ISOPROPYL TRIAZOLO PYRIDINE COMPOUNDS
This invention relates to triazolo-pyridine compounds or pharmaceutically
acceptable salts thereof, and for use of compounds in therapy. Triazolo-pyridine
compounds of this invention are activators of GPR-40.
GPR-40, also known as Free Fatty Acid Receptor 1 (FFA1 or FFAR1), is
reported as predominately expressed at high levels in rodent pancreatic beta cells,
insulinoma cell lines, and human islets. The glucose modulation of insulin secretion is
an important feature of activating GPR-40. Compounds that effectuate GPR-40
activation are associated with stimulation of insulin secretion in a patient with type II
diabetes (T2D). Compounds that are GPR-40 activators are desired for use in
treatment of GPR-40 mediated conditions.
WO2004/041266 discloses GPR-40 receptor function regulators comprising a
compound having an aromatic ring and a group capable of releasing a cation.
The present invention provides a compound of the Formula I below:
Wherein
R is selected from the group consisting of H, CH , CN, CH2CN, C(CH )2CN, and F;
R2 is selected from the group consisting of H, 0(Ci-C alkyl)R5, CH2CN, and CN;
R3 is selected from the group consisting of H, OCH , CN, C(CH )2CN, and CH2CN;
R4 is selected from the group consisting of H and CH ; and
R5 is selected from the group consisting of H, CN, C(CH )2CN, OCH , S(0) 2CH , and
C(CH3)2OH; provided that at least one selected from the group consisting of Rl, R2, R3
and R4 is H;
or a pharmaceutically acceptable salt thereof.
The compounds of the present invention have a chiral carbon identified in the
structure above with an asterisk (*). Preferred compounds have the configuration shown
above, which by convention is known as the S configuration. For avoidance of doubt, the
present invention embraces all chiral carbon configurations, as illustrated by Formula la:
In an embodiment R is selected from the group consisting of H, CH and F. In
an embodiment R is selected from the group consisting H and CH3.
In another embodiment R2 is selected from the group consisting of H, and -0(Cr
C3alkyl)R5. In an embodiment R2 is selected from the group consisting of H and OCH 3.
In an embodiment R5 is selected from the group consisting of H, -S(0) 2CH3 and -
C(CH3)2OH.
Another embodiment is a compound wherein R3 is H, R is CH3 and R4 is CH3. In
another embodiment R3 is H, R is CH3,R4 is CH3,and R2 is -OCH 3.
In an embodiment R3 is selected from the group consisting of H and OCH 3. In an
embodiment R3 is H.
In an embodiment R4 is CH3. A compound wherein R is CH3, R2 is H or -OCH 3,
R3 is H and R4 is CH3 is an embodiment. In an embodiment R is CH3 and R4 is CH3.
One preferred compound of the present invention is (S)-3-{4-[2-Isopropyl-8-(4-
methoxy-2,6-dimethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridin-6-ylmethoxy]-phenyl}-hex-
4-ynoic acid, or a pharmaceutically acceptable salt thereof. One preferred compound of
the present invention is (S)-3-{4-[8-(2,6-Dimethyl-phenyl)-2-isopropyl-
[l,2,4]triazolo[l,5-a]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid , or a
pharmaceutically acceptable salt thereof.
The present invention also provides a pharmaceutical composition comprising a
compound of Formula I as described above or a pharmaceutically acceptable salt thereof
together with one or more pharmaceutically acceptable carriers, diluents or excipients.
The present invention also provides a pharmaceutical composition comprising a
compound of Formula I as described above or a pharmaceutically acceptable salt thereof
together with one or more pharmaceutically acceptable carriers, diluents or excipients,
and optionally one or more therapeutic agents. Additional therapeutic agents include for
example, metformin and/or Januvia.
The present invention also provides a method for treating diabetes in a mammal.
The method comprises administering to the mammal in need of treatment an effective
amount of a compound as described above for Formula I, or a pharmaceutically
acceptable salt thereof. More preferably the present invention provides a method of
treating type two diabetes in a mammal in need of treatment comprising administering an
effective amount of a compound as described above for Formula I or a pharmaceutically
acceptable salt thereof.
The present invention provides a compound according to Formula I or a
pharmaceutically acceptable salt thereof as described above for use in therapy.
In yet another form, the present invention provides a compound as described
above according to Formula I, a pharmaceutically acceptable salt thereof, or
pharmaceutical composition for use in the treatment of diabetes in a mammal in need
thereof. Preferably the use is for the treatment of type two diabetes and the mammal is a
human.
The present invention provides use of a compound according to Formula I, or a
pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the
treatment of diabetes. Preferably the medicament is for the treatment of type two
diabetes.
In yet another form, the present invention provides an intermediate compound of
the Formula II
II
wherein R is selected from the group consisting of H, CH , CN, CH2CN, C(CH )2CN,
and F;
R2 is selected from the group consisting of H, 0(Ci-C alkyl)R5, CH2CN, and CN;
R3 is selected from the group consisting of H, OCH , CN, C(CH )2CN, and CH2CN;
R4 is selected from the group consisting of H and CH3;
R5 is selected from the group consisting of H, CN, C(CH )2CN, OCH , S(0) 2CH , and
C(CH3)2OH; provided that at least one selected from the group consisting of Rl, R2, R3
and R4 is H; and
R is selected from the group consisting of C 4 alkyl, C -4 haloalkyl, C3-6 cycloalkyl, Cr
alkyl-C3-6 cycloalkyl, phenyl, and C1-5 alkylphenyl to provide a compound of Formula
I, or a pharmaceutically acceptable salt thereof. Preferred R groups include Ci-2 alkyl, -
Ci-2 haloalkyl, phenyl, and Ci-2 alkylphenyl. Particularly preferred R groups include
methyl, ethyl, phenyl, and benzyl; or a pharmaceutically acceptable salt thereof.
The present invention also provides a process or method for preparing a
compound described above for Formula I . The method comprises de-protecting or deesterifying
the intermediate compound according to Formula II to prepare the compound
of Formula 1, or a pharmaceutically acceptable salt thereof.
One skilled in the art would readily understand and be able to implement deprotecting
reactions without undue experimentation. It will be recognized by those
skilled in the art that in addition to the carboxylic acid and protected carboxylic acid,
other functional groups that can be readily converted to a carboxylic acid can be used in
place of the carboxylic acid or protected acid. Such functional groups, preparations, and
transformations of these groups to carboxylic acids can be found in "Comprehensive
Organic Transformations: A Guide to Functional Group Preparations" by Larock. R.C,
Wiley VCH, 1999 and in "March's Advanced Organic Chemistry, Reactions,
Mechanisms and Structure" Smith, M.B., and March, J., Wiley-Interscience, 6th Ed.
2007.
A compound of the present invention can be provided as a pharmaceutically
acceptable salt. "Pharmaceutically acceptable salt" refers to salts 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, etal., 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.
Individual isomers, enantiomers, or diastereomers may be separated at any
convenient point in the synthesis of the compound of Formula I by methods such as chiral
chromatography. Additionally, the intermediates described in the following Schemes and
preparations contain a number of nitrogen, hydroxy, and acid protecting groups such as
esters. 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. e.g., Greene and Wuts, Protective Groups
in Organic Synthesis, (T. Greene and P. Wuts, eds., 2d ed. 1991).
The abbreviations used herein are defined according to Aldrichimica Acta, Vol.
17, No. 1, 1984. Other abbreviations are defined as follows: "ADDP" refers to 1-
(azodicarbonyl)dipiperidine ; "BSA" refers to Bovine Serum Albumin; "n-BuLi" refers to
n-butyl lithium; "DIBAL" refers to diisobutylaluminum hydride;; "DCM" refers to
dichloromethane; "DMEM" refers to Dulbecco's Modified Eagle's Medium; "DMF'
refers to dimethylformamide; "DEAD" refers to diethyl azodicarboxylate; "DMF" refers
to dimethylformamide; "DMSO" refers to dimethylsulf oxide; "EC5 0" refers to the
effective concentration at half the maximal response; "EtOAc" refers to ethyl acetate ;
"EtOH" refers to ethyl alcohol or ethanol; "F12" refers to Ham's F12 medium; "FA"
refers to fatty acid; "FBS" refers to Fetal Bovine Serum; "HEK" refers to human
embryonic kidney; "IC50" refers to the concentration of an agent that produces 50% of the
maximal inhibitory response possible for that agent; "MeOH" refers to methyl alcohol or
methanol; "MTBE" refers to methyl i-butyl ether; "NBS" refers to N-bromosuccinimide;
"Pd(amphos)Cl 2" refers to bis(di- ri-butyl(4-
dimethylaminophenyl)phosphine)dichloropalladium (II); "Pd(dppf)Cl 2" refers to [1,1 ' -
bis(diphenylphosphino)ferrocene-palladium(II) dichloride; "Pd(PPh3)2Cl2" refers to
bis(triphenylphosphine)palladium(II) chloride; "PPAR" refers to peroxisome proliferatoractivated
receptor; "PPRE" refers to peroxisome proliferator response element; "RFU"
refers to relative fluorescence unit; "RPMI" refers to Roswell Park Memorial Institute;
"TFA" refers to trifluoroacetic acid; "THF" refers to tetrahydrofuran; "TK" refers to
thymidine kinase; and "TAK875" refers to the Takeda compound known as fasiglifam.
The term alkyl as used herein is a straight chain alkyl such as ethyl or n-propyl, or
a branched chain alkyl such as isopropyl or r -butyl. The term C1-4 haloalkyl refers to
an alkyl group that has 1, 2, 3, or more halo groups attached to the carbons of the alkyl
chain. If there are two or more halogens the halogens need not be attached to the same
carbon. This term also includes perhalo alkyls where all the hydrogen atoms of the alkyl
group are replaced with a halogen.
In the schemes below, all substituents unless otherwise indicated, are as
previously defined. The reagents and starting materials are generally readily available to
one of ordinary skill in the art. Others may be made by standard techniques of organic
and heterocyclic chemistry which are analogous to the syntheses of known structurallysimilar
compounds and the procedures described in the Preparations and Examples which
follow including any novel procedures.
Scheme 1
A compound
of Formula I can be prepared in accordance with reactions as depicted in Scheme 1. PG
is a protecting group developed for an acid such as esters, see above. Scheme 1 (Step 1)
depicts the formation of the of the phenyl sulfonic acid substituted diamino pyridine
quaternary salt. A mono methyl or trimethyl phenyl aminosulfonate (1) can be reacted
with a substituted 2-amino pyridine (2) to provide a diamino pyridine quaternary salt (3).
The quaternary salt (3) can then be reacted with 2-methylpropanal (4, Step 2a) in an
organic base such as triethylamine using a polar protic solvent such as MeOH to form the
substituted [l,2,4]triazolo[l,5-a]pyridine (6). Alternatively 2-methylpropanoyl chloride
(5, Step 2b) can be reacted with the quaternary salt (3) in a basic organic solvent such as
pyridine to form the substituted [l,2,4]triazolo[l,5-a]pyridine (6). The ester of compound
(6) can be reduced to the methyl hydroxy under standard conditions using a reducing
agent such as diisobutyl aluminum hydride (DIBAL) at a temperature such as -78 °C in a
polar aprotic solvent such as DCM to give the hydroxy compound (7, Step 3). Other
reducing reagents well known in the art are lithium aluminum hydride or sodium
borohydride. Compound (7) can be alkylated under Mitsunobu conditions to the ether
(10, Step 5b). Mitsunobu conditions are well known in the art and involve reacting an
alcohol (7) with a nucleophile such as a phenol (9) using a phosphine such as triphenyl
phosphine, tributyl phosphine, or triethylphosphine and an azodicarboxylate such as
diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) or an
azodicarbonyl such as ADDP. Alternatively the alcohol (7) can be converted to a halogen
(8, Step 4) such as bromide or chloride using thionyl chloride to form the chloride or
phosphorus tribromide in DCM to form the bromide. The halogenated compound (8) can
then be alkylated with the phenol (9) under basic conditions using an inorganic base such
as cesium carbonate or potassium acetate in a polar aprotic solvent such as acetonitrile to
give compound (10, Step 5a). The 8-halogen substituted [l,2,4]triazolo[l,5-a]pyridine
(10) can be coupled under Suzuki-Miyaura cross coupling conditions using a boronic acid
reagent. The skilled artisan will recognize that there are a variety of conditions useful for
facilitating such cross coupling reactions. Accordingly, a suitable palladium reagent
includes bis(triphenylphosphine)palladium(II) dichloride, Pd(amphos)Cl2,
tris(dibenzylideneacetone)dipalladium (0) with tricyclohexylphosphine, (, -
bis(diphenylphosphino)ferrocene)palladium (II) chloride, palladium
tetrakistriphenylphosphine, or palladium(II) acetate. A suitable base includes cesium
carbonate, sodium carbonate, potassium carbonate, or potassium phosphate tribasic
monohydrate in a suitable non-polar solvent such as 1,4-dioxane to give the 8-substituted
[l,2,4]triazolo[l,5-a]pyridine (II, Step 6). The protected acid of II can be deprotected
under standard basic conditions well known in the art to give compounds of Formula I,
Step 7. Conditions for deprotection of esters are well known in the art using a base such
as sodium hydroxide or lithium hydroxide in a polar protic solvent such as ethanol or
MeOH or a water/THF solvent mixture. Other alternative deprotection conditions include
using trimethyltin hydroxide or potassium trimethylsilanolate as a base in dichloroethane
or THF to give compounds of Formula I.
Scheme 2
In another variation, shown in Scheme 2, the 8-bromo substituted
[l,2,4]triazolo[l,5-a]pyridine (7, Step 1) can be coupled under Suzuki-Miyaura cross
coupling conditions using a boronic acid reagent to give compound (12) as described in
Scheme 1, Step 6. This alcohol (12) can then be reacted with a phenol (9) under
Mitsunobu conditions as described above in Scheme 1, Step 5b, to give compound II in
Step 2a. Alternatively, the alcohol of compound 12 can be halogenated to give compound
13 as described in Scheme 1, Step 4. The halogenated compound, (13) can then be
alkylated under basic conditions as described in Scheme 1, Step 5b to give compound II,
Step 2b. The compound of Formula II can then be deprotected as described for Scheme
1, Step 7 to give compounds of Formula I .
Preparations and Examples
The following preparations and examples further illustrate the invention and
represent typical synthesis of the compounds of Formula (I). Unless noted to the
contrary, the compounds illustrated herein are named and numbered using Accelrys Draw
4.0, IUPACNAME ACDLABS or MDL ISIS, version 2.5 SP2.
Preparation 1
6-Amino-nicotinic acid methyl ester
To a stirred solution of 6-amino-nicotinic acid (25 g, 181.1 mmol) in MeOH (200
mL) is added concentrated H2SO4 (7 mL) at 0 °C and the reaction mixture is heated at 80
°C for overnight. The reaction mixture is cooled to room temperature and neutralized
with saturated NaHCC>3 solution (100 mL). The precipitated solid is filtered and dried
under vacuum to give the title compound as a yellow solid (22 g, 81.5%). LCMS m/z 153
(M+H) +.
Preparation 2
Ethyl 6-aminonicotinate
To a stirred solution of 6-aminonicotinic acid (3 Kg, 21.61 mol) in ethanol (30 L)
is added concentrated H2SO4 (3 L) and the reaction mixture is heated at 78 °C for 16
hours. The reaction mixture is cooled to room temperature and evaporated under reduced
pressure. The residue is neutralized to pH -7.5 using saturated NaHCC>3 solution and
extracted with EtOAc (3x5 L). The combined organic extracts are washed with water
(2x5 L), brine solution (5 L), dried over sodium sulphate, and evaporated to give the title
compound as an off white solid (3.4 Kg, 93.87%). LCMS m/z 167 (M+H) +.
The following compound is prepared essentially by the method of preparation 2.
Table 1
Preparation 4
6-Amino-5-bromo-nicotinic acid methyl ester
To a stirred solution of methyl 6-amino nicotinate (22 g, 143.7 mmol) in THF
(500 mL) at 0 °C is added NBS (27.9 g, 158.1 mmol) and the reaction mixture is stirred at
room temperature for overnight. Ammonium chloride (100 mL) is added to the reaction
mixture and the mixture is extracted with EtOAc (2x100 mL). The combined organic
extracts are washed with brine solution (100 mL), dried over sodium sulphate, filtered,
and evaporated under reduced pressure. The crude material is purified by silica gel
column chromatography (combiflash) and eluted with 35% EtOAc in hexanes to give the
title compound as a pale brown solid (28 g, 84.8%). LCMS m/z ( yBr/ Br) 231/233
(M+H)+.
The following compound is prepared essentially by the method of preparation 4.
Table 2
Preparation 6
(E)-Ethyl N- (p-toluene sulfonyl) oxyacetimidate
To a stirred solution of (E)-ethyl N-hydroxyacetimidate (47.2 g, 458.7 mmol) in
DMF (300 mL) is added triethylamine (128 mL, 917.4 mmol) at room temperature and
the mixture is stirred for 20 minutes. p-Toluenesulphonyl chloride (100 g, 458.7 mmol)
is added and the reaction mixture is stirred for 16 hours at room temperature. The
reaction mixture is diluted with water (200 mL) and extracted with EtOAc (3x150 mL).
The combined organic extracts are dried over sodium sulphate, filtered, and evaporated
to give the title compound as a white solid (94 g, 80.3%). LCMS m/z 258 (M+H)+.
Preparation 7
(E)-Ethyl N-(mesitylsulfonyl)oxyacetimidate
To a stirred solution of N-hydroxy-acetimidic acid ethyl ester (42g, 183 mmol) in
DMF (100 mL) is added triethylamine (49.2 mL, 366 mmol) at 0 °C. The reaction
mixture is stirred at room temperature for 10 minutes and cooled again to 0 °C. 2,4,6-
Trimethyl-benzenesulfonyl chloride (40 g, 183 mmol) is added portion wise. The
reaction mixture is stirred overnight at room temperature. The reaction mixture is diluted
with EtOAc (100 mL), washed with ice water (2x500 mL), brine solution (50 mL), dried
over anhydrous sodium sulphate, filtered, and evaporated to give the title compound as a
pale yellow solid (40 g, crude) that is used without further purification. LC-MS m/z
286.1 [M+H]+.
Preparation 8
r -Butyl (mesitylsulfonyl)oxycarbamate
To a stirred solution of 2,4,6-trimethylbenzene-l-sulfonyl chloride (5.5 Kg, 25.14
mol) in MTBE (55 L) is added r -butyl hydroxycarbamate (4 Kg, 30.17 mol) and cooled
to 0 °C. Triethylamine (3.05 Kg, 30.17 mol) is added to the reaction mixture over a
period of 1 hour and the reaction mixture is stirred at 0 °C for 2 hours. The reaction
mixture is filtered and washed with MTBE (2x5 L). The filtrate is concentrated to a
volume of 12 L and n-hexane (6 L) is added and the mixture is redistilled up to a volume
of 12 L. To the crude compound 5% solution of MTBE in n-hexane (60 L) is added and
the mixture is stirred for 2 hours. The reaction mixture is filtered to give the first crop as
an off white solid compound (6.13 Kg). The filtrate is concentrated to dryness and 5%
solution of MTBE in n-hexane (10 L) is added. The reaction mixture is stirred for 30
minutes and filtered to give a second crop of the title compound (0.86 Kg) which is
combined with the first crop to give the title compound (6.99 g, 88%).
Preparation 9
0-(p-Toluene sulfonyl) hydroxylamine
To a stirred solution of (E)-ethyl N-(p-toluene sulfonyl) oxyacetimidate (10 g,
38.9 mmol) in 1,4 dioxane (40 mL), HC104 (3.0 mL) is added at 0 °C and the reaction
mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with
water and extracted with DCM (2x10 mL). The combined organic extracts are dried
over sodium sulphate and filtered. The solution is used directly without concentration (9
g, 100% crude).
Preparation 10
O-(Mesitylsulfonyl) hydroxylamine
To a stirred solution of (E)-ethyl N-(mesitylsulfonyl) oxyacetimidate (16 g,
62.167 mmol) in 1,4-dioxane (200 mL) is added perchloric acid (8 mL) at 0 °C and the
reaction mixture is stirred at room temperature for 1.5 hours. The reaction mixture is
diluted with water (30 mL) and extracted with DCM (2x20 mL). The combined organic
layer is washed with brine solution (20 mL), dried over anhydrous sodium sulphate,
filtered and the filtrate is used without concentration.
Alternate Preparation 10
To a 100 L reactor containing trifluoroacetic acid (19.74 L) is added r -butyl
(mesitylsulfonyl)oxycarbamate (6.99 Kg, 22.18 mol) at 0 °C over a period of 45 minutes
and the reaction mixture is stirred at 0 °C for 2 hours. The reaction mixture is quenched
with crushed ice (8 L) followed by ice cold water (16 L) and stirred for 15 minutes.
Additional ice cold water (24 L) is added and the mixture is stirred for 15 minutes. The
solid precipitate is filtered, washed with water and dried to give a white solid which is
used without further purification (4.77 Kg, 100%).
Preparation 11
1, 2-Diamino-3-bromo-5-methoxycarbonyl-pyridinium 4-methylbenzenesulfonate
To a stirred solution of o-(p-toluene sulfonyl) hydroxylamine (9 g, 48.1 mmol) in
DCM (50 mL) is added 6-amino-5-bromo-nicotinic acid methyl ester (11.1 g, 48.1 mmol)
at room temperature and the mixture is stirred for 16 hours. The reaction mixture is
cooled to 0 °C and diethyl ether is added. The precipitated solid is filtered and dried
under vacuum to give the title compound as an off-white solid (9 g, 45%). H NMR (400
MHz, d6-DMSO) 9.09 (bs, 2H), 8.69 (d, = 1.6 Hz, 1H), 8.46 (q, = 8.0 Hz, 1H), 7.06
(s, 3H), 6.71 (s, 2H), 4.31 (q, = 11.6 Hz, 2H), 2.14 (s, 3H), 1.25-1.32 (m, 4H).
The following compound is prepared essentially by the method of preparation 11.
Table 3
= 8.0 Hz, 1H), 7.06 (s, 3H), 6.71 (s, 2H), 4.31 (q, = 11.6 Hz, 2H), 2.14 (s, 3H), 1.25-
1.32 (m, 4H).
Alternate Preparation 12
O-(Mesitylsulfonyl) hydroxylamine (assumed 4.77 Kg, 22.17 mol) as a wet cake
is dissolved in DCM (25 L) and the aqueous layer is separated, the organic layer is
washed with water (2x10 L) and brine solution (10 L). The organic layer is transferred to
a 100 L reactor and diluted with additional DCM (45 L). The reaction mixture is cooled
to 10 °C - 15 °C and 6-amino-5-bromo-nicotinic acid ethyl ester (4.24 Kg, 17.29 mol) is
added portion wise over a period of 15 minutes. The reaction mixture is stirred at room
temperature for 16 hours. The reaction mixture is filtered and the solid cake is washed
with DCM (3x10 L) and dried to give the first crop as a white solid (2.7 Kg). The filtrate
is concentrated to give a thick mass which is triturated in DCM (20 L) for 2 hours. A
solid is filtered and the wet cake is washed with DCM (2x5 L) and dried to give a second
crop as an off white solid (1.1 Kg) which is combined with the first crop to give the title
compound (3.8 Kg, 37.25%). LCMS m/z ( Br/ Br) 260/262 (M+H)+.
Preparation 13
3-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzonitrile
To a stirred solution of 3-amino-benzonitrile (0.5 g, 4.23 mmol) in acetonitrile (30
mL) is added ieri-butylnitrite (0.7 mL, 6.34 mmol) and bispinacolatodiboron (1.29 g,
5.076 mmol) at 0 °C. The mixture is heated at 80 °C for 2 hours. The reaction mixture is
cooled to room temperature and concentrated under reduced pressure. The crude material
is purified by silica gel column chromatography (combiflash) eluting in 4%
EtOAc/hexanes to obtain the title compound (0.35 g, 99.8%). LCMS m/z 294 (M+H)+.
The following compound is prepared essentially by the method of preparation 13.
5 Table 4
Preparation 15
3,5-Dimethyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzonitrile
To a stirred solution of 4-bromo-3,5-dimethyl-benzonitrile (0.5 g, 2.38 mmol) and
bispinacolatodiboron (0.9 g, 3.57 mmol) in DMF (20 mL) is added CH COOK (1.051 g,
10.71 mmol). The mixture is purged with argon for 30 minutes, then Pd(dppf)2Cl2.DCM
(0.097 g, 0.119 mmol) is added and the mixture is heated at 100°C for overnight. The
reaction mixture is cooled to room temperature and filtered through diatomaceous earth.
J The filtrate is diluted with water (30 mL) and extracted with EtOAc (2x30 mL). The
combined organic extracts are washed with saturated brine solution (20 mL), dried over
sodium sulphate, filtered, and concentrated. The crude material is purified by silica gel
column chromatography (combiflash) eluting with 6% EtOAc/hexanes to obtain the title
compound as a brown liquid (0.4 g, 65%). LCMS m/z 288(M+H)+.
2 Preparation 16
2-(4-Bromo-phenyl)-2-methyl-propionitrile
To a solution of (4-bromo-phenyl)-acetonitrile ( 1 g, 5.10 mmol) in DMF (10 mL)
is added sodium hydride (0.408 g, 10.20 mmol, 60% in mineral oil) at 0 °C. The
reaction mixture is stirred at 0 °C for 15 minutes and then methyl iodide (0.69 mL, 11.22
mmol) is added at 0 °C. The reaction mixture is stirred at room temperature for
overnight. The reaction mixture is quenched with aqueous ammonium chloride solution
(5 mL) and extracted with EtOAc (2x20 mL). The combined organic extracts are
washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2S04, filtered,
and evaporated. The crude material is purified over silica gel column chromatography
(combiflash) eluting with 5-10% EtOAc in hexanes to give an off white solid (0.9 g,
78%). H NMR (400 MHz, CDC1 ) 7.51 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H),
1.77 (s, 3H).
The following compound is prepared essentially by the method of preparation 16.
Table 5
Preparation 18
4-Chloro-2,2-dimethylbutanenitrile
To a stirred solution of diisopropylamine (2.43 mL, 17.36 mmol) in dry THF (20
mL) is added n-BuLi (14.4 mL, 17.36 mmol) drop wise at -60 °C, and gradually allowed
to warm to 0 °C and stirred for 20 minutes. The reaction mixture is cooled to -78 °C and
anhydrous acetonitrile (1.42 mL, 14.47 mmol) is added and the reaction is stirred for 45
minutes at the same temperature. l-Bromo-4-chloro butane (1.3 mL, 15.91 mmol) is
added at -78 °C, allowed to warm to room temperature and stirred for 3 hours. The
reaction mixture is quenched with saturated NH4C 1 solution (25 mL), extracted with
EtOAc (2x50 mL). The combined organic extracts are washed with water (50 mL) and
brine (50 mL), dried over anhydrous sodium sulphate, and evaporated to dryness. The
crude product is purified by silica gel column chromatography (combiflash) eluting with
5% EtOAc in hexanes to give the title compound (0.5 g, 25.2%). H NMR (400 MHz,
CDC13); 3.67-3.63 (m, 2H), 2.06-2.02 (m, 2H), 1.45-1.36 (m, 6H).
Preparation 19
4-Bromo-2-methyl-butan-2-ol
To a stirred solution of 4-bromo-butyric acid methyl ester (2 g, 12.27 mmol) in
diethyl ether (20 mL) is added methyl magnesium bromide (16.4 mL, 49.08 mmol) at 0
°C and the mixture is stirred at room temperature for 2 hours. The reaction mixture is
quenched with 1 N HC1 and extracted with diethyl ether (2x20 mL). The combined
organic extracts are washed with saturated brine solution (20 mL), dried over sodium
sulphate, filtered, and concentrated. The crude material is purified with silica gel column
chromatography (combiflash) eluting in 20% EtOAc/hexanes to give the title compound
(1.3 g, 65%). H NMR (400 MHz, CDC1 ) : 3.48 (t, = 8.0 Hz, 2H), 2.16 (t, = 7.4
Hz, 2H), 1.89 (s, 6H), 1.76 (s, 3H), 1.27 (s, 6H).
Preparation 20
8-Bromo-2-isopropyl-[l, 2, 4]triazolo[l,5-a]pyridine-6-carboxylic acid methyl ester
To a stirred solution of l,2-diamino-3-bromo-5-methoxycarbonyl-pyridinium 4-
methyl benzenesulfonate (9 g, 21.4 mmol) in MeOH (35 mL) is added 2-methylpropanal
(0.98 mL, 10.7 mmol) and triethylamine (8.6 mL, 64.2 mmol) at room temperature and
the mixture is stirred for 48 hours. The reaction mixture is evaporated to dryness, the
residue is diluted with water (50 mL), and extracted with EtOAc (2x50 mL). The
combined organic extracts are washed with brine solution (50 mL), dried over sodium
sulphate, filtered, and evaporated to dryness. The crude material is purified by silica gel
column chromatography (combiflash) eluting with 15-20% EtOAc in hexane to give the
title compound as a pale yellow solid (1.5 g, 12%). LCMS m/z ( Br/ Br) 298/300
(M+H)+.
Alternate Preparation 20
To a stirred solution of 2,4,6-trimethyl-benzenesulfonatel,2-diamino-3-bromo-5-
methoxy carbonyl-pyridinium (10 g, 22.3 mmol) in MeOH (100 mL) is added 2-
methylpropanal (0.8 g, 1 mL, 11.1 mmol) and triethylamine (9 mL, 66.9 mmol) at 0 °C
and the reaction mixture is stirred at room temperature for 48 hours. The reaction
mixture is evaporated, diluted with water, and extracted with EtOAc (2x100 mL). The
combined organic extracts are washed with water (2x50 mL), saturated ammonium
chloride solution (50 mL), brine (50 mL), dried over anhydrous sodium sulphate, filtered,
and evaporated to dryness. The crude material is purified by silica gel column
chromatography (combiflash) eluting with 20-40% EtOAc in hexanes to give the title
compound as an off white solid (2.7 g, 43.5%). LC-MS m/z ( Br/ Br) 298/300
[M+H]+.
Preparation 2 1
-Bromo-2-isopropyl-[l, 2, 4]triazolo[l,5-a]pyridine-6-carboxylic acid ethyl ester
To a stirred solution of l,2-diamino-3-bromo-5-(ethoxycarbonyl)pyridin-l-ium
2,4,6-trimethyl benzenesulfonate (2.2 Kg, 4.78 mol) in pyridine (6.6 L) is added 2-
methylpropanoyl chloride (2.55 Kg, 23.90 mol) at room temperature and the reaction
mixture is heated at 100 °C for 5 hours. The reaction mixture is evaporated to dryness,
the residue is diluted with water (20 L), and stirred for 1 hour. The precipitated solid is
filtered, washed with water (3x5 L) and dried. The crude product is purified by silica gel
flash chromatography, eluting with hexanes: EtOAc (8.0:2.0) to give the title compound
as an off white solid (800 g, 53.7%). LC-MS m/z ( Br/ Br) 312/314 [M+H]+.
Preparation 22
(8-Bromo-2-isopropyl-[l, 2, 4] triazolo [1, 5-a] pyridin-6-yl)-methanol
To a solution 8-bromo-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridine-6-carboxylic
acid methyl ester (1.4 g, 4.70 mmol) in DCM (30 mL) is added diisobutyl aluminum
hydride (9.5 mL, 9 mmol, 1M in hexane) at -78 °C. The reaction mixture is warmed to
0 °C and stirred for 3 hours. The reaction mixture is quenched with MeOH (20 mL) and
filtered through diatomaceous earth, washed with EtOAc (30 mL), and evaporated under
reduced pressure to give the title product (1.8 g, 100% crude). LCMS m/z ( Br/ Br)
270/272 (M+H)+.
The following compounds are prepared essentially by the method of preparation
22 using the appropriate carboxylic acid ester.
Table 6
0
(8-(2,6-Dimethyl-4-(3-
(methylsulfonyl)propox
27 y)phenyl)-2-isopropyl- 432
[l,2,4]triazolo[l,5-
a]pyridin-6-yl) methanol
[2-Isopropyl-8-(2-
methoxy-ethoxy)-
28 [l,2,4]triazolo[l,5- 266
a]pyridin-6-yl]-
methanol
Preparation 29
8-Bromo-6-chloromethyl-2-isopropyl- [1,2,4]triazolo [1,5-ajpyridine
A mixture (8-bromo-2-isopropyl-[l, 2, 4] triazolo [1, 5-a] pyridin-6-yl)-methanol
(1.8 g, 0.57 mmol) and thionyl chloride (10 mL) is stirred at room temperature for 2
hours. The reaction mixture is quenched with saturated sodium bicarbonate solution (20
mL) and extracted with EtOAc (3x20 mL). The combined organic extracts are dried
over sodium sulphate, filtered, and evaporated under vacuum to give the title compound
(1.1 g, 67%). LCMS m/z ( Br/ Br) 288/290 [M+H]+.
The following compounds are prepared essentially by the method of preparation
29.
Table 7
Preparation 32
l-Bromo-3-bromomethyl-2-methyl-benzene
To a solution of (3-bromo-2-methyl-phenyl)-methanol (2 g, 9.9 mmol) in DCM
(25 mL) is added phosphorous tribromide (1.76 mL, 14.9 mmol) at 0 °C and the reaction
mixture is allowed to warm to room temperature and stirred 1 hour. The reaction
mixture is diluted with DCM (20 mL), quenched with aqueous NaHCC>3 solution, and
extracted with DCM (3x50 mL). The combined organic extracts are washed with water
(10 mL) and brine (10 mL), dried over anhydrous Na2S04, filtered, and evaporated to
dryness to give the title compound (2 g,77%). LC-MS m/z 264 [M+H] +.
The following compounds are prepared essentially by the method of preparation
32.
Table 8
ES/MS
Prep.
Chemical Name Structure (m/z)
No.
(M+l)
6-Bromomethyl-2-
isopropyl-8- (4-
33 methoxy-2,6-dimethyl- 388/390
phenyl)-
[l,2,4]triazolo[l,5-
ajpyridine
2-[2-(6-Bromomethyl-2-
isopropyl-
34 [l,2,4]triazolo[l,5- 397/399
a]pyridin-8-yl)-phenyl]-
2-methyl-propionitrile
6-Bromomethyl-2-
isopropyl-8-[4-(2-
35 methoxy-ethoxy) -2,6- 432/434
dimethyl-phenyl] -
[l,2,4]triazolo[l,5-
ajpyridine
Preparation 36
(3-Bromo-2-methyl-phenyl)-acetonitrile
To a solution of bromo-3-bromomethyl-2-methyl-benzene (0.2 g, 7.6 mmol) in
DMF (15 mL) is added sodium cyanide (0.55 g, 11.4 mmol) at room temperature. The
reaction mixture is heated at 100 °C for 12 hours and quenched with potassium
permanganate solution, filtered, and the filtrate is diluted with water and extracted with
EtOAc (2x20 mL). The organic extracts are dried over Na2S0 4, filtered, and evaporated.
The crude material is purified over silica gel column chromatography (combiflash),
eluting with EtOAc 10-25% in hexanes to give the title compound (0.8 g, 28.2%). LCMS
m/z 211 [M+H]+.
Preparation 37
2-Isopropyl-8-(4-methoxy-2,6-dimethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridine-6-
carboxylic acid methyl ester
To a stirred solution of 8-bromo-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridine-6-
carboxylic acid methyl ester (0.8 g, 2.6 mmol) and 4-methoxy 2,6-dimethyl phenyl
boronic acid (0.522 g, 2.9 mmol) in toluene (12 mL) and EtOH (3 mL) is added 2 M
K2CO solution (3.9 mL, 7.8 mmol). The mixture is purged with argon for 30 minutes,
Pd(PPh )2Cl2 (0.182 g, 0.26 mmol) is added and the reaction mixture is heated at 100 °C
for 16 hours. The reaction mixture is cooled to room temperature, filtered through
diatomaceous earth, the filtrate is diluted with water (20 mL) and extracted with EtOAc
(2x20 mL). The combined organic extracts are washed with saturated brine solution (10
mL), dried over sodium sulphate, filtered, and concentrated. The crude material is
purified by silica gel column chromatography (combiflash) eluting with 15-20% EtOAc
in hexanes to give the title compound as a yellow liquid (0.26 g, 27.4%). LCMS m/z 354
(M+H)+.
Alternate Preparation 37
To a stirred solution of 8-bromo-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridine-6-
carboxylic acid methyl ester (2.5 g, 8.8 mmol) and 4-methoxy 2,6-dimethyl phenyl
boronic acid (1.4 g, 8.83 mmol) in toluene (16 mL) is added potassium phosphate tribasic
(5.3 g, 12.4 mmol) at room temperature and the reaction mixture is purged with nitrogen
for 20 minutes and then added Pd(amphos)Cl 2 (0.57 g, 0.802 mmol). The reaction
mixture is heated at 70 °C for overnight. The reaction mixture is filtered through
diatomaceous earth, washed with EtOAc (2x20 mL) and the filtrate is evaporated. The
crude material is purified by silica gel column chromatography (combiflash) eluting with
30% EtOAc in hexanes to give the title compound as a brown solid (1.5 g, 65.54%). LC
MS m/z 354 [M+H]+.
Alternate Preparation 37
To a stirred solution of 8-bromo-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridine-6-
carboxylic acid methyl ester (1.05 g, 3.52 mmol) and 4-methoxy 2,6-dimethyl phenyl
boronic acid (0.63 g, 3.52 mmol) in 1,4-dioxane (20 mL) is added 2 M K2CO solution
(1.4 mL, 2.9 mmol). The mixture is purged with argon for 30 minutes, then Pd(PPh )2Cl2
(0.041 g, 0.059 mmol) is added and the reaction mixture is heated to 100 °C for 16 hours.
The reaction mixture is cooled to room temperature, filtered through diatomaceous earth,
the filtrate is diluted with water (20 mL) and extracted with EtOAc (2x20 mL). The
combined organic extracts are washed with brine (10 mL), dried over sodium sulphate,
filtered, and concentrated. The crude material is purified by silica gel column
chromatography (combiflash) eluting with 14% EtOAc in hexanes to give the title
compound (0.13 g, 16%). LCMS m/z 354 (M+H)+.
Preparation 38
2-Isopropyl-8-(4-methoxy-2,6-dimethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridine-6-
carboxylic acid ethyl ester
To a stirred solution of 8-bromo-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridine-6-
carboxylic acid ethyl ester (400 g, 1.28 mol) and 4-methoxy 2,6-dimethylpheneyl
boronic acid (276.8 g, 1.54 mol) in toluene (8 L) is added a solution of K3PO4 (816 g,
3.84 mol) in water (3.84 L) and the reaction mixture is purged with nitrogen for 1 hour,
then Pd(amphos)Cl 2 ( 45.36 g, 0.064 mol) is added and the reaction mixture is purged
with nitrogen for 20 minutes. The reaction mixture is heated at 75 °C for 16 hours. The
reaction mixture is cooled to room temperature, filtered through diatomaceous earth, and
washed with EtOAc (3x1 L). The filtrate is diluted with water (5 L) and extracted with
EtOAc (2x1.5 L). The combined organic extracts are washed with water (2.5 L), brine
(2.5 L), dried over sodium sulfate, filtered, and concentrated to dryness. The crude
product (600 g) is combined with another crude lot (400 g) and purified on silica gel
column chromatography eluting with 15-20% EtOAc in hexanes to give the title
compound as a light yellow solid (901 g, 95.68%).
Preparation 39
8-(2-Fluoro-5-methoxy-phenyl)-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridine-6-carboxylic
acid ethyl ester
To a stirred solution of 8-bromo-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridine-6-
carboxylic acid ethyl ester (0.45 g, 1.509 mmol) and 2-flouro 4-methoxy phenyl boronic
acid (0.512 g, 3.018 mmol) in 1,4-dioxane (6 mL) is added 2 M K2C0 (0.624 g, 4.527
mmol). The mixture is purged with argon for 30 minutes, Pd(PPh )4 (0.087 g, 0.075
mmol) is added and the mixture is heated at 100 °C for 1 hour in a microwave. The
reaction mixture is cooled to room temperature and filtered through diatomaceous earth.
The filtrate is diluted with water (20 mL) and extracted with EtOAc (2x10 mL). The
combined organic layer is washed with brine (10 mL), dried over sodium sulphate,
filtered, and concentrated. The crude material is purified by silica gel column
chromatography (combiflash) eluting with 15-20% EtOAc in hexanes to give the title
compound (0.17 g, 33%). LCMS m/z 344 (M+H)+.
Preparation 40
6-Chloromethyl-2-isopropyl-8-(4-methoxy-2,6-dimethyl-phenyl)-[l,2,4]triazolo[l,5-
ajpyridine
To a solution [2-isopropyl-8-(4-methoxy-2,6-dimethyl-phenyl)-
[l,2,4]triazolo[l,5-a]pyridin-6-yl]-methanol (0.21 g, 0.64 mmol) in DCM (10 mL) is
added S0C12 (0.12 mL, 1.61 mmol) at 0°C. Then the mixture is allowed to warm to
room temperature over 1 hour. The reaction mixture is cooled to 0 °C, quenched with
saturated sodium bicarbonate solution (20 mL) and extracted with DCM (3x20 mL). The
combined organic extracts are washed with brine solution, dried over sodium sulphate,
filtered, and evaporated to dryness to give the title compound as a brown solid (0.06 g,
29%). LCMS m/z; 344 (M+H)+.
Preparation 4 1
2-[2-(6-Hydroxymethyl-2-isopropyl-[l ,2,4]triazolo[l ,5-a]pyridin-8-yl)-ph
methyl-propionitrile
To a stirred solution of 2-{2-[6-(ieri-butyl-dimethyl-silanyloxymethyl)-2-
isopropyl-[l,2,4]triazolo[l,5-a]pyridin-8-yl]-phenyl}-2-methyl-propionitrile (0.6 g, 1.33
mmol) in THF (10 mL) is added tetra-n-butyl ammonium fluoride (0.52 g, 2 mmol) at 0
°C and the reaction mixture is stirred at room temperature for 1 hour. The reaction
mixture is diluted with water (10 mL) and extracted with EtOAc (2x20 mL). The
combined organic extracts are washed with water (10 mL) and brine (10 mL), dried over
anhydrous sodium sulphate, filtered, and evaporated to dryness. The crude material is
purified by silica gel column chromatography (combiflash), eluting with 40% EtOAc in
hexanes to give the title compound as a white solid (0.4 mg, 50%). LC-MS m/z 335
[M+H]+.
Preparation 42
8-Bromo-6-(ier^butyl-dimethyl-silanyloxymethyl)-2-isopropyl-[l,2,4]triazolo[l,5-
ajpyridine
To a stirred solution of 8-bromo-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-
methanol (0.25 g , 0.92 mmol) in DMF (5 mL) at 0 °C is added imidazole (0.209 g, 1.38
mmol) and the reaction mixture is stirred at room temperature for 5 minutes, cooled to 0
°C and ieri-butylchlorodimethylsilane (0.209 g, 1.38 mmol) is added. The reaction
mixture is stirred at room temperature for 12 hours. The reaction mixture is diluted water
and extracted with EtOAc (2x25 mL). The combined organic extracts are washed with
brine (20 mL), dried over Na2SC>4, filtered, and evaporated to dryness. The crude product
is purified by silica gel column chromatography (combiflash) eluting with 10-30% EtOAc
in hexanes to give the title compound (0.32 g, 90%). LCMS m/z 384/386 [M+H] +.
Preparation 43
{2-[6-(½ri-Butyl-dimethyl-silanyloxymethyl)-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridin-
8-yl] -phenyl }-acetonitrile
To a stirred solution of 8-bromo-6-(½ri-butyl-dimethyl-silanyloxymethyl)-2-
isopropyH 1,2,4] triazolo[l,5-a]pyridine (1.3 g, 3.38 mmol) and [2-(4,4,5,5-tetramethyl[
l,3,2]dioxaborolan-2-yl)-phenyl]-acetonitrile (0.82 g, 3.38 mmol) in dioxane (10 mL) is
added potassium acetate (0.93 g, 6.76 mmol) at room temperature and the reaction
mixture is purged with nitrogen for 20 minutes. Pd(PPh )4 (0.195 g, 0.16 mmol) is added
and the reaction mixture is heated at 100 °C for 12 hours in a sealed tube. The reaction
mixture is cooled and filtered through diatomaceous earth and the filtrate is evaporated to
dryness. The crude product is purified by silica gel column chromatography
(combiflash) eluting with 10-30% EtOAc in hexanes to give the title compound (0.6 g,
42%). LCMS m/z 421 [M+H]+.
Preparation 44
2-(3-Bromo-2-methyl-phenyl)-2-methyl-propionitrile
To a solution of NaH (0.22 g, 5.6 mmol, 60% in paraffin oil) in THF at 0 °C is
added a solution of (3-bromo-2-methyl-phenyl)-acetonitrile (0.6 g, 2.8 mmol) in THF (4
mL). The reaction mixture is stirred at room temperature for 30 minutes and then methyl
iodide (0.43 mL, 7 mmol) is added. The reaction mixture is stirred at room temperature
for 12 hours, quenched with saturated aqueous NH4C 1 solution, and extracted in EtOAc
(2x25 mL). The organic layer is washed with brine (10 mL), dried over Na2S0 4, filtered,
and evaporated. The crude of another lot ( 1 g) is combined with this lot and purified
over silica gel column chromatography (combiflash), eluting with 10-30% EtOAc in
hexanes to give the title compound (1.2 g, 75.9%). LC-MS m/z 239 [M+H]+.
The following compounds are prepared essentially by the method of Preparation
Table 9
Preparation 47
2-Isopropyl-8-(4-methoxy-2,6-dimethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridine-6-
carboxylic acid methyl ester
To a stirred solution of 8-bromo-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridine-6-
carboxylic acid methyl ester (0.8 g, 2.6 mmol) and 4-methoxy 2,6-dimethyl phenyl
boronic acid (0.522 g, 2.9 mmol) in toluene (12 mL) and EtOH (3 mL) is added 2 M
K2CO solution (3.9 mL, 7.8 mmol). The mixture is purged with argon for 30 minutes,
Pd(PPh )2Cl2 (0.182 g, 0.26 mmol) is added and the reaction mixture is heated at 100 °C
for 16 hours. The reaction mixture is cooled to room temperature, filtered through
diatomaceous earth, the filtrate is diluted with water (20 mL) and extracted with EtOAc
(2x20 mL). The combined organic extracts are washed with saturated brine solution (10
mL), dried over sodium sulphate, filtered, and concentrated. The crude material is
purified by silica gel column chromatography (combiflash) eluting with 15-20% EtOAc
in hexanes to give the title compound as a yellow liquid (0.26 g, 27.4%). LCMS m/z 354
(M+H)+.
Alternate Preparation 47
To a stirred solution of 8-bromo-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridine-6-
carboxylic acid methyl ester (2.5 g, 8.8 mmol) and 4-methoxy 2,6-dimethyl phenyl
boronic acid (1.4 g, 8.83 mmol) in toluene (16 mL) is added potassium phosphate tribasic
(5.3 g, 12.4 mmol) at room temperature and the reaction mixture is purged with nitrogen
for 20 minutes and then Pd(amphos)Cl 2 (0.57 g, 0.802 mmol) is added. The reaction
mixture is heated at 70 °C for overnight. The reaction mixture is filtered through
diatomaceous earth, washed with EtOAc (2x20 mL) and the filtrate is evaporated. The
crude material is purified by silica gel column chromatography (combiflash) eluting with
30% EtOAc in hexanes to give the title compound as a brown solid (1.5 g, 65.54%). LC
MS m/z 354 [M+H]+.
Alternate Preparation 47
To a stirred solution of 8-bromo-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridine-6-
carboxylic acid methyl ester (1.05 g, 3.52 mmol) and 4-methoxy 2,6-dimethyl phenyl
boronic acid (0.63 g, 3.52 mmol) in 1,4-dioxane (20 mL) is added 2 M K2C0 solution
(1.4 mL, 2.9 mmol). The mixture is purged with argon for 30 minutes, then Pd(PPh3)2Cl2
(0.041 g, 0.059 mmol) is added and the reaction mixture is heated at 100 °C for 16 hours.
The reaction mixture is cooled to room temperature, filtered through diatomaceous earth,
the filtrate is diluted with water (20 mL) and extracted with EtOAc (2x20 mL). The
combined organic extracts are washed with brine (10 mL), dried over sodium sulphate,
filtered, and concentrated. The crude material is purified by silica gel column
chromatography (combiflash) eluting with 14% EtOAc in hexanes to give the title
compound (0.13 g, 16%). LCMS m/z 354 (M+H)+.
Preparation 48
2-Isopropyl-8-(4-methoxy-2,6-dimethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridine-6-
carboxylic acid ethyl ester
To a stirred solution of 8-bromo-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridine-6-
carboxylic acid ethyl ester (400 g, 1.281 mol) and 4-methoxy 2,6-dimethylpheneyl
boronic acid (276.8 g, 1.538 mol) in toluene (8 L) is added a solution of K3PO4 (816 g,
3.844 mol) in water (3.84 L) and the reaction mixture is purged with nitrogen for 1 hour,
then Pd(amphos)Cl 2 ( 45.36 g, 0.064 mol) is added and the reaction mixture is purged
with nitrogen for 20 minutes. The reaction mixture is heated at 75 °C for 16 hours. The
reaction mixture is cooled to room temperature, filtered through diatomaceous earth, and
washed with EtOAc (3x1 L). The filtrate is diluted with water (5 L) and extracted with
EtOAc (2x1.5 L). The combined organic extracts are washed with water (2.5 L), brine
(2.5 L), dried over sodium sulfate, filtered, and concentrated to dryness. The crude
product (600 g) is combined with another crude lot (400 g) and purified on silica gel
column chromatography eluting with 15-20% EtOAc in hexanes to give the title
compound as a light yellow solid (901 g, 95.68%).
Preparation 49
8-Bromo-2-isopropyl-[l, 2, 4]triazolo[l,5-a]pyridine-6-carboxylic acid methyl ester
To a stirred solution of l,2-diamino-3-bromo-5-methoxycarbonyl-pyridinium 4-
methyl benzenesulfonate (9 g, 21.4 mmol) in MeOH (35 mL) is added isobutyraldehyde
(0.98 mL, 10.7 mmol) and triethylamine (8.6 mL, 64.2 mmol) at room temperature and
the mixture is stirred for 48 hours. The reaction mixture is evaporated to dryness, the
residue is diluted with water (50 mL), and extracted with EtOAc (2x50 mL). The
combined organic extracts are washed with brine solution (50 mL), dried over sodium
sulphate, filtered, and evaporated to dryness. The crude material is purified by silica gel
column chromatography (combiflash) eluting with 15-20% EtOAc in hexanes to give the
title compound as a pale yellow solid (1.5 g, 12%). LCMS m/z ( Br/ Br) 298/300
(M+H)+.
Alternate Preparation 49
To a stirred solution of 2,4,6-trimethyl-benzenesulfonatel,2-diamino-3-bromo-5-
methoxy carbonyl-pyridinium (10 g, 22.3 mmol) in MeOH (100 mL) is added 2-methylpropionaldehyde
(0.8 g, 1 mL, 11.1 mmol) and triethylamine (9 mL, 66.9 mmol) at 0 °C
and the reaction mixture is stirred at room temperature for 48 hours. The reaction
mixture is evaporated, diluted with water, and extracted with EtOAc (2x100 mL). The
combined organic extracts are washed with water (2x50 mL), saturated ammonium
chloride solution (50 mL), brine (50 mL), dried over anhydrous sodium sulphate, filtered,
and evaporated to dryness. The crude material is purified by silica gel column
chromatography (combiflash) eluting with 20-40% EtOAc in hexanes to give the title
compound as an off white solid (2.7 g, 43.5%). LC-MS m/z ( Br/ Br) 298/300
[M+H] .
Preparation 50
-Bromo-2-isopropyl-[l, 2, 4]triazolo[l,5-a]pyridine-6-carboxylic acid ethyl ester
To a stirred solution of l,2-diamino-3-bromo-5-(ethoxycarbonyl)pyridin-l-ium
2,4,6-trimethyl benzenesulfonate (2.2 Kg, 4.779 mol) in pyridine (6.6 L) is added
isobutyryl chloride (2.546 Kg, 23.895 mol) at room temperature and the reaction mixture
is heated at 100 °C for 5 hours. The reaction mixture is evaporated to dryness, the residue
is diluted with water (20 L), and stirred for 1 hour. The precipitated solid is filtered,
washed with water (3x5 L) and dried. The crude product is purified by silica gel flash
chromatography, eluting with hexane: EtOAc (8.0:2.0) to give the title compound as an
off white solid (800 g, 53.7%). LC-MS m/z ( Br/ Br) 312/314 [M+H]+.
Preparation 51
(8-Bromo-2-isopropyl-[l, 2, 4] triazolo [1, 5-a] pyridin-6-yl)-methanol
To a solution 8-bromo-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridine-6-carboxylic
acid methyl ester (1.4 g, 4.70 mmol) in DCM (30 mL) is added diisobutyl aluminum
hydride (9.5 mL, 9 mmol, 1M in hexane) at -78 °C. The reaction mixture is warmed to
0 °C and stirred for 3 hours. The reaction mixture is quenched with MeOH (20 mL) and
filtered through diatomaceous earth, washed with EtOAc (30 mL), and evaporated under
reduced pressure to give the title product (1.8 g, 100% crude). LCMS m/z ( Br/ Br)
270/272 (M+H)+.
The following compounds are prepared essentially by the method of preparation
51.
Table 10
0
(8-(2,6-Dimethyl-4-(3-
(methylsulfonyl)propox
56 y)phenyl)-2-isopropyl- 432
[l,2,4]triazolo[l,5-
a]pyridin-6-yl) methanol
[2-Isopropyl-8-(2-
methoxy-ethoxy)-
57 [l,2,4]triazolo[l,5- 266
a]pyridin-6-yl]-
methanol
Preparation 58
8-Bromo-6-chloromethyl-2-isopropyl- [1,2,4]triazolo [1,5-ajpyridine
A mixture (8-bromo-2-isopropyl-[l, 2, 4] triazolo [1, 5-a] pyridin-6-yl)-methanol
(1.8 g, 0.57 mmol) and thionyl chloride (10 mL) is stirred at room temperature for 2
hours. The reaction mixture is quenched with saturated sodium bicarbonate solution (20
mL) and extracted with EtOAc (3x20 mL). The combined organic extracts are dried
over sodium sulphate, filtered, and evaporated under vacuum to give the title compound
(1.1 g, 67%). LCMS m/z ( Br/ Br) 288/290 [M+H]+.
The following compounds are prepared essentially by the method of preparation
58.
Table 11
Preparation 6 1
(S)-3-[4-(8-Bromo-2-isopropyl-[l, 2, 4] triazolo [1, 5-a] pyridin-6-ylmethoxy)-phenyl]-
hex-4-ynoic acid ethyl ester
To a stirred solution of (S)-3-(4-hydroxy-phenyl)-hex-4-ynoic acid ethyl ester
(l.lg, 3.8 mmol) and 8-bromo-6-chloromethyl-2-isopropyl-[l, 2, 4] triazolo [1,5-
ajpyridine in acetonitrile (20 mL) is added cesium carbonate (2.48 g, 7.62 mmol). The
reaction mixture is stirred overnight at room temperature. The reaction mixture is
filtered through diatomaceous earth, washed with EtOAc (20 mL) and evaporated to
dryness. The residue is dissolved in EtOAc (30 mL), washed with water (2x30 mL) and
brine solution (20 mL), dried over sodium sulphate, and evaporated under reduced
pressure. The crude material is purified by silica gel column chromatography
(combiflash), eluting with 35-40% EtOAc in hexanes to give the title compound (1.0 g,
53.4%). LCMS m/z ( Br/ Br) 484/486 (M+H)+.
The following compounds are prepared essentially by the method of preparation
61.
Table 12
ES/MS
Prep.
Chemical Name Structure (m/z)
No.
(M+l)
S)-3-{4-[2-Isopropyl-8- o
(4-methoxy-2,6-
dimethyl-phenyl)-
62 [l,2,4]triazolo[l,5- 540
a]pyridin-6-ylmethoxy]-
phenyl }-hex-4-ynoic
acid ethyl ester
N
(S)-3-(4-{8-[2-(Cyano- II 1 0
dimethyl-methyl)-
phenyl]-2-isopropyl-
63 [l,2,4]triazolo[l,5- 549
a]pyridin-6-ylmethoxy }-
phenyl)-hex-4-ynoic acid
ethyl ester
(S)-3-{4-[8-(2-Fluoro-5- 1 0
methoxy-phenyl)-2-
isopropyl-
[l,2,4]triazolo[l,5- 530
a]pyridin-6-ylmethoxy] -
phenyl }-hex-4-ynoic
acid ethyl ester
(S)-Ethyl 3-(4-((8-(2,6-
dimethyl-4-(3- 1 0
(methylsulfonyl)propoxy o
)phenyl)-2-isopropyl-
646
[1,2,4] triazolo[l,5-
a]pyridin-6-
yl)methoxy)phenyl)hex-
4-ynoate
(S)-3-(4-{2-Isopropyl-8-
[4-(2-methoxy-ethoxy)- 1 0
2,6-dimethyl-phenyl]-
[l,2,4]triazolo[l,5- 584
a]pyridin-6-ylmethoxy }-
phenyl)-hex-4-ynoic acid
ethyl ester
Preparation 67
(S)-3-{4-[8-(4-Cyano-phenyl)-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridin-6-ylmethoxy]-
phenyl}-hex-4-ynoic acid ethyl ester
To a stirred solution of (S)-3-[4-(8-bromo-2-isopropyl-[l,2,4]triazolo[l,5-
a]pyridin-6-ylmethoxy)-phenyl]-hex-4-ynoic acid ethyl ester (1.0 g, 2.07 mmol) and 4-
cynophenylboronic acid (0.602 g, 9.6 mmol) in 1,4 dioxane (10 mL) is added a solution
of 2 M potassium carbonate (0.542 g, 6.18 mmol). The mixture is purged under nitrogen
atmosphere for 20 minutes and Pd(PPh )4 (0.117 g, 0.103 mmol) is added. The reaction
mixture is stirred at 100 °C in a microwave for 4 hours. The reaction mixture is diluted
with EtOAc (30 mL), washed with water (2x30 mL) and brine solution (30 mL), dried
over anhydrous sodium sulphate, filtered, and evaporated under reduced pressure. The
residue is purified by silica gel column chromatography (combiflash) eluting with 30-
40% EtOAc in hexanes to give the title compound as a colorless liquid (0.500 g, 47.8%).
LCMS m/z 507 (M-H)+.
The following compounds are prepared essentially by the method of preparation
Table 13
Preparation 72
(S)-3-(4-{8-[4-(Cyano-dimethyl-methyl)-phenyl]-2-isopropyl-[l,2,4]triazolo[l,5-
a]pyridin-6-ylmethoxy}-phenyl)-hex-4-ynoic acid ethyl ester
To a stirred solution of 2-methyl-2-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-
yl)-phenyl]-propionitrile (0.184 g, 0.680 mmol) and (S)-3-[4-(8-bromo-2-isopropyl-
[l,2,4]triazolo[l,5-a] pyridine-6-ylmethoxy)-phenyl]-hex-4-ynoic acid ethyl ester (0.3 g,
0.619 mmol) in 1,4-dioxane (10 mL) is added 2 M potassium carbonate (0.619 mL,
1.238 mmol) at room temperature. The reaction mixture is purged under a nitrogen
atmosphere for 20 minutes and Pd(PPh )2Cl2 (0.021 g, 0.0309 mmol) is added. The
reaction mixture is heated at 100 °C for 16 hours. The reaction mixture is filtered
through diatomaceous earth and washed with EtOAc (2x20 mL). The filtrate is washed
with cold water (2x10 mL), brine solution (10 mL), dried over anhydrous sodium
sulphate, filtered, and evaporated to dryness. The crude material is purified on silica gel
column chromatography (combiflash), eluting with 30-50% EtOAc in hexanes to give
the title compound as a colorless liquid (0.13 g, 38%). LC-MS m/z 547 [M+H]+.
The following compound is prepared essentially by the method of preparation 72.
Table 14
Preparation 74
(S)-3-{4-[8-(2-Cyano-phenyl)-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridin-6-ylmethoxy]-
phenyl}-hex-4-ynoic acid ethyl ester
To a stirred solution (S)-3-[4-[8-(8-bromo-2-isopropyl-[l,2,4]triazolo[l,5-
a]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid ethyl ester (0.200 g, 1.64 mmol) and
2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzonitrile (0.110 g, 1.96 mmol) in 1,4
dioxane (9 mL) is added solid potassium carbonate (0.172 g, 4.92 mmol). The mixture is
purged under a nitrogen atmosphere for 20 minutes and Pd(PPh )4 (0.024 g, 0.800 mmol)
is added. The reaction mixture is heated at 100 °C for overnight, filtered through
diatomaceous earth, washed with EtOAc, and evaporated under reduced pressure to
dryness. The residue is purified by silica gel column chromatography (combiflash)
eluting with 29-32% EtOAc in hexanes to give the title compound. (0.140 g, 66%).
LCMS m/z 507 (M+H)+.
Preparation 75
(S)-3-(4-{8-[3-(Cyano-dimethyl-methyl)-phenyl]-2-isopropyl-[l,2,4]triazolo[l,5-
a]pyridin-6-ylmethoxy}-phenyl)-hex-4-ynoic acid ethyl ester.
To a stirred solution of (S)-3-[4-(8-bromo-2-isopropyl-[l,2,4]triazolo[l,5-
a]pyridin-6-ylmethoxy)-phenyl]-hex-4-ynoic acid ethyl ester (0.4 g, 0.82 mmol) and 2-
methyl-2-[3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-propionitrile (0.23 g,
0.9 mmol) in 1,4-dioxane (40 mL) is added K2CO (0.33 g, 2.4 mmol). The mixture is
purged with nitrogen for 10 minutes. Then Pd(dppf)2Cl2 .DCM (0.066 g, 0.08 mmol) is
added and the mixture is heated at 100 °C for 12 hours. The reaction mixture is cooled to
room temperature and filtered through diatomaceous earth. The filtrate is washed with
EtOAc (2x30 mL), dried over anhydrous sodium sulphate, filtered, and concentrated.
The crude material is purified on silica gel column chromatography (combiflash), eluting
with 15-20% EtOAc in hexanes to give the title compound (0.1 g, 22.22%). LCMS m/z
549.5 (M+H)+.
Preparation 76
8-(4-Hydroxy-2,6-dimethyl-phenyl)-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridine-6-
carboxylic acid methyl ester
To a solution of 2-isopropyl-8-(4-methoxy-2,6-dimethyl-phenyl)-
[l,2,4]triazolo[l,5-a]pyridine-6-carboxylic acid methyl ester (1.25 g, 3.5 mmol) in DCM
(30 mL) is added borontribromide (0.51 mL, 5.3 mmol) at -40°C. The reaction mixture
is stirred at room temperature for 1 hour. The reaction mixture is quenched with aqueous
sodium bicarbonate solution (5 mL) and extracted with EtOAc (2x20 mL). The
combined organic extracts are washed with water (10 mL) and brine solution (10 mL),
dried over anhydrous sodium sulphate, filtered, and evaporated to give the title
compound (0.9 g, 76%). LC-MS m/z 340 [M+H]+.
Preparation 77
8-[4-(ieri-Butyl-dimethyl-silanyloxy)-2,6-dimethyl-phenyl]-2-isopropyl-
[l,2,4]triazolo[l,5-a]pyridine-6-carboxylic acid methyl ester
To a stirred solution of 8-(4-hydroxy-2,6-dimethyl-phenyl)-2-isopropyl-
[l,2,4]triazolo[l,5-a] pyridine-6-carboxylic acid methyl ester (0.9 g, 2.65 mmol) in DMF
(30 mL) is added imidazole (0.540 g, 7.96 mmol) and ieri-butyldimethylchlorosilane (1.2
g, 7.96 mmol) at 0°C. The reaction mixture is stirred at room temperature for 16 hours.
The reaction mixture is diluted with water (30 mL) and extracted with EtOAc (2x50
mL). The combined organic extracts are washed with water (30 mL) and brine solution
(30 mL), dried over anhydrous sodium sulphate, filtered, and evaporated. The crude
material is purified by silica gel column chromatography (combiflash), eluting with 8%
EtOAc in hexanes to give the title compound (1.1 g, 92%). LC-MS m/z 454 [M+H]+.
Preparation 78
((S)-3-(4-{8-[4-(iiri-Butyl-dimethyl-silanyloxy)-2,6-dimethyl-phenyl]-2-
isopropyl[l,2,4]triazolo[l,5-a]pyridin-6-ylmethoxy}-phenyl)-hex-4-ynoic acid ethyl
ester
To a stirred solution of {8-[4-(ieri-butyl-dimethyl-silanyloxy)-2,6-dimethylphenyl]-
2-isopropyl-[l,2,4]triazolo[l,5-a]pyridin-6-yl}-methanol (0.8 g, 1.8 mmol) in
DCM (20 mL) is added (S)-3-(4-hydroxy-phenyl)-hex-4-ynoic acid ethyl ester (0.655 g,
2.8 mmol), DEAD (0.43 mL, 2.8 mmol), and triphenylphosphine (0.566 g, 2.16 mmol).
The reaction mixture is stirred at room temperature for 90 minutes. The reaction mixture
is evaporated and the crude material is purified by silica gel column chromatography
(combiflash), eluting with 18% EtOAc in hexanes to give the title compound ( 1 g, 91%).
LC-MS m/z 640 [M+H]+.
Preparation 79
(S)-3-{4-[8-(4-Hydroxy-2,6-dimethyl-phenyl)-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridin-
6-ylmethoxy]-phenyl }-hex-4-ynoic acid ethyl ester
To a stirred solution of (S)-3-(4-{8-[4-(ieri-butyl-dimethyl-silanyloxy)-2,6-
dimethyl-phenyl]-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridin-6-ylmethoxy}-phenyl)-hex-4-
ynoic acid methyl ester (0.1 g, 1.56 mmol) in THF (20 mL) is added tetra-n-butyl
ammonium fluoride (0.8 g, 3.12mmol) at 0 °C. The reaction mixture is stirred at room
temperature for 1 hour. The mixture is diluted with water (10 mL) and extracted with
EtOAc (2x20 mL). The combined organic extracts are washed with water (10 mL) and
brine (10 mL), dried over anhydrous sodium sulphate, filtered, and evaporated to
dryness. The crude material is purified by silica gel column chromatography
(combiflash), eluting with 40% EtOAc in hexanes to give the title compound as a white
solid (0.4 g, 50%). LC-MS m/z 526 [M+H]+.
Preparation 80
2-Isopropyl-8-[4-(2-methoxy-ethoxy)-2,6-dimethyl-phenyl]-[l,2,4]triazolo[l,5-
a]pyridine-6-carboxylic acid methyl ester
To a stirred solution of 8-(4-hydroxy-2,6-dimethyl-phenyl)-2-isopropyl-
[l,2,4]triazolo[l,5-a] pyridine-6-carboxylic acid methyl ester (0.40 g, 1.185 mmol) and
l-bromo-2-methoxy-ethane (0.82 mL, 9.06 mmol) in acetonitrile (15 mL) is added
cesium carbonate (0.734 g, 2.26 mmol) at room temperature. The reaction mixture is
stirred at room temperature overnight. The mixture is filtered through diatomaceous
earth, washed with EtOAc (20 mL), and concentrated to give a residue. The residue is
dissolved in EtOAc (30 mL), washed with water (2x30 mL), brine solution (30 mL),
dried over sodium sulphate, filtered, and evaporated under reduced pressure. The crude
compound is purified with silica gel column chromatography (combiflash), eluting with
30% EtOAc in hexanes to give the title compound as a white semi solid (0.350 g, 87%).
LCMS m/z 397 (M+H)+.
Preparation 8 1
Ethyl 8-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-2-isopropyl-[l,2,4]triazolo[l,5-a]
pyridine-6-carboxylate
To a stirred solution of ethyl 8-(4-hydroxy-2,6-dimethylphenyl)-2-isopropyl-
[l,2,4]triazolo [l,5-a]pyridine-6-carboxylate (1.1 g, 3.11 mmol) and 3-
(methylsulfonyl)propyl-4-methylbenzenesulfonate (1.09 g, 3.73 mmol) in DMF (15 mL)
is added potassium carbonate (1.29 g, 9.34 mmol) at room temperature. The reaction
mixture is heated at 80 °C for 16 hours. The mixture is then quenched with water and
extracted with EtOAc (2x70 mL). The organic extracts are washed with brine, dried over
sodium sulphate, and evaporated under reduced pressure. The crude compound is
purified by silica gel column chromatography (combiflash) eluting with 45% EtOAc in nhexane
to give the title compound (0.8 g, 54.27%). LCMS m/z 474.41 (M+H)+.
Preparation 82
((S)-3-(4-{8-[4-(3-Hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenyl]-2-isopropyl-[l,2,4]
triazolo[l,5-a]pyridin-6-ylmethoxy}-phenyl)-hex-4-ynoic acid ethyl ester
To a stirred solution of ((S)-3-(4-{8-[4-(3-hydroxy-3-methyl-butoxy)-2,6-
dimethyl-phenyl]-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridin-6-ylmethoxy}-phenyl)-hex-4-
ynoicacidethylester (0.09 g, 0.17 mmol) in acetonitrile (10 mL) is added 4-bromo-2-
methyl-butan-2-ol (0.114 g, 0.68 mmol) and cesium carbonate (0.168 g, 0.51 mmol).
The reaction mixture is stirred at 100 °C for 4 hours. The reaction mixture is dissolved
in water (10 mL) and extracted with EtOAc (2x20 mL). The combined organic extracts
are washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium
sulphate, filtered, and evaporated. The crude material is purified by silica gel column
chromatography eluting with 40% EtOAc in hexanes to give the title compound as
brown solid (0.05 g, 50%). LC-MS m/z 612 [M+H]+.
Preparation 83
(S)-3-(4-{8-[4-(3-Cyano-3,3-dimethyl-propoxy)-2,6-dimethyl-phenyl]-2-isopropyl-
[1,2,4] triazolo[l,5-a]pyridin-6-ylmethoxy}-phenyl)-hex-4-ynoic acid ethyl ester
To a stirred solution of (S)-3-{4-[8-(4-hydroxy-2,6-dimethyl-phenyl)-2-
isopropyH 1,2,4] triazolo[l,5-a]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid ethyl
ester (0.16 g, 0.304 mmol) and 4-chloro-2,2-dimethylbutanenitrile (0.047 g, 0.364 mmol)
in DMF (10 mL) is added cesium carbonate (0.29 g, 0.912 mmol) and stirred for 4 hours
at 90 °C. The reaction mixture is filtered through diatomaceous earth, the filtrate is
diluted with water (30 mL), and extracted with EtOAc (2x30 mL). The combined
organic extracts are washed with brine solution (2x30 mL), dried over anhydrous
Na2S04, and evaporated to dryness. The crude compound is purified by silica gel
column chromatography (combiflash), eluting with 30% EtOAc/hexanes to give the title
compound (0.17 g, 94%). ES/MS m/z 621.4 [M+H]+.
Preparation 84
(S)-3-{4-[8- (4-Cyanomethoxy-2,6-dimethyl-phenyl)-2-isopropyl-[l,2,4]tria
a]pyridin-6-ylmethoxy] -phenyl }-hex-4-ynoic acid ethyl ester
To a stirred solution of (S)-3-(4-{8-[4-hydroxy-2,6-dimethyl-phenyl]-2-isopropyl-
[1,2,4] triazolo[l,5-a]pyridin-6-ylmethoxy}-phenyl)-hex-4-ynoic acid methyl ester (0.09
g, 0.17 mmol) in acetonitrile (10 mL) is added bromoacetonitrile (0.26 g, 0.22 mmol) and
potassium carbonate (0.046 g,0.34 mmol). The reaction mixture is stirred at 100 °C for 4
hours. The reaction mixture is diluted with water (10 mL) and extracted with EtOAc
(2x20 mL). The combined organic extracts are washed with water (10 mL), brine (10
mL), dried over anhydrous sodium sulphate, filtered, and evaporated to dryness. The
crude material is purified by silica gel column chromatography (combiflash), eluting with
35% EtOAc in hexanes to give the title compound as a brown solid (0.08 g, 82.4%). LCMS
m/z 565 [M+H]+.
Example 1
(S)-3-{4-[2-Isopropyl-8-(4-methoxy-2,6-dimethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridin-
6-ylmethoxy] -phenyl }-hex-4-ynoic acid
To a solution of (S)-3-{4-[2-isopropyl-8-(4-methoxy-2,6-dimethyl-phenyl)-[l,2,4]
triazolo[l,5-a] pyridin-6-ylmethoxy] -phenyl }-hex-4-ynoic acid ethyl ester (0.11 g, 0.2
mmol) in EtOH (15 mL) is added 5 N NaOH (0.12 mL, 0.61 mmol). The mixture is
stirred at room temperature for 2 hours. The mixture is evaporated to dryness, the residue
washed with n-pentane, dried and re-dissolved in water (5 mL). The solution is acidified
with saturated citric acid solution to about pH 5. The solid precipitate is filtered, washed
with water, and dried to give the title compound as a white solid (0.068 g, 65%). LCMS
m/z 512 (M+H)+. H NMR (400 MHz, d6-DMSO) 12.17 (bs, 1H), 8.95 (s, 1H), 7.40 (s,
1H), 7.26 (t, J = 8.0 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.73 (s, 2H), 5.20 (s, 2H), 3.92 (s,
1H), 3.76 (s, 3H), 3.08 (t = 8.0 Hz, 2H), 2.65 (s, 2H), 1.89 (s, 6H), 1.75 (s, 3H), 1.27 (d,
= 6.4 Hz, 6H).
The following compounds are prepared essentially by the method of Example 1.
Table 15
ES/MS
Ex.
Chemical Name Structure (m/z)
No.
(M+l)
(S)-3-(4-{8-[4-(3-
Hydroxy-3-methylbutoxy)-
2,6-dimethyl-
2 phenyl]-2-isopropyl- 584
[l,2,4]triazolo[l,5-
a]pyridin-6-
ylmethoxy }-phenyl)-
hex-4-ynoic acid
(S)-3-{4-[8-(2-Fluoro-
5-methoxy-phenyl)-2- 11 o
isopropyl-
3 [l,2,4]triazolo[l,5- 502
a]pyridin-6-
ylmethoxy]-phenyl}-
hex-4-ynoic acid
(S)-3-(4-{2-Isopropyl-
8-[4-(2-methoxy- I I
ethoxy)-2,6-dimethyl-
4 phenyl]- 556
[l,2,4]triazolo[l,5-
a]pyridin-6-
ylmethoxy }-phenyl)-
hex-4-ynoic acid
hex-4-ynoic acid
Alternate preparation, Example 1
To a solution of (5')-3-{4-[2-isopropyl-8-(4-methoxy-2,6-dimethyl-phenyl)-
[l,2,4]triazolo [l,5-a]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid ethyl ester (419 g,
0.776 mol) in EtOH (8.38 L) and THF (1 L) is added a solution of NaOH (62.1 g, 1.55
mol) in water (310 mL) at 10-15°C. The reaction mixture is warmed to 25 °C and stirred
for 2 hours. Additional solution of NaOH (31.05 g, 0.78 mol) in water (155 mL) is added
and the reaction is stirred for another 1.5 hours. The reaction mixture is evaporated to
dryness to give a viscous material which is diluted with water (4.5 L) and washed with
diethyl ether (3x2.5 L). The aqueous layer is cooled to 0 °C and acidified with saturated
citric acid solution to pH 4.2 and stirred for 30 minutes. The resulting white emulsion is
extracted with DCM (3x5 L). The combined organic extracts are washed with water (3x4
L) and brine (4 L), dried over anhydrous sodium sulphate, filtered, and evaporated to
dryness to give a viscous oil. This oil is dissolved in DCM (5 L) and filtered to remove
any particles that could be present. The resulting filtrate is concentrated to a viscous oil.
Diethyl ether (2.5 L) is added followed by n-hexanes (5 L) and the mixture is stirred for 4
hours. From the resulting gummy material, the solvent is removed at 40 °C for 12 hours
to give a light yellow solid as the title compound (341.9 g, 86%). LCMS m/z 512
(M+H)+.
Tris Salt Preparation
The tris salt of (S)-3-{4-[8-(2,6-Dimethyl-phenyl)-2-isopropyl-[l,2,4]triazolo[l,5-
a]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid is prepared by dissolving (S)-3-{4-[8-
(2,6-Dimethyl-phenyl)-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridin-6-ylmethoxy]-phenyl}-
hex-4-ynoic acid (492 mg) in acetonitrile (10 mL) while stirring at 80 °C (plate temp) at
1000 rpm. Tromethamine (tris) (492 mg) is added (dissolved in 1mL of water). The
sample is slurried at 80 °C/1000 rpm for 15 minutes. Heat and stirring are turned off and
the plate is permitted to reach room temperature. The stirring is resumed for a short time
at room temperature. The sample is placed in the 5 °C refrigerator for 30 minutes after
reaching room temperature. The white solid tris salt form is isolated by vacuum filtration
and dried in place on the filter paper under vacuum and air stream for 15 minutes. The
resulting sparkling white solid (due to the plate like morphology) is dried using the 70 °C
vacuum oven. The resulting tris salt of (S)-3-{4-[8-(2,6-Dimethyl-phenyl)-2-isopropyl-
[l,2,4]triazolo[l,5-a]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid is recovered (458
mg, 74% yield).
Example 6
(S)-3-(4-((8-(2,6-Dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-2-isopropyl-
[l,2,4]triazolo[l,5-a] pyridin-6-yl)methoxy)phenyl)hex-4-ynoic acid
To a stirred solution of (S)-ethyl 3-(4-((8-(2,6-dimethyl-4-(3-
(methylsulfonyl)propoxy)phenyl)-2-isopropyl-[l,2,4] triazolo[l,5-a]pyridin-6-
yl)methoxy)phenyl)hex-4-ynoate (0.200 g, 0.309 mmol) in EtOH (15 mL), is added 5 N
sodium hydroxide (0.18 mL, 0.93 mmol). The reaction mixture is stirred at room
temperature for 16 hours. The reaction mixture is concentrated and the residue is washed
with diethyl ether (2x10 mL), dissolved in water (25 mL), and acidified with 1.0 N HC1
(pH 4-5). The compound is extracted with DCM (2x25 mL) and the organic extracts are
dried over anhydrous Na2S04, filtered and concentrated to dryness. The crude material is
further purified by prep HPLC. Prep HPLC conditions: Column: X BRIDGE C18 (19 x
250) mm, 5; Mobile phase (A): 0.1% TFA; Mobile phase (B): acetonitrile; Flow rate:
gradient, 15 ml/min. to give the title compound as a white solid (0.070 g, 36.64%).
LCMS m/z 318.50 (M+H)+.
Example 7
(S)-3-(4-{8-[4-(3-Cyano-3,3-dimethyl-propoxy)-2,6-dimethyl-phenyl]-2-isopropyl-
[l,2,4]triazolo[l,5-a]pyridin-6-ylmethoxy}-phenyl)-hex-4-ynoic acid
To a stirred solution of (S)-3-(4-{8-[4-(3-cyano-3,3-dimethyl-propoxy)-2,6-
dimethyl-phenyl]-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridin-6-ylmethoxy}-phenyl)-hex-4-
ynoic acid ethyl ester (0.16 g, 0.258 mmol) in EtOH (10 mL) is added 5 N lithium
hydroxide (0.15 mL, 0.774 mmol) and the mixture is stirred at 80 °C for 2 hours. The
reaction mixture is concentrated under reduced pressure and the residue is triturated with
ether/n-pentane (1:1). This material is dissolved in water and acidified with citric acid
solution to about pH of 5. The solid precipitate is filtered and freeze dried to give the
title compound as a white solid (0.145 g, 79.7%). LCMS m/z 593.4[M+H]+.
The following compounds are prepared essentially by the method of Example 7.
Table 16
Example 9
(S)-3-(4-{8-[2-(Cyano-dimethyl-methyl)-phenyl]-2-isopropyl-[l,2,4]triazolo[l,5-
a]pyridin-6-ylmethoxy }-phenyl)-hex-4-ynoic acid
To a solution of (S)-3-(4-{8-[2-(cyano-dimethyl-methyl)-phenyl]-2-isopropyl-
[l,2,4]triazolo[l,5-a]pyridin-6-ylmethoxy}-phenyl)-hex-4-ynoic acid ethyl ester (0.06 g,
0.109 mmol) in THF/water (6 mL/2 mL) is added 2 M LiOH (0.109 mL, 0.218 mmol).
The mixture is stirred at room temperature for 12 hours. THF is evaporated under
reduced pressure. The crude material is acidified with saturated citric acid solution
(pH~5). The solid precipitate is then filtered and dried over vacuum to give the title
compound as an off white solid (0.043 g, 75.7%). LC-MS m/z 521 [M+H]+.
The following compounds are prepared essentially by the method of Example 9.
Table 17
Example 12
((S)-3-{4-[8-(3-Cyanomethyl-phenyl)-2-isopropyl-[l,2,4]triazolo[l,5-a]pyridin-6-
lmethoxy]-phenyl }-hex-4-ynoic acid.
To a solution of (S)-3-(4-{8-[3-(cyano-dimethyl-methyl)-phenyl]-2-isopropyl-
[l,2,4]triazolo[l,5-a]pyridin-6-ylmethoxy}-phenyl)-hex-4-ynoic acid ethyl ester (0.07 g,
0.13 mmol) in THF (7 mL) and water (3 mL) is added LiOH.H20 (0.028 g, 0.67 mmol).
The reaction mixture is stirred at room temperature for 48 hours. The reaction mixture is
2 evaporated to dryness, then diluted with water (10 mL), acidified with citric acid (pH ~5)
and extracted with DCM (2x30 mL). The combined organic extracts are dried over
anhydrous sodium sulphate and concentrated. The crude material is purified on silica gel
column chromatography (combiflash), eluting with 15-50% EtOAc/hexanes to give the
title compound (0.025 g, 29.41%). LCMS m/z 493.3 (M+H)+.
10 The following compounds are prepared essentially by the method of Example 12.
Table 18
ES/MS
Ex.
Chemical Name Structure (m/z)
No.
(M+l)
(S)-3-[4-(3-Bromo-2-phenyl-
13 pyrazolo[l,5-b]pyridazin-6- 493
ylmethoxy)-phenyl] -3-
isoxazol-3-yl-propionic acid
(S)-3-(4-{8-[3-(Cyanodimethyl-
methyl)-phenyl]-2-
1 O
14 521a
isopropyl-[l,2,4]triazolo[l,5-
a]pyridin-6-ylmethoxy }-
phenyl)-hex-4-ynoic acid
(S)-3-(4-{8-[3-(Cyanodimethyl-
methyl)-2-methyl- O H
15 phenyl] -2-isopropyl- 535
[l,2,4]triazolo[l,5-a]pyridin-
6-ylmethoxy }-phenyl) -hex-
4-ynoic acid
aPurified by preparative HPLC using column: Kinetex C18 (50 mm x 2.1 mm x 1.7 )
with mobile phase (A) 0.01% TFA in water and (B) acetonitrile with flow rate of 0.3
mL/min.
Example 16
(S) -3-{4-[8- (4-Cyanomethoxy-2,6-dimethyl-phenyl)-2-isopropyl- [1,2,4]triazolo [1,5-
a]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
To a stirred solution of (S)-3-{4-[8- (4-cyanomethoxy-2,6-dimethyl-phenyl)-2-
isopropyl-[l,2,4]tiazolo[l,5-a]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid ethyl ester
(0.07 g, 0.12 mmol) in dichloroethane (10 mL) is added trimethyltin hydroxide (0.224 g,
1.23 mmol) and the mixture is heated at 80 °C for 96 hours. The reaction mixture is
cooled to room temperature and washed with 1.5 N HC1 solution (20 mL) and extracted
with EtOAc (2x20 mL). The combined organic extracts are washed with saturated brine
solution (10 mL), dried over sodium sulphate, filtered and concentrated. The crude
material is purified on silica gel column chromatography (combiflash) eluting with 49%
EtOAc/hexanes to give the title compound as a yellow solid (0.023 g, 34.8%). LCMS
m/z 536 (M+H)+.
The following compound is prepared essentially by the method of Example 16.
Table 19
GPR40: Information
Results of studies using transgenic mice over-expressing the human GPR40 gene
under control of the insulin II promoter recently reported by Nagasumi further support
that GPR40 plays an important role in the regulation of GDIS and plasma glucose levels
in-vivo, especially in rodent models of insulin resistance. Nagasumi K, et. al.,
Overexpression of GPR40 in pancreatic -cells augments glucose- stimulated insulin
secretion and improves glucose tolerance in normal and diabetic mice, Diabetes 58:
1067-1076, 2009. See also, Briscoe CP et al., The orphan Gprotein-coupled receptor
GPR40 is activated by medium and long chain fatty acids, Journal Biological Chemistry
278: 11303 - 11311, 2003. These findings further support that the development of new
GPR40 modulator compounds may be particularly desired for use in the treatment of
T2D.
Assays
Calcium Flux Primary Assays
The compounds exemplified herein are tested essentially as described below and
exhibit an EC5 0 value for the Calcium Flux Primary assay of lower than 500 nM, and
exhibited efficacy of >50%.
These assays are used to screen compounds by measuring the increase in
intracellular calcium levels that results when a ligand binds and activates GPR40, thus
demonstrating the potency and efficacy of GPR40 agonists. HEK293 cells over
expressing the human GPR40 cDNA maintained in Dulbecco' s modified Eagle's medium
with F12 medium in 3:1 ratio supplemented with 10% FBS and 800 g/ml geneticin at 37
°C and 5% C0 2 are employed for the study. Agonist assays are performed using a
Calcium 4 Dye assay kit (Molecular Devices) in the presence or absence of 0.1% fatty
acid free BSA in the assay buffer ( 1 x HBSS (Hank's Balanced Salt Solution) & 20 mM
HEPES (4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid). Receptor activation is
measured as an increase in intracellular calcium using the Fluorometric Imaging Plate
Reader (FLIPR). Maximum change in fluorescence over the base line is used to
determine the agonist response. The EC5 0 value of the compound is calculated using
Excel Fit software (version 4; IDBS) by plotting concentration vs relative fluorescence
units (RFUs). Percent efficacy is calculated based on the maximal response exhibited by
compound compared to the natural ligand, linoleic acid. The test compound of Example
1 has an EC50 of 247 nM (+23.9, n=12) and 78.7% efficacy (+ 12.5, n=12) when
examined in this assay. These results further demonstrate the desired potency and
efficacy of this compound as a GPR40 agonist. (Mean + SEM; SEM = standard error of
the mean.)
Selectivity Assays
Peroxisome Proliferator-Activated Receptor (PPAR) , , and Functional Assays
Because GPR40 is known to be activated by ligands to PPARy, exemplified
compounds are examined in Gal4 PPARa, Gal4 PPAR5, and PPARy reporter assays to
determine the selectivity of exemplified compounds. CV1 cells, which are derived from
the renal tissue of an African green monkey, are transfected with various receptor and
reporter plasmids using Fugene. For the Gal4 PPARa and PPAR5 assays, a reporter
plasmid containing five tandem copies of the yeast transcription protein Gal4 response
element, cloned upstream of a firefly luciferase gene driven by the major late promoter of
adenovirus, is transfected together with a Simian Virus 40 (SV40) driven plasmid
constitutively expressing a hybrid protein containing the Gal4 DNA binding domain
(DBD), and either the PPARa or PPAR5 ligand binding domain. For the PPARy assay,
plasmids encoding PPARy and RXRa, both driven by a cytomegalovirus (CMV)
promoter are transfected together with a plasmid containing luciferase reporter cDNA
driven by the TK promoter and a receptor response element (2 x PPRE). Cells are
transfected in T225 cm2 cell culture flasks in DMEM media with 5% charcoal-stripped
FBS and the specific plasmids for the individual assay. After an overnight incubation,
transfected cells are trypsinized, plated in opaque 96 well dishes (15,000 cells/well) in
DMEM media containing 5% charcoal-stripped FBS, incubated for 4 hours, and exposed
to 0.17 to 10 of test compounds or reference compound in half log dilutions.
After 24 hours incubation with compounds, cells are lysed and luciferase activity is
determined as a measure of receptor activation by luminescence. Data are fitted to a four
parameter-fit logistics model to determine EC5 0 values. The maximum percent
stimulation is determined versus maximum stimulation obtained with 10 of an
appropriated PPAR agonist reference compound, 2-methyl-2-(4-{2-methyl -3-[2-
(phenylcarbonyl)-4-(trifluoromethoxy)phenoxy]propoxy}phenoxy)propanoic acid.
Efficacy of < 20% is considered negative. EC5 0S for the compound of Example 1 in
PPAR functional assays are as follows: PPARa > 10 ; PPAR5 = 4 ; PPARy =
2.26 . These data indicate that the exemplified compound of Example 1 has weak
PPAR activity. Thus, these assays support that the exemplified compounds have weak or
negative PPAR efficacy in the assay described, as desired.
In vitro Binding Affinity to GPR40
Radioligand competition binding assays using rapid-wash filtration with a custom
prepared radiolabel (5 nM [ H]- TAK-875)and membranes prepared from HEK293 cells
overexpressing the human GPR40 (hGPR40) construct are run to determine equilibrium
dissociation constants (¾) for test compounds. Competition curves are plotted as the
percent specific inhibition versus concentration of compound and analyzed using a four
parameter nonlinear regression fit with variable slope. K values are calculated using the
Cheng-Prusoff equation K = IC5o/(l+(D/K d)), where IC50 is the concentration of
compound resulting in 50% inhibition of binding, D is the concentration of radioligand
used in the assay and Kd is the equilibrium dissociation constant for the receptor and the
radioligand, determined from saturation binding analysis experiments (K< for [ H] TAK-
875 = 6.2). For Example 1, K = 15.8 nM ± 3.86, n=5/6. See Cheng, Y. and Prusoff,
W.H. (1973) "Relationship between the inhibition constant (K ) and the concentration of
inhibitor which causes 50 per cent inhibition (IC50) of an enzymatic reaction", Biochem
Pharmacol 22(23):3099-108. (Mean + SEM; SEM = standard error of the mean.) These
data demonstrate that the Example 1 compound is a high affinity ligand for human
GPR40.
Competition Binding Kinetics - Determination of Receptor Residence Time
The association and dissociation rates of unlabeled compounds are quantified
using the method described by Motulsky, H. J . and L. C. Mahan (1984), "The kinetics of
competitive radioligand binding predicted by the law of mass action" Mol Pharm 25(1):
1-9 . Human GPR40 membranes are incubated at various time points with 6-8 nM [ H]
TAK875 in the absence or presence of l x ¾ , 3x ¾ , or lOx K unlabeled compound.
Separation of bound and free radioligand is performed using rapid-wash filtration onto
glass fiber filters and counted in a liquid scintillation counter. Rates are calculated by
fitting the data to the kinetics of competitive binding model in GraphPad Prism 6, version
6.03 for Windows, GraphPad Software, La Jolla California USA, www.graphpad.com .
The compound of Example 1 showed a GPR40 Residence time, , to be 169 min (+ 52.1,
n=4), which suggests that this GPR40 ligand has sufficient residence time on the receptor
to produce an in-vivo response (Mean + SEM; SEM = standard error of the mean.)
Human and mouse beta-arrestin agonist assay with 1%FBS to determine betaarrestin
recruitment:
Human embryonic kidney (hEK293)-hFFARl cells are purchased from
DiscoveRx. Human osteosarcoma (U20S) cells expressing mFFARl are developed by
DiscoveRX. These cells co-express the Prolink (PK)-tagged GPR40 and the Enzyme
Acceptor (EA)-tagged beta-arrestin fusion proteins. If activation of the GPR40 stimulates
beta-arrestin recruitment, it would force complementation of the beta galactosidase (Bgal)
enzyme fragments, forming a B-gal enzyme that generates a chemiluminescent signal
using the DiscoveRx PathHunter detection kit. Cells are incubated overnight at 5,000
cells/well in 384 well plates in culture media containing 1% FBS (fetal bovine serum).
Serial diluted compounds in DMSO (2x dilutions to generate 20 concentrations) are step
down diluted in culture media containing 1% FBS (fetal bovine serum) and added to cells
with a final top concentration starting of 100 . After addition of compounds, cells are
incubated for 90 min at 37 °C in 5% C0 2 incubator, and DiscoveRX kit detection
reagents are added. Measurement of the chemiluminescent signal is ascertained with the
Envision reader, after a 1-hour incubation at room temperature. Data are fit to a 4
parameter-fit logistics to determine EC5 0 values, % activity is measured versus maximum
response to an internal standard GPR40 agonist standard, TAK875, at 1 . Example 1,
has an hGPR40 b-arrestin EC50 of 30.6 nM (+ 12.3, n=2) with a % stimulation max (FA)
of 170 (± 5.95, n=2) and mGPR40 b-arrestin of 4.87 nM (± 1.48, n=3) with a %
stimulation max (FA) of 149 (+ 11.8, n=3). (Mean + SEM; SEM = standard error of the
mean.) These data indicate that Example 1 is a GPR40 agonist which can signal through
beta arrestin.
The exemplified compounds of the present invention can be readily formulated
into pharmaceutical compositions in accordance with accepted practices known in the art
such as found in Remington's "Pharmaceutical Sciences", Gennaro, Ed., Mack Publishing
Co. Easton Pa. 1990 such as tablets, solid or gel filled capsules, powders, suspensions, or
solutions. The composition can also include one or more pharmaceutically acceptable
carriers, excipients, and diluents.
Preferred pharmaceutical compositions include those formulated as a tablet or
capsule for oral administration. The tablet or capsule can include a compound of the
present invention in an amount effective to treat diabetes particularly type two diabetes.
The artisan will appreciate that a compound of Formula I may be administered with one
or more additional therapeutic agents. It may be preferred that pharmaceutical
compositions are formulated to include a compound of Formula I and one or more
additional therapeutic agents.
The pharmaceutical composition is administered to a patient in amounts effective
to treat diabetes, more particularly, type two diabetes. An appropriate amount or dose
effective to treat a patient can be determined by a health care provider.
What is claimed is:
1. A compound which is:
wherein
R is selected from the group consisting of H, CH , CN, CH2CN, C(CH )2CN, and F;
R2 is selected from the group consisting of H, 0(Ci-C alkyl)R5, CH2CN, and CN;
R3 is selected from the group consisting of H, OCH , CN, C(CH )2CN, and CH2CN;
R4 is selected from the group consisting of H and CH3; and
R5 is selected from the group consisting of H, CN, C(CH )2CN, OCH , S(0) 2CH , and
C(CH3)2OH; provided that at least one selected from the group consisting of Rl, R2, R3
and R4 is H;
or a pharmaceutically acceptable salt thereof.
2. A compound or pharmaceutically acceptable salt thereof as claimed by
Claim 1 wherein R3 is H.
3. A compound or pharmaceutically acceptable salt thereof as claimed by any
one of Claims 1 to 2 wherein R is selected from the group consisting of H and CH3.
4. A compound or pharmaceutically acceptable salt thereof as claimed by any
one of Claims 1 to 3 wherein R2 is selected from the group consisting of H and 0(Cr
C alkyl)R5.
5. A compound or pharmaceutically acceptable salt thereof as claimed by any
one of Claims 1 to 4 wherein R2 is selected from the group consisting of H and OCH3.
6. A compound or pharmaceutically acceptable salt thereof as claimed by any
one of Claims 1 to 5 wherein R4 is CH3.
7. A compound or pharmaceutically acceptable salt thereof as claimed by any
one of Claims 1 to 6 wherein R is CH .
8. A compound as claimed by Claim 1 that is (S)-3-{4-[2-Isopropyl-8-(4-
methoxy-2,6-dimethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridin-6-ylmethoxy]-phenyl}-hex-
4-ynoic acid, or a pharmaceutically acceptable salt thereof.
9. A compound as claimed by Claim 1 that is (S)-3-{4-[8-(2,6-Dimethylphenyl)-
2-isopropyl-[l,2,4]triazolo[l,5-a]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid
or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound according to any
one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, and at least one of a
pharmaceutically acceptable carrier, diluent, or excipient.
11. A method of treating diabetes in a mammal in need thereof, comprising
administering an effective amount of a compound, or a pharmaceutically acceptable salt
thereof, as claimed by any one of Claims 1 to 9.
12. A method of treating type two diabetes in a mammal in need thereof,
comprising administering an effective amount of a compound, or a pharmaceutically
acceptable salt thereof as claimed by any one of Claims 1 to 9.
13. A compound, or a pharmaceutically acceptable salt thereof, as claimed by
any one of Claims 1 to 9 for use in therapy.
14. A compound, or a pharmaceutically acceptable salt thereof, as claimed by
any one of Claims 1 to 9 for use in the treatment of type two diabetes.
15. A compound according to formula II
wherein R is selected from the group consisting of H, CH , CN, CH2CN, C(CH )2CN,
and F;
R2 is selected from the group consisting of H, 0(Ci-C alkyl)R5, CH2CN, and CN;
R3 is selected from the group consisting of H, OCH , CN, C(CH )2CN, and CH2CN;
R4 is selected from the group consisting of H and CH3;
R5 is selected from the group consisting of H, CN, C(CH )2CN, OCH , S(0) 2CH , and
C(CH )2OH; provided that at least one selected from the group consisting of Rl, R2, R3
and R4 is H; and
R is selected from the group consisting of C 4 alkyl, C 4 haloalkyl, C3-6 cycloalkyl, Cr
4 alkyl-C3-6 cycloalkyl, phenyl, and C1-5 alkylphenyl, or a pharmaceutically acceptable
salt thereof.
16. A compound of Claim 15 wherein R and R4 are each CH3.
17. A compound of Claim 15 wherein R and R4 are each H.
18. A compound as claimed by any one of Claims 15 to 17 wherein R2 is
selected from the group consisting of H and OCH3.
19. A method for preparing a compound of Formula I, below,
or a pharmaceutically acceptable salt thereof, said method comprising de-esterifying a
compound of formula II;
wherein
R is selected from the group consisting of H, CH , CN, CH2CN, C(CH )2CN, and F;
R2 is selected from the group consisting of H, 0(Ci-C alkyl)R5, CH2CN, and CN;
R3 is selected from the group consisting of H, OCH , CN, C(CH )2CN, and CH2CN;
R4 is selected from the group consisting of H and CH ;
R5 is selected from the group consisting of H, CN, C(CH )2CN, OCH , S(0) 2CH , and
C(CH3)2OH; provided that at least one selected from the group consisting of Rl, R2, R3
and R4 is H; and
R is selected from the group consisting of C 4 alkyl, C 4 haloalkyl, C3-6 cycloalkyl, Cr
4 alkyl-C3-6 cycloalkyl, phenyl, and C1-5 alkylphenyl to provide a compound of Formula
I, or a pharmaceutically acceptable salt thereof.