NOVEL SUBSTITUTED IMIDAZOPYRIMIDINES AS GPBAR1 RECEPTOR MODULATORS
FIELD OF THE INVENTION
The present invention relates to novel substituted imidazo[l,2-a]pyrimidine compounds of
formula (I), their pharmaceutically acceptable salts, and their isomers, stereoisomers,
conformers, tautomers, polymorphs, hydrates and solvates. The present invention also
encompasses pharmaceutically acceptable compositions of said compounds and process for
preparing the same. The invention further relates to the use of the above-mentioned
compounds for the preparation of medicament for use as pharmaceuticals.
BACKGROUND OF THE INVENTION
Diabetes is a clinical condition in which the blood glucose levels elevate because of
inadequate insulin secretion to handle blood glucose and/or inadequate response to insulin
(insulin resistance). Type II Diabetes (NIDDM) is a growing threat to the global health by
virtue of its association with cluster of diseases that includes glucose intolerance, insulin
resistance, obesity, dyslipidemia and hypertension, collectively known as metabolic
syndrome. Data from global studies demonstrates that the number of people with diabetes in
2011 has reached a staggering 366 million and 4.6 million deaths are due to diabetes
(International Diabetes Federation, Sept, 2011). Obesity, a common metabolic syndrome
associated with diabetes, is second leading cause of preventable death which results from a
complex interaction of genetic, behavioral and environmental factors causing an imbalance
between energy intake and energy expenditure. It is well documented that patient with
metabolic syndrome have higher risk for coronary heart disease and stroke (Grundy et. al.
Circulation, 112: 2735, 2005).
Type II diabetes and obesity are currently treated at several levels, starting from first level
therapy of diet and/or exercise alone or in combination of therapeutic agents to insulin
injections.
Available therapies have proved inadequate to fulfill existing need for treatment of diabetes,
obesity and associated metabolic disorders as it is evident by the figure demonstrating
increased incidence and complications. Therefore, there exists need for better therapeutic
approach which can treat primary conditions such as diabetes and obesity and reduces the
risk of associated complications such as metabolic syndromes.
Bile acids play essential roles in the absorption of dietary lipids and cholesterol catabolism.
In recent years, an important role for bile acids as signaling molecules has emerged that can
activate bile acid receptors to initiate signaling pathways and regulate gene expression. Bile
acids are ligands for variety of receptors including Farnesoid X receptor (FXR) and TGR5
(Gpbarl). Through activation of these receptors, bile acids can regulate their own synthesis,
storage, enterohepatic circulation and also triglyceride, cholesterol, energy and glucose
homeostasis.
TGR5, in the literature termed, Gpbarl, GPR131 or BG37, was identified as a G-protein
coupled receptor (GPCR) responsive to bile acids (Kawamata et al, JBC 2003, 278, 9435).
TGR5 is ubiquitously expressed but its expression levels vary in different tissues, with high
expression in liver, intestine, brown adipose tissue and spleen. Watanabe (Nature 2006, 439,
7075) showed that the administration of bile acid to mice increases energy expenditure in
brown adipose tissue, preventing obesity and insulin resistance. Bile acid binds to TGR5 and
induces thyroid hormone activating enzyme type 2 idothyronine deiodinase (D2), which
converts locally available thyroxine (T4) to tri-iodothyronine (T3), resulting in increased
energy expenditure without leading to changes in circulating thyroid hormone levels (Trends
in pharmacological sciences, 30, 11, 2009 570-580).
In addition to involvement of TGR5 in energy homeostasis, bile acid activation of membrane
receptor has also been reported to promote the production of glucagon-like peptide 1 (GLP-
1) in murine enteroendocrine cell lines (Katsuma et al BBRC 2005, 329, 386-390). GLP-1
stimulates insulin release in glucose dependent manner in humans. Studies have also
demonstrated that GLP-1 is necessary for normal glucose homeostasis. In addition, GLP-1
can exert several effects in diabetes and obesity including 1) increased glucose disposal, 2)
suppression in glucose production, 3) reduced gastric emptying, and 4) reduction in food
intake and weight loss.
It has been also demonstrated that activation of TGR5 prevents atherosclerotic lesion
formation in Ldlr-/- mice, a commonly used mouse model of atherosclerosis, through an
effect on macrophage foam cell formation (Pols et al., 2011 Cell Metabolism 14, 747-757).
TGR5 is highly expressed in resting CD14+ monocytes in fractionated human leukocytes,
adherent alveolar macrophage cells, and Kupffer cells in liver, indicating a potential role of
TGR5 in modulating inflammation. Activation of TGR5 in Kupffer cells (Keitel et al.,
Biochemical and Biophysical Research Communications, 372, 1, 78-84, 2008) and THP-1
cells over expressing TGR5 (Kawamata et al., Journal of Biological Chemistry, 278, 11,
9435-9440, 2003) suppressed lipopolysaccharide- (LPS-)induced productions of cytokines,
suggesting that TGR5 is a mediator in the suppression of macrophage functions by BAs.
These effects of TGR5 receptors are very relevant in metabolic syndrome as the low grade
inflammation contributes to the development of metabolic syndrome. Thus, TGR5 agonist
has shown potential in the intervention of metabolic syndrome and vascular and hepatic
inflammatory conditions such as atherosclerosis and Non Alcoholic Fatty Liver Disease
(NAFLD) (Pols et al., 2011 J Hepatol. 2011 Jun;54(6): 1263-72).
Experimental evidences leads to the fact that TGR 5 may play a potential role in type-2
diabetes and energy metabolism and inflammation & foam cell formation, which makes it a
novel attractive target for the treatment of cardiometabohc disorders including diabetes,
obesity, dyslipidemia, metabolic syndrome, atherosclerosis and non alcoholic fatty liver
disease.
Recently, 3-Aryl-4-isoxazolecarboxamides have been disclosed by Evans et al, as TGR5
receptor agonists which are potentially useful therapeutics for metabolic disorders such as
type II diabetes and its associated complications (JMC, 2009, vol 52, no 24, 7962-65).
US 20080031968 discloses a method of treating a human for a disease or condition selected
from the group consisting of hypothyroidism; hypertriglyceridemia occurring without obesity
or diabetes; thyroid dysfunction; resistance to thyroid hormone; low T3 syndrome; Wilson's
syndrome; depression; attention deficit disorder; insulin resistance occurring without diabetes
or obesity; glucose intolerance occurring without diabetes or obesity; hypertension;
infertility; cardiac insufficiency; Alzheimer's disease, Parkinson's disease; autism; and the
aging process; said process comprising administering to said human a therapeutically
effective amount of an agonist of the G protein coupled receptor TGR5.
WO 2004067008 discloses fused heterocyclic compounds as TGR5 receptor agonist, which
is useful in treating various diseases.
International publications WO 2008067222 Al discloses pyrrolo[l,2-a][l,4-diazepine
derivatives useful as modulators of TGR5 and method for the treatment of prevention of
metabolic, cardiovascular and inflammatory disease.
WO 2011057145 and WO 2011113606 discloses certain organic compounds like
imidazopyridines, synthesis thereof and method of using same to treat or prevent tuberculosis
in a subject or to inhibit fungal growth on plant species.
There still exists need in art to provide novel small compounds, which are TGR5 modulators.
The compounds of the present invention provide a novel substituted imidazo[l,2-
a]pyrimidine compounds that binds to Gpbarl receptors and thus useful for treatment of
cardiometabolic disorders including diabetes, obesity, dyslipidemia, metabolic syndrome,
atherosclerosis and non alcoholic fatty liver disease.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides novel compounds of formula (I),
their pharmaceutically acceptable salts and their isomers, stereoisomers, conformers,
tautomers, polymorphs, hydrates and solvates;
wherein,
n = 0 o l ;
m = 0, 1, 2 or 3;
Y = CH, N or S, wherein ring containing Y group, may be optionally attached to imidazole
ring through -NH, -N(alkyl), O or S;
Alk is optionally substituted straight chain alkyl, branched chain alkyl or cycloalkyl;
R is selected from the group consisting of hydrogen, halo, cyano, nitro, Ci_8alkyl, hydroxy, -
0-Ci_8alkyl, -CF3, -OCF3, -N^XCO-alkyl), -N(R4)(S0 2-aryl), -N(R4)(S0 2- heteroaryl), -
N(R4)(S0 2-heterocyclyl), -N(R4)(C(0)0-R 4), -N(R4)(C(0)0-aryl),
-N(R4)(C(0)0-heteroaryl), -N(R4)(C(0)0-heterocyclyl), -N(R4)C(0)N(R 4)(R4),
-N(R4)C(0)N(R 4)(aryl), -N(R4)C(0)N(R 4)(heteroaryl), -N(R4)C(0)N(R 4)(heterocyclyl), -
N(R4)S0 2N(R4)(R4), -N(R4)S0 2N(R4)(aryl), -N(R4)S0 2N(R4)(heteroaryl),
-N(R4)S0 2N(R4)(heterocyclyl), -OC(0)(R4), -O(aryl), -O(heteroaryl), -O(heterocyclyl), -
S(R4), -S-aryl, -S-heteroaryl, -S-heterocyclyl, -N(R4)(R4), -N(R4)(aryl), -N(R4)(heteroaryl), -
N(R4)(heterocyclyl), -C(0)(R 4), -C(0)(aryl), -C(0)(heteroaryl),-C(0)(heterocyclyl), -
C(0)N(R 4)(R4), -C(0)N(R 4)(aryl), -C(0)N(R 4)(heteroaryl), -C(0)N(R 4)(heterocyclyl), -
C(0)0-(R4), -C(0)0-aryl, -C(0)0-heteroaryl, -C(0)0-heterocyclyl, -S(0)(aryl), -
S(0)(heteroaryl), -S(0)(heterocyclyl), -S0 2(aryl), -S0 2(heteroaryl), -
S0 2(heterocyclyl), -S0 2N(R4)(R4), -S0 2N(R4)(aryl), -S0 2 N(R4)(heteroaryl), -S0 2
N(R4)(heterocyclyl), aryl, heteroaryl and heterocyclyl;
R2 is selected from the group consisting of halo, cyano, nitro, Ci-salkyl, hydroxy, CF3, -
OCF3, -amino, -0(Ci_8alkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), -S(R4), -S-aryl, -Sheteroaryl,
-S-heterocyclyl, -C(0)0-(R4), -C(0)0-aryl, -C(0)0-heteroaryl, -C(0)0-
heterocyclyl, -S0 2N(R4)(R4), -S0 2N(R4)(aryl), -S0 2N(R4)(heteroaryl), -S0 2
N(R4)(heterocyclyl), aryl, heteroaryl and heterocyclyl; or
R & R2 when present on adjacent carbon atom may join together to form cycloalkenyl, aryl,
heteroaryl or heterocyclyl ring;
R3 is selected from the group consisting of hydrogen, cyano, nitro, hydroxy, -0(Ci_8 alkyl),
-OCF3, -N(R4)(CO-R4), -N^XCO-aryl), -N(R4)(CO-heteroaryl), -N(R4)(S0 2-R4), -
N(R4)(S0 2-CF3), -N(R4)(S0 2-aryl), -N(R4)(S02-heteroaryl), -N(R4)(S02- heterocyclyl), -
N(R4)(C(0)0-R 4), -N(R4)(C(0)0-aryl), -N(R4)(C(0)0-heteroaryl), -N(R4)(C(0)0-
heterocyclyl), -N(R4)C(0)N(R 4)(R4), -N(R4)C(0)N(R 4)(aryl), -N(R4)C(0)N(R 4)(heteroaryl),
-N(R4)C(0)N(R 4)(heterocyclyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), -S(R4), -S-aryl, -
S-heteroaryl, -S-heterocyclyl, -N(R4)(R4), -N(R4)(aryl), -N(R4)(heteroaryl),
N(R4)(heterocyclyl), -C(0)(R 4), -C(0)(aryl), -C(0)(heteroaryl), -C(0)(heterocyclyl), -
C(0)N(R4)(R 4), -C(0)N(R4)(aryl), -C(0)N(R 4)(heteroaryl), -C(0)N(R 4)(heterocyclyl), -
C(0)0-(R4), -C(0)0-aryl, -C(0)0-heteroaryl, -C(0)0-heterocyclyl, S(0)-(Ci_8alkyl), -
S(0)(aryl), -S(0)(heteroaryl), -S(0)(heterocyclyl), -S0 2(Ci_8alkyl), -S0 2(aryl), -
S0 2(heteroaryl), -S0 2(heterocyclyl), -S0 2N(R4)(R4), -S0 2N(R4)(aryl),
S0 2N(R4)(heteroaryl), -S0 2N(R4)(heterocyclyl) and -S0 2 N(R4)(cycloalkyl); and
R is hydrogen or -Ci-salkyl.
In another embodiment, the present invention provides novel compounds of formula (I),
their pharmaceutically acceptable salts and their isomers, stereoisomers, conformers,
tautomers, polymorphs, hydrates and solvates;
wherein,
n = 0 or 1;
m = 0, 1, 2 or 3;
Y = CH, N or S, wherein ring containing Y group, may be optionally attached to imidazole
ring through -NH, -N(alkyl), O or S;
Alk is optionally substituted straight chain alkyl, branched chain alkyl or cycloalkyl;
R is selected from the group consisting of hydrogen, halo, cyano, Ci-salkyl, hydroxy, -O-Cigalkyl,
-CF3, -OCF3, -N(R4)(S0 2-aryl), -N(R4)(S0 2-heteroaryl), -N(R4)(S0 2-heterocyclyl), -
N(R4)(C(0)0-R 4), -N(R4)(C(0)0-aryl), -N(R4)(C(0)0-heteroaryl), -N(R4)(C(0)0-
heterocyclyl), -N(R4)C(0)N(R 4)(R4), -N(R4)S0 2N(R4)(aryl), _-0(aryl), -S(R4), -N(R4)(R4), -
N(R4)(aryl), -C(0)(heterocyclyl), -C(0)N(R 4)(R4), -C(0)N(R 4)(aryl), -S0 2(aryl), -
S0 2N(R )(R ), -S0 2N(R )(aryl), aryl, heteroaryl and heterocyclyl;
R2 is selected from the group consisting of halo, cyano, Ci-salkyl, hydroxy, CF3, -OCF3, -
amino, -0(Ci_8alkyl), -O(aryl), -S-aryl, -C(0)0-(R 4), -S0 2N(R4)(R4), -S0 2N(R4)(aryl), aryl,
heteroaryl and heterocyclyl; or
R & R2 when present on adjacent carbon atom may join together to form cycloalkenyl, aryl,
heteroaryl or heterocyclyl ring;
R is selected from the group consisting of hydrogen, cyano, nitro, hydroxy, -0(Ci_8alkyl), -
N(R4)S0 2(aryl), -N(R4)(C(0)0-R 4), -N(R4)C(0)N(R 4)(R4), - N(R4)C(0)N(R 4)(aryl), -
N(R4)(R4), -C(OXheterocyclyl), - C(0)0-(R 4), -S0 2(aryl) and -S0 2N(R4)(aryl); and
R is hydrogen or -Ci-salkyl.
In another embodiment, the present invention provides novel compounds of formula (I),
(I)
their pharmaceutically acceptable salts and their isomers, stereoisomers, conformers,
tautomers, polymorphs, hydrates and solvates;
wherein,
n = 0 or 1;
m = 0, 1 or 2;
Y = CH, N or S, wherein ring containing Y group, may be optionally attached to imidazole
ring through -NH or O;
Alk is optionally substituted straight chain alkyl, branched chain alkyl or cycloalkyl;
R is selected from the group consisting of hydrogen, halo, cyano, Ci-salkyl, hydroxy, -0-Ci_
8alkyl, -CF3, -OCF3, - , -SC , aryl, heteroaryl and heterocyclyl;
R2 is selected from the group consisting of halo, Ci-salkyl, hydroxy, -0(Ci_ 8alkyl), -C(0)0-
(R4), -S0 2N(R4)(R4) and heterocyclyl; or
R &R2 when present on adjacent carbon atom may join together to form cycloalkenyl, ring;
R3 is selected from the group consisting of hydrogen, hydroxy, -N(R4)(C(0)0-R 4),
N(R4)C(0)N(R 4)(R4), -N , -C(0)(heterocyclyl), C(0)0-(R 4) and S0 2(aryl); and
R is hydrogen or -Ci-salkyl.
In another embodiment, the present invention pertains to compounds as above, however only
including pharmaceutically acceptable salts thereof.
In another embodiment, the present invention provides a compound N-(4-chlorophenyl)-2-(4-
fluorophenyl)-N-methylimidazo[l ,2-a]pyrimidine-3-carboxamide or pharmaceutically
acceptable salts and their isomers, stereoisomers, conformers, tautomers, polymorphs,
hydrates and solvates thereof.
In another embodiment, the present invention provides a compound N-(4-chlorophenyl)-2-(4-
fluorophenoxy)-N-methylimidazo[l,2-a]pyrimidine-3-carboxamide or pharmaceutically
acceptable salts and their isomers, stereoisomers, conformers, tautomers, polymorphs,
hydrates and solvates thereof.
In another embodiment, the present invention includes synthetic intermediates that are useful
in preparing the compounds of formula (I) and process for preparing such intermediates.
Another embodiment of the present invention is a method for preparation of compounds of
formula (I) as herein described in Scheme I & II.
Another embodiment of the present invention is a pharmaceutical composition comprising
compounds of formula (I), optionally in admixture with a pharmaceutically acceptable
adjuvant, diluent or carrier.
Another embodiment of the present invention is a method for treating cardiometabolic
disorders including diabetes, obesity, dyslipidemia, metabolic syndrome, atherosclerosis and
non alcoholic fatty liver disease by administering a therapeutically effective amount of
compounds of formula (I) to a mammal in need thereof.
Another embodiment of the present invention is the use of compounds of formula (I) for the
preparation of a medicament for treating cardiometabolic disorders including diabetes,
obesity, dyslipidemia, metabolic syndrome, atherosclerosis and non alcoholic fatty liver
disease.
Another embodiment of the present invention is a pharmaceutical composition comprising N-
(4-chlorophenyl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-carboxamide or
pharmaceutically acceptable salts and their isomers, stereoisomers, conformers, tautomers,
polymorphs, hydrates and solvates thereof, optionally in admixture with a pharmaceutically
acceptable adjuvant, diluent or carrier.
Another embodiment of the present invention is a pharmaceutical composition comprising N-
(4-chlorophenyl)-2-(4-fluorophenoxy)-N-methylimidazo[l,2-a]pyrimidine-3-carboxamide or
pharmaceutically acceptable salts and their isomers, stereoisomers, conformers, tautomers,
polymorphs, hydrates and solvates thereof, optionally in admixture with a pharmaceutically
acceptable adjuvant, diluent or carrier.
Another embodiment of the present invention is a method of treating cardiometabolic
disorders including diabetes, obesity, dyslipidemia, metabolic syndrome, atherosclerosis and
non alcoholic fatty liver disease by administering a therapeutically effective amount of a N-
(4-chlorophenyl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-carboxamide or
pharmaceutically acceptable salts and their isomers, stereoisomers, conformers, tautomers,
polymorphs, hydrates and solvates thereof to a mammal in need thereof.
Another embodiment of the present invention is a method of treating cardiometabolic
disorders including diabetes, obesity, dyslipidemia, metabolic syndrome, atherosclerosis and
non alcoholic fatty liver disease by administering a therapeutically effective amount of a N-
(4-chlorophenyl)-2-(4-fluorophenoxy)-N-methylimidazo[l,2-a]pyrimidine-3-carboxamide or
pharmaceutically acceptable salts and their isomers, stereoisomers, conformers, tautomers,
polymorphs, hydrates and solvates thereof to a mammal in need thereof.
Another embodiment of the present invention is the use of a N-(4-chlorophenyl)-2-(4-
fluorophenyl)-N-methylimidazo[l ,2-a]pyrimidine-3-carboxamide or pharmaceutically
acceptable salts and their isomers, stereoisomers, conformers, tautomers, polymorphs,
hydrates and solvates thereof for the preparation of a medicament for treating
cardiometabolic disorders including diabetes, obesity, dyslipidemia, metabolic syndrome,
atherosclerosis and non alcoholic fatty liver disease.
Another embodiment of the present invention is the use of a N-(4-chlorophenyl)-2-(4-
fluorophenoxy)-N-methylimidazo[l ,2-a]pyrimidine-3-carboxamide or pharmaceutically
acceptable salts and their isomers, stereoisomers, conformers, tautomers, polymorphs,
hydrates and solvates thereof for the preparation of a medicament for treating
cardiometabolic disorders including diabetes, obesity, dyslipidemia, metabolic syndrome,
atherosclerosis and non alcoholic fatty liver disease.
Another embodiment of the present invention provides the use of compound of formula (I)
for the preparation of salts, polymorphs, hydrates and solvates of compound of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides novel compounds of formula (I),
(I)
their pharmaceutically acceptable salts and their isomers, stereoisomers, conformers,
tautomers, polymorphs, hydrates, and solvates, wherein Ri, R2, R3, R4, Y, m and n are as
defined herein above.
A family of specific compounds of particular interest within the above formula (I) consists of
compound and pharmaceutically acceptable salts thereof as follows:
Chemical Name
N-(4-chlorophenyl)-N-methyl-2-phenylimidazo[l,2-a]pyrimidine-3-
carboxamide
N-(3-chlorophenyl)-N-methyl-2-phenylimidazo[l,2-a]pyrimidine-3-
carboxamide
(4- {methyl[(2-phenylimidazo[ 1,2-a]pyrimidin-3-yl)carbonyl] amino }phenyl)
acetic acid
2-(4-chlorophenyl)-N-(2,3-dihydro-lH-inden-5-yl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide
N,2-bis(4-chlorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-carboxamide
N-(2,3-dihydro-lH-inden-5-yl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide
2-(biphenyl-4-yl)-N-(4-chlorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide
2-(biphenyl-4-yl)-N-(2,3-dihydro-lH-inden-5-yl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(3,4-dimethoxyphenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-N-methyl-2-(pyridin-2-yl)imidazo[l,2-a]pyrimidine-3-
carboxamide
N-(4-chlorophenyl)-N-methyl-2,6-diphenylimidazo[l,2-a]pyrimidine-3-
carboxamide
N-(2,3-dihydro-lH-inden-5-yl)-2-(3,4-dimethoxyphenyl)-Nmethylimidazo[
l,2-a]pyrimidine-3-carboxamide
Chemical Name
N-(4-chlorophenyl)-2-(3,4-dichlorophenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(2,3-dihydro-lH-inden-5-yl)-2-(3,4-dihydroxyphenyl)-Nmethylimidazo[
1,2-a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-methoxyphenyl)-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide
N-(2,3-dihydro-lH-inden-5-yl)-N-methyl-2-(pyridin-2-yl)imidazo[l,2-a]
pyrimidine-3-carboxamide
2-(4-chlorophenyl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide
2-(4-chlorophenyl)-N-(3,4-dimethoxyphenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-N-methyl-2-(pyridin-3-yl)imidazo[l,2-a]pyrimidine-3-
carboxamide
2-(2,4-dichlorophenyl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N,2-bis(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-N-methyl-2-[2-(trifluoromethyl)phenyl]imidazo[l,2-a]
pyrimidine-3-carboxamide
2-(4-chlorophenyl)-N-[4-(dimethylsulfamoyl)phenyl]-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide
2-(4-chlorophenyl)-N-(2,4-dimethoxyphenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-fluorophenyl)-N-methyl-2-phenylimidazo[l,2-a]pyrimidine-3-
carboxamide
2-(4-chlorophenyl)-N-(3,4-dihydroxyphenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
2-(l,3-benzodioxol-5-yl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
Chemical Name
2-(l,3-benzodioxol-5-yl)-N-(4-chlorophenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-hydroxyphenyl)-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide
N-(4-chlorophenyl)-N-methyl-2-[3-(trifluoromethyl)phenyl]imidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenyl)imidazo[l,2-a]pyrimidine-3-
carboxamide
N-(4-fluorophenyl)-N-methyl-2-[3-(trifluoromethyl)phenyl]imidazo[l,2-a]
pyrimidine-3-carboxamide
N-(2,4-dimethoxyphenyl)-2-(4-fluorophenyl)imidazo[l,2-a]pyrimidine-3-
carboxamide
2-(3-cyanophenyl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-2-(3-cyanophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide
N-(4-chlorophenyl)-2-[4-(dimethylsulfamoyl)phenyl]-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide;
2-[4-(dimethylsulfamoyl)phenyl]-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide
N-(2,4-difluorophenyl)-2-(4-fluorophenyl)imidazo[l,2-a]pyrimidine-3-
carboxamide
N-(2,4-difluorophenyl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide
2-(3-fluoro-4-methoxyphenyl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide
2-(3-fluoro-4-hydroxyphenyl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide
N-(2,4-difluorophenyl)-2-(3-fluoro-4-methoxyphenyl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide
Chemical Name
N-(4-chlorophenyl)-2-(3-fluoro-4-methoxyphenyl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide
N-(3-chloro-4-fluorophenyl)-2-(3-fluoro-4-methoxyphenyl)-Nmethylimidazo[
l,2-a] pyrimidine-3-carboxamide
N-(2,4-difluorophenyl)-2-(4-fluorophenoxy)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-N-methyl-2-phenoxyimidazo[l,2-a]pyrimidine-3-
carboxamide
2-(4-chlorophenoxy)-N-(4-chlorophenyl)-N-methylimidazo[l,2-a]pyrimidine
3-carboxamide
N-(4-chlorophenyl)-2-(4-methoxyphenoxy)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fl uorophenoxy)-N-methylimidazo[l ,2-a]pyrimidine
3-carboxamide
2-(4-chlorophenoxy)-N-(4-fl uorophenyl)-N-methylimidazo[l ,2-a]pyrimidine
3-carboxamide
2-(4-fluorophenoxy)-N-(4-methoxyphenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(3-fluoro-4-hydroxyphenyl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-cyanophenyl)-N-methylimidazo[l ,2-a]pyrimidine-3
carboxamide
2-(4-cyanophenyl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide
N-(3-chloro-4-fluorophenyl)-2-(4-cyanophenyl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide
N-(4-chlorophenyl)-N-(4-fluorobenzyl)-2-(4-fluorophenyl)imidazo[l,2-a]
pyrimidine-3-carboxamide
2-(2,6-dichlorophenoxy)-N-(2,4-difluorophenyl)-N-methylimidazo [1,2-a]
pyrimidine-3-carboxamide
Chemical Name
2-(2,6-dichlorophenoxy)-N-(4-fluorophenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(2,4-difluorophenoxy)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
2-(5-chlorothiophen-2-yl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(5-chlorothiophen-2-yl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-N-methyl-2-[4-(trifluoromethyl)phenyl]imidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-fluorophenyl)-N-methyl-2-[4-(trifluoromethyl)phenyl]imidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-(propan-2-yl)imidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenoxy)imidazo[l,2-a]pyrimidine-3-
carboxamide
N-(4-fluorophenyl)-2-[3-(trifluoromethyl)phenyl]imidazo[l,2-a]pyrimidine-3
carboxamide
N-cyclopropyl-N,2-bis(4-fluorophenyl)imidazo[l,2-a]pyrimidine-3-
carboxamide
N-cyclopropyl-N-(4-fluorophenyl)-2-[3-(trifluoromethyl)phenyl]imidazo[l,2
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-N-cyclopropyl-2-[3-(trifluoromethyl)phenyl]imidazo[l,2
a]pyrimidine-3-carboxamide
methyl {2-(4-fluorophenyl)-3- [(4-fluorophenyl)(methyl)carbamoyl]
imidazo[1,2-a]pyrimidin-6-yl }carbamate
methyl {3-[(4-chlorophenyl)(methyl)carbamoyl]-2-(4-fluorophenyl)
imidazo[1,2-a]pyrimidin-6-yl }carbamate
6-(carbamoylamino)-N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methyl
imidazo[l,2-a]pyrimidine-3-carboxamide
Chemical Name
6-(carbamoylamino)-N,2-bis(4-fluorophenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
6-(carbamoylamino)-2-(4-fluorophenyl)-N-(4-methoxyphenyl)-Nmethylimidazo[
1,2-a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-[3-(dimethylamino)phenyl]-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
2-[3-(dimethylamino)phenyl]-N-(4-fluorophenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(5-fluoro-2-hydroxyphenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
2-(5-fluoro-2-hydroxyphenyl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
2-(5-fluoro-2-hydroxyphenyl)-N-(4-methoxyphenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-N-methyl-2-[4-(propan-2-yl)phenyl]imidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-fluorophenyl)-N-methyl-2-[4-(propan-2-yl)phenyl]imidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(2,6-dihydroxyphenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
2-(2,6-dihydroxyphenyl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(2-hydroxy-6-methoxyphenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-fluorophenyl)-2-(2-hydroxy-6-methoxyphenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-N-methyl-2-(thiophen-2-yl)imidazo[l,2-a]pyrimidine-3-
carboxamide
N-(4-fluorophenyl)-N-methyl-2-(thiophen-2-yl)imidazo[l,2-a]pyrimidine-3-
carboxamide
Chemical Name
N-(4-chlorophenyl)-2-(5-fluoro-2-hydroxyphenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
2-(5-fluoro-2-hydroxyphenyl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(furan-2-yl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide
N-(4-fluorophenyl)-2-(furan-2-yl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide
N-(4-chlorophenyl)-2-(2,3-dihydro-l,4-benzodioxin-5-yl)-Nmethylimidazo[
1,2-a]pyrimidine-3-carboxamide
2-(2,3-dihydro-l,4-benzodioxin-5-yl)-N-(4-fluorophenyl)-Nmethylimidazo[
1,2-a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(2-fluoro-4-methoxyphenyl)- N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
2-(2-fluoro-4-methoxyphenyl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-N-methyl-2-[3-(trifluoromethoxy)phenyl]imidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-fluorophenyl)-N-methyl-2-[3-(trifluoromethoxy)phenyl]imidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-N-methyl-2-[4-(methylsulfonyl)phenyl]imidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-fluorophenyl)-N-methyl-2- [4-(methylsulfonyl)phenyl]imidazo[1,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-[(4-methoxyphenyl)amino]-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-fluorophenyl)-2-[(4-methoxyphenyl)amino]-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-[(4-chlorophenyl)amino]-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
Comp. Chemical Name
No.
104 2-[(4-chlorophenyl)amino]-N-(4-fluorophenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
105 N-(4-chlorophenyl)-2-[(4-fluorophenyl)amino]-N-methylimidazo[1,2-
a]pyrimidine-3-carboxamide
106 N-(4-fluorophenyl)-2-[(4-fluorophenyl)amino]-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
107 N-(4-chlorophenyl)-2-[(4-methoxyphenyl)amino]-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
108 N-(4-fluorophenyl)-2-[(4-methoxyphenyl)amino]-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
109 N-(4-chlorophenyl)-2-[(3-fluoro-4-hydroxyphenyl)amino]-Nmethylimidazo[
l,2-a]pyrimidine-3-carboxamide
110 N-(4-chlorophenyl)-N-methyl-2-{ [2-
(trifluoromethyl)phenyl]amino}imidazo[l,2-a]pyrimidine-3-carboxamide
111 N-(4-fluorophenyl)-N-methyl-2-{ [2-
(trifluoromethyl)phenyl]amino}imidazo[l,2-a]pyrimidine-3-carboxamide
112 N-(4-chlorophenyl)-N-methyl-2-{ [3-
(trifluoromethyl)phenyl]amino}imidazo[l,2-a]pyrimidine-3-carboxamide
113 N-(4-fluorophenyl)-N-methyl-2-{ [3-
(trifluoromethyl)phenyl]amino}imidazo[l,2-a]pyrimidine-3-carboxamide
114 N-(4-chlorophenyl)-6-(dimethylamino)-2-(4-fluorophenyl)-Nmethylimidazo[
l,2-a]pyrimidine-3-carboxamide
115 N-(4-chlorophenyl)-2-[(4-fluorophenyl)amino]-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
116 methyl {3-[(4-chlorophenyl)(methyl)carbamoyl]-2-(4-
fluorophenyl)imidazo[l,2-a]pyrimidin-6-yl}methylcarbamate
117 N-(4-chlorophenyl)-2-(4-fluorophenyl)-5,7-dihydroxy-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
118 N-(4-chlorophenyl)-2-(4-fluorophenyl)-N,7-dimethylimidazo[l ,2-
a]pyrimidine-3-carboxamide
Chemical Name
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methyl-6-[methyl(propan-2-
ylcarbamoyl)amino]imidazo[l,2-a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenyl)-7-hydroxy-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenyl)-7-hydroxyimidazo[l,2-a]pyrimidine-3
carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenyl)-5-hydroxy-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenyl)-5-hydroxyimidazo[l,2-a]pyrimidine-3
carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenyl)-7-hydroxy-N-
(hydroxymethyl)imidazo[l,2-a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-(hydroxymethyl)imidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluoro-2-hydroxyphenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chloro-2-hydroxyphenyl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
3-[(4-chlorophenyl)(methyl)carbamoyl]-2-(4-fluorophenyl)imidazo[l,2-
a]pyrimidine-6-carboxylic acid
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methyl-6-
(phenylsulfonyl)imidazo[l,2-a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methyl-6-(pyrrolidin-lylcarbonyl)
imidazo[l,2-a]pyrimidine-3-carboxamide
N-(4-fl uorophenyl)-N-methyl-2-(morpholin-4-yl)imidazo[l ,2-a]pyrimidine-3
carboxamide
N-(4-chlorophenyl)-2-(3-fluorophenoxy)-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide
2-(4-fluorophenyl)-N-(4-methoxyphenyl)-N-methylimidazo[l,2-a]pyrimidine
3-carboxamide
Chemical Name
ethyl 4-[{ [2-(4-fluorophenyl)imidazo[l,2-a]pyrimidin-3-
yl]carbonyl}(methyl)amino]benzoate
N-(4-chlorophenyl)-2-(4-fluoro-2-methoxyphenyl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide
N-(4-chlorophenyl)-N-cyclopropyl-2-(4-fluorophenyl)imidazo[l,2-a]
pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fl uorophenyl)-N-methylimidazo[l ,2-a]pyrimidinecarboxamide
hydrochloride (1:1)
N-(4-chlorophenyl)-2-(4-fl uorophenyl)-N-methylimidazo[l ,2-a]pyrimidinecarboxamide
sulfate (1:1)
N-(4-chlorophenyl)-2-(4-fl uorophenyl)-N-methylimidazo[l ,2-a]pyrimidinecarboxamide
4-methylbenzenesulfonate (1:1)
N-(4-chlorophenyl)-2-(4-fl uorophenyl)-N-methylimidazo[l ,2-a]pyrimidinecarboxamide
methanesulfonate (1:1)
2-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-carboxamide
N-(4-cyclohexylphenyl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide
2-(4-fluorophenyl)-N-methyl-N-[4-(morpholin-4-yl)phenyl]imidazo[l,2-
a]pyrimidine-3-carboxamide
N-(biphenyl-3-yl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide
N-(4-cMorophenyl)-2-(4-fluoro-3-methoxyphenyl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide
N-(4-chlorophenyl)-N-methyl-2- {4-[(phenylsulfonyl) amino] phenyl }
imidazo[l,2-a]pyrimidine-3-carboxamide
methyl (4-{3-[(4-chlorophenyl)(methyl)carbamoyl]imidazo[l,2-a]pyrimidinyl
}phenyl)carbamate
N-(4-chlorophenyl)-N-methyl-2- {4-
[(methylcarbamoyl)amino]phenyl}imidazo[l,2-a]pyrimidine-3-carboxamide
Chemical Name
N-(4-chlorophenyl)-N-methyl-2-{4-
[(phenylsulfamoyl)amino]phenyl}imidazo[l,2-a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-[4-(4-fluorophenoxy)phenyl]-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide
N-(4-chlorophenyl)-N-methyl-2-[4-(methylsulfanyl)phenyl]imidazo[l,2-a]
pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-{4-[(4-fluorophenyl)amino]phenyl}-N-methylimidazo
[l,2-a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-N-methyl-2-[4-(piperazin-l-ylcarbonyl)phenyl] imidazo
[l,2-a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-N-methyl-2-{4-
[methyl(phenyl)carbamoyl]phenyl}imidazo[l,2-a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-{4-[(4-fluorophenyl)sulfonyl]phenyl}-N-methylimidazo
[l,2-a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-{4-[(4-fluorophenyl)sulfamoyl]phenyl}-N-methyl
imidazo[l,2-a]pyrimidine-3-carboxamide
N-[4-(4-chlorophenoxy)phenyl]-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide
N-{4-[(4-chlorophenyl)sulfanyl]phenyl}-2-(4-fluorophenyl)-N-methylimidazo
[l,2-a]pyrimidine-3-carboxamide
N-methyl-2-phenyl-N-[4-(phenylsulfamoyl)phenyl]imidazo[l,2-a]pyrimidine-
3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methyl-6-[(phenylcarbonyl)
amino]imidazo[l,2-a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methyl-6-[(phenylsulfonyl)
amino]imidazo[l,2-a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methyl-6-[(phenylcarbamoyl)
amino]imidazo[l,2-a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenyl)-6-hydroxy-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide
Chemical Name
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methyl-6-(phenylsulfamoyl)
imidazo[1,2-a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenoxy)-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide 4-methylbenzenesulfonate (1:1)
N-(4-chlorophenyl)-2-(4-fluorophenoxy)-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide benzenesulfonate (1:1)
N-(4-chlorophenyl)-2-(4-fluorophenoxy)-6-hydroxy-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenoxy)-5-hydroxy-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenoxy)-7-hydroxy-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenoxy)-6-hydroxyimidazo[l,2-a]pyrimidine
3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenoxy)-5-hydroxyimidazo[l,2-a]pyrimidine
3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenoxy)-7-hydroxyimidazo[l,2-a]pyrimidine
3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenoxy)-N-(hydroxymethyl)imidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluoro-3-hydroxyphenoxy)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluoro-3-hydroxyphenoxy)imidazo[l,2-a]pyrimidine
3-carboxamide
N-(4-chloro-3-hydroxyphenyl)-2-(4-fluorophenoxy)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chloro-3-hydroxyphenyl)-2-(4-fluorophenoxy)imidazo[l,2-a]pyrimidine
3-carboxamide
2-(4-fluorophenoxy)imidazo[l,2-a]pyrimidine-3-carboxamide
In preferred embodiment, the present invention provides a compound selected from the group
comprising of:
Comp Chemical Name
No.
1 N-(4-chlorophenyl)-N-methyl-2-phenylimidazo[l,2-a]pyrimidine-3-
carboxamide;
7 N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
20 N-(4-chlorophenyl)-N-methyl-2-(pyridin-3-yl)imidazo[l,2-a]pyrimidine-3-
carboxamide;
22 N,2-bis(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-carboxamide;
30 N-(4-chlorophenyl)-2-(4-hydroxyphenyl)-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide;
33 N-(4-fluorophenyl)-N-methyl-2-[3-(trifluoromethyl)phenyl]imidazo[l,2-
a]pyrimidine-3-carboxamide;
50 N-(4-chlorophenyl)-2-(4-fluorophenoxy)-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide;
45 N-(3-chloro-4-fluorophenyl)-2-(3-fluoro-4-methoxyphenyl)-Nmethylimidazo[
l,2-a]pyrimidine-3-carboxamide;
136 N-(4-chlorophenyl)-N-cyclopropyl-2-(4-fluorophenyl)imidazo[l,2-a]
pyrimidine-3-carboxamide; and
65 N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-(propan-2-yl)imidazo[l,2-a]
pyrimidine-3-carboxamide or pharmaceutically acceptable salts thereof.
In another embodiment, present invention provides the use of compound of formula (I) for
the preparation of salts, isomers, stereoisomers, conformers, tautomers, polymorphs, hydrates
and solvates of compound of formula (I).
In preferred embodiment present invention provides the use of compound of formula (I) for
the preparation of salts, polymorphs, hydrates and solvates of compound of formula (I).
In another embodiment, present invention provides the process of preparation of polymorph
of compound of formula (I), comprises contacting compound of formula (I) with suitable
solvent or mixture of solvent.
Another embodiment of the present invention provides the process of preparation of salt of
compound of formula (I), comprises contacting compound of formula (I) with suitable acid
or base, optionally in the presence of suitable solvent or mixture of solvent.
DEFINITIONS:
The following definitions apply to the terms as used throughout this specification, unless
otherwise limited in specific instances:
The term "compound" employed herein refers to any compound encompassed by the generic
formula disclosed herein. The compounds described herein may contain one or more double
bonds and therefore, may exist as isomers, stereoisomers, such as geometric isomers, E and Z
isomers, and may possess asymmetric carbon atoms (optical centers) and therefore may exist
as enantiomers, diastereoisomers. Accordingly, the chemical structures described herein
encompasses all possible stereoisomers of the illustrated compounds including the
stereoisomerically pure form (e.g., geometrically pure) and stereoisomeric mixtures
(racemates). The compound described herein, may exist as a conformational isomers such as
chair or boat form. The compounds may also exist in several tautomeric forms including the
enol form, the keto form and mixtures thereof. Accordingly, the chemical structures
described herein encompass all possible tautomeric forms of the illustrated compounds. The
compounds described also include isotopically labeled compounds where one or more atoms
have an atomic mass different from the atomic mass conventionally found in nature.
Examples of isotopes that may be incorporated into the compounds of the invention include,
but are not limited to H, H, 1 C, 14C, 15N, 1 0 , 1 0 , etc. Compounds may exist in nonsolvated
forms as well as solvated forms, including hydrated forms. In general, compounds
may be hydrated or solvated. Certain compounds may exist in multiple crystalline or
amorphous forms. The polymorphic forms can be prepared by the techniques known in the
art. Preferably, a compound of formula (I) is treated with suitable solvent or mixture of
solvents at suitable temperature to produce a polymorphic form of compound of formula (I).
The polymorphic form of compound of formula (I) is crystalline or amorphous form and can
be characterized by techniques known in the art such as XRPD or IR spectrum. In general, all
physical forms are equivalent for the uses contemplated herein and are intended to be within
the scope and spirit of the present invention.
The use of the terms "a" and "an" and "the" and similar referents in the context of describing
the invention (especially in the context of the following claims) are to be construed to cover
both the singular and the plural, unless otherwise indicated herein or clearly contradicted by
context.
Further, it should be understood, when partial structures of the compounds are illustrated, a
dash ("-") indicate the point of attachment of the partial structure to the rest of the molecule.
The nomenclature of the compounds of the present invention as indicated herein is according
to ACD LABS/Chemsketch ® (Product version: 12) IUPAC NAME.
"Pharmaceutically acceptable salt" refers to a salt of a compound, which possesses the
desired pharmacological activity of the parent compound. Such salts include: (1) acid
addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like; or formed with organic
acids such as acetic acid, propionic acid, isobutyric acid, hexanoic acid,
cyclopentanepropionic acid, oxalic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid,
succinic acid, suberic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,
benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, phthalic acid, cinnamic acid, mandelic
acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-
hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-
naphthalenesulfonic acid, 4-toluenesulfonic acid or 4-methylbenzenesulfonic acid,
camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic
acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric
acid, gluconic acid, glucuronic acid, galactunoric acid, glutamic acid, hydroxynaphthoic acid,
salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic
proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an
alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as
ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Also
included are salts of amino acids such as arginate and the like (see, for example, Berge, S.M.,
et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).
As used herein, the term "polymorphs" pertains to compounds having the same chemical
formula, the same salt type and having the same form of hydrate/solvate but having different
crystallographic properties.
As used herein, the term "hydrates" pertains to a compound having a number of water
molecules bonded to the compound.
As used herein, the term "solvates" pertains to a compound having a number of solvent
molecules bonded to the compound.
The term "substituted", as used herein, includes mono- and poly-substitution by a named
substituent to the extent such single and multiple substitution (including multiple
substitution at the same site) is chemically allowed and which means that any one or more
hydrogen on the designated atom is replaced with a selection from the indicated group,
provided that the designated atom's normal valence is not exceeded, and that the
substitution results in a stable compound, for example, when a substituent is keto, then the
two hydrogen on the atom are replaced. All substituents (R, Ri, R2 ....) and their further
substituents described herein may be attached to the main structure at any heteroatom or
carbon atom which results in formation of stable compound.
As used herein, a "halo" or "halogen" substituent is a monovalent halogen radical chosen
from chloro, bromo, iodo and fluoro.
The term "alkyl" or "Alk" used either alone or in attachment with another group refers to a
cyclic, branched, or straight chain saturated aliphatic hydrocarbon radical, which may be
optionally substituted. When a subscript is used with reference to an alkyl, the subscript
refers to the number of carbon atoms that group may contain. For example, a "Ci-Cs" would
refer to any alkyl group containing one to eight carbons in the structure. Alkyl may be
straight chain, branched chain or cyclic. The said alkyl or "alk" may be optionally substituted
with one or more substituent independently selected from the group consisting of -OH, -SH, -
COOH, -oxo, -thioxo, -halo, -amino, -mono(Ci_3alkyl)amino, -di(Ci_3alkyl)amino, -S(Ci_
3alkyl), -aryl, -heteroaryl and -Ci_3 alkoxy.
The term "alkoxy" refers to any alkyl group as defined herein above attached to the parent
molecular moiety through an oxygen bridge.
The term "aryl" refers to an aromatic group which is a 6 to 10 membered monocyclic or
bicyclic carbon-containing ring system, which may be unsubstituted or substituted. The said
aryl may be optionally substituted with one or more substituent independently selected from
the group consisting of halo, cyano, -N(R4)(R4), -OH, -OCi_8 alkyl, -OCF3, -CF3, -N02, -
SCi_8alkyl, -S(0 2)Ci_8alkyl, -COOH, -CON(R 4)(R4), wherein R4 is as defined herein above.
The term "amine" refers to NH2, which is optionally substituted by one or more alkyl, aryl,
heteroaryl, heterocyclyl, urea or carbamate.
The term "cycloalkenyl" refers to a monovalent group derived from a monocyclic or bicyclic
unsaturated carbocyclic ring compound containing between three and twenty carbon atoms
by removal of a single hydrogen atom.
The term "heteroaryl" refers to an aromatic group, which is a 5 to 10 membered monocyclic
or bicyclic ring system, which has at least one heteroatom, which may be unsubstituted or
substituted. The term "heteroatom" as used herein includes oxygen, sulfur and nitrogen. The
said heteroaryl may be optionally substituted with one or more substituent independently
selected from the group consisting of halo, cyano, -N(R4)(R4), -OH,-OCi_8 alkyl, -OCF3, -
CF3, -N02, -SCi-galkyl, -S(0 2)Ci_8alkyl, -COOH,-CON(R 4 )(R4), wherein R4 is as defined
herein above.
The term "heterocyclyl" refers to a fully or partially saturated cyclic group, which is a 5 to 10
membered monocyclic or bicyclic ring system, which has at least one heteroatom, which may
be unsubstituted or substituted. The term "heteroatom" as used herein includes oxygen, sulfur
and nitrogen. The said heterocyclyl may be optionally substituted with one or more
substituent independently selected from the group consisting of halo, cyano, -N(R4)(R4), -
OH, -OCi_8 alkyl, -OCF3, -CF3, -N02, -SCi_8alkyl, -S(0 2)Ci_8alkyl, -COOH,-CON(R 4)(R4),
wherein R4 is as defined herein above.
As used herein the term "contacting" includes coming together, to bring or put in contact,
mixing, interacting, reacting, suspending, dissolving or more than one act as mentioned.
As used herein, the term "mammal" means a human or an animal such as monkeys, primates,
dogs, cats, horses, cows, etc.
The terms "treating" or "treatment" of any disease or disorder as used herein to mean
administering a compound to a mammal in need thereof. The compound may be administered
to provide a prophylactic effect in terms of completely or partially preventing or delaying the
onset of a disease or disorder or sign or symptom thereof; and/or the compound may be
administered to provide a partial or complete cure for a disease or disorder and/or sign or
symptom attributable to the disease or disorder.
The phrase "a therapeutically effective amount" means the amount of a compound that, when
administered to a patient for treating a disease, is sufficient to effect such treatment for the
disease. The "therapeutically effective amount" will vary depending on the compound, mode
of administration, the disease and its severity and the age, weight, etc., of the patient to be
treated.
Throughout this specification and the appended claims it is to be understood that the words
"comprise" and "include" and variations such as "comprises", "comprising", "includes",
"including" are to be interpreted inclusively, unless the context requires otherwise. That is,
the use of these words may imply the inclusion of an element or elements not specifically
recited.
In another embodiment, present invention provides the process for preparing the compounds
of formula (I).
The following reaction schemes are given to disclose the synthesis of the compounds
according to the present invention.
The compound of formula (I) can be prepared by the following methods described in
schemes I & II.
Scheme - 1
In Step (h), the compound of formula (I) can be prepared by reacting the compound of the
formula (VI) with the appropriate secondary amine in the presence of inorganic or organic
base such as triethylamine, potassium carbonate, sodium ethoxide, potassium tert-butoxide or
l'8-diazabicyclo[5,4,0]undec-7-ene in the polar protic or non-polar aprotic solvent like
toluene, xylene, ethanol, acetonitrile or N,N- Dimethyl formamide at a temperature in the
range of 80°C to 130°C for 4 h to 10 h to give the compound of formula (I).
In alternate way, the compound of formula (I) can be prepared by reacting the compound of
the formula (VI) with the appropriate primary amine in the presence of inorganic or organic
base such as triethylamine, potassium carbonate, sodium ethoxide, potassium tert-butoxide or
l'8-diazabicyclo[5,4,0]undec-7-ene in the polar protic or non-polar aprotic solvent like
toluene, xylene, ethanol, acetonitrile or N,N- Dimethyl formamide at a temperature in the
range of 80°C to 130°C for 4 h to 10 h to give the corresponding amide derivative. The
obtained amide derivatives is reacted with appropriate alkyl halide in the presence of
inorganic or organic base such as N-ethyldiisopropylamine, triethylamine, cesium carbonate
or potassium carbonate in polar protic or non-polar aprotic solvent like tetrahydrofuran, N,
N-dimethyl formamide or acetonitrile at a temperature in the range of 0 °C to 60°C for a
period of 30 min to 4 h to give the compound of formula (I).
In Step (i), alternatively, the compound of the formula (VI) is treated with inorganic base
such as sodium hydroxide or potassium hydroxide in a polar protic solvent like ethanol,
methanol, isopropanol at the temperature in the range of 0°C to 60°C for lh to 12 h to give
the corresponding carboxylic acid, which is further treated with N-ethyldiisopropylamine, 1-
hydroxybenzotraizole and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI) or benzotriazole-l-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate
(BOP); or with thionyl chloride or oxalyl chloride in the presence of catalytic amount of
dimethylformamide in a polar protic or non-polar aprotic solvent such as tetrahydrofuran,
acetonitrile or N,N Dimethyl formamide at temperature from 0°C to 60°C for lh to 3 h , then
the appropriate amine is added and stirred at room temperature in the presence of inorganic
or organic base like triethylamine or potassium carbonate for lh tol2 h to give the compound
of formula (I).
In an alternate way, the corresponding carboxylic acid as obtained in step (i) is treated with
alkyl chloroformate in the presence of organic or inorganic base such as Nethyldiisopropylamine,
triethylamine or potassium carbonate in a solvent like
tetrahydrofuran, acetonitrile or toluene at room temperature for a period of 1 h to 4 h to give
the mixed anhydride, which is further reacted with the appropriate amine at the temperature
in the range of 0 °C to 110°C for a period of lh to 6 h to give the compound of formula (I).
In step (g), the compound of the formula (VI) is prepared by reacting the compound of
formula (IV) with formula (V) in the polar protic or aprotic solvent like methanol, ethanol,
isopropanol, N, N-dimethylformamide or N-methyl 2-pyrrolidinone at the temperature in the
range of 90°C to 140°C for 4 -12 h.
In step (f), the compound of the formula (IV) is prepared by reacting the compound of
formula (III) with suitable halogenating reagents such as N-bromosuccinimide or Nchlorosuccinimide
in the presence of catalyst such as ammonium acetate and in the suitable
solvent like diethyl ether, diisopropyl ether or 1, 4-dioxane at the room temperature 1-12
hour.
In step (e), the compound of formula (III) is prepared by reacting the acid chloride with alkyl
acetoacetate in the presence of inorganic or organic base such as pyridine, sodium ethoxide,
sodium hydroxide or anhydrous magnesium chloride and in the non-polar aprotic or polar
aprotic solvent like toluene, tetrahydrofuran under inert atmosphere at the temperature in the
range of 0°C to 60°C for 1-12 hour. Further, the product is treated with suitable base like
sodium hydroxide or potassium hydroxide in the alcoholic solvent like ethanol, methanol or
isopropanol.
In step (c, d), alternatively, the compound of formula (III) is prepared by reacting the acid
chloride with isopropylidene malonate (Meldrum's acid) in the presence of inorganic or
organic base such as triethylamine, pyridine, sodium ethoxide, sodium hydroxide or
anhydrous magnesium chloride and in the non-polar aprotic or polar aprotic solvent like
dichloromethane, toluene, tetrahydrofuran under inert atmosphere at the temperature in the
range of 0°C to 60°C for 1-12 h to give the compound of formula (II), which is refluxed in
alcoholic solvent such as methanol or ethanol.
In step (b), alternatively, the compound of formula (III) is prepared by reacting acid chloride
with alkyl acetate in the presence of suitable base such as sodium hydride or lithium
bis(trimethylsilyl)amide in the non-polar aprotic or polar aprotic solvent like toluene,
tetrahydrofuran or dimethylformamide under inert atmosphere at the temperature in the range
of -20°C to 60°C for 1-6 hour.
In step (a), alternatively, the compound of formula (III) is prepared by reacting acetophenone
derivative with the dialkyl carbonate or alkyl chloroformate in the presence of suitable base
such as sodium hydride, potassium tert-butoxide or lithium bis (trimethylsilyl) amide in the
non-polar aprotic or polar aprotic solvent like toluene, tetrahydrofuran, dimethylformamide
and N-methyl pyrrolidinone under inert atmosphere at the temperature in the range of -20 °C
to 100°C for 1 - 12 hour.
In step (k), the compound of formula (XI) is prepared by reacting the compound of formula
(IX) with the appropriate phenol, thiophenol and aniline in the presence of inorganic or
organic base such as potassium carbonate, sodium carbonate, triethylamine or cesium
carbonate in the non-polar aprotic or polar aprotic solvent like toluene, tetrahydrofuran,
dimethylformamide, N, N-dimethylacetamide and N-methyl pyrrolidinone at the temperature
in the range of 30°C to 140°C for 1 - 12 hour.
The compound of formula (I) can be prepared from compound of formula (XI) in analogues
manner as described in scheme I.
In step (j), the compound of the formula (IX) is prepared by reacting the compound of
formula (V) with dialkyl bromomalonate in the polar protic or polar aprotic solvent like
methanol, ethanol, isopropanol, N, N-dimethylformamide or N-methyl 2-pyrrolidinone at the
temperature in the range of 90°C to 140°C for 4 -12 hr to give the hydroxy-cyclized product,
which is treated with phosphorus oxychloride in the aprotic solvent like toluene,
tetrahydrofuran, under inert atmosphere at the temperature in the range of 20°C to 100°C for
1 - 12 hour.
In step (m), the compound of formula (XI) is prepared by reacting the compound of the
formula (VIII) with triethylamine in the polar protic solvent like ethanol, isopropanol at the
temperature in the range of 30°C to 140°C for 1 - 12 hour.
In step (o), the compound of the formula (XI) is prepared by reacting the compound of
formula (X) with the aryl boronic acid in the non-polar aprotic solvent like 1,2-
dichloroethane or dichloromethane in the presence of base like triethylamine or pyridine
using copper acetate as a catalyst at the temperature in the range of 30°C to 80°C for 4 -12 hr.
In step (n), the compound of the formula (X) is prepared by reacting the compound of
formula (V) with alkyl cyanoacetate such as ethyl cyanoacetate in the polar protic or polar
aprotic solvent like methanol, ethanol, isopropanol, N, N-dimethylformamide or N-methyl 2-
pyrrolidinone at the temperature in the range of 90°C to 140°C for 4 -12 hr to give the aminocyclized
product.
In step (1), the compound of formula (VIII) is prepared by treating the compound of the
formula (VII) with 2-chloropyrimidine derivatives under inert atmosphere at the temperature
in the range of 100 °C to 140°C for 1 - 4 h. The compound of the formula (VII) is prepared
by procedure given in the literature (ARKIVOC 2005 (xiv), 59-70).
A general synthetic method is provided for each of the disclosed groups of chemical
compounds. One of ordinary skill will recognize to substitute appropriately modified starting
material containing the various substituents. One of ordinary skill will readily synthesize the
disclosed compounds according to the present invention using conventional synthetic organic
techniques and microwave techniques from starting material which are either purchased or
may be readily prepared using known methods.
The novel compounds of the present invention were prepared according to the procedure of
the schemes as described herein above, using appropriate materials and are further
exemplified by the following specific examples. The examples are not to be considered nor
construed as limiting the scope of the invention set forth.
EXAMPLES:
Example 1
Preparation of N-(4-chlorophenyl)-2-(4-fluorophenyl) imidazo [1, 2-a] pyrimidine-3-
carboxamide (Compound No. 32)
Step A : Preparation of ethyl 3-(4-fluorophenyl)-3-oxopropanoate
To a stirred solution of 4-fluoroacetophenone (20 g, 144 mmol) and diethyl carbonate (85 ml,
720 mmol), sodium hydride (6.9 g, 144 mmol) was added portion wise at temperature (0°C -
5°C) under nitrogen atmosphere in lhour. The reaction mixture was heated to 60 °C and
stirred for 30 minutes. The reaction mixture was cooled to 0° C and was poured into ice cold
water (150 ml) and extracted with dichloromethane (2 x 100 ml). The combined organic
layer was dried over sodium sulphate, concentrated under vacuo to give 30 g of the titled
product as brown viscous oil.
H NMR (400 MHz, DMSO-d6) d :1.15 -1.18 (3H, t), 4.10 - 4.14 (2H, q), 4.20 (2H, s), 7.61 -
7.64 (2H, d), 7.94 -7.97 (2H,d).
m/z = 211 (M+H)+
Step B : Preparation of ethyl 2-bromo-3-(4-fluorophenyl)-3-oxopropanoate
To a stirred solution of ethyl 3-(4-fluorophenyl)-3-oxopropanoate (30 g,144 mmol) in
diethyl ether (150 ml) , N-Bromo succinimide (25.2 g,144 mmol) was added portionwise at 5
- 10 °C followed by addition of ammonium acetate (2.2 g, 28.8 mmol). The reaction mixture
was stirred at room temperature (25°C- 27°C) for 4 h. The reaction mixture was filtered and
the filtrate was washed with aqueous sodium bicarbonate solution (2 x 50 ml) and finally
with water. The organic layer was dried over sodium sulfate and concentrated under vacuo to
give 30 g of the titled product as brown viscous oil.
1HNMR (400 MHz, DMSO-d6) d : 1.16 (3H, t), 4.20 -4.23 (2H, q), 6.68 (1H, s), 7.43 - 7.45
(2H,m), 8.10 - 8.14 (2H,m).
m/z = 289, 291 (M+2H)+
Step C: Preparation of ethyl 2-(4-fluorophenyl) imidazoH, 2-alpyrimidine-3-
carboxylate
To a stirred solution of ethyl 2-bromo-3-(4-fluorophenyl)-3-oxopropanoate (30 g,104 mmol)
in isopropyl alcohol (150 ml), 2-aminopyrimidine (9.8 g, 104 mmol) was added and further
stirred for 6 hours at 90 °C. The reaction mixture was cooled to 30 °C and isopropyl alcohol
was removed. The crude product was stirred in cold ethyl acetate (50 ml) and solid was
filtered to give the titled compound as brown solid (35 g).
H NMR (400 MHz, DMSO-d6) d :1.20-1.24 (3H, t), 4.27 - 4.32 (2H, q), 7.30 -7.34 (2H, t),
7.37 - 7.39 (1H, q), 7.87 - 7.91 (2H, m), 8.80 - 8.82 (1H, dd), 9.59 -9.61 (1H, dd).
m/z =286 (M+H)+
Step D: Preparation of 2-(4-fluorophenyl) imidazo 1 2-al pyrimidine-3-carboxylic acid
To a stirred solution of Ethyl 2-(4-fluorophenyl)imidazo[l, 2-a]pyrimidine-3-carboxylate 35
g (120 mmol) in methanol (150 ml), aqueous solution of sodium hydroxide (9.8 g, 240 mmol
in 50 ml water) was added slowly at 10 °C and stirred 4 hours at room temperature (30-
32°C). The reaction mixture was quenched with water (100 ml). Methanol was removed
under vacuo at 40 °C and aqueous layer was washed with ethyl acetate (2 x 200 ml). The
aqueous layer was acidified to pH 3-4 with 2N hydrochloric acid and the separated solid was
filtered, washed with water, dried under vacuo to give 19 g of the titled compound as brown
solid.
H NMR (400 MHz, DMSO-d6) d : 7.29 - 7.39 (4H, m), 7.89 - 7.92 (2H, t), 8.77 - 8.79 (1H,
dd), 9.65 - 9.67 (1H, dd),13.4 (1H, bs).
m/z = 258 (M+H)+
Step E: Preparation of N-(4-chlorophenyl)-2-(4-fluorophenyl) imidazo G1, 2-al
pyrimidine-3-carboxamide
To a stirred solution of 2-(4-fluorophenyl) imidazo [1, 2-a] pyrimidine-3-carboxylic acid
(llg ,40 mmol) in toluene (100 ml), thionyl chloride (6.3 ml, 80 mmol) was added under
nitrogen atmosphere, followed by 2-3 drops of N, N Dimethylformamide. The reaction
mixture was stirred for 2 hour at 60 °C. The reaction mixture was concentrated under vacuo
and the obtained crude product was dissolved in dichloromethane (80 ml) and added drop
wise to the solution of 4-chloroaniline (5.1g, 40mmol) and triethylamine (17ml, 120 mmol)
in dichloromethane (20ml) at 0 °C. The reaction mixture was stirred at room temperature
(28-30°C) for 4 hours and the separated solid was filtered, washed with water (2 x 30 ml),
saturated sodium bicarbonate solution (2 x 20 ml) and ethyl acetate (2 x 30 ml). Then the
solid was dried under vacuo to give 9.0 g of desired compound as an orange color solid.
H NMR (400MHz, DMSO-d6) d : 7.22 - 7.25 (1H, q), 7.29 - 7.33 (2H, t), 7.39 -7.41 (2H, d),
7.62 - 7.64 (2H, d), 7.94 - 7.97 (2H, q), 8.70 - 8.72 (1H, dd), 9.25-9.27 (1H, dd), 10.50 (1H,
bs).
m/z = 367 (M+H)+
Example 2
Preparation of N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methylimidazo [1,2-a]
pyrimidine-3-carboxamide (Compound no. 7)
To a stirred solution of N-(4-chlorophenyl)-2-(4-fluorophenyl) imidazo [1, 2-a] pyrimidine-
3-carboxamide (9g, 24 mmol) (as prepared in Example- 1) in N,N dimethylformamide (45
ml), cesium carbonate (15.9 g, 48 mmol) was added portion wise and stirred for 30 min,
followed by addition of iodomethane (10.34 g, 72 mmol) at 0 -10°C. The reaction mixture
was stirred for 4 h at 10°C. Reaction mixture was poured in ice water under stirring. The
obtained solid was filtered, washed with water (2x30ml) and dried under vacuum to give 7.0
g of desired compound as light orange color solid.
(CDC13)5:3.41(3H,s),6.32-6.34(2H,m),6.85-6.88(2H,d),7.03-7.07(3H,m),7.33-7.37 (2H,m)
,8.66-8.67(lH,m),9.01-9.03(lH,dd).
m/z = 381 (M+H)+
Example 3
Preparation of N-(4-chlorophenyl)-N-methyl-2-(pyridin-2-yl)imidazo[l,2-a]pyrimi dine-
3-carboxamide (Compound no. 11)
Step A: Preparation of ethyl 3-oxo-3-(pyridin-2-yl) propanoate
The titled compound was prepared in analogous manner as described in Step-A of example 1.
H NMR (400 MHz, DMSO-d6) d : 1.22 - 1.24 (3H, t), 4.17 - 4.22 (2H, q), 4.21 (2H, s), 7.48
- 7.51 (1H, m), 7.81 - 7.86 (lH,m), 8.07 - 8.09( 1H, dd), 8.64 -8.66 (1H, dd).
m/z = 194 (M+H)+
Step B : Preparation of ethyl 2-bromo-3-oxo-3-(pyridin-2-yl) propanoate
The titled compound was prepared in analogous manner as described in Step-B of example 1.
H NMR (400 MHz, DMSO-d 6) d : 1.12 - 1.16 (3H, t), 4.18 -4.23 (2H, q), 6.42 (1H, s), 7.70 -
7.73 (1H, q), 8.07 - 8.08 (2H, d), 8.71 - 8.72 (1H, dd).
m/z = 272 (M+H)+, 274 (M+2H)+
Step C: Preparation of ethyl 2-(pyridin-2-yl) imidazo 1 2-al pyrimidine-3-carboxylate
The titled compound was prepared in analogous manner as described in Step-C of example 1.
H NMR (400 MHz, DMSO-d6) d : 1.08 - 1.12 (3H, t), 4.19 - 4.25 (2H, q), 7.39 -7.40 (1H,
m), 7.80 - 7.82 (1H, dd), 8.68 - 8.70 (1H, d), 8.82 - 8.84 (1H, dd), 9.50 -9.52 (1H, dd).
m/z =269 (M+H)+
Step D : Preparation of 2-(pyridin-2-yl) imidazo 1 2-al pyrimidine-3-carboxylic acid
The titled compound was prepared in analogous manner as described in Step-D of example 1.
H NMR (400 MHz, DMSO-d6) d : 7.29 (1H, m), 7.61 (1H, dd), 8.13 (1H, m), 8.42 - 8.55
(1H, m), 8.76 (2H, s), 10.00 - 10.02 (lH,d).
m/z = 239 (M-H)+
Step E: Preparation of N-(4-chlorophenyl)-2-(pyridin-2-yl) imidazo 1 2-al pyrimidine-
3-carboxamide
To a stirred solution of 2-(pyridin-2-yl) imidazo [1, 2-a] pyrimidine-3-carboxylic acid (0.5 g,
2.1 mmol) in dichloromethane (20 ml), N-disopropylethylamine (1.1ml, 6 mmol), 1-hydroxy
benzotriazole (0.56g, 4.2mmol) and l-ethyl-3-(3-dimethylamino) propylcarbdiimide
hydrochloride (0.768 g, 4.2 mmol) was added at 10 °C and stirred for 30 min, followed by
addition of 4-chloroaniline (0.33 g, 2.2 mmol). The reaction mixture was stirred at room
temperature for 4 hour. The reaction mixture was concentrated under vacuo, water (20 ml)
was added and the precipitated solid was filtered and dried under vacuo to give 0.35 g of the
desired compound as yellow color solid.
H NMR (400MHz, CDC13) d : 7.10 (1H, s), 7.27 (2H, s), 7.37 -7.39 (1H, d), 7.51 (1H, s),
7.77 - 7.79 (2H, d), 8.03 (1H, d), 8.75 -8.82 (2H, d), 10.34 (1H, s), 14.95 (1H, s).
m/z = 350 (M+H)+
Step F: Preparation of N-(4-chlorophenyl)-N-methyl-2-(pyridin-2-yl) imidazo 1 2-al
pyrimidine-3-carboxamide
To a stirred solution of N-(4-chlorophenyl)-N-methyl-2-(pyridin-2-yl) imidazo [1, 2-a]
pyrimidine-3-carboxamide ( 0.35 g, 1 mmol) in tetrahydrofuran (10 ml), sodium hydride (0.1
g, 2 mmol) was added portion wise and stirred for 30 min, followed by addition of
iodomethane (0.28 g, 2 mmol) at 10 -15°C. The reaction mixture was stirred for 4 h at 10 °C.
The reaction mixture was concentrated under vacuo and ice water was added, extracted with
dichloromethane (3 x 100 ml) and dried over sodium sulphate. The crude product was
purified on column chromatography using 30% ethyl acetate in hexane as eluent to give 0.2 g
of the titled compound as light yellow solid.
H NMR (400 MHz, DMSO-d 6) d : 3.39 (3H, s), 6.98 - 7.04 (4H, m), 7.20 -7.23 (1H, m),
7.38 - 7.41 (1H, t), 7.76 (1H, m), 7.82 - 7.84 (1H, t), 8.65 -8.67 (1H, m), 8.68 - 8.69 (1H, d),
8.98 - 9.0 (1H, d).
m/z = 364 (M+H)+
Example 4
Preparation of N-(2,4-difluorophenyl)-2-(4-fluorophenoxy)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide (Compound no. 46)
Step A: Preparation of ethyl 2-hydroxyimidazo 1 2-al pyrimidine-3-carboxylate
To a stirred solution of 2-aminopyrimidine( 40 g ,421 mmol) in ethanol (200 ml), diethyl
bromomalonate (125.7 g, 526 mmol) was added and refluxed for 24 h. The reaction mixture
was concentrated under vacuo and ethyl acetate (100 ml) was added. The reaction mixture
was stirred for 30 min and separated solid was filtered, washed with hexane (2 x 50 ml) and
dried under vacuo to yield 45 g of the desired compound as brown solid.
H NMR (400MHz, CDC13) d : 1.46 - 1.48 (3H, t), 4.47 - 4.52 (2H, q), 7.14 -7.17 (1H, m),
8.74 - 8.77 (1H, m), 9.61 - 9.64 (1H, dd).
m/z = 208 (M+H)+
Step B: Preparation of ethyl 2-chloroimidazo G1, 2-al pyrimidine-3-carboxylate
Ethyl 2-hydroxyimidazo [1, 2-a] pyrimidine-3-carboxylate ( 45 g ,217 mmol) was refluxed in
phosphorus oxychloride (260 ml, 2.71 mol) for 8 hours. The reaction mixture was cooled and
concentrated under vacuo. The reaction mixture was neutralized with saturated sodium
bicarbonate solution (100 ml) and extracted with ethyl acetate (3 x 400 ml). The combined
ethyl acetate layer was dried over sodium sulfate and concentrated under vacuo. The obtained
crude product was stirred in hexane (100 ml) and separated solid was filtered to give 23.0 g
of the desired compound as brown solid.
H NMR (400MHz, CDC13) d : 1.46 - 1.48 (3H, t), 4.47 - 4.52 (2H, q), 7.14 -7.17 (1H, m),
8.74 - 8.77 (1H, m), 9.61 - 9.64 (1H, dd).
m/z = 226 (M+H)+
Step C: Preparation of ethyl 2-(4-fluorophenoxy) imidazo 1 2-al pyrimidine-3-
carboxylate
To a stirred solution of Ethyl 2-chloroimidazo [1, 2-a] pyrimidine-3-carboxylate 12.5 g (55
mmol) in N, N-dimethylacetamide (60 ml), 4-fluorophenol (7.8 g, 69 mmol) was added and
heated at 140 °C for 10 hours. The reaction mixture was concentrated under vacuo and
quenched with water (200 ml) and the reaction mixture was extracted with ethyl acetate (3 x
200 ml). The combined organic layer was dried over sodium sulfate and concentrated under
vacuo to give crude product. The crude product was stirred in hexane (100 ml) and separated
solid was filtered to give 4.2 g of the desire product as brown solid.
H NMR (400MHz, DMSO-d6) d : 1.46 - 1.48 (3H, t), 4.47 - 4.52( 2H, q), 7.28 -7.33 (5H,
m), 8.68 - 8.70 (1H, dd), 9.57 - 9.59 (1H, dd).
m/z = 302 (M+H)+
Step D: Preparation of 2-(4-fluorophenoxy) imidazo 1 2-al pyrimidine-3-carboxylic
acid
To a stirred solution of ethyl 2-(4-fluorophenoxy) imidazo [1, 2-a] pyrimidine-3-carboxylate
(3.8 g ,12.6 mmol) in ethanol (25 ml), aqueous solution of sodium hydroxide ( 1 g, 25.2
mmol) in water (10 ml) was added slowly at 10°C -12 °C and stirred at room temperature
for 4 hours. The reaction mixture was concentrated under vacuo to remove ethanol and water
(10 ml) was added. The aqueous layer was washed with ethyl acetate (2 x 100 ml) and pH of
aqueous layer was adjusted to 5 with dilute hydrochloric acid. The separated solid was
filtered, washed with water and dried under vacuo to give 2.0 g desired product as brown
colored solid.
H NMR (400 MHz, DMSO-d6) d : 1.46 - 1.48 (3H, t), 4.47 - 4.52 (2H, q), 7.28 -7.33 (5H,
m), 8.68 - 8.70 (1H, dd), 9.57 - 9.59 (1H, dd), 13.2 (1H, bs).
m/z = 274 (M+H)
Step E: Preparation of N-(2,4-difluorophenyl)-2-(4-fluorophenoxy)imidazori.,2-
alpyrimidine-3-carboxamide
To a stirred solution of 2-(4-fluorophenoxy) imidazo [1, 2-a] pyrimidine-3-carboxylic acid
(0.2 g ,0.7 mmol), N-disopropylethylamine (0.4 ml, 2.2 mmol), 1-hydroxy benzotriazole
(0.56 g, 4.2 mmol) and and l-ethyl-3-(3-dimethylamino)propylcarbdiimide hydrochloride
(0.28 g, 1.4 mmol) in dichloromethane (20 ml), 2, 4-difluoroaniline (0.11 g, 0.7 mmol) was
added at 10°C-15 °C and stirred for 30 minutes. The reaction mixture was stirred at room
temperature for 4 hours and concentrated under vacuo. The reaction mixture was diluted with
water (20 ml) and the separated solid was filtered, dried under vacuo to give 0.11 g of the
desired compound as brown solid.
H NMR (400 MHz, DMSO-d6) d : 7.13 - 7.18 (1H, t), 7.32 - 7.41 (4H, m), 7.49 -7.52 (2H,
m), 8.00 - 8.06 (1H, m), 8.71 - 8.73 (1H, dd), 9.17 (1H, s), 9.72 -9.74 (1H, dd).
m/z = 338.5 (M+H)+
Step F: Preparation of N-(2, 4-difluorophenyl)-2-(4-fluorophenoxy)-N-methylimidazo
G1, 2-al pyrimidine-3-carboxamide
To a stirred solution of N-(2,4-difluorophenyl)-2-(4-fluorophenoxy)imidazo[l,2-
a]pyrimidine-3-carboxamide (O.lg ,0.26 mmol) in tetrahydrofuran (10 ml), sodium hydride
(0.03 g, 0.52 mmol) was added portionwise and stirred for 30 minutes. The iodomethane (0.3
g, 7.8 mmol) was added at 10 -15 °C and stirred for 4 hours. The reaction mixture was
concentrated under vacuo and then cooled water was added and extracted with
dichloromethane (3 x 100 ml). The combined dichloromethane layer dried over sodium
sulphate and evaporated under vacuo to yield crude product .The crude product was purified
on column chromatography using 30% ethyl acetate in hexane as eluent to give 0.05 g of the
desired product as light brown solid.
H NMR (400 MHz, CDC13) d : 3.46 (3H, s), 6.73 - 6.79 (4H, m), 6.97 -6.99 (2H, m), 7.06 -
7.09 (1H, m), 7.17 - 7.20 (1H, m), 8.57 - 8.58 (1H, m), 9.28 -9.30 (1H, dd).
m/z = 399 (M+H)+
The following representative compounds of the present invention were prepared in analogues
manner by using the synthetic schemes as described above:
Table-1:
Comp. NMR (400 MHz) Mass
No.
1 (CDC13) d : 3.38(3H,s),6.29(2H,d),6.81-6.83(2H,d),7.03- m/z : 363
7.05(lH,t),7.35-7.37(5H,m),8.65-8.67(lH,d),9.01-9.03(lH,d). (M+H)+
2 (CDCI 3) d : 3.38(3H,s),6.33(2H,dd),6.81(lH,d),6.93(lH,d),7.04- m/z : 363
7.06(lH,d),7.35-7.40(5H,m),8.66-8.68(lH,d),9.03-9.05(lH,d). (M+H)+
3 (DMSO-d6 + D20 ) d : 3.37(5H,s),6.59-6.61(2H,d),6.81- m/z : 387
6.83(2H,d),7.22-7.25(lH,m),7.39-7.43(4H,m),7.52-7.58(lH,t),8.64- (M+H)+
8.65(lH,d),8.98-9.00(lH,d).
4 (CDC13) 0 :1.95-2.07(2H,m),2.60(2H,t),2.71- m/z : 403
2.75(2H,t),3.45(3H,s),6.12-6.23(2H,dd),6.71(lH,d),7.02- (M+H)+
7.06(lH,m),7.23-7.3295H,m),8.65-8.67(lH,m),8.99-9.02(lH,dd).
5 (CDCI 3) d : 3.41(3H,s),6.33-6.35(2H,dd),6.86-6.88(2H,dd),7.04- m z : 397
7.07(lH,m),7.26-7.52(4H,m),8.67-8.68(lH,m),9.00-9.02(lH,dd). (M+H)+
6 (CDCI3) d : 1.94-1.98(2H,m),2.56(2H,t),2.69- m/z : 387
2.71(2H,t),3.41(3H,s),6.13-6.21(2H,m),6.71(2H,m),7.01- (M+H)+
7.03(2H,m),7.37(2H,m),8.63(lH,m),8.96-8.98(lH,d).
8 (CDCI 3) d : 3.42(3H,s),6.34(2H,m),6.80-6.82(2H,d),7.04- m/z : 439
7.07(lH,m),7.39-7.42(3H,m),7.49-7.53(2H,t),7.58-7.60(2H,d),7.66- (M+H)+
7.68(2H,d),8.67-8.69(lH,m),9.04-9.06(lH,dd).
Comp. NMR (400 MHz) Mass
No.
(CDC13) d : 1.90-1.94(2H,m),2.47-2.49(2H,t),2.70-
2.73(2H,t),3.43(3H,s),6.15(2H,m),6.68(2H,m),6.99-
7.02(2H,m),7.38-7.41(lH,m),7.47-7.51(4H,t),7.57-7.59(2H,d),7.65-
7.67(2H,d),8.62-8.63(lH,m),8.96-8.98(lH,d).
3.40(3H,s),3.85(3H,s),3.96(3H,s),6.31(2H,m),6.82(2H,m),6.85-
6.87(2H,m),6.95-6.97(lH,m),7.02-7.05(lH,m),8.64-
8.66(lH,m),9.00-9.02(lH,dd).
(CDCI 3) d : 3.40(3H,s),6.34(2H,m),6.83(2H,d),7.35-
7.38(5H,m),7.49-7.50(lH,d),7.53-7.57(2H,t),7.68(2H,d),8.92-
8.93(lH,d)9.16-9.17(lH,d).
C ) d : 1.94-
2.0(2H,q),2.48(2H,t),2.71(2H,t),3.4O(3H,s),3.83(3H,s),3.96(3H,s),6
.14-6.15(2H,d),6.69-6.71(lH,d),6.86-6.88(2H,d),6.98-
7.01(2H,m),8.60-8.61(lH,m),8.94-8.96(lH,dd).
(CDCI3) d : 3.44(3H,s),6.37(2H,m),6.88-6.90(2H,d),7.06-
7.09(lH,m),7.23(lH,m),7.41-7.45(2H,m),8.69-8.70(lH,d),9.02-
9.04(lH,dd).
(CDCI3) d : 1.92(2H,m),2.58-2.66(2H,m),3.37-3.38(2H,m),5.98-
6.07(2H,m),6.50-6.68(2H,m),6.70-6.81(2H,d),7.05-
7.08(lH,m),8.65-8.66(lH,d),9.01-9.03(lH,dd),9.48(lH,s).
(CDCI 3) d : 3.38(3H,s),3.88(3H,s),6.36(2H,m),6.85-
6.90(3H,m),6.99-7.02(lH,m),7.33-7.35(2H,m),8.62-
8.64(lH,m),8.97-9.00(lH,dd).
(CDCI3) d : 1.90(2H,m),2.48(2H,m),2.66(2H,m),3.52(3H,s),6.33-
6.44(2H,m),6.66(lH,m),6.96-6.99(lH,m),7.24-7.26(lH,m),7.65-
7.72(2H,m),8.60(lH,s),8.69-8.70(lH,d),8.74-8.76(lH,dd).
(CDCI3) d : 3.41(3H,s),6.38(2H,m),6.59(2H,m),7.03-
7.05(lH,m),7.34(4H,m),8.65-8.67(lH,m),8.97-9.00(lH,dd).
Comp. NMR (400 MHz) Mass
No.
19 (CDC13) d : 3.38(3H,s),3.43(3H,s),3.79(3H,s),5.93-6.10(2H,d),6.34- m/z : 423
6.35(lH,m),7.01-7.03(lH,m),7.34-7.41(4H,m),8.63- (M+H)+
8.64(lH,m),8.91-9.16(lH,dd).
20 (DMSO-d6) d : 3.39(3H,s),6.71-6.73(2H,d),6.97-6.99(lH,d),7.25- m/z : 364
7.28(lH,m),7.41-7.44(lH,m),7.73-7.75(lH,d),8.57- (M+H)+
8.60(2H,dd),8.69-8.70(lH,m),9.09-9.11(lH,dd).
2 1 (CDCI 3) d : 3.43(3H,s),6.43-6.45(2H,m),6.57-6.61(2H,t),6.94- m z : 415,
6.96(lH,d),7.07-7.11(2H,m),7.41-7.42(lH,d),8.69- 417
8.71(lH,m),9.18-9.20(lH,dd). (M+H)+
22 (CDCI 3) d : 3.41(3H,s),6.37(2H,m),6.59-6.76(2H,t),6.94- m/z : 365
6.96(lH,d),7.02-7.07(2H,m),7.39(2H,m),8.65-8.66(lH,m),8.98- (M+H)+
9.00(lH,dd).
23 (CDCI 3) d : 3.32(3H,s),6.30-6.32(2H,d),6.86-6.88(2H,d),6.95- m/z : 431
6.96(lH,d),7.10-7.13(lH,m),7.43-7.47(lH,t),7.50-7.53(lH,t),7.66- (M+H)+
7.68(lH,d),8.70-8.71(lH,m),9.18-9.20(lH,dd).
24 (CDCI 3) d : 2.67(6H,s),3.48(3H,s),6.59-6.61(2H,d),7.08- m/z : 470
7.11(lH,m),7.32-7.35(6H,m),8.70-8.72(lH,m),9.06-9.09(lH,dd). (M+H)+
25 (CDCI 3) d :3.24(3H,s),3.34(3H,s),3.64(3H,s),5.91- m/z : 423
5.92(lH,d),5.99(lH,s),6.11-6.13(lH,d),6.94-6.97(lH,m),7.33- (M+H)+
7.35(2H,d),7.46-7.48(2H,d),8.58(lH,m),8.85-8.87(lH,dd).
26 (CDCI 3) d : 3.38(3H,s),6.34-6.55(4H,m),7.01-7.04(lH,m),7.35- m/z : 347
7.40(5H,m),8.65(lH,m),8.98-9.00(lH,dd). (M+H)+
27 (DMSO-d6) d : 3.36(3H,s),6.04-(lH,m),6.16-6.27(2H,dd),7.12- m/z : 395
7.15(lH,m),7.52-7.54(2H,d),7.67-7.69(2H,d),8.58- (M+H)+
8.59(lH,m),8.78(lH,m),8.91-8.96(2H,dd).
(CDCI 3) d : 3.40(3H,s),6.02(2H,s),6.46(2H,m),6.65(2H,m),6. m/z : 391
6.82(lH,d),6.90-6.95(2H,m),6.99-7.02(lH,m),8.62- (M+H)+
8.63(lH,m),8.95-8.97(lH,dd).
29 (CDCI 3) d : 3.40(3H,s),6.02(2H,s),6.42(2H,m),6.79- m/z : 407
6.81(lH,d),6.86(lH,m),6.90-6.92(3H,m),7.00- (M+H)+
7.03(lH,m),8.64(lH,m),8.98-9.00(lH,dd).
Comp. NMR (400 MHz) Mass
No.
30 (CDC13) d : 3.35(3H,s),6.35(2H,m),6.72- m/z : 379
6.74(2H,d),6.85(2H,m),7.04-7.10(3H,m),8.66- (M+H)+
8.67(lH,m),8.85(lH,bs),9.02-9.03(lH,dd).
3 1 (DMSO-d6) d : 3.38(3H,s),6.35-6.55(2H,d),6.93-6.95(2H,d),7.27- m/z :431
7.30(lH,m),7.52(lH,s),7.65-7.69(2H,m),7.78-7.80(lH,d),8.71- (M+H)+
8.72(lH,m),9.10-9.12(lH,dd).
33 (CDCI 3) d : 3.44(3H,s),6.32(2H,m),6.55(2H,m),7.08- m z : 415
7.1 l(lH,m),7.47-7.51(lH,m),7.61-7.67(3H,m),8.71- (M+H)+
8.72(lH,m),9.06-9.08(lH,dd).
34 (DMSO-d6) d : 3.63(3H,s),3.75(3H,s),6.53- m/z : 393
6.54(lH,d),6.60(lH,m),7.29-7.31(lH,q),7.38- (M+H)+
7.43(2H,t),7.91(3H,m),8.74(lH,m),8.85(lH,s),9.48-9.49(lH,d).
35 (DMSO-d6) 0 : m/z : 372
3.46(3H,s),6.39(2H,m),6.60(2H,m).7.10(lH,m),7.28(lH,s),7.49- (M+H)+
7.50(lH,t),7.68-7.74(2H,m),8.72(lH,m),9.02-9.04(lH,dd).
36 (CDCI 3) d : 3.46(3H,s),6.32-6.34(2H,d),6.85-6.87(2H,d).7.09- m/z : 388
7.12(lH,m),7.45-7.49(lH,t),7.62-7.64(lH,d),7.67-7.68(2H,d),8.71- (M+H)+
8.73(lH,m),9.04-9.07(lH,dd).
37 (CDCl3) 0 : 2.75(6H,s),3.43(3H,s),6.31(2H,d),6.84- m/z : 470
6.86(2H,d).7.09-7.12(lH,m),7.54-7.56(2H,d),7.74- (M+H)+
7.76(2H,dd),8.71-8.73(lH,m),9.04-9.07(lH,dd).
38 (CDCI 3) d : 2.75(6H,s),3.44(3H,s),6.36(2H,m),6.60(2H,m).7.10- m/z : 454
7.12(lH,m),7.59-7.60(2H,m),7.77-7.79(2H,d),8.71(lH,m),9.02- (M+H)+
9.04(lH,dd).
39 (DMSO-d6) 0 : 7.14(lH,m),7.28- m/z : 369
7.35(4H,m),7.75(lH,m),7.95(2H,m),8.74(lH,s),9.24(lH,dd),10.04( (M+H)+
lH,s).
40 C ) d : 3.41(3H,s),6.27(lH,d),6.40(2H,m).7.03- m/z : 383
7.05(lH,m),7.10(2H,m),7.42(2H,m),8.67(lH,m),8.95(lH,dd). (M+H)+
4 1 (CDCI 3) d : 3.43(3H,s),3.98(3H,s),6.46(2H,m),6.64(2H,m),6.94- m/z : 395
6.98(lH,t),7.03-7.05(lH,m),7.22-7.28(2H,m),8.66-8.67(lH,d),8.97- (M+H)+
8.98(lH,d).
Comp. NMR (400 MHz) Mass
No.
42 (CDC13) : 3.42(3H,s),6.44(2H,m),6.65(2H,m),6.91- m z : 381
6.99(lH,t),7.01-7.05(lH,m),7.28-7.34(2H,m),8.66-8.67(lH,d),8.99- (M+H)+
9.00(lH,d).
43 (CDC13) : 3.43(3H,s),3.93(3H,s),6.35-6.43(3H,m),6.99- m z : 413
7.05(3H,m),7.14-7.22(2H,m),8.66-8.67(lH,d),8.99-9.00(lH,d). (M+H)+
44 (CDC13) : 3.43(3H,s),3.98(3H,s),6.37-6.43(2H,m),6.90- m z : 411
6.97(3H,m),7.04-7.06(lH,m),7.19-7.23(2H,d),8.66- (M+H)+
8.67(lH,m),8.99-9.01(lH,dd).
45 (CDC13) d : 3.42(3H,s),3.99(3H,s),6.33(lH,bs),6.55(lH,bs),6.70- m/z : 429
6.74(lH,t),6.96-6.98(lH,m),7.06-7.08(lH,m),7.16- (M+H)+
7.19(2H,m),8.68-8.69(lH,m),9.03-9.05(lH,dd).
47 (CDCI 3) d : 3.52(3H,s),6.72-6.74(2H,d),7.06-7.12(3H,m),7.14- m/z : 379.5
7.19(3H,m),7.27-7.31(2H,m),8.56-8.58(lH,m),9.34-9.36(lH,dd). (M+H)+
48 (CDCI 3) d : 3.52(3H,s),6.66-6.68(2H,d),7.07-7.10(3H,m),7.17- m/z : 413,
7.19(2H,d),7.24-7.27(2H,m),8.58-8.59(lH,m),9.34-9.36(lH,dd). 415
(M+H)+
49 (CDCI 3) d : 3.53(3H,s),3.80(3H,s),6.63-6.65(2H,d),6.80- m/z : 409
6.86(2H,d),7.05-7.12(3H,m),7.20-7.22(2H,d),8.54- (M+H)+
8.56(lH,m),9.33-9.36(lH,dd).
50 (CDCI 3) d : 3.51(3H,s),6.63-6.67(2H,d),6.93-6.97(2H,t),7.05- m/z : 397.5
7.09(3H,m),7.16-7.18(2H,d),8.55(lH,m),9.32-9.33(lH,dd). (M+H)+
5 1 (CDCI 3) d : 3.52(3H,s),6.69-6.72(2H,d),6.90-6.94(2H,t),7.07- m/z : 397.5
7.09(lH,m),7.11-7.14(2H,m),7.23-7.28(2H,d),8.57- (M+H)+
8.59(lH,m),9.31-9.35(lH,dd).
52 (CDCI 3) d : 3.36(3H,s),3.71(3H,s),6.54-6.69(3H,m),6.92- m/z : 393
6.95(2H,t),7.04-7.06(3H,m),8.54(lH,d),9.30-9.32(lH,d). (M+H)+
53 (CDCI 3) d : 3.43 (3H,s), 6.41(2H, d), 6.81(1H, s),6.92 - 6.98(3H, m/z : 397
m), 7.04 - 7.08(3H, m), 8.69QH, s), 9.03 - 9.04 (1H, dd ). (M+H)+
54 (CDCI 3) d : 3.46(3H, s), 6.33(2H, d), 6.86 - 6.87(2H ,d), 7.1 1(1H, m/z :388
m), 7.54(2H , m), 7.66(2H, d), 8.73QH, s), 9.04(1H, s). (M+H)+
55 (CDCI 3) d : 3.46 (3H , s), 6.38 (2H , d), 6.61 (2H, d), 7.11 (lH , m) m/z : 372
, 7.58 (2H , m), 7.68 (2H , d), 8.72 (1H , d), 9.04 ( 1H , dd ). (M+H)+
Comp. NMR (400 MHz) Mass
No.
56 (CDC13) d : 3.43(3H, s) , 6.28-6.42(2H, dd), 6.70 (IH, d), 7.11QH, m/z : 406
) , 7.53(2H, d) , 7.71 - 7.79(2H, d), 8.74(1H, s), 9.04QH, dd). (M+H)+
57 (CDCI 3) d : 4.92 - 5.02 (2H , s), 6.17 - 6.18 (2H , dd), 6.79 - 6.81 ( m/z : 475
2H, dd), 7.01 - 7.07 (4H , m), 7.27 - 7.29 (2H , m), 7.35 (2H , d), (M+H)+
8.68 (IH , d), 9.01 - 9.02 (IH , dd).
58 (CDCI 3) d : 3.52(3H, s), 6.84 - 6.87(2H, m), 7.07 - 7.16(2H, m), m z : 449
7.33 - 7.34(3H, m), 8.55 (IH, d), 9.31 - 9.32QH, dd ). (M+H)+ &
451
(M+2H)+
59 (CDCI 3) d : 3.59(3H, s) , 7.02 - 7.07(3H, m), 7.12 - 7.13 (IH, m), m/z : 431
7.25 - 7.32(2H, m), 7.34(2H, m), 8.55(1H, d), 9.34 - 9.35QH, dd ). (M+H)+&
433
(M+2H)+
60 (CDCI 3) d : 3.55(3H, s), 6.67 - 6.68QH, d) , 6.80QH, ) , 6.86 - m/z : 415
6.90QH, d), 7.15(1H, m), 7.24(2H, m), 7.29(2H, ) , 8.58 (IH, d), (M+H)+
9.37 - 9.38QH, dd).
6 1 (CDCI 3) d : 3.37 (3H, s), 6.56 - 6.74 (4H , m), 6.91 - 6.92 (IH, d) , m/z : 387
6.99 - 7.01 (IH , ) , 7.11 - 7.12 (IH, d) , 8.62 - 8.63 (IH, d), 8.80 (M+H)+
- 8.82 (IH, dd).
62 (CDCI 3) d : 3.38 (3H , s), 6.38 - 6.47 (2H, d) , 6.79 - 6.84 (IH, d) , m/z : 404
6.84 - 7.00 (4H, ) , 8.64 - 8.65 (IH, d), 8.83 - 8.84 (IH, dd). (M+H)+
63 (CDCI 3) d : 3.43 (3H, s) , 6.28 - 6.29 (2H , d) , 6.80 - 6.82 (2H, d) m/z : 431
, 7.09 (IH, s), 7.48 - 7.50 (2H, d), 7.60 - 7.62 (2H,d ), 8.71 (IH , s), (M+H)+
9.05 - 9.07 (IH , d).
64 (CDCI 3) d : 3.44 (3H, s) , 6.33 - 6.55 (4H, ) , 7.07 - 7.10 (IH, ) m/z : 415
, 7.54 - 7.63 (4H, ) ,8.70 - 8.71 (IH, m), 9.03 - 9.05 (IH, m). (M+H)+
65 (DMSO-d 6) d : 0.96 - 1.22 ( 6H,s ),4.97(lH,s),6.52- m/z : 409
6.62(2H,s),7.05(2H,s),7.23-7.26(lH,m),7.37- (M+H)+
7.39(2H,m),7.58(2H,m),8.65 - 8.66(lH,d),9.04-9.06(lH,dd).
(CDCI 3) d : 7.14 - 7.20 (3H, ) , 7.35 - 7.54 (4H , ) , 7.60 - m/z : 383
(2H , d) , 8.65 - 8.67 (2H , m), 9.91 - 9.93 (IH , dd). (M+H)+
Comp. NMR (400 MHz) Mass
No.
67 (DMSO-d 6) :7.18 - 7.22 (2H,m ), 7.25 - 7.28 (lH,m), 7.59(2H,s) m z : 401
,7.68 - 7.72 (lH,m),7.77 - 7.79 (lH,m ), 8.14 - 8.18 (2H,m ),8.74 - (M+H)+
8.75 ) 1 H,dd ), 9.18-9.20(lH,dd).
68 (CDC13) d : 0.48 ( 2H,d),0.79 - 0.81(2H, d),2.91(lH , ) , 6.72 - m/z : 390
6.76 (2H , ) , 7.01 - 7.04 (1H, ) , 7.60 - 7.62 (2H , ) ,7.48 - (M+H)+
7.59 (2H , m), 8.66 - 8.68 (1H , m), 8.92 - 8.94 (1H, )
69 (DMSO-d6) d : 0.44 - 0.56 (2H, d),0.76 - 0.86 (2H, d),3.03 (1H, ) m z : 441
, 6.80 (2H , s) , 6.85 - 6.89 (2H , t) , 7.24 - 7.27 (1H, ) , 7.40 - (M+H)+
7.77 (2H , m), 7.83 - 7.90 (2H , m), 8.69 - 8.70 (1H, dd) , 9.06 -
9.08 (1H, dd).
70 (DMSO-d6) d : 0.35 - 0.54 (4H, m),3.01 (1H, m) , 6.76 (2H, m) , m/z : 457
7.07 (2H , m) , 7.27 - 7.33 (1H , m) , 7.72 - 7.84 (4H , m), 8.70 (M+H)+
(1H, d) , 9.06 - 9.07 (1H, dd).
131 (CDC13) d : 3.34 - 3.39(4H,m),3.51 (3H,s), 3.72 - 3.86(4H,m),6.89 m/z : 356
- 6.99(5H,m), 8.48-8.49(lH,d), 8.97 - 9.00 (lH,d). (M+H) +
132 (CDC13) d : 3.53 (3H,s),6.43 - 6.55(2H,m),6.85 - 6.86(lH,m),7.07 - m/z : 397
7.28 (6H,m),8.59 - 8.61(lH,dd),9.34 - 9.37 (lH,dd). (M+H)+
133 (CDC13) d : 3.46 (3H,s),3.67 (3H.s),6.30 - 6.39(4H,m),7.01 - m/z : 377
7.08(3H,m),7.42 (2H,s),8.64 - 8.65(lH,dd),8.94 - 8.96 (lH,dd). (M+H)+
134 (CDC13) d :1.27 - 1.32(3H,t), 3.51 (3H,s),4.33 - 4.36 (2H.q),6.44 - m/z : 419
6.46(2H,d),6.89 - 7.08(3H,m),7.28 - 7.31 (2H,m),7.58 - (M+H)+
7.60(2H,m),8.69(lH,dd),9.05 - 9.06 (lH,dd).
135 (CDC13) d : 3.41 (3H,s),3.78 (3H.s),6.35 - 6.37(2H,d),6.58 - m/z : 4 11
6.62(2H,m),6.83 - 6.85 (2H,d),7.01 - 7.03 (lH,m),7.10 - (M+H)+
7.12(lH,m),8.63 - 8.64(lH,dd),9.03 - 9.05 (lH,dd).
(CDC13) d : 0.50 ( 2H,d ),0.82 - 0.83( 2H,d ),2.89 - 2.90( 1H , m ) , m/z : 407
6.54 - 6.57 ( 2H , d ) , 7.00 - 7.02 ( 2H , d ) ,7.05 -7.07(lH,m),7.12 (M+H)+
- 7.16(2H , m), 7.52 - 7.56 ( 2H , m ) , 8.67 - 8.69 ( 1H , m ), 8.94 -
8.96 ( lH,dd).
137 (DMSO-d6) d : 3.36 (3H,s),6.74 - 6.76 (2H,d), 6.98 - 7.00 m/z : 381
Comp. NMR (400 MHz) Mass
No.
(2H,d),7.22 - 7.28 (3H,m),7.41 - 7.44 (2H,m),8.68 - 8.70 (M+H)+
(lH,m),9.06 - 9.08 (lH,dd).
138 (DMSO-d6) : 3.39 (3H,s),6.78 - 6.80 (2H,d), 6.99 - 7.03 m z : 381
(2H,d),7.27 - 7.31 (2H,m),7.36 - 7.39QH , m), 7.42 - 7.46 (2H ,m ), (M+H)+
8.78 - 8.79 (lH,m) , 9.14 - 9.16 (lH,dd).
139 (DMSO-d6) d : 2.30 (3H , s), 3.39 (3H,s) , 6.78 - 6.80 (2H,d), 7.01 m/z : 381
- 7.03 (2H,d) , 7.12 - 7.14(2H ,d) , 7.27 - 7.31 (2H,m) , 7.34 - (M+H)+
7.37(2H , m), 7.44 - 7.50 (3H ,m ), 8.76 - 8.77 (lH,m) , 9.13 - 9.15
(lH,dd).
140 (DMSO-d6) d : 3.38 (3H,s), 3.73 (3H , s) , 6.78 - 6.80 (2H,d), 7.01 m z : 381
- 7.03 (2H,d) , 7.27 - 7.31 (2H,m) , 7.35 - 7.40 (1H , m) , 8.76 - (M+H)+
8.78 (1H , m) , 9.14 - 9.16 (lH,dd).
141 (DMSO-d6) : 2.80 - 2.81(3H,d),7.09 - 7.12 (lH,q), 7.32 - 7.40 m/z : 271
(2H,m),7.87 - 7.91 (2H,q) , 8.28 - 8.29 (lH,m) , 8.67 - 8.70 (M+H)+
(lH,m),9.12 - 9.14 (lH,dd).
142 (CDC13) d : 1.16 - 1.39 (6H , m) , 1.71 - 1.74 (2H , m) , 1.80 - 1.83 m/z : 429
(2H , m) , 2.28 - 2.31QH , m) , 3.44 (3H , s) , 6.27(2H , m) , 6.70 (M+H)+
(2H , m) , 6.98 - 7.05 (3H , m) , 7.28 - 7.31(2H , m) , 8.65 - 8.66
(1H , m) , 9.01 - 9.03 (1H , dd).
143 (CDC13) d : 3.00 (4H , m) , 3.43 (3H , s) , 3.80 - 3.82 (4H , m) , m/z : 429
6.28 (2H , m) , 6.37(2H , m) , 7.01 - 7.06 (3H , m) , 7.43 (2H , m) , (M+H)+
8.63 - 8.65 (1H , m) , 8.95 - 8.97 (1H , dd).
165 (DMSO-d6) d : 2.29 ( 3H , s ) , 3.42 ( 3H , s ) , 6.70 - 6.73 ( 2H , dd m/z :
) , 7.11 - 7.15 ( 4H , m ) , 7.22 - 7.24 ( 2H , d ) , 7.29 - 7.32 ( 1H , m 397.2(M+
) , 7.34 - 7.36 ( 2H , d ) , 7.46 - 7.48 ( 2H , d ) , 8.61 - 8.62 ( 1H , m H)+
) , 9.26 - 9.27 ( 1H , dd ).
166 (DMSO-d6) d : 3.42 ( 3H , s ) , 6.1 1 ( 1H , bs ) , 6.70 - 6.73 ( 2H , m/z : 397.2
dd ) , 7.11 - 7.13 ( 2H , t ) , 7.22 - 7.25 ( 2H , d ) , 7.29 - 7.37 ( 6H , (M+H)+
m ) , 7.59 - 7.61 ( 2H , dd ) , 8.61 - 8.62 ( 1H , m ) , 9.26 - 9.28 (
1H , dd ).
Combination Therapy
Compounds of the present invention may be administered in combination with other drugs
that are used in the treatment/prevention/suppression or amelioration of the diseases or
conditions for which compounds of Formula (I) are useful. Such other drugs may be
administered contemporaneously or sequentially with a compound of Formula (I). When a
compound of Formula (I) is used contemporaneously with one or more other drugs, a
pharmaceutical composition containing such other drugs in addition to the compound of
Formula (I) 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 Formula (I).
Pharmaceutical compositions
In another embodiment of the invention, there is provided a pharmaceutical composition
comprising a therapeutically effective amount of one or more of a compound of formula (I).
While it is possible to administer therapeutically effective quantity of compounds of formula
(I) either individually or in combination, directly without any formulation, it is common
practice to administer the compounds in the form of pharmaceutical dosage forms comprising
pharmaceutically acceptable excipient(s) and at least one active ingredient. These dosage
forms may be administered by a variety of routes including oral, topical, transdermal,
subcutaneous, intramuscular, intravenous, intreperitoneal, intranasal, pulmonary etc.
Oral compositions may be in the form of solid or liquid dosage form. Solid dosage form may
comprise pellets, pouches, sachets or discrete units such as tablets, multi-particulate units,
capsules (soft & hard gelatin) etc. Liquid dosage forms may be in the form of elixirs,
suspensions, emulsions, solutions, syrups etc. Composition intended for oral use may be
prepared according to any method known in the art for the manufacture of the composition
and such pharmaceutical compositions may contain in addition to active ingredients,
excipients such as diluents, disintegrating agents, binders, solubilizers, lubricants, glidants,
surfactants, suspending agents, emulsifiers, chelating agents, stabilizers, flavours,
sweeteners, colours etc. Some example of suitable excipients include lactose, cellulose and
its derivatives such as microcrystalline cellulose, methylcellulose, hydroxy propyl methyl
cellulose & ethylcellylose, dicalcium phosphate, mannitol, starch, gelatin, polyvinyl
pyrolidone, various gums like acacia, tragacanth, xanthan, alginates & its derivatives,
sorbitol, dextrose, xylitol, magnesium Stearate, talc, colloidal silicon dioxide, mineral oil,
glyceryl mono stearate, glyceryl behenate, sodium starch glycolate, cross povidone,
crosslinked carboxymethylcellulose, various emulsifiers such as polyethylene glycol,
sorbitol, fatty acid esters, polyethylene glycol alkylethers, sugar esters, polyoxyethylene
polyoxypropyl block copolymers, polyethoxylated fatty acid monoesters, diesters and
mixtures thereof.
Sterile compositions for injection can be formulated according to conventional
pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as
water for injection, N -Methyl-2-Pyrrolidone, propylene glycol and other glycols, alcohols, a
naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cotton sead oil or a
synthetic fatty vehicle like ethyl oleate or the like. Buffers, anti-oxidants, preservatives,
complexing agents like cellulose derivatives, peptides, polypeptides and cyclodextrins and
the like can be incorporated as required.
The dosage form can have a slow, delayed or controlled release of active ingredients in
addition to immediate release dosage forms.
The amount of active ingredient which is required to achieve a therapeutic effect will, of
course, vary with the particular compound, the route of administration, the subject under
treatment, and the particular disorder or disease being treated. The compounds of the
invention may be administered orally or parenteraly at a dose of from 0.001 to 1500 mg/kg
per day, preferably from 0.01 to 1500 mg/kg per day, more preferably from 0.1 to 1500
mg/kg per day, most preferably from 0.1 to 500 mg/kg per day. The dose range for adult
humans is generally from 5 mg to 35 g per day and preferably 5 mg to 2 g per day.
Dosage forms of presentation provided in discrete units may conveniently contain an amount
of compound of the invention which is effective at such dosage or as a multiple of the same,
for example units containing 5 mg to 1500 mg.
Biological testing:
In vitro screening:
(A) cAMP responsive element (CRE) - reporter assay:
CHO cells (ATCC) were transfected with human TGR5 (oriGene) and CRE-luciferase
reporter vector. Transfected cells were treated with vehicle control or test compounds (Cone
10mM) for five hours and then lysed. Cell lysates were monitored for luciferase acivity.
Increase in luciferase activity is considered as a result of TGR5 activation. Results were
expressed as fold induction as compared to vehicle control.
Results:
Results are summarized in Table 2 where, + indicates 1.5-2 fold while ++, +++, ++++
indicate 2^3 fold, 3^4 fold, and >4 fold induction respectively relative to vehicle control when
tested at 10 mM concentration.
Table -2
Comp. Fold Induction
No.
1 ++++
2 +++
3 +
4 +++
5 ++++
6 +++
7 ++++
8 +++
9 ++
10 +++
Comp. Fold Induction
No.
11 +
12 4-4-
13 4-4-4-
14 4-4-4-
15 4-4-
16 4-4-
17 4-4-
18 4-4-
19 4-4-
20 4-4-
2 1 4-4-4-
22 4-4-4-
23 +++
24 + +
25 + +
26 + +
27 +
28 ++
29 +++
30 +++
3 1 +++
32 +
33 +++4
34 +
35 ++
36 ++
37 +
38 +
39 +
40 + +
4 1 + +
42 + +
43 +
44 +++
45 +++4
46 + +
47 +++
48 + +
49 +++
50 +++4
Comp. Fold Induction
No.
5 1 ++
52 +++
136 +++
65 +++
(B) cAMP measurement assay:
CHO cells (ATCC) were transfected with human TGR5 vector (oriGene). Transfected cells
were treated with vehicle control or test compounds for one hour and then lysed. Levels of
cAMP were measured in cell lysates employing Alphascreen cAMP assay kit (Perkin Elmer)
and results were expressed EC50 values which are summarized in Table 3.
Table - 3
Comp. No. EC 50 nM
1 35
7 90
33 155
50 354
(C) Measurement of glucagon like peptide-1 (GLP-1):
Human enteroendocrine cell-line (NCI-H716) were incubated with vehicle or test compounds
for one hour. At the end of incubation period, levels of secreted GLP-1 in culture medium
were measured by GLP-1 ELISA kit (Millipore). Results are summarized as fold increase in
GLP secretion with respect to vehicle control in Table 4.
Table - 4
Comp. No. Fold increase in
GLP Release
7 3.72
22 2.13
28 2.03
30 1.69
33 1.83
50 1.74
In vivo studies:
i) Evaluation of single dose efficacy of test compounds on glucose tolerance in diabetic
hamster
ii) Evaluation of efficacy of test compounds on repeated dosing in diabetic hamster and DIO
mice.
i) Evaluation of single dose efficacy of test compounds on glucose tolerance:
TGR5 receptor activation results in GLP-1 secretion which, in turn, stimulates insulin release
from pancreatic b cells & hence effectively controls the post prandial glucose excursions.
Thus efficacy can be assessed through the effect of test compounds on lowering of plasma
glucose during OGTT through stimulating glucose stimulated insulin secretion. Hence the
effect of test compounds on glucose lowering during OGTT was assessed in diabetic hamster
model.
The potential of test compounds in lowering of Plasma Glucose was evaluated in Oral
glucose tolerance test (OGTT) in Diabetic Hamster Model, where diabetes has been induced
by administration of low dose of Streptozotocin (STZ) to the High fat diet (HFD) fed glucose
intolerant animals. The diabetic hamsters show impaired glucose stimulated insulin secretion
and higher plasma glucose excursions than the normal animals, which remains elevated
beyond 2 hrs post glucose load. Thus the animal model can be used for evaluating the
potential of test compounds to lower plasma glucose through stimulating glucose stimulated
insulin secretion. On the day of study post 6 hrs of fasting, test compounds or vehicle was
administered orally at dose volume of 2 ml/kg to the hamsters of the respective treatment
groups. Subsequent to dosing, a pre-glucose load blood sample was taken. A glucose load of
40 % solution at 5 ml/Kg dose volume was administered orally. Blood samples through
retroorbital plexus were taken at 15, 30 60 & 120 min. post glucose load and plasma was
separated for glucose measurement. Post glucose load percentage change in plasma glucose
and AUC of % change glucose by the treatment was assessed.
Table-5: Effect of compounds on glucose excursion during OGTT in Diabetic Hamster
Treatment Dose Decrease in AUC of glucose %
change w.r.t. vehicle control group
1 Compound no. 1 36 mg/kg 33 %
2 Compound no. 7 38 mg/kg 39 %
3 Compound no. 33 4 1 mg/kg 20%
4 Compound no. 28 39 mg/kg 5 %
5 Compound no. 22 36 mg/kg 20 %
6 Compound no. 50 40 mg/kg 10 %
7 Compound no. 36 38 mg/kg 8 %
8 Compound no. 65 4 1 mg/kg 10 %
ii) Evaluation of efficacy of test compounds on repeated dosing in diabetic hamster and
DIO mice.
TGR5 plays a role in regulating energy expenditure by increasing basal metabolism by
increasing cellular conversion of T4 to T3 through TGR5-dependent induction of
deiodinase 2 (Dio2). Dio2 is a gene whose protein product is the enzyme 2-iodothyronine
deiodinase or D2. D2 actually converts locally available thyroxine (T4) to tri-iodothyronine
(T3), resulting in increased energy expenditure without leading to changes in circulating
thyroid hormone levels. TGR5 also found to be expressed in liver sinusoidal endothelial
cells as well as in Kupffer cells. TGR5 activation induces glucose stimulated insulin release
through increasing incretin secretion, increases energy expenditure, inhibit cytokine
production, induces body weight reduction, improve insulin resistance and glycemic profile
and reduces hepatic steatosis. Thus TGR5 activation has potential to improve various
cardiometabolic risk factors associated with obesity and type 2 diabetes. Hence, the efficacy
of test compounds was evaluated in diabetic hamster and mouse model with these metabolic
derangements.
a) Efficacy study in diabetic hamster
Diabetic hamsters were randomized to two treatment groups viz. vehicle treated and test
compound treated group. Then the animals were treated with compound 7 of present
invention or vehicle for 2 weeks to assess the efficacy potential of the compound. Effect of
treatment on glucose excursion and insulin secretion during OGTT, change in body weight
& fasting and random plasma triglycerides (TG) was evaluated during the treatment period.
The effect of repeated administration of compound on energy expenditure was evaluated
through monitoring oxygen consumption (V0 2) over 2 1 hrs period by indirect calorimetry
(Oxymax System, Columbus Instruments). HOMA-IR an index of insulin resistance was
estimated using fasting glucose and insulin levels estimated during OGTT.
Similarly, the study was conducted using compound no 50 of the present invention for the
duration of four week period in Diabetic hamsters.
In diabetic hamster, treatment with compound no. 7 increased energy expenditure, reduced
body weight, reduced glucose excursion and improved insulin secretion in response to oral
glucose load, improved insulin resistance as evident by decrease in HOMA-IR and
decreased plasma TG levels (Table 6). The treatment with compound no. 7 also shown
improvement in HDL:LDL ratio by 24% (increase in HDL by 7% and decrease in non HDL
& LDL by 24% & 14% respectively). Similarly, compound no. 50 increased energy
expenditure, reduced body weight, reduced glucose excursion and decreased plasma TG
levels in diabetic hamsters (Table 7). The treatment with compound no. 50 also shown
improvement in HDL:LDL ratio by 16%, and decrease in non HDL & LDL by 24% & 16%
respectively
b) Efficacy study in DIO mice
Male C57B1/6J mice were made insulin resistant by feeding on High fat diet (45.5 % Kcal
from Fat, Research Diet) from the age of 6-8 week onwards. After being on High fat diet for
6-8 weeks the animals with similar body weights & fasting plasma glucose were further
randomized into treatment groups. Then the animals were treated with compounds 7 to
assess the efficacy potential during treatment duration. Effect of treatment on glucose
excursion and insulin secretion during OGTT, Fasting Plasma Glucose & Insulin, lipid
profile and body weight were evaluated. The compound for enhancing energy expenditure
was evaluated by monitoring oxygen consumption (V0 2) and carbon dioxide release
(VC0 2) over 24 hrs period by indirect calorimetry (Oxymax System, Columbus
Instruments).
Similarly, the study was conducted in DIO mice with compound no 50 of the present
invention.
In DIO mice treatment with compound no. 7 increased energy expenditure, reduced body
weight, reduced glucose excursion and improved insulin secretion in response to oral
glucose load, improved insulin resistance as evident by decrease in HOMA-IR and
decreased plasma TG levels (Table 8). Similarly, treatment with compound no. 50 in DIO
mice increased energy expenditure, reduced body weight, reduced glucose excursion and
improved insulin secretion in response to oral glucose load, improved insulin resistance as
evident by decrease in HOMA-IR (Table 9).
Table 6: Effect of compound no. 7 on various metabolic parameters on repeated
administration in diabetic hamster
Table 7: Effect of compound no. 50 on various metabolic parameters on repeated
administration in diabetic hamster
% Change AUC_gluco Fasting
in body Oxygen se % change plasma
Treatment wt from consumptio during TG
(dose) basal n, ml/kg/h OGTT (mg/dl)
Vehicle 1.32 + 1446.25 + 9604.5 + 132.9 +
control 0.59 28.95 1953.1 12.2
Compound
no. 50, (6 -1.56 + 1500.55 + 6225.7 + 97.8 +
mg/kg, i.p. 0.46 38.95 1502.6 9.5
OD)
Table 8: Effect of compound no. 7 on various metabolic parameters on repeated
administration in DIO mice
Table 9: Effect of compound no. 50 on various metabolic parameters on repeated
administration in DIO mice
Oxygen AUC_gluco
% Change consumpti se % change AUCJnsulin
Treatment in body wt on, during % change
(dose) from basal ml/kg/h OGTT during OGTT HOMAVehicle
- 1.16 2561.02 8484.9 + 10604.4 3.48 +
control + 1.29 + 38.9 1218.3 + 2555.3 1.07
Compoun
d no. 50 - 3.29 2767.50 + 7763.5 + 12938.8 + 1.96 ¾ 5
(9 mg/kg, + 1.02 98.4 1251.2 1923.5 0.45
od)
CLAIMS
1. N-(4-chlorophenyl)-2-(4-fluorophenoxy)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide or pharmaceutically acceptable salts thereof.
2. A pharmaceutical composition comprising a therapeutically effective amount of a
compound as claimed in claim 1, in association with a pharmaceutically acceptable adjuvant,
diluent or carrier.
3. A method of treating cardiometabolic disorders including diabetes, obesity, dyslipidemia,
metabolic syndrome, atherosclerosis and non alcoholic fatty liver disease by administering a
therapeutically effective amount of a compound as claimed in claim 1 to a mammal in need
thereof.
4. Use of a compound as claimed in claim 1 for the preparation of a medicament for treating
cardiometabolic disorders including diabetes, obesity, dyslipidemia, metabolic syndrome,
atherosclerosis and non alcoholic fatty liver disease.
5. A compound of formula (I),
(I)
their pharmaceutically acceptable salts and their isomers, stereoisomers, conformers,
tautomers, polymorphs, hydrates and solvates;
wherein,
n = 0 or 1;
m = 0, 1, 2 or 3;
Y = CH, N or S, wherein ring containing Y group, may be optionally attached to imidazole
ring through -NH, -N(alkyl), O or S;
Alk is optionally substituted straight chain alkyl, branched chain alkyl or cycloalkyl;
R is selected from the group consisting of hydrogen, halo, cyano, nitro, Ci-salkyl, hydroxy, -
0-Ci_8alkyl, -CF3, -OCF3, -N(R4)(CO-alkyl), -N(R4)(S0 2-aryl), -N(R4)(S0 2- heteroaryl), -
N(R4)(S0 2-heterocyclyl), -N(R4)(C(0)0-R 4), -N(R4)(C(0)0-aryl),
-N(R4)(C(0)0-heteroaryl), -N(R4)(C(0)0-heterocyclyl), -N(R4)C(0)N(R 4)(R4),
-N(R4)C(0)N(R 4)(aryl), -N(R4)C(0)N(R 4)(heteroaryl), -N(R4)C(0)N(R 4)(heterocyclyl), -
N(R4)S0 2N(R4)(R4), -N(R4)S0 2N(R4)(aryl), -N(R4)S0 2N(R4)(heteroaryl),
-N(R4)S0 2N(R4)(heterocyclyl), -OC(0)(R 4), -O(aryl), -O(heteroaryl), -O(heterocyclyl), -
S(R4), -S-aryl, -S-heteroaryl, -S-heterocyclyl, -N(R4)(R4), -N(R4)(aryl), -N(R4)(heteroaryl), -
N(R4)(heterocyclyl), -C(0)(R 4), -C(0)(aryl), -C(0)(heteroaryl),-C(0)(heterocyclyl), -
C(0)N(R 4)(R4), -C(0)N(R 4)(aryl), -C(0)N(R 4)(heteroaryl), -C(0)N(R 4)(heterocyclyl), -
C(0)0-(R 4), -C(0)0-aryl, -C(0)0-heteroaryl, -C(0)0-heterocyclyl, -S(0)(aryl), -
S(0)(heteroaryl), -S(0)(heterocyclyl), -S0 2(aryl), -S0 2(heteroaryl), -
S0 2(heterocyclyl), -S0 2N(R4)(R4), -S0 2N(R4)(aryl), -S0 2 N(R4)(heteroaryl), -S0 2
N(R4)(heterocyclyl), aryl, heteroaryl and heterocyclyl;
R2 is selected from the group consisting of halo, cyano, nitro, Ci_8alkyl, hydroxy, CF3, -
OCF3, -amino, -0(Ci_8alkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), -S(R4), -S-aryl, -Sheteroaryl,
-S-heterocyclyl, -C(0)0-(R 4), -C(0)0-aryl, -C(0)0-heteroaryl, -C(0)0-
heterocyclyl, -S0 2N(R4)(R4), -S0 2N(R4)(aryl), -S0 2N(R4)(heteroaryl), -S0 2
N(R4)(heterocyclyl), aryl, heteroaryl and heterocyclyl; or
R & R2 when present on adjacent carbon atom may join together to form cycloalkenyl, aryl,
heteroaryl or heterocyclyl ring;
R 3 is selected from the group consisting of hydrogen, cyano, nitro, hydroxy, -0(Ci_ alkyl),
-OCF 3, -N(R4)(CO-R4), -N(R4)(CO-aryl), -N(R4)(CO-heteroaryl), -N(R4)(S0 2-R4), -
N(R4)(S0 2-CF3), -N(R4)(S0 2-aryl), -N(R4)(S0 2-heteroaryl), -N(R4)(S0 2- heterocyclyl), -
N(R4)(C(0)0-R 4), -N(R4)(C(0)0-aryl), -N(R4)(C(0)0-heteroaryl), -N(R4)(C(0)0-
heterocyclyl), -N(R4)C(0)N(R 4)(R4), -N(R4)C(0)N(R 4)(aryl), -N(R4)C(0)N(R 4)(heteroaryl),
-N(R4)C(0)N(R 4)(heterocyclyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), -S(R4), -S-aryl, -
S-heteroaryl, -S-heterocyclyl, -N(R )(R ), -N(R )(aryl), -N(R )(heteroaryl),
N(R4)(heterocyclyl), -C(0)(R 4), -C(0)(aryl), -C(0)(heteroaryl), -C(0)(heterocyclyl), -
C(0)N(R 4)(R4), -C(0)N(R 4)(aryl), -C(0)N(R 4)(heteroaryl), -C(0)N(R 4)(heterocyclyl), -
C(0)0-(R 4), -C(0)0-aryl, -C(0)0-heteroaryl, -C(0)0-heterocyclyl, S(0)-(Ci_8alkyl), -
S(0)(aryl), -S(0)(heteroaryl), -S(0)(heterocyclyl), -S0 2(Ci_8alkyl), -S0 2(aryl), -
S0 2(heteroaryl), -S0 2(heterocyclyl), -S0 2N(R4)(R4), -S0 2N(R4)(aryl),
S0 2N(R4)(heteroaryl), -S0 2N(R4)(heterocyclyl) and S0 2 N(R4)(cycloalkyl); and
R 4 is hydrogen or -Ci_8alkyl.
6. The compound of formula (I) as claimed in claim 5, wherein,
R is selected from the group consisting of hydrogen, halo, cyano, Ci-salkyl, hydroxy, -O-Ci-
8alkyl, -CF3, -OCF3, -N(R4)(S0 2-aryl), -N(R4)(S0 2-heteroaryl), -N(R4)(S0 2-heterocyclyl), -
N(R4)(C(0)0-R 4), -N(R4)(C(0)0-aryl), -N(R4)(C(0)0-heteroaryl), -N(R4)(C(0)0-
heterocyclyl), -N(R4)C(0)N(R 4)(R4), -N(R4)SQ2N(R4)(aryl), _-0(aryl), -S(R4), -N(R4)(R4), -
N(R4)(aryl), -C(0)(heterocyclyl), -C(0)N(R 4)(R 4), -C(0)N(R 4)(aryl), -S0 2(aryl), -
S0 2N(R4)(R4), -S0 2N(R4)(aryl), aryl, heteroaryl and heterocyclyl;
R2 is selected from the group consisting of halo, cyano, Ci-salkyl, hydroxy, CF3, -OCF3, -
amino, -0(Ci_ 8alkyl), -O(aryl), -S-aryl, -C(0)0-(R 4), -S0 2N(R4)(R4), -S0 2N(R4)(aryl), aryl,
heteroaryl and heterocyclyl; and
R3 is selected from the group consisting of hydrogen, cyano, nitro, hydroxy, -0(Ci_ 8alkyl), -
N(R4)S0 2(aryl), -N(R4)(C(0)0-R 4), -N(R4)C(0)N(R 4)(R4), - N(R4)C(0)N(R 4)(aryl), -
N(R4)(R4), -C(0)(heterocyclyl), - C(0)0-(R 4), -S0 2(aryl) and -S0 2N(R4)(aryl).
7. The compound of formula (I) as claimed in claim 5, wherein,
m = 0, 1 or 2;
Y = CH, N or S, wherein ring containing Y group, may be optionally attached to imidazole
ring through -NH or O;
R is selected from the group consisting of hydrogen, halo, cyano, Ci-salkyl, hydroxy, -0-Ci_
galkyl, -CF3, -OCF3, -N(R4)(R4), -S0 2N(R4)(R4), aryl, heteroaryl and heterocyclyl;
R2 is selected from the group consisting of halo, Ci_8alkyl, hydroxy, -0(Ci_ 8alkyl), -C(0)0-
(R4), -S0 2N(R4)(R4) and heterocyclyl; or
R & R2 when present on adjacent carbon atom may join together to form cycloalkenyl, ring;
and
R is selected from the group consisting of hydrogen, hydroxy, -N(R4)(C(0)0-R 4),
N(R4)C(0)N(R 4)(R4), -N , -C(0)(heterocyclyl), C(0)0-(R 4) and S0 2(aryl).
8. The compound as claimed in claim 5, which is selected from the group consisting of:
N-(4-chlorophenyl)-N-methyl-2-phenylimidazo[l,2-a]pyrimidine-3-carboxamide;
N-(3-chlorophenyl)-N-methyl-2-phenylimidazo[l,2-a]pyrimidine-3-carboxamide;
(4-{methyl[(2-phenylimidazo[l,2-a]pyrimidin-3-yl)carbonyl] amino }phenyl) acetic
acid;
2-(4-chlorophenyl)-N-(2,3-dihydro-lH-inden-5-yl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide;
N,2-bis(4-chlorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-carboxamide;
N-(2,3-dihydro-lH-inden-5-yl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide
2-(biphenyl-4-yl)-N-(4-chlorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
2-(biphenyl-4-yl)-N-(2,3-dihydro-lH-inden-5-yl)-N-methylimidazo[l,2-a] pyrimidine-
3-carboxamide;
N-(4-chlorophenyl)-2-(3,4-dimethoxyphenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-N-methyl-2-(pyridin-2-yl)imidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-N-methyl-2,6-diphenylimidazo[l,2-a]pyrimidine-3-carboxamide;
N-(2,3-dihydro-lH-inden-5-yl)-2-(3,4-dimethoxyphenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2-(3,4-dichlorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(2,3-dihydro-lH-inden-5-yl)-2-(3,4-dihydroxyphenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2-(4-methoxyphenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(2,3-dihydro-lH-inden-5-yl)-N-methyl-2-(pyridin-2-yl)imidazo[l,2-a] pyrimidine-3-
carboxamide;
2-(4-chlorophenyl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
2-(4-chlorophenyl)-N-(3,4-dimethoxyphenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-N-methyl-2-(pyridin-3-yl)imidazo[l,2-a]pyrimidine-3-
carboxamide;
2-(2,4-dichlorophenyl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N,2-bis(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-N-methyl-2-[2-(trifluoromethyl)phenyl]imidazo[l,2-a] pyrimidine-
3-carboxamide;
2-(4-chlorophenyl)-N-[4-(dimethylsulfamoyl)phenyl]-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide;
2-(4-chlorophenyl)-N-(2,4-dimethoxyphenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-fluorophenyl)-N-methyl-2-phenylimidazo[l,2-a]pyrimidine-3-carboxamide;
2-(4-chlorophenyl)-N-(3,4-dihydroxyphenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
2-(l,3-benzodioxol-5-yl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
2-(l,3-benzodioxol-5-yl)-N-(4-chlorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-2-(4-hydroxyphenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-N-methyl-2-[3-(trifluoromethyl)phenyl]imidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(4-chlorophenyl)-2-(4-fluorophenyl)imidazo[l,2-a]pyrimidine-3-carboxamide;
N-(4-fluorophenyl)-N-methyl-2-[3-(trifluoromethyl)phenyl]imidazo[l,2-a] pyrimidine-
3-carboxamide;
N-(2,4-dimethoxyphenyl)-2-(4-fluorophenyl)imidazo[l,2-a]pyrimidine-3-carboxamide;
2-(3-cyanophenyl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-2-(3-cyanophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-2-[4-(dimethylsulfamoyl)phenyl]-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide;
2-[4-(dimethylsulfamoyl)phenyl]-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide;
N-(2,4-difluorophenyl)-2-(4-fluorophenyl)imidazo[l,2-a]pyrimidine-3-carboxamide;
N-(2,4-difluorophenyl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
2-(3-fluoro-4-methoxyphenyl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide;
2-(3-fluoro-4-hydroxyphenyl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-a] pyrimidine-
3-carboxamide;
N-(2,4-difluorophenyl)-2-(3-fluoro-4-methoxyphenyl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2-(3-fluoro-4-methoxyphenyl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide;
N-(3-chloro-4-fluorophenyl)-2-(3-fluoro-4-methoxyphenyl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide;
N-(2,4-difluorophenyl)-2-(4-fluorophenoxy)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-N-methyl-2-phenoxyimidazo[l,2-a]pyrimidine-3-carboxamide;
2-(4-chlorophenoxy)-N-(4-chlorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-2-(4-methoxyphenoxy)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
2-(4-chlorophenoxy)-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
2-(4-fluorophenoxy)-N-(4-methoxyphenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-2-(3-fluoro-4-hydroxyphenyl)-N-methylimidazo[l,2-a]
pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2-(4-cyanophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
2-(4-cyanophenyl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(3-chloro-4-fluorophenyl)-2-(4-cyanophenyl)-N-methylimidazo[l,2-a] pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-N-(4-fluorobenzyl)-2-(4-fluorophenyl)imidazo[l,2-a] pyrimidine-
3-carboxamide;
2-(2,6-dichlorophenoxy)-N-(2,4-difluorophenyl)-N-methylimidazo [1,2-a] pyrimidine-
3-carboxamide;
2-(2,6-dichlorophenoxy)-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-2-(2,4-difluorophenoxy)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
2-(5-chlorothiophen-2-yl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-2-(5-chlorothiophen-2-yl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-N-methyl-2-[4-(trifluoromethyl)phenyl]imidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(4-fluorophenyl)-N-methyl-2-[4-(trifluoromethyl)phenyl]imidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-(propan-2-yl)imidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-2-(4-fluorophenoxy)imidazo[l,2-a]pyrimidine-3-carboxamide;
N-(4-fluorophenyl)-2-[3-(trifluoromethyl)phenyl]imidazo[l,2-a]pyrimidine-3-
carboxamide;
N-cyclopropyl-N,2-bis(4-fluorophenyl)imidazo[l,2-a]pyrimidine-3-carboxamide;
N-cyclopropyl-N-(4-fluorophenyl)-2-[3-(trifluoromethyl)phenyl]imidazo[l,2-
a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-N-cyclopropyl-2-[3-(trifluoromethyl)phenyl]imidazo[l,2-
a]pyrimidine-3-carboxamide;
methyl {2-(4-fluorophenyl)-3-[(4-fluorophenyl)(methyl)carbamoyl]imidazo[l,2-
a]pyrimidin-6-yl }carbamate;
methyl {3-[(4-chlorophenyl)(methyl)carbamoyl]-2-(4-fluorophenyl)imidazo[l ,2-
a]pyrimidin-6-yl }carbamate;
6-(carbamoylamino)-N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide;
6-(carbamoylamino)-N,2-bis(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
6-(carbamoylamino)-2-(4-fluorophenyl)-N-(4-methoxyphenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2-[3-(dimethylamino)phenyl]-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide;
2-[3-(dimethylamino)phenyl]-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(4-chlorophenyl)-2-(5-fluoro-2-hydroxyphenyl)-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide;
2-(5-fluoro-2-hydroxyphenyl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide;
2-(5-fluoro-2-hydroxyphenyl)-N-(4-methoxyphenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-N-methyl-2-[4-(propan-2-yl)phenyl]imidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-fluorophenyl)-N-methyl-2-[4-(propan-2-yl)phenyl]imidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-2-(2,6-dihydroxyphenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
2-(2,6-dihydroxyphenyl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-2-(2-hydroxy-6-methoxyphenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide;
N-(4-fluorophenyl)-2-(2-hydroxy-6-methoxyphenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-N-methyl-2-(thiophen-2-yl)imidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-fluorophenyl)-N-methyl-2-(thiophen-2-yl)imidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-2-(5-fluoro-2-hydroxyphenyl)-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide;
2-(5-fluoro-2-hydroxyphenyl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(4-chlorophenyl)-2-(furan-2-yl)-N-methylimidazo[l,2-a]pyrimidine-3-carboxamide;
N-(4-fluorophenyl)-2-(furan-2-yl)-N-methylimidazo[l,2-a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2-(2,3-dihydro-l,4-benzodioxin-5-yl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide;
2-(2,3-dihydro-l,4-benzodioxin-5-yl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2-(2-fluoro-4-methoxyphenyl)- N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide;
2-(2-fluoro-4-methoxyphenyl)-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(4-chlorophenyl)-N-methyl-2-[3-(trifluoromethoxy)phenyl]imidazo[l,2-
a]pyrimidine-3-carboxamide;
N-(4-fluorophenyl)-N-methyl-2-[3-(trifluoromethoxy)phenyl]imidazo[l,2-
a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-N-methyl-2-[4-(methylsulfonyl)phenyl]imidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(4-fluorophenyl)-N-methyl-2-[4-(methylsulfonyl)phenyl]imidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(4-chlorophenyl)-2-[(4-methoxyphenyl)amino]-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(4-fluorophenyl)-2-[(4-methoxyphenyl)amino]-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(4-chlorophenyl)-2-[(4-chlorophenyl)amino]-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
2-[(4-chlorophenyl)amino]-N-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-2-[(4-fluorophenyl)amino]-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-fluorophenyl)-2-[(4-fluorophenyl)amino]-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-2-[(4-methoxyphenyl)amino]-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(4-fluorophenyl)-2-[(4-methoxyphenyl)amino]-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(4-chlorophenyl)-2-[(3-fluoro-4-hydroxyphenyl)amino]-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-N-methyl-2- {[2-(trifluoromethyl)phenyl]amino }imidazo[1,2-
a]pyrimidine-3-carboxamide;
N-(4-fluorophenyl)-N-methyl-2-{[2-(trifluoromethyl)phenyl]amino}imidazo[l,2-
a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-N-methyl-2- {[3-(trifluoromethyl)phenyl]amino }imidazo[1,2-
a]pyrimidine-3-carboxamide;
N-(4-fluorophenyl)-N-methyl-2-{[3-(trifluoromethyl)phenyl]amino}imidazo[l,2-
a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-6-(dimethylamino)-2-(4-fluorophenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2-[(4-fluorophenyl)amino]-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
methyl {3-[(4-chlorophenyl)(methyl)carbamoyl]-2-(4-fluorophenyl)imidazo[l ,2-
a]pyrimidin-6-yl}methylcarbamate;
N-(4-chlorophenyl)-2-(4-fluorophenyl)-5,7-dihydroxy-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N,7-dimethylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methyl-6-[methyl(propan-2-
ylcarbamoyl)amino]imidazo[l,2-a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2-(4-fluorophenyl)-7-hydroxy-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(4-chlorophenyl)-2-(4-fluorophenyl)-7-hydroxyimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-2-(4-fluorophenyl)-5-hydroxy-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(4-chlorophenyl)-2-(4-fluorophenyl)-5-hydroxyirmdazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-2-(4-fluorophenyl)-7-hydroxy-N-(hydroxymethyl)imidazo[l,2-
a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-(hydroxymethyl)imidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(4-chlorophenyl)-2-(4-fluoro-2-hydroxyphenyl)-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(4-chloro-2-hydroxyphenyl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide;
3-[(4-chlorophenyl)(methyl)carbamoyl]-2-(4-fluorophenyl)imidazo[l,2-a]pyrimidine-
6-carboxylic acid;
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methyl-6-(phenylsulfonyl)imidazo[l,2-
a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methyl-6-(pyrrolidin-lylcarbonyl)
imidazo[l,2-a]pyrimidine-3-carboxamide;
N-(4-fluorophenyl)-N-methyl-2-(morpholin-4-yl)imidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-2-(3-fluorophenoxy)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
2-(4-fluorophenyl)-N-(4-methoxyphenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
ethyl 4-[{[2-(4-fluorophenyl)imidazo[l,2-a]pyrimidin-3-yl]carbonyl} (methyl)
amino]benzoate;
N-(4-chlorophenyl)-2-(4-fluoro-2-methoxyphenyl)-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(4-chlorophenyl)-N-cyclopropyl-2-(4-fluorophenyl)imidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide hydrochloride (1:1);
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide sulfate (1:1);
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide 4-methylbenzenesulfonate (1:1);
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide methanesulfonate (1:1);
2-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-carboxamide;
N-(4-cyclohexylphenyl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
2-(4-fluorophenyl)-N-methyl-N-[4-(morpholin-4-yl)phenyl]imidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(biphenyl-3-yl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-2-(4-fluoro-3-methoxyphenyl)-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(4-chlorophenyl)-N-methyl-2-{4-[(phenylsulfonyl) amino] phenyl} imidazo[ 1,2-a]
pyrimidine-3-carboxamide;
methyl (4-{3-[(4-chlorophenyl)(methyl)carbamoyl]imidazo[l,2-a]pyrimidin-2-
yl }phenyl)carbamate;
N-(4-chlorophenyl)-N-methyl-2-{4-[(methylcarbamoyl)amino]phenyl}imidazo[l,2-a]
pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-N-methyl-2- {4-[(phenylsulfamoyl)amino]phenyl }imidazo[ 1,2-a]
pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2-[4-(4-fluorophenoxy)phenyl]-N-methylimidazo[ 1,2-a]
pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-N-methyl-2-[4-(methylsulfanyl)phenyl]imidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(4-chlorophenyl)-2-{4-[(4-fluorophenyl)amino]phenyl}-N-methylimidazo [1,2-a]
pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-N-methyl-2-[4-(piperazin-l-ylcarbonyl)phenyl] imidazo[l,2-a]
pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-N-methyl-2-{4-[methyl(phenyl)carbamoyl]phenyl}imidazo[l,2-a]
pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2-{4-[(4-fluorophenyl)sulfonyl]phenyl}-N-methylimidazo [1,2-a]
pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2- {4-[(4-fluorophenyl)sulfamoyl]phenyl }-N-methyl imidazo[ 1,2-
a] pyrimidine-3-carboxamide;
N-[4-(4-chlorophenoxy)phenyl]-2-(4-fluorophenyl)-N-methylimidazo[ 1,2-a]
pyrimidine-3-carboxamide;
N-{4-[(4-chlorophenyl)sulfanyl]phenyl }-2-(4-fluorophenyl)-N-methylimidazo [1,2-a]
pyrimidine-3-carboxamide;
N-methyl-2-phenyl-N- [4-(phenylsulfamoyl)phenyl]imidazo [1,2-a]pyrimidine-3 -
carboxamide;
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methyl-6-[(phenylcarbonyl) amino]
imidazo[l,2-a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methyl-6-[(phenylsulfonyl) amino]
imidazo[l,2-a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methyl-6-[(phenylcarbamoyl) amino]
imidazo[l,2-a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2-(4-fluorophenyl)-6-hydroxy-N-methylimidazo[l,2-a]pyrimidine-
3-carboxamide; and
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methyl-6-(phenylsulfamoyl) imidazo[l,2-
a]pyrimidine-3-carboxamide or pharmaceutically acceptable salt thereof.
N-(4-chlorophenyl)-2-(4-fluorophenoxy)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide 4-methylbenzenesulfonate (1:1)
N-(4-chlorophenyl)-2-(4-fluorophenoxy)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide benzenesulfonate (1:1)
N-(4-chlorophenyl)-2-(4-fluorophenoxy)-6-hydroxy-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenoxy)-5-hydroxy-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenoxy)-7-hydroxy-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluorophenoxy)-N-(hydroxymethyl)imidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chlorophenyl)-2-(4-fluoro-3-hydroxyphenoxy)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
N-(4-chloro-3-hydroxyphenyl)-2-(4-fluorophenoxy)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide
9. The compound as claimed in claim 8, which is selected from the group consisting of:
N-(4-chlorophenyl)-N-methyl-2-phenylimidazo[l,2-a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-chlorophenyl)-N-methyl-2-(pyridin-3-yl)imidazo[l,2-a]pyrimidine-3-
carboxamide;
N,2-bis(4-fluorophenyl)-N-methylimidazo[l,2-a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-2-(4-hydroxyphenyl)-N-methylimidazo[l,2-a]pyrimidine-3-
carboxamide;
N-(4-fluorophenyl)-N-methyl-2-[3-(trifluoromethyl)phenyl]imidazo[l,2-a]pyrimidine-
3-carboxamide;
N-(3-chloro-4-fluorophenyl)-2-(3-fluoro-4-methoxyphenyl)-N-methylimidazo[l,2-
a]pyrimidine-3-carboxamide;
N-(4-chlorophenyl)-N-cyclopropyl-2-(4-fluorophenyl)imidazo[l,2-a]pyrimidine-3-
carboxamide; and
N-(4-chlorophenyl)-2-(4-fluorophenyl)-N-(propan-2-yl)imidazo[l,2-a]pyrimidine-3-
carboxamide or pharmaceutically acceptable salt thereof
10. A pharmaceutical composition comprising a therapeutically effective amount of one or
more compound as claimed in claim 5, in association with a pharmaceutically acceptable
adjuvant, diluent or carrier.
11. A method for treating cardiometabolic disorders including diabetes, obesity,
dyslipidemia, metabolic syndrome, atherosclerosis and non alcoholic fatty liver disease by
administering a therapeutically effective amount of a compound of formula (I) as claimed in
claim 5 to a mammal in need thereof.
12. Use of a compound of formula (I) as claimed in claim 5 for the preparation of a
medicament for treating cardiometabolic disorders including diabetes, obesity, dyslipidemia,
metabolic syndrome, atherosclerosis and non alcoholic fatty liver disease.
13. Use of a compound of formula (I) as claimed in claim 5 for the preparation of salts,
polymorphs, hydrates and solvates of compound of formula (I).
14. A process of preparation of polymorph of compound of formula (I) as claimed in claim 5,
comprises contacting compound of formula (I) with suitable solvent or mixture of solvent
15. A compound of formula (I), its method for preparation and pharmaceutical composition,
as herein described with reference to the examples accompanying the specification.