Note: Descriptions are shown in the official language in which they were submitted.
WO 2012/015693 CA 02805078 2013-01-10PCT/US2011/045022
IMIDAZOLE DERIVATIVES
TECHNICAL FIELD
The present invention is directed to novel imidazole derivative compounds.
Specifically, the
compounds act as diacylglycerol 0-acyltransferase type 1 inhibitors
(hereinafter also referred to as
"DGATI"), and can be useful in preventing, treating or acting as a remedial
agent for hyperlipidernia,
diabetes mellitus and obesity.
BACKGROUND
Obesity is a medical condition in which excess body fat has accumulated to the
extent
that it may have an adverse effect on health, leading to reduced life
expectancy and increased
health problems. As such, obesity is recognized as an upstream risk factor for
many conditions
such as diabetes mellitus, lipidosis and hypertension (Journal of Japan
Society for the Study of
Obesity, Vol. 12, Extra Edition, 2006). Although the need to treat obesity is
recognized to be
important, there are extremely-limited drug therapies for obesity that are
currently available, and
thus, the advent of novel antiobestic drugs having a more definite action and
few side-effects is
desired.
In general, obesity is caused by the accumulation of triacylglycerol (TO) in
adipose tissue
which is a result of lack of exercise, intake of excessive calories and
ageing. In the body there
are two TG synthesis pathways, a glycerol phosphate pathway, which is present
in most organs
and causes de novo TO synthesis, and a monoacylglycerol pathway, which is
involved principally
in absorption of aliphatic acid from the small intestine. Diacylglycerol
acyltransferases (DGATs,
EC 2.3.1.20), which are membrane-bound enzymes present in the endoplasmic
reticulum,
catalyze the final step of the TO synthesis common to the two TG synthesis
pathways. The final
reaction consists of transferring an acyl group of acyl-coenzyme A to the 3-
position of 1,2-
diacylglycerol to generate TO (Prog. Lipid Res., 43.134-176. 2004 and Ann.
Med., 36, 252-261,
2004). There are two subtypes of DGATs, DGAT1 and DGAT2. There is no
significant
homology at the generic or amino acid level between the DGAT1 and DGAT2, which
are
encoded by different genes (Proc.Natl.Acad.Sci.USA.,95,13018-13023,1998 and
JBC,276,38870-38876,2001). DGATI, is present in the small intestine, adipose
tissue and liver
and is believed to be involved in lipid absorption in the small intestine;
lipid accumulation in the
fat cell; and VLDL secretion and lipid accumulation in the liver
(Ann.Med.,36,252-261,2004 and
JBC,280,21506-21514,2005). In consideration of these functions, a DGAT1
inhibitor is
expected to be an effective obesity treatment through inhibition of lipid
absorption in the small
intestine, lipid accumulation in the adipose tissue and the liver, and lipid
secretion from the liver.
In order to carry out in vivo examination of the physiological function(s) of
DGAT1 and
inhibitory activity against DGAT1, DGAT1-knockout mice deficient in DGAT1 at
the genetic
level was produced and analized. As a result, the DGAT1-knockout mice have
been found to
MRL-DO WOB-0004 2012/0156935
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have smaller fat masses than those of wild-type mice and became resistant to
obesity, abnormal
glucose tolerance, insulin resistance and fatty liver due when fed a high-fat
diet (Nature
Genetics,25,87-90,2000 and JCI,109,1049-1055,2002). In addition, energy
expense has been
reported to be accelerated in the DGATI -knockout mice; and transplantation of
the adipose
tissues of DGAT1-knockout mice into wild-type mice has been reported to make
the wild-type
mice resistant to obesity and abnormal glucose tolerance, induced by a high-
fat diet
(JC1,111,1715-1722,2003 and Diabetes,53,1445-1451,2004). In contrast, obesity
and diabetes
mellitus due to a high-fat diet have been reported to worsen in mice with
overexpression of
DGAT1 in adipose tissue (Diabetes,51,3189-3195,2002 and Diabetes,54,3379-
3386).
From the results, DGAT1 inhibitors are likely to be therapeutic drugs with
efficacy for
obesity, type 2 diabetes mellitus, lipidosis, hypertension, fatty liver,
arteriosclerosis,
cerebrovascular disorder, coronary artery disease and metabolic syndrome,
associated with the
obesity.
SUMMARY OF THE INVENTION
Described herein are compound of formula (I):
HN ' A R2 R1
R3
\X
r IZ
or pharmaceutically acceptable salts thereof, wherein in rings A and B are
selected from the group
consisting of benzene, pyridine, pyrazine and pryimidine; X, Y, Z, W, V, U,
RI, R2 and R3are defined
herein.
The compounds of formula I act as DGAT I inhibitors and can be useful in
preventing, treating or
acting as a remedial agent for hyperlipidemia, diabetes mellitus and obesity.
DETAILED DESCRIPTION
Compounds
A compound of formula (I):
2
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MIRL-oLns-uvwka
R2
A
HNI
R3 r
v_
Iii
\;.v Z
or pharmaceutically acceptable salts thereof, wherein in rings A and B are
selected from the group
consisting of benzene, pyridine, pyrazine and pryimidine;
X and Y are independently selected from the group consisting of -N- and -CH-;
Z is -N- or C=0;
W is -N-, -N(R.4)-, -C(R5)- or -0-;
V and U are independently selected from the group consisting of-C(R6)- and -N-
; and
R1, R2, R3, R4, R5 and R6 are independently selected from the group a, C3-
Cl0cycloalkyl, aryl,
heteroaryl, cycloheteroalkyl, CI-C6alky1C3-C10cycloalkyl, C1-C6alkylaryl, C1-
C6allcylheteroaryl and C1-
C6alkyleycloheteroalkyl, wherein C3-C10cycloalkyl, aryl, heteroaryl,
cycloheteroalkyl, CI-C6allcylC3-
C10cycloalkyl, C1-C6alkylaryl, CI-C6alkylheteroaryl and C1-
C6alkylcyeloheteroalkyl are independently
unsubstituted or substituted with one or more substituents selected from the
group consisting of a;
a is selected from the group consisting of hydrogen, halogen, C1-C6alkyl,
ha1ogen-substitutedC1-
C6alkyl, COC1-C6alkyl, oxo, -OH, CI-C6alkylOH, halogen-substitutedC1-
C6alkylOH, -0C1-C6alkyl, -
Ohalogen-substitutedCi-C6allcyl, -COOH, -COOCI-C6alkyl, -C1-C6alkylCOOCI-
C6alkyl, -C1-
C6alkylCOOH, -0C1-C6alkylCOOH, -CN, C1-C6alkylCN, -NO2, NH2, NHCI-C6alky1,
N(CI-C6alicY1)2, -
NHCOOH, -NHCOOCI-C6alkyl, -CONH2, -CONHCI-C6allcyl, -CON(C1-C6alky1)2, -
S02C1-C6alkyl, C3-C10cycloalkyl, aryl, heteroaryl, cycloheteroalkyl,
eycloheteroalkylCOOH, C1-
C6alkyIC3-C10cycloalkyl, C1-C6alkylaryl, C1-C6alkylheteroaryl and C1-
C6alkyloyeloheteroalkyl.
In certain embodiments of the compounds described herein, ring A and ring B
are individually
selected from the group consisting of pyrazine or pyrimidine. In other
embodiments, ring A and ring B
are individually selected from the group consisting of benzene and pyridine.
In one embodiment, ring A
and ring B are both benzene. In one embodiment, ring A and ring B are both
pyridine.
In still other embodiments of the compounds described herein, ring A is
pyrazine. In another
embodiment, ring A is pyrimidine. In yet another embodiment, ring A is
pyridine. In still another
embodiment, ring A is benzene.
In still other embodiments of the compounds described herein, ring B is
pyrazine. In another
embodiment, ring B is pyrimidine. In yet another embodiment, ring B is
pyridine. In still another
embodiment, ring B is benzene. In certain embodiments, ring B is pyridine,
pyrazine or pryimidine,
wherein the pyridine, pyrazine or pryimidine is bonded to the two bicyclic
rings of formula I via a -C-C-
3
CA 02805078 2013-01-10
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mR.L-uk.).0-vuu4D
bond. In other embodiments, ring B is pyridine wherein the pyridine is bonded
to the two bicyclic rings
of formula I via a -C-C- bond.
In one example of the embodiments of the compounds described herein, ring A is
formula H:
R2
ri.
In certain embodiments of the compounds described herein X is independently
selected from the
group consisting of -N- and -CH-. In one embodiment, X is -CH-. In another
embodiment, X is -N-.
In certain embodiments of the compounds described herein Y is independently
selected from the
group consisting of -N- and -CH-. In one embodiment, Y is -CH-. In another
embodiment, Y is -N-.
In other embodiments of the compounds described herein Z is independently
selected from the
group consisting of -N- and C=O. In one embodiment, Y is -N-. In another
embodiment, Y is
In certain embodiments of the compounds described herein, W is -N(R4)-, -C(R5)-
or -0-. In
some embodiments, W is-N(R4)-. In other embodiments, W is -C(R5)-. In still
other embodiments, W is
-0-. In yet other embodiments, W is -N-.
In other embodiments of the compounds described herein, V is independently
selected from the
group consisting of -C(R6)- and -N-. In one embodiment, V is -N-. In another
embodiment, V is -
C(R6)-. In still other embodiments, V is -CH-.
In other embodiments of the compounds described herein, U is independently
selected from the
group consisting of -C(R6)- and -N-. In one embodiment, U is -N-. In another
embodiment, U is -
C(R6)-. In still other embodiments, U is -CH-.
Described herein are compounds of formula I wherein, R.1, R2, R3, R4, R5 and
R6 are
independently selected from the group a, C3-C10cycloalkyl, aryl, heteroaryl,
cycloheteroalkyl, C1-
C6alkyIC3-C1ocycloalkyl, C1-C6allcylaryl, C1-C6alkylheteroaryl and C1-
C6alkylcycloheteroalkyl, wherein
C3-C10cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, C1-C6alkyIC3-
C10eycloalkyl, C1-C6alkylaryl, C1-
C6alkylheteroaryl and C1-C6alkylcycloheteroalkyl are independently
unsubstituted or substituted with one
or more substituents selected from the group consisting of a;
a is selected from the group consisting of hydrogen, halogen, C1-C6alkyl,
halogen-substitutedC1-
C6alkyl, COCi -Caalkyl, oxo, -OH, C1-C6alkylOH, halogen-substitutedC1-
C6alkylOH, -0C1-C6allcyl, -
Ohalogen-substitutedC1-C6alkyI, -COOH, -COOC1-C6alkyl, -C1-C6alkylCOOCI-
C6alkyl, -C1-
C6alkylCOOH, -OCI-CGalkylCOOH, -CN, C1-C6alkylCN, -NO2, NH2, NHCI-C6alkyl,
N(CI-C6alicy1)2, -
NFICOOH, -NHCOOCI-C6alkyl, -CONH2, -CONHCI-Coalkyl, -CON(CI-C6alky1)2, -
NRSO2CI-C6alkyl, -
SO2C1-C6alkyl, C3-C10cycloalkyl, aryl, heteroaryl, cycloheteroalkyl,
cycloheteroalkylCOOH, Cr
C6alky1C3-Ciocycloalkyl, Ci-C6alkylaryl, C1-C6alkylheteroaryl and C1-
C6alkylcycloheteroalkyl.
In certain embodiments described herein, RI, R2, R3, R4, R5 and R6 are
independently selected
from the group a.
4
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In certain embodiments of the compounds described herein, RI and R2a.re
independently selected
from the group consisting of hydrogen, -CN, -0C1-C6alkyl, -Ohalogen-
substitutedC1-C6allcyl, halogen
and halogen-substitutedC1-C6alkyl. In other embodiments, RI and R2 are
independently selected from the
group consisting of hydrogen, halogen, -CN-, aryl, -0C1-C6alkyl, -Ohalogen-
substitutedCI-C6alkyl and
halogen-substitutedC1-C6allcyl.
In other embodiments of the compounds described herein, RI is independently
selected from the
group consisting of hydrogen, -CN, aryl, -0C1-C6alkyl, -Ohalogen-substitutedC1-
C6alkyl, halogen and
halogen-substitutedC1-C6alkyl. In other embodiments, RI is independently
selected from the group
consisting of -CN, -0C1-C6alkyl, -Ohalogen-substitutedCi-C6alkyl, halogen and
halogen-substitutedCr
C6alkyl. In some embodiments, RI is selected from the group consisting of
halogen and halogen-
substitutedC1-C6alkyl. In one embodiment, RI is hydrogen. In another
embodiment, R1 is ¨CN. In
another embodiment, RI is -0C1-C6alkyl. In another embodiment, RI is halogen.
Suitable halogens
include, but are not limited to, chlorine and fluorine. In yet another
embodiment, RI is halogen-
substitutedCI-C6alkyl. Suitable halogen-substitutedCl-C6alkyls include, but
are not limited to,
trifluoromethyl. In yet another embodiment, RI is -Ohalogen-substitutedC1-
C6alkyl. Suitable -Ohalogen-
substitutedC1-C6alkyls include, but are not limited to, trifluoromethoxy. In
some embodiments, R' is
phenyl. Suitable examples of an aryl substituent, include but are not limited
to, phenyl.
In certain embodiments, R2 is selected from the group consisting of hydrogen
and halogen. In
one embodiment, R2 is hydrogen. In another embodiment, R2 is halogen. Suitable
halogens include, but
are not limited to, chlorine and fluorine.
In specific examples, of the compounds described herein, R2 is halogen or
hydrogen and R1 is
selected from the group consisting of halogen, -CN-, aryl, -0C1-C6allcyl, -
Ohalogen-substitutedC)-C6alkyl
and halogen-substitutedC1-C6alkyl.
In certain embodiments, R3 is selected from the group consisting of hydrogen,
halogen, halogen-
substitutedCI-C6alkyl and aryl. For example in one embodiment, R3 is aryl,
halogen and halogen-
substitutedCI-C6alkyl wherein the aryl is substituted with ¨COOH, -OH or
halogen-substitutedC1-
C6alkyI. In one embodiment, R3 is hydrogen. In another embodiment, R3 is
halogen. Suitable halogens
include, but are not limited to, chlorine, bromine and fluorine. In yet
another embodiment, R3 is halogen-
substitutedCI-C6alkyl. Suitable halogen-substitutedC1-C6alkyls include but are
not limited to,
trifluoromethyl. In still yet another embodiment, R3 is aryl. Suitable aryl
groups include, but are not
limited to, phenyl. In certain embodiments, when R3 is phenyl, the phenyl can
be unsubstituted or
substituted with at least one substituents selected from cr. In one embodiment
of the compounds
described herein, when R3 is phenyl, the phenyl is substituted with ¨COOH.
In certain embodiments of the compounds described herein, wherein W is¨N(R4)-,
R4 is selected
from the group consisting of hydrogen, C1-C6alkyl, C1-C6alkylaryl, aryl, -C1-
C6alkylCOOH, - C1-
C6a1kylCOOCI-C6alkyl and -COOCI-C6alkyl wherein the C1-C6alkylaryl and aryl
are unsubstituted or
substituted with ¨COOI-1, -CI-C6allcylCOOH, -C1-C6alkylCOOCI-C6alkyl and -
COOCI-C6alkyl. In one
embodiment, R4 is hydrogen. In another embodiment, R4 is C1-C6alkyl, C1-
C6alkylaryl, -C1-
MRL-uub-vuu4DWO 2012/015693 CA 02805078 2013-01-10
PCT/US2011/045022
ColkylCOOH, -CI-C6alky1COOC1-C6alkyl and -COOCI-C6alkyl. Suitable C1-C6alkyls
include, but are
not limited to, methyl, ethyl, propyl, t-butyl and butyl. Suitable C1-
C6alkylatyls include, but are not
limited to, CH2phenyl. Suitable CI-C6allcylCOOCI-C6alkyls include, but are not
limited to,
CH2COOCH2CH3. Suitable -C1-C6a1kylCOOHs include, but are not limited to,
CH2COOH. In yet
another embodiment, R4 is aryl, wherein the aryl is substituted with ¨COOH, -
C1-C6alkylCOOH, - C1-
C6alkylCOOCI-C6allvl and -COOCI-C6alkyl. For example in one embodiment, le is
phenyl substituted
with ¨00011.
Also described herein are compounds, or pharmaceutically acceptable salt
thereof of formula Ia.:
Ri
NR4.-Lo Ia
wherein R1 is halogen or halogen-substitutedCI-C6alkyl; and
R4 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-
C6alkylaryl, aryl, -C1-C6alkylCOOH,
- C1-C6alkylCOOC1-C6alkyl and -COOCI-C6alkyl wherein the Ci-C6alkylaryl and
aryl are unsubstituted
or substituted with ¨COOH, -C1-C6alkylCOOH, C1-C6alkylCOOCI-C6alkyl and -COOCI-
C6alkyl.
In some embodiments, R1 is selected from the group consisting of halogen and
halogen-
substitutedCI-C6alkyl In one embodiment, R1 is hydrogen. In another
embodiment, R1 is halogen. In yet
another embodiment, R1 is halogen-substitutedCi-C6alkyl. Suitable halogen-
substitutedC1-C6alkyls
include, but are not limited to, trifluorornethyl. Suitable halogens include,
but are not limited to, chlorine
and fluorine.
In certain embodiments, R4 is selected from the group consisting of hydrogen,
C1-C6alkyl, C1-
C6alkylatyl, aryl, -C1-C6alkylCOOH, - C1-C6alkylCOOCI-C6alkyl and -COOC1-
C6alkyl wherein the C1-
C6alkylaryl and aryl are unsubstituted or substituted with ¨COOH, -C1-
C6allcylCOOH,
C6alkylCOOCI-C6alkyl and -COOCI-C6alkyl. In one embodiment, R4 is hydrogen. In
another
embodiment, R4 is C1-C6alkyl, Ci-C6allcylaryl, -C1-C6alkylCOOH, -C1-
C6alkylCOOCI-C6alkyl and..
COOC1-C6alkyl. Suitable C1-C6alkyls include, but are not limited to, methyl,
ethyl, propyl, t-butyl and
butyl. Suitable C1-C6allcylaryls include, but are not limited to, CH2phenyl.
Suitable C1-C6alkylCOOC1-
C6alkyls include, but are not limited to, CH2COOCH2CH3. Suitable -C1-
C6allcylCOOHs include, but are
not limited to, CH2COOH. In yet another embodiment, R4 is aryl, wherein the
aryl is substituted with ¨
COOH, -C1-C6alkylCOOH, - C1-C6alkylCOOCI-C6alkyl and -COOCI-C6alkyl. For
example in one
embodiment, R4 is phenyl substituted with ¨COOH.
In certain embodiment, R4 is CI-C6alkyl or aryl. In one embodiment, R4 is C1-
C6alkyl. Suitable
C1-C6alkyls include, but are not limited to, methyl, ethyl, propyl, t-butyl
and butyl. In another
embodiment, R4 is aryl, wherein the aryl is phenyl. In other embodiment when
R4 is aryl, the aryl group
6
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iviRL-ukm5-vvv+3
is substituted with --COOH, -C1-C6alkylCOOH, - C1-C6alkylCOOC1-C6alkyl and -
COOCI-C6alkyl. In yet
another embodiment, R4 is hydrogen.
Examples of the compounds described herein include, but are not limited to,
the following:
7 =
=
0
1110 F
N
H
0
11,
N \\N F
H
0
N F
H
0
0
HO
N
0
7
CA 02805078 2013-01-10
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11
N4.\\
0
\ Cl
H
0
1 1110
1111
H
0
N
\\N N
H
0
H FxF
N 0 F
N \\N
H
0
8
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MRL-vi_y0-vvv,+
7 =
1.1
0 N
/ 0
HC
11
0 N
0
HO
HN 41,
QNS
N
H 0
7
v,
N N
0
0
H30
9
MRL-uk.n5-vvvQNSWO 2012/015693
CA 02805078 2013-01-10
PCT/US2011/045022
7 11 ri
0
HC
11
100
0
0 111
HO
= CI
N 's 0
0
HO
10
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MR.1,-.Uk/t5-VVv4.3
=F
N \
\ NH
\ N
----- 0
N N
,CH
0\\
H
F 14, N
N
\ CI
0
CH3
N
NN ,N \11111,
0
CH3
IN1=/111 =
1 \
/
H3C 0
11
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MRL-LArn-uuu4o
0 OH
N
So 1 /
N
NriN CI
0
CH3
\N F
0
0
N F
N
Br
0
F F
F
NH
C
12
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MRL-1".1115-UW,1--1
F F
F
NH
CLN
o
F
NH
=
F N
N 1
N
H3C \\o
0
N 111 / 01
0
13
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\N 1101 F
0
/
B
N N
N F 3
/
N
0
1.11
N .F,
N , IP
N 0
14I I I
N CFHN43
0
Definitions
Examples of "halogen" include a fluorine atom, a chlorine atom, a bromine
atom, and an
iodine atom.
The term "C1-C 6alkyl" encompasses straight alkyl having a carbon number of 1
to 6 and
branched alkyl having a carbon number of 3 to 6. Specific examples thereof
include methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-
pentyl, isopentyl, neopentyl,
14
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MRL-vtdis-vut.m-
tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl,
n-hexyl, isohexyl,
1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-
dimethylbutyl, 2,2-
dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-
ethy1-2-
methylpropyl, 1-ethyl-1-methylpropyl, and the like.
"C3-C6cyc1oa1ky1" encompasses cycloalkyls having 3 to 6 carbons, foiniing one
or more
carbocyclic rings that are fused. "Cycloalkyl" also includes monocyclic rings
fused to an aryl
group in which the point of attachment is on the non-aromatic portion.
Examples of cycloalkyl
include cyclopropyl, cyclobutyl, cyelopentyl, cyclohexyl, cycloheptyl,
tetrahydronaphthyl,
decahydronaphthyl, indanyl and the like.
The term "-0C1-C 6alkyl " refers to an alkyl group having 1 to 6 carbons
linked to
oxygen, also known as an alkoxy group. Examples include methoxy, etboxy,
butoxy and
propoxy.
The term "-0C1-C 6alkylCOOH" refers to an alkoxy group having 1 to 6 carbons
substituted with a carboxylic acid (-COOH) group.
The term "halogen-substitutedCi-C6 alkyl" encompasses Ci-C6 alkyl with the
hydrogen
atoms thereof being partially or completely substituted with halogen, examples
thereof include
fluoromethyl, difluoromethyl, trifiuoromethyl, 2-fluoroethyl, 1,2-
difluoroethyl, 2,2-difiuoroethyl
and the like.
The term "-Ohalogen-substitutedC1-C6alkyl" means a -OCI-C6alkyl as defined
above,
which is substituted with 1-3 halogen atoms which are identical or different,
and specifically
includes, for example, a trifluoromethoxy group.
The tent! "-COC1-C6alkyl" means groups having Ci-C6alkyl bonded to carbonyl,
and
encompasses alkylcarbonyl having a carbon number of 1 to 6. Specific examples
thereof include
acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and the
like.
The term "-COhalogen-substitutedC1-C6a1ky1" means a -COCI-C6alkyl as defined
above,
which is substituted with 1-3 halogen atoms which are identical or different.
The tem! "Ci-C6alkylOH" means a C1-C6alkyl substituted with a hydroxyl group (-
OH),
also known as an alcohol. Examples include methanol, propanol, butanol and t-
butanol.
The term "C1-C6a1kylCN" means a C1-C6alkyl substituted with an cyano group (-
CN).
The term "halogen-substituted Ci-C6alkylOH" means a halogen-substituedC1-
C6alkyl
substituted with an alcohol (-OH).
The term "COOCI-C6alkyl" means a -COOH group wherein the ¨OH is replaced with
an
alkoxy group as defined above. Examples include methoxycarbonyl,
ethoxycarbonyl and
butoxycarbonyl.
The term "SO2C1-C6alkyl" means a group having Ci-C6alkyl bonded to sulfonyl (-
SO2-).
Specific examples thereof include methanesulfonyl, ethanesulfonyl, n-
propanesulfonyl,
isopropanesulfonyl, n-butanesulfonyl, sec-butanesulfonyl, tert-butanesulfonyl,
and the like.
15
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Wf.)
The term "oxo" means the functional group "=0", such as, for example, (1)
"C=(0)", that
is a carbonyl group; (2) "S=(0)", that is, a sulfoxide group; and (3) "N=(0)",
that is, an N-oxide
group, such as pyridyl-N-oxide.
The term "NHCI-C6alkyl" means a group with one of the hydrogen atoms of amino
(-
NH2) being substituted with a CI_C6alkyl group. Specific examples thereof
include methylamino,
ethylamino, n-propylamino, isopropylarnino, n-butylamino, sec-butylamino, tert-
butyla.mino, and
the like.
The tem' "N(CI-C6alky1)2" means a group with the two amino hydrogen atoms each
being substituted with a C1.C6alkyl group. Specific examples thereof include
dimethylamino,
diethylamino, ethylmethylamino, di(n-propyeamino, methyl(n-propyl)amino,
diisopropylamino,
and the like.
The term "NHCO2C i-C6alkyl" means a group with one of the amino hydrogen atoms
being substituted with C1_C6 alkoxycarbonyl and encompasses
alkoxycarbonylamino having a
carbon number of 1 to 6. Specific examples thereof include
methoxycarbonylamino,
ethoxycarbonylamino, n-propyloxycarbonylamino, isopropyloxycarbonylamino, n-
butoxycarbonylamino, isobutoxycarbonylamino, tert-butoxycarbonylamino, n-
pentyloxycarbonylamino, and the like.
The term "NHCOCI-Coalkyl" means a group with one of the amino hydrogen atoms
being substituted with C1.C6 alkylcarbonyl. Specific examples thereof include
acetylamino,
propionylamino, isobutyryl amino, valerylamino, isovalerylamino,
pivaloylamino, and the like.
The term "CONHCI-C6alkyl" means a group with one of the hydrogen atoms of
carbamoyl (-CONH2) being substituted with C1,C6alkyl. Specific examples
thereof include
methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, n-
butylcarbamoyl,
sec-butylearbamoyl, tert-butylcarbamoyl, and the like.
The term "CON(Ci-C6alkyl)2" means a group with the two carbamoyl hydrogen
atoms
each being substituted with CI_C6alkyl. Specific examples thereof include
dimethylcarbamoyl,
diethylcarbamoyl, ethylmethylcarbamoyl, di(n-propyl)carbamoyl, methyl(n-
propyl)carbamoyl,
diisopropylcarbamoyl, and the like.
The term "NHSO2CI-Csalkyl" means a group with one of the amino hydrogen atoms
being substituted with Cl_C6 alkylsulfonyl. Specific examples thereof include
methanesulfonylamino, ethanesulfonylamino, n-propanesulfonylamino,
isopropanesulfonylamino, n-butanesulfonylamino, sec-butanesulfonylamino, tert-
butanesulfonylamino, and the like.
Examples of "aryl" include phenyl, naphthyl, tolyl, and the like.
The term "heteroaryl" means 5-membered or 6-membered monocyclic heteroaryl
containing one or more, preferably one to three, same or different heteroatoms
selected from the
group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, or
otherwise means
condensed-ring heteroaryl formed by condensation of such monocyclic heteroaryl
and the above-
16
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mentioned heteroaryl or alternatively by mutual condensation of the same or
different
monocyclic heteroaryl groups. Examples thereof include pyrrolyl, furyl,
thienyl, imidazolyl,
pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl,
tetrazolyl, oxadiazolyl, 1,2,3-
thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl,
1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl,
benzimidazolyl,
benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,
benzisothiazolyl, indazolyl,
purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalitayl,
quinazolinyl,
cinnolinyl, pteridinyl, pyrido[3,2-b]pyridyl, and the like.
"Cycloheteroalkyl" means mono- or bicyclic or bridged saturated rings
containing at least
one hetero atom selected from N, S and 0, each of said ring having from 3 to
10 atoms in which
the point of attachment may be carbon or nitrogen. The term also includes
monocyclic
heterocycle fused to an aryl or heteroaryl group in which the point of
attachment is on the non-
aromatic portion. Examples of "cycloheteroalkyl" include tetrahydropyranyl,
tetrahydrofuranyl,
pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-
dihydrofuro(2,3-b)pyridyl,
benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolinyl, benzoxazepinyl,
5,6-
dihydroimidazo[2,1-b]thiazolyl, tetrahydroquinolinyl, morpholinyl,
tetrahydroisoquinolinyl,
dihydroindolyl, and the like. The term also includes partially unsaturated
monocyclic rings that
are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or N-
substituted-(1H,
3I-1)-pyrimidine-2,4-diones (N-substituted uracils). The term also includes
bridged rings such as
5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-
azabicyclo[2.2.1]heptyl, 7-
azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 2-
azabicyclo[2.2.2]octyl, and 3-
azabicyclo[3.2.2]nonyl, and azabicyclo[2.2.1]heptanyl. The cycloheteroalkyl
ring may be
substituted on the ring carbons and/or the ring nitrogens.
The term "cycloheteroalkylCOOH" refers to a cycloheteroalkyl, as defined
above,
substituted with a carboxylic group (-COOH).
C1-C6alky1C3-Ci0cycloalkyl, CE-C6alkylaryl, C1-C6alkylheteroaryl and C1-
C6alkylcycloheteroalkyl refer to a C1-C6alkylgroup substituted with a C3-
C10cycloalkyl, aryl,
heteroaryl and cycloheteroalkyl, as defined above.
The term "pharmaceutically acceptable salt" refers to salts prepared from
pharmaceutically acceptable non-toxic bases or acids including inorganic or
organic bases and
inorganic or organic acids. Salts of basic compounds encompassed within the
tem'
"pharmaceutically acceptable salt" refer to non-toxic salts of the compounds
of this invention
which are generally prepared by reacting the free base with a suitable organic
or inorganic acid.
Representative salts of basic compounds of the present invention include, but
are not limited to,
the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,
bitartrate, borate,
bromide, camsylate, carbonate, chloride, clavulanate, citrate,
dihydrochloride, edetate, edisylate,
estolate, esylate, fumarate, gluceptate, gluconate, glutamate,
glycollylarsanilate, hexylresorcinate,
hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,
isothionate, lactate,
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mRt..,-LA.n.5-vut
lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide,
methylnitrate,
methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt,
oleate, oxalate,
pamoate (embonate), palmitaie, pantothenate, phosphate/diphosphate,
polygalacturonate,
salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate,
teoclate, tosylate, triethiodide
and valerate. Furthermore, where the compounds of the invention carry an
acidic moiety,
suitable pharmaceutically acceptable salts thereof include, but are not
limited to, salts derived
from inorganic bases including aluminum, ammonium, calcium, copper, ferric,
ferrous, lithium,
magnesium, manganic, mangamous, potassium, sodium, zinc, and the like.
Particularly preferred
are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts
derived from
pharmaceutically acceptable organic non-toxic bases include salts of primary,
secondary, and
tertiary amines, cyclic amines, and basic ion-exchange resins, such as
arginine, betaine, caffeine,
choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-
dimethylaminoethanol, ethanolamine, ethylenediarnine, N-ethylmorpholine, N-
ethylpiperidine,
glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine,
morpholine, piperazine, piperidine, polyamine resins, procaine, purines,
theobromine,
triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
The compounds of the present invention contain one or more asymmetric centers
and can
thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric
mixtures, and
individual diastereomers. The present invention is meant to comprehend all
such isomeric forms
of these compounds.
Some of the compounds described herein contain olefinic double bonds, and
unless
specified otherwise, are meant to include both E and Z geometric isomers.
The independent syntheses of these diastereomers or their chromatographic
separations
may be achieved as known in the art by appropriate modification of the
methodology disclosed
herein. Their absolute stereochemistry may be determined by the X-ray
crystallography of
crystalline products or crystalline intermediates which are derivatized, if
necessary, with a
reagent containing an asymmetric center of known absolute configuration.
If desired, racemic mixtures of the compounds may be separated so that the
individual
enantiomers are isolated. The separation can be carried out by methods well
known in the art,
such as the coupling of a racemic mixture of compounds to an enantiomerically
pure compound
to form a diastereomeric mixture, followed by separation of the individual
diastereomers by
standard methods, such as fractional crystallization or chromatography. The
coupling reaction is
often the formation of salts using an enantiomerically pure acid or base. The
diasteromeric
derivatives may then be converted to the pure enantiomers by cleavage of the
added chiral
residue. The racemic mixture of the compounds can also be separated directly
by
chromatographic methods utilizing chiral stationary phases, which methods are
well known in
the art.
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Alternatively, any enantiomer of a compound may be obtained by stereoselective
synthesis using optically pure starting materials or reagents of known
configuration by methods
well known in the art.
It will be understood that, as used herein, references to the compounds of the
formulas
described herein are meant to also include the pharmaceutically acceptable
salts, and also salts
that are not pharmaceutically acceptable when they are used as precursors to
the free compounds
or their pharmaceutically acceptable salts or in other synthetic
manipulations.
Solvates, and in particular, the hydrates of the compounds of the formulas
described
herein are included in the present invention as well.
Some of the compounds described herein may exist as tautomers, which have
different
points of attachment of hydrogen accompanied by one or more double bond
shifts. For example,
a ketone and its enol form are keto-enol tautomers. The individual tautomers
as well as mixtures
thereof are encompassed with compounds of the present invention.
In the compounds of the formulas described herein, the atoms may exhibit their
natural
isotopic abundances, or one or more of the atoms may be artificially enriched
in a particular
isotope having the same atomic number, but an atomic mass or mass number
different from the
atomic mass or mass number predominantly found in nature. The present
invention is meant to
include all suitable isotopic variations of the compounds of the formulas
described herein. For
example, different isotopic forms of hydrogen (H) include protium (1H) and
deuterium (2H).
Protium is the predominant hydrogen isotope found in nature. Enriching for
deuterium may
afford certain therapeutic advantages, such as increasing in vivo half-life or
reducing dosage
requirements, or may provide a compound useful as a standard for
characterization of biological
samples. Isotopically-enriched compounds within generic formula can be
prepared without
undue experimentation by conventional techniques well known to those skilled
in the art or by
processes analogous to those described in the Schemes and Examples herein
using appropriate
isotopically-enriched reagents and/or intermediates.
Methods of Treatment
Also encompassed by the present invention are methods of treating DGAT1-
related
diseases. The compounds described herein are effective in preventing or
treating various
DGAT1-related diseases, such as metabolic diseases such as obesity, diabetes,
hormone secretion
disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases
such as angina pectoris,
acute/congestive cardiac insufficiency, myocardial infarction, coronary
arteriosclerosis,
hypertension, nephropathy, electrolyte abnoin ality, and the like; central and
peripheral nervous
system diseases such as bulimia, affective disorder, depression, anxiety,
epilepsy, delirium,
dementia, schizophrenia, attention deficit/hyperactivity disorder, dysmnesia,
somnipathy,
cognitive impairment, dyskinesia, dysesthesia, dysosrnia, morphine resistance,
drug dependence,
alcohol dependence, and the like; reproductive system diseases such as
infertility, premature
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-L'uo-vvv,EJ
delivery, sexual dysfunction, and the like; and other conditions including
digestive diseases,
respiratory diseases, cancer, and chromatosis. The compound of the invention
is especially
useful as a preventive or a remedy for obesity, diabetes, fatty liver,
bulimia, depression, or
anxiety.
One aspect of the invention described herein provides a method for the
treatment and
control of obesity or metabolic syndrome, which comprises administering to a
patient in need of
such treatment a therapeutically effective amount of a compound having the
formulas described
herein or a pharmaceutically acceptable salt thereof. For example, the
compounds described
herein are useful for treating or preventing obesity by administering to a
subject in need thereof a
composition comprising a compound of formula I or formula Ia.
Methods of treating or preventing obesity and conditions associated with
obesity refer to the
administration of the pharmaceutical formulations described herein to reduce
or maintain the body
weight of an obese subject or to reduce or maintain the body weight of an
individual at risk of becoming
obese. One outcome of treatment may be reducing the body weight of an obese
subject relative to that
subject's body weight immediately before the administration of the compounds
or combinations of the
present invention. Another outcome of treatment may be preventing body weight,
regain of body weight
previously lost as a result of diet, exercise, Or pharmacotherapy and
preventing weight gain from
cessation of smoking. Another outcome of treatment may be decreasing the
occurrence of and/or the
severity of obesity-related diseases. Yet another outcome of treatment may be
decreasing the risk of
developing diabetes in an overweight or obese subject. The treatment may
suitably result in a reduction
in food or calorie intake by the subject, including a reduction in total food
intake, or a reduction of intake
of specific components of the diet such as carbohydrates or fats; and/or the
inhibition of nutrient
absorption; and/or the inhibition of the reduction of metabolic rate; and in
weight reduction in patients in
need thereof. The treatment may also result in an alteration of metabolic
rate, such as an increase in
metabolic rate, rather than or in addition to an inhibition of the reduction
of metabolic rate; and/or in
minimization of the metabolic resistance that normally results from weight
loss.
Prevention of obesity and obesity-related disorders refers to the=
administration of the
pharmaceutical formulations described herein to reduce or maintain the body
weight of a subject
at risk of obesity. One outcome of prevention may be reducing the body weight
of a subject at
risk of obesity relative to that subject's body weight immediately before the
administration of the
compounds or combinations of the present invention. Another outcome of
prevention may be
preventing body weight regain of body weight previously lost as a result of
diet, exercise, or
pharmacotherapy. Another outcome of prevention may be preventing obesity from
occurring if
the treatment is administered prior to the onset of obesity in a subject at
risk of obesity. Another
outcome of prevention may be decreasing the occurrence and/or severity of
obesity-related
disorders if the treatment is administered prior to the onset of obesity in a
subject at risk of
obesity. Moreover, if treatment is commenced in already obese subjects, such
treatment may
prevent the occurrence, progression or severity of obesity-related disorders,
such as, but not
20
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rviru..-LA_PLI-UUW4)
limited to, arteriosclerosis, type 2 diabetes, polycystic ovary disease,
cardiovascular diseases,
osteoarthritis, dermatological disorders, hypertension, insulin resistance,
hypercholesterolemia,
hypertriglyceridemia, and cholelithiasis.
Another aspect of the invention that is of interest relates to a method of
treating
hyperglycemia, diabetes or insulin resistance in a mammalian patient in need
of such treatment
which comprises administering to said patient a compound in accordance with
the formulas
described herein or a pharmaceutically acceptable salt thereof in an amount
that is effective to
treat hyperglycemia, diabetes or insulin resistance.
More particularly, another aspect of the invention that is of interest relates
to a method of
treating type 2 diabetes in a mammalian patient in need of such treatment
comprising
administering to the patient a compound in accordance with the formulas
described herein or a
pharmaceutically acceptable salt thereof in an amount that is effective to
treat type 2 diabetes.
Yet another aspect of the invention that is of interest relates to a method of
treating non-
insulin dependent diabetes mellitus in a mammalian patient in need of such
treatment comprising
administering to the patient a compound in accordance with the formulas
described herein or a
pharmaceutically acceptable salt thereof in an amount that is effective to
treat non-insulin
dependent diabetes mellitus.
The present invention is also directed to the use of a compound of formula I
or formula Ia
in the manufacture of a medicament for use in treating various DGATI -related
diseases, such as
metabolic diseases such as obesity, diabetes, hormone secretion disorder,
hyperlipemia, gout,
fatty liver, and the like; circulatory diseases such as angina pectoris,
acute/congestive cardiac
insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension,
nephropathy,
electrolyte abnormality, and the like; central and peripheral nervous system
diseases such as
bulimia, affective disorder, depression, anxiety, epilepsy, delirium,
dementia, schizophrenia,
attention deficit/hyperactivity disorder, dystnnesia, somnipathy, cognitive
impairment,
dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence,
alcohol dependence,
and the like; reproductive system diseases such as infertility, premature
delivery, sexual
dysfunction, and the like; and other conditions including digestive diseases,
respiratory diseases,
cancer, and chromatosis. The compounds described herein are especially useful
as a preventive
or a remedy for obesity, diabetes, fatty liver, bulimia, depression, or
anxiety.
For example, the present invention is directed to the use of a compound of
formula I or
formula Ia in the manufacture of a medicament for use in treating obesity,
diabetes, hoinione
secretion disorder, hyperlipemia, gout and fatty liver.
Additionally, the present invention is directed to the use of a compound of
formula I or
formula Ia in the manufacture of a medicament for use in treating obesity.
Pharmaceutical Compositions
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-.1JULI-VIJUg D
Compounds of the invention may be administered orally or parenterally. As
formulated
into a dosage foim suitable for the administration route, the compound of the
invention can be
used as a pharmaceutical composition for the prevention, treatment, or remedy
of the above
diseases.
In clinical use of the compound of the invention, usually, the compound is
formulated into
various preparations together with pharmaceutically acceptable additives
according to the dosage form,
and may then be administered. By "pharmaceutically acceptable" it is meant the
additive, carrier, diluent
or excipient must be compatible with the other ingredients of the formulation
and not deleterious to the
recipient thereof. As such additives, various additives ordinarily used in the
field of pharmaceutical
preparations are usable. Specific examples thereof include gelatin, lactose,
sucrose, titanium oxide,
starch, crystalline cellulose, hydroxypropyl methylcellulose,
carboxymethylcellulose, corn starch,
microcrystalline wax, white petrolatum, magnesium metasilicate aluminate,
anhydrous calcium
phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol,
sorbitan fatty acid ester,
polysorbate, sucrose fatty acid ester, polyoxyethylene, hardened castor oil,
polyvinylpyrrolidone,
magnesium stearate, light silicic acid anhydride, talc, vegetable oil, benzyl
alcohol, gum arabic,
propylene glycol, polyalkylene glycol, cyclodextrin, hydroxypropyl
cyclodextrin, and the like.
Preparations to be formed with those additives include, for example, solid
preparations such as
tablets, capsules, granules, powders, suppositories; and liquid preparations
such as syrups, elixirs,
injections. These may be formulated according to conventional methods known in
the field of
pharmaceutical preparations. The liquid preparations may also be in such a
form that may be dissolved
or suspended in water or in any other suitable medium in their use. Especially
for injections, if desired,
the preparations may be dissolved or suspended in physiological saline or
glucose liquid, and a buffer or
a preservative may be optionally added thereto.
The pharmaceutical compositions may contain the compound of the invention in
an amount of
from 1 to 99.9 % by weight, preferably from 1 to 60 % by weight of the
composition. The compositions
may further contain any other therapeutically-effective compounds.
In case where the compounds of the invention are used for prevention or
treatment for the above-
mentioned diseases, the dose and the dosing frequency may be varied, depending
on the sex, the age, the
body weight and the disease condition of the patient and on the type and the
range of the intended
remedial effect. In general, when orally administered, the dose may be from
0.001 to 50 mg/kg of body
weight/day, and it may be administered at a time or in several times. The dose
is preferably from about
0.01 to about 25 mg/kg/day, more preferably from about 0.05 to about 10
mg/kg/day. For oral
administration, the compositions are preferably provided in the form of
tablets or capsules containing
from 0.01 mg to 1,000 mg, preferably 0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5,
10, 15, 20, 25, 30, 40, 50, 75,
100, 125, 150, 175, 200, 225, 250, 500, 750, 850 and 1,000 milligrams of a
compound described herein.
This dosage regimen may be adjusted to provide the optimal therapeutic
response.
Combination Therapy
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MRL-vvt
The compounds of the present invention are further useful in methods for the
prevention or treatment of
the aforementioned diseases, disorders and conditions in combination with
other therapeutic agents.
The compounds of the present invention may be used in combination with one or
more other drugs in the
treatment, prevention, suppression or amelioration of diseases or conditions
for which compounds of formula I or
formula Ia or the other drugs may have utility, where the combination of the
drugs together are safer or more
effective than either drug alone. Such other drug(s) may be administered, by a
route and in an amount commonly
used therefor, contemporaneously or sequentially with a compound of formula I
or formula Ia. When a
compound of formula I or formula Ia is used contemporaneously with one or more
other drugs, a pharmaceutical
composition in unit dosage form containing such other drugs and the compound
of formula I or formula Ia is
preferred. However, the combination therapy may also include therapies in
which the compound of formula I or
formula Ia and one or more other drugs are administered on different
overlapping schedules. It is also
contemplated that when used in combination with one or more other active
ingredients, the compounds of the
present invention and the other active ingredients may be used in lower doses
than when each is used singly.
Accordingly, the pharmaceutical compositions of the present invention include
those that contain one or more
other active ingredients, in addition to a compound of formula I or formula
Ia.
Examples of other active ingredients that may be administered in combination
with a compound of
formula I or formula Ia, and either administered separately or in the same
pharmaceutical composition, include,
but are not limited to:
(1) dipeptidyl peptidase-IV (DPP-4) inhibitors;
(2) insulin sensitizers, including (i) PPARy agonists, such as the glitazones
(e.g. pioglitazone,
rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PPAR
ligands, including (1) PPARa/y
dual agonists, such as muraglitazar, aleglitazar, sodelglitazar, and
naveglitazar, (2) PPARa agonists, such as
fenofibric acid derivatives (geinfibrozil, clofibrate, ciprofibrate,
fenofibrate and bezafibrate), (3) selective PPARy
modulators (SPPARyM's), such as those disclosed in WO 02/060388, WO 02/08188,
WO 2004/019869, WO
2004/020409, WO 2004/020408, and WO 2004/066963, and (4) PPARy. partial
agonists; (ii) biguanides, such as
metformin and its pharmaceutically acceptable salts, in particular, metformin
hydrochloride, and extended
release formulations thereof, such as Glumetza , Fortamete, and GlucophageXR ;
(iii) protein tyrosine
phosphatase- I B (PTP- B) inhibitors;
(3) insulin or insulin analogs, such as insulin lispro, insulin detemir,
insulin glargine, insulin glulisine,
and inhalable formulations of each thereof;
(4) leptin and leptin derivatives and agonists;
(5) amylin and amylin analogs, such as pramlintide;
(6) sulfonylurea and non-sulfonylurea insulin secretagogues, such as
tolbutamide, glyburide, glipizide,
glirnepiride, mitiglinide, and meglitinides, such as nateglinide and
repaglinide;
(7) a-glucosidase inhibitors (such as acarbose, voglibose and miglitol);
(8) glucagon receptor antagonists, such as those disclosed in WO 98/04528, WO
99/01423, WO
00/39088, and WO 00/69810;
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(9) incretin naimetics, such as GLP-1, GLP-1 analogs, derivatives, and
mirnetics; and GLP-1 receptor
agonists, such as exenatide, liraglutide, taspoglutide, AVE0010, CJC-1131, and
BIM-51077, including intranasal,
transdermal, and once-weekly formulations thereof;
(10) LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors
(lovastatin, simvastatin,
pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and
rosuvastatin), (ii) bile acid sequestering agents
(such as cholestyramine, colestimide, colesevelam hydrochloride, colestipol,
and dialkylaminoalkyl derivatives of
a cross-linked dextran, (iii) inhibitors of cholesterol absorption, such as
ezetimibe, and (iv) acyl CoA:cholesterol
acyltransferase inhibitors, such as avasimibe;
(11) HDL-raising drugs, such as niacin or a salt thereof and extended-release
versions thereof; MK-
524A, which is a combination of niacin extended-release and the DP-1
antagonist MK-524; and nicotinic acid
receptor agonists;
(12) antiobesity compounds;
(13) agents intended for use in inflammatory conditions, such as aspirin, non-
steroidal anti-inflammatory
drugs (NSArDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2)
inhibitors;
(14) antihypertensive agents, such as ACE inhibitors (such as enalapril,
lisinopril, rarnipril, captopril,
quinapril, and tandolapril), A-II receptor blockers (such as losartan,
candesaitan, irbesartan, olmesartan
medoxornil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as
aliskiren), beta blockers (such as and
calcium channel blockers (such as;
(15) glucokinase activators (GKAs), such as LY2599506;
(16) inhibitors of 1113-hydroxysteroid dehydrogenase type 1, such as those
disclosed in U.S, Patent No.
6,730,690; WO 03/104207; and WO 04/058741;
(17) inhibitors of cholesteryl ester transfer protein (CETP), such as
torcetrapib and MK-0859;
(18) inhibitors of fructose 1,6-bisphosphatase, such as those disclosed in
U.S. Patent Nos. 6,054,587;
6,110,903; 6,284,748; 6,399,782; and 6,489,476;
(19) inhibitors of acetyl CoA carboxylase-1 or 2 (ACCI or ACC2);
(20) AMP-activated Protein Kinase (AMPK) activators;
(21) agonists of the G-protein-coupled receptors: GPR-109, GPR-119, and GPR-
40;
(22) SSTR3 antagonists, such as those disclosed in WO 2009/011836;
(23) neurornedin U receptor agonists, such as those disclosed in
W02009/042053, including, but not
limited to, neurornedin S (NMS);
(24) inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD);
(25) GPR-105 antagonists, such as those disclosed in WO 2009/000087;
(26) inhibitors of glucose uptake, such as sodium-glucose transporter (SGLT)
inhibitors and its various
isofonns, such as SGLT-1; SGLT-2, such as dapagliflozin and remogliflozin; and
SGLT-3;
(27) inhibitors of acyl coenzyme A:diacylglycerol acyltransferase 1 and 2
(DGAT-1 and DGAT-2);
(28) inhibitors of fatty acid synthase;
(29) inhibitors of acyl coenzyme A:monoacylglycerol acyltransferase 1 and 2
(MGAT-1 and MGAT-2);
24
CA 02805078 2013-01-10
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L-V2012/015693
(30) agonists of the TGR5 receptor (also known as GPBAR1, B037, GPCR19,
GPR131, and M-BAR);
and
(31) bromocriptine mesylate and rapid-release formulations thereof.
Dipeptidyl peptidase-IV (DPP-4) inhibitors that can be used in combination
with compounds of formula
I or formula Ia include, but are not limited to, sitagliptin (disclosed in US
Patent No. 6,699,871), vildagliptin,
saxagliptin, aloglipti , denagliptin, cannegliptin, dutogliptin, melogliptin,
linagliptin, and pharmaceutically
acceptable salts thereof, and fixed-dose combinations of these compounds with
metformin hydrochloride,
pioglitazone, rosiglitazone, simvastatin, atorvastatin, or a sulfonylurea.
Other dipeptidyl peptidase-IV (DPP-4) inhibitors that can be used in
combination with compounds of
formula I or formula Ia include, but are not limited to:
(2R,35,5R)-5-(1 -methyl-4,6-dihydropyrrolo [3 ,4-c]pyrazol-5( 1H)-y1)-2-(2,4,5
-
trifluorophenyl)tetrahydro-21/-pyran-3-amine;
(2R,3S,5R)-5-(1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-y1)-2-(2,4,5-
trifluorophenyl)tetrahydro-2H-pyran-3-amine;
(2R,3S,5R)-2-(2,5-difluorophenyptetrahydro)-5-(4,6-dihydropyrrolo[3,4-
elpyrazol-5(1H)-y1)
tetrahydro-2H-pyran-3-amine;
(3R)-4-[(3R)-3 -amin o-4-(2,4,5-trifluoropb enyl)butanoy1]-hexahydro-3-methy1-
2H-1,4-di azep in-2-one;
44(3R)-3-amino-4-(2,5-difluorophenyl)butanoylihexahydro-l-methyl-2H-1,4-
diazepin-2-one
hydrochloride; and
(3R)-4-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyli-hexahydro-3-(2,2,2-
trifluoroethyl)-2H-1,4-diazepin-2-
one; and
pharmaceutically acceptable salts thereof.
Antiobesity compounds that can be combined with compounds of formula I or
formula Ia include
topirainate; zonisamide; naltrexone; phentermine; bupropion; the combination
of bupropion and naltrexone; the
combination of bupropion and zonisamide; the combination of topiramate and
phentennine; fenfluramine;
dexfenfluramine; sibutramine; lipase inhibitors, such as orlistat and
cetilistat; melanocortin receptor agonists, in
particular, melanocortin-4 receptor agonists; CCK-1 agonists; melanin-
concentrating hormone (MCH) receptor
antagonists; neuropeptide Yi or Y5 antagonists (such as MK-0557); CBI receptor
inverse agonists and
antagonists (such as rimonabant and taranabani); 133 adrenergic receptor
agonists; ghrelin antagonists; bombesin
receptor agonists (such as bombesin receptor subtype-3 agonists); and 5-
hydroxytryptamine-2c (5-HT2c)
agonists, such as lorcaserin. For a review of anti-obesity compounds that can
be combined with compounds of
the present invention, see S. Chaki et al., "Recent advances in feeding
suppressing agents: potential therapeutic
strategy for the treatment of obesity," Expert Op in. Ther. Patents, 11: 1677-
1692 (2001); D. Spanswick and K.
Lee, "Emerging antiobesity drugs," Expert Ooin. Emerging Drugs, 8: 217-237
(2003); J.A. Fernandez-Lopez, et
al., "Pharmacological Approaches for the Treatment of Obesity," Drugs, 62: 915-
944 (2002); and K.M. Gacide, et
al., "Combination pharmaceutical therapies for obesity," Exp. Opin.
Pharmacother., 10: 921-925 (2009).
Glucagon receptor antagonists that can be used in combination with the
compounds of formula
or formula Ia include, but are not limited to:
25
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MRL-uub-vvv4)
N- [44(1 S) - 1- f 3-(3,5-dichloropheny1)-5- [6-(tri fluoromethoxy)-2-
naphthyl]- IH-pyrazo 1- 1-
yl}ethypbenzoy11-13-alanine;
N-[4-((1 R) 1- (3-(3,5-dichloropheny1)-5-[6-(trifluoromethoxy)-2-naphthyl]-1H-
pyrazol-1-
y1}ethyl)benzoyll-P-alanine;
N-(4- { 1- [3 -(2,5-dichloropheny1)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-
yllethyllbenzoy1)-3-
alanine;
N-(4-1( I S) - 1 4343 ,5-dichloropheny1)-5-(6-methoxy-2-naphthyl)- 1H-pyrazol-
1-yliethyllbenzoy1)-13-
alanine;
N-(4- {( 1 S)-1 -{(R)-(4-chlorophenyl)(7-fluoro-5-methyl- -
ypinethylibutyllbenzoy1)-13-alanine;
and
N-(4- {(1S)-1-[(4-chlorophenyl)(6-chloro-8-methylquinolin-4-
yOmethylibutyllbenzoy1)-13-alanine; and
pharmaceutically acceptable salts thereof.
Inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) that can be used in
combination with
the compounds of formula I or formula Ia include, but are not limited to:
[5-(5-{442-(trifluorotnethyl)phenoxyipiperidin-1-y1}-1,3,4-thiadiazol-2 -y1)-
2H-tetrazol-2-
yliacetic acid;
(2'- 4[2-(trifluoromethyl)phenoxy]piperidin- 1 -yl -2,5t-bi- 1 ,3 -thiazol-4-
y1)acetic acid;
(5- {3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yllisoxazol-5-y1}-2H-tetrazol-2-
ypacetic acid;
(3- {3 44-(2-bromo-5-fluorophenoxy)piperidin- 1 -yli - 1 ,2,4-oxadiazol-5-y1} -
1 H-pyrrol- 1 -yl)acetic
acid;
(5- {5- [4-(2-bromo-5-fluorophenoxy)piperidin- 1-yljpyrazin-2-y1}-2H-tetrazol-
2-ypacetic acid; and
(5- (244-(5-bromo-2-chlorophenoxy)piperidin-1-Apyrimidin-5-y1}-2H-tetrazol-2-
y1)acetic acid;
and pharmaceutically acceptable salts thereof.
Glueokinase activators that can be used in combination with the compounds of
formula I
or formula Ia include, but are not limited to:
3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-rnethyl-ethoxy)-N-(1-methy1-
1H-pyrazol-3-
y1)benzamide;
5-(2-hydroxy-l-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-
1H-pyrazol-3-
yl)benzamide;
5-(1-hydroxymethyl-propoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-
11-1-pyrazol-3-
yebenzamide;
3-(6-methanesulfonylpyridin-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(1-methy1-
1H-pyrazo1-3-
y1)benzamide;
5-isopropoxy-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-
yl)benzamide;
5-(2-fluoro- 1 -f1uoromethyl-ethoxy)-3 -(6-methanesulfonylpyridin-3-yloxy)-N-(
I -methy1-1H-pyrazol-3-
yl)benzamide;
3-({4-[2-(dimethylamino)ethoxy]phenyllthio)-N-(3-methyl-1,2,4-thiadiazol-5-y1)-
6-[(4-methy1-4H-1,2,4-
triazol-3-yl)thio]pyridine-2-carboxamide;
26
WO 2012/015693 CA 02805078 2013-01-10PCT/US2011/045022
3-(14-[(1-methylazetidin-3-yfloxyiphenyl}thio)-N-(3-methy1-1,2,4-thiadiazol-5-
y1)-6-[(4-methyl-4H-
1,2,4-triazol-3-y1)thiolpyridine-2-carboxamide;
N-(3-methyl-1,2,4-thiadiazol-5-y1)-6-[(4-methyl-4H-1,2,4-triazol-3-y1)thio]-3-
1 [4-(2-pyrrol idin-l-
ylethoxy)phenyl]ihio}pyridine-2-carboxamide; and
3-[(4-{ 2- [(2R)-2-rnethylpyrrolidin-l-yl] ethoxy} phenyl)thio-N-(3-methyl- 1
,2,4-thiadiazol-5-y1)-6-[(4-
methyl-4H- 1 ,2,44riazo 1-3 -yethio]pyridine-2-carboxamide; and
pharmaceutically acceptable salts
thereof.
Agonists of the GPR-119 receptor that can be used in combination with the
compounds of formula I or
formula Ia include, but are not limited to:
rac-cis 5-chloro-2-1442-(2-{[5-(methylsulfonyl)pyridin-2-
yl]oxylethypcyclopropyll piperidin-1-y1}pyrimidine;
5-chloro-2- {4-[(1R,2S)-2-(2- { [5-(methylsulfonyppyridin-2-yl]oxy}
ethyl)cyclopropyllpiperidin- 1 -
yl}pyrimidine;
rac cis-5 -thloro-244-(2- {2- [4-(methylsulfonyl)phenoxy]ethyl
cyclopropyl)piperidin- 1-
yl]pyrimidine;
5-chloro-2-[4-((lS,2R)-2-{2-[4-(methylsulfonyl)phenoxylethyl}cyclopropyl)
piperidin-l-
yl]pyrimidine;
5-chloro-2-[441R,2S)-2-{2-[4-(methylsulfonyl)phenoxy]ethyl} cyclopropyl)
piperidin-1-
Apyrimidine;
rac cis-5-chloro-2-[4-(2- {2[3-(methylsulfonyl)phenoxy] ethyl }
cyclopropyppiperidin-1 -ylipyrimidine;
and
rac cis -5-chloro-2-[4-(2-{2-[3-(5-methy1-1,3,4-oxadiazol-2-
ypphenoxylethyl}cyclopropyl) piperid in-1-
yllpyrirnidine; and pharmaceutically acceptable salts thereof.
Selective PPARy modulators (SPPARyM's) that can be used in combination with
the compounds of
formula I or formula La include, but are not limited to:
(2,5)-2-({6-chloro-346-(4-chlorophenoxy)-2-propylpyridin-3-y1]-1,2-
benzisoxazo1-5-yl}oxy)propanoic
acid;
(251-2-({6-chloro-346-(4-fluorophenoxy)-2-propylpyridin-3-y1]-1,2-benzisoxazol-
5-yl}oxy)propanoic
acid;
(28)-2- {[6-chloro-3-(6-phenoxy-2-propylpyridin-3-y1)-1,2-benzisoxazol-5-
ylloxy}propanoic acid;
(2R)-2-({6-chloro-346-(4-chlorophenoxy)-2-propylpyridin-3-y1]-1,2-benzisoxazol-
5-ylloxy)propanoic
acid;
(2R)-2-{3-[3-(4-methoxy)benzoy1-2-methy1-6-(trifluoromethoxy)-1H-indol-1-
yl]phenoxylbutanoic acid;
(2S)-2-{3-[3-(4-methoxy)benzoy1-2-methy1-6-(trifluoromethoxy)-1H-indol-1-
yl]phenoxylbutanoic acid;
2- { 3 43 -(4-methoxy)benzoy1-2-methyl-6-(tri flu oromethoxy)- 1H-indol- 1 -
yljphenoxy} -2-
methylpropanoic acid; and
27
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2013-01-10 PCT/US2011/045022
(2R)-2-13-[3-(4-chloro)benzoy1-2-methy1-6-(trifluoromethoxy)-1H-indol-1-
y1]phenoxy]propanoic acid; and pharmaceutically acceptable salts thereof.
Inhibitors of 1113-hydroxysteroid dehydrogenase type 1 that can be used in
combination
with the compounds of formula I or formula Ia include, but are not limited to:
341 -(4-chloropheny1)-trans-3 -fluorocyclobutyl] -4,5-dicyclopropyl-r-4H- 1
,2,4-triazole ; 3 - [1 -(4-
chlorophenyI)-trans-3 -fluorocyclobuty1]-4-cyclopropy1-5 -(1 -
methylcyclopropy1)-r-4H-1,2,4-
triazole;
3-[1-(4-chloropheny1)-trans-3-fluorocyclobutyl]-4-methyl-5-[2-
(trifluoromethoxy)phenyl]-r-4H-
1,2,4-triazole;
3 - [1 -(4-chlorophenyl)cyclobuty1]-4-methy1-5 [2-(trifluoromethyl)phenyl]-4H-
I ,2,4-triazole;
3- {4- [3 -(ethylsulfonyl)propyl]bicyclo [2.2.2] oct- 1-y1 -4-methyl- 5 - [2-
(trifluoromethyl)pheny1]-411
-1,2,4-triazole;
4-methyl-3 - {4- [4-(methylsulfonyl)phenyl]bicyclo [2.2.2] oct- 1 -yll -5- [2-
(trifluoromethyl)phenyl] -
4H- 1 ,2,4-triazo le ;
3 -(4- {4-methy1-542-(tritluoromethypphenyl]-4H-1,2,4-triazol-3-y1) bicyclo
[2.2.2]4)ot-1-y1)-5 -(3,3,3 -
trifluoropropy1)- 1,2,4-oxadiazole;
3-(4-14-methy1-542-(trifluoromethyl)pbenyli-4H-1,2,4-triazol-3-
yllbicyclo[2.2.2]oct-1-y1)-5-(3,3,3-
trifluoroethyl)-1 ,2,4-oxadiazole;
543 ,3-difluorocyclobuty1)-3-(4- {4-metby1-5-[2-(trifluoromethyl)phenyl]-4H-
1,2,4-triazol-3-
ylIbicyclo[2 .2.2]oct- 1 -y1)-1,2,4-oxadiazole;
5-(1 -fluoro-l-rnethylethyl)-3-(4- (4-methy1-542-(trifluoromethyl)pheny11-4H-
1,2,4-triazol-3-
y1 bicyclo [2.2 .2]oct-1 -y1)-1,2,4-oxadiazole;
2-( i ,1 -difluoroethyl)-5-(4- 4-methyl-5[2-(trifluoromethyl)phenyli -4H-1,2,4-
triazol-3-
yl } bicyclo[2 .2.2]oct- 1 -y1)-1,3 ,4-oxadiazole;
2-(3 ,3 -difluorocyclobuty1)-5 -(4- {4-methy1-542-(trifluoromethyl)phenyll-4H-
1,2,4-triazol-3-
ylIbicyclo[2 .2.2] oct- 1 -y1)-1,3 ,4-oxadiazole; and
5-( 1, 1 -difluoroethyl)-3-(4-14-methyl-5-[2-(trifluoromethypphenyl]-41/-1,2,4-
triazol-3-
y1) bicyclo[2.2.2]oct- 1 -y1)-1,2,4-oxadiazole; and pharmaceutically
acceptable salts thereof.
Somatostatin subtype receptor 3 (SSTR3) antagonists that can be used in
combination
with the compounds of formula I or formula Ia include, but are not limited to:
HN
HN
NH
NHo'L N N
/NN / 0 N¨
N¨N / 0 0N¨H
28
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MRL-vuts-vuu4D
HN \ ¨ HN \ ¨
,,.\\\L-------N\ / F \ / F
N = N =
I NH NH
OP N N
H N H N
----- \ .---- \
-----. N¨ ----- N
",----N % /NN
-------/ 0 0
,
HN \ ¨ HN \ ¨
,
NH N \ / F N N
AL--:.-,õ 1 NH
1101 N 40 N
H H õ..._.N
.---- F4 \ ( \
------ N --' \
/ 0
/NN --- \O-0 ---i N\ ------(
0 , 0 ,
and
F
/ \
--N
N \
N \
111 1 H
I
NH
N
H 0
N
\ I > 0
/
11 I/ --- N>
/
¨0 I ;
and pharmaceutically acceptable salts thereof.
AMP-activated Protein Kinase (AMPK) activators that can be used in combination
with the compounds
of formula I or formula ía include, but are not limited to:
ill
1001HO 0
0 N)¨ 0 14111 0 N)-0
CO2 H 110 CO2H
CI N CI N
H H
OH
Ae \--) E
N
11111 0 li \ 410 0 0 N)_,,, 0 41
CO2H CO2H
CI N CI N
H H
29
CA 02805078 2013-01-10
WO 2012/015693 PCT/US2011/045022
MRL-uub-vvv4)
0 OH
\
N
\ 40
0 N___.0 0 40 40 N)____0 4111
co,H CO2H
N N
Ci F
H H
7 7
F
\
N
4111
410 N) 0 I. \ 411 F
CO2H CO2H
N N
CI
H H F
7 7
H3C0 0 F CI
5N) 0 10
4111 )-o Si CO2H CO2H
N N
CI CI
H H
7 7
HO2C 0
A
1.CO2H 0 HO
0 N )_0 s N
CO2H is --Ci 141111
N
F H ci =
NH , and ,
and pharmaceutically acceptable salts thereof.
Inhibitors of acetyl-CoA carboxylase-1 and 2 (ACC-1 and ACC-2) that can be
used in combination with
the compounds of formula I or formula Ia include, but are not limited to:
3- { I'-[(1-cyclopropy1-4-methoxy-1H-indo1-6-yl)carbonyl]-4-o.xospiro[chrornan-
2,4'-piperidini-6-
ylIbenzoic acid;
5-(1'-[(1-cyclopropy1-4-methoxy-1H-indo1-6-yl)carbonyl]-4-oxospiro[chroinan-
2,4'-piperidinj-6-
yl} nicotinic acid;
1r[( 1-cyclopropy1-4-methoxy- 1H-indo1-6-yl)carbonyll-64 1H-tetrazol-5 -
yl)spiro [chroman-2,4'-piperidini -
4-one;
I'-[( 1 -cyclopropy1-4-ethoxy-3 -methyl- 1H-indo1-6-yl)carbonyl]-64 1 H-
tetrazol-5-y1)spiro[chroman-2,4'-
piperidin]-4-one; and
5-{1'-[(1-cyc1opropy1-4-rnethoxy-3-methy1-1H-indol-6-yl)carbony1]-4-oxo-
spiro[chrornan-2,4'-piperidin]-
6-yl}nicotinic acid; and
pharmaceutically acceptable salts thereof.
In another aspect of the invention, a pharmaceutical composition is disclosed
which comprises one or
more of the following agents:
(a) a compound of formula I or formula La;
30
mRL-LA.,15-uvuWO 2012/015693 ,+..=
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(b) one or more compounds selected from the group consisting of:
(I) dipeptidyl peptidase-Br (DPP-4) inhibitors;
(2) insulin sensitizers, including (i) PPARy agonists, such as the glitazones
(e.g. pioglitAzone,
rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PPAR
ligands, including (1) PPARa/y
, dual agonists, such as rnuraglitazar, aleglitazar, sodelglitazar, and
naveglitazar, (2) PPARa agonists, such as
fenofibric acid derivatives (gemfibrozil, cloflbrate, ciprofibrate,
fenofibrate and bezafibrate), (3) selective PPARy
modulators (SPPARyM's), and (4) PPARy partial agonists; (ii) biguanides, such
as metformin and its
pharmaceutically acceptable salts, in particular, metformin hydrochloride, and
extended-release formulations
thereof, such as Glumetza , Fortamet , and GlucophageXRe; (iii) protein
tyrosine phosphatase-1B (PTP-1B)
inhibitors;
(3) sulfonylurea and non-sulfonylurea insulin secretagogues, such as
tolbutamide, glyburide,
glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and
repaglinide;
(4) a-glucosidase inhibitors (such as acarbose, voglibose and miglitol);
(5) glueagon receptor antagonists;
(6) LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors
(lovastatin,
simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin,
pitavastatin, and rosuvastatin), (ii) bile acid
sequestering agents (such as cholestyramine, eolestimide, colesevelam
hydrochloride, colestipol, and
dialkylarninoalkyl derivatives of a cross-linked dextran, (iii) inhibitors of
cholesterol absorption, such as
ezetimibe, and (iv) acyl CoA:cholesterol acyltransferase inhibitors, such as
avasimibe;
(7) HDL-raising drugs, such as niacin or a salt thereof and extended-release
versions thereof;
MK-524A, which is a combination of niacin extended-release and the DP-1
antagonist MK-524; and nicotinic
acid receptor agonists;
(8) antiobesity compounds;
(9) agents intended for use in inflammatory conditions, such as aspirin, non-
steroidal anti-
inflammatory drugs (NSA1Ds), glueocorticoids, and selective cyclooxygenase-2
(COX-2) inhibitors;
(10) antihypertensive agents, such as ACE inhibitors (such as enalapril,
lisinopril, ramipril,
eaptopril, quinapril, and tandolapril), A-II receptor blockers (such as
losartan, candesartan, irbesartan, olmesartan
medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as
aliskiren), beta blockers (such as and
calcium channel blockers;
(11) glueokinase activators (GKAs), such as LY2599506;
(12) inhibitors of 1113-hydroxysteroid dehydrogenase type I;
(13) inhibitors of cholesteryl ester transfer protein (CETP), such as
toreetrapib and MK-0859;
(14) inhibitors of fructose 1,6-bisphosphatase;
(15) inhibitors of acetyl CoA carboxylase-1 or 2 (ACC I or ACC2);
(16) AMP-activated Protein Kinase (AMPK) activators;
(17) agonists of the G-protein-coupled receptors: GPR-I 09, GPR-119, and GPR-
40;
(18) SSTR3 antagonists;
(19) neuromedin U receptor agonists, including, but not limited to, neuromedin
S (NMS);
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02805078 2013-01-10
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(20) inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD);
(21) GPR-105 antagonists;
(22) inhibitors of glucose uptake, such as sodium-glucose transporter (SGLT)
inhibitors and its
various isoforms, such as SGLT-1; SGLT-2, such as dapagliflozin and
remogliflozin; and SGLT-3;(23) inhibitors of acyl coenzyme A:diacylglycerol
acyltransferase 1 and 2 (DGAT-1 and DGAT-
2);
(24) inhibitors of fatty acid synthase;
(25) inhibitors of acetyl-CoA carboxylase-1 and 2 (ACC-1 and
ACC-2);
(26) inhibitors of acyl coenzyme A:monoacylglycerol
acyltransferase 1 and 2 (MGAT-1 and
MGAT-2);
(27) agonists of the TGR5 receptor (also known as GPBAR1, BG37,
GPCR19, GPR131, and M-
BAR); and
(28) bromocriptine mesylate and rapid-release formulations
thereof; and
(c) a pharmaceutically acceptable carrier.
When a compound of the present invention is used contemporaneously with one or
more other drugs, a
pharmaceutical composition containing such other drugs in addition to the
compound of the present invention is
preferred. Accordingly, the pharmaceutical compositions of the present
invention include those that also contain
one or more other active ingredients, in addition to a compound of the present
invention.
The weight ratio of the compound of the present invention to the second active
ingredient may be varied
and will depend upon the effective dose of each ingredient. Generally, an
effective dose of each will be used.
Thus, for example, when a compound of the present invention is combined with
another agent, the weight ratio of
the compound of the present invention to the other agent will generally range
from about 1000:1 to about 1:1000,
preferably about 200:1 to about 1:200. Combinations of a compound of the
present invention and other active
ingredients will generally also be within the aforementioned range, but in
each case, an effective dose of each
active ingredient should be used.
In such combinations the compound of the present invention and other active
agents may be
administered separately or in conjunction. In addition, the administration of
one element may be prior
to, concurrent to, or subsequent to the administration of other agent(s).
Examples
General synthetic methods:
32
CA 02805078 2013-01-10
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MR.1 ,-LAJD-vvv4i12/o
Method A:
0 1) EDC, HOBT 0
R2 NH2 DMF, 100 C R2
a N\ YLz
HOOC 11
R1 NH \ X 2) AcOH, 200 C
R1 tX
Method B:
1) EDC, HOBT
- DMF, 100 C R2
111) N\ H ppN
HOOC 411 I I +
NH2 2) AcOH, 200 C R1
Cul, K2CO3, MS 4A, 0
Dioxane, 110 C R2 r\I\
NZ'R
cr? Ri
MeHN NHMe
Intermediate 1
NH
N
HOOC
Ethyl 4-(2-oxo-1.2-dihydroimidazo[4,5-b]pyridin-3-yl)benzoate
Reference: J. Med. Chem. 1978, 21(9), 965-978.
Step A: ethyl 4-(3-nitropyridin-2-ylamino)benzoate
A mixture of 2-chloro-3-nitropyridine (50 g, 318.47 rranol, 1.00 equiv) and
ethyl 4-
aminobenzoate (157.6 g, 955.15 mmol, 3.00 equiv) was stirred for 90 min at 170
C in an oil
bath. The reaction mixture was cooled to room temperature, then it was applied
onto a silica gel
column and eluted with ethyl acetate/petroleum ether (1:10). This resulted in
ethyl 4-(3-
nitropyridin-2- ylamino)berizoate as a white solid. LC-MS (ES, nilz)
Cl4F113N30 4: 287; Found:
288 [M+H].
Step B: ethyl 4-(3-aminopyridin-2-ylamino)benzoate
33
WO 2012/015693 CA 02805078 2013-01-10PCT/US2011/045022
A mixture of ethyl 4-(3-nitropyridin-2-ylamino)benzoate (5 g, 17.42 mmol, 1.00
equiv)
and Palladium carbon (10%, 1 g) in methanol (500 mL) and THF (100 mL) was
stirred overnight
at room temperature under a hydrogen atmosphere. The solid was filtered out.
The filtrate was
concentrated under vacuum, which resulted in product ethyl 4-(3-aminopyridin-2-
ylamino)benzoate as a gray solid. LC-MS (ES, m/z): C141-115N302: 257; Found:
258 [M+H].
Step D: ethyl 4-(2-oxo-1,2-dihydroimidazo[4,5-blpyridin-3-yl)benzoate
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert
atmosphere of nitrogen was placed a solution of ethyl 4-(3-aminopyridin-2-
ylamino)benzoate (2
g, 7.78 mmol, 1.00 equiv) in toluene (20 mL). This was followed by the
addition of a solution of
triphosgene (3.7 g, 12.58 mmol, 1.61 equiv) in toluene (30 mL) dropwise with
stirring at 25 C
over 10 min. The resulting solution was stirred overnight at room temperature,
and then
quenched by the addition of 200 mL of water/ice, followed by extraction with
3x50 mL of ethyl
acetate. The organic layers were combined, washed with 2x50 mL of saturated
brine, dried over
anhydrous sodium sulfate and concentrated under vacuum. The residue was washed
with 3x20
mL of ether and dried to afford product ethyl 4-(2-oxo-1,2-dihydroimidazo[4,5-
b]pyridin-3-
yl)benzoate as a red solid. LC-MS (ES, m/z): C151-113N303: 283; Found: 284
[M+1.-1]4-. 11-INMR
(400 MHz, CDC13, ppm): 5 1.41 (3H, t), 4.42(2H, m), 7.11(11-1, m), 7.41(11-1,
d, J=8I-1z),
7.92(2H, d, J=8.8Hz), 8.11(1H, t), 8.24(2H, d, J= 8.8Hz), 10.05(1H, s).
Step E: 4-(2-oxo-1,2-dihydroimidazo[4,5-blpyridin-3-yl)benzoic acid
Into a 100-mL 3-necked round-bottom flask was placed a solution of ethyl 4-(2-
oxo-1,2-
dihydroimidazo[4,5-b]pyridin-3-yl)benzoate (2 g, 7.07 mmol, 1.00 equiv) in
tetrahydrofttran (30
mL). This was followed by the addition of a solution of sodium hydroxide (3N,
840 mg, 21.00
mmol, 3.00 equiv) in water (7 mL) in portions at <25 C over 5 min. The
resulting solution was
stirred overnight at room temperature, and then concentrated under vacuum. The
residue was
dissolved in 150 mL of water, then adjusted to pH 2-3 with HC1 (6 mol/L). The
isolated solid
was collected by filtration, then dried in an oven under reduced pressure to
afford product 4-(2-
oxo-1,2-dihydroimidazo[4,5-bipyridin-3-yl)benzoic acid as a white solid. LC-
MS: (ES, m/z)
C131-19N303: 255; Found: 256 [M+H1+.111NMR (400MHz, DMSO-D6, ppm): 6 7.13-
7.16(1H,
m), 7.43-7.45(1H, m), 7.92-7.94(2H, t), 7.98-7.99(1H, m), 8.09-8.11(2H, m),
11.51(11-I, s),
12.89(11-1, s).
Intermediate 2
34
WO 2012/015693 CA 02805078 2013-01-10 PCT/US2011/045022
HO * ).-NH 0
0 \
4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-blpyridin-1-yl)benzoic acid
Step A: 2-nitro_pyridin-3-yltrifluoromethanesulfonate
Into a 3000 ml 3-neck round-bottom flask was placed a suspension of NaH (95 g,
2.77
mol, 1.96 equiv, 70%) in THF (150 ml), then added 2-nitropyridirt-3-ol (A-1)
(390 g, 2,78 mol,
1.00 equiv) while maintaining the contents at room temperature. To the above
mixture was added
trifluoromethanesulfonic anhydride (786 g, 2.79 mol, 1.09 equiv) dropwise with
stirring. The
resulting solution was stirred for 72 hours while the temperature was
maintained at reflux in an
oil bath. The reaction mixture was cooled and quenched by the addition of
water, followed by
extraction 2 times with 1000 mL of CH3C1. The combined organic layer was dried
and
concentrated under vacuum. The residue was purified by eluting through a
silica gel column with
a 1:10 Et0Ae/PE solvent system to provide product 2-nitropyridin-3-y1
trifluoromethanesulfonate as a colorless solid. LC-MS: m/e = 273 [M+H]
Step B: ethyl 4-[(2-nitropyridin-3-yl)arnino]benzoate
Into a 2000 ml 3-neck round-bottom flask purged and maintained with an inert
atmosphere of nitrogen were placed a solution of 2-nitropyridin-3-
yltrifluoromethanesulfonate
(350 g, 1.29 mol, 1.00 equiv) in toluene (1500 ml), ethyl 4-aminobenzoate
(255.5 g, 1.55 mol,
1.10 equiv), K3PO4 (409.5 g, 1.93 mol, 1.50 equiv), Pd(dppf)C12 (47 g, 64.38
mmol, 0.05 equiv)
and dppf (70 g, 130.11 mmol, 0.01 equiv). The resulting mixture was stirred
for 24 hours at 90
C. The reaction mixture was cooled, dried over Na2SO4 and concentrated under
vacuum. The
residue was purified by eluting through a column with a 1:2 Et0Ac/hexane
solvent system to
provide ethyl 4-(2-nitropyridin-3-ylamino)benzoate as a yellow solid. LC-MS:
m/e = 288
[M+Hr
Step C: ethyl 4-1(2-aminopyridin-3-yl)amino]benzoate
A 1000 ml round-bottom flask was purged, flushed and maintained with a
hydrogen
atmosphere, then were added a solution of ethyl 4-(2-nitropyridin-3-
ylamino)benzoate (100 g,
348.43 mmol, 1.00 equiv) in Me0H (500 ml) and Pd/C (10 g, 0.10 equiv). The
resulting solution
was stirred overnight at room temperature under a hydrogen atmosphere. A
filtration was
35
CA 02805078 2013-01-10
WO 2012/015693 PCT/US2011/045022
rviRL-ift..na-uvvi-d
performed. The filtrate was concentrated under vacuum which resulted product
ethyl 4-(2-
aminopyridin-3-ylamino)benzoate as a white solid. LC-MS: /Die = 258 [M+Hr
Step D: ethyl 4-(2-oxo-2,3-dihydroimidazo[4,5-b1pyridin-1 -yl)benzoate
Into a 500 ml round-bottom flask were placed a solution of ethyl 4-(2-
aminopyridin-3-ylamino)benzoate (10 g, 38.91 mmol, 1.00 equiv) in THF (500
ml), di(1H-
imidazol-1-y1)methanone (25 g, 154.32 mmol, 4.00 equiv) and Et3N (16 g, 158.42
mmol, 4.00
equiv). The resulting solution was stirred for 72 hours at room temperature. A
filtration was
performed. The filter cake was washed 3 times with 100 ml of ether and dried
to afford product
ethyl 4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-y1)benzoate as a white
solid. LC-MS: mile =
284 [M+Hr
Step E: 4-(2-oxo-2,3-dihydroirnidazo[4,5-b1pyridin-1-v1)benzoic acid
Into a 1000 ml round-bottom flask was placed a solution of ethyl 4-(2-oxo-2,3-
dihydroimidazo[4,5-b]pyridin- I -yl)ben.zoate (85 g, 300.35 mmol, 1.00 equiv)
in THF/water(1:1)
(700 m1). This was followed by the addition of a solution of LiOH (62.5 g) in
water (100 ml)
dropwise with stirring. The resulting solution was stirred for 3 hours at room
temperature, then
concentrated under vacuum. The residual solution was washed three times with
300 ml of
Et0Ac. The aqueous layer was adjusted to pH 5 by the addition of HCI (1
mo1/1). The isolated
solid was collected and dried to afford product 4-(2-oxo-2,3-
dihydroimidazo[4,5-b]pyridin-1-
yl)benzoic acid as a pink solid. LC-MS: m/e = 256 [M+Hr. 1H-NMR (400MHz, DMSO-
d6,
ppm): 8.10 (2H, d), 7.99 (114, s), 7.71 (2H, d) 7.45 (1H, d), 7.03 (1H, s).
Intermediate 3
COOK
\ N
>-0
5-(2-oxo-2,3-dihydro-1/1-imidazo14,5-blpyridin-1-y1)pyridine-2-carboxylic acid
Intermediate 3 was prepared using the same synthetic sequence as that of
Intermediate 2
using methyl 5-arninopyridine-2-carboxylate in StepB. 5-(2-oxo-2,3-dihydro-1H-
imidazo[4,5-
36
CA 02805078 2013-01-10
MRL-9J&15693 WO 2012/015693 PCT/US2011/045022
s-vuvq-)
bipyridin-111)pyridine-2-carboxylic acid: LC-MS (ES, m/z): C12H18N403: 256;
Found: 257
[M+11}+.
Intermediate 4
0
) 0 12\--NH
0
tert-butyl 4-(2-oxo-2,3-dihydro-1H-imidazoi4,5-b1pyridin-l-yObenzoate
Intermediate 4 was prepared using the same synthetic sequence as that of
Intermediate 2
using tert-butyl 4-aminobenzoate. tert-butyl 4-(2-oxo-2,3-dihydro-1H-
imidazo[4,5-b]pyridin-1-
yObenzoate: LC-MS (ES, rn/z): C171117N303: 311; Found: 312 [M+Fl]+. 1HNMR (500
MHz,
CDC13) 5: 10.9 (1H, br), 8.17 (3H, m), 7.64 (2H, d, 8.5 Hz), 7.37 (111, d, 7.5
Hz), 7.07 (1H, dd,
5.5, 2.0 Hz), 1.62 (9H, s) ppm.
Intermediate 5
N\
F3C
2-(4-iodopheny1)-6-(trifluoromethy1)-1H-benzimidazole
A solution of 4-(trifluoromethyl)benzene-1,2-diamine (4.0 g, 22.71 mmol) in
DMF (80
mL) was added water (2.0 mL) followed by 44odobenzaldehyde (5.8 g, 24.98 mmol)
slowly and
then OXONE (9.77 g, 15.9 mmol). The mixture was then stirred at room
temperature for 1.5 hr
and poured slowly into a 1 M solution 50 mL K2CO3 in 250 mL water. The
resulting mixture was
stirred for 10 min, diluted with Et0Ac and layers separated. The aqueous layer
was extracted
with Et0Ac twice and the combined organic phases were dried over MgSO4 and
concentrated in
vacuo. Residue was purified by MPLC (120 gr Redi Sep Rf filter column on
CombiFlash with 0-
20% Hexane/Et0Ac) to afford product 2-(4-iodopheny1)-6-(trifluoromethyl)-1H-
benzimidazole.
LC-MS (ES, m/z): C14148F3IN2: 388; Found: 389 [M+Hr.
Example 1:
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CA 02805078 2013-01-10
MRL-Litin-vvvWO 2012/015693
PCT/US2011/045022
µi a
N 4.0 CF3
410
N =
IN
0
RN
1¨ {446-(tifluoromethyl)-1H-benzimidazol-2-yllpheny1}-1,3-dihydro-21/-
imidazo[4,5-
b]pyridin-2-one
To a 5 mL Pyrex vial was charged with Intermediate 2 (100 mg, 0.392 mmol)
along with
EDC (98 mg, 0.509 mmol) and HOBT (68.8 mg, 0.509 mmol) in DMF (1mL) before the
addition
of 4-trifluoromethy1-1,2-phenyldiamine (69.0 mg, 0.392 mmol). The mixture was
stirred at room
temperature for 10 min and then under microwave at 120 C for 20 mm. Then
acetic acid (imp
was added and the mixture was exposed to microwave at 200 C for 40 mm. The
mixture was
filtered and concentrated and the residue was purified by RP HPLC (loading as
solution of
DMSO:CH3CN:H20, 20 to 80% acetonitrile in water on YMC column) to afford
product 1-{4-
[6-(trifluoromethyl)- I H-benzimidazol-2-yl]phenyl -1,3-dihydro-2H-imidazo
[4,5-b]pyridin-2-
one. LC-MS (ES, m/z): C20H12F3N50: 395; Found: 396 [M+H]. 1HNMR (500 MHz,
CD30D) 8:
8.32 (21-1, dd, 6.5, 1.5 Hz), 8.06 (1H, d, 5.0 Hz), 8.04 (1H, s), 7.90 (3H,
m), 7.73 (1H, d, 8.5 Hz),
7.55 (1H, dd, 8.5, 1.5 Hz), 7.13 (1H, dd, 8.0, 2.5 Hz).
Using the above sample procedures and Intermediates 1 - 3, Examples 2-9 were
prepared:
N
R2
\CY\
H
)(---ryZ
HN¨ks=0
Example
Ri
X,Y,Z
Parent Ion m/z
(M+H)
21
CF3
CH,N,CH
396
3
H
F
N,CH,CH
346
4
F
F
N,CH,CH
364
H
Cl
N,CH,CH
362
6
H 1 Ph _ N,CH,CH
404
38
MRL-IJUI5-UVV4.3WO 2012/015693 CA 02805078 2013-01-10
PCT/US2011/045022
7 H CN N,CH,CH 353
8 H OCF3 N,CH,CH 412
9H CF3 CH,CH,N 396
Example 10:
HN =
N N
0
mirL 3-dih c 5-b ridin-2-one
Step A: N-[4-(1H-indol-2-y1)phenyl]-2-nitropyridin-3-amine
To a Pyrex vial (20 mL) was charged with 3-bromo-2-nitropyridine (318 mg,
1.567
mmol) along with 4-(1H-indo1-2-yl)aniline (326 mg, 1.567 mmol), cesium
carbonate (1531 mg,
4.70 mmol), BINAP (98 mg, 0.157 mmol), and palladium acetate (35.2 mg, 0.157
mmol). The
vial was sealed with septum cap and was connected to manifold through a thin
needle. The
system was vacuumed and refilled with nitrogen three times before toluene was
added through
syringe. Then the mixture was exposed to Microwave irridation for 60 min at
120 C. LC-MS
showed complete conversion of starting material to product. The mixture was
filtered and
washed with ethyl acetate. Then the filtrate was concentrated and the residue
was purified by
MPLC (40 g silicagel, 0 to 30%ethyl acetate in hexanes) to afford orange
product N44-(1H-
indol-2-yl)pheny11-2-nitropyridin-3-amine. LC-MS (ES, m/z): C19H14N402: 330;
Found: 331
[M+H].
Step B: 1V-[4-(1H-indo1-2-yl)phenyl1pyridine-2,3-diamine
To a parshaker vessel (100 mL) was charged with N44-(1H-indo1-2-yl)pheny1]-2-
nitropyridin-3-amine (180 mg, 0.545 mmol) along with palladium on carbon (58.0
mg, 0.054
mmol) and methanol/water (25 / 2 mL). The system was treated on parshaker
under 40 psi
hydrogen for 15 hours overnight. LC-MS showed complete reduction of nitro to
amine. The
catalyst was filtered and washed with methanol. The filtrate was concentrated
and product was
39
WO 20p/015693 CA 02805078 2013-01-10 PCT/US2011/045022
purified by MPLC (12 silica gel, 40 to 100% ethyl acetate in hexanes) to N44-
(11/-indol-2-
y1)phenyl]pyridine-2,3-diamine. LC-MS (ES, rn/z): C19H16N4: 300; Found 301
[M+Hr.
Step: C: 144-(1H-indo1-2-yl)pheny11-13-dihydro-2/1-imidazo[4,5-b1pyridin-2-one
To a 20 mL sample vial was charged with N44-(1H-indo1-2-y1)phenyllpyridine-2,3-
diamine (83 mg, 0.276 mmol) along with CDI (67.2 mg, 0.415 mmol) and THF. The
vial was
capped and the mixture was stirred and heated in an oil bath of 80 0C for 6
hrs. LC-MS showed
almost complete conversion. The mixture was concentrated and the crude was
purified by MPLC
(12 g silica gel, 40 to 100% ethyl acetate in hexanes) to afford white solid
product 144-(1H-
indo1-2-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one. LC-MS (ES,
m/z): C20H14N40:
326; Found: 327 [1\4+H]t 1HNMR (500 MHz, CDC13) 8: 8.05 (1H, d, 4.5 Hz), 7.95
(2H, d, 8.5
Hz), 7.62 (1H, d, 8.0 Hz), 7.57 (2H, d, 8.0 Hz), 7.48 (1H, d, 8.5 Hz), 7.46
(1H, d, 8.0 Hz), 7.40
(1H,d, 7.5 Hz), 7.18 (1H, t, 7.5Hz), 7.09 (2H, t, 6.5 Hz), 6.89 (1H, s) ppm.
Example 11:
N = CF3
N \ N 11
N0
0
HO
[4-(2-oxo-1- { 4- [6-(trifluoromethyl)-1H-benzimidazol-2-yl]pheny11-1,2-
dihydro-31/-
imidazo l4,5-bjpyridin-3 -Aphenyllacetic acid
Step A: tert-butyl 4-{1-14-(2-ethoxy-2-oxoethyl)pheny11-2-oxo-1.2-dihydro-3H-
imidazo 4 5-b s idin-3- 1 benzoate
To a 5 mL microwave reaction vial was charged with Intermediate 4 (321 mg,
1.031 mmol) along with ethyl 4-iodo-phenylacetate (359 mg, 1.237 mmol), copper
iodide (19.64
mg, 0.103 mmol), CyDMEDA (29.3 mg, 0.206 mmol), potassium carbonate (285 mg,
2.062
mmol) (oven dried), molecular sieves 4A (300 mg) and dioxane (6 mL). The vial
was sealed and
connected to manifold through a syringe needle. The system was then vacuumed
and refilled
with nitrogen three times. The mixture was then stirred and heated in an oil
bath of 110 0C for
40
CA 02805078 2013-01-10
W 20/015693 PCT/US2011/045022
MRL-LtuO ts-uvu12qa
72 hrs. The mixture was then filtered and concentrated. The residue was
purified by MPLC (24 g
silica gel, 0 to 60% ethyl acetate in hexanes) to afford light color sticky
oil product tert-butyl 4-
{1- [4-(2-ethoxy-2-oxoethyl)pheny1]-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-
3-yllbenzoate.
LC-MS (ES, m/z): C27H27N305: 473; Found : 474 [M+Hr. iHNMR (500 MHz, CDC13) 5:
8.16
(2H, d, 8.5 Hz), 8.11 (1H, d, 1.0 Hz), 7.71 (2H, d, 8.5 Hz), 7.67 (2H, d, 8.5
Hz),
Step B: 4-{3-[4-(2-ethoxy-2-oxoethyl)pheny11-2-oxo-2,3-dihydro-1H-imidazo[4,5-
bipyridin-l-yllbenzoic acid
To a 20 mL sample vial was charged with tert-butyl 4-{144-(2-ethoxy-2-
oxoethyl)pheny1]-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yllbenzoate (300
mg, 0.634
mmol) along with methylene chloride. The mixture was stirred and TFA (1445 mg,
12.67 mmol)
was added by syringe drop-wise in 1 min. The resulting reaction mixture was
then stirred at room
temperature for 1 hour. LC-MS showed complete hydrolysis of t-butyl ester with
no effect on the
ethyl ester. The mixture was then concentrated by evaporation and the TFA was
traced out by
co-evaporation with HC1/dioxane to afford product HC1 salt 4-13-[4-(2-ethoxy-2-
oxoethyl)pheny1]-2-oxo-2,3-dihydro-1H-imidazo[4,5-bipyridin-l-yllbenzoic acid.
LC-MS (ES,
rn/z): C23H19N305: 417; Found: 418 [M+H].
Step C: ethyl [4-(2-oxo-1-{4-15-(trifluoromethyl)-2,3-dihydro-1H-benzimidazol-
2-
yllpheny1}-1,2-dihydro-3H-imidazo[4,5-b1pyridin-3-y1)phenyl]acetate
To a 5 mL Pyrex vial was charged with 4-{3-[4-(2-ethoxy-2-oxoethyl)pheny1]-2-
oxo-2,3-
dihydro-1H-imidazo[4,5-b]pyridin-l-ylIbenzoic acid (70 mg, 0.154 mmol) along
with HOBT
(31.3 mg, 0.231 mmol) and EDC (44.3 mg, 0.231 mmol) in DMF (1mL) before the
addition of
4-trifluoromethy1-1,2-phenyldiamine (32.6 mg, 0.185 mmol). The mixture was
stirred at room
temperature for 10 min and then under microwave at 120 C for 20 min. Then
acetic acid (imp
was added and the mixture was exposed to microwave at 200 0C for 40 min. LC-MS
showed
complete formation of irnidiazole. The mixture was filtered and concentrated
and the residue was
purified by PrepTLC (2x2000 nm, ethyl acetate:hexanes=3:2) to afford product
ethyl [4-(2-oxo-
1- {4- [5-(trifluoromethyl)-2,3-dihydro-1H-benzimidazol-2-yl] phenyl } -1,2-
dihydro-3 H-
imidazo[4,5-bipyridin-3-yl)phenyflacetate. LC-MS (ES, rn/z): C30H22N5F303:
557; Found: 558
[M+H]t ifINMR (500 MHz, CDC13) 5: 8.25 (2H, d, 8.0 Hz), 8.20 (1H, d, 4.0Hz),
7.80 (2H, d,
8.5Hz), 7.71 (1H, m), 7.70 (2H, d, 8.0Hz), 7.54 (2H, d, 8.5 Hz), 7.51 (1H, m)
7.44 (2H, m), 7.15
(1H, t, 5.0 Hz), 4.15 (21-1, q, 8.0 Hz), 3.69 (2H, s), 1.25 (3h, t, 8.0 Hz)
ppm.
41
Nnt520i2a15693 CA 02805078 2013-01-10 PCT/US2011/045022
Step D: [4-(2-oxo-1-{4-16-(trifluoromethyl)-1H-benzimidazol-2-yllphenyl}-1,2-
dihydro-
3H-imidazo[4,5-blpyridin-3-y1)phenyl]acetic acid
To a 20 mL sample vial was charged with ethyl [4-(2-oxo-1-{445-
(trifluoromethyl)-2,3-
dihydro-1H-benzimidazol-2-yl]phenyl}-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-
yl)phenyliacetate (25 mg, 0.045 mmol) along with ethanol and sodium hydroxide
(0.1 ml, 0.500
mmol). The resulting reaction mixture was then stirred at room temperature for
30 min. LC-MS
showed complete hydrolysis of ester to acid. The mixture was then neutralized
with HO (1N,
500 ul) and concentrated. The residue was purified by RP HPLC to afford
product TFA salt [4-
(2-oxo-1-{446-(tifluoromethyl)-1H-benzimidazol-2-yl]phenyl) -1,2-dihydro-3H-
imidazo[4,5-
b]pyridin-3-yl)phenyl]acetic acid. LC-MS (Es, m/z): C28H13N5F303: 529; Found:
530 [M+H]t
1HNMR (500 MHz, CDC13) 8: 8.37(211, d, 8.0 Hz), 8.12 (111, s), 8.09 (111, d,
5.0Hz), 8.05 (2H,
d, 8.5 Hz), 7.98 (111, d, 8.5 Hz), 9.84 (1H, d, 8.5 Hz), 7.67 (2H, d, 8.5 Hz),
7.52 92H, d, 8.5 Hz),
7.23 (1H, dd, 8.0, 5.0 Hz), 3.72 (2H, s) ppm.
Example 12:
N CI
2,,NOf [1
N
No
0 =
HO
(4-[144-(6-chloro-1H-benzimidazol-2-yl)pheny11-2-oxo-1õ2-dihydro-3H-
imidazo[4,5-
blpyridin-3-yllphenypacetic acid
In the same procedure as Example 11, (4- [144-(6-chloro-1H-benzimidazol-2-
yl)pheny11-
2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-y1}phenyl)acetic acid was
prepared. LC-MS (Es,
m/z): C271-113F3N5C103: 495; Found: 496 [M+H].
Example 13
42
CA 02805078 2013-01-10
mRL_Nr53.,9131915693 PCT/US2011/045022
N 411,CF3
N
HOOC
4-(2-oxo-1-4-[6-(trifluoromethyl)-11/-benzimidazol-2-yllpheny1}-1,2-dihydro-3
H-
imidazo[4,5-blpyridin-3-yl)benzoic acid
In the same procedure as Example 11, (4-{144-(6-chloro-1H-benzimidazol-2-
yl)phenyll-
2-oxo-1,2-dihydro-3H-imidazo[4,5-bipyridin-3-yllphenyl)acetic acid was
prepared. LC-MS (Es,
m/z): C27H16F31\1503: 515; Found: 516 [M+Hr.
Example 14:
=CF3
N
Br \ 1
N¨N
8-bromo-3 4- [6-(trifluoromethyl)-1H-benzimidazol-2-yl] phenyl}
[1,2,4]triazolo[43-
a]pyridine
Step A: 3-bromo-2-hydrazinylpyridine
To a stirring solution of 3-bromo-2-chloropyridine (3.74 g, 19.43 mmol) in
pyridine (40
mL) was added hydrazine (2 g, 62.4 mmol). The resulting mixture was stirred at
60 C for 24 h.
After cooled to room temperature and refrigerated, product precipitated out as
a white needle
solid. The product was filtered and washed with water, dried under high vacuum
overnight to
afford product 3-bromo-2-hydrazinylpyridine.
Step B: tert-butyl 4- [2-(3-bromopyridin-2-yl)hydrazinylicarbonyllbenzoate
To a 250 one neck round bottom flask was charged with 4-tert-
butoxycarbonylbenzoic
acid (1000 mg, 4.50 nunol) along with HOBT (912 mg, 6.75 mmol) and EDC (1294
mg, 6.75
43
MRL-WO 2012/015693 CA 02805078 2013-01-10PCT/US2011/045022
mmol) in CH2C12 (40 ml) before the addition of 3-bromo-2-hydrazinylpyridine
(846 mg, 4.50
mmol). The mixture was stirred at room temperature for 18 hrs overnight. LC-MS
showed
complete coupling and the mixture was concentrated by rotary evaporation. The
residue was
then suspended in ethyl acetate (15 niL) and water (50 rnL) and stirred for 1
hour. The solid was
filtered and washed with water 3 times and dried under vacuum for 4 hours for
afford white solid
product tert-butyl 4- { [2-(3-brornopyridin-2-yl)hydrazinyl]carbonyl)benzoate.
LC-MS (Es, in/z):
C17F118BrN303: 391; Found: 392 [M+H].
Step C: 4-(8-bromo[1,2,4]triazolo[4õ3-alpyridin-3-yl)benzoic acid
To a 25 ml microwave reaction vessel was charged with tert-butyl 4-1[243-
bromopyridin-2-yl)hydrazinyl]carbonyl)benzoate (500 mg, 1.275 mmol) along with
acetic Acid
(10 ml). The mixture was stirred at room temperature for 10 min and then under
microwave at
200 0C for 2 hrs. LC-MS showed complete formation of product as solid
precipitated out. The
product was then filtered and washed with water, dried under high vacuum
overnight to afford
light color, powder product 4-(8-bromo[1,2,4]triazolo[4,3-ctipyridin-3-
yl)benzoic acid. LC-MS
(ES, m/z): C13H8BrN302: 317; Found: 318 [M+H].
Step D: 8-bromo-3-046-(trifluoromethyl)-1H-benzimidazo1-2-
ylipheny1}[1,2,4jtriazolo [ 4,3-al pyridine
To a 5 mL Pyrex vial was charged with 4-(8-bromo[1,2,4]triazolo[4,3-alpyridin-
3-
yl)benzoic acid (300 mg, 0.943 mmol) along with HOBT (191 mg, 1.415 mmol) and
EDC (271
mg, 1.415 mmol) in DMF (1mL) before the addition of 4-trifluoromethy1-1,2-
diaminobenzene
(249 mg, 1.415 mmol). The mixture was stirred at room temperature for 10 min
and then under
microwave at 120 0C for 20 min. LC-MS showed complete coupling of the acid
with amine.
Then acetic acid (1mL) was added and the mixture was exposed to microwave at
200 0C for 40
min. LC-MS showed complete fon-nation of imidiazole. The reaction mixture was
then
concentrated and worked up regularly. The product had very small solubility
and filtered to
afford crude product, small amount was purified by RPHPLC to afford 8-bromo-3-
{446-
(trifluoromethyl)-1H-benzimidazol-2-yl]phenyll[1,2,4]triazolo[4,3 -a]
pyridine. LC-MS (ES,
rn/z): C201411BrF3N5: 457; Found: 458 [M+H]. 1HNMR (500 MHz, CDC13) 8: 8.66
(111, 2, 7.0
Hz), 8.37 (2H, d, 8.5 Hz), 8.19 (2H, 2, 8.5 Hz), 8.08 (1H, s), 7.93 (1H, d,
8.0 hz), 7.85 (1H, d,
6.0 Hz), 7.77 (1H, d, 8.0 Hz), 7.07 (1H, t, 7.5 Hz) ppm.
44
CA 02805078 2013-01-10
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MR1,-00ii-UUU4
Example 15:
HOOC 40. RN CF3
/ N =
N
3 -(2-oxo-1 {4-f54trifluoromethy1)-1H-benzimidazo1-2-yllpheny1}-23-dihydro-1H-
imidazo[4,5-blpyridin-6-y1)_benzoic acid
Step A: 4-(6-iodo-2-oxo-2,3-dihydro-1H-imidazof4,5-Mbyridin-1-y1)benzoic acid
A mixture of Intermediate 2 (1000 mg, 3.92 mmol) in acetic acid (2 mL), water
(0.4
mL), sulfuric acid (0.125 mL) and Periodic acid (179 mg, 0.784 mmol) was
allowed to stirred at
90 0C for 15 min. Iodine crystals (796 mg, 3.13 minol) were added in portions.
After it was
stirred for 1 hr, the reaction mixture was poured into water and the solid was
filtered and washed
with water, ethyl acetate to afford white solid product. 4-(6-iodo-2-oxo-2,3-
dihydro-1H-
imidazo[4,5-b]pyridin-l-yl)benzoic acid. LC-MS (ES, m/z): C13H8N303: 381;
Found: 382
[M+H]+.
StepB: 6-iodo-1-{415-(trifluoromethyl)-1H-benzimidazol-2-yllpheny1}-13-dihydro-
2H-
imidazo[4,5-b]pyridin-2-one
To a 5 mL Pyrex vial was charged with 4-(6-iodo-2-oxo-2,3-dihydro-1H-
imidazo[4,5-
bipyridin-l-ylkenzoic acid (52 mg, 0.136 mmol) along with EDC (34.0 mg, 0.177
mmol) and
HOBT (23.97 mg, 0.177 mmol) in DMF (1mL) before the addition of 4-
trifluoromethy1-1,2-
phenyldiamine (31.2 mg, 0.177 mmol). The mixture was stirred at room
temperature for 10 min
and then under microwave at 120 C for 20 min. LC-MS showed complete coupling
of the acid
with amine. Then acetic acid (lmL) was added and the mixture was exposed to
microwave at
200 0C for 40 mm. LC-MS showed complete formation of imidiazole. The mixture
was filtered
and concentrated and the residue was purified by RP HPLC (20 to 80%
acetonitrile in water on
YMC column) to afford product 6-iodo-1-1415-(trifluoromethyl)-1H-benzimidazol-
2-
Aphenyll-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one. LC-MS (ES, m/z):
C20H11F3IN50: 521;
Found: 522 {M Hr. 'FINMR (500 MHz, CD30D) 8: 8.35(211, d, 9.0 Hz), 8.29 (1H,
s), 8.11
(111, s), 7.98 (111, d, 5.5 Hz), 7.96 (211, d, 8.5 Hz), 7.83 (1H, d, 9.0 Hz),
7.78 (1H, s) ppm.
45
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MRL-uuts-uuv%)
Step C: ethyl 3-(2-oxo-1- {4-[5-(trifluoromethyl)-1H-benzimidazol-2-yl}phenyl)
-2 3-
dihydro- IThimidazo[4,5-blpyridin-6-y1)benzoate
To a 2 ml biotage micoreaction tube was charged with 6-iodo-1-{415-
(trifluoromethyl)-
1H-benzimidazol-2-ylipheny1}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (29
mg, 0.046
nunol) along with 3-ethoxycarbonylphenyl boronic acid (11.51 mg, 0.059 mmol),
Pd(dppf) (3.34
mg, 4.57 !Intel), sodium carbonate (14.52 mg, 0.137 mmol), DMF (1.5 mL) and
water (0.3 mL).
The flask was put under nitrogen and the reaction mixture was stirred and
heated in an oil bath of
60 C for 15 hours overnight. LC-MS showed almost complete conversion of
starting material to
product. After cooled to room temperature, the mixture was diluted with ethyl
acetate (50 mL)
and water (30 mL) and the insoluble solid was filtered and washed with ethyl
acetate. The
organic layer was separated and the aqueous layer was extracted with ethyl
acetate (2x). The
combined organic phases were washed with water, brine, dried over MgSO4,
filtered and
concentrated. The residue was purified by PrepTLC (1000 nm, ethyl acetate) to
afford solid
product ethyl 3-(2-oxo-1-{4-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]pheny1}-
2,3-dihydro-1H-
imidazo[4,5-b]pyridin-6-Abenzoate. LC-MS (ES, rn/z): C29H20F3IN503: 543;
Found: 5/11
[M+1-1] .
Step D: 3 -(2-oxo-1- {445-(trifluoromethyl)-1H-benzimidazol-2-yllphenyll -2,3-
dihydro-
1H-imidazo[4,5-blpyridin-6-yl)berizoic acid
To a 20 mL sample vial was charged with ethyl 3-(2-oxo-1-{445-
(trifluoromethyl)-1H-
benzimidazol-2-yllpheny11-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)benzoate
(17 mg, 0.031
mmol) along with methanol and NaOH (5N). The mixture was stirred at 45 C for
30 mm. LC-
MS showed complete hydrolysis of ester. The mixture was neutralized by HC1
(IN) and then
concentrated. The residue was purified by RP HPLC (YMC column, 20 to 80%
acetonitrile in
water) to afford product 3-(2-oxo- 1- {4-[5-(trifluoromethyl)-1H-benzimidazol-
2-yl]phenyll-2,3-
dihydro-1H-imidazo[4,5-b]pyridin-6-yl)benzoic acid. LC-MS (ES, m/z):
C271116F31N503: 515;
Found: 516 [M-1-111+.
Example 16:
46
CA 02805078 2013-01-10
WO 2012/015693 PCT/US2011/045022
MR1,¨L'uts¨vvucE
N 1111C 3
N N
\N
4-benzy1-1-4-1-6-(trifluoromethyl)-1/1-benzimidazo1-2-yl1pheny1}-1.4-dihydro-
211-
imidazo[4,5-b1pyridin-2-one
Step A:
To a 35 mL sealed vial was charged with inteimediate 2 (1000 mg, 3.92 mmol)
along
with potassium carbonate (650 mg, 4.70 mmol) and benzyl bromide (737 mg, 4.31
mmol) in
DMF (10mL). The mixture was stirred at room temperature for 18 hrs. LC-MS
showed
foimation of three products. The mixture was then partitioned between ethyl
acetate (40 mL) and
water (20 mL). The organic layer was separated and the aqueous layer was
extracted with ethyl
acetate (3x). The combined organic phases were washed with water, brine, dried
over MgSO4,
filtered and concentrated. The residue was purified by MPLC (solid load on
silica gel, 40 to
100% ethyl acetate in hexanes) to afford three products: benzyl 4-(3-benzy1-2-
oxo-2,3-dihydro-
1H-imidazo[4,5-b]pyridin-l-yl)benzoate. LC-MS (ES, in/z): C2711211\1305: 435;
Found: 436
[M+Hr. IHNMR (500 MHz, CDC13) 8: 8.22 (2H, d, 8.5 Hz), 8.12 (1H, d, 4.0Hz),
7.64 (21-1, d,
8.5 hz), 7.56 (2H, d, 7.4 Hz), 7.44 (2H, d, 7.4 Hz), 7.38 (2H, t, 6.1 Hz),
7.32 (4H, m), 7.25 (1H, t,
7.3Hz), 6.99 (1H, t, 5.2 Hz), 5.38 (2H, s), 5.21 (2H, s) ppm; benzyl 4-(2-oxo-
2,3-dihydro-111-
imidazo[4,5-b]pyridin-1-y1)benzoate, LC-MS (ES, m/z): C20H15N305: 345; Found:
346 [M+H]4.
IHNMR (500 MHz, CDC13) 6: 10. 9 (1H, br), 8.26 (2H, d, 8.5 Hz), 8.18 (1H, 4.1
Hz), 7.68 (2H,
d, 7.1 Hz), 7.47 (2H, d, 7.2 Hz), 7.36 (4H, m), 7.06 (1H,t, 6.2 Hz) ppm; and
benzyl 4-(4-benzy1-
2-oxo-2,4-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)benzoate): LC-MS (ES, m/z):
C27H211\1305:
435; Found: 436 [M+H]. IHNMR (500 MHz, CDCI3) 5: 8.19 (2H, d, 8.6 Hz), 7.64
(2H, d, 8.6
Hz), 7.46 (3H, m), 7.34 (6H, m), 7.07 (11-1, d, 7.2 Hz), 6.65 (1H, t, 7.2 Hz),
5.54 (2H, s), 5.39
(214, s).
StepB: lithium 4-{3-benzy1-2-oxo-2,3-dihydro-IH-imidazo[4,5-blpyridin-l-
yObenzoate
To a 20 mL sample vial was charged with benzyl 4-(3-benzy1-2-oxo-2,3-dihydro-
1H-
imidazo[4,5-b]pyridin-l-y1)benzoate (100 mg, 0.230 mmol) in THF/ water along
with lithium
47
CA 02805078 2013-01-10
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MRLrp2-vvv012/015693
hydroxide (11.56 mg, 0.276 mmol). The resulting reaction mixture was then
stirred at room
temperature for 2 hrs. LC-MS showed complete hydrolysis of the ester. The
mixture was then
concentrated and the residue was dried by coevaporated with toluene to afford
lithium 4-(3-
benzy1-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-l-yl)benzoate. LC-MS (ES,
rn/z):
C20H14LiN303: 345; Found: 346 [M+H]t
Step C: 4-benzy1-1-{4-1-6-(trifluoromethyl)-1H-benzimidazol-2-yllphenyll-1,4-
dihydro-
2H-imidazo[4,5-b]pyridin-2-one
To a 5 mL Pyrex vial was charged with lithium 4-(3-benzy1-2-oxo-2,3-dihydro-1H-
imidazo[4,5-11pyridin-l-y1)benzoate (81 mg, 0.231 rnmol) along with EDC (57,5
mg, 0.300
mrnol) and HOBT (40.5 mg, 0.300 trimol) in DMF (1mL) before the addition of 4-
trifluoromethy1-1,2-phenyldiamine (40.6 mg, 0.231 mrnol). The mixture was
stirred at room
temperature for 10 min and then under microwave at 120 oC for 20 min. LC-MS
showed
complete coupling of the acid with amine. Then acetic acid (1mL) was added and
the mixture
was exposed to microwave at 200 0C for 40 min. LC-MS showed complete formation
of
imidiazole. The mixture was filtered and concentrated and the residue was
purified by RP HPLC
to afford product TFA salt 4-benzy1-1-{4-[6-(trifluoromethyl)-1H-benzimidazol-
2-Apheny1}-
1,4-dihydro-2H-imidazo[4,5-b]pyridin-2-one. LC-MS (ES, rn/z): C27H18F3N50:
485; Found: 486
[M+Hr.
Example 17:
N C F3
N¨ N
No
4-benzy1-1-{446-(trifiuoromethyl)-1H-benzimidazol-2-yllpheny1}-1,4-dihydro-2H-
imidazo[4,5-blpyridin-2-one
Following the same synthesis for Example 15, using the intermediate benzyl 4-
(4-benzy1-
2-oxo-2,4-dihydro-1H-imidazo[4,5-b]pyridin-1-y1)benzoate) from Step A, 4-
benzy1-1-1446-
48
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MRL-D01:3-0004
(trifluoromethyl)-1H-benzimidazol-2-yripheny1}-1,4-dihydro-2H-imidazo[4,5-
b]pyridin-2-one
was prepared. LC-MS (ES, raiz): C271118F3N50: 485; Found: 486 [M+Hr.
Example 18:
=N/ CF3
N m
0 /
HO
(2-oxo-1-1446-(trifluoromethyl)-1H-benzimidazol-2-yl1pheny1}-1,2-dihydro-3H-
imidazo[4,5-blpyridin-3-yflacetic acid
Step A: benzyl 4-j3-(2-ethoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-
b]pyridin-1-
ylibenzoate and benzyl 444-(2-ethoxy-2-oxoethyl)-2-oxo-2,4-dihydro-IH-
imidazot4,5-
blpytidin-l-ylibenzoate
To a 35 mL sealed vial was charged with benzyl 4-(2-oxo-2,3-dihydro-1H-
imidazo[4,5-
b]pyridin-l-yl)benzoate (280 mg, 0.811 mmol) from Step A Example 15, along
with potassium
carbonate (146 mg, 1.054 mmol) and ethyl 2-bromoacetate (176 mg, 1.054 mmol)
in DMF
(10mL). The mixture was stirred at room temperature for 18 hrs. LC-MS showed
formation of
product plus two bisaellcylated product. The mixture was then partitioned
between ethyl acetate
(40 mL) and water (20 mL). The organic layer was separated and the aqueous
layer was extracted
with ethyl acetate (3x). The combined organic phases were washed with water,
brine, dried over
MgSO4, filtered and concentrated. The residue was purified by MPLC (solid load
on silica gel,
40 to 100% ethyl acetate in hexanes) to afford two products: benzyl 443-(2-
ethoxy-2-oxoethyl)-
2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yribenzoate: LC-MS (ES, m/z):
C24H21N305:
431; Found: 432 [M+H]. iFINMR (500 MHz, CDCI3) 8: 8.22 (2H, d, 6.5 Hz),
8.07(114, d, 1.0
Hz), 7.66 (2H, d, 8.5 Hz), 7.44 (214, d, 7.3 Hz), 7.37 (4H, m), 7.02 (1H, t,
5.1 Hz), 5.38 (214, s),
4.79 (2H, s), 4.25 (2H, q, 7.1 Hz), 1.28 (3H, t, 7.1 Hz) ppm; benzyl 444-(2-
ethoxy-2-oxoethyl)-
2-oxo-2,4-dihydro-1H-imidazo[4,5-bipyridin-l-yl]benzoate: LC-MS (ES, in/z):
C24H21N305:
431; Found: 432 [M+Hr. 'FINMR (500 MHz, CDC13) 6: 8.19 (2H, d, 8.5 Hz), 7.64
(2H, d, 8.5
Hz), 7.45 (2H, d, 7.4 Hz), 7.39 (214, t, 7.0 Hz), 7.35 (1H, d, 7.0 Hz), 7.25
(1H, 2, 6.8 Hz), 7.11
49
CA 02805078 2013-01-10
rsuu,,y WO 2012/015693
PCT/US2011/045022
,¨Iltit:5¨VUULD
(1H, d, 7.3 Hz), 6.69 (1H, t, 7.1 Hz), 5.38 (2H, s), 5.13 (2H, s), 4.26 (2H,
q, 7.1 Hz), 1.30 (3H, t,
7.1 Hz) ppm.
Step B: 443-(2-ethoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-iraidazof4,5-blnyridin-
1-
yllbenzoic acid
To a parshaker vessel (50 mL) was charged with benzyl 443-(2-ethoxy-2-
oxoethyl)-2-
oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl]benzoate (220 mg, 0.510
mmol)along with
Pd/C (100 mg, 0.094 mrnol)and ethyl acetate (20 mL). The system was treated on
parshaker
under 40 psi hydrogen for 15 hours overnight. LC-MS showed complete reduction
of nitro to
amine. The catalyst was filtered and washed with methanol. The filtrate was
concentrated to
afford white solid product 4-[3-(2-ethoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-
imidazo[4,5-
b]pyridin-l-yllbenzoic acid. LC-MS (ES, miz): C17H15N305: 341; Found: 342
[M+H]t
Step C: ethyl (2-oxo-1-{4-{6-(trifluoromethyl)-1H-benzimidazol-2-yllpheny1}-
1,2-
dihydro-3H-imidazo[4,5-bipyridin-3-yflacetate and (2-oxo-1-{446-
(trifluoromethyl)-111-
benzimidazol-2-yllpheny1}-1.2-dihydro-3H-imidazo[4õ5-blpyridin-3-yl)acetic
acid
To a 5 mL Pyrex vial was charged with 443-(2-ethoxy-2-oxoethyl)-2-oxo-2,3-
dihydro-
= 1H-imidazo[4,5-b]pyridin-1-yllbenzoic acid (89 mg, 0.261 mmol) along with
EDC (65.0 mg,
0.339 mmol) and HOBT (45.8 mg, 0.339 mmol) in DMF (1mL) before the addition of
4-
trifluoromethy1-1,2-phenyldiamine (50.5 mg, 0.287 mmol). The mixture was
stirred at room
temperature for 10 min and then under microwave at 120 C for 20 mm. LC-MS
showed
complete coupling of the acid with amine. Then acetic acid (1mL) was added and
the mixture
was exposed to microwave at 200 0C for 40 min. LC-MS showed complete formation
of
imidiazole. The mixture was filtered and concentrated and the residue was
purified by RP HPLC
to afford products ethyl (2-oxo-1-{446-(trifluoromethyl)-1H-benzimidazol-2-
yllpheny1}-1,2-
dihydro-3H-imidazo[4,5-b]pyridin-3-yOacetate: LC-MS (ES, m/z): C24H18F3N503:
481; Found:
482 [M+1-1] 4-; and (2-oxo-1-{4-[6-(trifluoromethyl)-1H-benzimidazol-2-
yl]pheny1}-1,2-dihydro-
3H-imidazo[4,5-17]pyridin-3-y1)acetic acid: LC-MS (ES, m/z): C22H14F3N503:
453; Found: 453
[M+H].
50
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4)
Example 19:
C F 3
H N
N
N
N
0
6-fluoro-1- { 446-(trifluoromethyl)-1H-benzimidazol-2-yllphenyl} -1,3-dihydro-
21/-
pyiTolor3,2-blpyridin-2-one
A 5 ml seal tube was treated with 6-fluoro-1,3-dihydro-2H-pyrrolo[3,2-
bipyridin-2-one
(100 mg, 0.657 mmol), inteimediate 5 (253 mg, 0.651 mmol), copper(I) iodide
(25.04 mg, 0.131
mmol) and potassium carbonate (182 mg, 1.315 mmol), capped and evacuated and
backfilled
with N2. Dioxane (6.0 ml) followed by trans-(1R,2R)-N,N'-bismethyl-1,2-
cyc1ohexanediamine
(0.021 ml, 0.131 mmol) was then added under N2 and the mixture stirred at 85
C for 20 hr. The
mixture was diluted with Et0Ac, filtered and washed with warm Et0Ac. The
filtrate was conc.
in vaccu and CombiFlash companion purification eluting with 5:35:40,
MeOH:Et0Ac:Hexane
afforded 6-fluoro-1-{446-(trifluoromethyl)-1H-benzimidazol-2-y1lpheny1}-1,3-
dihydro-2H-
PPT010[3,2-bipyridin-2-one: LC-MS (ES, rn/z): C21H13F4N40: 381; Found: 382
[M+H].
Following the same procedure for Example 18, the following compounds were
prepared:
c3
H N
N
W
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Example Ri
Name
Parent
Ion m/z
[M+I-1]+
20 ci
6-chloro-1-{445-(trifluoromethyl)-11-1-
427
/ 14\r benzimidazol-2-yllpheny11-1,3-
dihydro-2H-
0 pyrrolo[3,2-
b]pyridin-2-one
21 *
- 445-(trifluoromethyl)-1H-benzimidazol-
394
0 2-ylipheny1}-1,3-dihydro-2H-indo1-2-one
22
6-(trifluoromethyl)-
1-{4-[5-
463
N\- (trifluoromethyl)-1H-
benzimidazol-2-
0
yl]pheny1}-1,3-dihydro-2H-pyrrolo[3,2-
blpyridin-2-one
F3
23
methyl 2-oxo-6-(trifluoromethyl)-1-{4-[5-
521
/ (trifluoromethyl)-1H-
benzimidazol-2-
MeD2C Apheny1)-2,3-
dihydro-1H-pyrrolo[3,2-
blipyridine-3-carboxylate
24 Br cy_k*
7-bromo-3-{4-[5-(trifluoromethyl)-1H-
474
0 benzimidazol-2-yllpheny1}4,3-benzoxazol-
=
2(311)-one
25
3-{445-(trifluoromethyl)-1H-benzirnidazol-
396
A0 2-yllpheny1}-1,3-benzoxazol-
2(311)-one
Example 26:
N CI
N = NSi--Q-
[1
144-(6-chloro-1H-benzimidazol-2-y1)phenyl]-3-methyl-13 -dihydro-2H-imidazo
[4,5-
blpyridin-2-one
To a 20 nil sample vial was charged with 1-[4-(6-chloro-1H-benzimidazol-2-
yl)pheny11-
1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (example 4) ( 100 mg, 0.276 mmol)
along with
potassium carbonate (38 mg, 0.276 mmol) in DMF. Then methyl iodide (118 mg,
0.829 mmol)
before the reaction mixture was stirred at room temperature for 18 hr
overnight. The mixture
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WO 2012/015693 CA 02805078 2013-01-10 PCT/US2011/045022
was filtered and crude was purified directly by RP HPLC (20 to 80%
acetonitrile) to afford
product 1-[4-(6-chloro-1H-benzimidazol-2-yl)pheny1]-3-methy1-1,3-dihydro-2H-
imidazo[4,5-
b]pyridin-2-one. LC-MS (ES, m/z): C20H14C1N50: 375; Found: 376 [M+Hr.
N 11)6 CI
QNS [\11
R,( a
Example Ri Name Parent Ion
m/z
[M+H1+
27 Ethyl 1-[4-(6-chloro-1H-benzimidazol-2- 380
yl)pheny1]-3-ethy1-1,3-dihydro-2H-
irnidazo14,5-blpyridin-2-one
28 Butyl 1-[4-(6-chloro-1H-benzimidazol-2- 408
yl)pheny1]-3-buty1-1,3-dihydro-2H-
imidazo[4,5-b]pyridin-2-one
29 iPropyl 1-[4-(6-chloro-1H-benzimidazol-2- 394
yl)pheny1]-3-isopropy1-1,3-dihydro-2H-
imidazo[4,5-b]pyridin-2-one
DGAT1 CPM Assay
20uL substrate mixture of 300uM diolein, 40uM oleoyl-CoA, 10% ethanol and luL
of the
compound with different concentrations were delivered to a 384 well assay
plate (Coming 3573)
using a Tecan with TeM0 module. Later 19uL of enzyme mixture of 1.05ug/m1
human DGAT1
in buffer (200mM Tris, pH7, 200mM sucrose, 200mM MgC12 + 2Oug/m1 NEM-treated
BSA)
was added via a Multidrop Combi using a microcassette. 20uL of 90uM CPM
reagent in 90%
ethanol was added after 1 hour incubation at room temperature. After 30
minutes at room
temperature in dark, fluorescence measurement on Envision was carried out and
IC5Os were
calculated.
Example 1050 (nM) Example IC50 (DM)
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WO 2012/015693 CA 02805078 2013-01-10
PCT/US2011/045022
1 1 7.339 18
12.74
2 1134 19
116.8
3 39.98 20
868.2
4 21.62 21
88.08
13.16 22 7708
6 15.17 23
8363
7 86.76 24
, 38.05
8 9.123 25
62.11 A
2297 26 1089
11 532 _ 27
651.8
12 34.81 28
654.9
13 782.1 29
654.9
14 20.97
966.8
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