GPR142 AGONIST COMPOUNDS
This invention relates to imidazo benzamide compounds, or pharmaceutically
acceptable salts thereof, and therapeutic use thereof. Compounds of this invention are
GPR142 agonists.
GPR142 is reported to be expressed in pancreatic cells and associated with the
stimulation of insulin secretion under conditions of high blood glucose. Compounds that
effectuate GPR142 agonism are desired.
A series of phenylalanine based compounds for GPR142 agonism are disclosed in
M. Lizarzaburu, et al. "Discovery and Optimization of a novel series of GPR142 agonists
for the treatment of type 2 diabetes," Bioorganic and Medicinal Chemistry Letters 22
(2012) 5942-5947.
The present invention provides compounds with GPR142 agonist activity.
The present invention provides compounds of the Formula la below:
wherein R is selected from the group consisting of CH3, CH(CH3)2, CH2CN,
, CH2CH2OCH3, and CH2C(0)OCH(CH 3)2;
R1 is selected from the group consisting of CF3, OCF3, and CI;
R2 is selected from the group consisting of H and F;
or a pharmaceutically acceptable salt thereof.
The invention further provides a compound of the Formula
wherein R is selected from the group consisting of CH(CH3)2, CH2CN,
, CH2CH2OCH3, and CH2C(0)OCH(CH 3)2;
R1 is selected from the group consisting of CF3, OCF3, and CI;
R2 is selected from the group consisting of H and F;
or a pharmaceutically acceptable salt thereof.
The present invention provides compounds of the Formula I below:
I
or a pharmaceutically acceptable salt thereof.
The compounds of the present invention have chiral carbons identified by the
asterisks (*) in the structure above. The artisan will appreciate that the compounds of the
invention exist as cis and trans isomers. Both cis and trans isomers are contemplated by
the present invention. The cis configuration is preferred. The preferred isomer is isomer
1.
In an embodiment, R 2 is H ; R is selected from the group consisting o f CH 3 ,
CH(CH 3)2 , CH 2CN, C H 2CHF 2 , CH 2CF 3
, , , CH 2C H 2OCH 3 , and C H 2C(0)OCH(CH 3) 2;
R 1 is selected from the group consisting o f C F 3 , OCF 3 , and CI; or a
harmaceutically acceptable salt thereof.
embodiment, R 2 is H ; R 1 is CCFF
3
; aanndd R iiss sseelleecctteedd fifrrom the group consisting
o f CH 3 , CH(CH 3)2 , CH 2CN, C H 2CHF 2 , C H 2C F 3 ,
, CH 2C H 2OCH 3 , and C H 2C(0)OCH(CH 3) 2; or
a pharmaceutically acceptable salt thereof. In a n embodiment, R 2 is H ; R 1 is C F 3 ; and R
is selected from the group consisting o f CH 3 , CH(CH 3) 2, C H 2CN, CH 2CHF 2 , C H 2C F 3 ,
CH 2CH 2OCH 3 , and C H 2C(0)OCH(CH 3)2; or a pharmaceutically acceptable salt thereof.
In a n embodiment, R 2 is H ; R 1 is CF 3; and R is selected from the group consisting o f
a pharmaceutically acceptable salt thereof. In an embodiment, R 2 is H ; R 1 is C F 3 ; and R
is selected from the group consisting o f CH 3 , CH(CH 3) 2, C H 2CN, CH 2CHF 2 , C H 2C F 3,
CH 2CH 2OCH 3 , and C H 2C(0)OCH(CH 3)2; or a pharmaceutically acceptable salt thereof.
In an embodiment, R is selected from the group consisting o f CH 3 , CH(CH 3)2 ,
CH 2CN, C H 2CHF 2 , CH 2CF 3 ,
V °
CH 2CH 2OCH 3 , and CH 2C(0)OCH(CH 3)2;
R 1 is OCF 3; R 2 is H ; or a pharmaceutically acceptable salt thereof.
A preferred compound of the invention is Cis-(chiral)-N-[3-[(3,5-
Dimethylimidazol-4-yl)carbamoyl]cyclohexyl]-N-methyl-3-(trifluoromethyl)benzamide
or a pharmaceutically acceptable salt thereof.
The invention also provides a method for treating type II diabetes in a patient,
comprising administering to a patient in need of such treatment an effective amount of a
compound of Formula la, or a pharmaceutically acceptable salt thereof. The invention
provides a method of augmenting insulin levels in a patient with type II diabetes,
comprising administering to a patient in need of such treatment, an effective amount of a
compound of Formula la, or a pharmaceutically acceptable salt thereof. The invention
provides a method for treating a condition modulated by GPR142 agonism in a patient in
need of such treatment, comprising administering an effective amount of a compound of
Formula la, or a pharmaceutically acceptable salt thereof.
This invention provides a compound of Formula la, or a pharmaceutically acceptable
salt thereof, for use in therapy, in particular for use in the treatment of type II diabetes or for
use in the augmentation of insulin levels in a patient with type II diabetes. Even furthermore,
this invention provides the use of a compound of Formula la, or a pharmaceutically
acceptable salt thereof, for use in the manufacture of a medicament. This invention also
provides the use of a compound of Formula la, or a pharmaceutically acceptable salt thereof,
for use in the manufacture of a medicament for use in the treatment of type II diabetes. This
invention provides the use of a compound of Formula la, or a pharmaceutically acceptable
salt thereof, for use in the manufacture of a medicament for the augmentation of insulin levels
in a patient with type II diabetes.
The invention further provides a pharmaceutical composition, comprising a
compound of Formula la, or a pharmaceutically acceptable salt thereof, with one or more
pharmaceutically acceptable carriers, diluents, or excipients. Provided in another
embodiment of the invention, is a pharmaceutical composition comprising a compound of
Formula la, or a pharmaceutically acceptable salt thereof, with one or more
pharmaceutically acceptable carriers, diluents, or excipients. The invention provides a
pharmaceutical composition, comprising a compound of Formula la, or a
pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable
carriers, diluents, or excipients, and further comprising a second pharmaceutically active
agent. The skilled artisan will recognize that the second pharmaceutically active agent is
suitable for administration sequentially or concomitantly with a GPR142 agonist. A
preferred second pharmaceutical agent is, for example, metformin.
The term "pharmaceutically-acceptable salt" refers to a salt of the compound of
the invention considered to be acceptable for clinical and/or veterinary use.
Pharmaceutically acceptable salts and common methodology for preparing them are well
known in the art. See, e.g., P. Stahl, et al., Handbook of Pharmaceutical Salts: Properties,
Selection and Use, (VCHA/Wiley-VCH, 2002); S.M. Berge, et al, "Pharmaceutical
Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977.
The term "treating" (or "treat" or "treatment") as used herein refers to restraining,
slowing, or stopping the progression or severity of an existing symptom, condition, or
disorder. It is preferred that "treating" includes augmenting insulin levels in a patient
with type II diabetes.
Compounds of the present invention are GPR142 agonists, and may be useful for
treating a disease or condition associated with a decrease in GPR142. Compounds of the
present invention may be useful in the treatment of a disease or condition associated with
the modulation of GPR142.
As used herein, "patient" refers to an animal in need of treatment, preferably not
exclusively a mammal. A preferable embodiment is a patient that is a mammal, which is
preferably a human. Another preferable embodiment is a patient that is a companion
animal such as a dog, cat, or a fowl.
As used herein, the term "effective amount" refers to the amount or dose of
compound of the invention or a pharmaceutically acceptable salt thereof which upon
single or multiple dose administration to the patient, provides the desired effect in the
patient. It will be understood that the amount of active agent actually administered will
be determined by a physician, in light of the relevant circumstances, including the
condition to be treated, the chosen route of administration, the actual active agent
administered, the age, weight, and response of the individual patient, and the severity of
the patient's symptoms and other relevant circumstances.
A compound of the present invention is preferably formulated as pharmaceutical
compositions administered by any route which makes the compound bioavailable. Most
preferably, such compositions are for oral administration. Such pharmaceutical
compositions and processes for preparing same are well known in the art. See, e.g.,
Remington: The Science and Practice of Pharmacy (D.B. Troy, Editor, 21st Edition,
Lippincott, Williams & Wilkins, 2006).
Preparations and Examples
The following Preparations and Examples further illustrate the invention and
represent a typical synthesis of the compound of the invention. It should be understood
that the Preparations and Example are set forth by way of illustration and not limitation,
and that various modifications may be made by one of ordinary skill in the art.
The compounds of the present invention, or salts thereof, may be prepared by a
variety of procedures known in the art, some of which are illustrated in the Schemes,
Preparations, and Examples below. The specific synthetic steps for each of the routes
described may be combined in different ways, or in conjunction with steps from different
schemes, to prepare compounds of Formula la, or salts thereof. The products of each step
in the schemes below can be recovered by conventional methods well known in the art,
including extraction, evaporation, precipitation, chromatography, filtration, trituration,
and crystallization. In the schemes below, all substituents unless otherwise indicated, are
as previously defined. The reagents and starting materials are readily available to one of
ordinary skill in the art. The reagents and starting materials are generally available to one
of ordinary skill in the art. Others may be made by standard techniques of organic and
heterocyclic chemistry, techniques which are known to one of ordinary skill in the art,
and the procedures described in the Examples and Preparations which follow including
any novel procedures.
Individual isomers, enantiomers, or diastereomers may be separated or resolved by
one of ordinary skill in the art at any convenient point in the synthesis of a compound of
Formula la by methods such as chiral chromatography or elective crystallization
techniques (See for example, J . Jacques, et al., "Enantiomers, Racemates, and
Resolutions" , John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen,"
Stereochemistry of Organic Compounds", Wiley-Interscience, 1994). The designations
"isomer 1" and "isomer 2" refer to the compounds that elute from chiral chromatography
first and second, respectively, and if chiral chromatography is initiated early in the
synthesis, the same designation is applied to subsequent intermediates and examples. The
skilled artisan will recognize that the first eluting isomer may vary depending on the
elution conditions.
Additionally, the intermediates described in the following Schemes and
preparations may contain a number of nitrogen, hydroxy, or acid protecting groups. The
variable protecting group may be the same or different in each occurrence depending on
the particular reaction conditions and the particular transformations to be performed. The
protection and deprotection conditions are well known to the skilled artisan and are
described in the literature (See for example Greene 's Protective Groups in Organic
Synthesis, T.W. Greene and P.G. M. Wuts, eds., Fourth Edition, John Wiley and Sons,
Inc., 2006).
The abbreviations used herein are defined according to Aldrichimica Acta, Vol.
17, No. 1, 1984. Other abbreviations are defined as follows: "BSA" refers to Bovine
Serum Albumin; "CDI" refers to , -carbonyldiimidazole; "DCC" refers to 1,3-
dicyclohexylcarbodiimide; "DIC" refers to 1,3-diisopropylcarbodiimide; "DMSO" refers
to dimethylsulfoxide; "EC 50" refers to the effective concentration at half the maximal
response; "ee" refers to enantiomeric excess; "Ex" refers to example; "FBS" refers to
Fetal Bovine Serum; "HATU" refers to (dimethylamino)-N,N-dimethyl(3 H-
[ 1,2,3]triazolo[4,5-&]pyridin-3-yloxy)methaniminium hexafluorophosphate "HBSS"
refers to Hank's Balanced Salt Solution; "HEK" refers to human embryonic kidney;
"HEPES" refers to 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid; "HOAt" refers to
l-hydroxy-7-azobenzotriazole; "HOBt" refers to 1-hydroxylbenzotriazole hydrate;
"HBTU" refers to refers to 2-(l H-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium
hexafluorophosphate; "HPLC" refers to High Performance Liquid Chromatography;
"HTRF" refers to homogenous time resolved fluorescence; "IP-1" refers to inositol
monophosphate; "KRB" refers to Krebs ringer buffer; "PG" refers to protecting group;
"Prep" refers to preparation; "PyBOP" refers to benzotriazol-l-yloxytripyrrolidinophosphonium
hexafluorophosphate; "PyBrop" refers to bromo-tris-pyrrolidino
phosphoniumhexafiuoro phosphate; "RPMI" refers to Roswell Park Memorial Institute;
"PvT" refers to retention time; "SFC" refers to supercritical fluid chromatography; and
"TFA" refers to trifluoroacetic acid.
Scheme 1
In Scheme 1, an amide coupling is accomplished with the amine of a 3-amino
cyclohexanecarboxylic acid followed by an amide coupling on the carboxylic acid to give
an-N-[3-[(3-substituted,5 methyl imidazol-4-yl)carbamoyl]cyclohexyl]-N-methyl-3,5
substituted benzamide. For example in Step 1, the protected amine can be methylated and
the 3-carboxylic acid can be protected simultaneously under conditions well known in the
art with a base such as sodium hydride at a temperature of about 0 °C using a methylating
agent such as methyl iodide in a solvent such as dimethylformamide to give the product
of Step 1. In substep 1 of Step 2, the amine can be deprotected under conditions well
known in the art using an acid such as TFA at room temperature in a solvent such as
dichloromethane. In substep 2 of Step 2, an acid chloride can be reacted with the amine
using an organic base such as triethylamine in a solvent such as dichloromethane to give
the amide product of Step 2. One skilled in the art can recognize that a carboxylic acid
can be converted to the acid chloride using oxalyl chloride and a catalytic amount of
dimethylformamide in a solvent such as dichloromethane. Alternatively, an amide
coupling can be accomplished with an appropriate carboxylic acid and amine to give the
product of Step 2. For example, the amide product of Step 2 can be reacted with a
carboxylic acid using a coupling agent in a solvent such as pyridine, dimethformamide, or
dichloromethane at room temperature or with heating. One skilled in the art will
recognize that there are a number of methods and reagents for amide formation. For
example, the reaction of the amine compound with an appropriate carboxylic acid in the
presence of a coupling reagent with or without an organic base such as
diisopropylethylamine or triethylamine can provide a compound of Step 2. Coupling
reagents include carbodiimides, such as DCC, DIC, l-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride or a carbonyldiimidazole such as CDI. Amide coupling
additives, such as HOBt and HOAt can also be used to enhance the reaction.
Additionally, uronium or phosphonium salts of non-nucleophilic anions, such as HBTU,
HATU, PyBOP, and PyBrOP could be used in place of the more traditional coupling
reagents. An additive such as dimethylaminopyridine may be used to enhance the
reaction. In Step 3, substep 1, the protected carboxylic acid can be deprotected by
methods well known in the art such as using an aqueous solution of lithium hydroxide in
methanol or tetrahydrofuran to give the carboxylic acid. The acid product of substep 1,
Step 3 can be reacted with the desired amine as described above to give the products of
Formula la or alternatively the carboxylic acid compound of Step 3, substep 1 can be
converted to the acid chloride and reacted with the desired amide as described above in
Step 2, substep 2 to give compounds of Formula la. It should be pointed out that the
amide coupling of the carboxylic acid product of Step 2 can be accomplished initially and
then amide formation on the amine can be completed depending on artisan preference of
the reactions to give compounds of Formula la.
A pharmaceutically acceptable salt of a compound of Formulas la can be formed
by reaction of an appropriate free base of Formulas la with an appropriate
pharmaceutically acceptable acid in a suitable solvent under standard conditions well
known in the art. Additionally, the formation of such salts can occur simultaneously upon
deprotection of a nitrogen protecting group. The formation of such salts is well known
and appreciated in the art. See, for example, Gould, P.L., "Salt selection for basic drugs,"
InternationalJournal of Pharmaceutics, 33: 201-217 (1986); Bastin, R.J., et al. "Salt
Selection and Optimization Procedures for Pharmaceutical New Chemical Entities,"
Organic Process Research and Development, 4: 427-435 (2000); and Berge, S.M., et al.,
"Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66: 1-19, (1977).
Preparation 1
Cis-(racemic)-Methyl-3-[ter t-butoxycarbonyl(methyl)amino]cyclohexanecarboxylate
To a solution of cis-(racemic)-3-(ter tbutoxycarbonylamino)
cyclohexanecarboxylic acid (3 g, 12.33 mmol) in
dimethylformamide is added sodium hydride (1.48 g, 36.99 mmol) at 0 °C under
nitrogen. The mixture is warmed to room temperature and stirred for 1 hour and then it is
cooled to 0 °C and methyl iodide (8.75 g, 61.65 mmol) is added drop wise. The mixture
is stirred at room temperature for two days. To the mixture is added saturated NH4C 1
solution (150 mL) and the mixture is extracted with ethyl acetate (2 100 mL). The
combined organic layers are washed with brine(3x 100 mL), dried over Na2S0 4,
concentrated to give the title compound (3.34 g, 99.82%) as a yellow oil. The crude
product is used directly without purification. LC/MS (m/z): 172 (M-100+1).
Preparation 2
Cis-(chiral)-Methyl-3-[ter t-butoxycarbonyl(methyl)amino]cyclohexanecarboxylate,
Isomer 1
Cis-(racemic)-Methyl-3 -[ rtbutoxycarbonyl(
methyl)amino]cyclohexanecarboxylate is purified by chiral SFC with the
following conditions. SFC-200, Thar Waters, column: AY250 mm*50 mm, 10 ,
column temperature: 38 °C, mobile phase:C0 2/isopropanol 90/10, flow rate: 180 g/min,
detection wavelength: 220 nm to give Isomer 1: RT = 2.3 min, 100% ee, LC-MS: 272
(M+H).
Preparation 3
(racemic)-Methyl-3-(methylamino)cyclohexanecarboxylate; 2,2,2-trifiuoroacetic acid
To a solution of cis-(racemic)-methyl-3-[(ter tbutoxycarbonyl)(
methyl)amino]cyclohexanecarboxylate (3.34 g, 12.31 mmol) in
dichloromethane (20 niL) is added trifluoroacetic acid (10 niL, 132.25 mmol). The
mixture is stirred at room temperature overnight. The mixture is concentrated to give the
title compound (2.1 g, 99.63%) as a yellow oil. The crude product is used directly
without purification. LC/MS (m/z): 172 (M+H).
Preparation 4
Cis-(racemic)-Methyl-3-[methyl-[3-
(trifiuoromethyl)benzoyl] amino]cyclohexanecarboxylate
To a solution of cis-(racemic)-methyl-3-(methylamino)cyclohexanecarboxylate
(2.1 g, 12.26 mmol) in dichloromethane (50 mL) is added triethylamine (3.72 g, 36.79
mmol). The mixture is cooled to 0 °C under N and 3-trifiuoromethylbenzoyl chloride
(3.07 g, 14.72 mmol) is added drop wise. The mixture is warmed to room temperature
and stirred for 3 hours. The mixture is concentrated and the residue is purified by silica
gel chromatography (combi-fiash) eluting with petroleum ether/ethyl acetate from 100/0
to 60/40 to give the title compound (4.18 g, 99.27%) as a yellow oil. LC/MS (m/z): 344
(M+l).
Preparation 5
Cis-(racemic)-3 -[Methyl- [3-(trifiuoromethyl)benzoyl] amino]cyclohexanecarboxylic acid
To a solution of cis-(racemic)-methyl-3-[methyl-[3-
(trifluoromethyl)benzoyl]amino]cyclohexanecarboxylate (4.18 g, 12.17 mmol) in a
mixture of tetrahydrofuran (20 mL), methanol (20 mL) and H 0 (20 mL), is added LiOH
(2.55 g, 60.87 mmol). The mixture is stirred at room temperature overnight. The mixture
is concentrated and the residue is dissolved in H 0 (100 mL). The mixture is washed
with ethyl acetate (1x40 mL) and the pH adjusted to 2 with 1M HC1 solution. The
mixture is extracted with ethyl acetate (2 100 mL). The combined organic layers are
dried over Na2S0 4 and concentrated to give the title compound (4 g, 99.77%) as a
colorless oil. LC/MS (m/z): 330 (M+l).
Preparation 6
-(racemic)-Methyl-3-[(3-chlorobenzoyl)-methyl-amino]cyclohexanecarboxylate
To a solution of cis-(racemic) methyl-3-(methylamino)cyclohexanecarboxylate;
2,2,2-trifluoroacetic acid (2.13 g, 7.1 1 mmol) in dichloromethane (30 mL) is added
triethylamine (2.88 g, 28.4 mmol). The mixture is cooled to 0 °C under N and 3-
chlorobenzoyl chloride (1.67 g, 9.24 mmol) is added drop wise. The mixture is warmed
to room temperature and stirred for 1 hour. The mixture is concentrated and the residue is
purified by silica gel chromatography (combi-fiash) eluting with petroleum ether/ethyl
acetate from 100/0 to 60/40 to give the title compound (1.73 g, 74.6%) as a white solid.
LC/MS (m/z): 310 (M+H).
Preparation 7
Cis-(racemic)-Methyl-3-[(3-chlorobenzoyl)-methyl-amino]cyclohexanecarboxylic acid
To a solution of cis-(racemic)-methyl-3-[(3-chlorobenzoyl)-methylamino]
cyclohexanecarboxylate (1.73 g, 5.31 mmol) in a mixture of tetrahydrofuran (10
mL), methanol (10 mL) and H20 (5 mL), is added LiOH (1.11 g, 26.5 mmol). The
mixture is stirred at room temperature for 4 hours. The mixture is concentrated and the
residue is dissolved in H 0 (10 mL). The mixture is washed with ethyl acetate (1x20 mL)
and the pH adjusted to 2 with 1M HC1 solution. The mixture is extracted with ethyl
acetate (2x 100 mL). The combined organic layers are dried over Na S0 4 and
concentrated to give the title compound (1.5 g, 91%) as a white solid. LC/MS (m/z): 296
(M+H).
Preparation 8
Cis-(chiral)-Methyl-3-[methyl-[3-
(trifluoromethoxy)benzoyl] amino]cyclohexanecarboxylate, Isomer 1
To a solution of cis-(chiral)-methyl 3-(methylamino)cyclohexanecarboxylate,
Isomer 1 (1.36 g, 7.94 mmol) in dichloromethane (30 mL), is added triethylamine (3.3
mL). The mixture is cooled to 0 °C under N , then 3-(trifluoromethoxy)benzoyl chloride
(1.6 mL, 9.53 mmol) is added drop wise. The mixture is warmed to room temperature
and stirred for 3 hours. The reaction mixture is evaporated in vacuo and the crude
product is purified by silica gel flash chromatography to give the title compound (2.03 g,
69%) as yellow oil. LC/MS (m/z): 360 (M+H).
Preparation 9
Cis-(chiral)-3-[Methyl-[3-(trifluoromethoxy)benzoyl]amino]cyclohexanecarboxylic acid,
Isomer 1
To a solution of cis-(chiral) - methyl -3-[methyl-[3-(trifluoromethoxy)benzoyl]
amino]cyclohexanecarboxylate, Isomer 1 (800 mg, 2.2 mmol) in water (4 mL) and
methanol (15 mL) is added lithium hydroxide (467 mg, 11.1 mmol). The mixture is
stirred at room temperature overnight. The reaction mixture is evaporated in vacuo, and
the residue is dissolved in water (3 mL) and ethyl acetate (3 mL). The pH is adjusted to
pH = 2 with 1N HC1 solution. The mixture is extracted with ethyl acetate (10 mL 2).
The combined organic layers are washed with brine (5 mL), dried over Na2S0 4, and
evaporated to give the title compound (670 mg, 87%). LC/MS (m/z): 346 (M+H).
Preparation 10
Cis-(racemic)-Methyl-3-[benzyloxycarbonyl(methyl)amino]cyclohexanecarboxylate
Sodium hydride (0.55 g, 13.75 mmol) is added to a solution of cis-methyl-3-
(benzyloxycarbonylamino)cyclohexanecarboxylate (1.99 g, 6.83 mmol) in
dimethylformamide (20 mL) at 0 °C under N and stirred at ambient temperature. After 1
hour, the reaction mixture is cooled to 0 °C, methyl iodide (2.96 g, 20.87 mmol) is added,
and the reaction is warmed to ambient temperature. After 3 hours, saturated aqueous
ammonium chloride is added and the mixture is extracted with ethyl acetate. The organic
extracts are combined and washed with brine, dried over sodium sulfate, filtered, and
concentrated under reduced pressure to give the title compound (1.13 g, 54%). MS (m/z):
306 (M+H).
Preparation 11
Cis-(chiral)-Methyl-3-[benzyloxycarbonyl(methyl)amino]cyclohexanecarboxylate,
Isomer 1
Cis-(racemic)-Methyl-3-
[benzyloxycarbonyl(methyl)amino]cyclohexanecarboxylate is purified by chiral
resolution to give Isomer 1: MS (m/z): 292 (M+H). >99% ee, RT = 0.75 minutes (uv:
220 nm), LC column: 4.6 x 150 mm Chiralcel OD-H; column temperature: 40 °C; mobile
phase gradient: 30% 3A ethanol: 70% C0 2; flow rate: 5.0 mL/minutes.
Preparation 12
Cis-(chiral)-3-[Benzyloxycarbonyl(methyl)amino]cyclohexanecarboxylic acid, Isomer 1
Lithium hydroxide (156.85 mg, 6.55 mmol) in water (0.5 mL) is added to a
solution of cis-(chiral)-methyl-3-
[benzyloxycarbonyl(methyl)amino]cyclohexanecarboxylate, Isomer 1 (0.4 g, 1.31 mmol)
in methanol (5 mL) and the mixture is stirred at ambient temperature. After 7 hours, the
reaction is concentrated to remove methanol, 3 N aqueous hydrochloric acid is added, and
the reaction is extracted with ethyl acetate. The organic extracts are combined and
concentrated under reduced pressure to give the title compound (0.35 g, 9 1 >) . MS (m/z):
292 (M+H).
Preparation 13
1-(2-Methoxyethyl)-4-methyl-5 -nitro-imidazole
To a solution of 4-methyl-5-nitro-lH-imidazole (5.00 g, 39.3 mmol) in
tetrahydrofuran (50 mL) is added 2-methoxyethanol (3.29 g, 43.3 mmol) and
triphenylphosphine (15.6 g, 59.0 mmol) at 0 °C. Diisopropyl azodicarboxylate (12.2 g,
59.0 mmol) is slowly added under N2 and the mixture is stirred at room temperature
overnight. The solvent is removed, the residue is diluted with Et20 (80 mL), filtered, and
concentrated. The crude product is added to a solution of HC1 (9 M, 40 mL) and the
mixture is extracted with ethyl acetate (50 mL). The aqueous phase is adjusted to pH 8
with addition of Na2C0 3 and the aqueous solution is extracted with ethyl acetate (2x80
mL). The organic extracts are combined, dried over Na2S0 4, filtered, and concentrated to
dryness. The residue is purified by silica gel chromatography eluting with petroleum
ether to 1:2 petroleum ether to ethyl acetate to give the title compound (4 g, 54.9%) as a
yellow oil. LC/MS (m/z): 186 (M+H).
Preparation 14
3-(2-Methoxyethyl)-5-methyl-imidazol-4-amine
l-(2-methoxyethyl)-4-methyl-5-nitro-imidazole (4 g, 21.601 mmol) is added to
tetrahydrofuran (150 mL) under a N2 atmosphere followed by the addition of Raney
nickel (2.53 g, 43.1 mmol). The mixture is stirred at room temperature for 1.5 hours.
The mixture is filtered through a pad of diatomaceous earth and concentrated to dryness
to give the title compound (3.35 g, 99.9%) as a brown oil. LC/MS (m/z): 156 (M+H).
Preparation 15
4-[2-(4-Methyl-5-nitro-imidazol-l-yl)ethyl]morpholine
To a solution of 4-methyl-5-nitro-lH-imidazole (2.00 g, 15.7 mmol) in
tetrahydrofuran (50 niL) is added 2-morpholinoethanol (2.27 g, 17.3 mmol) and
triphenylphosphine (6.25 g, 23.6 mmol) at 0 °C. Diisopropyl azodicarboxylate (4.87 g,
23.6 mmol) is slowly added under N2. The mixture is stirred at room temperature for 3
days. The solvent is removed and the residue is diluted with Et20 (30 mL), filtered, and
concentrated. The crude product is purified by silica gel chromatography eluting with
petroleum ether to 1.2 petroleum ether and ethyl acetate to give the title compound ( 1 g,
26.5%) as a yellow oil. LC/MS (m/z): 241 (M+H).
Preparation 16
5-Methyl-3-(2-morpholinoethyl)imidazol-4-
To a solution of 4-[2-(4-methyl-5-nitro-imidazol-l-yl)ethyl]mo holine (450 mg,
1.87 mmol) in tetrahydrofuran (25 mL) is added raney nickel (16.2 mg, 0.187 mmol)
under H2 and the mixture is stirred at room temperature for 2 hours under H2. The
mixture is filtered, washed with tetrahydrofuran (20 mL) and concentrated to dryness to
give the title compound (0.36 g, 91.4%) as a yellow oil. LC/MS (m/z): 2 11 (M+H).
Preparation 17
Isopropyl 2-(4-methyl-5-nitro-imidazol-l-yl)acetate
4-Methyl-5-nitro-lH-imidazole (5 g, 39.34 mmol), isopropyl bromoacetate (7.1 g,
39.34 mmol), potassium carbonate (1.5 equiv., 59.01 mmol), N,N-dimethylformamide
(100 mL) are added together. The reaction is heated to 90 °C for 4 hours. The mixture is
cooled to room temperature, quenched with NaCl (aq) and extracted with ethyl acetate.
The combined organic phase is dried over anhydrous Na2S0 4 and concentrated under
reduced pressure. The residue is purified with silica gel flash chromatography on eluting
with dichloromethane: methanol (20:1) to give the title compound (0.6 g, 7%) as white
solid, which is the minor isomer. MS m/z 228.1 (M+H).
Preparation 18
Isopropyl 2-(5-amino-4-methyl-imidazol- 1-yl)acetate
Isopropyl 2-(4-methyl-5-nitro-imidazol-l-yl)acetate (0.600 g, 2.64 mmol) is added
to methanol (20 mL) followed by the addition of 10% palladium on carbon hydroxide
(200 mg, 0.142 mmol). The mixture is degassed with H2 and kept under balloon pressure
of H2 at 25 °C for 10 hours. The mixture is filtered over diatomaceous earth and
concentrated to give slightly yellow oil as a crude product, which is used without further
purification. MS m/z 198.1 (M+H).
Preparation 19
1-Isopropyl-4-methyl-5 -nitro-imidazole
4-Methyl-5-nitro-lH-imidazole (1.2 g , 9.44 mmol) and N-methylpyrrolidone (15
mL) are added together at room temperature Sodium hydride (453.1 mg, 11.33 mmol) is
added and the reaction is stirred for 10 minutes. Propane, 2-iodo- (1.04 mL, 10.39 mmol)
is added and the mixture is stirred at room temperature for 3.5 hours. Water and ethyl
acetate is added and the mixture is stirred until the phase is separated. The aqueous phase
is extracted with ethyl acetate (50 mL) and the organic phase is washed with brine, dried
with Na2S0 4, and evaporated in vacuo. The residue is purified by silica gel flash
chromatography eluting with 1:1 hexanes:ethyl acetate to give the title compound (320
mg,18.03%) as a yellow oil. LC/MS (m/z): 170 (M+H).
Preparation 20
3-Isopropyl-5 -methyl-imidazol-4-
l-Isopropyl-4-methyl-5 -nitro-imidazole (320 mg, 1.7 mmol), methanol (20 mL),
10% palladium on carbon (34 mg, 16.1 ΐ) are added together. The mixture is
degassed with H2 and then stirred under balloon pressure of H2 at room temperature for 5
hours. The mixture is filtered and concentrated, leading to slightly yellow oil, which is
used without further purification. LC/MS (m/z): 140 (M+H).
Preparation 21
1-(Cyclopropylmethyl)-4-methyl-5 -nitro-imidazole
4-Methyl-5-nitro-lH-imidazole (1.2 g, 9.44 mmol), N-methylpyrrolidone (15 mL)
are added together at room temperature. Sodium hydride (453. 13 mg, 11.33 mmol) is
added followed and the mixture is stirred 10 minutes. Cyclopropane, (bromomethyl)-
(1.01 mL, 10.39 mmol) is added and the mixture is stirred at room temperature for 3.5
hours. Water and ethyl acetate is added, stirring until the phase is separated, and the
aqueous phase is extracted with ethyl acetate (50 mL). The organic phase is washed with
brine and dried with Na2S0 4 and evaporated in vacuo. The residue is purified by silica
gel flash chromatography eluting with 1:1 hexanes: ethyl acetate to give the title
compound (524 mg, 21.44%) as a yellow oil. LC/MS (m/z): 182 (M+H)
Preparation 22
3-(Cyclopropylmethyl)-5-methyl-imidazol-4-
l-(Cyclopropylmethyl)-4-methyl-5 -nitro-imidazole (523 mg, 1.7 mmol), methanol
(20 mL), and 10% palladium on carbon (100 mg, 46.98 ΐ) are added together. The
mixture is degassed with H and then stirred under balloon pressure of H at room
temperature for 5 hours. The mixture is filtered and concentrated, leading to slightly
yellow oil, which is used without further purification. LC/MS (m/z): 152 (M+H).
Preparation 23
2-(4-Methyl-5-nitro-imidazol-l-yl)acetonitrile
4-Methyl-5-nitro-lH-imidazole (2.4 g, 18.88 mmol), N-methylpyrrolidone (30
mL), and cesium carbonate (7.46 g, 22.66 mmol) are added together and stirred for 10
minutes at room temperature. Bromoacetonitrile (1.45 mL, 20.77 mmol) is added and the
mixture is stirred at room temperature for 4 hours. Water and ethyl acetate is added and
the mixture is stirred until the phase is separated. The aqueous phase is extracted with
ethyl acetate (50 mL) and the organic phase is washed with brine, and dried with Na2S0 4,
and evaporated in vacuo. The residue is purified by silica gel flash chromatography
eluting with 1:1 hexanes:ethyl acetate to give the title compound (435 mg, 12.48%) as a
yellow solid. LC/MS (m/z): 167 (M+H)
Preparation 24
2-(5-Amino-4-methyl-imidazol- 1-yl)acetonitrile
2-(4-Methyl-5-nitro-imidazol-l-yl)acetonitrile (156 mg, 892.0 ΐ), methanol
(15 mL), and 10% palladium on carbon (30 mg, 14.1 ΐ) are added together. The
mixture is degassed with H and then stirred under balloon pressure of H at room
temperature for 3 hours. The mixture is filtered and concentrated, leading to slightly
yellow oil, which is used for without further purification. LC/MS (m/z): 137 (M+H).
Preparation 25
4-Methyl-5-nitro-l-(2,2,2-trifluoroethyl)-lH-imidazole
4-Methyl-5-nitro-lH-imidazole (10 g, 78.7 mmol), N-methylpyrrolidone (100
mL), and cesium carbonate (38.5 g, 118.0 mmol) are added together and stirred 10
minutes at room temperature. 2,2,2-Trifluoroethyl trifiuoromethanesulfonate (19.2 mL,
82.6 mmol) is added and the mixture is stirred for 2 hours. Water and ethyl acetate is
added, stirring until the phase is separated and the aqueous phase is extracted with ethyl
acetate (300mL*2), the combined organic phase is washed with brine and dried by
Na2S0 4, then evaporated in vacuo, the residue is purified by silica gel flash
chromatography eluting with 1:1 hexanes:ethyl acetate to give the title compound (5.5g,
33.43%) as a pink oil. LC/MS (m/z): 210 (M+H)
Preparation 26
5-Methyl-3-(2,2,2-trifluoroethyl)imidazol-4-
4-Methyl-5-nitro-l-(2,2,2-trifluoroethyl)-lH-imidazole (700 mg, 318.0 ΐ),
methanol (20 mL), and 10% palladium on carbon (140 mg, 131 ΐ) are added together.
The mixture is degassed with H2 and then stirred under balloon pressure of H2 at room
temperature for 5 hours. The mixture is filtered and concentrated, leading to slightly
yellow oil, which is used without further purification. LC/MS (m/z): 180 (M+H).
Preparation 27
2-(Cyclobutoxy)ethanol
N-Butyllithium( 2 mol/L) in cyclohexanes (19 niL, 38 mmol) is added drop wise
to an ice-cold solution of cyclobutanol ( 2.6 g, 35 mmol) in tetrahydrofuran (60 mL) so as
to maintain the reaction temperature below 10 °C. The mixture is then stirred for 2 hours
at 5-10 °C. A solution of ethylenesulfate (4.9 g, 38 mmol) in tetrahydrofuran (20 mL) is
added drop wise so as to maintain the reaction temperature below 15 °C. Once the
addition is complete, the reaction is stirred for a 3 hours at room temperature. Water ( 1
mL) followed by concentrated sulfuric acid in water (2 mL, 6.750 mol/L) is added and the
reaction is stirred for an additional 18 hours at room temperature. The reaction mixture is
neutralized by the addition of solid sodium bicarbonate, and the mixture is concentrated
under reduced pressure. The residue is diluted with water and ethyl acetate, stirring until
the two phases are separated. The aqueous phase is washed with ethyl acetate (2x80 mL),
and the combined organic phases are washed with water (20 mL), brine (30 mL), dried
with Na2S0 4, evaporated in vacuo and the residue is purified by silica gel flash
chromatography eluting with 5% to 10% methanol in dichloromethane to give the title
compound (2.23 g, 49%) as a white solid. LC/MS (m/z): 117 (M+H).
Preparation 28
l-[2-(Cyclobutoxy)ethyl]-4-methyl-5-nitro-imidazole
To a mixture of 4-methyl-5-nitro imidazole (1.90 g, 14.6 mmol) in tetrahydrofuran
(40 mL) is added 2-(cyclobutoxy)ethanol (2.27 g, 17.6 mmol) and triphenylphosphine
(4.66 g, 17.6 mmol). The reaction is cooled to 0 °C under N2 and diisopropyl
azodicarboxylate (3.49 mL, 17.6 mmol) is added drop wise. The mixture is warmed to
room temperature and stirred overnight. The reaction is evaporated in vacuo and diethyl
ether (50 mL) is added, stirring at room temperature for 30 minutes, and then filtered.
T e filter cake is washed with diethyl ether (50 mL), and the organic phase is washed
with water (30 mL), brine (30 mL), dried by Na2S0 4, and evaporated in vacuo. The crude
product is purified by reverse phase flash chromatography eluting with 25% to 50%
acetonitrile/water, 0.1% formic acid to give the title compound (1.74 g, 47.5%) as a
yellow oil. LC/MS (m/z): 226 (M+H).
Preparation 29
3-[2-(Cyclobutoxy)ethyl]-5-methyl-imidazol-4-
l-[2-(Cyclobutoxy)ethyl]-4-methyl-5-nitro-imidazole (0.641 g, 2.56 mmol),
methanol (30 mL), and 10% palladium on carbon (120 mg, 56.4 ΐ) are added
together. The mixture is degassed with H and then stirred under balloon pressure of H
at room temperature for 3 hours. The mixture is filtered and concentrated, leading to
slightly yellow oil, which is used without further purification. LC/MS (m/z): 196 (M+H).
Preparation 30
4-Methyl-5-nitro- 1-(oxetan-3-yl)imidazole
To a mixture of 4-methyl-5-nitro imidazole (3.0 g, 22.89 mmol) in tetrahydrofuran
(40 mL) is added N,N-diisopropylethylamine (4.03 mL, 22.89 mmol ), oxetan-3-ol (1.96
g, 25.18 mmol) and triphenylphosphine (6.67 g, 25.18 mmol). The reaction is cooled to 0
°C under N and diethyl azodicarboxylate (4.3 mL, 27.47 mmol) is added drop wise. The
mixture is warmed to room temperature and stirred overnight. The reaction is evaporated
in vacuo and diethyl ether (50 mL) is added, stirring at room temperature for 30 minutes.
The mixture is filtered, and the filter cake is washed with diethyl ether (50 mL). The
combined organic phase is washed with water (30 mL), brine (30 mL), dried by Na2S0 4,
and evaporated in vacuo. The crude product is purified by reverse phase flash
chromatography eluting with 25% to 50% acetonitrile/water, 0.1% formic acid to give the
title compound (3.56 g, 59.4%) as a white solid. LC/MS (m/z): 184 (M+H).
Preparation 31
5-Methyl-3-(oxetan-3-yl)imidazol-4-amine
4-Methyl-5-nitro-l -(oxetan-3-yl)imidazole (530 mg, 2.03 mmol), methanol (20
mL), and 10% palladium on carbon ( 110 mg, 0.5 mmol) are added together. The mixture
is degassed with H2 and then stirred under balloon pressure of H2 at room temperature for
4 hours. The mixture is filtered and concentrated to dryness, leading to a yellow solid,
which is used for without further purification. LC/MS (m/z): 154 (M+H).
Preparation 32
4-Methyl-5-nitro- 1-tetrahydropyran-4-yl-imidazole
To a mixture of 4-methyl-5-nitroimidazole (2.50 g, 19.08 mmol) in
tetrahydrofuran (40 mL) is added N,N-diisopropylethylamine (4.03 mL, 22.89 mmol ),
tetrahydro-4-pyranol (2.21 g, 20.99 mmol) and triphenylphosphine (5.56 g, 20.99 mmol).
The reaction is cooled to 0 °C under N2 and diethyl azodicarboxylate (5.6 mL, 22.19
mmol) is added drop wise. The mixture is warmed to room temperature and stirred
overnight. The reaction is evaporated in vacuo. Diethyl ether (50 mL) is added and the
mixture is stirred at room temperature for 30 minutes. The mixture is filtered, and the
filter cake is washed with diethyl ether (50 mL), and the combined organic phase is
washed with water (30 mL), brine (30 mL), dried by Na2S0 4, and evaporated it in vacuo.
T e crude product is purified by reverse phase flash chromatography eluting with 25% to
50% acetonitrile/water, 0.1%> formic acid to give the title compound (2.96 g, 54.8%) as a
yellow oil. LC/MS (m/z): 212 (M+H).
Preparation 33
5-Methyl-3-tetrahydropyran-4-yl-imidazol-4-amine
4-Methyl-5-nitro-l-tetrahydropyran-4-yl-imidazole (1.73 g, 6.55 mmol), methanol
(50 mL), and 10% palladium on carbon (320 mg, 0.15 mmol) are added together. The
mixture is degassed with H2 and then stirred under a balloon pressure of H2 at room
temperature for 5 hours. The mixture is filtered and concentrated, leading to slightly
yellow oil, which is used without further purification. LC/MS (m/z): 182 (M+H).
Preparation 34
4-Methyl-l-(l-methylazetidin-3-yl)-5-nitro-imidazole
To a mixture of 4-methyl-5-nitro imidazole (4.0 g, 3 1 mmol) in tetrahydrofuran
(100 mL) is added l-methylazetidin-3-ol (3.0 g, 35 mmol) and triphenylphosphine (9.9 g,
38 mmol), the reaction is cooled to 0 °C under N2 and diisopropyl azodicarboxylate (6.2
mL, 31 mmol) is added drop wise. The mixture is warmed to room temperature and
stirred overnight. The reaction is evaporated in vacuo and diethyl ether (50 mL) is added
and the mixture is stirred at room temperature for 30 minutes. The mixture is filtered and
the filter cake is washed with diethyl ether (50 mL). The combined organic phase is
washed with water (30 mL), brine (30 mL), dried with Na2S0 4, and evaporated in vacuo.
T e crude product is purified by reverse phase flash chromatography eluting with 25% to
50% acetonitrile/water, 0.1%> formic acid to give the title compound (4.8 g, 78%) as a
yellow oil. LC/MS (m/z): 197 (M+H).
Preparation 35
5-Methyl-3-( 1-methylazetidin-3-yl)imidazol-4-amine
4-Methyl-l-(l-methylazetidin-3-yl)-5-nitro-imidazole (1.60 g, 8.155 mmol),
tetrahydrofuran (50 mL), and 10% palladium on carbon hydroxide (600 mg, 0.42 mmol)
are added together. The mixture is degassed with H2 and then stirred under a balloon
pressure of H2 at room temperature for 15 hours. The mixture is filtered and concentrated
to a yellow oil, which is used without further purification. LC/MS (m/z): 167 (M+H).
Preparation 36
l-(2,2-Difiuoroethyl)-4-methyl-5-nitro-imidazole
To a solution of 4-methyl-5-nitro-lH-imidazole (6 g, 47.2 mmol) in
tetrahydrofuran (100 mL) is added difiuoroethanol (4.3 g, 52.2 mmol) and
triphenylphosphine (18.8 g, 70.8 mmol) at 0 °C under N2, then diisopropyl
azodicarboxylate (17.2 g, 85.0 mmol) is added drop wise. The mixture is allowed to
warm to room temperature and stirred overnight. The mixture is concentrated and diethyl
ether (250 mL) is added. The solid is removed and washed with diethyl ether. The
organic wash concentrated and the residue is purified by silica gel chromatography
(combi-flash) eluting with 100% ethyl acetate to 3:1 ethyl acetate:petroleum ether to give
the crude product. The mixture is diluted with diethyl ether (50 mL), and filtered. The
filtrate is concentrated to give the title compound (5.0 g, 55%) as a white solid. LC/MS
(m/z): 192 (M+H).
Preparation 37
3-(2,2-Difiuoroethyl)-5-methyl-imidazol-4-amine
To a solution of l-(2,2-difluoroethyl)-4-methyl-5-nitro-imidazole (0.5 g, 2.6
mmol) in ethyl acetate (15 mL) under ¾ , is added 5% palladium on carbon (0.1 g) at
room temperature. The mixture is stirred for 18 hours, filtered to remove the palladium
catalyst, and concentrated to give the title compound (0.38 g, 90%>). LC/MS (m/z): 162
(M+H).
Preparation 38
Cis-(chiral)-Benzyl N-[3-[[3-(2,2-difluoroethyl)-5-methyl-imidazol-4-
yl]carbamoyl]cyclohexyl]-N-methyl-carbamate, Isomer 1
To a solution of cis-(chiral)-3-[benzyloxycarbonyl(methyl)amino]
cyclohexanecarboxylic acid, Isomer 1 (1.2 g, 4.0 mmol) and 3-(2,2-difiuoroethyl)-5-
methyl-imidazol-4-amine (0.97 g, 6.0 mmol) in pyridine (30 mL), is added l-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.0 mmol) and the
reaction is warmed to 60 °C. The solution is concentrated and purified with silica gel
flash chromatography eluting with 15/1, dichloromethane/methanol to give the title
compound (0.63 g, 36%). LC/MS (m/z): 435 (M+H).
Preparation 39
Cis-(chiral)-(N-[3 -(2 ,2-Difluoroethyl)-5 -methyl-imidazol-4-yl] -3-
(methylamino)cyclohexanecarboxamide, Isomer 1
To a solution of cis-(chiral)-benzyl N-[3-[[3-(2,2-difluoroethyl)-5-methylimidazol-
4-yl]carbamoyl]cyclohexyl]-N-methyl-carbamate, Isomer 1 (0.63 g, 1.4 mmol)
in methanol (20 mL) is added 5% Pd/C (0.15 g) at room temperature under H2. The
reaction is stirred until completion and the solution is filtered to remove Pd/C,
concentrated, and dried to give the title compound (0.42 g, 96%). LC/MS (m/z): 301
(M+H).
Example 1
Cis-(chiral)-N-[3-[(3,5-Dimethylimidazol-4-yl)carbamoyl]cyclohexyl]-N-methyl-3-
(trifluoromethyl)benzamide, isomer 1
To a solution of cis-(racemic)-3-[methyl-[3-(trifluoromethyl)benzoyl]amino]
cyclohexanecarboxylic acid (0.4 g, 1.09 mmol) in pyridine (10 mL) is added 3,5-
dimethylimidazol-4-amine hydrochloride (249.52 mg, 1.64 mmol) and l-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (523.91 mg, 2.73 mmol). The
mixture is stirred at 58 °C for 22 hours. Then the mixture is concentrated and the crude
product is purified by preparative HPLC to give the racemic title compound, which is
resolved with chiral chromatography to give the title compound as the first eluting
isomer, (0.0889 g, 19.15%) as a light yellow solid. LC/MS (m/z): 432 (M+1), 100% ee,
RT = 1.58 minutes (UV), Instrument: SFC-80 (Thar, Waters), column: AD-H 20x250
mm, 5 (Regis), column temperature: 35 °C, mobile phase: C0 / methanol (0.1%
diethylamine)= 75/25, flow rate: 80 g/min, back pressure: 100 bar, detection wavelength:
214 nm, cycle time: 4.4 min, sample solution: 250 mg dissolved in 40 mL methanol,
injection volume: 5mL.
Example 2
Cis-(chiral) N-methyl-N-3-((4-methyl-l-(2,2,2-trifluoroethyl)-lH-imidazol-5-
yl)carbamoyl)cyclohexyl)-3-(trifluoromethoxy)benzamide, Isomer 1
Cis-(chiral)-3-[Methyl-[3-
(trifluoromethoxy)benzoyl] amino]cyclohexanecarboxylic acid, Isomer 1 (0.2 g, 0.58
mmol), 4-methyl-l-(2,2,2-trifluoroethyl)-lH-imidazol-5-amine (114.13 mg, 1.55 mmol),
l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (277.58 mg, 1.45 mmol),
and pyridine (5 mL) are added together and stirred at 50 °C for 20 hours. The mixture is
concentrated under reduced pressure and the residue is purified by preparative HPLC
eluting with 17-37% CH3CN in water, 0.1% formic acid to give the title compound (31
mg, 10.57%) as white solid. MS (m/z): 507.1 [M+H]+.
Example 3
Cis-(chiral) N-Methyl-N-3-((4-methyl-l-(l-methylazetidin-3-yl)-lH-imidazol-5-yl)
carbamoyl)cyclohexyl)-3-(trifluoromethoxy)benzamide, Isomer 1
Cis-(chiral)-3-[Methyl-[3-(trifluoromethoxy)benzoyl]
amino]cyclohexanecarboxylic acid, Isomer 1 (0.70 g, 2.027 mmol), 5-methyl-3-(lmethylazetidin-
3-yl)imidazol-4-amine (672 mg, 4.04 mmol), l-(3-dimethylaminopropyl-
3-ethylcarbodiimide hydrochloride (700 mg, 3.65 mmol), and pyridine (50 mL) are added
together. The reaction is stirred at 60 °C for 56 hours. The mixture is concentrated and
purified through silica gel flash chromatography eluting with dichloromethane and
methanol 20:1 to give the product (210 mg), which is then purified through preparative
HPLC eluting with 3% C¾CN in water, 0.1% formic acid to give the title compound
(32.0 mg, 3.04%) as slightly yellow solid. MS (m/z): 493.2[M+H] +.
The following Example is prepared essentially by the method of Example 3.
Example 5
Cis-(chiral)-N-3-((l-(2,2-Difiuoroethyl)-4-methyl-lH-imidazol-5-
yl)carbamoyl)cyclohexyl)-3-fluoro-N-methyl-5-(trifluoromethyl)benzamide, Isomer 1
3-Fluoro-5-(trifluoromethyl)benzoic acid (415 mg, 1.19 mmol), dichloromethane
(50.0 mL), oxalyl chloride (151mg, 1.19 mmol) are added together at 0 °C, 10 drops of
N,N-dimethylformamide (0.01 equiv.) is added drop wise. The mixture is warmed to 25
°C and stirred for 2 hours. The solvent is removed under reduced pressure. N-[3-(2,2-
Difluoroethyl)-5-methyl-imidazol-4-yl]-3-(methylamino) cyclohexanecarboxamide,
Isomer 1 (300 mg, 0.9987 mmol), dichloromethane (50.0 mL) and triethylamine (, 1.99
mmol) are added to the acyl chloride formed above. The mixture is stirred at 25 °C for 16
hours. The mixture is concentrated and purified through silica gel flash chromatography
eluting with 10:1 dichloromethane/methanol to give a yellow solid which is further
purified through preparative HPLC eluting with 14-29% CH3CN in water, 0.1% formic
acid to give the title product (170 mg, 34.71%) as white solid. MS (m/z): 435.1 [M+H]+.
Example 6
Cis-(chiral)-N-[-3-[(3-Isopropyl-5-methyl-imidazol-4-yl)carbamoyl]cyclohexyl]-Nmethyl-
3-(trifiuoromethyl)benzamide, Isomer 1
To a solution of cis-(chiral)-3-[methyl-[3-(trifluoromethyl)benzoyl]amino]
cyclohexanecarboxylic acid, Isomer 1 (160 mg, 485.9 ΐ) in dichloromethane (20.0
mL) is added 3-isopropyl-5-methyl-imidazol-4-amine (150.3 mg, 971.7 ΐ), HATU
(406.4 mg, 1.1 mmol) and diisopropylethylamine (288.1 , 1.7 mmol). The mixture is
stirred at room temperature overnight. Then the mixture is concentrated and the crude
product is purified by silica gel flash chromatography eluting with 5% MeOH in
dichloromethane followed by purification with preparative HPLC eluting with 30-40%
acetonitrile in water, 10 mM NH4HC0 3 to give the title compound (2.7 mg, 1.1 1%) as a
white solid. LC/MS (m/z): 451 (M+H).
Example 7
Cis-(chiral)-N-[-3-[[3-(Cyclopropylmethyl)-5-methyl-imidazol-4-
yl]carbamoyl]cyclohexyl]-N-methyl-3-(trifluoromethyl)benzamide, Isomer 1
To a solution of cis-(chiral)-3-[methyl-[3-(trifluoromethyl)benzoyl]amino]
cyclohexanecarboxylic acid, Isomer 1 (145 mg, 440.3 ΐ ) in dichloromethane (20.0
mL) is added 3-(cyclopropylmethyl)-5-methyl-imidazol-4-amine (190.2 mg, 880.6 ΐ),
HATU (368.3 mg, 968.7 ΐ) and diisopropylethylamine (261.1 , 1.5 mmol). The
mixture is stirred at room temperature overnight. The mixture is concentrated and the
crude product is purified by silica gel flash chromatography eluting with 5% to 10%
methanol in dichloromethane followed by preparative HPLC eluting with 32-42%
acetonitrile in water, 10 mM NH4HCO 3 to give the title compound (3.1 mg, 1.37%) as a
white solid. LC/MS (m/z): 463 (M+H).
Example 8
Cis-(chiral)-N-[3-[[3-(cyanomethyl)-5-methyl-imidazol-4-yl]carbamoyl]cyclohexyl]-Nmethyl-
3-(trifiuoromethyl)benzamide, Isomer 1
To a solution of cis-(chiral)-3-[methyl-[3-(trifiuoromethyl)benzoyl]amino]
cyclohexanecarboxylic acid, Isomer 1 (230 mg, 663.5 ΐ) in pyridine (10 mL) is added
2-(5-amino-4-methyl-imidazol-l-yl)acetonitrile (133.1 mg, 928.9 ΐ) and l-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (327.8 mg, 1.7 mmol). The
mixture is stirred at 50 °C for 22 hours. The mixture is concentrated and the crude
product is purified by silica gel flash chromatography eluting with 5% to 10% methanol
in dichloromethane followed by preparative HPLC eluting with 30-40% acetonitrile in
water, 10 mM NH4HCO 3 to give the title compound (39.0 mg, 12.48%) as a pale yellow
solid. LC/MS (m/z): 448 (M+H).
The following Example is prepared essentially by the method of Example 8.
Example 10
Cis-(chiral)-N-Methyl-N-[3-[[5-methyl-3-(2,2,2-trifluoroethyl)imidazol-4-
yl]carbamoyl]c clohexyl]-3-(trifluoromethyl)benzamide, Isomer 1
To a solution of added cis-(chiral)-3- [methyl-[3-(trifluoromethyl)benzoyl] amino]
cyclohexanecarboxylic acid, Isomer 1 (700 mg, 2.02 mmol) in pyridine (10 mL) is added
5-methyl-3-(2,2,2-trifluoroethyl)imidazol-4-amine (578.8 mg, 3.23 mmol) and l-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (718.4 mg, 3.64 mmol). The
mixture is stirred at 50 °C for 22 hours. The mixture is concentrated and the crude
product is purified by preparative HPLC eluting with 15-35% acetonitrile in water, 0.1%
formic acid to give the title compound (310 mg, 29.74%) as a white solid. LC/MS (m/z):
491 (M+H).
Example 11
Cis-(chiral)-N- [3-[[3-[2-(Cyclobutoxy)ethyl] -5-methyl-imidazol-4-
yl]carbamoyl]cyclohexyl]-N-methyl-3-(trifluoromethyl)benzamide, Isomer 1
To a solution of cis-(chiral)-3-[methyl-[3-(trifiuoromethyl)benzoyl]amino]
cyclohexanecarboxylic acid, Isomer 1 (250 mg, 721.2 ΐ) in pyridine (10 mL) is added
3-[2-(cyclobutoxy)ethyl]-5-methyl-imidazol-4-amine (273.8 mg, 1.26 mmol) and l-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (256.6 mg, 1.30 mmol). The
mixture is stirred at 60 °C for 2.5 hours. Then the mixture is concentrated and the crude
product is purified by silica gel flash chromatography eluting with 5% to 10% methanol
in dichloromethane followed by preparative HPLC eluting with 19-34% acetonitrile in
water, 0.1%> formic acid to give the title compound (140.0 mg, 36.40%>) as a pale yellow
solid. LC/MS (m/z): 507 (M+H).
Example 12
Cis-(chiral)-N-methyl-N-[3-[(5-methyl-3-tetrahydropyran-4-yl-imidazol-4-yl)
carbamoyl]cyclohexyl]-3-(trifluoromethyl)benzamide, Isomer 1
To a solution of cis-(chiral)-3-[methyl-[3-(trifiuoromethyl)benzoyl]amino]
cyclohexanecarboxylic acid, Isomer 1 (1050 mg, 3.03 mmol) in pyridine (40 mL) is
added 5-methyl-3-tetrahydropyran-4-yl-imidazol-4-amine (1.37 g, 6.06 mmol) and l-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.20 g, 6.06 mmol). The
mixture is stirred at 60 °C overnight. The mixture is concentrated and the crude product
is purified by silica gel flash chromatography eluting with 5% to 15% methanol in
dichloromethane followed by preparative HPLC eluting with 11-31% acetonitrile in
water, 0.1%> formic acid to give the title compound (440.0 mg, 28.02%) as a white solid.
LC/MS (m/z): 493 (M+H).
Example 13
Cis-(chiral)-N-Methyl-N-[(cis)-3-[(5-methyl-3-tetrahydropyran-4-yl-imidazol-4-
yl)carbamoyl]cyclohexyl]-3-(trifluoromethoxy)benzamide, Isomer 1
To a solution of cis-(chiral)-3-[methyl-[3-(trifluoromethoxy)benzoyl]amino]
cyclohexanecarboxylic acid, Isomer 1 (0.200 g, 0.58 mmol) in pyridine (20 mL) is added
5-methyl-3-tetrahydropyran-4-yl-imidazol-4-amine (0.23 g, 1.01 mmol) and l-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.206 g, 1.04 mmol). The
mixture is stirred at 60 °C overnight. Then the mixture is concentrated and the crude
product is purified by silica gel flash chromatography eluting with 5% to 15% methanol
in dichloromethane followed by preparative HPLC eluting with 11-31% acetonitrile in
water, 0.1% TFA to give the title compound (13 mg; 3.97%) as a white solid. LC/MS
(m/z): 509 (M+H).
Example 14
Cis-(chiral)-N-Methyl-N- [3- [[5-methyl-3 -( 1-methylazetidin-3 -yl)imidazol-4-
yl]carbamoyl] cyclohexyl] -3-(trifiuoromethyl)benzamide, Isomer 1
To a solution of cis-(chiral)-3-[methyl-[3-(trifiuoromethyl)benzoyl]amino]
cyclohexanecarboxylic acid, Isomer 1 (500 mg, 1.44 mmol) in pyridine (40 mL) is added
5-methyl-3 -(1 -methylazetidin-3 -yl)imidazol-4-amine (504.8 mg, 2.88 mmol) and l-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (570.2 mg, 2.88 mmol). The
mixture is stirred at 60 °C overnight. The mixture is concentrated and the crude product
is purified by silica gel flash chromatography eluting with 5% to 15% methanol in
dichloromethane followed by preparative HPLC eluting with 3-20% acetonitrile in water,
0 .1% formic acid to give the title compound (23.0 mg, 3.17%) as an orange solid.
LC/MS (m/z): 478 (M+H).
Example 15
Cis-(chiral)-N-Methyl-N- [-3 -[[5-methyl-3 -(oxetan-3 -yl)imidazol-4-
yl]carbamoyl] cyclohex l]-3-(trifiuoromethyl)benzamide, Isomer 1
To a solution of cis-(chiral)-3-[methyl-[3-(trifiuoromethyl)benzoyl]amino]
cyclohexane carboxylic acid, Isomer 1 (350 mg, 1.01 mmol) in pyridine (20 mL) is added
5-methyl-3-(oxetan-3-yl)imidazol-4-amine (442 mg, 2.02 mmol) and l-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (399 mg, 2.02 mmol). The
mixture is stirred at 60 °C overnight. The mixture is concentrated and the crude product
is purified by silica gel flash chromatography eluting with 5% to 15% methanol in
dichloromethane followed by preparative HPLC eluting with 12-32% acetonitrile in
water, 0.1%> formic acid to give the title compound (198.0 mg, 40. 11%) as a pale yellow
solid. LC/MS (m/z): 465 (M+H).
Example 16
Cis-(chiral)-3 -Chloro-N- [3-[[3 -(2 ,2-difiuoroethyl)-5 -methyl-imidazol-4-
yl]carbamoyl] cyclohexyl]-N-methyl-benzamide, Isomer 1
To a solution of cis-(racemic)-3-[methyl-[(3-chlorobenzoyl)amino]cyclohexane
carboxylic acid (650 mg, 2.09 mmol) in pyridine (10 mL) is added 3-(2,2-difluoroethyl)-
5-methyl-imidazol-4-amine (561 mg, 3.13 mmol) and l-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (743 mg, 3.76 mmol). The mixture is stirred at 60 °
overnight. The mixture is concentrated and the crude product is purified by silica gel
flash chromatography eluting with 5% to 15% methanol in dichloromethane followed by
preparative HPLC eluting with 12-32% acetonitrile in water, 0.1% formic acid to give the
title compound (660.0 mg, 64.83%>) as a white solid, which is resolved with chiral
chromatography utilizing the following conditions: Instrument: SFC-80 (Thar, Waters),
column: AD-H 20*250 mm, 5 (Daicel), column temperature: 35 °C, mobile phase:
C0 2/ MeOH= 65/35, flow rate: 80 g/min, back pressure: 100 bar, detection wavelength:
214 nm, cycle time: 4.8 min, sample solution: 660 mg dissolved in 48 mL methanol,
injection volume: 5 mL to give the title compound as the first eluting isomer (162 mg,
25.9%). LC/MS (m/z): 439 (M+H), 100% ee, RT = 1.98 minutes,
Example 17
Cis-(chiral)-N-3-[[3-(2-methoxyethyl)-5-methyl-imidazol-4-yl]carbamoyl]cyclohexyl]-Nmethyl-
3-(trifluoromethyl)benzamide, Isomer 1
To a solution of cis-(chiral)-3 -[methyl- [3-
(trifluoromethyl)benzoyl] amino] cyclohexane carboxylic acid, Isomer 1 (2 g, 6.073 mmol)
and 3-(2-methoxyethyl)-5-methyl-imidazol-4-amine (2.357 g, 15.18 mmol) in pyridine
(50 mL) is added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.851
g, 14.58 mmol) under N2 and the mixture is stirred at room temperature for 3 days. The
mixture is concentrated in vacuo and dissolved in dichloromethane (150 mL), washed
with water (3 150 mL), dried over anhydrous Na2S0 4, and purified by silica gel
combiflash chromatography eluting with 0-7% methanol in dichloromethane with 1%
NH4OH. The product is further purified by prep-HPLC to give the title compound as a
light yellow solid (0.419 g, 14.36%). LC/MS (m/z): 467 (M+H).
Example 18
Cis-(chiral)-N-Methyl-N-3 -[[5-methyl-3 -(2-morpholinoethyl)imidazol-4-
yl]carbamoyl] cyclohexyl] -3-(trifluoromethyl)benzamide, Isomer 1
To a solution of cis-(chiral)-3- [methyl- [3-(trifiuoromethyl)benzoyl] amino]
cyclohexane carboxylic acid, Isomer 1 (0.2 g, 0.579 mmol) in pyridine (5 mL) is added 1-
(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.2718 g, 1.39 mmol) and
5-methyl-3-(2-mo holinoethyl)imidazol-4-amine (0.18 g, 0.87 mmol) under N2 and the
mixture is stirred at room temperature for 4 days. The mixture is concentrated in vacuo
and the residue is purified by silica gel flash chromatography eluting with 10:1 :0. 1
dichloromethane:methanol N¾ Ή 20 followed by purification with preparative silica gel
thin layer chromatography eluting with 10:1:0.1 dichloromethane:methanol:NH 3H20 to
give the title compound (0.04 g, 13.24%) as a white solid. LC/MS (m/z): 522 (M+H).
Example 19
Cis-(chiral)-N-[3-[(3,5-Dimethylimidazol-4-yl)carbamoyl]cyclohexyl]-N-methyl-3-
(trifluoromethoxy)benzamide, Isomer 1
l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (888 mg, 4.6
mmol) is added to a solution of cis-(chiral)-3-[methyl-[3-
(trifluoromethoxy)benzoyl] amino] cyclohexanecarboxylic acid, Isomer 1 (640 mg, 1.9
mmol) and 3,5-dimethylimidazol-4-amine hydrochloride (410 mg, 2.8 mmol) in pyridine
(20 mL) at room temperature and warmed to 58 °C. The mixture is concentrated and the
residue is purified with silica gel flash chromatography eluting with 20:1
dichloromethane:methanol and further purified with HPLC to give the title compound
(253 mg, 31%). LC/MS (m/z): 439 (M+H).
Biological Assays
GPR142 Agonist Effect as Measured by IP-1 Assay
The purpose of this assay is to detect GPR142 agonist effect.
HEK293 cells expressing human GPR142 or mouse GPR142 are maintained in
Dulbecco's modified Eagle's medium supplemented with 10%> FBS and 800 g/ml G418
(Geneticin®) at 37 °C and 5% C0 2. The cells are plated in 384 well plates at 5000 cells
per well and allowed 18 hours for attachment. After addition of compounds at varying
concentrations ranging from 30 to 1 nM, cells are incubated for 1 hour. IP-1
measurements are performed using an IP-One HTRF® assay kit (Cisbio) according to
manufacturer's protocol using assay buffer containing 1 HBSS (+Ca, +Mg), 0.1% BSA,
50 n M LiCl and 20 n M HEPES, pH 7.2. The reaction is stopped by addition of IPl-d2
(IP-1 coupled to an organic HTRF acceptor) followed by cryptate solution
(http ://www.htrf .com/usa/htrf-chemistry) and the plates are incubated at 25 °C for 1 hour.
Fluorescence is read in an Envision instrument at 665 nm and 620 nm wavelength. The
ratio of 665 nm/620 nm is calculated and converted to IP-1 levels using an IP-1 standard
curve. The data is fit to a 4 parameter-fit logistics to determine EC50 values. All
exemplified compounds exhibited an EC50 < 150 nM using an assay substantially as
described herein above.
Example 1 is tested as described above and exhibits an in vitro EC50 of 52.6 nM
(+ 27.5, n=9) and 105% efficacy (+ 11.6, n=9) against human GPR142 receptor and an
EC50 of 5.46 nM (+ 1.22, n=5) against mouse GPR142 receptor, (Mean + SEM; SEM =
standard error of the mean.)
Glucose-dependent Insulin Secretion (GDIS) Assay
GDIS assays using primary murine pancreatic islets of Langerhans are used to
characterize compounds. Pancreatic islets are isolated from male C57BL/6 mice by
collagenase digestion and Dextran density gradient separation. The islets are cultured
overnight in RPMI-1640 medium containing 1 1 mM glucose, 10% FBS, 2 mM
glutamine. Insulin secretion is determined by a 60-minute incubation in KRB buffer
(NaCl 7 g/L, KC1 0.35 g/L, CaCl2 0.28 g/L, MgCl2-7H20 0.24 g/L, KH2P0 4 0.16 g/L,
NaHC0 3 2.1 g/L and HEPES 2.38 g/L, pH = 7.4, store at 4 °C) containing 0.1% BSA and
appropriate glucose concentration (2.8 mM or 11.1 mM) in 48-well plates. Briefly, islets
are preincubated in KRB buffer with 2.8 mM glucose and 0.5% BSA for 45 min. They
are then transferred to a 48-well plate (four islets/well) containing 300 ΐ/well of
compound solutions prepared in 2.8 mM or 11.1 mM glucose and 0.1% BSA, and
incubated at 37 °C and 5% C0 2 for 60 minutes. Incubation is stopped by refrigerating the
plates at 4 °C for 3 minutes. Supernatant is removed from the wells and assayed for
insulin levels using the Rat/Mouse Insulin Elisa kit (Millipore) or MA6000 Mouse/Rat
Insulin Kit (MSD). Insulin secretion activity is normalized against control treatment
(DMSO-1%) at 11mM glucose. Active compounds have insulin secretion activity > 1
fold (P<0.05) greater than DMSO control in the GDIS assay. For Example 1, it is
significant to GDIS at 10 for p<0.05 and is not significant at 1 .
Example 1 is tested as described above and exhibits glucose dependent insulin
secretion in a dose dependent manner in mouse islets.
Intraperitoneal glucose tolerance tests (IPGTT)
IPGTT assay is used to examine the ability of exemplified compounds to activate
GPR142 in vivo resulting in anti-diabetic efficacy, i.e. reduction in plasma glucose levels.
Male C57BL/6 mice (8-10 weeks of age) are fed normal rodent chow diet and water ad
libitum. On the night before the study, animals are fasted overnight in clean cages. On
the morning of the study, animals are dosed orally with vehicle or compound at the
indicated doses 30 minutes prior to the glucose challenge (2 g/kg) by intraperitoneal
injection. Blood glucose levels are determined from tail bleeds taken immediately prior
to compound dosing (-30 min) and 0, 15, 30, and 60 min after glucose challenge using
handheld glucometers. Plasma is isolated from tail bleeds taken at 7 minutes after
glucose challenge and used to determine insulin levels by the Rat/Mouse Insulin Elisa kit
(Millipore) or MA6000 Mouse/Rat Insulin Kit (MSD). The blood glucose profile from
t=0 to t=60 min is used to calculate an area under the curve (AUC) for each treatment.
Percent lowering in glucose AUC is calculated for each treatment group with respect to
the AUC of vehicle group. Compounds with a reduction in glucose AUC (P<0.05) is
considered positive in the assay.
Example 1 is tested as described above and exhibits glucose dependent insulin
secretion and glucose lowering in a dose dependent manner in an IPGTT assay compared
to the control, N-[(3-methylimidazol-4-yl)methyl]-l-[5-methyl-4-(2-thienyl)pyrimidin-2-
yl]-5-propyl-pyrazole-4-carboxamide as shown in Table 1 below with an ED of 4.2 mpk
and an ED 0 of 9.1 mpk in lean C57BL/6 mice.
Table 1: IPGTT in Normal C57BL/6Mice
Glucose AUC Increase of glucose-
Example suppression at 30 stimulated insulin release at
mg/kg compared to 30 mg/kg compared to
vehicle control (%) vehicle control (%)
WE CLAIM:
1. A compound of the Formula
wherein R is selected from the group consisting of CH3, CH(CH3)2, CH2CN,
, , CH2CH2OCH3, and CH2C(0)OCH(CH 3)2;
R1 is selected from the group consisting of CF3, OCF3, and CI;
R2 is selected from the group consisting of H and F;
or a pharmaceutically acceptable salt thereof.
2. A compound, or pharmaceutically acceptable salt thereof, as claimed by Claim
1, wherein R is selected from the group consisting of CH(CH3) , CH CN,
CH2CHF2, CH2CF3, , , , ,
, , CH2CH2OCH3, and CH2C(0)OCH(CH 3)2.
3. A compound, or pharmaceutically acceptable salt thereof, as claimed by any
one of Claims 1 to 2, wherein R2 is H.
4. A compound, or pharmaceutically acceptable salt thereof, as claimed by any
one of Claims 1 to 3 wherein R1 is selected from the group consisting of CF3
and OCF3.
5. A compound, or pharmaceutically acceptable salt thereof, as claimed by any
one of Claims 1 to 4 wherein R1 is CF3.
A compound, or pharmaceutically acceptable salt thereof, as claimed by any
one of Claims 1 to 5 wherein R is selected from the group consisting of
A compound, or pharmaceutically acceptable salt thereof, as claimed by any
one of Claims 1, 3, 4, and 5, wherein R is selected from the group consisting
of CH3, CH(CH3)2, CH2CN, CH2CHF2, CH2CF3, CH2CH2OCH3, and
CH2C(0)OCH(CH 3)2.
8. A compound of the Formula
or a pharmaceutically acceptable salt thereof.
A compound or salt as claimed by any one of Claims 1 to 8 wherein the
compound is the cis isomer.
A compound or salt as claimed by any one of Claims 1 to 9 wherein the
compound is isomer 1.
11.A compound or salt as claimed by Claim 1 wherein the compound is Cis-
(chiral)-N-[3-[(3,5-Dimethylimidazol-4-yl)carbamoyl]cyclohexyl]-N-methyl-
3-(trifiuoromethyl)benzamide.
12. A pharmaceutical composition comprising a compound as claimed by any one
of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, and at least
one of a pharmaceutically acceptable carrier, diluent, or excipient.
13. A method for treating type II diabetes in a mammal in need thereof,
comprising administering to the mammal an effective amount of a compound,
or a pharmaceutically acceptable salt thereof, as claimed by any one of
Claims 1 to 11.
14. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any
one of Claims 1 to 11 for use in the manufacture of a medicament.