, d, J
= 13.9 Hz), 2.30 (3H,
s), 1.42 (3H, t, J =
7.1 Hz , 1.33 3H, s
(CDCI3, 400 MHz): 7.90
(1H, d, J= 2.3
Hz), 7.41 (1 H, dd, J
= 8.5, 2.4 Hz), 6.61
(1 H, d, J = 8.3 Hz),
4.42 (2H, t J = 6.8
d-33 ~~~ I ; o o' Hz), 3.70 (3H, s), 3.28 for
o (3H, s), 3.00-2.93 LR
~ (1 H, m), 2.95 (1 H, 377
d, J = 14.2 Hz), 2.86 (M+H)
N (2H, t, J = 6.8 Hz),
2.86 (1 H, d, J = 14.2
Hz), 2.20 (3H, s), 1.33
(3H, s), 1.30 (3H,
s,1.28 3H,s
(CDCI3, 400 MHz): 7.91
(1H, d, J= 2.3
Hz), 7.42 (1 H, dd, J
= 8.5, 2.4 Hz), 6.61
o (1 H, d, J = 8.3 Hz),
6.48 (1 H, s), 4.51
o ~o~ (2H, t, J = 6.7 Hz), for
d-34 N 4.15 (3H, s) 3.71 LR
; N I 3H +
I 3
28
3H
2
1
, ( 429
o , s), (M+H)
N .
(
, s),
.96 (
H, d, J =
13.9 Hz), 2.94 (2H, t,
J = 6.6 Hz), 2.87
(1 H, d, J = 13.9 Hz),
2.30 (3H, s), 2.27
3H, s , 1.33 3H, s
(CDCI3, 400 MHz): 7.91
(1H, d, J= 2.3
Hz), 7.42 (1H, dd, J=
8.0, 9.9 Hz), 7.33-
7.28 (2H, m), 7.23 (2H,
d, J = 8.6 Hz),
7.08-7.04 (1 H, m), 6.99-6.92for
o (4H, m), LR
'
d-35 ~ 6.64 (1 H, d, J = 8.6
~ ~ o Hz), 4.45 (2H, t, J 422
I = (M+H
~
o 7.1 Hz), 3.70 (3H, s),
ri 3.20 (3H, s), 3.04
(2H, t, J = 7.0 Hz),
2.92 (1 H, d, J = 14.2
Hz), 2.87 (1H, d, J=
14.2 Hz), 1.33 (3H,
s
(CDCI3, 400 MHz): 7.90
(1 H, d, J = 2.3
Hz), 7.42 ( 1 H, dd,
J = 8.5, 2.4 Hz), 7.28
(2H, d, J = 8.6 Hz),
7.13 (2H, d, J = 8.1
d-36 F~'o ~ ~ o~ Hz), 6.63 (1 H, d, J for
F = 8.3 Hz), 4.46 (2H, LR
I I t, 414
O J=6 (M+H)'
~ 8 Hz)
3
71 (3H
s)
3
28 (3H
s)
F ~ .
, .
~ ,
.
,
,
,
,
o N 3.06 (2H, t, J = 6.8
Hz), 2.95 (1 H, d, J
=
14.2 Hz), 2.86 (1 H,
d, J = 13.9 Hz), 1.33
3H, s
(CDCI3, 400 MHz): 7.91
(1 H, d, J = 2.0
Hz), 7.74 (1 H, d, J
= 7.8 Hz), 7.41 (1 H,
dd, J = 8.2, 2.5 Hz)
d-37 ~ ~ ~~ I ~ 7.34 ( 1 M t, J = 7.7
Hz), 7.38 (1 H, s), 7.18
(1 H, d, J = 8.1
o 429
o N M H
( )
Hz), 6.62 (1 H, d, J
= 8.3 Hz), 4.51 (2H,
t,
J = 6.7 Hz), 3.70 (3H,
s), 3.28 (3H, s),
2.96 (2H, t, J = 6.8
Hz), 2.95 (1 H, d, J
=
CA 02521915 2005-10-07
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159
13.9 Hz), 2.86 (1 H,
d, J = 13.9 Hz), 2.32
(3H, s), 1.32 (3H, s)
(CDCI3, 400 MHz): 7.91
(1 H, d, J = 2.0
Hzj, 7.41 (1H, dd, J=
8.5, 2.4 Hz), 7.34-
0 7.29 (2H, m), 6.96-6.93
d-38~ ~ ~~ I ; o o~ (2H, m), 6.62 for
N p N ~ (1 H, d, J = 8.5 Hz), LR
4.52 (2H, t, J = 6.8 441
Hz), 3.70 (3H, s), 3.28 (M+H)
(3H, s), 2.96 (2H,
'o t, J = 6.8 Hz), 2.95
(1 H, d, J = 13.9 Hz),
2.86 (1H, d, J= 13.9
Hz), 2.32 (3H, s),
2.16 3H, s , 1.32 3H,
s
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The compounds of the invention have been tested for activities against PPAR-
gamma and PPAR-alpha. The activities are tabulated below in Ki (pm).
I PPAR-PPAR- I PPAR PPAR- I PPAR- PPAR-
ExampleI Ipha Exampleamma Ipha ExampleI alpha
# gammaKi m # Ki Ki # amma Ki
Ki m m Ki m m
m
-02 0.55 B-02 2.2 C-03 2.9
-03 10 19 B-03 31 9 C-05 15
-05 0.33 2.6 B-04 1.5 48 C-06 9.5 41
E/M
-05 3.4 7.5 B-05 1.33 2.04 C-07 11 22
SIE
-05 0.19 1.1 B-05 2.9 3.2 C-09 1.4 4.6
SIE
-07 0.12 B-05 2 3.6 C-10 2.1 19
-10 1.5 4.4 B-06 0.37 0.13 C-11 2 25
-11 0.58 0.12 B-07 0.65 12 C-12 1.6 9.4
-12 0.0510.35 B-08 0.48 3.1 C-14 8 3.2
-13 3.5 10 B-09 1.9 2.2 C-15 14 3.2
-14 1.3 0.15 B-10 0.17 0.19 C-17 26 3.2
-15 1.2 0.16 B-11 7.9 0.96 C-18 3.5 0.065
-16 2.8 1.5 B-12 33 0.3 C-20 1.5 3.1
-17 1.9 1.6 B-13 9 C-21 0.053 0.066
-18 1.7 14 B-14 2.3 0.021 C-22 0.8 2.1
-19 0.0590.7 B-16 1.8 0.084 C-23 0.19 2.5
-20 0.18 0.14 B-17 1.2 0.047 C-24 0.083 0.022
-21 0.0880.31 B-18 0.082 C-25 0.066 0.018
-22 0.17 0.85 B-19 0.74 0.34 C-26 0.068 0.016
-23 0.39 0.18 B-20 1.6 C-27 0.026 0.015
-24 0.78 0.018 B-21 0.99 4 C-28 0.03 0.088
-25 3.2 4.2 B-22 0.15 0.46 C-29 0.006 0.12
-26 0.15 0.33 8-23 3.4 2.7 C-30 0.033 0.11
-27 2.4 1.3 B-24 1.6 1 C-31 0.026 0.093
-28 0.0440.93 B-27 0.22 C-32 0.035 0.15
E/M
-28 0.0811.1 B-28 7.8 C-33 0.05 0.01
SIE
-28 0.94 2.9 C-02 0.39 C-36 1.7 21
S/E
E/M is defined as enantiomeric mixture, including racemic mixture.
S/E is defined as single enantiomer.
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161
PAR- PAR- PPAR- PAR- PAR- PAR-
Examplegammaalpha Example gamma alpha Examplegamma alpha
# i Ki # Ci i m # Ci m Ci
m m m m
C-38 7.2 C-64 0.052 0.014 C-90 0.017 0.11
C-40 3.7 0.7 C-66 0.023 0.031 C-91 0.39 1.8
C-42 33 13 C-67 0.044 0.25 C-92 1.1 2.8
C-44 36 C-68 4.2 C-93 0.011 0.3
C-45 0.22 7.7 C-69 1.1 2.5 C-94 7
C-46 2 3.5 C-70 6.4 C-95 0.97 8.6
C-47 3.5 8.3 C-71 9.7 D-02 0.46 0.29
C-48 0.0180.24 C-72 7.1 D-03 0.011 0.3
C-48 0.15 0.31 C-73 0.042 D-04 0.44 0.29
E/M
C-48 0.0140.047 C-74 0.64 0.9 D-05 2.8
S/E
C-48 2.4 C-74 D-06 0.027 0.13
S/E S/E
C-49 0.21 1.6 C-74 0.47 4.2 D-07 0.017 0.32
S/E
C-49 21 41 C-75 0.82 D-08 0.002 0.015
C-49 0.0430.34 C-76 2.3 7.3 D-09 0.061 0.05
C-50 0.0431.1 C-77 0.15 2.9 D-10 0.019 0.033
C-51 0.18 2.9 C-78 0.006 0.015 D-11 6.2 5.1
-52 0.3 0.15 C-78 3.9 D-12 8.1
S/E
-53 0.0930.64 C-78 0.003 0.014 D-13 0.36 0.19
S/E
-53 3.6 C-79 0.007 0.015 D-14 1.5 2.6
SIE
-53 0.0270.4 C-80 0.062 0.053 D-15 0.35 0.22
SIE
C-54 0.02 1.2 C-81 0.015 0.75 D-16 6.4
C-55 6 C-82 0.016 D-17 0.031 0.91
C-56 0.0810.078 C-83 0.008 0.004 D-18 0.45 0.62
C-57 1.1 1.8 C-84 0.021 0.064 D-19 1.7 6.4
C-59 0.0090.054 C-85 0.004 0.013 D-20 0.48 0.84
C-60 0.0150.065 C-86 0.005 0.013 D-21 2.1 10
C-61 0.31 0.24 C-87 0.012 0.025 D-23 0.073 6.5
E/M
C-63 0.0940.021 C-89 0.04 0.03 D-23 5
S/E
E/M is defined as enantiomeric mixture, including racemic mixture.
S/E is defined as single enantiomer
CA 02521915 2005-10-07
WO 2004/092145 PCT/IB2004/001159
162
PPAR-PPAR- PPAR- PPAR-
Examplegammaalpha Example gamma alpha
# Ki Ki # Ki Ki
m m m m
-23 0.0391.1 D-33 0.69 0.55
S/E
-24 no no D-34 9.1 3.2
SPA SPA
D-24 0.58 0.93 D-35 0.56 0.33
D-25 2.9 D-35 0.27 0.57
S/E
-26 no no D-35 4.8 9
SPA SPA S/E
D-26 1.9 D-36 0.23 0.73
SlE
D-26 0.0420.67 D-37 0.53 4.7
S/E
D-27 7.8 D-38 9.6
D-28 1.6 4.8 D-39 5
D-29 0.4 0.8 D-40 9.6 1.8
D-29 1.2 D-41 5.9
S/E
D-29 0.69 3 D-42 0.7 1
S/E
D-31 1 0.088 D-44 0.15 2.6
~32 I ~ 0.059D-45 0.058 0.09
1.5
E/M is defined as enantiomeric mixture, including racemic mixture.
S/E is defined as single enantiomer
While the invention has been illustrated by reference to specific and
preferred embodiments, those skilled in the art will recognize that variations
and
modifications may be made through routine experimentation and practice of the
invention. Thus, the invention is intended not to be limited by the foregoing
description, but to be defined by the appended claims and their equivalents.
