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DIACYLGLYCEROL ACYLTRANSFERASE INHIBITORS
The invention relates to inhibitors of diacylglycerol acyltransferase. The
inhibitors are
useful for the treatment of diseases such as obesity, type II diabetes
mellitus,
dyslipidemia and metabolic syndrome.
Triglycerides or triacylglycerols are the major form of energy storage in
eukaryotic
organisms. In mammals, these compounds are primarily synthesized in three
tissues: the
small intestine, liver, and adipocytes. Triglycerides or triacylglycerols
support the major
functions of dietary fat absorption, packaging of newly synthesized fatty
acids and
storage in fat tissue (see Subauste and Burant, Current Drug Targets ¨ Immune,
Endocrine & Metabolic Disorders (2003) 3, 263-270).
Diacylglycerol 0-acyltransferase, also known as diglyceride acyltransferase or
DGAT, is
a key enzyme in triglyceride synthesis. DGAT catalyzes the final and rate-
limiting step in
triacylglycerol synthesis from 1,2-diacylglycerol (DAG) and long chain fatty
acyl CoA
as substrates. Thus, DGAT plays an essential role in the metabolism of
cellular
diacylglycerol and is critically important for triglyceride production and
energy storage
homeostasis (see Mayorek et al, European Journal of Biochemistry (1989) 182,
395-400).
DGAT has a specificity for sn-1,2 diacylglycerols and will accept a wide
variety of fatty
acyl chain lengths (see Farese et al, Current Opinions in Lipidology (2000)
11, 229-234).
DGAT activity levels increase in fat cells as they differentiate in vitro and
recent
evidence suggests that DGAT may be regulated in adipose tissue post-
transcriptionally
(see Coleman et al, Journal of Molecular Biology (1978) 253, 7256-7261 and Yu
et al,
Journal of Molecular Biology (2002) 277, 50876-50884). DGAT activity is
primarily
expressed in the endoplasmic reticulum (see Colman, Methods in Enzymology
(1992)
209, 98-104). In hepatocytes, DGAT activity has been shown to be expressed on
both the
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cytosolic and luminal surfaces of the endoplasmic reticular membrane (see Owen
et al,
Biochemical Journal (1997) 323 (pt 1), 17-21 and Waterman et al, Journal of
Lipid
Research (2002) 43, 1555-156). In the liver, the regulation of triglyceride
synthesis and
partitioning, between retention as cytosolic droplets and secretion, is of
primary
importance in determining the rate of VLDL production (see Shelness and
Sellers,
Current Opinions in Lipidology (2001) 12, 151-157 and Owen et al, Biochemical
Journal
(1997) 323 (pt 1), 17-21).
Two forms of DGAT have been cloned and are designated DGAT1 and DGAT2 (see
Cases et al, Proceedings of the National Academy of Science, USA (1998) 95,
13018-
13023, Lardizabal et al, Journal of Biological Chemistry (2001) 276, 38862-
38869 and
Cases et al, Journal of Biological Chemistry (2001) 276, 38870-38876).
Although both
enzymes utilize the same substrates, there is no homology between DGAT1 and
DGAT2.
Both enzymes are widely expressed however some differences do exist in the
relative
abundance of expression in various tissues.
The gene encoding mouse DGAT1 has been used to create DGAT knock-out. These
mice, although unable to express a functional DGAT enzyme (Dgat-/- mice), are
viable
and continue to synthesize triglycerides (see Smith et al, Nature Genetics
(2000) 25, 87-
90). This would suggest that multiple catalytic mechanisms contribute to
triglyceride
synthesis, such as DGAT2. An alternative pathway has also been shown to form
triglycerides from two diacylglycerols by the action of diacylglycerol
transacylase (see
Lehner and Kuksis, Progress in Lipid Research (1996) 35, 169-210).
Dgat-/- mice are resistant to diet-induced obesity and remain lean. When fed a
high fat
diet, Dgat-/- mice maintain weights comparable to mice fed a diet with regular
fat
content. Dgat-/- mice have lower tissue triglyceride levels. The resistance to
weight gain
seen in the knockout mice, which have a slightly higher food intake, is due to
an
increased energy expenditure and increased sensitivity to insulin and leptin
(see Smith et
al, Nature Genetics (2000) 25, 87-90, Chen and Farese, Trends in
Cardiovascular
Medicine (2000) 10, 188-192, Chen and Farese, Current Opinions in Clinical
Nutrition
and Metabolic Care (2002) 5, 359-363 and Chen et al, Journal of Clinical
Investigation
(2002) 109, 1049-1055). Dgat-/- mice have reduced rates of triglyceride
absorption,
improved triglyceride metabolism, and improved glucose metabolism, with lower
glucose and insulin levels following a glucose load, in comparison to wild-
type mice (see
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Buhman et al, Journal of Biological Chemistry (2002) 277, 25474-25479 and Chen
and
Farese, Trends in Cardiovascular Medicine (2000) 10, 188-192).
Disorders or imbalances in triglyceride metabolism, both absorption as well as
de novo
synthesis, have been implicated in the pathogenesis of a variety of disease
risks. These
include obesity, insulin resistance syndrome, type II diabetes, dyslipidemia,
metabolic
syndrome (syndrome X) and coronary heart disease (see Kahn, Nature Genetics
(2000)
25, 6-7, Yanovski and Yanovski, New England Journal of Medicine (2002) 346,
591-
602, Lewis et al, Endocrine Reviews (2002) 23, 201, Brazil, Nature Reviews
Drug
Discovery (2002) 1, 408, Malloy and Kane, Advances in Internal Medicine (2001)
47,
111, Subauste and Burant, Current Drug Targets - Immune, Endocrine & Metabolic
Disorders (2003) 3, 263-270 and Yu and Ginsberg, Annals of Medicine (2004) 36,
252-
261). Compounds that can decrease the synthesis of triglycerides from
diacylglycerol by
inhibiting or lowering the activity of the DGAT enzyme would be of value as
therapeutic
agents for the treatment diseases associated with abnormal metabolism of
triglycerides.
Known inhibitors of DGAT include: dibenzoxazepinones (see Ramharack, et al,
EP1219716 and Burrows et al, 26th National Medicinal Chemistry Symposium
(1998)
poster C-22), substituted amino-pyrimidino-oxazines (see Fox et al,
W02004047755),
chalcones such as xanthohumol (see Tabata et al, Phytochemistry (1997) 46, 683-
687 and
Casaschi et al, Journal of Nutrition (2004) 134, 1340-1346), substituted
benzyl-
phosphonates (see Kurogi et al, Journal of Medicinal Chemistry (1996) 39, 1433-
1437,
Goto, et al, Chemistry and Pharmaceutical Bulletin (1996) 44, 547-551, Ikeda,
et al,
Thirteenth International Symposium on Athersclerosis (2003), abstract 2P-0401,
and
Miyata, et al, JP 2004067635), aryl alkyl acid derivatives (see Smith et al,
W02004100881 and U520040224997), furan and thiophene derivatives (see
W02004022551), pyrrolo[1,2b]pyridazine derivatives (see Fox et al,
W02005103907),
and substituted sulfonamides (see Budd Haeberlein and Buckett, W020050442500).
Also known to be inhibitors of DGAT are: 2-bromo-palmitic acid (see Colman et
al,
Biochimica et Biophysica Acta (1992) 1125, 203-9), 2-bromo-octanoic acid (see
Mayorek and Bar-Tana, Journal of Biological Chemistry (1985) 260, 6528-6532),
roselipins (see Noriko et al, (Journal of Antibiotics (1999) 52, 815-826),
amidepsin (see
Tomoda et al, Journal of Antibiotics (1995) 48, 942-7), isochromophilone,
prenylflavonoids (see Chung et al, Planta Medica (2004) 70, 258-260),
polyacetylenes
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(see Lee et al, Planta Medica (2004) 70, 197-200), cochlioquinones (see Lee et
al,
Journal of Antibiotics (2003) 56, 967-969), tanshinones (see Ko et al,
Archives of
Pharmaceutical Research (2002) 25, 446-448), gemfibrozil (see Zhu et al,
Atherosclerosis (2002) 164, 221-228), and substituted quinolones (see Ko, et
al, Planta
Medica (2002) 68, 1131-1133). Also known to be modulators of DGAT activity are
antisense oligonucleotides (see Monia and Graham, US20040185559).
A need exits in the art, however, for additional DGAT inhibitors that have
efficacy for
the treatment of metabolic disorders such as, for example, obesity, type II
diabetes
mellitus and metabolic syndrome. Further, a need exists in the art for DGAT
inhibitors
having IC50 values less than about 1 [tM.
The present invention relates to DGAT inhibitors. In particular, the invention
provides
compounds of the formula (I):
/R3 ----- R4 R6
R1¨R2 0
R5 C¨ N ¨X ¨ R7 ¨ Y¨ R8¨C ¨R9
11 H II
0 0
(I),
wherein:
R1 is tert-butyl;
phenyl optionally substituted with one to four substituents independently
selected from halogen, lower alkyl, alkoxy and -0-CF3; or
5- or 6-membered heteroaryl optionally substituted with one to four
substituents independently selected from halogen, lower alkyl, alkoxy and
-0-CF3;
R2 is C or N;
R3 iS C, N, 0 or S;
R4 is C or N;
R5 is C, N, 0 or S;
R6 is halogen, lower alkyl, haloloweralkyl or alkoxy;
R7 is N optionally substituted with lower alkyl;
0; or
absent;
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R8 is C optionally substituted with lower alkyl;
N optionally substituted with lower alkyl;
0; or
absent;
R9 is lower alkyl;
alkoxy;
hydroxyl;
amine;
lower alkyl amine;
haloloweralkyl;
lower alkoxy;
lower alkenyloxy;
cycloloweralkyl optionally substituted with one to four substituents
independently selected from lower alkyl, hydroxy, halogen, -C(0)0H,
-C(0)0-lower alkyl and -C(0)0-lower alkyl-phenyl;
5- or 6-membered heterocycloalkyl optionally substituted with one to four
substituents independently selected from lower alkyl, hydroxy, halogen,
-S02-loweralkyl, -C(0)0H, -C(0)0-lower alkyl and -C(0)0-lower alkyl-
phenyl;
5- or 6-membered aryl optionally substituted with one to four substituents
independently selected from lower alkyl, hydroxy, halogen, -C(0)0H,
-C(0)0-lower alkyl and -C(0)0-lower alkyl-phenyl;
5- or 6-membered heteroaryl optionally substituted with one to four
substituents independently selected from lower alkyl, hydroxy, halogen,
-C(0)0H, -C(0)0-lower alkyl and -C(0)0-lower alkyl-phenyl;
-(CH2)õC(0)0H;
-CH2C(lower alky1)2C(0)0H;
-CH2(cycloalkyl)C(0)0H;
-(cycloalkyl)C(0)0H;
-CH2C(CH3)3;
-(CH2)õ-cycloalkyl;
cycloalkenyl;
bicycloalkenyl-C(0)0H;
-(CH2)õ-0-alkyl;
-0-C(=C)-lower alkyl;
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-0-(CH2)õ-phenyl;
-NS02-loweralkyl;
-NS02-cycloalkyl;
-NS02-aryl;
-N-lower alkyl;
-N-cycloalkyl optionally substituted with -C(0)0H;
-N-heterocycloalkyl;
-N-aryl;
-N-(CH2)-aryl;
-N-heteroaryl optionally substituted with alkyl;
-N-CH(lower alkyl)C(0)0H;
-N-(cycloalkyl)C(0)0H;
-N-CH(lower alkyl)C(0)0-lower alkyl; or
phenyl-C(0)0H;
X is 5- or 6-membered aryl optionally substituted with one to four
substituents
independently selected from lower alkyl, halogen and cyano; or
5- or 6-membered heteroaryl optionally substituted with one to four
substituents independently selected from lower alkyl, halogen and cyano;
Y is phenyl optionally substituted with one to four substituents independently
selected from lower alkyl, halogen and cyano;
heteroaryl;
cycloloweralkyl optionally substituted with one to four substituents
independently selected from lower alkyl, halogen and cyano; or
5- or 6-membered heterocycloalkyl optionally substituted with one to four
substituents independently selected from lower alkyl, halogen and cyano; or
-N(CH2)õ)N-; and
n is 1, 2 or 3;
or pharmaceutically acceptable salts thereof.
In another embodiment of the present invention, provided is a pharmaceutical
composition, comprising a therapeutically effective amount of a compound
according to
formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable
carrier.
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In a further embodiment of the present invention, provided is a method of
treating
obesity, type II diabetes or metabolic syndrome, comprising the step of
administering a
therapeutically effective amount of a compound according to formula Ito a
patient in
need thereof.
As used herein, the term "alkyl" means, for example, a branched or unbranched,
cyclic
(i.e., "cycloalkyl") or acyclic, saturated or unsaturated (e.g. alkenyl or
alkynyl)
hydrocarbyl radical which may be substituted or unsubstituted. Where cyclic,
the alkyl
group is preferably C3 to C125 more preferably C4 to Ci05 more preferably C4
to C7. Where
acyclic, the alkyl group is preferably C1 to C10, more preferably Ci to C65
more preferably
methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl or
tertiary-butyl) or
pentyl (including n-pentyl and isopentyl), more preferably methyl. It will be
appreciated
therefore that the term "alkyl" as used herein includes alkyl (branched or
unbranched),
substituted alkyl (branched or unbranched), alkenyl (branched or unbranched),
substituted alkenyl (branched or unbranched), alkynyl (branched or
unbranched),
substituted alkynyl (branched or unbranched), cycloalkyl, substituted
cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, cycloalkynyl and substituted
cycloalkynyl.
In a preferred embodiment, the "cycloalkyl" moieties can optionally be
substituted with
one, two, three or four substituents, wherein each substituent is
independently, for
example, hydroxy, alkyl, alkoxy, halogen or amino, unless otherwise
specifically
indicated. Examples of cycloalkyl moieties include, but are not limited to,
optionally
substituted cyclopropyl, optionally substituted cyclobutyl, optionally
substituted
cyclopentyl, optionally substituted cyclopentenyl, optionally substituted
cyclohexyl,
optionally substituted cyclohexylene, optionally substituted cycloheptyl,
optionally
substituted adamantyl and the like or those which are specifically exemplified
herein.
The term "heterocycloalkyl" denotes a cyclic alkyl ring, wherein one, two or
three of the
carbon ring atoms is replaced by a heteroatom such as N, 0 or S. Examples of
heterocycloalkyl groups include, but are not limited to, morpholyl,
thiomorpholyl,
piperazyl, piperidyl, tetrahydrofuryl, pyrrolidyl, oxazolyl, 1H-pyrazolyl, 1H-
tetrazoly1
and the like. The heterocycloalkyl groups may be unsubstituted or substituted.
As used herein, the term "lower alkyl" means, for example, a branched or
unbranched,
cyclic (e.g., "cycloloweralkyl") or acyclic, saturated or unsaturated
hydrocarbyl radical
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wherein said cyclic lower alkyl group is C3, C4, C5, C6 or C7, and wherein
said acyclic
lower alkyl group is C1, C2, C3 or C4, and is preferably selected from methyl,
ethyl,
propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).
It will be
appreciated therefore that the term "lower alkyl" as used herein includes, for
example,
lower alkyl (branched or unbranched) and cycloloweralkyl.
As used herein, the term "aryl" means a carbocyclic aromatic group. Examples
of aryl
groups are phenyl, naphthyl and the like. A particularly preferred exemples of
aryl is
phenyl.
The term "heteroaryl", alone or in combination with other groups, means a
monocyclic or
bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring
containing one,
two, or three ring heteroatoms selected from N, 0, and S, the remaining ring
atoms being
C. One or two ring carbon atoms of the heteroaryl group may be replaced with a
carbonyl
group. The heteroaryl group described above may be substituted independently
with one,
two, or three substituents, preferably one or two substituents such as, for
example,
halogen, hydroxy, C1_6 alkyl, halo C1_6 alkyl, C1_6 alkoxy, C1_6 alkyl
sulfonyl, C1_6 alkyl
sulfinyl, C1_6 alkylthio, amino, amino C1_6 alkyl, mono- or di-substituted
amino-C1_6
alkyl, nitro, cyano, oxo, acyl, carbamoyl, mono- or di-substituted amino,
aminocarbonyl,
mono- or di-substituted amino-carbonyl, aminocarbonyl C1_6 alkoxy, mono- or di-
substituted amino-carbonyl-C1_6 alkoxy, hydroxy- C1_6 alkyl, carboxyl, C1_6
alkoxy
carbonyl, aryl C1_6 alkoxy, heteroaryl C1_6 alkoxy, heterocyclyl C1_6 alkoxy,
C1-6
alkoxycarbonyl C1_6 alkoxy, carbamoyl C1_6 alkoxy and carboxyl C1_6 alkoxy,
preferably
halogen, hydroxy, C1_6 alkyl, halo C1_6 alkyl, C1_6 alkoxy, C1_6 alkyl
sulfonyl, C1_6 alkyl
sulfinyl, C1_6 alkylthio, amino, mono-C1_6 alkyl substituted amino, di-C1_6
alkyl
substituted amino, amino C1_6 alkyl, mono-C1_6 alkyl substituted amino-C1_6
alkyl, di-C1-6
alkyl substituted amino-C1_6 alkyl, nitro, carbamoyl, mono- or di-substituted
amino-
carbonyl, hydroxy- C1_6 alkyl, carboxyl, C1_6 alkoxy carbonyl and cyano.
Examples of
heteroaryl are pyridyl, pyrimidyl, thiophenyl and tetrazolyl.
Preferred examples of 5- or 6-membered heteroaryl are pyridyl, pyrimidyl,
thiophenyl,
oxadiazolyl, pyrazolyl, oxazolyl, triazolyl, tetrazolyl and 1H-tetrazolyl.
Preferred examples of 5- or 6-membered heterocycloalkyl are tetrahydrofuryl,
pyrrolidyl,
piperidyl and piperazyl.
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The alkyl and aryl groups may be substituted or unsubstituted. Where
substituted, there
will generally be, for example, 1 to 3 substituents present, preferably 1
substituent.
Substituents may include, for example: carbon-containing groups such as alkyl,
aryl,
arylalkyl (e.g. substituted and unsubstituted phenyl, substituted and
unsubstituted
benzyl); halogen atoms and halogen-containing groups such as haloalkyl (e.g.
trifluoromethyl); oxygen-containing groups such as alcohols (e.g. hydroxyl,
hydroxyalkyl, aryl(hydroxyl)alkyl), ethers (e.g. alkoxy, aryloxy, alkoxyalkyl,
aryloxyalkyl), aldehydes (e.g. carboxaldehyde), ketones (e.g. alkylcarbonyl,
alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arycarbonylalkyl), acids
(e.g.
carboxy, carboxyalkyl), acid derivatives such as esters (e.g. alkoxycarbonyl,
alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl), amides (e.g.
aminocarbonyl, mono- or di-alkylaminocarbonyl, aminocarbonylalkyl, mono-or di-
alkylaminocarbonylalkyl, arylaminocarbonyl), carbamates (e.g.
alkoxycarbonylamino,
arloxycarbonylamino, aminocarbonyloxy, mono-or di-alkylaminocarbonyloxy,
arylminocarbonloxy) and ureas (e.g. mono- or di- alkylaminocarbonylamino or
arylaminocarbonylamino); nitrogen-containing groups such as amines (e.g.
amino,
mono- or di-alkylamino, aminoalkyl, mono- or di-alkylaminoalkyl), azides,
nitriles (e.g.
cyano, cyanoalkyl), nitro; sulfur-containing groups such as thiols,
thioethers, sulfoxides
and sulfones (e.g. alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl,
alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arysulfinyl, arysulfonyl,
arythioalkyl,
arylsulfinylalkyl, arylsulfonylalkyl); and heterocyclic groups containing one
or more,
preferably one, heteroatom, (e.g. thienyl, furanyl, pyrrolyl, imidazolyl,
pyrazolyl,
thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl,
azetidinyl,
pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,
tetrahydrofuranyl,
pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl,
hexahydroazepinyl,
piperazinyl, morpholinyl, thianaphthyl, benzofuranyl, isobenzofuranyl,
indolyl,
oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl,
coumarinyl,
isocoumarinyl, quinolinyl, isoquinolinyl, naphthridinyl, cinnolinyl,
quinazolinyl,
pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl,
phthalazinyl, carbolinyl, pyrimidyl and tetrazolyl).
The lower alkyl groups may be substituted or unsubstituted, preferably
unsubstituted.
Where substituted, there will generally be, for example, 1 to 3 substitutents
present,
preferably 1 substituent.
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As used herein, the term "alkoxy" means, for example, alkyl-0- and "alkoyl"
means, for
example, alkyl-CO-. Alkoxy substituent groups or alkoxy-containing substituent
groups
may be substituted by, for example, one or more alkyl groups.
As used herein, the term "halogen" means a fluorine, chlorine, bromine or
iodine radical,
preferably a fluorine, chlorine or bromine radical, and more preferably a
fluorine or
chlorine radical.
As used herein, the term "pharmaceutically acceptable salt" means any
pharmaceutically
acceptable salt of the compound of formula (I). Salts may be prepared from
pharmaceutically acceptable non-toxic acids and bases including inorganic and
organic
acids and bases. Such acids include, for example, acetic, benzenesulfonic,
benzoic,
camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric,
gluconic,
glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic,
malic,
mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic,
phosphoric,
succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like.
Particularly preferred
are fumaric, hydrochloric, hydrobromic, phosphoric, succinic, sulfuric and
methanesulfonic acids, and most preferred is hydrochloric acid. Acceptable
base salts
include alkali metal (e.g. sodium, potassium), alkaline earth metal (e.g.
calcium,
magnesium) and aluminium salts.
The compounds of formula I can also be solvated, e.g. hydrated. The solvation
can be
effected in the course of the manufacturing process or can take place e.g. as
a
consequence of hygroscopic properties of an initially anhydrous compound of
formula I
(hydration). The term "pharmaceutically acceptable salts" also includes
physiologically
acceptable solvates.
The compounds of formula I can contain several asymmetric centers and can be
present
in the form of optically pure enantiomers, mixtures of enantiomers such as,
for example,
racemates, optically pure diastereioisomers, mixtures of diastereoisomers,
diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
The term "asymmetric carbon atom" means a carbon atom with four different
substituents. According to the Cahn-Ingold-Prelog Convention the asymmetric
carbon
atom can be of the "R" or "S" configuration.
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As used herein, the term "optionally substituted with one to four
substituents" defines a
group which has one to four substituents, preferably one to three, more
preferably one to
two, and even more preferably one.
Preferred are compounds of formula (I) wherein:
R1 is phenyl optionally substituted with one to four substituents
independently
selected from halogen, lower alkyl, alkoxy and -0-CF3; or
5- or 6-membered heteroaryl optionally substituted with one to four
substituents independently selected from halogen, lower alkyl, alkoxy and
-0-CF3;
and wherein both R7 and R8 are not absent;
with the proviso that in case R2 and R4 are at the same time C, then R3 is C,
N or S
and R5 is C, 0 or S.
Also preferred are compounds of formula (I) wherein:
R1 is phenyl optionally substituted with one to four substituents
independently
selected from halogen, lower alkyl, alkoxy and -0-CF3; or
5- or 6-membered heteroaryl optionally substituted with one to four
substituents independently selected from halogen, lower alkyl, alkoxy and
-0-CF3;
and wherein both R7 and R8 are not absent;
with the proviso that in case R2 and R4 are at the same time C, then R3 is C,
N or S
and R5 is C, 0 or S.
Also preferred are compounds of formula (I) wherein:
R1 is phenyl optionally substituted with one to four substituents
independently
selected from halogen, lower alkyl, alkoxy and -0-CF3; or
5- or 6-membered heteroaryl optionally substituted with one to four
substituents independently selected from halogen, lower alkyl, alkoxy and
-0-CF3;
R2 is C;
R3 is 0;
R4 is C;
R5 is N;
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and wherein both R7 and R8 are not absent.
Also preferred are compounds of formula (I) wherein:
R1 is phenyl optionally substituted with one to four substituents
independently
selected from halogen, lower alkyl, alkoxy and -0-CF3; or
5- or 6-membered heteroaryl optionally substituted with one to four
substituents independently selected from halogen, lower alkyl, alkoxy and
-0-CF3;
R2 is C;
R3 is 0;
R4 is C;
R5 is N;
and wherein both R7 and R8 are absent.
Preferred are compounds of formula (I) wherein:
R1 is phenyl optionally substituted with one to four substituents
independently
selected from halogen, lower alkyl, alkoxy and -0-CF3; or
5- or 6-membered heteroaryl optionally substituted with one to four
substituents independently selected from halogen, lower alkyl, alkoxy and
-0-CF3.
Further preferred are compounds of formula (I) wherein R1 is 5- or 6-membered
heteroaryl optionally substituted with one to four substituents independently
selected
from halogen, lower alkyl, alkoxy and -0-CF3.
Preferred are compounds of formula (I) wherein R1 is phenyl optionally
substituted with
one to four substituents independently selected from halogen, lower alkyl,
alkoxy and
-0-CF3.
Preferred are compounds of formula (I) wherein R1 is phenyl optionally
substituted with
halogen.
Further preferred are compounds of formula (I) wherein R1 is phenyl,
fluorophenyl,
chlorophenyl, bromophenyl, thiophenyl, pyridyl, trifluoromethoxyphenyl or tert-
butyl.
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Preferred are compounds of formula (I) wherein R1 is pyridyl optionally
substituted with
halogen.
Most preferred are compounds of formula (I) wherein R1 is phenyl.
Preferred are compounds of formula (I) wherein:
R1 is phenyl optionally substituted with one to four substituents
independently
selected from halogen, lower alkyl, alkoxy and -0-CF3; and
X is 5- or 6-membered aryl optionally substituted with one to four
substituents
independently selected from lower alkyl, halogen and cyano.
Preferred are compounds of formula (I) wherein X is 5- or 6-membered aryl,
preferably
phenyl, optionally substituted with one to four substituents independently
selected from
lower alkyl, halogen and cyano.
Preferred are compounds of formula (I) wherein X is 5- or 6-membered
heteroaryl
optionally substituted with one to four substituents independently selected
from lower
alkyl, halogen and cyano.
Preferred are compounds of formula (I) wherein X is phenyl, pyridyl or
pyrimidyl and
most preferred phenyl or pyridyl.
Preferred are compounds of formula (I) wherein:
Y is cycloloweralkyl optionally substituted with one to four substituents
independently selected from lower alkyl, halogen and cyano; or
5- or 6-membered heterocycloalkyl optionally substituted with one to four
substituents independently selected from lower alkyl, halogen and cyano.
Preferred are compounds of formula (I) wherein Y is phenyl, pyridyl,
piperazyl,
piperidyl, pyrrolidyl or cyclopentyl, and most preferred phenyl, piperidyl or
piperazyl.
Preferred are compounds of formula (I) whereinY is phenyl optionally
substituted with
one to four substituents independently selected from lower alkyl, halogen and
cyano.
Preferred are compounds of formula (I) wherein X and Y are unsubstituted.
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Preferred are compounds of formula (I) wherein:
R1 is phenyl optionally substituted with one to four substituents
independently
selected from halogen, lower alkyl, alkoxy and -0-CF3; and
X is 5- or 6-membered optionally substituted with one to four substituents
independently selected from lower alkyl, halogen and cyano.
Preferred are compounds of formula (I) wherein:
R1 is 5- or 6-membered heteroaryl optionally substituted with one to four
substituents independently selected from halogen, lower alkyl, alkoxy and
-0-CF3; and
X is 5- or 6-membered aryl optionally substituted with one to four
substituents
independently selected from lower alkyl, halogen and cyano.
Preferred are compounds of formula (I) wherein:
R1 is 5- or 6-membered heteroaryl optionally substituted with one to four
substituents independently selected from halogen, lower alkyl, alkoxy and
-0-CF3; and
X is 5- or 6-membered heteroaryl optionally substituted with one to four
substituents independently selected from lower alkyl, halogen and cyano.
Preferred are compounds of formula (I) wherein:
R1 is phenyl, optionally substituted with one to four substituents
independently
selected from halogen, lower alkyl, alkoxy and -0-CF3; and
Y is phenyl optionally substituted with one to four substituents independently
selected from lower alkyl, halogen and cyano.
Preferred are compounds of formula (I) wherein:
R1 is 5- or 6-membered heteroaryl optionally substituted with one to four
substituents independently selected from halogen, lower alkyl, alkoxy and
-0-CF3; and
Y is phenyl optionally substituted with one to four substituents independently
selected from lower alkyl, halogen and cyano.
Preferred are compounds of formula (I) wherein:
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R1 is phenyl optionally substituted with one to four substituents
independently
selected from halogen, lower alkyl, alkoxy and -0-CF3; and
Y is cycloloweralkyl optionally substituted with one to four substituents
independently selected from lower alkyl, halogen and cyano; or
5- or 6-membered heterocycloalkyl optionally substituted with one to four
substituents independently selected from lower alkyl, halogen and cyano.
Preferred are compounds of formula (I) wherein:
R1 is 5- or 6-membered heteroaryl optionally substituted with one to four
substituents independently selected from halogen, lower alkyl, alkoxy and
-0-CF3; and
Y is cycloloweralkyl optionally substituted with one to four substituents
independently selected from lower alkyl, halogen and cyano; or
5- or 6-membered heterocycloalkyl optionally substituted with one to four
substituents independently selected from lower alkyl, halogen and cyano.
Preferred are compounds of formula (I) wherein:
X is 5- or 6-membered aryl optionally substituted with one to four
substituents
independently selected from lower alkyl, halogen and cyano; and
Y is phenyl optionally substituted with one to four substituents independently
selected from lower alkyl, halogen and cyano;
heteroaryl;
cycloloweralkyl optionally substituted with one to four substituents
independently selected from lower alkyl, halogen and cyano;
5- or 6-membered heterocycloalkyl optionally substituted with one to four
substituents independently selected from lower alkyl, halogen and cyano; or
-N(CH2)õ)N.
Preferred are compounds of formula (I) wherein:
X is 5- or 6-membered heteroaryl optionally substituted with one to four
substituents independently selected from lower alkyl, halogen and cyano; and
Y is phenyl optionally substituted with one to four substituents independently
selected from lower alkyl, halogen and cyano;
heteroaryl;
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cycloloweralkyl optionally substituted with one to four substituents
independently selected from lower alkyl, halogen and cyano;
5- or 6-membered heterocycloalkyl optionally substituted with one to four
substituents independently selected from lower alkyl, halogen and cyano; or
-N(CH2)õ)N.
Preferred are compounds of formula (I) wherein:
X is 5- or 6-membered aryl optionally substituted with one to four
substituents
independently selected from lower alkyl, halogen and cyano; or
5- or 6-membered heteroaryl optionally substituted with one to four
substituents independently selected from lower alkyl, halogen and cyano; and
Y is phenyl optionally substituted with one to four substituents independently
selected from lower alkyl, halogen and cyano.
Preferred are compounds of formula (I) wherein:
X is 5- or 6-membered aryl optionally substituted with one to four
substituents
independently selected from lower alkyl, halogen and cyano; or
5- or 6-membered heteroaryl optionally substituted with one to four
substituents independently selected from lower alkyl, halogen and cyano; and
Y is cycloloweralkyl optionally substituted with one to four substituents
independently selected from lower alkyl, halogen and cyano; or
5- or 6-membered heterocycloalkyl optionally substituted with one to four
substituents independently selected from lower alkyl, halogen and cyano.
Preferred are compounds of formula (I) wherein R2 is N.
Preferred are compounds of formula (I) wherein R3 is N.
Preferred are compounds of formula (I) wherein R4 is N.
Preferred are compounds of formula (I) wherein R5 is N.
Preferred are compounds of formula (I) wherein R2 and R3 are N.
Preferred are compounds of formula (I) wherein R3 and R4 are N.
Preferred are compounds of formula (I) wherein R2, R3 and R5 are N.
Preferred are compounds of formula (I) wherein one of R3 or R5 is N and the
other is S.
Also preferred are compounds of formula (I) wherein R2 is N, R3 is N, R4 is C
and R5 is
C.
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Also preferred are compounds of formula (I) wherein R2 is N, R3 is C, R4 is C
and R5 is
S.
Also preferred are compounds of formula (I) wherein R2 is N, R3 is N, R4 is C
and R5 is
N.
Further preferred are compounds of formula (I) wherein R2 is C, R3 is 0, R4 is
C and R5
is N.
Preferred are compounds of formula (I) wherein R6 is halogen, trifluoromethyl,
trifluoroethyl, methyl, ethyl, propyl, methoxymethyl or methoxyethyl.
Most preferred are compounds of formula (I) wherein R6 is trifluoromethyl.
Preferred are compounds of formula (I) wherein R7 is N optionally substituted
with lower
alkyl.
Preferred are compounds of formula (I) wherein R8 is N optionally substituted
with lower
alkyl.
Preferred are compounds of formula (I) wherein:
R9 is lower alkyl;
alkoxy;
hydroxyl;
lower alkyl amine;
cycloloweralkyl optionally substituted with one to four substituents
independently selected from loweralkyl, hydroxy, halogen, -C(0)0H,
-C(0)0-lower alkyl and -C(0)0-lower alkyl-phenyl;
5- or 6-membered heterocycloalkyl optionally substituted with one to four
substituents independently selected from lower alkyl, hydroxy, halogen,
-S02-loweralkyl, -C(0)0H, -C(0)0-lower alkyl and -C(0)0-lower alkyl-
phenyl;
-(CH2)õC(0)0H;
-CH2C(lower alky1)2C(0)0H;
-CH2(cycloalkyl)C(0)0H;
-(cycloalkyl)C(0)0H;
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-NS02-loweralkyl;
-N-lower alkyl;
-N-cycloalkyl optionally substituted with -C(0)0H;
-N-CH(lower alkyl)C(0)0H; or
-N-(cycloalkyl)C(0)0H.
Preferred are compounds of formula (I) wherein n is 1.
Preferred are compounds of formula (I) wherein R9 is hydroxyl, tert-butyl,
carboxy-ethyl,
2,2-dimethy1-2-carboxy-ethyl, 2-cyclopenty1-2-carboxy-ethyl, 2-cyclohexy1-2-
carboxyethyl, cyclopropyl, cyclopentenyl, tetrahydrofuryl, methoxy, ethoxy,
isobutyloxy,
methoxymethyl, trifluoromethyl, isopropyloxy, methyl, ethyl, propyl, butyl,
2,2-
dimethyl-propyl, 2,2-dimethyl-propyloxy, 3,3-dimethyl-propyl, 4-methyl-
pentanol,
methyl-cyclopentyl, carboxy-cyclohexyl, methoxycarbonyl-cyclohexyl, carboxy-
cyclopentyl, ethoxycarbonyl-cyclopentyl, methoxycarbonyl-cyclopentyl, N,N-
dimethylamino, tert.butoxy, benzyloxy, amino, butyl-amino, tert-butyl-amino,
isopropenyloxy, propyl-amino, cyclohexyl-amino, cyclopentyl-amino, benzyl-
amino,
methyl-amino, isopropyl-amino, methyl-pyridyl-amino, N-ethyl-N-methyl-amino, -
NH-
S02-C(CH3)3, -NH-S02-C2H5, -NH-S02-CH3, 1H-tetrazolyl, 1H-tetrazolyl-methyl,
oxadiazolyl, carboxy-pyrrolidyl, carboxy-piperidyl, methoxycarbonyl-
pyrrolidyl, methyl-
(2,4-dioxo-thiazolidy1), methane-sulfonyl-pyrrolidyl, dimethyl-sulfamoyl-
pyrrolidyl,
carboxy-adamantyl, hydroxy-isoxasolyl, cyclopentyl-methyl, 3-carboxy-2,2-
dimethyl-
propyl, 2,2-diethyl-methoxycarbonyl-ethyl, 2-carboxy-1,2,2-trimethyl-
cyclopentyl,
carboxy-cyclobutyl, ethoxycarbonyl-methyl, methoxycarbonyl-methyl, carboxy-N-
pyrolidyl, 2,2,2-trifluoro-ethyl, methyl-isoxazolyl-amino, methoxycarbonyl-
cyclopentyl-
amino, dihydroxy-cyclopentyl, methoxycarbonyl-isopropyl-methyl-amino, carboxy-
isopropy-methyl-amino, carboxy-piperidyl, N-((carboxy-cyclopropy1)-methyl)-
amino, N-
((carboxy-cyclobuty1)- methyl)-amino, N-((carboxy-cyclopentyp-methyl)-amino, N-
((carboxy-tert-butyp-methyl)-amino, N-((carboxy-isobutyp-methyl)-amino, N-
benzyloxycarbonyl-pyrrolidyl, N-ethoxycarbonyl-pyrrolidyl, carboxy-methyl-
piperidyl,
carboxy-ethyl-piperidyl, carboxy-propyl-piperidyl, carboxy-oxazolyl-ethyl, N-
methanesulfonyl-pyrrolidyl or N-dimethylsulfamoyl-pyrrolidyl.
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Most preferred are compounds of formula (I) wherein R9 is 2,2-dimethy1-2-
carboxy-
ethyl, carboxy-cyclohexyl, carboxy-cyclopentyl, cyclopropyl or tert-butyl-
sulfonyl-
amino.
Preferred examples of compounds of formula (I) are:
(S)-3- {5-[(1-Pyridin-2-y1-3-trifluoromethy1-1H-pyrazole-4-carbony1)-amino]-
pyridin-2-
ylamino}-pyrrolidine-1-carboxylic acid ethyl ester;
(S)-3- { 4- [( 1 -Phenyl-3 -trifluoromethyl- 1 H-pyrazo le-4-carbonyl)-amino] -
phenylamino 1 -
pyrrolidine-l-carboxylic acid ethyl ester;
(S)-3- {5-[(1-Pheny1-3-trifluoromethy1-1H-pyrazole-4-carbony1)-amino]-pyridin-
2-
ylamino}-pyrrolidine-1-carboxylic acid ethyl ester;
(S)-3- {5 -[(4-Methy1-2-pyridin-2-yl-thiazo le-5 -carbony1)-amino ] -pyridin-2-
ylamino 1 -
pyrrolidine-l-carboxylic acid ethyl ester;
(S)-3- {5 -[(4-Methy1-2-pyridin-2-yl-thiazo le-5 -carbony1)-amino ] -pyridin-2-
ylamino 1 -
pyrrolidine-l-carboxylic acid tert-butyl ester;
4- {4-[(1-Pyridin-2-y1-3-trifluoromethy1-1H-pyrazole-4-carbony1)-amino]-
pheny1}-
piperidine-1-carboxylic acid propylamide;
4- {4- [(5-Methyl-2-phenyl-2H- [ 1 ,2,3]triazole-4-carbony1)-amino]-phenyl} -
piperidine- 1 -
carboxylic acid propylamide;
2-Pyridin-2-y1-4-trifluoromethyl-oxazole-5-carboxylic acid [6-(4-
isobutylcarbamoyl-
pheny1)-pyridin-3-y1]-amide;
4- [4-(4- { [1 -(4-Fluoro-phenyl)-3-trifluoromethyl- 1 H-pyrazo le-4-carbonyl]
-amino} -
phenyl)-piperidine-l-carbonyl]-cyclohexanecarboxylic acid;
4-(5- { [ 1 -(4-Fluoro-phenyl)-3 -trifluoromethyl- 1 H-pyrazo le-4-carbonyl] -
amino 1 -pyridin-
2-y1)-benzoic acid;
1-Pyridin-2-y1-3-trifluoromethy1-1H-pyrazole-4-carboxylic acid [4-(1-
cyclopentanecarbonyl-piperidin-4-y1)-phenyl]-amide;
3 -Chloro -4-(5 - { [ 1 -(4-fluoro-phenyl)-3 -trifluoromethyl- 1 H-pyrazo le-4
carbonyl] -amino 1 -
pyridin-2-y1)-benzoic acid;
trans-4- [4-(4- { [ 1 -(4-F luoro-pheny1)-3 -trifluoromethyl- 1 H-pyrazo le-4-
carbonyl] -amino 1 -
phenyl)-piperidine-l-carbonyl]-benzoic acid;
pyridin-2-y1-3-trifluoromethy1-1H-pyrazole-4-carboxylic acid [4-(1-
cyclopropanecarbonyl-piperidin-4-y1)-phenyl]-amide;
4'- { [ 1 -(4-F luoro-pheny1)-3 -trifluoromethyl- 1 H-pyrazo le-4-carbonyl] -
amino 1 -biphenyl-4-
carboxylic acid;
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(1R,2R)-2-{4'-[(2-Pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-biphenyl-
4-
ylcarbamoy1}-cyclopentanecarboxylic acid;
(1 S,2S)-2- {4'-[(2-Pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
biphenyl-4-
ylcarbamoyl} -cyclopentanecarboxylic acid;
(S)-3-(5-{[2-(2-Trifluoromethoxy-pheny1)-5-trifluoromethyl-oxazole-4-carbony1]-
amino}-pyrimidin-2-yloxy)-pyrrolidine-1-carboxylic acid ethyl ester;
(S)-3-{5-[(2-Pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-
yloxy}-
pyrrolidine-1-carboxylic acid ethyl ester;
(S)-3-(4- {[2-(2-Trifluoromethoxy-pheny1)-5-trifluoromethyl-oxazole-4-
carbony1]-
amino}-phenylamino)-pyrrolidine-l-carboxylic acid ethyl ester;
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-1-isobutyryl-
pyrrolidin-3-
ylamino)-pyridin-3-y1]-amide;
2,2-Dimethy1-3-{5'-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
3,4,5,6-
tetrahydro-2H-[1,21bipyridinyl-4-y1}-propionic acid;
(S)-3-(5-{[2-(2-Trifluoromethoxy-pheny1)-5-trifluoromethyl-oxazole-4-carbony1]-
amino}-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl ester;
(S)-3- { 4- [(2-Phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -
phenylamino } -
pyrrolidine-l-carboxylic acid ethyl ester;
(S)-3-(5- {[2-(2-Trifluoromethoxy-pheny1)-5-trifluoromethyl-oxazole-4-
carbony1]-
amino}-pyrimidin-2-ylamino)-pyrrolidine-l-carboxylic acid ethyl ester;
2,2-Dimethy1-4-oxo-4-(4-{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
pheny1}-piperazin-1-y1)-butyric acid;
trans-4-(4-{4-[(2-Pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-pheny1}-
piperazine-1-carbony1)-cyclohexanecarboxylic acid;
(1R,2R)-2-(4-{4-[(2-Pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
pheny1}-
piperidine-1-carbony1)-cyclopentanecarboxylic acid;
trans-4-(4-{4-[(2-Pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-pheny1}-
piperidine-1-carbony1)-cyclohexanecarboxylic acid;
cis-4-(4-{4-[(2-Pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-phenyl} -
piperidine-l-carbony1)-cyclohexanecarboxylic acid;
(15,25)-2-{4'-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-biphenyl-
4-
carbony1}-cyclopentanecarboxylic acid;
(1R,2R)-2-(4-{4-[(2-Pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
pheny1}-
piperazine-1-carbony1)-cyclopentanecarboxylic acid;
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cis-4-(4-{4-[(2-Pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-pheny1}-
piperazine-1-carbony1)-cyclohexanecarboxylic acid;
(1R,3S)-3-(4-{4-[(2-Pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
pheny1}-
piperazine-1-carbony1)-cyclohexanecarboxylic acid;
2,2-Dimethy1-4-oxo-4-{4'-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
biphenyl-4-y1}-butyric acid;
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-
cyclopropylcarbamoyl-
pheny1)-pyridin-3-y1]-amide;
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(2-methyl-propane-2-
sulfonylaminocarbony1)-piperidin- 1 -y1]-phenyl} -amide;
(S)-3-{4-[(1-Pheny1-3-trifluoromethy1-1H-pyrazole-4-carbony1)-amino]-phenoxy}-
pyrrolidine-1-carboxylic acid ethyl ester;
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4- {4-[4-(1H-tetrazol-5-
y1)-
cyclo hexanecarbonyl] -piperazin- 1 -y1} -phenyl)-amide;
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4- {1-[4-(1H-tetrazol-5-
y1)-
cyclo hexanecarbonyl] -piperidin-4-y4 -phenyl)-amide;
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4- {1-[4-(5-oxo-4,5-
dihydro-
1 ,2,4]oxadiazo1-3 -y1)-cyclo hexanecarbonyl] -pip eridin-4-y4 -phenyl)-amide;
5'-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-3,4,5,6-tetrahydro-
2H-
1,21bipyridiny1-4-carboxylic acid amide;
[ 1 -(4- {4-[(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbony1)-amino] -
phenyl} -piperidine-
1-carbony1)-piperidin-4-y1]-acetic acid;
1 -(4- {4-[(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} -
piperidine- 1 -
carbony1)-piperidine-4-carboxylic acid;
1 -(4- {4-[(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} -
piperidine- 1 -
carbony1)-pyrrolidine-3 -carboxylic acid;
3 - [ 1 -(4- {4- [(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -
phenyl} -piperidine-
1-carbony1)-piperidin-4-y1]-propionic acid;
4- [ 1 -(4- {4- [(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -
phenyl} -piperidine-
1-carbony1)-piperidin-4-y1]-butyric acid;
(R)-3-{5-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-pyrimidin-2-
yloxy}-
pyrrolidine-1-carboxylic acid ethyl ester;
1 -(1- {4-[(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} -
piperidine-4-
carbonyl)-piperidine-4-carboxylic acid ethyl ester;
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1-(1- {4-[(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} -
piperidine-4-
carbony1)-piperidine-4-carboxylic acid;
1 -(1- {4-[(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} -
piperidine-4-
carbony1)-piperidine-3-carboxylic acid ethyl ester;
1 -(1- {4-[(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} -
piperidine-4-
carbony1)-piperidine-3-carboxylic acid;
2,2-dimethy1-4-oxo-4-(4-{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
phenoxy}-piperidin-1-y1)-butyric acid;
2,2-dimethy1-4-oxo-4-((S)-3-{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-phenoxy}-pyrrolidin-l-y1)-butyric acid;
4-((S)-3-{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-phenoxy}-
pyrrolidine-1-carbony1)-trans-cyclohexanecarboxylic acid;
1-[2-oxo-2-((S)-3-{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
phenoxy}-pyrrolidin-1-y1)-ethyl]-cyclopentanecarboxylic acid;
2,2-dimethy1-4-(4-{4-[(5-methy1-2-phenyl-oxazole-4-carbony1)-amino]-pheny1}-
piperidin-1-y1)-4-oxo-butyric acid;
(1R,2R)-2-((S)-3-{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
phenoxy}-pyrrolidine-1-carbony1)-cyclopentanecarboxylic acid;
1 -(1- {4-[(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} -
piperidine-4-
carbonyl)-pyrrolidine-3-carboxylic acid methyl ester; hydrochloride;
(S)-1-(1-{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-pheny1}-
piperidine-4-carbony1)-pyrrolidine-2-carboxylic acid methyl ester;
hydrochloride;
(S)-1-(1-{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-pheny1}-
piperidine-4-carbony1)-pyrrolidine-2-carboxylic acid;
1 -(1- {4-[(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} -
piperidine-4-
carbony1)-piperidine-2-carboxylic acid; hydrochloride;
(1 S,2S)-2-(4- {4-[(2-tert-butyl-5 -methyl-oxazo le-4-carbonyl)-amino] -
phenyl} -piperazine-
1-carbony1)-cyclopentanecarboxylic acid; hydrochloride;
4-((S)-3-{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-phenoxy} -
pyrrolidine-l-carbony1)-cis-cyclohexanecarboxylic acid;
2-phenyl-thiazole-4-carboxylic acid (4- {4-[2-(2,4-dioxo-thiazolidin-5-y1)-
acety1]-
piperazin- 1 -y1} -phenyl)-amide; hydrochloride;
(1 S,2S)-2-(4- {3 -fluoro-4- [(2-phenyl-5 -trifluoromethyl-oxazo le-4-
carbony1)-amino]-
pheny1}-piperazine-1-carbony1)-cyclopentanecarboxylic acid;
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trans-4-(4- {3 -fluoro-4- [(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-
amino] -
phenyl} -piperazine- 1 -carbonyl)-cyclohexanecarboxylic acid;
trans-2- [methyl-( 1- {4- [(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-
amino] -
phenyl} -piperidin-4-y1)-carbamoy1]-cyclopentanecarboxylic acid;
( 1R,2R)-2-[methyl-( 1- {4- [(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-
amino] -
phenyl} -piperidin-4-y1)-carbamoy1]-cyclopentanecarboxylic acid;
(1 S ,2 S)-2-[methyl-( 1- {4- [(2-phenyl-5 -trifluoromethyl-oxazo le-4-
carbonyl)-amino] -
phenyl} -piperidin-4-y1)-carbamoy1]-cyclopentanecarboxylic acid;
(1 S,2S)-2-(methyl- {5 '- [(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-
amino] -3,4,5,6-
tetrahydro-2H-[ 1 ,21bipyridiny1-4-y4 -carbamoy1)-cyclopentanecarboxylic acid;
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4- [4-((R)- 1 -
methanesulfonyl-
pyrrolidine-2-carbony1)-piperazin- 1 -yl] -phenyl} -amide;
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4- [4-((R)- 1 -
dimethylsulfamoyl-
pyrrolidine-2-carbony1)-piperazin- 1 -yl] -phenyl} -amide;
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4- [4-((S)- 1 -
methanesulfonyl-
pyrrolidine-2-carbony1)-piperazin- 1 -yl] -phenyl} -amide;
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4- [4-((S)- 1 -
dimethylsulfamoyl-
pyrrolidine-2-carbony1)-piperazin- 1 -yl] -phenyl} -amide;
2-(4- {5 -[(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino]-pyridin-2-
y4 -
benzoy1)-cyclopentanecarboxylic acid methyl ester;
2-(4- {5 -[(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino]-pyridin-2-
y4 -
benzoy1)-cyclopentanecarboxylic acid;
3- {5 - [(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino]-pyridin-2-
ylo xy} -
piperidine- 1 -carboxylic acid ethyl ester;
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4- [4-(3 -propyl- 1 -
methyl-ureido)-
piperidin- 1 -y1]-phenyl} -amide;
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4- [4-(3 -ethyl-1 -
methyl-ureido)-
piperidin- 1 -y1]-phenyl} -amide;
2,2,N-trimethyl-N-( 1- {4- [(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-
amino] -
phenyl} -piperidin-4-y1)-succinamic acid;
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4- [4-(2- 1H-tetrazol-5 -
yl-acety1)-
piperazin- 1 -y1]-phenyl} -amide;
3 -(4- {4-[(2-phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} -
piperazine- 1 -
carbony1)-adamantane- 1 -carboxylic acid;
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2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[1-(2-1H-tetrazol-5-yl-
acety1)-
piperidin-4-y1]-phenyl} -amide;
1-methy1-4-(4-{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
pheny1}-
piperidine-1-carbony1)-cyclohexanecarboxylic acid;
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4- {1-[2-(2,4-dioxo-
thiazolidin-5-
y1)-acety1]-piperidin-4-y1} -phenyl)-amide;
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4- {1-[3-(3-hydroxy-
isoxazol-5-
y1)-propionyl] -piperidin-4-y1} -phenyl)-amide;
2,2-dimethy1-4-oxo-4-(3- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
phenoxy}-piperidin-l-y1)-butyric acid;
2,2-dimethy1-5-oxo-5-(3- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
phenoxy}-piperidin-1-y1)-pentanoic acid; and
3,3-dimethy1-5-oxo-5-(3- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
phenoxy}-piperidin-1-y1)-pentanoic acid.
Particularly preferred examples of compounds of formula (I) are:
2,2-Dimethy1-4-oxo-4-(4- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
pheny1}-piperazin-1-y1)-butyric acid;
4-(4- {4-[(2-Phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} -
piperazine- 1-
carbonyl)-cyclohexanecarboxylic acid;
(1R,2R)-2-(4-{4-[(2-Pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
pheny1}-
piperidine-1-carbony1)-cyclopentanecarboxylic acid;
4-(4- {4-[(2-Phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} -
piperidine- 1 -
carbony1)-cyclohexanecarboxylic acid;
4-(4- {4-[(2-Phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} -
piperidine- 1 -
carbony1)-cyclohexanecarboxylic acid;
(1 S,2S)-2- {4'- [(2-Phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -
biphenyl-4-
carbonyl} -cyclopentanecarboxylic acid (or enantiomer);
(1R,2R)-2-(4-{4-[(2-Pheny1-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
phenyl} -
piperazine-l-carbony1)-cyclopentanecarboxylic acid;
4-(4- {4-[(2-Phenyl-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} -
piperazine- 1 -
carbony1)-cyclohexanecarboxylic acid;
(1R,3S)-3-(4-{4-[(2-Pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
pheny1}-
piperazine-1-carbony1)-cyclohexanecarboxylic acid;
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2,2-Dimethy1-4-oxo-4-{4'-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
biphenyl-4-y1}-butyric acid;
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-
cyclopropylcarbamoyl-
pheny1)-pyridin-3-y1]-amide; and
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(2-methyl-propane-2-
sulfo nylamino carbony1)-p ip eridin- 1 -yl] -phenyl} -amide.
The invention also relates to a pharmaceutical composition, comprising a
therapeutically
effective amount of a compound of formula (I) or a pharmaceutically acceptable
salt
thereof and a pharmaceutically acceptable carrier.
The invention also relates to a method of treating obesity, type II diabetes,
dyslipidemia
or metabolic syndrome, comprising the step of administering a therapeutically
effective
amount of a compound of formula (I) to a patient in need thereof.
It is to be understood that the terminology employed herein is for the purpose
of
describing particular embodiments, and is not intended to be limiting.
Further, although
any methods, devices and materials similar or equivalent to those described
herein can be
used in the practice or testing of the invention, the preferred methods,
devices and
materials are now described.
Compounds of the present invention can be prepared beginning with commercially
available starting materials and utilizing general synthetic techniques and
procedures
known to those skilled in the art. Outlined below are reaction schemes
suitable for
preparing such compounds. Further exemplification is found in the specific
examples
listed below.
Scheme 1
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L\/,z) 4
r: N _______________________________________ Y \ 0
N ¨(-----
X N (CH2)n 0 N
NI/ N __ .(
I ¨X \ _____ / \c,
R
iii v
0 \ 0
,........1 _________ % 1(\
NI/ N /,
\ ________________________________________________ / 0 (
ii iv
0
I+
0- N
' \y
1
XHal
Na12)n
/
N N ) __ (CH2)m 0
\\
R1 R20
vi
viii
R
¨Y) _Y /
\
N ____________ / __ I1(cH )nN0 N N ) __ (CH2)m 0
X 2 g )c \ __ X \
R1)\ ( R
R20
vii ix
0 õ,- 0
'N
XY
I
Hal
N COO i
(CH2)n \ Nn¨COOR'
(CH2)n
x xii
/ Y
/ Y
¨X (CH2)n N¨C
)¨Nn¨COOR'
(CH2)n
COOR' ¨X
Xi xiii
In Scheme 1, compound i (X and Y can be CH or N, Hal can be F, Cl, Br or I)
can be
treated with various cyclic amines (ii, iv, vi, viii, x, xii) in the presence
of base and
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through nucleophilic aromatic substitution gave the corresponding nitro adduct
(iii, v, vii,
ix, xi, xiii). The resulting nitro compounds can be reduced to the
corresponding amines
by catalytic hydrogenation. Each arrow in Scheme 1 represents two individual
reactions.
For the formation of compound iii, the cyclic amine can be 3-amino-pyrrolidine-
1-
carboxylic acid tert-butyl ester (compound ii, n=1) or 4-amino-piperidine- 1-
carboxylic
acid tert-butyl ester (compound ii, n=2) and the exocyclic nitrogen can be
alkylated or
non-alkylated (compound ii, R=H or lower alkyl group). The configuration of 3-
amino-
pyrrolidine can be (R) or (S)-stereoisomer.
When the cyclic amine is piperazine- 1-carboxylic acid tert-butyl ester
(compound iv),
substitution and subsequent reduction will generate compound v.
Alternatively, the cyclic amine can be pyrrolidin-3-yl-carbamic acid tert-
butyl ester
(compound vi, n=1) or piperidin-4-yl-carbamic acid tert-butyl ester (compound
vi, n=2)
and the carbamate nitrogen can be alkylated or non-alkylated (compound vi, R=H
or
lower alkyl group). The stereochemistry of pyrrolidin-3-yl-carbamic acid tert-
butyl ester
can be (R) or (S)-configuration.
Additionally, the cyclic amine can also be a 4-substituted piperidine
derivative as in
compound viii for the preparation of compound ix (m=0 or 1, R' can be methyl
or ethyl).
Applying the same methodology, compounds xi and xiii (n=1 or 2, R' can be
methyl or
ethyl) can be prepared by reacting compound i with the ester of amino-
cycloalkyl-
carboxylic acid (compound x) or the ester of pyrrolidine-3-carboxylic acid
(compound
xii, n=1).
Scheme 2
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/C)
13
0
+
0
I ,
N/
\XLHal
0 OvC 0
xiv xv
In Scheme 2, the cross-coupling of aryl halide (compound i, Hal can be Cl, Br
or I) with
a pinacol borate (compound xiv) can be accomplished through a palladium
catalyzed
reaction according to known procedure (Tetrahedron Letters, 2000, 41, 3705).
The
pinacol borate (compound xiv) can be prepared from 4-
trifluoromethylsulfonyloxy-3,6-
dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as described in the
literature
(Synthesis, 1991, 11, 993). The nitro group and the olefin in the coupling
product can
both be hydrogenated to generate compound xv.
Scheme 3
,
Aryl¨Zis I
Xi
Z/C\S--\(N / Q
0 Aryl¨
0
00vC¨ 0
xvi xvii xviii
In Scheme 3, amide formation of an aryl-substituted five membered ring
heterocyclic
carboxylic acid (compound xvi, where Zi can be carbon or nitrogen, X1 and Y1
can be
oxygen, nitrogen, or sulfur, R can be halogen, lower alkyl, fluorine
substituted alkyl or
alkoxy group) with an aryl amine xvii can be carried out by using general
amide coupling
methods such as acid chloride, mixed anhydride or coupling reagents. It is
understood
that a variety of coupling reagents such as EDCI, PyBroP and many others can
be
applied.
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The chemical structure of compound xvii is meant to encompass those
represented by
compounds iii, v, vii and xv with the different cyclic amines being
represented by spacer
Q. The nitrogen that links spacer Q and the tert-butyloxycarbonyl group can be
part of
the ring (e.g. compound v) or outside of the ring (e.g. compound vii). The
tert-
butyloxycarbonyl group in the coupling product can be cleaved under acidic
condition to
generate the corresponding amine xviii.
In addition, heterocyclic carboxylic acid xvi can also be coupled with amine
ix, xi and
xiii under the same amide formation conditions. The esters of the amide
coupling product
can further be hydrolyzed to generate the corresponding carboxylic acids.
Scheme 4
0
¨Y
Zi
Aryl' 1 X
0
xix
R'COCI or R'COOH
A
Aryl\ ryl
Aryl Z1¨y
R X\1N\\
(D'N
0
0 N
R'NCOCI R'OCOCI
XY
XY
or R'NCO X y
QõN, R'
" R'
0
0
xx xviii xxi
0
0
E 0
0 or 0
I E
0
xxii xxiii
0 0
Aryl'Z"Cx
X
0
xxiv
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The key intermediate xviii in Scheme 3 can be functionalized to form various
amides,
carbamates and ureas. As shown in Scheme 4, compound xviii can be treated with
acyl
chloride or carboxylic acid to form amide xix (R' can be cyclic or acyclic
alkyl group).
For the formation of urea xx, compound xviii can be treated with isocyanate or
alkylaminocarbonyl chloride. Finally, the reaction of xviii with
alkoxycarbonyl chloride
will generate carbamate xxi.
To prepare amides with terminal carboxylic acids, xviii can be treated with
anhydride
xxiii (E can be cyclic or acyclic alkyl group) to form carboxylic acid xxiv.
In case when
xxiii is not readily available, the direct coupling of xviii with dicarboxylic
acid xxii using
coupling reagents can also lead to xxiv.
Alternatively, the dicarboxylic acid in xxii can be transformed to a mono-
ester mono-
carboxylic acid which can be coupled with xviii, and the cleavage of the
resulting ester
will generate compound xxiv.
For compound xxii, when spacer E is cyclic, the dicarboxylic acid can be in
cis or trans-
conformation. For cases where spacer E has stereogenic centers, single
enantiomers of
compound xxiv can be prepared through chiral separation.
Scheme 5
Y --/
/
Ny Aryl¨Zi. I
Aryl¨Z1.
µX1 COONX Hal 0
xvi xxv xxvi X Hal
B(OR)2
R'
xxvii
/Y1
Aryl¨Z1.
N
'Xi y
0 R'
\X
xxviii
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Compounds with the structure xxviii, where a biarylamine is linked to a
heterocyclic
carboxylic acid through an amide linkage, can be prepared by using Suzuki
coupling
reactions. In Scheme 5, 5-amino-2-halogen substituted aromatic compound xxv
(Hal=C1,
Br or I, X and Y can be CH or N) can be coupled with aryl substituted
heterocyclic
carboxylic acid xvi using general amide coupling conditions as described above
to
generate compound xxvi. Suzuki coupling of xxvi with aryl boronic acid
derivative xxvii
(A can be CH or N, R'=H, halogen or simple alkyl, R"=H or alkyl, the boronic
acid ester
can also be cyclic such as pinocolate, W can be amide, carbamate, urea, ester
or
carboxylic acid) will generate compound xxviii.
Scheme 6
B(0 R" )2
N
N
IX ,
\ Hal Ay X
xxv xx ix
xxvii Y
/1iR
Aryl ¨Zi I
X1 COO I-1
xvi
Y
/
Aryl¨Z1.
=X;Thr N
0
X
xxviii
An alternative route to prepare compound xxviii is shown in Scheme 6. Compound
xxv
can be coupled with aryl boronic acid derivative xxvii first to form a
biarylamine
derivative xxix under Suzuki coupling conditions. The resulting biarylamine
can then be
reacted with heterocyclic carboxylic acid xvi under amide formation conditions
to form
compound xxviii.
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Scheme 7
o o o
1*
eH2)n 0........6 i*
o, 0-" y-N----"'-k-
N
I N---1
I I L-\,N4
XHal 0
xxx X 0 (CH2)n 0 (
__________________________________ 3.-
xxxi
i
R
1
AI¨Z1
X1 COOH
xvi
Yi----/iR
R
Y --..../
Aryl¨Zii. I / 1 1
N X A 1.ryl¨Z I
= N
xxxiii xxxii
Shown in Scheme 7 is a general method to prepare claimed compounds with an
ether
linkage. The hydroxyl substituted heterocycle xxx (n=1 or 2) can be reacted
with aryl
halide i in the presence of sodium hydride or 4-dimethylaminopyridine to
generate an
aryl ether xxxi. The nitro group in xxxi can be reduced and the resulting
amine can be
coupled with heterocyclic carboxylic acid xvi to generate compound xxxii. The
tert-
butyloxycarbonyl group in xxxii can be cleaved under acidic condition and the
resulting
amine can be functionalized to generate compound xxxiii, where R represents
alkyl,
alkoxy, cycloalkyl, and alkylicycloalkyl with carboxylic acid.
In the practice of the method of the present invention, an effective amount of
any one of
the compounds of this invention or a combination of any of the compounds of
this
invention or a pharmaceutically acceptable salt thereof, is administered via
any of the
usual and acceptable methods known in the art, either singly or in
combination. The
compounds or compositions can thus be administered orally (e.g., buccal
cavity),
sublingually, parenterally (e.g., intramuscularly, intravenously, or
subcutaneously),
rectally (e.g., by suppositories or washings), transdermally (e.g., skin
electroporation) or
by inhalation (e.g., by aerosol), and in the form or solid, liquid or gaseous
dosages,
including tablets and suspensions. The administration can be conducted in a
single unit
dosage form with continuous therapy or in a single dose therapy ad libitum.
The
therapeutic composition can also be in the form of an oil emulsion or
dispersion in
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conjunction with a lipophilic salt such as pamoic acid, or in the form of a
biodegradable
sustained-release composition for subcutaneous or intramuscular
administration.
Useful pharmaceutical carriers for the preparation of the compositions hereof,
can be
solids, liquids or gases; thus, the compositions can take the form of tablets,
pills,
capsules, suppositories, powders, enterically coated or other protected
formulations (e.g.
binding on ion-exchange resins or packaging in lipid-protein vesicles),
sustained release
formulations, solutions, suspensions, elixirs, aerosols, and the like. The
carrier can be
selected from the various oils including those of petroleum, animal, vegetable
or
synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and
the like. Water,
saline, aqueous dextrose, and glycols are preferred liquid carriers,
particularly (when
isotonic with the blood) for injectable solutions. For example, formulations
for
intravenous administration comprise sterile aqueous solutions of the active
ingredient(s)
which are prepared by dissolving solid active ingredient(s) in water to
produce an
aqueous solution, and rendering the solution sterile. Suitable pharmaceutical
excipients
include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice,
flour, chalk, silica,
magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride,
dried skim
milk, glycerol, propylene glycol, water, ethanol, and the like. The
compositions may be
subjected to conventional pharmaceutical additives such as preservatives,
stabilizing
agents, wetting or emulsifying agents, salts for adjusting osmotic pressure,
buffers and
the like. Suitable pharmaceutical carriers and their formulation are described
in
Remington's Pharmaceutical Sciences by E. W. Martin. Such compositions will,
in any
event, contain an effective amount of the active compound together with a
suitable
carrier so as to prepare the proper dosage form for proper administration to
the recipient.
The invention also relates to a process for the preparation of a compound of
formula (I)
comprising one of the following reactions:
(a) the reaction of a compound according to formula
/R3 ----- R /R6
R1¨R2 a 4
R5 OH
C
11
0
(Ia)
in the presence of of a compound according to formula
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NO2¨X ¨ R7 ¨ Y¨ R8¨C ¨R9
II
0 (Ha);
(b) the reaction of a compound according to formula
R6
/R3 ------.R /
Ri ¨R2 0 4
OH
R5 C
11
0
(Ib)
in the presence of a compound according to formula
NH2¨X ¨ R7 ¨ Y¨ R8¨C ¨R9
II
0 (JIb);
(c) the reaction of a compound according to formula
/R3 ------.R /R6
R1¨R2 0 4
NHX Hal
¨ ¨
R5 C
11
0
(Ic)
in the presence of a compound according to formula
B(OR)2¨ Y¨ R8¨C ¨R9
II
0 MO;
wherein R1 to R9, X and Y are as defined above, wherein Hal represents F, Cl,
Br or I,
and wherein R represents hydrogen, alkyl or cycloalkyl.
The invention also relates to a compound of formula (I) for use as
therapeutically active
substance.
The invention also relates to a pharmaceutical composition, comprising a
therapeutically
effective amount of a compound of formula (I) or a pharmaceutically acceptable
salt
thereof and a pharmaceutically acceptable carrier.
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The invention also relates to the use of a compound of formula (I) for the
preparation of
medicaments for the treatment or prophylaxis of obesity, type II diabetes,
dyslipidemia or
metabolic syndrome, and preferably type II diabetes.
The invention also relates to compounds of formula (I) for use as medicaments
for the
treatment and prophylaxis of obesity, type II diabetes, dyslipidemia or
metabolic
syndrome, and preferably type II diabetes.
The invention also relates to a compound according of formula (I), when
manufactured
according to a process according to the invention.
The invention also relates to a method of treating obesity, type II diabetes,
dyslipidemia
or metabolic syndrome, and preferably type II diabetes, comprising the step of
administering a therapeutically effective amount of a compound of formula (I)
to a
patient in need thereof.
The dose of a compound of the present invention depends on a number of
factors, such
as, for example, the manner of administration, the age and the body weight of
the subject,
and the condition of the subject to be treated, and ultimately will be decided
by the
attending physician or veterinarian. Such an amount of the active compound as
determined by the attending physician or veterinarian is referred to herein,
and in the
claims, as a "therapeutically effective amount". For example, the dose of a
compound of
the present invention is typically in the range of about 1 to about 1000 mg
per day.
Preferably, the therapeutically effective amount is in an amount of from about
1 mg to
about 500 mg per day.
A compound of formula I can be used in a manner known per se as the active
ingredient
for the production of tablets of the following composition:
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Per tablet
Active ingredient 200 mg
Microcrystalline cellulose 155 mg
Corn starch 25 mg
Talc 25 mg
Hydroxypropylmethylcellulose 20 mg
425 mg
A compound of formula I can be used in a manner known per se as the active
ingredient
for the production of capsules of the following composition:
Per capsule
Active ingredient 100.0 mg
Corn starch 20.0 mg
Lactose 95.0 mg
Talc 4.5 mg
Magnesium stearate 0.5 mg
220.0 mg
The invention will now be further described in the Examples below, which are
intended
as an illustration only and do not limit the scope of the invention.
PART I: PREPARATION OF PREFERRED INTERMEDIATES
Amines
Preparation of (5'-amino-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-y1)-acetic
acid
methyl ester
0 /
,-0
N-C\ -1\1/-)
N
To a mixture of 2-chloro-5-nitropyridine (476 mg, 3.0 mmol) and 4-piperidine
acetic acid
methyl ester (471 mg, 3.0 mmol) in tetrahydrofuran (10 mL) was added
diisopropylethylamine (1.0 mL, 5.74 mmol). The mixture was heated in a
microwave at
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120 C for 30 minutes. The mixture was evaporated to dryness and extracted
with ethyl
acetate and water. The organic layer was dried over sodium sulfate and
solvents were
evaporated. The residue was purified using flash chromatography (eluting with
ethyl
acetate and hexanes) to give (5'-nitro-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-
4-y1)-acetic
acid methyl ester as a yellow solid. The NMR spectrum obtained on the sample
is
compatible with its structure.
To a solution of (5'-nitro-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-y1)-acetic
acid methyl
ester (279 mg, 1 mmol) from above in a mixture of tetrahydrofuran (10 mL) and
ic, methanol (50 mL) was added 10% palladium on carbon (50 mg). The mixture
was
hydrogenated at 50 psi for 1 hr. The mixture was filtered and the solvents
were
evaporated to give (5'-amino-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-y1)-
acetic acid
methyl ester that was used in the next step without further purification.
Preparation of 2-(5'-amino-3,4,5,6-tetrahydro-2H- [1,21 bipyridiny1-4-y1)-2-
methyl-
propionic acid ethyl ester
¨0 ¨/
N d __ ) (
N \ 0
To a solution of diisopropylamine (7.64 mL, 54.5 mmol) in dry tetrahydrofuran
(5 mL) at
-78 C was added n-butyl lithium (2.5 M, 20 mL, 50.0 mmol). The mixture was
stirred at
-65 C for 30 minutes. Then ethyl isobutyrate (6.09 mL, 45.6 mmol) in
tetrahydrofuran (5
mL) was added. The mixture was stirred at -60 C for 45 minutes. To this
solution was
added 1-benzylpiperidone (6.15 g, 32.5 mmol) in 5 mL of tetrahydrofuran. The
mixture
was allowed to warm up to room temperature and stirred overnight. The mixture
was
quenched with ammonium chloride solution (30 mL) and extracted with ether (100
mL).
The organic layer was first washed with brine and then dried over sodium
sulfate.
Solvents were evaporated and the residue was purified using flash
chromatography
(eluting with ethyl acetate and hexanes) to give 2-(1-benzy1-4-hydroxy-
piperidin-4-y1)-2-
methyl-propionic acid ethyl ester (5.87 g) as an oily material. The NMR
spectrum
obtained on the sample is compatible with its structure. LC-MS calcd for
Cl8H27NO3
(m/e) 305.43, obsd 306.2 (M+H).
2-(1-benzy1-4-hydroxy-piperidin-4-y1)-2-methyl-propionic acid ethyl ester
(3.24 g, 10.6
mmol) from above was dissolved in chloroform (13 mL) containing N,N-
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dimethylformamide (34 4). To this solution was added thionyl chloride (1.56
mL). The
mixture was refluxed overnight. Solvents were evaporated and the residue was
extracted
with ethyl acetate and sodium hydroxide (1N) solution. The organic layer was
washed
with brine and dried over sodium sulfate. After evaporation of solvents, the
residue was
purified using flash chromatography (eluting with ethyl acetate and hexanes)
to give 2-
(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propionic acid ethyl ester
(1.17 g) as
an oily material. The NMR spectrum obtained on the sample is compatible with
its
structure. LC-MS calcd for C18H25NO2 (m/e) 287.4, obsd 288.2 (M+H).
2-(1-benzy1-1,2,3,6-tetrahydro-pyridin-4-y1)-2-methyl-propionic acid ethyl
ester from
above (1.15 g, 4.0 mmol) was dissolved in 50 mL of ethanol and 10% palladium
on
carbon (600 mg) was added. The mixture was hydrogenated at 50 psi for 20 hrs.
The
mixture was filtered and solvents were evaporated to give 2-methy1-2-piperidin-
4-yl-
propionic acid ethyl ester (760 mg) as an oil. The NMR spectrum obtained on
the sample
is compatible with its structure. LRMS calcd for C11H21NO2 (m/e) 199.29, obsd
200.1
(M+H).
The above 2-methyl-2-piperidin-4-yl-propionic acid ethyl ester (606 mg, 3.82
mmol) was
mixed with 2-chloro-5-nitropyridine (760 mg, 3.82 mmol) in 10 mL of
tetrahydrofuran.
To this solution was added diisopropylethylamine (1.33 mL). The mixture was
heated in
a microwave at 140 C for 30 minutes. Solvents were evaporated and the residue
was
extracted with methylene chloride and water. The organic layer was dried over
sodium
sulfate, filtered and concentrated. The residue was purified using flash
chromatography
(eluting with ethyl acetate and hexanes) to give 2-methy1-2-(5'-nitro-3,4,5,6-
tetrahydro-
2H- [1 acid ethyl ester as a solid (1.13 g, 92%). The NMR
spectrum obtained on the sample is compatible with its structure.
With a method similar to that used for the preparation of (5'-amino-3,4,5,6-
tetrahydro-
2H-[1,21bipyridiny1-4-y1)-acetic acid methyl ester above, 2-(5'-amino-3,4,5,6-
tetrahydro-
2H41,21bipyridinyl-4-y1)-2-methyl-propionic acid ethyl ester was prepared from
the
hydrogenation of 2-methyl-2-(5'-nitro -3,4,5,6-tetrahydro -2H- [1,21
bipyridiny1-4-y1)-
propionic acid ethyl ester. This compound was used in the next step without
further
purification.
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Preparation of 2-(5'-amino-3,4,5,6-tetrahydro-2H- [1,21 bipyridiny1-4-y1)-2-
methyl-
propionic acid
N----0____ 0
To a solution of 2-methy1-2-(5'-nitro-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-
y1)-
propionic acid ethyl ester (321 mg, 1.0 mmol) in tetrahydrofuran (2 mL) and
methanol (6
mL) was added sodium hydroxide solution (1N, 2 mL). The mixture was heated in
a
microwave at 140 C for 1.5 hr. The mixture was evaporated and the residue was
dissolved in hot methanol and water. The clear solution was then acidified
with 1N
hydrochloric acid (2.5 mL). The resulting pale yellow precipitate was filtered
and dried
to give 2-methyl-2-(5'-nitro-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-0-
propionic acid
(210 mg). LC-MS calcd. for C14H19N304 (m/e) 293.1, obsd 294.1.
With a method similar to that used for the preparation of (5'-amino-3,4,5,6-
tetrahydro-
2H-[1,21bipyridiny1-4-y1)-acetic acid methyl ester above, 2-(5'-amino-3,4,5,6-
tetrahydro-
2H41,21bipyridinyl-4-y1)-2-methyl-propionic acid was prepared from the
hydrogenation
of 2-methyl-2-(5'-nitro-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-y1)-propionic
acid. This
compound was used in the next step without further purification.
Preparation of 3-(5'-amino-3,4,5,6-tetrahydro-2H- [1,21 bipyridiny1-4-y1)-2,2-
dimethyl-propionic acid
) 0
-N _____________________________________
)\40
To a solution of 3-(N-Boc-piperidine-4-y1)-propionic acid (4.0 g, 15.6 mmol)
in ether
(100 mL) was added a solution of diazomethane in ether (0.2 M, 100 ml) in
portions until
the solution became lightly yellow. The mixture was stirred at room
temperature for 1 hr
and the solvents were evaporated to give 3-(N-Boc-piperidine-4-y1)-propionic
acid
methyl ester (4.2 g) as an oil.
3-(N-Boc-piperidine-4-y1)-propionic acid methyl ester (2.0 g, 7.38 mmol) from
above
was dissolved in tetrahydrofuran (50 mL). The solution was cooled to -78 C
and sodium
bis(trimethylsilyl)amide (1.0 M, 9.0 mL) was added. The mixture was stirred at
-78 C
for 1 hr and methyl iodide (1.2 mL, 19.5 mmol) was added. The mixture was
warmed to
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room temperature and stirred for 2 hrs. The mixture was extracted with ether
and washed
with dilute hydrochloric acid. The organic layer was dried, filtered and
concentrated. The
residue was purified using flash chromatography (eluting with ethyl acetate
and hexanes)
to give 2-methyl-3-(N-Boc-piperidine-4-y1)-propionic acid methyl ester as an
oil (789
mg).
2-methyl-3-(N-Boc-piperidine-4-y1)-propionic acid methyl ester (789 mg, 2.77
mmol)
from above was dissolved in dry tetrahydrofuran (2 mL) and cooled to -78 C.
To this
solution was added lithium diisopropylamide (5.5 mmol, prepared from
diisopropylamine and n-butyl lithium). The mixture was stirred at -78 C for 1
hr and
methyl iodide (0.7 mL, 11.24 mmol) was added. The mixture was stirred at -78
C for 2
hrs until complete consumption of the starting material. The mixture was
treated with
hydrochloric acid (1N, 10 mL) and extracted with ether. The organic layer was
washed
with brine and dried over sodium sulfate. After evaporation of the solvents,
the residue
was purified using flash chromatography (eluting with hexanes and ethyl
acetate) to give
2,2-dimethy1-3-(N-Boc-piperidine-4-y1)-propionic acid methyl ester as a
colorless oil that
slowly turned into a solid (598 mg).
2,2-dimethy1-3-(N-Boc-piperidine-4-y1)-propionic acid methyl ester (598 mg)
from
above was dissolved in methylene chloride (2 mL) and trifluoroacetic acid (1
mL) was
added. The mixture was stirred at room temperature for 1 hr and the solvents
were
evaporated. The mixture was partitioned between ether and sodium hydroxide
solution
(1N). The organic layer was washed with brine and dried. Evaporation of
solvents gave
2,2-dimethy1-3-(piperidine-4-y1)-propionic acid methyl ester (370 mg) as an
oil.
2,2-Dimethy1-3-(piperidine-4-y1)-propionic acid methyl ester (156 mg, 0.78
mmol) from
above was mixed with 2-chloro-5-nitropyridine (124 mg, 0.78 mol) in
tetrahydrofuran (2
mL) containing triethylamine (0.24 mL). The mixture was heated in a microwave
at 140
C for 30 minutes. The mixture was extracted with ethyl acetate and water. The
organic
layer was washed with brine and dried. Solvents were evaporated and the
residue was
triturated with ether to give 2,2-dimethy1-3-(5'-nitro-3,4,5,6-tetrahydro-2H-
[1,21bipyridiny1-4-y1)-propionic acid methyl ester (199 mg) as a crystalline
material. The
NMR spectrum obtained on the sample is compatible with its structure.
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propionic acid
methyl ester (199 mg, 0.62 namol) from above was dissolved in tetrahydrofuran
(2 mL).
Then methanol (4 mL) and sodium hydroxide solution (1N, 2 mL) were added. The
mixture was stirred and refluxed for 8 hrs. Solvents were evaporated and the
residue was
dissolved in hot methanol. The solution was cooled to room temperature and
hydrochloric acid (IN, 2 mL) was added. The resulting mixture was cooled in an
ice bath
and the solid was filtered and washed with water. The solid was dried in air
to give 2,2-
dimethy1-3-(5'-nitro-3 ,4,5,6-tetrahydro-2H- [1,21bipyridiny1-4-y1)-propionic
acid (181.5
mg). The NMR spectrum obtained on the sample is compatible with its structure.
LC-MS
cakd for C15H21N304 (m/e) 307.34, obsd 308.1 (M+H).
With a method similar to that used for the preparation of (5'-amino-3,4,5,6-
tetrahydro-
2H-D,TThipyridiny1-4-y1)-acetic acid methyl ester above, 3-(5'-amino-3,4,5,6-
tetrahydro-
2H-[1,21bipyridiny1-4-y1)-2,2-dimethyl-propionic acid was prepared from the
hydrogenation of 2,2-dimethy1-3-(5'-nitro-3,4,5,6-tetrahydro-2H-
[1,21bipyridinyl-4-y1)-
propionic acid. This compound was used in the next step without further
purification.
Preparation of (S)-3-(5-amino-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid
tert-butyl ester
NreCN¨µoX
0
A mixture of 2-chloro-5-nitro-pyridine (3.4 g, 0.021 mol), (S)-(-)-3-amino-
pyrrolidine-1-
carboxylic acid tert-butyl ester (4 g, 0.021 mol), and potassium carbonate
(14.5 g, 0.105
mol) in acetonitrile (50 nip was heated at reflux for 24 h. The reaction was
monitored by
LCMS and additional (S)-(-)-3-amino-pyrrolidine-l-carboxylic acid tert-butyl
ester was
added until the reaction was driven to completion. The reaction mixture was
then filtered
and concentrated to give (S)-3-(5-nitro-pyridin-2-ylamino)-pyrrolidine-1-
carboxylic acid
tert-butyl ester (5.1 g, 78.6%) as a yellow solid. LCMS calcd for C14H20N404
(rule)
308, obsd 307.1(M-H).
A mixture of (S)-3-(5-nitro-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid
tert-butyl
ester (500 mg, 1.67 rnmol), 10 % palladium on carbon (80 mg) in methanol (10
mL) was
hydrogenated at 50 psi in a Parr Shaker at room temperature for 2 h. The
reaction
mixture was then filtered through a plug of celitemaind the filtration pad was
washed with
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ethyl acetate. The organic layers were collected and concentrated to give (S)-
3-(5-amino-
pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (490 mg,
crude) as a
light red solid, which was directly used in the next step without further
purification.
Preparation of (R)-3-(5-amino-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid
tert-butyl ester
N.
I 0--eX
NNI's 0
With a method similar to that used for the preparation of (S)-3-(5-nitro-
pyridin-2-
ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (R)-3 -(5 -
nitro -pyridin-2-
ylamino)-pyrrolidine-l-carboxylic acid tert-butyl ester was prepared from 2-
chloro-5-
nitro-pyridine and (R)-(-)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl
ester. LCMS
calcd for C14H20N404 (m/e) 308.3, obsd 309 (M+H). This material was a mixture
of
product and starting material (6:1 ratio) and was used in the next step
without further
purification.
With a method similar to that used for the preparation of (S)-3-(5-amino-
pyridin-2-
ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (R)-3 -(5 -
amino -pyridin-2-
ylamino)-pyrro lidine-l-carboxylic acid tert-butyl ester was prepared by the
hydrogenation of (R)-3 -(5 -nitro -pyridin-2-ylamino)-pyrro lidine-l-
carboxylic acid tert-
butyl ester. This material was used in the next step without further
purification.
Preparation of [(S)-1-(5-amino-pyridin-2-y1)-pyrrolidin-3-y1]-carbamic acid
tert-
butyl ester
N
1
1\1-Nli
t----, 0
N--
0
With a method similar to that used for the preparation of (S)-3-(5-nitro-
pyridin-2-
ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (S)-1-(5 -nitro
-pyridin-2-
y1)-pyrrolidin-3-y1]-carbamic acid tert-butyl ester was prepared from 2-chloro-
5-nitro-
pyridine and (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester. LCMS calcd
for
C14H20N404 (m/e) 308.34, obsd 309 (M+H).
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With a method similar to that used for the preparation of (S)-3-(5-amino-
pyridin-2-
ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (S)-1-(5-amino-
pyridin-2-
y1)-pyrrolidin-3-y1]-carbamic acid tert-butyl ester was prepared by the
hydrogenation of
(S)-1-(5-nitro-pyridin-2-y1)-pyrrolidin-3-y1]-carbamic acid tert-butyl ester.
This material
was directly used in the next step without further purification.
Preparation of [(R)-1-(5-amino-pyridin-2-y1)-pyrrolidin-3-y1]-carbamic acid
tert-
butyl ester
0
With a method similar to that used for the preparation of (S)-3-(5-nitro-
pyridin-2-
ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (R)-1 -(5-nitro
-pyridin-2-
y1)-pyrro lidin-3 -yl] -carbamic acid tert-butyl ester was prepared from 2-
chloro-5-nitro-
pyridine and (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester. LCMS calcd
for
C14H20N404 (m/e) 308.34, obsd 309 (M+H). This material was a mixture of
product
and starting material (10:1 ratio) and was used in the next step without
further
purification.
With a method similar to that used for the preparation of (S)-3-(5-amino-
pyridin-2-
ylamino)-pyrrolidine-l-carboxylic acid tert-butyl ester above, (R)-1 -(5-amino
-pyridin-2-
y1)-pyrro lidin-3-yl] -carbamic acid tert-butyl ester was prepared by the
hydrogenation of
(R)-1-(5-nitro-pyridin-2-y1)-pyrrolidin-3-y1]-carbamic acid tert-butyl ester.
This material
was directly used in the next step without further purification.
Preparation of racemic [1-(5-amino-pyridin-2-y1)-pyrrolidin-3-ylpmethyl-
carbamic
acid tert-butyl ester
NNQ
0
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With a method similar to that used for the preparation of (S)-3-(5-nitro-
pyridin-2-
ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, racemic [1-(5-
nitro-
pyridin-2-y1)-pyrrolidin-3-y1]-methyl-carbamic acid tert-butyl ester was
prepared from 2-
chloro-5-nitro-pyridine and racemic 3-
(N-tert-butoxycarbonyl-N-
methylamino)pyrrolidine. LCMS calcd for C15H22N404 (m/e) 322.37, obsd 323.1
(M+H).
With a method similar to that used for the preparation of (S)-3-(5-amino-
pyridin-2-
ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, racemic [1-(5-
amino-
pyridin-2-y1)-pyrrolidin-3-y1]-methyl-carbamic acid tert-butyl ester was
prepared by the
hydrogenation of racemic [1-(5-nitro-pyridin-2-y1)-pyrrolidin-3-y1]-methyl-
carbamic acid
tert-butyl ester. This material was directly used in the next step without
further
purification.
Preparation of racemic 1-(5-amino-pyridin-2-y1)-pyrrolidine-3-carboxylic acid
methyl ester
N
1
NN
0
0 \
With a method similar to that used for the preparation of (S)-3-(5-nitro-
pyridin-2-
ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, racemic 1-(5-
nitro-pyridin-
2-y1)-pyrrolidine-3-carboxylic acid methyl ester was prepared from 2-chloro-5-
nitro-
pyridine and racemic Pyrrolidine-3-carboxylic acid methyl ester. LCMS calcd
for
Cl 1H15N304 (m/e) 251.3, obsd 252 (M+H).
With a method similar to that used for the preparation of (S)-3-(5-amino-
pyridin-2-
ylamino)-pyrrolidine- 1 -carboxylic acid tert-butyl ester above, racemic 1-(5-
amino-
pyridin-2-y1)-pyrrolidine-3-carboxylic acid methyl ester was prepared by the
hydrogenation of racemic 1-(5-nitro-pyridin-2-y1)-pyrrolidine-3-carboxylic
acid methyl
ester. This material was directly used in the next step without further
purification.
Preparation of (1S,3S)-3-(5-amino-pyridin-2-ylamino)-cyclopentanecarboxylic
acid
methyl ester
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- 45 -
N,
1 weci) 0--
1 ...i
N 0
With a method similar to that used for the preparation of (S)-3-(5-nitro-
pyridin-2-
ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (1 S ,3 S)-3 -
(5-nitro-pyridin-
2-ylamino)-cyclopentanecarboxylic acid methyl ester was prepared from 2-chloro-
5-
nitro-pyridine and (1 S ,3 S)-3-amnio cyc lop entane carbo xylic acid methyl
ester
hydrochloride salt. LCMS calcd for C12H15N304 (m/e) 265.3, obsd 266 (M+H).
This
material was a mixture of product and starting material (76:24 ratio) and was
used in the
next step without further purification.
With a method similar to that used for the preparation of (S)-3-(5-amino-
pyridin-2-
ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (1 S ,3 S)-3 -
(5-amino -
pyridin-2-ylamino)-cyclopentanecarboxylic acid methyl ester was prepared by
the
hydrogenation of (1 S ,3 S)-3-(5 -nitro -pyridin-2-ylamino)-cyc lop
entanecarbo xylic acid
methyl ester. This material was directly used in the next step without further
purification.
Preparation of (1R,3S)-3-(5-amino-pyridin-2-ylamino)-cyclopentanecarboxylic
acid
ethyl ester
N
0-I
I ,
..?..--..,N.,õ,..0
N 0
With a method similar to that used for the preparation of (S)-3-(5-nitro-
pyridin-2-
ylamino)-pyrrolidine-l-carboxylic acid tert-butyl ester above, (1R,3 S)-3-(5 -
nitro -pyridin-
2-ylamino)-cyclopentanecarboxylic acid methyl ester was prepared from 2-chloro-
5-
nitro-pyridine and (1R,3 S)-3 -amnio cyc lop entane carbo xylic acid methyl
ester
hydrochloride salt. LCMS calcd for C12H15N304 (m/e) 265.3, obsd 266 (M+H).
With a method similar to that used for the preparation of (S)-3-(5-amino-
pyridin-2-
ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (1R,3 S)-3 -(5 -
amino -
pyridin-2-ylamino)-cyclopentanecarboxylic acid methyl ester was prepared by
the
hydrogenation of (1R,3 S)-3 -(5-nitro-pyridin-2-ylamino)-cyc lop entanecarbo
xylic acid
methyl ester. This material was directly used in the next step without further
purification.
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Preparation of 5'-amino-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-carboxylic
acid
ethyl ester
N.
I
NN
H.(0
0
With a method similar to that used for the preparation of (S)-3-(5-nitro-
pyridin-2-
ylamino)-pyrrolidine-l-carboxylic acid tert-butyl ester above, 5'-nitro-
3,4,5,6-tetrahydro-
2H41,21bipyridiny1-4-carboxylic acid ethyl ester was prepared from 2-chloro-5-
nitro-
pyridine and piperidine-4-carboxylic acid ethyl ester. LCMS calcd for
C13H17N304
(m/e) 279.3, obsd 280 (M+H).
With a method similar to that used for the preparation of (S)-3-(5-amino-
pyridin-2-
ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, 5'-amino-
3,4,5,6-
tetrahydro-2H-[1,21bipyridiny1-4-carboxylic acid ethyl ester was prepared by
the
hydrogenation of 5'-nitro-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-carboxylic
acid ethyl
ester. This material was directly used in the next step without further
purification.
Preparation of (S)-3-(5-amino-pyrimidin-2-ylamino)-pyrrolidine-1-carboxylic
acid
tert-butyl ester
NN
I N¨ex
LI\ re-C
N 0
With a method similar to that used for the preparation of (S)-3-(5-nitro-
pyridin-2-
ylamino)-pyrrolidine-l-carboxylic acid tert-butyl ester above, (S)-3-(5-nitro-
pyrimidin-2-
ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 2-
chloro-5-
nitro-pyrimidine and (S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl
ester. LCMS
calcd for C13H19N504 (m/e) 309.3, obsd 310 (M+H).
With a method similar to that used for the preparation of (S)-3-(5-amino-
pyridin-2-
ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (S)-3 -(5 -
amino -pyrimidin-
2-ylamino)-pyrro lidine- 1 -carboxylic acid tert-butyl ester was prepared by
the
hydrogenation of (S)-3 -(5 -nitro -pyrimidin-2-ylamino)-pyrro lidine-l-
carboxylic acid tert-
butyl ester. This material was directly used in the next step without further
purification.
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Preparation of 4-(5-amino-pyridin-2-y1)-piperazine-1-carboxylic acid tert-
butyl
ester
N
1
NN
N,O)
0
With a method similar to that used for the preparation of (S)-3-(5-nitro-
pyridin-2-
ylamino)-pyrrolidine- 1-carboxylic acid tert-butyl ester above, 4-(5-nitro-
pyridin-2-y1)-
piperazine- 1-carboxylic acid tert-butyl ester was prepared from 2-chloro-5-
nitro-pyridine
and piperazine- 1-carboxylic acid tert-butyl ester. LCMS calcd for C14H20N404
(m/e)
308.3, obsd 309 (M+H). This material was a mixture of product and starting
material (5:2
ratio) and was used in the next step without further purification.
With a method similar to that used for the preparation of (S)-3-(5-amino-
pyridin-2-
ylamino)-pyrrolidine- 1-carboxylic acid tert-butyl ester above, 4-(5-amino-
pyridin-2-y1)-
piperazine- 1-carboxylic acid tert-butyl ester was prepared by the
hydrogenation of 4-(5-
nitro-pyridin-2-y1)-piperazine- 1-carboxylic acid tert-butyl ester. This
material was
directly used in the next step without further purification.
Preparation of (S)-3-(4-amino-phenylamino)-pyrrolidine-1-carboxylic acid ethyl
ester
N 0 e_i
0
With a method similar to that used for the preparation of (S)-3-(5-nitro-
pyridin-2-
ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (S)-3 -(4-nitro
-
phenylamino)-pyrrolidine- 1-carboxylic acid tert-butyl ester was prepared from
1-fluoro-
4-nitrobenzene and (S)-3-amino-pyrrolidine- 1-carboxylic acid tert-butyl
ester. LCMS
calcd for C15H21N304 (m/e) 307.4, obsd 306.2 (M-H).
(S)-3-(4-nitro-phenylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester was
deprotected with trifluoro acetic acid according to known procedures. After
concentration,
the amine trifluoro acetate salt was treated with ethyl chloroformate (1
equiv.) and
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triethylamine (3 equiv.) in methylene chloride to afford (S)-3-(4-nitro-
phenylamino)-
pyrrolidine-1-carboxylic acid ethyl ester. LCMS calcd for C13H17N304 (m/e)
279.3,
obsd 280.1 (M+H).
With a method similar to that used for the preparation of (S)-3-(5-amino-
pyridin-2-
ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (S)-3 -(4-amino
-
phenylamino)-pyrrolidine-l-carboxylic acid ethyl ester was prepared by the
hydrogenation of (S)-3-(4-nitro-phenylamino)-pyrrolidine-1-carboxylic acid
ethyl ester.
This material was directly used in the next step without further purification.
Preparation of [4-(4-amino-phenylarnino)-cyclohexyll-carbarnic acid tert-butyl
ester
N 0 -\----
= .....,C),0N40
N
With a method similar to that used for the preparation of (S)-3-(4-amino-
phenylamino)-
pyrrolidine-1-carboxylic acid ethyl ester, [4-(4-amino -p henylamino)-cyc lo
hexyl] -
carbamic acid tert-butyl ester was prepared from (4-amino-cyclohexyl)-carbamic
acid
tert-butyl ester and 1-fluoro-4-nitro-benzene. LCMS calcd for C17H27N302 m/e
305.2,
obsd 306 (M+H).
Preparation of (S)-3-[(5-amino-pyridin-2-y1)-methyl-aminoppyrrolidine-1-
carboxylic acid tert-butyl ester
N
I vCN--eX
N 0
I
To a solution of (S)-3-(5-nitro-pyridin-2-ylamino)-pyrrolidine-1-carboxylic
acid tert-
butyl ester described previously (300 mg, 0.97 mmol) in tetrahydrofuran cooled
at 0 C
was added sodium hydride (47 mg, 1.95 mmol) gradually. The mixture was stirred
at
room temperature for 15 min followed by the addition of methyl iodide (166 mg,
1.17
mmol). The reaction mixture was stirred for 2 h and then extracted with ethyl
acetate and
washed with water. The organic layer was dried over sodium sulfate, filtered
and
concentrated to give (S)-3 -[(5 -nitro -pyridin-2-y1)-methyl-amino ] -
pyrro lidine-1-
carboxylic acid tert-butyl ester (295 mg, crude) as a yellow solid, which was
directly
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used in the next step without further purification. LCMS calcd for C15H22N404
(m/e)
322, obsd 323 (M+H).
With a method similar to that used for the preparation of (S)-3-(5-amino-
pyridin-2-
ylamino)-pyrrolidine-l-carboxylic acid tert-butyl ester above, (S)-3-[(5-amino-
pyridin-2-
y1)-methyl-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared
by the
hydrogenation of (S)-3 -[(5 -nitro -pyridin-2-y1)-methyl-amino ] -pyrro lidine-
l-carboxylic
acid tert-butyl ester. This material was directly used in the next step
without further
purification.
Preparation of 4-(2-cyano-4-nitro-pheny1)-piperazine-1-carboxylic acid tert-
butyl
ester
00 __
\N 411 N/ \N
\- <-/ \ 0
0
\\
N
A solution of 2-fluoro-5-nitrobenzonitrile (500 mg, 3.0 mmol) in ethanol (35
mL) was
treated with potassium carbonate (420 mg, 3.0 mmol) and piperazine-l-
carboxylic acid
tert-butyl ester (560 mg, 3.0 mmol). The reaction mixture was stirred at 80 C
for 1 h,
then cooled and partitioned between ethyl acetate and water. The organic layer
was then
collected, dried over sodium sulfate, filtered and evaporated to a yellow
residue.
Purification using flash chromatography yielded 4-(2-cyano-4-nitro-pheny1)-
piperazine-
1-carboxylic acid tert-butyl ester (590 mg, 59% yield) as a bright yellow
solid. HRMS
calcd for C16H20N404 (M+Na) 355.1377, obsd 355.1376.
Preparation of 4-(5-amino-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-
butyl ester
0
N
N 0
1
N
N
A mixture of 2-bromo-5-nitro-pyridine (5 g, 24.6 mmol), 4-amino-piperidine-1-
carboxylic acid tert-butyl ester (5 g, 25 mmol), and triethylamine (5 mL) in
N,N-
dimethylformamide (30 mL) was stirred at 90 C for 14 h. The reaction mixture
was then
partitioned between water and ethyl acetate, and the two layers were
separated. The
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aqueous layer was extracted with ethyl acetate three times. The organic layers
were
combined, washed with brine, dried over sodium sulfate, filtered, and
concentrated. The
residue was purified by flash chromatography to give 7.15 g (90 %) 4-(5-nitro-
pyridin-2-
ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid. LCMS
calcd for
C15H22N404 (m/e) 322, obsd 323 (M+H).
With a method similar to that used for the preparation of (S)-3-(5-amino-
pyridin-2-
ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, 4-(5-amino-
pyridin-2-
ylamino)-piperidine-1-carboxylic acid tert-butyl ester was prepared by the
hydrogenation
of 4-(5-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl
ester. This
material was directly used in the next step without further purification.
Preparation of (5'-amino-3,4,5,6-tetrahydro-2H- [1,2] bipyridiny1-4-y1)-methyl-
carbamic acid tert-butyl ester
N
I
NN 0
NA0/<
I
A mixture of 2-bromo-5-nitro-pyridine (4.74 g, 23.3 mmol), methyl-piperidin-4-
yl-
carbamic acid tert-butyl ester (5 g, 23.3 mmol), and triethylamine (5 mL) in
N,N-
dimethylformamide (30 mL) was stirred at 90 C for 14 h. Upon completion of
the
reaction, the reaction mixture was partitioned between water and ethyl
acetate. The
aqueous layer was extracted with ethyl acetate twice. The combined organic
layers were
washed with brine, dried over sodium sulfate, filtered, and concentrated. The
residue was
recrystallized from methanol and water to give methyl (5'-nitro-3,4,5,6-
tetrahydro-2H-
[1,21bipyridiny1-4-y1)-carbamic acid tert-butyl ester (6.7 g, 85.5%) as brown
crystals.
LCMS calcd for C16H24N404 (m/e) 336, obsd 337 (M+H).
A solution of methyl (5 '-nitro-3 ,4,5 ,6-tetrahydro-2H- [1,21 bipyridiny1-
4-y1)-carbamic
acid tert-butyl ester (1.4 g, 4.2 mmol) in ethyl acetate (5 mL) in the
presence of 10%
palladium on carbon (0.15 g) was shaken under 40 psi of hydrogen at room
temperature
for 2 h. The reaction mixture was filtered through a plug of celite and the
filtration pad
was washed with ethyl acetate. The combined washings were concentrated and
dried to
give 5 '-amino-3 ,4,5 ,6-tetrahydro -2H-[1,21 bipyridiny1-4-y1)-methyl-
carbamic acid tert-
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- 51 -
butyl ester (1.25 g, 98%) as a brown solid. This material was used in the next
step
without further purification.
Preparation of (S)-3-(5-nitro-pyridin-2-yloxy)-pyrrolidine-1-carboxylic acid
tert-
butyl ester
..,.ov0.......0
0,N +'1
I I
0 NO-cy
A solution of (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester
(500 mg, 2.67
mmol) in anhydrous tetrahydrofuran (10 mL) was added to sodium hydride (60% in
mineral oil, 215 mg, 5.34 mmol) gradually, and the resulting mixture was
stirred at room
temperature for 1 h. 2-Chloro-5-nitropyridine (425 mg, 2.68 mmol) was added,
and the
reaction mixture was stirred at room temperature for 3 h, then quenched with
water,
extracted with ethyl acetate, washed with water, dried over anhydrous sodium
sulfate,
and concentrated to afford (S)-3-(5 -nitro -pyridin-2-ylo xy)-pyrro lidine-l-
carboxylic acid
tert-butyl ester as a brown oil (800 mg, 98% yield). The NMR spectrum obtained
on the
sample is compatible with its structure.
Preparation of (S)-3-(4-nitro-phenoxy)-pyrrolidine-1-carboxylic acid tert-
butyl
ester
0......0
N
O.,N+ 10111
I I 0¨ )/
0
With a method similar to that used for the preparation of (S)-3-(5-nitro-
pyridin-2-yloxy)-
pyrrolidine-1-carboxylic acid tert-butyl ester, (S)-3-(4-nitro -pheno xy)-
pyrro lidine-1-
carboxylic acid tert-butyl ester was prepared from (S)-3-hydroxy-pyrrolidine-1-
carboxylic acid tert-butyl ester and 1-fluoro-4-nitrobenzene. The NMR spectrum
obtained on the sample is compatible with its structure.
Preparation of (S)-3-(5-nitro-pyrimidin-2-yloxy)-pyrrolidine-1-carboxylic acid
tert-
butyl ester
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N y 0......0
0,N+7N N
0
With a method similar to that used for the preparation of (S)-3-(5-nitro-
pyridin-2-yloxy)-
pyrrolidine-1-carboxylic acid tert-butyl ester, (S)-3 -(5 -nitro -pyrimidin-2-
ylo xy)-
pyrrolidine-l-carboxylic acid tert-butyl ester was prepared from (S)-3-hydroxy-
pyrrolidine-l-carboxylic acid tert-butyl ester and 2-fluoro-5-nitropyrimidine.
The NMR
spectrum obtained on the sample is compatible with its structure.
Preparation of (2-amino-ethyl) methyl carbamic acid ethyl ester
trifluoroacetate
salt
I
N N y()
0
To a solution of N-tert-butoxycarbony1-2-methylamino-ethylamine hydrochloride
salt (1
g, 4.7 mmol) in methylene chloride (30 mL) was added triethylamine (1.63 mL),
followed by ethyl chloroformate (450 ilL, 4.7 mmol). The reaction mixture was
allowed
to stir at room temperature overnight. After solvent removal, the residue was
extracted
with ethyl acetate, dried over anhydrous sodium sulfate and concentrated. The
resulting
material was treated with trifluoro acetic acid without further purification.
The reaction
mixture was stirred at room temperature for 1 h and concentrated to yield (2-
amino-
ethyl) methyl carbamic acid ethyl ester trifluoro acetate salt which was
carried on to the
next step without further purification.
Preparation of racemic trans-2-(4'-amino-bipheny1-4-carbony1)-
cyclopentanecarboxylic acid
o 0,
N * 41=1 0
A mixture of 4-aminophenylboronic acid hydrochloride (0.21 g, 1.2 mmol), trans-
2-(4-
bromo-benzoy1)-cyclopentanecarboxylic acid (0.30 g, 1
mmol),
tetrakis(triphenylphosphine) palladium (0) (10 mg), 2 M aqueous sodium
carbonate
solution (0.5 mL), ethanol (2 mL), and ethylene glycol dimethyl ether (3 mL)
was heated
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under microwave condition to 160 C for 30 min. The crude reaction mixture was
adsorbed onto silica gel and flash chromatography (eluting with ethyl acetate
and
hexanes) yielded 0.2 g of
trans-2-(4'-amino-bipheny1-4-carbony1)-
cyclopentanecarboxylic acid as a brown solid. LCMS calcd for C19H19NO3 (m/e)
309,
obsd 310 (M+H).
Preparation of trans-2-(4'-amino-bipheny1-4-carbony1)-cyclohexanecarboxylic
acid
o 0
N 441
=
With a method similar to that used for the preparation of trans-2-(4'-amino-
biphenyl-4-
carbonyl)-cyclopentanecarboxylic acid, trans-2-(4'-amino-bipheny1-4-carbony1)-
cyclohexanecarboxylic acid was prepared from 4-aminophenylboronic acid
hydrochloride and trans-2-(4-bromo-benzoy1)-cyclohexanecarboxylic acid. LCMS
calcd
for C20H21NO3 (m/e) 323, obsd 324 (M+H).
Preparation of 4-(5-amino-pyridin-2-y1)-N-isobutyl-benzamide
N
1
(00
N
0
With a method similar to that used for the preparation of trans-2-(4'-amino-
bipheny1-4-
carbony1)-cyclopentanecarboxylic acid, 4-(5-amino-pyridin-2-y1)-N-isobutyl-
benzamide
was prepared from 5 -amino -2-bromopyridine and 4-
(isobutylaminocarbonyl)benzeneboronic acid. LCMS calcd for C16H19N30 (m/e)
269,
obsd 270 (M+H).
Acids
Preparation of rac-trans-cyclopentane-1,2-dicarboxylic acid monoethyl ester
0
n-A0---\
77-0
0
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A solution of trans-DL-cyclopentane-1,2-dicarboxylic acid (316 mg, 2 mmol) in
25 mL
ethanol was saturated with hydrogen chloride gas by bubbling for 5 minutes.
The mixture
was heated under reflux overnight, cooled and evaporated under reduced
pressure. The
residue was dissolved in ethyl acetate, washed with water, dried over
magnesium sulfate,
filtered and evaporated to dryness under vacuum to give rac-trans-cyclopentane-
1,2-
dicarboxylic acid diethyl ester (393 mg) that was used in the next step
without further
purification.
To a solution of rac-trans-cyclopentane-1,2-dicarboxylic acid diethyl ester
(393 mg, 1.84
mmol) was added a solution of lithium hydroxide (75.5 mg, 1.8 mmol) in water
(7 mL).
The reaction mixture was stirred at room temperature for 30 minutes and then
heated to
55 C for 1 hr. The reaction mixture was cooled and evaporated under reduced
pressure.
The residue was dissolved in 25 mL water and washed with diethyl ether (2 x 5
mL). The
pH of the aqueous layer was adjusted to pH 5 with 1N hydrochloric acid and
extracted
with methylene chloride (2 x 5 mL) and ethyl acetate (5 mL). The combined
organic
layers were dried over magnesium sulfate, filtered and evaporated to dryness
under
vacuum to give rac-trans-cyclopentane-1,2-dicarboxylic acid monoethyl ester
(95 mg)
that was used without further purification.
Preparation of 2,2-diethyl-succinic acid 1-methyl ester
0 0
0 0'
With a method similar to that used for the preparation of rac-trans-
cyclopentane-1,2-
dicarboxylic acid monoethyl ester, 2,2-diethyl-succinic acid 1-methyl ester
was prepared
from 2,2-diethyl-succinic acid. This material was used in the next step
without further
purification.
Preparation of 1-pheny1-3-trffluoromethyl-1H-pyrazole-4-carboxylic acid
F
F
= I"
\ _ F
0
0
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A mixture of 3-trifluoromethy1-1H-pyrazole-4-carboxylic acid ethyl ester (2.5
g, 12.0
mmol), copper (I) iodide (0.69 g, 3.6 mmol) and potassium carbonate (3.49 g,
25.3
mmol) in toluene (12 mL) in a round bottom flask was purged with argon. To the
reaction mixture was then added iodobenzene (1.61 mL, 14.4 mmol) and racemic
trans-
N,N'-dimethyl-cyclohexane-1,2-diamine (1.16 mL, 7.2 mmol). The slurry was
heated
under Ar in an oil bath at 110 C for 24 hours. After cooling to room
temperature, the
reaction mixture was diluted with ethyl acetate and filtered over a bed of
celite. The
organic washings were combined and concentrated to give a crude which was
purified by
silica gel chromatography (Isco 120 g column, 0 30%
ethyl acetate/hexanes) to give 1-
phenyl-3-trifluoromethy1-1H-pyrazole-4-carboxylic acid ethyl ester (2.91 g,
85%) as an
off-white solid. The NMR spectrum obtained on the sample is compatible with
its
structure.
A mixture of 1-pheny1-3-trifluoromethy1-1H-pyrazole-4-carboxylic acid ethyl
ester (1.25
g, 4.4 mmol) and 1N aqueous sodium hydroxide solution (17.3 mL) in methanol
(20 mL)
was stirred at room temperature overnight. The reaction mixture was
concentrated and
acidified to pH ¨ 1 with 1N aqueous hydrochloric acid. The slurry was
extracted with
methylene chloride and the combined organic layers were washed with saturated
sodium
chloride and dried over sodium sulfate. Filtration and concentration gave 1-
pheny1-3-
trifluoromethy1-1H-pyrazole-4-carboxylic acid (1 g, 89% yield) as an off-white
solid,
which was directly used in the next step without further purification. LCMS
calcd for
Cl1H7F3N202 (m/e) 256, obsd 255 (M-H).
Preparation of 1-(4-fluoro-pheny1)-3-trifluoromethy1-1H-pyrazole-4-carboxylic
acid
F al
,N
N N F
F
- F
0
0
With a method similar to that used for the preparation of 1-pheny1-3-
trifluoromethy1-1H-
pyrazo le-4-carboxylic acid above, 1-(4-fluoro-pheny1)-3-trifluoromethy1-1H-
pyrazo le-4-
carboxylic acid was prepared from 3-trifluoromethy1-1H-pyrazole-4-carboxylic
acid
ethyl ester and 1-fluoro-4-iodobenzene. LCMS calcd for Cl1H6F4N202 (m/e) 274,
obsd
273 (M-H).
Preparation of 1-(2-chloro-pheny1)-3-trifluoromethy1-1H-pyrazole-4-carboxylic
acid
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CI
F
F
411 N'NN
\ ¨ F
0
0
With a method similar to that used for the preparation of 1-pheny1-3-
trifluoromethy1-1H-
pyrazo le-4-carboxylic acid above, 1-(2-chloro-pheny1)-3-trifluoromethy1-1H-
pyrazo le-4-
carboxylic acid was prepared from 3-trifluoromethy1-1H-pyrazole-4-carboxylic
acid
ethyl ester and 1-chloro-2-iodobenzene. LCMS calcd for Cl1H6C1F3N202 (m/e)
290,
obsd 289 (M-H).
Preparation of 1-pyridin-2-y1-3-triflu o ro methyl- 1H-pyrazo le-4-ca rb o
xylic acid
----- N N
\ ¨ F
0
0
With a method similar to that used for the preparation of 1-pheny1-3-
trifluoromethy1-1H-
pyrazo le-4-carboxylic acid above, 1-pyridin-2-y1-3 -trifluoromethy1-1H-pyrazo
le-4-
carboxylic acid was prepared from 3-Trifluoromethy1-1H-pyrazole-4-carboxylic
acid
ethyl ester and 2-bromopyridine. LCMS calcd for C10H6F3N302 (m/e) 257, obsd
258
(M+H).
Preparation of 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic
acid
F
Fi....F
411 N ,
, N
0
0
To a mixture of 5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester (500 mg,
2.31 mmol)
in N,N-dimethylformamide (30 mL) at 0 C was added sodium hydride (60% in
mineral
oil, 110 mg, 2.75 mmol). The mixture was stirred at 0 C for 10 minutes and
stirred at
room temperature for 40 minutes. After the reaction mixture was re-cooled to 0
C, 2,2,2-
trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (500 mg, 2.39 mmol)
was added
dropwise. The mixture was warmed up to room temperature and stirred overnight.
The
reaction was quenched carefully with ice water and neutralized with 1N aqueous
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hydrochloric acid. The mixture was extracted with methylene chloride and the
organic
layer was dried over sodium sulfate. Filtration and concentration gave a crude
which was
purified by silica gel chromatography (Isco 120 g column, 10% ethyl
acetate/hexanes) to
give 5-pheny1-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid ethyl
ester (360
mg, 52%) as a white solid. The NMR spectrum obtained on the sample is
compatible
with its structure.
A mixture of 5-pheny1-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid
ethyl ester
(360 mg, 1.21 mmol) and 1N aqueous sodium hydroxide solution (3.6 mL, 3.6
mmol) in
methanol (10 mL) was stirred at room temperature overnight. The reaction
mixture was
acidified to pH ¨ 2 with 1N aqueous hydrochloric acid and concentrated to give
5-
pheny1-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid as an off-white
solid,
which was directly used in the next step without further purification. LCMS
calcd for
C12H9F3N202 (m/e) 270, obsd 271 (M+H).
Preparation of 5-phenyl-2-propy1-2H-pyrazole-3-carboxylic acid
411 N,
0
0
With a method similar to that used for the preparation of 5-pheny1-2-(2,2,2-
trifluoro-
ethyl)-2H-pyrazo le-3 -carboxylic acid
above, 5 -phenyl-2-propy1-2H-pyrazo le-3 -
carboxylic acid was prepared from 5-phenyl-2H-pyrazole-3-carboxylic acid ethyl
ester
and 1-iodopropane. LCMS calcd for C13H14N202 (m/e) 230, obsd 229 (M-H).
Preparation of 2-(2-methoxy-ethyl)-5-phenyl-2H-pyrazole-3-carboxylic acid
al N,
\
0
0
With a method similar to that used for the preparation of 5-pheny1-2-(2,2,2-
trifluoro-
ethyl)-2H-pyrazo le-3 -carboxylic acid above, 2-(2-metho xy-ethyl)-5 -p heny1-
2H-pyrazo le-
3-carboxylic acid was prepared from 5-pheny1-2H-pyrazole-3-carboxylic acid
ethyl ester
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and 1-iodo-2-methoxy-ethane. LCMS calcd for C13H14N203 (m/e) 246, obsd 245 (M-
H).
Preparation of 2-propy1-5-thiophen-2-y1-2H-pyrazole-3-carboxylic acid
, N-----\____--
SN
0
With a method similar to that used for the preparation of 5-pheny1-2-(2,2,2-
trifluoro-
ethyl)-2H-pyrazo le-3 -carboxylic acid above, 2-propy1-5-thiophen-2-y1-2H-
pyrazo le-3 -
carboxylic acid was prepared from 5-thiophen-2-y1-2H-pyrazole-3-carboxylic
acid ethyl
ester and 1-iodo-propane. LCMS calcd for Cl1H12N202S (m/e) 236, obsd 235 (M-
H).
Advanced Intermediates
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-
piperazin-1-
yl-pyridin-3-y1)-amide; hydrochloride
F F
. \N \ N
I
0 NN
CI N
4-(5-Amino-pyridin-2-y1)-piperazine- 1-carboxylic acid tert-butyl ester
described above
was mixed with 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid (771 mg,
3.0
mmol) and bromotrispyrrolidinophosphonium hexafluorophosphate (1.40 g, 3.0
mmol) in
N,N-dimethylformamide (20 mL) and methylene chloride (5 mL) containing
triethylamine (0.85 mL). The mixture was stirred at room temperature overnight
and the
solvents were evaporated. The residue was partitioned between ethyl acetate
and water.
The organic layer was dried over sodium sulfate and solvent was evaporated.
The residue
was triturated with ethyl acetate and the solid was filtered to give 4- {5-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester (1.09 g). LC-MS calcd for C25H26F3N504 (m/e) 517.5, obsd
518.1
(M+H). The NMR spectrum obtained on the sample is compatible with its
structure.
4- {5 - [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -pyridin-2-
y1} -p ip erazine-
1-carboxylic acid tert-butyl ester (300 mg, 0.58 mmol) from above was
suspended in
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methylene chloride (5 mL) and methanol (5 mL). To this mixture was added
hydrogen
chloride in ether (4N, 3 mL). The mixture was stirred at room temperature
overnight. The
solvents were evaporated and the residue was dried in vacuum. The resulting
solid was
triturated with dry ether and then filtered to give a hydrochloride salt of 2-
phenyl-5-
trifluoromethyl-oxazole-4-carboxylic acid (6-p ip erazin-l-yl-pyridin-3 -y1)-
amide (274
mg). LC-MS calcd C20H18F3N502 (m/e) 417.39, obsd 418.0 (M+H). The NMR
spectrum obtained on the sample is compatible with its structure.
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-
piperazin-1-
yl-pyrimidin-5-y1)-amide; hydrochloride
F F
0...F
.\N NN
I
0
N N
CI N
To a solution of 4-(5-nitro-pyrimidin-2-y1)-piperazine-1-carboxylic acid tert-
butyl ester
(927 mg, 3 mmol, prepared from 2-chloro-5-nitropyrimidine and N-Boc-
piperazine) in
tetrahydrofuran (20 mL) and methanol (30 mL) was added 10% palladium on carbon
(240 mg) and the mixture was hydrogenated at 50 psi for 1 hr. The mixture was
filtered
and the solvents were evaporated. The residue was dried in vacuum to give 4-(5-
amino-
pyrimidin-2-y1)-piperazine-1-carboxylic acid tert-butyl ester.
To a suspension of 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid (771
mg, 3
mmol) in methylene chloride (10 mL) was added oxalyl chloride (2M, 3 mL, 6.0
mmol)
and one drop of N,N-dimethylformamide. The mixture was stirred at room
temperature
for 1 hr and the solvents were evaporated. The residue was treated with
benzene (5 mL)
and the solvents were again evaporated. The oily residue was dried in vacuum
and then
dissolved in methylene chloride (10 mL). The solution was cooled in an ice
bath. To this
solution was added a methylene chloride solution of 4-(5-amino-pyrimidin-2-y1)-
piperazine-1-carboxylic acid tert-butyl ester (3 mmol) and pyridine (0.73 mL).
The
mixture was stirred at 0 C for 10 minutes and room temperature for 2 hrs.
After
concentration, the residue was partitioned between methylene chloride and
water. The
organic layer was washed with aqueous citric acid solution and dried over
sodium
sulfate. The solvents were evaporated and the residue was dried in vacuum. The
resulting
material was triturated with ethyl acetate and the precipitate was filtered to
give 4- {5-[(2-
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phenyl-5-trifluoromethyl-oxazo le-4-carbonyl)-amino]-pyrimidin-2-y4 -p ip
erazine-1-
carboxylic acid tert-butyl ester (1.38 g). LC-MS calcd for C24H25F3N604 (m/e)
518.5,
obsd 519.1 (M+H). The NMR spectrum obtained on the sample is compatible with
its
structure.
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid (6-p ip erazin-l-yl-pyridin-3 -y1)-amide above,
hydrochloride
salt of 2-phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid (2-p ip erazin-
l-yl-
pyrimidin-5 -y1)-amide was prepared from 4- {5-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbonyl)-amino]-pyrimidin-2-y1}-piperazine-l-carboxylic acid tert-butyl
ester. LC-MS
calcd for the free base C19H17F3N602 (m/e) 418.39, obsd 419.0 (M+H). The NMR
spectrum obtained on the sample is compatible with its structure.
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-
piperidin-4-
yl-phenyl)-amide
F F
0
N
0 N 0
N
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyrimidin-2-y4 -piperazine-l-
carboxylic
acid tert-butyl ester above, 4- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-phenyl}-piperidine-l-carboxylic acid tert-butyl ester was prepared from
2-
phenyl-5 -trifluoromethylo xazo le-4-carboxylic acid and 4-(4-aminop heny1)-p
ip eridine-1-
carboxylic acid tert-butyl ester. The NMR spectrum obtained on the sample is
compatible
with its structure.
4- {4- [(2-Phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -phenyl} -p
ip eridine-1-
carboxylic acid tert-butyl ester (245 mg, 0.475 mmol) from above was dissolved
in
methylene chloride (2 mL) and trifluoro acetic acid (1 mL). The mixture was
stirred at
room temperature and the solvents were evaporated. The residue was partitioned
between
methylene chloride and dilute sodium hydroxide solution. The organic layer was
washed
with brine and dried over sodium sulfate. Evaporation of solvents gave 2-
pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (183
mg) as a
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white solid. LC-MS calcd for C22H20F3N302 (m/e) 415.41, obsd 416Ø The NMR
spectrum obtained on the sample is compatible with its structure.
Preparation of 2-phenyl-5-trffluoromethyl-oxazole-4-carboxylic acid
(1 ',2 ',3 ',4',5',6'-hexahydro- [2,4,1 bipyridiny1-5-y1)-amide
F F
ilt \N \ N
I
0 e\/
N
4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-
butyl
ester (prepared according to known procedures Synthesis, 1991, 11, 993) was
reacted
with bis(pinacolato)diboron to generate N-
tert-butoxycarbonyl-1,2,3,6-
tetrahydropyridine-4-boronic acid pinacol ester according to literature
procedures
(Tetrahedron Letters, 2000, 41, 3705).
To a mixture of 2-bromo-5-nitropyridine (0.5 g, 2.46 mmol) and N-tert-
butoxycarbonyl-
1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.913 g, 2.95 mmol)
in toluene
(4 mL) and ethanol (1.0 mL) was added potassium carbonate solution (2M, 2 mL)
and
PdC12dppf (180 mg, 0.246 mmol). The mixture was degassed with argon and heated
to
100 C in a microwave for 40 minutes with stirring. The solvents were
evaporated and
the residue was extracted with ethyl acetate. After evaporation of the
solvents, the residue
was purified using flash chromatography (eluting with ethyl acetate and
hexanes) to give
5-nitro-3',6'-dihydro-2'H-[2,41bipyridiny1-1'-carboxylic acid tert-butyl ester
as a solid
(400 mg). The NMR spectrum obtained on the sample is compatible with its
structure.
5-nitro-3',6'-dihydro-2'H-[2,41bipyridiny1-1'-carboxylic acid tert-butyl ester
(400 mg)
from above was dissolved in methanol (50 mL) and tetrahydrofuran (10 mL). To
this
mixture was added 10% palladium on carbon (100 mg). The mixture was
hydrogenated
at 50 psi for 2 hrs. The mixture was filtered and the solvents were evaporated
to give 5-
amino-3',4',5',6'-tetrahydro-2'H-[2,41bipyridiny1-1'-carboxylic acid tert-
butyl ester as a
white solid (363 mg). The NMR spectrum obtained on the sample is compatible
with its
structure.
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyrimidin-2-y1} -piperazine-l-
carboxylic
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acid tert-butyl ester above, 5-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-amino]-
3',4',5',6'-tetrahydro-2'H-[2,41bipyridinyl-1'-carboxylic acid tert-butyl
ester was prepared
from 2-phenyl-5 -trifluoromethylo xazo le-4-carboxylic acid and 5 -amino -3
',4',5 ',6'-
tetrahydro -2'H- [2,41bipyridinyl- F-carboxylic acid tert-butyl ester. The NMR
spectrum
obtained on the sample is compatible with its structure.
5- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -3 ',4',5 ',6'-
tetrahydro -2'H-
[2,41bipyridinyl- F-carboxylic acid tert-butyl ester (535 mg) from above was
dissolved in
a mixture of methylene chloride (35 mL) and trifluoroacetic acid (9 mL). The
mixture
was stirred at room temperature for 2 hrs. The solvents were evaporated and
the residues
were partitioned between methylene chloride and dilute sodium hydroxide
solution. The
organic layer was washed with brine and dried over sodium sulfate. Evaporation
of
solvents gave 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid
(1',2',3',4',5',6'-
hexahydro-[2,41bipyridiny1-5-y1)-amide (360 mg) as a solid. LC-MS calcd for
C21H19F3N402 (m/e) 416.1, obsd 417.1 (M+H). The NMR spectrum obtained on the
sample is compatible with its structure.
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-
piperazin-1-
yl-pheny1)-amide
F F
0
fa
N
0 N 0
A solution of di-tert-butyldicarbonate (5.79 g, 26.5 mmol) in 20 mL dioxane
was added
dropwise to a solution of 1-(4-nitro-phenyl)-piperazine (5 g, 24.1 mmol) in
150 mL
dioxane and stirred at room temperature for 1 hr. The reaction mixture was
diluted with
250 mL ethyl acetate, washed with water, dried over sodium sulfate and
filtered. The
organic filtrate was evaporated under reduced pressure to yield 7.9 g of 4-(4-
nitro-
pheny1)-piperazine- 1-carboxylic acid tert-butyl ester that was used in the
next step
without further purification.
A mixture of 4-(4-nitro-phenyl)-piperazine- 1-carboxylic acid tert-butyl ester
(3 g, 9.76
mmol) and 10% palladium on carbon (300 mg) in 50 mL ethanol and 20 mL ethyl
acetate
was hydrogenated at room temperature under a 50 psi hydrogen atmosphere for 2
hrs.
The reaction mixture was filtered through a plug of Celite and evaporated
under reduced
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pressure to give 4-(4-amino-phenyl)-piperazine- 1-carboxylic acid tert-butyl
ester that
was used in the in the next step without further purification.
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2.5 g, 9.76 mmol), 4-(4-
amino-
pheny1)-piperazine-1-carboxylic acid tert-butyl ester (2.65 g, 10.34 mmol),
and
triethylamine (4.1 mL, 29.3 mmol) were dissolved in 50 mL of 1-methy1-2-
pyrrolidinone. To this solution was added
(benzotriazol-1-
ylo xy)tris(dimethylamino)pho sp honium hexafluorophosphate (BOP, 4.51 g,
10.34 mmol)
in one portion. The mixture was stirred at room temperature overnight and then
diluted
with 250 mL of ethyl acetate. The organic layer was washed with saturated
sodium
bicarbonate (2 x 50 mL), dried over magnesium sulfate, filtered and evaporated
to
dryness under vacuum. The residue was purified by chromatography over a silica
gel
plug (eluting with ethyl acetate/methylene chloride) to yield 4- {4-[(2-pheny1-
5-
trifluoromethyl-oxazole-4-carbony1)-amino]-phenyl} -piperazine-l-carboxylic
acid tert-
butyl ester as an amorphous solid. ES-MS calcd for C26H27F3N404 (m/e) 516.52,
obsd
517 (M+H).
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid (1',2',3 ',4',5 ',6'-hexahydro- [2,41 bipyridiny1-5 -
y1)-amide above,
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-p ip erazin-l-yl-p
heny1)-amide
was
prepared from 4- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
pheny1}-piperazine-1-carboxylic acid tert-butyl ester. LC-MS calcd. for
C21H19F3N402
(m/e) 416.1, obsd 417.1 (M+H). The NMR spectrum obtained on the sample is
compatible with its structure.
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3-cyano-4-
piperazin-1-yl-pheny1)-amide
F
0
0 \ /4
/-- \
N N 111 N N
IP
\
\
N
4-(2-Cyano-4-nitro-pheny1)-piperazine-1-carboxylic acid tert-butyl ester (587
mg, 1.77
mmol) was dissolved in methanol (50 mL) and to this solution was added
ammonium
chloride (945 mg, 17.66 mmol) and zinc (1155 mg, 17.66 mmol). The mixture was
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magnetically stirred for 3 hr and the mixture was filtered through a pad of
celite. The
solids were rinsed with methanol and the combined filtrate was concentrated to
a yellow
solid. This crude intermediate was dissolved in ethyl acetate (400 mL) and the
resulting
solution was washed with water (400 mL) and brine (200 mL). The organic layer
was
collected, dried over sodium sulfate, and concentrated to give 4-(4-amino-2-
cyano-
pheny1)-piperazine-1-carboxylic acid tert-butyl ester that was used in the
next step
without further purification.
Crude 4-(4-amino-2-cyano-pheny1)-piperazine-1-carboxylic acid tert-butyl ester
from
above was dissolved in methylene chloride (10 mL) and to the resulting
solution was
added 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (454 mg),
triethylamine
(247 L) and 1-[3-(dimethylamino)propy1]-3-ethylcarbodiimide hydrochloride
(EDCI,
337 mg). The reaction mixture was stirred at room temperature for 3 hr.
Another portion
of 1-[3-(dimethylamino)propy1]-3-ethylcarbodiimide hydrochloride (0.5 eq) was
added.
The reaction mixture was stirred at 50 C for 3 hr and at room temperature for
3.5 days.
The reaction mixture was partitioned between ethyl acetate and water. The
organic layer
was dried over sodium sulfate, filtered and evaporated. Purification by flash
chromatography afforded 4-
{2-cyano -4- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbony1)-amino]-pheny1}-piperazine-1-carboxylic acid tert-butyl ester (240
mg, 25 %
yield) as a yellow solid. LCMS calcd for C27H26F3N504 (m/e) 541, obsd 542
(M+H).
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid (1',2',3 ',4',5 ',6'-hexahydro- [2,41 bipyridiny1-5 -
y1)-amide above,
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic
acid (3 -cyano -4-pip erazin-l-yl-
phenyl)-amide was prepared from 4- {2-cyano-4-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbony1)-amino]-pheny1}-piperazine-1-carboxylic acid tert-butyl ester. LCMS
calcd for
C22H18F3N502 (m/e) 441, obsd 442 (M+H).
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-
(piperidin-
4-ylarnino)-pyridin-3-ylparnide trifluoroacetate salt
0 F
F , __ F
F
\
fi \ N N, N
I
0 = . . , . - 7 - - . . ,
..........,....., 1
N N
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A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (0.67 g, 2.6
mmol),
4-(5-amino-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester
(0.76 g, 2.6
mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrop, 1.45 g,
3.1
mmol), and diisopropylethylamine (0.9 mL, 5.2 mmol) in anhydrous
dichloromethane
(15 mL) was stirred at room temperature overnight. The reaction mixture was
then
concentrated and purified by flash chromatography (Merck silica gel 60, 230-
400 mesh,
eluted with ethyl acetate and hexane) to give 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-
4-carbony1)-amino] -pyridin-2-ylamino}-p ip eridine-l-carboxylic acid tert-
butyl ester
(0.78 g, 56 %) as a white solid. LCMS calcd for C26H28F3N504 (m/e) 531, obsd
532
(M+H).
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid (1',2',3 ',4',5 ',6'-hexahydro- [2,41 bipyridiny1-5 -
y1)-amide above,
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-
pyridin-
3-y1]-amide trifluoroacetate salt was prepared from 4- {5-[(2-pheny1-5-
trifluoromethyl-
o xazo le-4-carbony1)-amino] -pyridin-2-ylamino}-pip eridine-l-carboxylic acid
tert-butyl
ester. LCMS calcd for C21H20F3N502 (m/e) 431, obsd 432 (M+H).
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-
methylamino-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-5'-y1)-amide
trifluoroacetate
salt
F
=
F
\NN 0 F
0
N N
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (0.91 g,
3.54 mmol),
5'-amino-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-y1)-methyl-carbamic acid
tert-butyl
ester (1.25 g, 4 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate
(PyBrop, 1.86 g, 4 mmol), and diisopropylethylamine (0.8 mL, 4.6 mmol) in
anhydrous
dichloromethane (15 mL) was stirred at room temperature overnight.
After
concentration, the crude was partitioned between water and ethyl acetate. The
organic
layer was washed with brine, dried over sodium sulfate, and concentrated to
give a solid.
The crude product was purified by flash chromatography (Merck silica gel 60,
230-400
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mesh, 0%-100% ethyl acetate in hexane) to give methyl- {5'-[(2-phenyl-
trifluoromethyl-
o xazo le-4-carbony1)-amino] -3,4,5 ,6-tetrahydro -2H- [1,21 bipyridiny1-4-yl}
-carbamic acid
tert-butyl ester in quantitative yield (1.9 g) as an off-white solid. LCMS
calcd for
C27H30F3N504 (m/e) 545, obsd 546 (M+H).
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid (1',2',3 ',4',5 ',6'-hexahydro- [2,41 bipyridiny1-5 -
y1)-amide above,
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino -3
,4,5 ,6-
tetrahydro-2H-[1,21bipyridiny1-5'-y1)-amide trifluoroacetate salt was prepared
from
methyl- {5 '- [(2-phenyl-trifluoromethyl-o xazo le-4-carbonyl)-amino] -3,4,5
,6-tetrahydro -
2H- [1,21bipyridiny1-4-y1} -carbamic acid tert-butyl ester.
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo-
pyridin-3-y1)-amide
0 F
...<F
NI
N
0 N Br
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3.0 g, 11.7
mmol),
6-bromo-pyridin-3-ylamine (2.0 g, 11.7 mmol), 1-hydroxy-7-azabenzotriazole
(HOAT)
(2.4 g, 17.5 mmol), and 1-ethy1-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride
(3.4 g, 17.5 mmol) in anhydrous dichloromethane (100 mL) was stirred at room
temperature overnight. The reaction mixture was concentrated and partitioned
between
water and ethyl acetate. The organic layer was washed with brine, dried and
concentrated
to give a solid. Recrystallization of the crude solid from ethyl
acetate/hexane/methanol
gave 4.04 g of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo-
pyridin-
3-y1)-amide. The mother liquor was purified by flash chromatography (Merck
silica gel
60, 230-400 mesh, 0%-100% ethyl acetate in hexane) to give an additional 200
mg of 2-
pheny1-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo-pyridin-3-y1)-
amide (4.24
g in total, 88 %) as a light brown solid. LCMS calcd for Cl6H9BrF3N302 (m/e)
412,
obsd 413 (M+H).
Preparation of 2-phenyl-5-trffluoromethyl-oxazole-4-carboxylic acid (4-iodo-
pheny1)-amide
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F
0 -FF
\
. \N N
0
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid (6-bromo-pyridin-3-y1)-amide above, 2-pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid (4-iodo-phenyl)-amide was prepared
from 2-
phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 4-iodo-phenylamine.
LCMS
calcd for C17H10F3IN202 (m/e) 458, obsd 459 (M+H).
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-bromo-3-
fluoro-phenyl)-amide
OFC(FF
\
= \N N
0 1.1 Br
F
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid (6-bromo-pyridin-3-y1)-amide above, 2-pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid (4-bromo-3-fluoro-pheny1)-amide was
prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 4-bromo-
3-
fluoro-phenylamine. LCMS calcd for C17H9BrF4N202 (m/e) 429, obsd 430 (M+H).
Preparation of 2,2-dimethy1-4-oxo-4-14'-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-aminol-biphenyl-4-y1}-butyric acid methyl ester
F
FF
1
0
401 0
0
0
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid (6-bromo-pyridin-3-y1)-amide, 2,2-dimethy1-4-oxo-4-
{4'-[(2-
pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-biphenyl-4-y1} -butyric
acid
methyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic
acid
and 4-(4'-amino-biphenyl-4-y1)-2,2-dimethy1-4-oxo-butyric acid methyl ester
(prepared
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according to the procedure described in US 20040224997). LCMS calcd for
C30H25F3N205 (m/e) 550, obsd 551 (M+H).
Preparation of 1-(2-chloro-pheny1)-3-trifluoromethy1-1H-pyrazole-4-carboxylic
acid
(4-piperidin-4-yl-phenyl)-amide; hydrochloride
F
34--
F
CI N F N
- =
N / N
lel 0
HCI
To 1-(2-chloro-pheny1)-3-trifluoromethy1-1H-pyrazole-4-carboxylic acid
described
above (320 mg, 1.10 mmol) in methylene chloride (10 mL) was added
bromotrispyrrolidinophosphonium hexafluorophosphate (770 mg, 1.65 mmol). The
reaction was stirred for 10 minutes and then 4-(4-amino-pheny1)-piperidine-1-
carboxylic
acid tert-butyl ester (320 mg, 1.10 mmol) followed by diisopropylethylamine
(0.60 mL,
3.30 mmol) were added. The reaction was stirred at room temperature overnight.
The
crude mixture was diluted in methanol (100 mL), loaded onto silica gel and
purified
using Isco chromatography (eluting with ethyl acetate and hexanes) to give 4-
(4- {[1-(2-
chloro-pheny1)-3-trifluoromethyl-1H-pyrazo le-carbonyl] -amino} -p heny1)-p ip
eridine-1-
carboxylic acid tert-butyl ester. The NMR spectrum obtained on the sample is
compatible
with its structure.
4-(4- { [1-(2-chloro-pheny1)-3-trifluoromethyl-1H-pyrazo le-carbonyl] -amino} -
p heny1)-
piperidine- 1 -carboxylic acid tert-butyl ester (400 mg, 0.73 mmol) from above
was
dissolved in dioxane (10 mL). To this reaction mixture was bubbled in HC1 gas
for 1
minute. Reaction was stirred at room temperature for 2 hours. The solvents
were
evaporated to give 400 mg of 1-(2-chloro-pheny1)-3-trifluoromethy1-1H-pyrazole-
4-
carboxylic acid (4-piperidin-4-yl-phenyl)-amide hydrochloride salt. The NMR
spectrum
obtained on this sample is compatible with its structure.
Preparation of 4-14-[(1-pyridin-2-y1-3-trifluoromethy1-1H-pyrazole-4-carbony1)-
amino] -phenylt-piperidine-1-carboxylic acid tert-butyl ester
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F F
N____ F
i
0
--- N 0
N.,(0---f.._
0
With a method similar to that used for the preparation of 4- {4-[(1-(2-chloro-
pheny1-3-
trifluoromethyl- 1 H-pyrazo le-4-carbonyl] -amino 1 -phenyl)-p ip eridine- 1 -
carboxylic acid
tert butyl ester, 4- { 4-[( 1 -pyridin-2-y1-3 -trifluoromethyl- 1 H-pyrazo le-
4-carbonyl] -
amino} -pheny1)-piperidine- 1 -carboxylic acid tert butyl ester was prepared
from 1-
pyridin-2-y1-3-trifluoromethy1-1H-pyrazole-carboxylic acid and 4-(4-amino-
pheny1)-
piperidine- 1 -carboxylic acid tert butyl ester. The NMR spectrum obtained on
the sample
is compatible with its structure.
Preparation of 1-pyridin-2-y1-3-trifluoromethy1-1H-pyrazole-4-carboxylic acid
(4-
piperidin-4-yl-pheny1)-amide ; hydrochloride
F
F
I , N
N N 7
I
Ha
With a similar method to that used for the preparation of 1-(2-chloro-pheny1)-
3-trifluoro-
methyl- 1 H-pyrazo le-4-carboxylic acid (4-p ip eridine-4-yl-p heny1)-amide
hydrochloride,
1 -pyridin-2-y1-3 -trifluoromethyl- 1 H-pyrazo le-4-carbo xylic acid (4-
p ip eridine-4-yl-
pheny1)-amide hydrochloride was prepared from 4- {4-[(1-pyridin-2-y1-3-
trifluoromethyl-
1H-pyrazo le-4-carbonyl)-amino]-pheny1)-piperidine- 1 -carboxylic acid tert-
butyl ester.
Preparation of 4-14-1(5-pheny1-2-trifluoromethyl-furan-3-carbony1)-aminop
phenylt-piperazine-1-carboxylic acid tert-butyl ester
illF F0
0 F
\ N 41 Nr----\Ne +---
\
With a method similar to that used for the preparation of 4-(4- {[1-(2-chloro-
pheny1)-3-
trifluoromethyl- 1 H-pyrazo le-carbonyl] -amino 1 -phenyl)-p ip eridine- 1 -
carboxylic acid
tert-butyl ester, 4- {4-[(5-pheny1-2-trifluoromethyl-furan-3-carbony1)-amino]-
phenyl} -
piperazine-l-carboxylic acid tert-butyl ester was prepared from 5-phenyl-2-
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trifluoromethyl-furan-3-carboxylic acid and 4-[4-amino-pheny1]-piperazine-1-
carboxylic
acid tert-butyl ester. HRMS m/z calcd. for C27H29F3N304 [M+H]': 516.2105;
found :
516.2105.
Preparation of (1R,2R)-2-(4-14-[(5-pheny1-2-trifluoromethyl-furan-3-carbony1)-
amino] -phenylt-piperazine-1-carbony1)-cyclopentanecarboxylic acid benzyl
ester
0 \ N r---\ 0
N
F N
(it0
USOO
With a method similar to that used for the preparation of 4-(4-{[1-(2-chloro-
pheny1)-3-
trifluoromethy1-1H-pyrazo le-carbonyl] -aminoI-pheny1)-p ip eridine-l-
carboxylic acid
tert-butyl ester, (1R,2R)-2-(4-{4-[(5-pheny1-2-trifluoromethyl-furan-3-
carbony1)-amino]-
pheny1}-piperazine-1-carbony1)-cyclopentanecarboxylic acid benzyl ester was
prepared
from 5 -phenyl-2-trifluoromethyl- furan-3 -carboxylic acid (4-p ip erazin-l-yl-
p heny1)-
amide and (1R,2R)-cyclopentane-1,2-dicarboxylic acid monobenzyl ester. The
product
was isolated as a white solid (225 mg, 61 % yield). HRMS m/z calcd. for
C36H35F3N305 [M+H]': 646.2524; found: 646.2524.
Preparation of (4-14-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
phenylaminot-cyclohexyl)-carbamic acid tert-butyl ester
F F
0
ilk N
N
With a method similar to that used for the preparation of 4-(4-{[1-(2-chloro-
pheny1)-3-
trifluoromethy1-1H-pyrazo le-carbonyl] -aminoI-pheny1)-p ip eridine-l-
carboxylic acid
tert-butyl ester, (4-
{4- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbony1)-amino ] -
phenylamino}-cyclohexyl)-carbamic acid tert-butyl ester was prepared from [4-
(4-
amino-phenylamino)-cyclohexyl]-carbamic acid tert-butyl ester and 2-phenyl-5 -
trifluoromethyl-oxazole-4-carboxylic acid. HRMS m/z calcd. for C28H32F3N404
[M+H]': 545.2370; found: 545.2370.
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Preparation of rac-trans-2-(4'-nitro-bipheny1-4-ylcarbamoy1)-
cyclopentanecarboxylic acid
o-
i*
0õN lei
401 3 ii:...0 0
With a method similar to that used for the preparation of 4-(4-{[1-(2-chloro-
pheny1)-3-
trifluoromethy1-1H-pyrazo le-carbonyl] -amino{ -phenyl)-p ip eridine-l-
carboxylic acid
tert-butyl ester, rac-trans-2-(4'-nitro-bipheny1-4-ylcarbamoy1)-
cyclopentanecarboxylic
acid was prepared from 4'-nitro-biphenyl-4-ylamine and rac-trans-cyclopentane-
1,2-
dicarboxylic acid. LCMS calcd for C19H18N205 (m/e) 354, obsd 355 (M+H).
Preparation of rac-trans-2-[(4'-amino-biphenyl-4-y1)-methyl-carbamoy1]-
cyclopentanecarboxylic acid
N,
is 1, cii..0 0
I
To a solution of rac-trans-2-(4'-nitro-bipheny1-4-ylcarbamoy1)-
cyclopentanecarboxylic
acid (3.54 g, 10 mmol) in DMF cooled at 0 C was added sodium hydride (0.48 g,
12
mmol) gradually. The mixture was stirred at room temperature for 15 min
followed by
the addition of methyl iodide (0.7 mL). The reaction mixture was stirred for 2
h. The
reaction was then mixed with water and extracted with ethyl acetate. The
organic layer
was washed with water and brine. The organic layer dried over sodium sulfate,
filtered
and concentrated to give rac-trans-2-[methyl-(4'-nitro-bipheny1-4-y1)-
carbamoyl]-
cyclopentanecarboxylic acid as a yellow solid. With a method similar to that
used above,
trans-2-[(4'-amino-bipheny1-4-y1)-methyl-carbamoyl]-cyclopentanecarboxylic
acid was
prepared by the hydrogenation of trans-2-[methyl-(4'-nitro-biphenyl-4-y1)-
carbamoy1]-
cyclopentanecarboxylic acid. This material was directly used in the next step
without
further purification. LCMS calcd for C20H22N203 (m/e) 338, obsd 339 (M+H).
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-
piperazin-1-
yl-pyrimidin-5-y1)-amide hydrochloride salt
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F F
0----(F \N NN
I
0 %I\
N N.
CI N
To a solution of 4-(5-nitro-pyrimidin-2-y1)-piperazine-1-carboxylic acid tert-
butyl ester
(927 mg, 3 mmol, prepared from 2-chloro-5-nitropyrimidine and N-Boc-
piperazine) in
tetrahydrofuran (20 mL) and methanol (30 mL) was added 10% palladium on carbon
(240 mg) and the mixture was hydrogenated at 50 psi for 1 hr. The mixture was
filtered
and the solvents were evaporated. The residue was dried in vacuum to give 4-(5-
amino-
pyrimidin-2-y1)-piperazine-1-carboxylic acid tert-butyl ester.
To a suspension of 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid (771
mg, 3
mmol) in methylene chloride (10 mL) was added oxalyl chloride (2M, 3 mL, 6.0
mmol)
and one drop of N,N-dimethylformamide. The mixture was stirred at room
temperature
for 1 hr and the solvents were evaporated. The residue was treated with
benzene (5 mL)
and the solvents were again evaporated. The oily residue was dried in vacuum
and then
dissolved in methylene chloride (10 mL). The solution was cooled in an ice
bath. To this
solution was added a methylene chloride solution of 4-(5-amino-pyrimidin-2-y1)-
piperazine-1-carboxylic acid tert-butyl ester (3 mmol) and pyridine (0.73 mL).
The
mixture was stirred at 0 C for 10 minutes and room temperature for 2 hrs.
After
concentration, the residue was partitioned between methylene chloride and
water. The
organic layer was washed with aqueous citric acid solution and dried over
sodium
sulfate. The solvents were evaporated and the residue was dried in vacuum. The
resulting
material was triturated with ethyl acetate and the precipitate was filtered to
give 4- {5-[(2-
phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino]-pyrimidin-2-y4 -p ip
erazine-1-
carboxylic acid tert-butyl ester (1.38 g). LC-MS calcd for C24H25F3N604 (m/e)
518.5,
obsd 519.1 (M+H). The NMR spectrum obtained on the sample is compatible with
its
structure.
4- {5 - [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino]-pyrimidin-2-
y4 -
piperazine-l-carboxylic acid tert-butyl ester from above was suspended in
methylene
chloride and methanol. To this mixture was added hydrogen chloride in ether
(4N, 3
mL). The mixture was stirred at room temperature overnight. The solvents were
evaporated and the residue was dried in vacuum. The resulting solid was
triturated with
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dry ether and then filtered to give 2-phenyl-5-trifluoromethyl-oxazole-4-
carboxylic acid
(2-pip erazin-l-yl-pyrimidin-5 -y1)-amide hydrochloride salt. LC-MS calcd for
C19H17F3N602 (m/e) 418.39, obsd 419.0 (M+H). The NMR spectrum obtained on the
sample is compatible with its structure.
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [2-(4-
methylamino-piperidin-1-y1)-pyrimidin-5-ylparnide hydrochloride salt
0
= NTNfNHCI
0
N N
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid (2-piperazin-1-yl-pyrimidin-5-y1)-amide above, 2-
pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid [2-(4-methylamino-piperidin-1-y1)-
pyrimidin-
5-y1]-amide hydrochloride salt was prepared from 2-pheny1-5-
trifluoromethyloxazole-4-
carboxylic acid, 2-chloro-5-nitropyrimidine and methyl-piperidin-4-yl-carbamic
acid
tert-butyl ester. LCMS calcd for C21H21F3N602 (m/e) 446, obsd 447 (M+H).
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [2-(4-
amino-
piperidin-1-y1)-pyrimidin-5-y1Parnide hydrochloride salt
OF
N HCI
0
N N
With a method similar to that used for the preparation of hydrochloride salt
of 2-phenyl-
5 -trifluoromethyl-o xazo le-4-carboxylic acid (2-p ip erazin-l-yl-pyrimidin-5
-y1)-amide
above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [2-(4-amino-
piperidin-1-
y1)-pyrimidin-5-y1]-amide hydrochloride salt was prepared from 2-pheny1-5-
trifluoromethyloxazole-4-carboxylic acid, 2-chloro-5-nitropyrimidine and
piperidin-4-yl-
carbamic acid tert-butyl ester. LCMS calcd for C20H19F3N602 (m/e) 432, obsd
433
(M+H).
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PART II: PREPARATION OF PREFERRED COMPOUNDS
Example 1
Preparation of 4-oxo-4-(4-14-[(2-phenyl-5-trffluoromethyl-oxazole-4-carbonyl)-
amino] -phenylt-piperazin-1-y1)-butyric acid
F
0...F
. \ \ F
N 0 N s
N 0
Nr)0
0
A solution of dioxane (10 mL) that was saturated with hydrogen chloride gas
was added
to 4-
{4- [(2-Phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -phenyl} -p ip
erazine-1-
carboxylic acid tert-butyl ester (300 mg, 0.581 mmol). The reaction mixture
was stirred
for 30 minutes at room temperature and then the volatiles were evaporated
under reduced
pressure. The residue was triturated with diethyl ether to yield 2-phenyl-5-
trifluoromethyl-oxazole-4-carboxylic acid (4-pip
erazin-l-yl-p heny1)-amide
hydrochloride as a white powder (226 mg).
2-Phenyl-5-trifluoromethyl-oxazo le-4-carboxylic acid (4-p ip erazin-l-yl-p
heny1)-amide
hydrochloride (100 mg, 0.204 mmol), triethylamine (57.5 ilL, 0.408 mmol) and
succinic
anhydride (22.4 mg, 0.224 mmol) in 5 mL toluene and 3 mL dimethylsulfoxide
were
stirred at room temperature. After 3 hrs, an additional 5.5 mg of succinic
anhydride was
added and stirred for an additional 1 hr. The reaction mixture was diluted
with 50 mL
ethyl acetate, washed with 500 mL water, dried over magnesium sulfate,
filtered and
evaporated to dryness under vacuum. The residue was dissolved in acetonitrile
and water
and lyophilized to yield 4-oxo-4-(4-{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-amino]-pheny1}-piperazin-1-y1)-butyric acid as an amorphous, light
yellow
solid (83 mg, 78%). ES-MS calcd for C25H23F3N405 (m/e) 516.48, obsd 517 (M+H).
Example 2
Preparation of 2,2-dimethy1-4-oxo-4-(4-14-[(2-phenyl-5-trifluoromethyl-oxazole-
4-
carbonyl)-amino]-phenylt-piperazin-1-y1)-butyric acid
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F
0--F
=\ \ F N
N
0 SI N 0
0
With a method similar to that used for the preparation of 4-oxo-4-(4-{4-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-phenyl} -piperazin-l-y1)-butyric
acid above,
2,2-dimethy1-4-oxo-4-(4- {4- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbonyl)-amino] -
pheny1}-piperazin-l-y1)-butyric acid was prepared from 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid (4-p ip erazin-l-yl-pheny1)-amide hydrochloride and
dimethylsuccinic anhydride. ES-MS calcd for C27H27F3N405 (m/e) 544.53, obsd
545.1
(M+H).
Example 3
Preparation of 142-oxo-2-(4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-
amino] -phenylt-piperazin-1-y1)-ethylPcyclopentanecarboxylic acid
F
=\ \ F N
N
1401
0 N 0
N1((3Lo
With a method similar to that used for the preparation of 4-oxo-4-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazin-l-y1)-
butyric acid above,
1- [2-o xo -2-(4- {4- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbony1)-
amino ] -phenyl} -
piperazin- 1 -y1)-ethyl] -cyclopentanecarboxylic acid was prepared from 2-
Pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid (4-
pip erazin-l-yl-p heny1)-amide
hydrochloride and 2-oxa-spiro[4.4]nonane-1,3-dione. ES-MS calcd for
C29H29F3N405
(m/e) 570.57, obsd 571 (M+H).
Example 4
Preparation of 142-oxo-2-(4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-
amino] -phenylt-piperazin-1-y1)-ethylPcyclohexanecarboxylic acid
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F
0--F
= \N I F N
0 IW
N 0
N)or60
With a method similar to that used for the preparation of 4-oxo-4-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -piperazin-l-y1)-butyric
acid above,
1- [2-o xo -2-(4- {4- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbony1)-
amino ] -phenyl} -
piperazin-l-y1)-ethyl]-cyclohexanecarboxylic acid was prepared from 2-pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid (4-
pip erazin-l-yl-p heny1)-amide
hydrochloride and 2-oxa-spiro[4.5]decane-1,3-dione. ES-MS calcd for
C30H31F3N405
(m/e) 584.60, obsd 585.1 (M+H).
Example 5
Preparation of 2,2-dimethy1-4-oxo-4-(4-15-[(2-phenyl-5-trifluoromethyl-oxazole-
4-
carbonyl)-aminoppyridin-2-y1}-piperazin-1-y1)-butyric acid
F
0 F
=\N I F N
, I
kJ -,N.--...........N.,-........
0
II\IHLo
0
With a method similar to that used for the preparation of 4-oxo-4-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -piperazin-l-y1)-butyric
acid above,
2,2-dimethy1-4-oxo-4-(4- {5- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbony1)-amino]-
pyridin-2-y1}-piperazin-1-y1)-butyric acid was prepared from 2-Pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid (6-
pip erazin-l-yl-pyridin-3 -y1)-amide
hydrochloride and dimethylsuccinic anhydride. ES-MS calcd for C26H26F3N505
(m/e)
545.2, obsd 546.1 (M+H). The NMR spectrum obtained on the sample is compatible
with
its structure.
Example 6
Preparation of 4-oxo-4-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino] pyridin-2-y1}-piperazin-l-y1)-butyric acid
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F
it
I
0 ,.....e.,N.....".....,
0
0
0
With a method similar to that used for the preparation of 4-oxo-4-(4-{4-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-phenyl} -piperazin-l-y1)-butyric
acid above,
4-o xo-4-(4- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbony1)-amino ] -
pyridin-2-y1} -
piperazin- 1 -y1)-butyric acid was prepared from 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid (6-piperazin-1-yl-pyridin-3-y1)-amide hydrochloride and
succinic
anhydride. ES-MS calcd for C24H22F3N505 (m/e) 517.2, obsd 518.1 (M+H). The NMR
spectrum obtained on the sample is compatible with its structure.
Example 7
Preparation of 2,2-dimethy1-4-oxo-4-(4-15-[(2-phenyl-5-trifluoromethyl-oxazole-
4-
carbonyl)-aminoppyrimidin-2-y1}-piperazin-1-y1)-butyric acid
F
(:)-F
. \ N \ F NI N
0
N N 0
Nr)o
0
With a method similar to that used for the preparation of 4-oxo-4-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazin-l-y1)-
butyric acid above,
2,2-dimethy1-4-oxo-4-(4- {5- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbony1)-amino]-
pyrimidin-2-y1}-piperazin-1-y1)-butyric acid was prepared from 2-pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid (2-p ip erazin-l-yl-pyrimidin-5 -y1)-
amide and
2,2-dimethylsuccinic anhydride. ES-MS calcd for C25H25F3N605 (m/e) 546.2, obsd
547.0 (M+H). The NMR spectrum obtained on the sample is compatible with its
structure.
Example 8
Preparation of 4-oxo-4-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino] pyrimidin-2-y1}-piperazin-l-y1)-butyric acid
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F
F
=\ \ F
N(:)- NI N
0
N N 0
Nr)o
0
With a method similar to that used for the preparation of 4-oxo-4-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazin-l-y1)-
butyric acid above,
4-o xo-4-(4- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbony1)-amino ] -
pyrimidin-2-
yl} -piperazin-l-y1)-butyric acid was prepared from 2-phenyl-5-trifluoromethyl-
oxazo le-
4-carboxylic acid (2-piperazin- 1 -yl-pyrimidin-5-y1)-amide and succinic
anhydride. ES-
MS calcd for C23H21F3N605 (m/e) 518.2, obsd 519.0 (M+H). The NMR spectrum
obtained on the sample is compatible with its structure.
Example 9
Preparation of 2,2-dimethy1-4-oxo-4-(4-14-[(2-phenyl-5-trifluoromethyl-oxazole-
4-
carbonyl)-aminopphenylt-piperidin-1-y1)-butyric acid
F
(:)-F
= \ \ F N 401
0
0
N).r.).0
0
With a method similar to that used for the preparation of 4-oxo-4-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazin-l-y1)-
butyric acid above,
2,2-Dimethy1-4-oxo-4-(4- {4-[(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbonyl)-amino] -
phenyl} -piperidin- 1 -y1)-butyric acid was prepared from 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and 2,2-
dimethylsuccinic
anhydride. ES-MS calcd for C28H28F3N305 (m/e) 543.2, obsd 544.0 (M+H). The NMR
spectrum obtained on the sample is compatible with its structure.
Example 10
Preparation of rac-2-(4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino] -phenylt-piperazine-1-carbonyl)-cyclopentanecarboxylic acid ethyl ester
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F
¨
F N
0
0
To a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-
piperazin-l-yl-
pheny1)-amide hydrochloride (212 mg, 0.435 mmol), racemic trans-cyclopentane-
1,2-
dicarboxylic acid monoethyl ester (81 mg, 0.435 mmol) and triethylamine (305
tL, 2.17
MM01) in 5 mL 1-methyl-2-pyrrolidinone was added (benzotriazol-1-
ylo xy)tris(dimethylamino) phosphonium hexafluorophosphate (BOP, 202 mg, 0.456
mmol) in one portion and the mixture was stirred at room temperature
overnight. The
reaction mixture was diluted with ethyl acetate, washed with water, saturated
aqueous
sodium bicarbonate, dried over magnesium sulfate, filtered, and evaporated
under
reduced pressure. The residue was purified by flash chromatography (eluted
with ethyl
acetate/hexane) to yield rac-2-(4-{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-pheny1}-piperazine-1-carbony1)-cyclopentanecarboxylic acid ethyl ester
as an
amorphous solid (236 mg, 93%). ES-MS calcd for C30H31F3N405 (m/e) 584.60, obsd
585 (M+H).
Example 11
Preparation of 2,2-diethyl-4-oxo-4-(4-14- [(2-phenyl-5-trifluoromethyl-oxazole-
4-
carbonyl)-amino] -phenylt-piperazin-1-y1)-butyric acid methyl ester
= F N
0 io
0
LNyJ
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, 2,2-diethyl-4-oxo-4-(4- {4-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-phenyl} -piperazin-l-y1)-butyric
acid methyl
ester was prepared from 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid
(4-
piperazin-l-yl-pheny1)-amide hydrochloride and 2,2-diethyl-succinic acid 1-
methyl ester.
ES-MS calcd for C30H33F3N405 (m/e) 586.61, obsd 587 (M+H).
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Example 12
Preparation of 4-(4-14-[(2-phenyl-5-trffluoromethyl-oxazole-4-carbonyl)-amino]-
phenylt-piperazine-1-carbonyl)-cyclohexanecarboxylic acid methyl ester
F
0--F
N
N 0
N
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-oxazo le-4-carbony1)-amino]-phenyl} -pip erazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, 4-(4- {4-[(2-pheny1-5-
trifluoromethyl-
oxazo le-4-carbony1)-amino]-phenyl} -piperazine-l-carbony1)-
cyclohexanecarboxylic acid
methyl ester was prepared from 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic
acid
(4-piperazin-1-yl-pheny1)-amide hydrochloride and cis-cyclohexane-1,4-
dicarboxylic
acid monomethyl ester. ES-MS calcd for C30H31F3N405 (m/e) 584.60, obsd 585.1
(M+H).
Example 13
Preparation of 2,2-diethyl-4-oxo-4-(4-14- [(2-phenyl-5-trifluoromethyl-oxazole-
4-
carbonyl)-amino] -phenylt-piperazin-1-y1)-butyric acid
F
0...F
.\ \ F N
N
0 401 N. 0
N
0
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl} -pip erazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, 2,2-diethyl-4-oxo-4-(4- {4-[(2-
pheny1-5-
trifluoromethyl-oxazo le-4-carbony1)-amino] -phenyl} -pip erazin-l-y1)-butyric
acid was
prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-pip
erazin-l-yl-
pheny1)-amide hydrochloride and 2,2-diethylsuccinic acid. ES-MS calcd for
C29H31F3N405 (m/e) 572.58, obsd 573 (M+H).
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Example 14
Preparation of 4-(4-14-[(2-phenyl-5-trffluoromethyl-oxazole-4-carbonyl)-amino]-
phenylt-piperazine-1-carbonyl)-cyclohexanecarboxylic acid
F
0
= \4F
N
OON ,r0' 0
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, 4-(4- {4-[(2-pheny1-5-
trifluoromethyl-
oxazole-4-carbony1)-amino]-phenyl} -piperazine-l-carbony1)-
cyclohexanecarboxylic acid
was prepared from 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-
piperazin-1-
yl-phenyl)-amide hydrochloride and trans-1,4-cyclohexanedicarboxylic acid. ES-
MS
calcd for C29H29F3N405 (m/e) 570.57, obsd 571 (M+H).
Example 15
Preparation of rac-3-(4-14-[(2-phenyl-5-trffluoromethyl-oxazole-4-carbonyl)-
amino] -phenylt-piperazine-1-carbonyl)-cyclohexanecarboxylic acid methyl ester
F
0 F
fa \ -4 N
0 401 Nar
0
0 0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, rac-3-(4- {4-[(2-pheny1-5-
trifluoromethyl-
o xazo le-4-carbony1)-amino] -phenyl} -piperazine-l-carbony1)-
cyclohexanecarboxylic acid
methyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic
acid (4-
p ip erazin-l-yl-p heny1)-amide hydrochloride and racemic cis-cyc lo hexane-
1,3 -
dicarboxylic acid monomethyl ester. ES-MS calcd for C30H31F3N405 (m/e) 584.57,
obsd 585.1 (M+H).
Example 16
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Preparation of (1R,38)-1,2,2-trimethy1-3-(4-14-[(2-phenyl-5-trffluoromethyl-
oxazole-4-carbonyl)-amino] -phenylt-piperazine-1-carbonyl)-
cyclopentanecarboxylic
acid
F
N
0 401 N 0
0
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, (1R,3S)-1,2,2-trimethy1-3-(4-
{4- [(2-
phenyl-5-trifluoromethyl-o xazo le-4-carbonyl)-amino] -phenyl} -piperazine-l-
carbony1)-
cyclopentanecarboxylic acid was prepared from 2-Phenyl-5-trifluoromethyl-oxazo
le-4-
carboxylic acid (4-piperazin- 1 -yl-phenyl)-amide hydrochloride and d-
camphoric acid.
ES-MS calcd for C31H33F3N405 (m/e) 598.62, obsd 599.2 (M+H).
Example 17
Preparation of rac-2-(4-14-[(2-phenyl-5-trffluoromethyl-oxazole-4-carbonyl)-
amino] -phenylt-piperidine-1-carbonyl)-cyclopentanecarboxylic acid
F
10..F
. \N1 F N
0 401
NQ
0 o:-----c)
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4- {4-[(2-phenyl-5-
20trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperidine-l-
carbony1)-
cyclopentanecarboxylic acid was prepared from 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid (4-piperidin-4-yl-phenyl)-amide and racemic 1,2-trans-
cyclopetane
dicarboxylic acid. ES-MS calcd for C29H28F3N305 (m/e) 555.2, obsd 556.1 (M+H).
The NMR spectrum obtained on the sample is compatible with its structure.
Example 18
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Preparation of (1R,2R)-2-(4-14-[(2-Phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-
amino] -phenylt-piperidine-1-carbonyl)-cyclopentanecarboxylic acid
= F
N
µ1µ
0 0
0
The racemic mixture of 2-(4- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-pheny1}-piperidine-1-carbony1)-cyclopentanecarboxylic acid from above
was
separated under supercritical fluid chromatography (SFC) conditions (chiral OJ
column,
25% methanol in liquid carbon dioxide, flow rate 70 mL/min, pressure 100 bar
at 30 C).
The earlier eluting fraction provided (1R,2R)-2-(4-{4-[(2-pheny1-5-
trifluoromethyl-
oxazole-4-carbony1)-amino]-phenyl} -p ip eridine-l-carbony1)-cyc lop
entanecarbo xylic
acid [a]D=-24.2 (4.5 mg/mL in ethyl acetate). HRMS calcd for C29H28F3N305
(M+H)'
556.2054, obsd 556.2052. The NMR spectrum obtained on the sample is compatible
with
its structure.
Example 19
Preparation of (1S,2S)-2-(4-14-[(2-Phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-
amino] -phenylt-piperidine-1-carbonyl)-cyclopentanecarboxylic acid
= 0
\ F N
0 SI
NJ
0
The racemic mixture of 2-(4-{44(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-phenyl}-piperidine-1-carbonyl)-cyclopentanecarboxylic acid from above
was
separated under supercritical fluid chromatography (SFC) conditions (chiral OJ
column,
25% methanol in liquid carbon dioxide, flow rate 70 mL/min, pressure 100 bar
at 30 C).
The later eluting fraction provided (1S,2S)-2-(4-{4-[(2-pheny1-5-
trifluoromethyl-
oxazole-4-carbony1)-amino]-phenyl} -p ip eridine-l-carbony1)-cyc lop
entanecarbo xylic
acid. [a]D=+25.3 (3.2 mg/mL in ethyl acetate). LC-MS calcd for C29H28F3N305
(m/e)
555.2, obsd 556.1 (M+H). The NMR spectrum obtained on the sample is compatible
with
its structure.
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Example 20
Preparation of 4-(4-14-[(2-phenyl-5-trffluoromethyl-oxazole-4-carbonyl)-amino]-
phenylt-piperidine-1-carbonyl)-cyclohexanecarboxylic acid
0
= \N F N
0 IW 0
N.J
(C)' 0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, 4-(4- {4-[(2-pheny1-5-
trifluoromethyl-
oxazole-4-carbony1)-amino]-phenyl} -piperidine-l-carbony1)-
cyclohexanecarboxylic acid
was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-
piperidin-4-
yl-pheny1)-amide and 1,4-trans-cyclohexane dicarboxylic acid. HRMS calcd for
C30H30F3N305 (M+H) 570.2211 obsd 570.2210
Example 21
Preparation of rac-2-(4-14-[(2-phenyl-5-trffluoromethyl-oxazole-4-carbonyl)-
amino] -phenylt-piperidine-1-carbonyl)-cyclobutanecarboxylic acid
0 F
N
0 IW 0 4
NQ
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-phenyl} -p ip erazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4- {4-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperidine-l-carbony1)-
cyclobutanecarboxylic acid was prepared from 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid (4-piperidin-4-yl-phenyl)-amide and racemic 1,2-trans-
cyclobutane
dicarboxylic acid. LC-MS calcd for C28H26F3N305 (m/e) 541.2, obsd 542.3 (M+H).
Example 22
Preparation of rac-2-(4-15-[(2-phenyl-5-trffluoromethyl-oxazole-4-carbonyl)-
amino] -pyridin-2-y1}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid
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F
=
0
0 o
With a method similar to that used for the preparation of rac-2-(4-{4-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4-{5-[(2-pheny1-5 -
trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-y1} -piperazine-l-
carbony1)-
cyclopentanecarboxylic acid was prepared from 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid (6-piperazin-1-yl-pyridin-3-y1)-amide and racemic 1,2-trans-
cyclopentane dicarboxylic acid. LC-MS calcd for C27H26F3N505 (m/e) 557.2, obsd
558.1 (M+H).
Example 23
Preparation of (1S,2S)-2-(4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-
amino] -pyridin-2-y1}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid]
=\ F
0
0
The racemic mixture of 2-(4-{5-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-pyridin-2-y1} -p ip erazine-l-carbony1)-cyc lop entanecarbo xylic acid
from above
was separated under supercritical fluid chromatography (SFC) conditions as
described
earlier. The earlier eluting fraction provided (1S,2S)-2-(4-{5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -p ip erazine-l-
carbony1)-
cyclopentanecarboxylic acid. [a]D=+21.8 (4.3 mg/mL in ethyl acetate). LC-MS
calcd for
C27H26F3N505 (m/e) 557.2, obsd 558.1 (M+H).
Example 24
Preparation of (1R,2R)-2-(4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-
amino] -pyridin-2-y1}-piperazine-l-carbonyl)-cyclopentanecarboxylic acid
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F
=\ F
0
00 0
0
The racemic mixture of 2-(4-{5-[(2-Pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-pyridin-2-y1} -p ip erazine-l-carbony1)-cyc lop entanecarbo xylic acid
from above
was separated under supercritical fluid chromatography (SFC) conditions as
described
earlier. The later eluting fraction provided (1R,2R)-2-(4-{5-[(2-pheny1-5-
trifluoromethyl-
oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid. [a]D=-21.6 (4.2 mg/mL in ethyl acetate). LC-MS
calcd for
C27H26F3N505 (m/e) 557.2, obsd 558.1 (M+H).
Example 25
Preparation of rac-2-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino] -pyrimidin-2-y1}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid
= \ F
N
fN
N N']
0 o
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4-{5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyrimidin-2-y1} -piperazine-l-
carbony1)-
cyclopentanecarboxylic acid was prepared from 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid (2-piperazin-1-yl-pyrimidin-5-y1)-amide and racemic 1,2-trans-
cyclopentane dicarboxylic acid. LC-MS calcd for C26H25F3N605 (m/e) 558.2, obsd
559.1 (M+H).
Example 26
Preparation of (1R,2R)-2-(4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-
amino] -pyrimidin-2-y1}-piperazine-l-carbonyl)-cyclopentanecarboxylic acid
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F
= \ F
N,
I I
0
N
00 0
0
The racemic mixture of 2-(4-{5-[(2-Pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-pyrimidin-2-y1}-piperazine-1-carbony1)-cyclopentanecarboxylic acid from
above
was separated under supercritical fluid chromatography (SFC) conditions as
described
earlier. The earlier eluting fraction provided (1R,2R)-2-(4-{5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyrimidin-2-y1} -piperazine-l-
carbony1)-
cyclopentanecarboxylic acid. [a]D=-19.3 (4.2 mg/mL in ethyl acetate). LC-MS
calcd for
C26H25F3N605 (m/e) 558.2, obsd 559.1 (M+H).
Example 27
Preparation of (18,28)-2-(4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-
amino] -pyrimidin-2-y1}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid
= \ F
N,
I I
0
N
00 0
0
The racemic mixture of 2-(4- {5-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-pyrimidin-2-y1}-piperazine-l-carbony1)-cyclopentanecarboxylic acid from
above
was separated under supercritical fluid chromatography (SFC) conditions as
described
earlier. The later eluting fraction provided (1S,2S)-2-(4-{5-[(2-pheny1-5-
trifluoromethyl-
oxazole-4-carbony1)-amino]-pyrimidin-2-y1} -p ip erazine-l-carbony1)-cyc lop
entane
carboxylic acid. [a]D=+20.6 (4.4 mg/mL in ethyl acetate). LC-MS calcd for
C26H25F3N605 (m/e) 558.2, obsd 559.1 (M+H).
Example 28
Preparation of 4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino] -
3 ',4 ',5 ',6 '-tetrahydro-2 'H- [2,4] bipyridinyl- V-carbonylt-
cyclohexanecarboxylic acid
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F
0 F
0
a
,s 0
k
0 Ir
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, 4- {5-[(2-pheny1-5-
trifluoromethyl-
o xazo le-4-carbony1)-amino] -3',4',5',6'-tetrahydro -2'H- [2,41 bipyridiny1-
1'-carbonyl} -
cyclohexanecarboxylic acid was prepared from 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid (1',2',3',4',5',6'-hexahydro-[2,41bipyridiny1-5-y1)-amide and
1,4-trans-
cyclohexane dicarboxylic acid. LC-MS calcd for C29H29F3N405 (m/e) 570.2, obsd
571.4 (M+H).
Example 29
Preparation of 4-(4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
pyridin-2-y1}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid
0 F
\ N 0
0
= 0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, 4-(4- {5-[(2-pheny1-5-
trifluoromethyl-
oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-carbony1)-
cyclohexanecarboxylic acid was prepared from 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid (6-p ip erazin-l-yl-pyridin-3 -y1)-amide and 1,4-trans-cyc lo
hexane
dicarboxylic acid. LC-MS calcd for C28H28F3N505 (m/e) 571.2, obsd 572.2 (M+H).
Example 30
Preparation of rac-2-15-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
aminoP
3 ',4 ',5 ',6 '-tetrahydro-2 'H- [2,4] bipyridinyl-1 '-carbonyl}-
cyclopentanecarboxylic
acid
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F
=
0
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, racemic 2- {5-[(2-phenyl-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -3',4',5',6'-tetrahydro -2'H-
[2,41 bipyridinyl-
l'-carbony1}-cyclopentanecarboxylic acid was prepared from 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid (1',2',3 ',4',5 ',6'-hexahydro - [2,41 bipyridiny1-5
-y1)-amide and
1,2-trans-cyclopentane dicarboxylic acid. LC-MS calcd for C28H27F3N405 (m/e)
556.2, obsd 557.3 (M+H).
Example 31
Preparation of racemic 2-(4-15-[(5-phenyl-2-propy1-2H-pyrazole-3-carbonyl)-
amino] -pyridin-2-y1}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid
0
N
\
0
10-0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4-{5-[(5-pheny1-2-
propyl-2H-
pyrazo le-3 -carbonyl)-amino] -pyridin-2-y1} -piperazine-l-
carbonyl)cyclopentanecarboxylic acid was prepared from 5-pheny1-2-propy1-2H-
pyrazole-3-carboxylic acid (6-piperazin-1-yl-pyridin-3-y1)-amide and racemic
trans-
cyclopentane-1,2-dicarboxylic acid. LCMS calcd for C29H34N604 (m/e) 530, obsd
531
(M+H).
Example 32
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Preparation of racemic 2-(4-15-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4-
carbonyl)-amino] -pyridin-2-y1}-piperazine-1-carbonyl)-cyclopentanecarboxylic
acid
leiõNv\..-F
N F
\- F
N
0 0
N-
/N--
\---Nip
0 i
0\()
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
phenyl-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, 2-(4-{5-[(1-pheny1-3-
trifluoromethyl-1H-
pyrazo le-4-carbonyl)-amino] -pyridin-2-y1} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid was prepared from 1-pheny1-3-trifluoromethy1-1H-
pyrazole-
4-carboxylic acid (6-piperazin-1-yl-pyridin-3-y1)-amide and racemic trans-
Cyclopentane-
1,2-dicarboxylic acid. LCMS calcd for C27H27F3N604 (m/e) 556, obsd 557 (M+H).
Example 33
Preparation of racemic 2-(4-14-[(5-phenyl-2-propy1-2H-pyrazole-3-carbonyl)-
amino] -phenylt-piperazine-1-carbonyl)-cyclopentanecarboxylic acid
4N
,
¨
N
0 0
N----
C-N...._C
0 i
o=
o
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4-{4-[(5-pheny1-2-
propyl-2H-
pyrazo le-3 -carbonyl)-amino] -phenyl} -p ip erazine-l-carbony1)-cyc lop
entanecarbo xylic
acid was prepared from 5-pheny1-2-propy1-2H-pyrazole-3-carboxylic acid (4-
piperazin-
1-yl-pheny1)-amide and racemic trans-cyclopentane-1,2-dicarboxylic acid. LCMS
calcd
for C30H35N504 (m/e) 529, obsd 530 (M+H).
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Example 34
Preparation of racemic 2-(4-14-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4-
carbonyl)-amino] -phenylt-piperazine-1-carbonyl)-cyclopentanecarboxylic acid
go,
N
\- F
411
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4- {4-[(1-pheny1-3-
trifluoromethy1-1H-pyrazo le-4-carbonyl)-amino] -phenyl} -piperazine-l-
carbony1)-
cyclopentanecarboxylic acid was prepared from 1-pheny1-3-trifluoromethy1-1H-
pyrazole-
4-carboxylic acid (4-piperazin-1-yl-pheny1)-amide and racemic trans-
cyclopentane-1,2-
dicarboxylic acid. LCMS calcd for C28H28F3N504 (m/e) 555, obsd 556 (M+H). The
NMR spectrum obtained on the sample is compatible with its structure.
Example 35
Preparation of racemic 2-(4-15-[(5-Methyl-2-phenyl-2H-[1,2,3]triazole-4-
carbonyl)-
aminoppyridin-2-y1}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid
=N'I\IV
N-
0
N-
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -p ip erazine-l-
carbony1)-
cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4- {5-[(5-Methy1-2-
pheny1-2H-
[1,2,3]triazo le-4-carbonyl)-amino]-pyridin-2-y1} -pip erazine-l-carbonyl)cyc
lop entane
carboxylic acid was prepared from 5-Methy1-2-pheny1-2H-[1,2,3]triazole-4-
carboxylic
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acid (6-p ip erazin-l-yl-pyridin-3-y1)-amide and racemic trans-cyc lop entane-
1,2-
dicarboxylic acid. LCMS calcd for C26H29N704 (m/e) 503, obsd 504 (M+H).
Example 36
Preparation of racemic 244-(5-1[1-(4-fluoro-phenyl)-3-trifluoromethy1-1H-
pyrazole-4-carbonyll-aminot-pyridin-2-y1)-piperazine-1-carbonyll-
cyclopentanecarboxylic acid
F
N
\- F
0
N-
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, 2-[4-(5-{[1-(4-fluoro-pheny1)-3-
trifluoromethyl-1H-pyrazo le-4-carbonyl]-aminoI-pyridin-2-y1)-piperazine-1-
carbonyl]-
cyclopentanecarboxylic acid was prepared from 1-(4-fluoro-pheny1)-3-
trifluoromethyl-
1H-pyrazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-y1)-amide and
racemic trans-
cyclopentane-1,2-dicarboxylic acid. LCMS calcd for C27H26F4N604 (m/e) 574,
obsd
575 (M+H).
Example 37
Preparation of racemic 244-(5-1[2-(2-methoxy-ethyl)-5-phenyl-2H-pyrazole-3-
carbonyl] -aminot-pyridin-2-y1)-piperazine-l-carbonyll-cyclopentanecarboxylic
acid
N,
7NO
0
0
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With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, racemic 244-(5-{[2-(2-methoxy-
ethyl)-5-
pheny1-2H-pyrazo le-3 -carbonyl] -aminoI-pyridin-2-y1)-p ip erazine-l-
carbonyl] ¨
cyclopentanecarboxylic acid was prepared from 2-(2-methoxy-ethyl)-5-pheny1-2H-
pyrazole-3-carboxylic acid (6-piperazin-1-yl-pyridin-3-y1)-amide and racemic
trans-
cyclopentane-1,2-dicarboxylic acid. LCMS calcd for C29H34N605 (m/e) 546, obsd
547
(M+H).
Example 38
Preparation of racemic 2-(4-15-[(2-propy1-5-thiophen-2-y1-2H-pyrazole-3-
carbonyl)-
amino] -pyridin-2-y1}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid
S
Ns
N
N
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4- {5-[(2-propy1-5-
thiophen-2-
y1-2H-pyrazo le-3 -carbonyl)-amino] -pyridin-2-y1} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid was prepared from 2-propy1-5-thiophen-2-y1-2H-
pyrazole-
3-carboxylic acid (6-piperazin-1-yl-pyridin-3-y1)-amide and racemic trans-
cyclopentane-
1,2-dicarboxylic acid. LCMS calcd for C27H32N604S (m/e) 536, obsd 537 (M+H).
Example 39
Preparation of racemic 2-(4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-
amino] -phenylt-piperazine-1-carbonyl)-cyclopentanecarboxylic acid methyl
ester
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F
0
0 ,
o
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4-{4-[(2-pheny1-5 -
trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid methyl ester was prepared from 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid (4-piperazin-1-yl-pheny1)-amide and racemic trans-
cyclopentane-1,2-dicarboxylic acid methyl ester. LCMS calcd for C29H29F3N405
(m/e)
570, obsd 571 (M+H). The NMR spectrum obtained on the sample is compatible
with its
structure.
Example 40
Preparation of rac-2-(4-14-[(1-phenyl-3-trilluoromethyl-1H-pyrazole-4-
carbonyl)-
amino] -phenylt-piperidine-1-carbonyl)-cyclopentanecarboxylic acid
=N
\- F
0 ilk
0
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4-{4-[(1-pheny1-3-
trifluoromethy1-1H-pyrazo le-4-carbonyl)-amino] -phenyl} -p ip -carbonyl)-
acid was prepared from 1-pheny1-3-trifluoromethy1-1H-pyrazole-
4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and racemic trans-
cyclopentane-1,2-
dicarboxylic acid. LCMS calcd for C29H29F3N404 (m/e) 554, obsd 555 (M+H).
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Example 41
Preparation of 4-(4-14-[(1-phenyl-3-trifluoromethy1-1H-pyrazole-4-carbonyl)-
amino] -phenylt-piperidine-1-carbonyl)-cyclohexanecarboxylic acid
*N N
\- F
44,
0
......
0
0
With a method similar to that used for the preparation of rac-2-(4-{4-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, 4-(4-{4-[(1-pheny1-3-
trifluoromethyl-1H-
pyrazo le-4-carbonyl)-amino] -phenyl} -piperidine-l-carbony1)-
cyclohexanecarboxylic
acid was prepared from 1-pheny1-3-trifluoromethy1-1H-pyrazole-4-carboxylic
acid (4-
piperidin-4-yl-pheny1)-amide and trans-1,4-cyclohexanedicarboxylic acid. LCMS
calcd
for C30H31F3N404 (m/e) 568, obsd 569 (M+H).
Example 42
Preparation of racemic 244-(4-1[1-(4-fluoro-phenyl)-3-trifluoromethy1-1H-
pyrazole-4-carbonyl] -aminot-phenyl)-piperidine-1-carbonylp
cyclopentanecarboxylic acid
F4
o,
\-- F
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, racemic 24444- {[1-(4-fluoro-
pheny1)-3-
trifluoromethy1-1H-pyrazo le-4-carbonyl]-aminoI-pheny1)-piperidine-1-carbonyl]-
cyclopentanecarboxylic acid was prepared from 1-(4-fluoro-pheny1)-3-
trifluoromethyl-
1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and racemic
trans-
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cyclopentane-1,2-dicarboxylic acid. LCMS calcd for C29H28F4N404 (m/e) 572,
obsd
573 (M+H).
Example 43
Preparation of 444-(4-1[1-(4-fluoro-phenyl)-3-trifluoromethy1-1H-pyrazole-4-
carbonyl] -aminot-phenyl)-piperidine-1-carbonylPcyclohexanecarboxylic acid
F 4 NIõ.N.svFk...F
\ _ F
N
0 .
0
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -p ip erazine-l-
carbony1)-
cyclopentanecarboxylic acid ethyl ester above, 4-[4-(4-{[1-(4-fluoro-pheny1)-3-
trifluoromethyl-1H-pyrazo le-4-carbonyl]-aminoI-pheny1)-piperidine-1-carbonyl]-
cyclohexanecarboxylic acid was prepared from 1-(4-fluoro-pheny1)-3-
trifluoromethyl-
1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and cis-
cyclohexane-1,4-
dicarboxylic acid. LCMS calcd for C30H30F4N404 (m/e) 586, obsd 585 (M-H).
Example 44
Preparation of 444-(4-1[1-(2-chloro-phenyl)-3-trifluoromethy1-1H-pyrazole-4-
carbonyl] -aminot-phenyl)-piperidine-1-carbonylPcyclohexanecarboxylic acid
0
N
\¨ F
CI
N
0 =
o.....0_400
N
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, 4-[4-(4-{[1-(2-chloro-pheny1)-3-
trifluoromethyl-1H-pyrazo le-4-carbonyl]-aminoI-pheny1)-piperidine-1-carbonyl]-
cyclohexanecarboxylic acid was prepared from 1-(2-chloro-pheny1)-3-
trifluoromethyl-
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1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and cis-
cyclohexane-1,4-
dicarboxylic acid. LCMS calcd for C30H30C1F3N404 (m/e) 603, obsd 602 (M-H).
The
NMR spectrum obtained on the sample is compatible with its structure.
Example 45
Preparation of 444-(4-1[1-(2-chloro-phenyl)-3-trifluoromethy1-1H-pyrazole-4-
carbonyl] -aminot-phenyl)-piperidine-1-carbonyll-cyclohexanecarboxylic acid
CI N
\- F
0 =
......
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, 4-[4-(4-{[1-(2-chloro-pheny1)-3-
trifluoromethyl-1H-pyrazo le-4-carbonyl] -amino{ -phenyl)-p ip eridine-l-
carbonyl] -
cyclohexanecarboxylic acid was prepared from 1-(2-chloro-pheny1)-3-
trifluoromethyl-
1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and trans-
cyclohexane-
1,4-dicarboxylic acid. LCMS calcd for C30H30C1F3N404 (m/e) 603, obsd 602 (M-
H).
The NMR spectrum obtained on the sample is compatible with its structure.
Example 46
Preparation of racemic 244-(4-1[1-(2-chloro-phenyl)-3-trifluoromethy1-1H-
pyrazole-4-carbonylpaminot-phenyl)-piperidine-1-carbonylp
cyclopentanecarboxylic acid
N
\- F
CI
0 =
0
0
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With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, racemic 24444- {[1-(2-chloro-
pheny1)-3-
trifluoromethyl-1H-pyrazo le-4-carbonyl] -amino{-pheny1)-p ip eridine-l-
carbonyl] -
cyclopentanecarboxylic acid was prepared from 1-(2-chloro-pheny1)-3-
trifluoromethyl-
1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and racemic
trans-
cyclopentane-1,2-dicarboxylic acid. LCMS calcd for C29H28C1F3N404 (m/e) 589,
obsd
588 (M-H). The NMR spectrum obtained on the sample is compatible with its
structure.
Example 47
Preparation of 444-(4-1[1-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4-
carbonyl] -aminot-phenyl)-piperidine-1-carbonyll-cyclohexanecarboxylic acid
F
- F
410
0
......
0
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, 4-[4-(4-{[1-(4-fluoro-pheny1)-3-
trifluoromethyl-1H-pyrazo le-4-carbonyl]-amino{-pheny1)-piperidine-1-carbonyl]-
cyclohexanecarboxylic acid was prepared from 1-(4-fluoro-pheny1)-3-
trifluoromethyl-
1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and trans-
cyclohexane-
1,4-dicarboxylic acid. LCMS calcd for C30H30F4N404 (m/e) 586, obsd 585 (M-H).
Example 48
Preparation of (1R,2R)-2-08)-3-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-aminoppyridin-2-ylaminot-pyrrolidine-1-carbonyl)-
cyclopentanecarboxylic acid
\ I F Nj
N'Thr
0
00
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With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, (1R,2R)-2-((S)-3- {5-[(2-pheny1-
5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-ylaminoI-pyrro lidine-1 -
carbonyl)-cyclopentanecarboxylic acid was prepared from (S)-2-pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid [6-(pyrro lidin-3 -ylamino)-pyridin-
3 -yl] -amide
and racemic trans-cyclopentane-1,2-dicarboxylic acid. The mixture of
diasteriomers were
then separated by chiral SFC to give (1R,2R)-2-((S)-3- {5-[(2-pheny1-5-
trifluoromethyl-
oxazole-4-carbony1)-amino]-pyridin-2-ylaminoI -pyrro lidine-l-carbony1)-
cyclopentanecarboxylic acid. LCMS calcd for C27H26F3N505 (m/e) 557.53, obsd
558.53 (M+H). The NMR spectrum obtained on the sample is compatible with its
structure.
Example 49
Preparation of (1S,2S)-2-0S)-3-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-aminoppyridin-2-ylaminot-pyrrolidine-1-carbonyl)-
cyclopentanecarboxylic acid
F
0---)\--F
4I \ I F
0 I
00
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, (1S ,2S)-2-((S)-3- {5-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-ylaminoI-pyrro lidine-l-
carbony1)-cyclopentanecarboxylic acid was prepared from (S)-2-pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid [6-(pyrro lidin-3 -ylamino)-pyridin-
3 -yl] -amide
and racemic trans-cyclopentane-1,2-dicarboxylic acid. The mixture of
diasteriomers were
then separated by chiral SFC to give (1S ,2S)-2-((S)-3- {5-[(2-pheny1-5-
trifluoromethyl-
oxazole-4-carbony1)-amino]-pyridin-2-ylaminoI -pyrro lidine-l-carbony1)-
cyclopentanecarboxylic acid. LCMS calcd for C27H26F3N505 (m/e) 557.53, obsd
558.53 (M+H). The NMR spectrum obtained on the sample is compatible with its
structure.
Example 50
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Preparation of 4-0S)-3-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
aminol-
pyridin-2-ylaminot-pyrrolidine-1-carbonyl)-cyclohexanecarboxylic acid
0
\ F
N"-ThrN
0 I
0
With a method similar to that used for the preparation of rac-2-(4-14-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, 4-((S)-3-15-[(2-pheny1-5-
trifluoromethyl-
oxazole-4-carbony1)-amino]-pyridin-2-ylaminoI-pyrrolidine-1-carbony1)-
cyclohexanecarboxylic acid was prepared from 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid [6((S)-pyrrolidin-3-ylamino)-pyridin-3-y1]-amide and trans-
cyclohexane-1,4-dicarboxylic acid. LCMS calcd for C28H28F3N505 (m/e) 571.55,
obsd
572.21 (M+H).
Example 51
Preparation of 4-(4-14-[(2-phenyl-5-trffluoromethyl-oxazole-4-carbonyl)-aminol-
phenylt-piperidine-1-carbonyl)-cyclohexanecarboxylic acid
\ I F
N Thr N
0
0
yO)L0
0
With a method similar to that used for the preparation of rac-2-(4-14-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, 4-(4-14-[(2-pheny1-5-
trifluoromethyl-
o xazo le-4-carbony1)-amino] -phenyl} -piperidine-l-carbony1)-
cyclohexanecarboxylic acid
was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-
piperidin-4-
yl-pheny1)-amide and cis-cyclohexane-1,4-dicarboxylic acid. LCMS calcd for
C30H30F3N305 (m/e) 569.58, obsd 570.22 (M+H).
Example 52
Preparation of rac-2-(4-12-cyano-4-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-aminopphenylt-piperazine-1-carbonyl)-cyclopentanecarboxylic acid
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F
0
0 \
/--\
N NIIN Nor
IP \\ 0
N
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, racemic 2-(4- {2-cyano-4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid was prepared from 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid (3-cyano-4-piperazin-1-yl-pheny1)-amide and racemic trans-
cyclopentane-1,2-dicarboxylic acid. LCMS calcd for C29H26F3N505 (m/e) 581,
obsd.
582 (M+H).
Example 53
Preparation of rac-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {441-
(tetrahydro-fu ran-2-ca rb o nyl)-pip e ridin-4-yl] -ph enyl} -amide
F
0 F
. \N-4N 0
0
N.rQ
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, racemic 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid {4- [1-(tetrahydro -furan-2-carbony1)-p ip eridin-4-
yl] -phenyl} -
amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid
(4-
piperidin-4-yl-phenyl)-amide and racemic tetrahydrofuran-2-carboxylic acid. LC-
MS
calcd for C27H26F3N304 (m/e) 513.2, obsd 514.4 (M+H). The NMR spectrum
obtained
on the sample is compatible with its structure.
Example 54
Preparation of rac-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {441-
(tetrahydro-fu ran-3-ca rb o nyl)-pip e ridin-4-yl] -ph enyl} -amide
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F
(:)..F
* \N\ F
0 N 0
NrCO
0
With a method similar to that used for the preparation of rac-2-(4-{4-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, racemic 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid {4- [1-(tetrahydro -furan-3 -carbonyl)-p ip eridin-4-
yl] -phenyl} -
amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid
(4-
piperidin-4-yl-pheny1)-amide and racemic tetrahydrofuran-3-carboxylic acid. LC-
MS
calcd for C27H26F3N304 (m/e) 513.2, obsd 514.4 (M+H). The NMR spectrum
obtained
on the sample is compatible with its structure.
Example 55
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {644-
(cyclopent-3-enecarbony1)-piperazin-l-ylppyridin-3-y1}-amide
F
*\ \ F
N N
, I
,_,
N N
N .
0
With a method similar to that used for the preparation of rac-2-(4-{4-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid {6- [4-(cyc lop ent-3 -enecarbony1)-p ip erazin-l-yl] -pyridin-
3 -y1} -amide
was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-
piperazin-1-
yl-pyridin-3-y1)-amide and 3-cyclopentene carboxylic acid. LC-MS calcd for
C26H24F3N503 (m/e) 511.2, obsd 512.1 (M+H). The NMR spectrum obtained on the
sample is compatible with its structure.
Example 56
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {441-
(cyclopent-3-enecarbony1)-piperidin-4-yll-phenylt-amide
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F
(:)..F
. \ \ F N 0
0
N*
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid {4- [1-(cyc lop ent-3 -enecarbony1)-p ip eridin-4-yl] -phenyl}
-amide was
prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-
piperidin-4-yl-
pheny1)-amide and 3-cyclopentene carboxylic acid. LC-MS calcd for C28H26F3N303
(m/e) 509.2, obsd 510.2 (M+H). The NMR spectrum obtained on the sample is
compatible with its structure.
Example 57
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (V-
cyclop ropanecarbonyl-1 ',2 ',3 ',4',5',6'-hexahydro- [2,4,1 bipyridiny1-5-y1)-
amide
F
0
=N N
I
0 ..,.N.-5.-...,......õ,-.)
.N.1'
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid (1 '-cyclopropanecarbony1-1 ',2',3',4',5 ',6'-hexahydro -
[2,41bipyridiny1-5 -
y1)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic
acid
(1',2',3',4',5',6'-hexahydro-[2,41bipyridiny1-5-y1)-amide and cyclopropane
carboxylic
acid. LC-MS calcd for C25H23F3N403 (m/e) 484.2, obsd 485.1 (M+H). The NMR
spectrum obtained on the sample is compatible with its structure.
Example 58
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(4-
cyclopropanecarbonyl-piperazin-1-y1)-phenylpamide
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F
0
= \ F N
0 N
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid ethyl ester above, 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid [4-(4-cyclopropanecarbonyl-piperazin-1-y1)-pheny1]-amide was
prepared
from 2-phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid (4-p ip erazin-l-
yl-p heny1)-
amide and cyclopropane carboxylic acid. LC-MS calcd for C25H23F3N403 (m/e)
484.2,
obsd 485.1 (M+H). The NMR spectrum obtained on the sample is compatible with
its
structure.
Example 59
Preparation of 4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
pyridin-2-y1}-piperazine-1-carboxylic acid tert-butyl ester
F F
OF
N"
0
Ny0.*
4-(5-Amino-pyridin-2-y1)-piperazine-1-carboxylic acid tert-butyl ester was
mixed with 2-
pheny1-5 -trifluoromethylo xazo le-4-carbo xylic acid (771 mg, 3.0 mmol) and
bromotrispyrrolidinophosphonium hexafluorophosphate (1.40 g, 3.0 mmol) in N,N-
dimethylformamide (20 mL) and methylene chloride (5 mL) containing
triethylamine
(0.85 mL). The mixture was stirred at room temperature overnight and the
solvents were
evaporated. The residue was extracted with ethyl acetate and water. The
organic layer
was dried over sodium sulfate, filtered and concentrated. The residue was
triturated with
ethyl acetate and the solid was filtered to give 4- {5-[(2-pheny1-5-
trifluoromethyl-
oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-carboxylic acid tert-
butyl ester
(1.09 g). LC-MS calcd for C25H26F3N504 (m/e) 517.5, obsd 518.1 (M+H). The NMR
spectrum obtained on the sample is compatible with its structure.
Example 60
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Preparation of (1-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
phenylt-piperidin-4- y1)-acetic acid ethyl ester
F F
. = \ N
N 0 00
N
/\)L0
With a method similar to that used for the preparation of 4- {5-[(2-phenyl-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (1- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-amino]-
phenyl} -piperidin-4-y1)-acetic acid ethyl ester was prepared from 2-pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid and [1-(4-aminop heny1)-p ip eridine-
4-yl] -
acetic acid ethyl ester. LC-MS calcd for C26H26F3N304 (m/e) 501.2, obsd 502.1
(M+H). The NMR spectrum obtained on the sample is compatible with its
structure.
Example 61
Preparation of 15'-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
3,4,5,6-
tetrahydro-2H-[1,21bipyridinyl-4-y1}-acetic acid methyl ester
F
0 F
iit
I
0 --...e--..N..----, 0
/\)Lc)
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, {5'-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
3,4,5,6-tetrahydro-2H41,21bipyridinyl-4-y1} -acetic acid methyl ester was
prepared from
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (5 '-amino-3 ,4,5 ,6-
tetrahydro -
2H41,21bipyridiny1-4-y1)-acetic acid methyl ester. LC-MS calcd for
C24H23F3N404
(m/e) 488.2, obsd 489.1 (M+H). The NMR spectrum obtained on the sample is
compatible with its structure.
Example 62
Preparation of 2-Methy1-2-15'-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-3,4,5,6-tetrahydro-2H-[1,21bipyridinyl-4-y1}-propionic acid ethyl ester
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F F
0_4<rF
46. \N 1
N
0 1,...N.-:',..N.,---, 0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 2-methyl-2- {5'-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-y1}-propionic acid ethyl ester
was
prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 2-(5'-
amino-
3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-y1)-2-methyl-propionic acid ethyl
ester. LC-MS
calcd for C27H29F3N404 (m/e) 530.2, obsd 531.1 (M+H). The NMR spectrum
obtained
on the sample is compatible with its structure.
Example 63
Preparation of 4-15-[(1-phenyl-3-trifluoromethy1-1H-pyrazole-4-carbonyl)-
amino]-
pyridin-2-y1}-piperazine-1-carboxylic acid tert-butyl ester
F
40, ,1\1....\...-F
N
\- F
N
0 0
N-
N
C--N
--0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 4- {5-[(1-pheny1-3-trifluoromethy1-1H-pyrazole-4-
carbony1)-
amino]-pyridin-2-y1}-piperazine- 1 -carboxylic acid tert-butyl ester was
prepared from 1-
phenyl-3 -trifluoromethy1-1H-pyrazo le-4-carboxylic acid and 445 -amino -
pyridin-2-y1)-
piperazine- 1 -carboxylic acid tert-butyl ester. LCMS calcd for C25H27F3N603
(m/e)
516, obsd 517 (M+H).
Example 64
Preparation of 4-(5-1[5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-
carbony1]-
aminot-pyridin-2-y1)-piperazine-1-carboxylic acid tert-butyl ester
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III N,
F F
N
0
N-
N--\
C--Ni
--0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 4-(5- { [5-pheny1-2-(2,2,2-trifluoro-ethyl)-
2H-pyrazo le-3 -
carbonyl]-amino}-pyridin-2-y1)-piperazine-l-carboxylic acid tert-butyl ester
was
prepared from 5-pheny1-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid
and 445-
amino-pyridin-2-y1)-piperazine- 1 -carboxylic acid tert-butyl ester. LCMS
calcd for
C26H29F3N603 (m/e) 530, obsd 531 (M+H). The NMR spectrum obtained on the
sample is compatible with its structure.
Example 65
Preparation of 4-15-[(5-phenyl-2-propy1-2H-pyrazole-3-carbonyl)-aminoppyridin-
2-
y1}-piperazine-1-carboxylic acid tert-butyl ester
*N
N
0 0
N-
N
C-N
>,---0
6'
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 4- {5-[(5-pheny1-2-propy1-2H-pyrazo le-3-carbony1)-
amino]-
pyridin-2-y1} -piperazine- 1 -carboxylic acid tert-butyl ester was prepared
from 5-phenyl-
2-propy1-2H-pyrazo le-3 -carboxylic acid and 445 -amino -pyridin-2-y1)-p ip
erazine-1-
carboxylic acid tert-butyl ester. LCMS calcd for C27H34N603 (m/e) 490, obsd
491
(M+H). The NMR spectrum obtained on the sample is compatible with its
structure.
Example 66
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Preparation of 4-15-[(5-methoxymethy1-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-
aminoppyridin-2-y1}-piperazine-1-carboxylic acid tert-butyl ester
# Nµ,1\0_......
N-
N
0 0
N-
N
C-N
--0
0
With a method similar to that used for the preparation of 4- {5-[(2-phenyl-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 4- {5 -[(5 -metho xymethy1-2-pheny1-2H41,2,3]triazo le-
4-carbony1)-
amino]-pyridin-2-y1}-piperazine-1-carboxylic acid tert-butyl ester was
prepared from 5-
methoxymethy1-2-pheny1-2H-[1,2,3]triazole-4-carboxylic acid and 4-(5-amino-
pyridin-2-
y1)-piperazine-1-carboxylic acid tert-butyl ester. LCMS calcd for C25H31N704
(m/e)
493, obsd 494 (M+H). The NMR spectrum obtained on the sample is compatible
with its
structure.
Example 67
Preparation of 4-(5-1[2-(2-methoxy-ethyl)-5-phenyl-2H-pyrazole-3-carbonyl]-
aminot-pyridin-2-y1)-piperazine-1-carboxylic acid tert-butyl ester
$N
\
N
0 0
N-
N---N\
C--Ni
--0
0 With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 4-(5- {[2-(2-methoxy-ethyl)-5-pheny1-2H-pyrazole-3-
carbonyl]-
amino}-pyridin-2-y1)-piperazine-l-carboxylic acid tert-butyl ester was
prepared from 2-
(2-metho xy-ethyl)-5 -phenyl-2H-pyrazo le-3 -carboxylic acid and 445 -amino -
pyridin-2-
y1)-piperazine-l-carboxylic acid tert-butyl ester. LCMS calcd for C27H34N604
(m/e)
506, obsd 507 (M+H). The NMR spectrum obtained on the sample is compatible
with its
structure.
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Example 68
Preparation of 4-(5-1[1-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole-4-
carbonyl] -aminot-pyridin-2-y1)-piperazine-1-carboxylic acid tert-butyl ester
F
N
\- F
0
N-
>-0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 4-(5- { [1-(4-fluoro-pheny1)-3-trifluoromethyl-1H-
pyrazo le-4-
carbonyl]-amino}-pyridin-2-y1)-piperazine-1-carboxylic acid tert-butyl ester
was
prepared from 1-(4-fluoro-pheny1)-3-trifluoromethy1-1H-pyrazole-4-carboxylic
acid and
4-(5-amino-pyridin-2-y1)-piperazine- 1 -carboxylic acid tert-butyl ester. LCMS
calcd for
C25H26F4N603 (m/e) 534, obsd 535 (M+H).
Example 69
Preparation of 4-15-[(2-propy1-5-thiophen-2-y1-2H-pyrazole-3-carbonyl)-aminol-
pyridin-2-y1}-piperazine-1-carboxylic acid tert-butyl ester
s
0
N-
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 4- {5-[(2-propy1-5-thiophen-2-y1-2H-pyrazole-3-
carbony1)-amino]-
pyridin-2-y1} -piperazine- 1 -carboxylic acid tert-butyl ester was prepared
from 2-propy1-5-
thiophen-2-y1-2H-pyrazo le-3 -carbo xylic acid and 445 -amino -pyridin-2-y1)-p
ip erazine-1-
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carboxylic acid tert-butyl ester. LCMS calcd for C25H32N603S (m/e) 496, obsd
497
(M+H). The NMR spectrum obtained on the sample is compatible with its
structure.
Example 70
Preparation of 4-15-[(1-phenyl-3-trifluoromethy1-1H-pyrazole-4-carbonyl)-
amino]-
pyridin-2-y1}-benzoic acid
40, NF.....\...-F
N'
\- F
N
0 /\
N-
=
0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 4- {5-[(1-pheny1-3-trifluoromethy1-1H-pyrazole-4-
carbony1)-
amino]-pyridin-2-y1} -benzoic acid was prepared from 1-pheny1-3-
trifluoromethy1-1H-
pyrazole-4-carboxylic acid and 4-(5-amino-pyridin-2-y1)-benzoic acid methyl
ester
followed by basic hydrolysis of the methyl ester. LCMS calcd for C23H15F3N403
(m/e)
452, obsd 453 (M+H). The NMR spectrum obtained on the sample is compatible
with its
structure.
Example 71
Preparation of 4'-{[1-(4-fluoro-phenyl)-3-trifluoromethy1-1H-pyrazole-4-
carbonyl]-
aminot-biphenyl-4-carboxylic acid
F 4101 N,Nv.v.F F
\- F
N
0 0,
lif
0
o
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 4'- { [1-(4-fluoro-pheny1)-3-trifluoromethyl-
1H-pyrazo le-4-
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carbonyll-amino}-bipheny1-4-carboxylic acid was prepared from 1-(4-fluoro-
pheny1)-3-
trifluoromethy1-1H-pyrazole-4-carboxylic acid and 4'-amino-biphenyl-4-
carboxylic acid
methyl ester followed by basic hydrolysis of the methyl ester. LCMS calcd for
C24H15F4N303 (m/e) 469, obsd 470 (M+H).
Example 72
Preparation of 4-15-[(4-methy1-2-pyridin-2-yl-thiazole-5-carbony1)-amino]-
pyridin-
2-y1}-benzoic acid
___________________________________ \N---..../
0 I
N SThrN \
0 I
N 0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 4- {5-[(4-methy1-2-pyridin-2-yl-thiazole-5-carbony1)-
amino]-
pyridin-2-y1}-benzoic acid was prepared from 4-methy1-2-pyridin-2-yl-thiazole-
5-
carboxylic acid and 4-(5-amino-pyridin-2-y1)-benzoic acid methyl ester
followed by
basic hydrolysis of the methyl ester. LCMS calcd for C22H16N403S (m/e) 416,
obsd
417 (M+H).
Example 73
Preparation of 4-(5-111-(4-fluoro-pheny1)-3-trifluoromethyl-1H-pyrazole-4-
carbonyl] aminol-pyridin-2-y1)-benzoic acid
F 40, N_Nvv_F F
N
0 /\
N-
41
0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 4-(5- { [1 -(4-fluoro -pheny1)-3 -trifluoromethy1-1H-
pyrazo le-4-
carbonyl]-amino}-pyridin-2-y1)-benzoic acid was prepared from 1-(4-fluoro-
pheny1)-3-
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trifluoromethy1-1H-pyrazo le-4-carboxylic acid and 445 -amino -pyridin-2-y1)-
benzo ic
acid methyl ester followed by basic hydrolysis of the methyl ester. LCMS calcd
for
C23H14F4N403 (m/e) 470, obsd 471 (M+H). The NMR spectrum obtained on the
sample is compatible with its structure.
Example 74
Preparation of 4-15-[(1-phenyl-5-trifluoromethy1-1H-pyrazole-4-carbonyl)-
amino]-
pyridin-2-y1}-piperazine-1-carboxylic acid tert-butyl ester
tip ,N
N V
F)-
N
F F0
0
N-
N--)
C-N
>--0
0 \---
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 4- {5-[(1-pheny1-5-trifluoromethy1-1H-pyrazole-4-
carbony1)-
amino]-pyridin-2-y1}-piperazine-1-carboxylic acid tert-butyl ester was
prepared from 1-
phenyl-5 -trifluoromethy1-1H-pyrazo le-4-carboxylic acid and 445 -amino -
pyridin-2-y1)-
piperazine-l-carboxylic acid tert-butyl ester. LCMS calcd for C25H27F3N603
(m/e)
516, obsd 517 (M+H). The NMR spectrum obtained on the sample is compatible
with its
structure.
Example 75
020 Preparation of 4-14-[(1-pyridin-2-y1-3-
trifluoromethy1-1H-pyrazole-4-carbonyl)-
amino] -phenylt-piperidine-1-carboxylic acid tert-butyl ester
......_ ,NF....\_-F
--- N
N
0 =
N
--0
0
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With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 4- {4- [(1-pyridin-2-y1-3 -trifluoromethy1-1H-pyrazo
le-4-carbonyl)-
amino]-phenyl} -piperidine-l-carboxylic acid tert-butyl ester was prepared
from 1-
pyridin-2-y1-3-trifluoromethy1-1H-pyrazole-4-carboxylic acid and 4-(4-amino-
pheny1)-
piperidine- 1 -carboxylic acid tert-butyl ester. LCMS calcd for C26H28F3N503
(m/e)
515, obsd 516 (M+H). The NMR spectrum obtained on the sample is compatible
with its
structure.
Example 76
Preparation of 2-methy1-2-15'-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-3,4,5,6-tetrahydro-2H-[1,2,1bipyridiny1-4-y1}-propionic acid
F F
/Th.._
0
* \N 1 NN
0 N 0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 2-methy1-2-{5'-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-3,4,5,6-tetrahydro-2H-[1,21bipyridinyl-4-y1}-propionic acid was
prepared from
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and
2-(5'-amino -3 ,4,5 ,6-
tetrahydro -2H-[1,21bipyridiny1-4-0-2-methyl-propionic acid. LC-MS calcd for
C25H25F3N404 (m/e) calcd 502.2, obsd 503.1 (M+H). The NMR spectrum obtained on
the sample is compatible with its structure.
Example 77
Preparation of (S)-3-15-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino] -
pyridin-2-ylaminol-pyrrolidine-1-carboxylic acid tert-butyl ester
F F
0--F
= \N 1 N
N 0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (S)-3- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbonyl)-
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amino]-pyridin-2-ylamino}-pyrrolidine-l-carboxylic acid tert-butyl ester was
prepared
from 2-phenyl-5 -trifluoromethyl-o xazo le-4-carbo xylic acid and (S)-3 -(5 -
amino -pyridin-
2-ylamino)-pyrro lidine-l-carbo xylic acid tert-butyl ester. LCMS calcd for
C25H26F3N504 (m/e) 517.6, obsd 518.2 (M+H).
Example 78
Preparation of (S)-3-(5-1[2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-
oxazole-
4-carbonyl] -aminot-pyrimidin-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl
ester
F
F¨(---F F
0
0----)\---F
4100 \ I F
N'ThrNN
0 I N N CN--\( ¨\
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (S)-3-(5-{[2-(2-trifluoromethoxy-pheny1)-5-
trifluoromethyl-
oxazole-4-carbony1]-aminoI-pyrimidin-2-ylamino)-pyrrolidine-1-carboxylic acid
ten'-
butyl ester was prepared from 2-(2-trifluoromethoxy-pheny1)-5-trifluoromethyl-
oxazole-
4-carboxylic acid and (S)-3 -(5-amino -pyrimidin-2-ylamino)-pyrro lidine-l-
carboxylic
acid ethyl ester. LCMS calcd for C23H20F6N605 (m/e) 574.4, obsd 575.2 (M+H).
Example 79
0 Preparation of (S)-3-15-[(4-methyl-2-pyridin-2-yl-thiazole-5-carbonyl)-
aminop
pyridin-2-ylaminot-pyrrolidine-1-carboxylic acid tert-butyl ester
\
1
N SThrN
0 I
N 1\10N¨(0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (S)-3- {5 -[(4-methyl-2-pyridin-2-yl-thiazo le-5 -
carbonyl)-amino] -
pyridin-2-ylamino 1 -pyrrolidine- 1 -carboxylic acid tert-butyl ester was
prepared from 4-
methy1-2-pyridin-2-yl-thiazo le-5 -carbo xylic acid and
(S)-3 -(5-amino -pyridin-2-
ylamino)-pyrro lidine- 1 -carboxylic acid tert-butyl ester. LCMS calcd for
C24H28N603S
(m/e) 480.6, obsd 481.2 (M+H).
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Example 80
Preparation of 4-15-[(4-methy1-2-pyridin-2-yl-thiazole-5-carbony1)-amino]-
pyridin-
2-y1}-piperazine-1-carboxylic acid tert-butyl ester
c->_ii.rN
0 i
N N
Nyc*0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 4- {5-[(4-methy1-2-pyridin-2-yl-thiazole-5-carbony1)-
amino]-
pyridin-2-y1}-piperazine-1-carboxylic acid tert-butyl ester was prepared from
4-methyl-
2-pyridin-2-yl-thiazo le-5 -carbo xylic acid and 445 -amino -pyridin-2-y1)-p
ip erazine-1-
carboxylic acid tert-butyl ester. LCMS calcd for C24H28N603S (m/e) 480.6, obsd
481.2
(M+H).
Example 81
Preparation of 4-15-1(2-pyridin-3-yl-thiazole-4-carbony1)-aminoppyridin-2-y1}-
piperazine-l-carboxylic acid tert-butyl ester
_____________________________ s,
0 I
0 I
N'N
Ny010
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 4- {5-[(2-pyridin-3-yl-thiazole-4-carbony1)-amino]-
pyridin-2-y1}-
piperazine-l-carboxylic acid tert-butyl ester was prepared from 2-pyridin-3-yl-
thiazole-
4-carboxylic acid and 4-(5-amino-pyridin-2-y1)-piperazine-1-carboxylic acid
tert-butyl
ester. LCMS calcd for C23H26N603S (m/e) 466.6, obsd 467.2 (M+H).
Example 82
Preparation of 4-15-[(4-methy1-2-pyridin-3-yl-thiazole-5-carbony1)-amino]-
pyridin-
2-y1}-piperazine-1-carboxylic acid tert-butyl ester
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____________________________ N,/
J I N
N -----
I
0
NN
Nyolo
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 4- {5-[(4-methy1-2-pyridin-3-yl-thiazole-5-carbony1)-
amino]-
pyridin-2-y1}-piperazine-1-carboxylic acid tert-butyl ester was prepared from
4-methyl-
2-pyridin-3 -yl-thiazo le-5 -carbo xylic acid and 445 -amino -pyridin-2-y1)-p
ip erazine-1-
carboxylic acid tert-butyl ester. LCMS calcd for C24H28N603S (m/e) 480.6, obsd
481.2
(M+H).
Example 83
Preparation of (S)-3-(5-1[2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-
oxazole-
4-carbonyl] -aminot-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl
ester
F
F¨Ã-F
F
0
OF
=\ I FN
N \/
0 I 0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (S)-3-(5-{[2-(2-trifluoromethoxy-pheny1)-5-
trifluoromethyl-
oxazole-4-carbony1]-amino} -pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid
tert-butyl
ester was prepared from 2-(2-trifluoromethoxy-pheny1)-5-trifluoromethyl-
oxazole-4-
carboxylic acid and (S)-3-(5-amino-pyridin-2-ylamino)-pyrrolidine-1-carboxylic
acid
tert-butyl ester. LCMS calcd for C26H25F6N505 (m/e) 601.5, obsd 601.9 (M+H).
To a flask containing (S)-3-(5-{[2-(2-trifluoromethoxy-pheny1)-5-
trifluoromethyl-
oxazole-4-carbony1]-amino} -pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid
tert-butyl
ester (150 mg, 0.249 mmol) was added trifluoroacetic acid (5 mL). When all the
starting
material was consumed, as indicated by TLC, the reaction mixture was
concentrated to
dryness. The residue was dissolved in dichloromethane (10 mL) and then cooled
to 0 C.
Ethyl chloroformate (24 L, 0.249 mmol) and triethylamine (75.5 mg, 0.747
mmol) were
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added dropwise, and the reaction mixture was stirred for 2 h at room
temperature and
then concentrated. The crude product was purified by flash chromatography
(Merck
silica gel 60, 230-400 mesh, gradient elution with 0%-100% ethyl acetate in
hexane) to
give (S)-3 -(5- { [2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazo
le-4-carbonyl] -
amino} -pyridin-2-ylamino)-pyrrolidine-l-carboxylic acid ethyl ester (61 mg,
42.7%
yield) as a light yellow solid. LCMS for C24H21F6N505 calculated (m/e) 573.46,
found
574.15 (M+H).
Example 84
Preparation of (S)-3-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
phenylaminot-pyrrolidine-1-carboxylic acid ethyl ester
F
NThrN
0 SI NCN-?-----\
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (S)-3-{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-phenylamino}-pyrrolidine-1-carboxylic acid tert-butyl ester was
prepared from
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-3-(4-amino-
phenylamino)-
pyrrolidine- 1 -carboxylic acid tert-butyl ester. The NMR spectrum obtained on
the sample
is compatible with its structure.
With a method similar to that used for the preparation of (S)-3-(5- {[2-(2-
trifluorometho xy-p heny1)-5 -trifluoromethyl-o xazo le-4-carbonyl] -amino } -
pyridin-2-
ylamino)-pyrrolidine-1-carboxylic acid ethyl ester above, (S)-3- {4-[(2-Pheny1-
5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenylamino } -pyrro lidine-l-
carboxylic acid
ethyl ester was from (S)-3-{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
phenylamino}-pyrrolidine-1-carboxylic acid tert-butyl ester and ethyl
chloroformate.
LCMS calcd for C24H23F3N404 (m/e) 488.47, obsd 489.17 (M+H).
Example 85
Preparation of (R)-3-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
pyridin-2-ylaminot-pyrrolidine-1-carboxylic acid tert-butyl ester
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F
= \ I F
0
N N"
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (R)-3- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbonyl)-
amino]-pyridin-2-ylamino}-pyrrolidine-l-carboxylic acid tert-butyl ester was
prepared
from 2-phenyl-5-trifluoromethyl-oxazo le-4-carboxylic acid and (R)-3 -(5 -
amino -pyridin-
2-ylamino)-pyrro lidine-l-carbo xylic acid tert-butyl ester. LCMS calcd for
C25H26F3N504 (m/e) 517.6, obsd 518.2 (M+H).
Example 86
Preparation of (R)-(1-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
aminol-
pyrimidin-2-y1}-pyrrolidin-3-y1)-carbamic acid tert-butyl ester
411 \ I F
0
N-NR
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (R)-(1- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbonyl)-
amino] -pyrimidin-2-y1} -pyrrolidin-3-y1)-carbamic acid tert-butyl ester was
prepared
from 2-phenyl-5-trifluoromethyl-oxazo le-4-carboxylic acid and (R)-1-(5 -amino
-
pyrimidin-2-ylamino)-pyrrolidin-3-yl-carbamic acid tert-butyl ester. LCMS
calcd for
C24H25F3N604 (m/e) 518.5, obsd 519.2 (M+H).
Example 87
Preparation of (S)-3-(methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-
amino] -pyridin-2-y1}-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester
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F
0----)\--F
4. \ I F m
NTh.r"
0 I
N NCI\j--io-
I 0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (S)-3-(methyl- {5 - [(2-phenyl-5 -
trifluoromethyl-o xazo le-4-
carbonyl)-amino]-pyridin-2-y1}-amino)-pyrrolidine-l-carboxylic acid tert-butyl
ester was
prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-3-
[(5-
amino-pyridin-2-y1)-methyl-amino]-pyrrolidine-1-carboxylic acid tert-butyl
ester. LCMS
calcd for C26H28F3N504 (m/e) 531.5, obsd 532.2 (M+H).
Example 88
Preparation of (S)-(1-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
aminol-
pyridin-2-y1}-pyrrolidin-3-y1)-carbamic acid tert-butyl ester
F
0----)\--F
ii. , 1 F
N"--"yN
0 I
NNLD
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (S)-(1- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbonyl)-
amino] -pyridin-2-y1} -pyrro lidin-3-y1)-carbamic acid tert-butyl ester was
prepared from
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-[1-(5-amino-
pyridin-2-y1)-
pyrrolidin-3-y1]-carbamic acid tert-butyl ester. LCMS calcd for C25H26F3N504
(m/e)
517.6, obsd 518.2 (M+H).
Example 89
Preparation of (R)-(1-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
aminol-
pyridin-2-y1}-pyrrolidin-3-y1)-carbamic acid tert-butyl ester
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F
0----__A--F
lit\ I F
N-----(N
0 I
NNR
N---\(0-(
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (R)-(1- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbonyl)-
amino]-pyridin-2-y1}-pyrrolidin-3-y1)-carbamic acid tert-butyl ester was
prepared from
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (R)- [145 -amino -
pyridin-2-y1)-
pyrrolidin-3-y1]-carbamic acid tert-butyl ester. LCMS calcd for C25H26F3N504
(m/e)
517.6, obsd 518.2 (M+H).
Example 90
Preparation of rac-methyl-(1-15-1(2-phenyl-5-trifluoromethyl-oxazole-4-
carbony1)-
aminoppyridin-2-y1}-pyrrolidin-3-y1)-carbamic acid tert-butyl ester
F
0----)\--F
= \ I F
N-ThrN
0 (
N NO_N/
o¨c'---
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, racemic methyl-(1-{5-[(2-phenyl-5-trifluoromethyl-
oxazole-4-
carbony1)-amino]-pyridin-2-y1}-pyrrolidin-3-y1)-carbamic acid tert-butyl ester
was
prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic
[145-
amino-pyridin-2-y1)-pyrrolidin-3-y1]-methyl-carbamic acid tert-butyl ester.
LCMS calcd
for C26H28F3N504 (m/e) 531.5, obsd 532.2 (M+H).
Example 91
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid 16-[(R)-3-
(acetyl-methyl-amino)-pyrrolidin-1-y11-pyridin-3-y1}-amide
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F
0----)\--F
4. \ I F
0 I
NNR0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid
{6-[(R)-3-
(acetyl-methyl-amino)-pyrro lidin-l-yl] -pyridin-3 -y1} -amide was prepared
from 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid and racemic N- [145 -
amino -pyridin-
2-y1)-pyrro lidin-3-yl] -N-methyl-acetamide followed by chiral SFC. LCMS calcd
for
C23H22F3N503 (m/e) 473.45, obsd 474.17 (M+H). [a] D= -15.2
Example 92
Preparation of rac-1-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
pyridin-2-y1}-pyrrolidine-3-carboxylic acid methyl ester
F
0-...)\---F
4. \ I F
N ----"ri \I \/
0 I
0
0 \
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, racemic 1- {5-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-pyridin-2-y1} -pyrrolidine-3-carboxylic acid methyl ester was prepared
from 2-
pheny1-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic 1-(5-amino-
pyridin-2-
y1)-pyrrolidine-3-carboxylic acid methyl ester. LCMS calcd for C22H19F3N404
(m/e)
460.4, obsd 461.1 (M+H).
Example 93
Preparation of 5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
3,4,5,6-
tetrahydro-2H-[1,2]bipyridiny1-4-carboxylic acid ethyl ester
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F
\ I F
0 I
Hr0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 5'-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-carboxylic acid ethyl ester was
prepared from
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 5 '-amino-3 ,4,5 ,6-
tetrahydro -
2H41,21bipyridiny1-4-carboxylic acid ethyl ester. LCMS calcd for C24H23F3N404
(m/e) 488.46, obsd 489.17 (M+H).
Example 94
Preparation of (1S,3S)-3-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino] -pyridin-2-ylaminot-cyclopentanecarboxylic acid methyl ester
\ F
NTh./N
0 I
N N
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (1 S ,3 S)-3 - {5 -[(2-phenyl-5 -trifluoromethyl-o
xazo le-4-carbonyl)-
amino] -pyridin-2-ylamino -cyclopentanecarboxylic acid methyl ester was
prepared from
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (1 S ,3 S)-3 -(5 -
amino -pyridin-2-
ylamino)-cyclopentanecarboxylic acid methyl ester. LCMS calcd for C23H21F3N404
(m/e) 474.44, obsd 475.16 (M+H).
Example 95
Preparation of (1R,3S)-3-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino] -pyridin-2-ylaminot-cyclopentanecarboxylic acid ethyl ester
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F
0---)\--F
N'ThiN\/
0
N
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (1R,3S)-3- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-
4-carbonyl)-
amino]-pyridin-2-ylamino}-cyclopentanecarboxylic acid ethyl ester was prepared
from
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (1R,3 S)-3 -(5 -amino
-pyridin-2-
ylamino)-cyclopentanecarboxylic acid ethyl ester. LCMS calcd for C24H23F3N404
(m/e) 488.46, obsd 489.17 (M+H).
Example 96
Preparation of (S)-3-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
aminol-
pyrimidin-2-ylaminot-pyrrolidine-1-carboxylic acid tert-butyl ester
F
OF
I F
4. \N Nr I
0---
N
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (S)-3- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbony1)-
amino]-pyrimidin-2-ylamino}-pyrrolidine-1-carboxylic acid tert-butyl ester was
prepared
from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-3-(5-amino-
pyrimidin-2-ylamino)-pyrrolidine- 1-carboxylic acid tert-butyl ester. LCMS
calcd for
C24H25F3N604 (m/e) 518.49, obsd 519.2 (M+H).
Example 97
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-
((1S,3R)-3-
dimethylcarbamoyl-cyclopentylamino)-pyridin-3-yll-amide
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F
O----)\--F
4. \ 1 F
1\1"---.(N\/% \
0 I .....0_7(N-
NN
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid
[6-((1S,3R)-
3 -dimethylc arb amo yl-cyc lop entylamino)-pyridin-3 -yl] -amide was prepared
from
(1R,3S)-3- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -
pyridin-2-
ylamino 1 -cyclopentanecarboxylic acid and dimethylamine hydrochloride. LCMS
calcd
for C24H24F3N503 (m/e) 487.48, obsd 488.19 (M+H).
Example 98
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [64(18,38)-
3-
dimethylcarbamoyl-cyclopentylamino)-pyridin-3-y1]-amide
F
0--)\--F
4. \ I F
\
N
Nr r\IL> N---
.,,i
N
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid
[6-((1S,3S)-
3 -dimethylc arb amo yl-cyc lop entylamino)-pyridin-3 -yl] -amide was prepared
from
(1 S ,3 S)-3 - {5- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -
pyridin-2-
ylamino 1 -cyclopentanecarboxylic acid and dimethylamine hydrochloride. LCMS
calcd
for C24H24F3N503 (m/e) 487.48, obsd 488.19 (M+H).
Example 99
Preparation of 5'-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
3,4,5,6-
tetrahydro-2H-[1,2]bipyridinyl-4-carboxylic acid dimethylamide
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F
0---)\--F
4. \ 1 F
N-Th..(N
0 I
NNO)r I
N \
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 5'-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-carboxylic acid dimethylamide was
prepared
from 5'- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -3,4,5 ,6-
tetrahydro -2H-
[1,21bipyridiny1-4-carboxylic acid and dimethylamine hydrochloride. LCMS calcd
for
C24H24F3N503 (m/e) 487.48, obsd 488.19 (M+H).
Example 100
Preparation of racemic trans- 2- {4 '- [(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-aminoj -biphenyl-4-carbonyl}-cyclopentanecarboxylic acid
F
0 F
ii ---)?
\ 1
N_ThrN 0
S.
0 ,,,..,,
0 .
To a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (0.25 g,
1 mmol)
and bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (0.47 g, 1 mmol) in
methylene chloride was added racemic trans-2-(4'-amino-bipheny1-4-carbony1)-
cyclopentanecarboxylic acid (0.20 g, 0.78 mmol) and diisopropylethylamine
(0.35 mL, 2
mmol). The mixture was stirred at ambient temperature for 3 h. The reaction
mixture was
concentrated and the residue was re-dissolved in DMSO and acetonitrile. HPLC
reverse
phase purification with acetonitrile and water afforded 44 mg of racemic trans-
2-{4'-[(2-
pheny1-5-trifluoromethyl-oxazo le-4-carbonyl)-amino] -biphenyl-4-carbonyl} -
cyclopentanecarboxylic acid as a white solid. LCMS calcd for C30H23F3N205
(m/e)
548, obsd 549 (M+H).
Example 101
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Preparation of (1R,2R)-2-14'-[(2-phenyl-5-tritluoromethyl-oxazole-4-carbonyl)-
amino]-biphenyl-4-carbonyll-cyclopentanecarboxylic acid (or enantiomer)
FF
441 \
NThiN
0 el
0 0
0
Racemic trans-2- {4'-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-aminc]-
biphenyl-
4-carbonyl}-cyclopentanecarboxylic acid from above was separated by chiral SFC
to
afford (1R,2R)-2- }4'-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
biphenyl-
4-carbonyl} -cyclopentanecarboxylic acid (or enantiomer). [a]D: -36.7 in
CHC13.
Example 102
Preparation of (1S,2S)-2-14'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-biphenyl-4-carbonyll-cyclopentanecarboxylic acid (or enantiomer)
NyN
OF
0 1410)
=o
0 -
Racemic trans-2- {4'- [(2-phenyl-5 -trifluoromethyl-oxazole-4-carbonyl)-amino]
-biphenyl-
4-carbonyl}-cyclopentanecarboxylic acid from above was separated by chiral SFC
to
afford (1S ,2S)-2- }4'- [(2-phenyl-5-trifluoromethyl-oxazo le-4-carbonyl)-
amino] -biphenyl-
4-carbonyl} -cyclopentanecarboxylic acid (or enantiomer). [a]D: +37.6 in
CHC13.
Example 103
Preparation of (1R,2R)-2-14'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-biphenyl-4-carbonyll-cyclohexanecarboxylic acid (or enantiomer)
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F F
0--F
1
. \N N
0 lel
0 0 0
With a method similar to that used for the preparation of racemic trans-2-{4'-
[(2-phenyl-
-trifluoromethyl-o xazo le-4-carbonyl)-amino] -biphenyl-4-carbonyl} -
cyclopentanecarboxylic acid above, racemic 2- {4'-[(2-pheny1-5-trifluoromethyl-
oxazole-
5 4-carbonyl)-amino]-bipheny1-4-carbonyl}-cyclohexanecarboxylic acid was
prepared
from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic trans-2-
(4'-
amino-biphenyl-4-carbonyl)-cyclohexanecarboxylic acid. The racemic product
obtained
was separated by chiral SFC to afford (1R,2R)-2-{4'-[(2-pheny1-5-
trifluoromethyl-
oxazole-4-carbony1)-amino]-biphenyl-4-carbonyl} -cyclohexanecarboxylic
acid (or
enantiomer). [4): +25.4 in DMSO. LCMS calcd for C31H25F3N205 (m/e) 562, obsd
563 (M+H).
Example 104
Preparation of (1S,2S)-2-14'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino] -biphenyl-4-carbonyl}-cyclohexanecarboxylic acid (or enantiomer)
F F
0---__Y-F
4.
0 el
el O
0
C"c)
With a method similar to that used for the preparation of racemic trans-2-{4'-
[(2-phenyl-
5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -biphenyl-4-carbonyl} -
cyclopentanecarboxylic acid above, racemuc 2- {4'-[(2-pheny1-5-trifluoromethyl-
oxazole-
4-carbonyl)-amino]-bipheny1-4-carbonyl}-cyclohexanecarboxylic acid was
prepared
from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic trans-2-
(4'-
amino-biphenyl-4-carbonyl)-cyclohexanecarboxylic acid. The racemic product
obtained
was separated by chiral SFC to afford (1S,2S)-2-{4'-[(2-pheny1-5-
trifluoromethyl-
oxazole-4-carbony1)-amino]-bipheny1-4-carbonyl} -cyclohexanecarboxylic
acid (or
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enantiomer). [a]D: -23 in DMSO. LCMS calcd for C31H25F3N205 (m/e) 562, obsd
563 (M+H).
Example 105
Preparation of (1R,2S)-2-14'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-biphenyl-4-carbonyll-cyclohexanecarboxylic acid (or enantiomer)
\ N
=
0 el
0
0 o
With a method similar to that used for the preparation of racemic trans-2-{4'-
[(2-phenyl-
5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -biphenyl-4-carbonyl} -
cyclopentanecarboxylic acid above, racemic 2- {4'- [(2-phenyl-5 -
trifluoromethyl-oxazo le-
4-carbonyl)-amino] -biphenyl-4-carbonyl} -cyclohexanecarboxylic acid was
prepared
from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic cis-2-
(4'-amino-
bipheny1-4-carbony1)-cyclohexanecarboxylic acid. The racemic product was
separated by
chiral SFC to afford (1R,2S)-2- {4'-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-biphenyl-4-carbonyl}-cyclohexanecarboxylic acid (or enantiomer). [a]D:
+11.7
in DMSO. LCMS calcd for C31H25F3N205 (m/e) 562, obsd 563 (M+H).
Example 106
Preparation of (1S,2R)-2-14'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-biphenyl-4-carbonyll-cyclohexanecarboxylic acid (or enantiomer)
F F
\ N
0 ei
40 .0
0
With a method similar to that used for the preparation of racemic trans-2-{4'-
[(2-phenyl-
5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -biphenyl-4-carbonyl} -
cyclopentanecarboxylic acid above, racemic 2- {4'-[(2-pheny1-5-trifluoromethyl-
oxazole-
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- 129 -4-carbony1)-amino]-bipheny1-4-carbony1}-cyclohexanecarboxylic acid was
prepared
from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and cis-2-(4'-amino-
bipheny1-4-carbony1)-cyclohexanecarboxylic acid. The racemic product was
separated by
chiral SFC to afford (1S ,2R)-2- {4'-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino] -biphenyl-4-carbonyl} -cyclohexanecarboxylic acid (or enantiomer).
[a]D: -23.8
in DMSO. LCMS calcd for C31H25F3N205 (m/e) 562, obsd 563 (M+H).
Example 107
Preparation of 2,2-dimethy1-3-15'-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-y1}-propionic acid
F F
F
0 ,
j....\.(N-___C-A___
N
0 0 N
0
To a suspension of 2,2-dimethy1-3-(5'-nitro-3,4,5,6-tetrahydro-2H-
[1,21bipyridiny1-4-y1)-
propionic acid (153.5 mg, 0.5 mmol) in methanol (30 mL) and tetrahydrofuran (5
mL)
was added 10% of palladium on carbon (30 mg). The mixture was hydrogenated at
50 psi
for 2 hrs. The mixture was filtered and the solvents were evaporated. The
resulting
aminopyridine derivative was reacted with 2-pheny1-5-trifluoromethyl-oxazole-4-
carbonyl chloride (prepared from the corresponding carboxylic acid (128.5 mg,
0.5
mmol), oxalyl chloride and catalytic amount of N,N-dimethylformamide) at room
temperature. After concentration, the residue was partitioned between
methylene chloride
and water. The organic layer was washed with aqueous citric acid solution and
dried over
sodium sulfate. The solvents were evaporated and the residue was dried in
vacuum. The
crude product was triturated with methanol (4 mL) and the solid was filtered
to give 2,2-
dimethy1-3 - {5 '- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbony1)-amino ]
-3,4,5,6-
tetrahydro-2H-[1,21bipyridiny1-4-y1} -propionic acid (87 mg). LC-MS calcd. For
C26H27F3N404 (m/e) 516.1984, obsd 517.1 (M+H). The NMR spectrum obtained on
the sample is compatible with its structure.
Example 108
Preparation of rac-2-(4-14-[(2-pheny1-5-trffluoromethyl-oxazole-4-carbony1)-
amino] -phenyll-piperazine-1-carbony1)-cyclopentanecarboxylic acid
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F
= , F N
0 NC)N,p
0
0
To a solution of racemic 2-(4-{44(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-phenylI-piperazine-1-carbonyl)-cyclopentanecarboxylic acid ethyl ester
(100 mg,
0.171 mmol) in 10 mL ethanol was added a solution of lithium hydroxide (14 mg,
0.342
mmol) in 5 mL water. The reaction mixture was stirred at room temperature for
4 hrs and
then heated to 50 C for 1 hr. The reaction mixture was cooled, diluted with
water, and
washed with diethyl ether. The pH of the aqueous layer was adjusted to pH 5
with 1N
hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layers
were dried
over magnesium sulfate, filtered and evaporated to dryness. The residue was
purified by
flash chromatography (eluted with ethyl acetate/methylene chloride) to yield
rac-2-(4- {4-
[(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -phenyl} -
piperazine-l-
carbony1)-cyclopentanecarboxylic acid (27 mg, 28%). ES-MS calcd for
C28H27F3N405
(m/e) 556.54, obsd 557.1 (M+H).
Example 109
Preparation of (1R,2R)-2-(4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-
amino] -phenylt-piperazine-1-carbonyl)-cyclopentanecarboxylic acid
O F N
0
rN ..0
0
0 0
The racemic mixture of 2-(4- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-phenyl}-piperazine-1-carbony1)-cyclopentanecarboxylic acid described
above
was purified by chiral supercritical fluid chromatography (first eluting peak)
to yield
(1R,2R)-2-(4- {4-[(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbony1)-amino ] -
phenyl} -
piperazine- 1 -carbony1)-cyclopentanecarboxylic acid as an off-white solid. ES-
MS calcd
for C28H27F3N405 (m/e) 556.54, obsd 557 (M+H); [c]p -16.7 .
Example 110
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Preparation of (1S,2S)-2-(4-14-[(2-phenyl-5-trffluoromethyl-oxazole-4-
carbonyl)-
amino] -phenylt-piperazine-1-carbonyl)-cyclopentanecarboxylic acid
= F N
0 Nalro
o
The
racemic mixture of 2-(4- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-pheny1}-piperazine-l-carbony1)-cyclopentanecarboxylic acid described
above
was purified by chiral supercritical fluid chromatography (second eluting
peak) to yield
(S,S)-2-(4- {4-[(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -
phenyl} -
piperazine- 1 -carbony1)-cyclopentanecarboxylic acid as an off-white solid. ES-
MS calcd
for C28H27F3N405 (m/e) 556.54, obsd 557 (M+H); [c]p +16.7 .
Example 111
Preparation of 4-(4-14-[(2-phenyl-5-trffluoromethyl-oxazole-4-carbonyl)-amino]-
phenylt-piperazine-1-carbonyl)-cyclohexanecarboxylic acid
0
\N-4F 0
0 101 N IrcrA
0
With a method similar to that used for the preparation of rac-2-(4-{4-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid above, 4-(4- {4-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-cyclohexanecarboxylic
acid was
prepared from 4-
(4- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
pheny1}-piperazine-l-carbony1)-cyclohexanecarboxylic acid methyl ester and
lithium
hydroxide. ES-MS calcd for C29H29F3N405 (m/e) 570.57, obsd 571.2 (M+H).
Example 112
Preparation of (1R,3S)-3-(4-14-[(2-phenyl-5-trffluoromethyl-oxazole-4-
carbonyl)-
amino] -phenylt-piperazine-1-carbonyl)-cyclohexanecarboxylic acid
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F
it\ \ F N
N
0
0
Nalrar
0
0 0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid above, racemic 3-(4- {4-[(2-pheny1-5-
trifluoromethyl-
o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclohexanecarboxylic acid
was prepared from 3-(4-{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
pheny1}-piperazine-1-carbony1)-cyclohexanecarboxylic acid methyl ester and
lithium
hydroxide. The crude racemate was purified by chiral supercritical fluid
chromatography
to yield (1R,3 S)-3 -(4- {4- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbony1)-amino ] -
phenyl} -piperazine-l-carbony1)-cyclohexanecarboxylic acid as an off-white
solid (first
eluting peak). ES-MS calcd for C29H29F3N405 (m/e) 570.57, obsd 571.1 (M+H).
Example 113
Preparation of (1S,3R)-3-(4-14-[(2-phenyl-5-trffluoromethyl-oxazole-4-
carbonyl)-
amino] -phenylt-piperazine-1-carbonyl)-cyclohexanecarboxylic acid
F
0-F
.\ 1 F N
N
0 10 N Ifa r
0 0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid above, racemic 3-(4- {4-[(2-pheny1-5-
trifluoromethyl-
o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclohexanecarboxylic acid
was prepared from 3-(4-{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
pheny1}-piperazine-1-carbony1)-cyclohexanecarboxylic acid methyl ester and
lithium
hydroxide. The crude racemate was purified by chiral supercritical fluid
chromatography
(second eluting peak) to yield (1 S ,3R)-3 -(4- {4- [(2-phenyl-5 -
trifluoromethyl-o xazo le-4-
carbonyl)-amino] -phenyl} -piperazine-l-carbony1)-cyclohexanecarboxylic acid
as an off-
white solid. ES-MS calcd for C29H29F3N405 (m/e) 570.57, obsd 571.1 (M+H).
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Example 114
Preparation of (1-14-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
phenyll-piperidin-4-y1)-acetic acid
F F
0...F
. \N \ N
0101
N 0
/\A 0
With a method similar to that used for the preparation of rac-2-(4-{4-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid above, (1-{4-[(2-pheny1-5-trifluoromethyl-oxazole-
4-
carbony1)-amino]-pheny1}-piperidin-4-y1)-acetic acid was prepared from (1-{4-
[(2-
pheny1-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -phenyl} -piperidin-4-
y1)-acetic
acid ethyl ester and lithium hydroxide. LC-MS calcd for C24H22F3N304 (m/e)
473.2,
obsd 474.0 (M+H). The NMR spectrum obtained on the sample is compatible with
its
structure.
Example 115
Preparation of {5'-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
3,4,5,6-
tetrahydro-2H-[1,21bipyridiny1-4-y1}-acetic acid
F F
0...F
. \N \ N
I
0 NN\ 0
/\A 0
With a method similar to that used for the preparation of rac-2-(4-{4-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-phenyl} -p ip erazine-l-carbony1)-
cyclopentanecarboxylic acid above, {5'-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-amino]-3,4,5,6-tetrahydro-2H-[1,21bipyridinyl-4-y1}-acetic acid was
prepared
from {5 '- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -
3,4,5 ,6-tetrahydro -
2H-[1,21bipyridinyl-4-y1} -acetic acid ethyl ester and lithium hydroxide. LC-
MS calcd
for C23H21F3N404 (m/e) 474.2, obsd 475.1 (M+H). The NMR spectrum obtained on
the sample is compatible with its structure.
Example 116
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Preparation of rac-2- [(4- {4- [(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-
amino] -phenyl}-piperazine- 1-carbonyl)-amino] -cyclopentanecarboxylic acid
= 0
\
0 N 0
II 111411
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
phenyl-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid above, racemic 2-[(4- {4-[(2-pheny1-5-
trifluoromethyl-
o xazo le-4-carbony1)-amino ] -phenyl} -p ip erazine-l-carbony1)-amino -
cyclopentanecarboxylic acid was prepared from racemic 2-[(4- {4-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -p ip erazine-l-
carbony1)-amino -
cyclopentanecarboxylic acid methyl ester and lithium hydroxide. LC-MS calcd
for
C28H28F3N505 (m/e) 571.6, obsd 572 (M+H).
Example 117
Preparation of rac-1-(4-14-[(2-phenyl-5-trffluoromethyl-oxazole-4-carbonyl)-
amino] -phenylt-piperazine-1-carbonyl)-pyrrolidine-3-carboxylic acid
0
= \N--4N
0
-D
KNN
[1 0
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid above, racemic 1-(4- {4-[(2-pheny1-5-
trifluoromethyl-
o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-pyrrolidine-3-
carboxylic
acid was prepared from racemic 1-(4- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-pyrrolidine-3-carboxylic
acid methyl
ester and lithium hydroxide. LC-MS calcd for C27H26F3N505 (m/e) 557.5, obsd
558.1
(M+H).
Example 118
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Preparation of (1S,3S)-3-15-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino] -pyridin-2-ylaminot-cyclopentanecarboxylic acid
F
0----)\---F
4. \ I F
0
\N-N
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
phenyl-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -p ip erazine-l-
carbony1)-
cyc lop entanecarbo xylic acid above, (1 S ,3 S)-3 - {5- [(2-phenyl-5 -
trifluoromethyl-o xazo le-
4-carbony1)-amino]-pyridin-2-ylamino}-cyclopentanecarboxylic acid was prepared
from
(1 S ,3 S)-3 - {5- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -
pyridin-2-
ylamino 1 -cyclopentanecarboxylic acid methyl ester and lithium hydroxide.
LCMS calcd
for C22H19F3N404 (m/e) 460.41, obsd 461.14 (M+H).
Example 119
Preparation of (1R,3S)-3-15-[(2-Pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino] -pyridin-2-ylaminot-cyclopentanecarboxylic acid
F
0----)\---F
4. \ I F
N"---"yN\/
0
\ .--%-
N N
o
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -p ip erazine-l-
carbony1)-
cyc lop entanecarbo xylic acid above, (1R,3S)-3- {5- [(2-phenyl-5 -
trifluoromethyl-o xazo le-
4-carbony1)-amino]-pyridin-2-ylamino}-cyclopentanecarboxylic acid was prepared
from
(1R,3S)-3- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -
pyridin-2-
ylamino 1 -cyclopentanecarboxylic acid methyl ester and lithium hydroxide.
LCMS calcd
for C22H19F3N404 (m/e) 460.41, obsd 461.14 (M+H).
Example 120
Preparation of 5'-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
3,4,5,6-
tetrahydro-2H-[1,2]bipyridinyl-4-carboxylic acid
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F
0----)\---F
.\ I F
N"---rN
0 I
NNOr 0
0
With a method similar to that used for the preparation of rac-2-(4-{4-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid above, 5'-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-3,4,5,6-tetrahydro-2H41,21bipyridiny1-4-carboxylic acid was prepared
from 5'-
[(2-pheny1-5-trifluoromethyl-oxazo le-4-carbonyl)-amino] -3,4,5 ,6-tetrahydro -
2H-
[1,21bipyridiny1-4-carboxylic acid methyl ester and lithium hydroxide. LCMS
calcd for
C22H19F3N404 (m/e) 460.41, obsd 461.14 (M+H).
Example 121
Preparation of 2,2-dimethy1-4-oxo-4-14'-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-aminol-biphenyl-4-y1}-butyric acid
F
0._ F
N
\N \
0 I.1 0
00
0
With a method similar to that used for the preparation of rac-2-(4- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-carbony1)-
cyclopentanecarboxylic acid above, 2,2-
dimethy1-4-oxo-4- {4'-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-bipheny1-4-y1} -butyric acid was
prepared
from 2,2-
dimethy1-4-o xo -4- {4'-[(2-pheny1-5-trifluoromethyl-oxazo le-4-carbony1)-
amino ] -bipheny1-4-y1} -butyric acid methyl ester and lithium hydroxide. LCMS
calcd for
C29H23F3N205 (m/e) 536, obsd 537 (M+H).
Example 122
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-
acetyl-
piperazin-1-y1)-pyridin-3-y1]-amide
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F F
= \N \ N
I
Ny
0
To a suspension of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-
piperazin-1-
yl-pyridin-3-y1)-amide hydrochloride salt (65 mg, 0.13 mmol) in methylene
chloride (5
mL) was added triethylamine (0.15 mL). The mixture was cooled in an ice bath
and
acetyl chloride (12 ilL) was added. The mixture was stirred at room
temperature for 30
minutes and partitioned between methylene chloride and brine. The organic
layer was
dried over sodium sulfate and the solvents were evaporated. The residue was
first dried
in vacuum and then triturated with methanol (3 mL) to give 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide (21
mg) as a
solid. LC-MS calcd for C22H20F3N503 (m/e) 459.2, obsd 460.0 (M+H). The NMR
spectrum obtained on the sample is compatible with its structure.
Example 123
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-
isobutyryl-piperazin-1-y1)-pyridin-3-ylpamide
F F
. \N \ N
I
0
N
0
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid [6-(4-isobutyryl-p ip
erazin-l-y1)-
pyridin-3 -yl] -amide was prepared from 2-phenyl-5 -trifluoromethyl-o xazo le-
4-carboxylic
acid (6-piperazin-1-yl-pyridin-3-y1)-amide hydrochloride salt and isobutyryl
chloride.
LC-MS calcd for C24H24F3N503 (m/e) 487.2, obsd. 488.1 (M+H). The NMR spectrum
obtained on the sample is compatible with its structure.
Example 124
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-
cyclopropanecarbonyl-piperazin-1-y1)-pyridin-3-ylpamide
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F F
0---F
. \N \ N
I
0
N
0
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic
acid [6-(4-cyc loprop anec arbonyl-
piperazin-l-y1)-pyridin-3-y1]-amide was prepared from 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-y1)-amide hydrochloride
salt and
cyclopropanecarbonyl chloride. LC-MS calcd for C24H22F3N503 (m/e) 485.2, obsd
486.1 (M+H). The NMR spectrum obtained on the sample is compatible with its
structure.
Example 125
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-
propionyl-piperazin-1-y1)-pyridin-3-y11-amide
F F
0---F
. \N \ N
I
0
1...õ....õ.N y^,......
0
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid [6-(4-propionyl-p ip
erazin-1 -y1)-
pyridin-3 -yl] -amide was prepared from 2-phenyl-5 -trifluoromethyl-o xazo le-
4-carboxylic
acid (6-piperazin-1-yl-pyridin-3-y1)-amide hydrochloride salt and propionyl
chloride.
LC-MS calcd for C23H22F3N503 (m/e) 473.2, obsd 474.1 (M+H). The NMR spectrum
obtained on the sample is compatible with its structure.
Example 126
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid 164442,2-
dimethyl-propiony1)-piperazin-1-yl] -pyridin-3-y1} -amide
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F F
fat \N\ N
I
0 NN/'
Nr<
0
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid {6- [4-(2,2-dimethyl-
propiony1)-
p ip erazin-l-y1]-pyridin-3 -y1} -amide was prepared from 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid (6-piperazin- 1 -yl-pyridin-3-y1)-amide
hydrochloride salt and
pivaloyl chloride. LC-MS calcd for C25H26F3N503 (m/e) 501.2, obsd 502.1 (M+H).
The NMR spectrum obtained on the sample is compatible with its structure.
Example 127
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [441-
cyclopropanecarbonyl-piperidin-4-y1)-phenylpamide
F F
0
. N
N
0 10
N
0
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic
acid [4-(1-cyclopropanecarbonyl-
piperidin-4-y1)-phenyl] -amide was prepared from 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid (4-piperidin-4-yl-phenyl)-amide and cyclopropanecarbonyl
chloride. LC-
MS calcd for C26H24F3N303 (m/e) 483.2, obsd 484.3 (M+H). The NMR spectrum
obtained on the sample is compatible with its structure.
Example 128
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-1-
isobutyryl-pyrrolidin-3-ylamino)-pyridin-3-y1]-amide
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F
0 ----)\-- F
11\ 1 F
NrThrN \/
0
N
0
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid [6-((S)-1-isobutyryl-
pyrrolidin-3 -
ylamino)-pyridin-3-y1]-amide was prepared from 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid [6-((S)-pyrrolidin-3-ylamino)-pyridin-3-y1]-amide and
isobutyryl
chloride. LCMS calcd for C24H24F3N503 (m/e) 487.48, obsd 488.19 (M+H).
Example 129
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-1-
methanesulfonyl-pyrrolidin-3-ylamino)-pyridin-3-y1Pamide
F
0---)\--"F
411 \ I F
Nr"--y" m
.
0 I /0
N \ \
0
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid [6-((S)-1-
methanesulfonyl-
pyrrolidin-3-ylamino)-pyridin-3-y1]-amide was prepared from 2-pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid [6((S)-pyrro lidin-3 -ylamino)-
pyridin-3 -yl] -
amide and methane sulfonyl chloride. LCMS calcd for C21H20F3N504S (m/e) 495.5,
obsd 496.1 (M+H).
Example 130
Preparation of rac-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {643-
(isobutyryl-methyl-amino)-pyrrolidin-1-yll-pyridin-3-y1}-amide
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F
0----)\---F
.\ I F m
N"--"y-
0 I
R0
/N----5_
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-p ip erazin-1 -y1)-pyridin-3 -yl] -
amide above,
racemic 2-phenyl-5-trifluoromethyl-oxazo le-4-carboxylic acid {6- [3 -
(isobutyryl-methyl-
amino)-pyrro lidin-l-yl] -pyridin-3 -y1} -amide was prepared from
2-pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid [6-(3 -methylamino -pyrro lidin-1 -
y1)-pyridin-3 -
yl] -amide and isobutyryl chloride. LCMS calcd for C25H26F3N503 (m/e) 501.51,
obsd
502.21 (M+H).
Example 131
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-
(1-cyclopropanecarbonyl-piperidin-4-ylamino)-pyridin-3-ylpamide
F
4. = \
I
0 -.... õI:2 -..,.. ...---......)
N N
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic
acid [6-(1 -cyc loprop anec arbonyl-
piperidin-4-ylamino)-pyridin-3 -yl] -amide was prepared from 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-y1]-amide
trifluoroacetate
and cyclopropanecarbonyl chloride. LCMS calcd for C25H24F3N503 (m/e) 499, obsd
500 (M+H).
Example 132
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [641-
phenylacetyl-piperidin-4-ylamino)-pyridin-3-y1]-amide
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F
0 --FF 0 el
\
. \N N N
I
0 ..... õ1:2..... ...---......)
N N
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4- carbo xylic
acid [6-(1 - cyc loprop anec arbonyl-
piperidin-4-ylamino)-pyridin-3-y1]-amide was prepared from 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-y1]-amide
trifluoroacetate
and phenyl-acetyl chloride. LCMS calcd for C29H26F3N503 (m/e) 549, obsd 550
(M+H).
Example 133
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {64142,2,2-
trifluo ro-acety1)-piperidin-4-ylamino] -pyridin-3-y1} -amide
o F FF o
= I \N N N)Y F
I F
0 F
N N
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4- carbo xylic
acid {6- [1 -(2,2,2-trifluoro - acety1)-
piperidin-4-ylamino]-pyridin-3-y1} -amide was prepared
from 2-pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-
y1]-amide
trifluoroacetate and trifluoroacetic anhydride. LCMS calcd for C23H19F6N503
(m/e)
527, obsd 528 (M+H).
Example 134
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {64143,3-
dimethyl-butyry1)-piperidin-4-ylamino]-pyridin-3-y1}-amide
F
\
= \N N N )..L.X
I
0 ..... õ...-:2' --.... ..---....õ...)
N N
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
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phenyl-5-trifluoromethyl-oxazo le-4-carboxylic
acid {6- [1 -(3,3 -dimethyl-butyry1)-
piperidin-4-ylamino]-pyridin-3-y1} -amide was prepared from 2-
pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-
y1]-amide
trifluoroacetate and 3,3-dimethyl-butyryl chloride. LCMS calcd for
C27H30F3N503
(m/e) 529, obsd 530 (M+H).
Example 135
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1-
butyryl-
piperidin-4-ylamino)-pyridin-3-y1]-amide
F
0---F 0
N
I
0 -...... õ-i-..... õ...--,..,,,,....õ--1
N N
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid [6-(1 -butyryl-p ip
eridin-4-ylamino)-
pyridin-3 -yl] -amide was prepared from 2-phenyl-5 -trifluoromethyl-o xazo le-
4-carboxylic
acid [6-(piperidin-4-ylamino)-pyridin-3-y1]-amide trifluoroacetate and butyryl
chloride.
LCMS calcd for C25H26F3N503 (m/e) 501, obsd 502 (M+H).
Example 136
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1-
isobutyryl-piperidin-4-ylamino)-pyridin-3-y1]-amide
F
_.
fi0 F 0
\ \ N
N N).
I
0 -.., 1(...--... ....--,õ,....õ...-1
N N
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic
acid [6-(1 -isobutyryl-p ip eridin-4-
ylamino)-pyridin-3-y1]-amide was prepared from 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-y1]-amide trifluoroacetate
and
isobutyryl chloride. LCMS calcd for C25H26F3N503 (m/e) 501, obsd 502 (M+H).
Example 137
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Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1-
propionyl-piperidin-4-ylamino)-pyridin-3-y11-amide
o<iF FF o
I. \N \ N N
I
0
N N
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid [6-(1-propionyl-p
ip eridin-4-
ylamino)-pyridin-3 -yl] -amide was prepared from 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-y1]-amide trifluoroacetate
and
propionyl chloride. LCMS calcd for C24H24F3N503 (m/e) 487, obsd 488 (M+H).
Example 138
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1-
pentanoyl-piperidin-4-ylamino)-pyridin-3-y11-amide
F
\
fa
I
0 -..., .--..--- -.... .....---
õ,....-I
N N
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid [6-(1-p entanoyl-p
ip eridin-4-
ylamino)-pyridin-3 -yl] -amide was prepared from 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-y1]-amide trifluoroacetate
and
pentanoyl chloride. LCMS calcd for C26H28F3N503 (m/e) 515, obsd 516 (M+H).
Example 139
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {64142-
cyclopentyl-acety1)-piperidin-4-ylamino1-pyridin-3-y1}-amide
=o<rF FF
\N \ N Nj.)j)
I
0
N N
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With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic
acid {6- [1 -(2-cyc lop entyl-acety1)-
piperidin-4-ylamino]-pyridin-3-y1} -amide was prepared
from 2-phenyl-5 -
trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-
y1]-amide
trifluoroacetate and cyclopentyl-acetyl chloride. LCMS calcd for C28H30F3N503
(m/e)
541, obsd 542 (M+H).
Example 140
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {64143-
methyl-butyry1)-piperidin-4-ylaminol-pyridin-3-y1}-amide
F
0 F 0
= N--- \ \ N N )-
I
0 -...... .,=*--..... õ....---...,,)
N N
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid {6- [1 -(3 -methyl-
butyry1)-p ip eridin-
4-ylamino]-pyridin-3-y1} -amide was prepared from 2-pheny1-5-trifluoromethyl-
oxazole-
4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-y1]-amide
trifluoroacetate and 3-
methyl-butyryl chloride. LCMS calcd for C26H28F3N503 (m/e) 515, obsd 516
(M+H).
Example 141
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6- II
F
...
0 F 0
.\ \
N N N
I
0
N N
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic
acid {6- [1 -(4-methyl-p entano y1)-
piperidin-4-ylamino]-pyridin-3-y1} -amide was prepared
from 2-pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-pyridin-3-
y1]-amide
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trifluoroacetate and 4-methyl-pentanoyl chloride. LCMS calcd for C27H30F3N503
(m/e) 529, obsd 530 (M+H).
Example 142
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(methyl-
pentanoyl-amino)-3,4,5,6-tetrahydro-2H-11,21 bipyridiny1-5'-y11-amide
)F
=
0
\NJc NI
0 1;1",
N N 0
N
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(methyl-pentanoyl-amino)-
3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-5'-y1]-amide was prepared from 2-pheny1-
5-
trifluoromethyl-oxazole-4-carboxylic acid (4-
methylamino -3 ,4,5 ,6-tetrahydro -2H-
[1,21bipyridiny1-5'-y1)-amide trifluoroacetate and pentanoyl chloride. LCMS
calcd for
C27H30F3N503 (m/e) 529, obsd 530 (M+H).
Example 143
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid 144(2-
cyclopentyl-acety1)-methyl-amino] -3,4,5,6-tetrahydro-2H-11,2 '1bipyridiny1-5
'-y1} -
amide
=N
0
N N
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid }4- [(2-cyc lop entyl-
acety1)-methyl-
amino]-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-5'-y1} -amide was prepared from
2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid (4-methylamino -3 ,4,5
,6-tetrahydro -
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- 147 -2H-[1,21bipyridiny1-5'-y1)-amide trifluoroacetate and cyclopentylacetyl
chloride. LCMS
calcd for C29H32F3N503 (m/e) 555, obsd 556 (M+H).
Example 144
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-
(cyclop ropanecarbonyl-methyl-amino)-3,4,5,6-tetrahydro-2H- [1,21 bipyridiny1-
5'-
y1]-amide
=
o
\ N N
N N
N "Cy
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
pheny1-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(cyclopropanecarbonyl-
methyl-
amino)-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-5'-y1]-amide was prepared from 2-
phenyl-
5 -trifluoromethyl-o xazo le-4-carboxylic acid (4-methylamino -3 ,4,5 ,6-
tetrahydro -2H-
[1,21bipyridiny1-5 '-y1)-amide trifluoroacetate and cyclopropanecarbonyl
chloride. LCMS
calcd for C26H26F3N503 (m/e) 513, obsd 514 (M+H).
Example 145
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(methyl-
propionyl-amino)-3,4,5,6-tetrahydro-2H-[1,21 bipyridiny1-5'-yl] -amide
0
411
,-, I
N N 0
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
pheny1-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(methyl-propionyl-amino)-
3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-5'-y1]-amide was prepared from 2-phenyl-
5 -
trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino -3 ,4,5 ,6-
tetrahydro -2H-
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[1,21bipyridiny1-5'-y1)-amide trifluoroacetate and propionyl chloride. LCMS
calcd for
C25H26F3N503 (m/e) 501, obsd 502 (M+H).
Example 146
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {44(3,3-
dimethyl-butyry1)-methyl-amino] -3,4,5,6-tetrahydro-2H- [1,2 '1bipyridiny1-5 '-
y1} -
amide
)F
0
= \I\1 N
0
N jo<0
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazole-4-carboxylic acid }4-[(3,3-dimethyl-
butyry1)-methyl-
amino]-3,4,5,6-tetrahydro-2H-[1,21bipyridinyl-5'-y1}-amide was prepared from 2-
phenyl-5 -trifluoromethyl-o xazole-4-carboxylic acid (4-methylamino -3 ,4,5 ,6-
tetrahydro -
2H- [1,21bipyridiny1-5'-y1)-amide trifluoroacetate and tert-butylacetyl
chloride. LCMS
calcd for C28H32F3N503 (m/e) 543, obsd 544 (M+H).
Example 147
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-
(isobutyryl-
methyl-amino)-3,4,5,6-tetrahydro-2H-[1,21 bipyridiny1-5'-yl] -amide
0
= \NljN
0
N N 0
N)\/
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
pheny1-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(isobutyryl-methyl-
amino)-
3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-5'-y1]-amide was prepared from 2-phenyl-
5
trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino -3 ,4,5 ,6-
tetrahydro -2H-
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[1,21bipyridiny1-5'-y1)-amide trifluoroacetate and isobutyryl chloride. LCMS
calcd for
C26H28F3N503 (m/e) 515, obsd 516 (M+H).
Example 148
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[methyl-
(3-
methyl-butyry1)-amino]-3,4,5,6-tetrahydro-2H-[1,2,1bipyridiny1-5 '-y1} -amide
F F
0 F
.
I
0 N.....-i-,,N,--......, 0
N).
I
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid }4- [methyl-(3 -
methyl-butyry1)-
amino]-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-5'-y1} -amide was prepared from
2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid (4-methylamino -3 ,4,5
,6-tetrahydro -
2H-[1,21bipyridinyl-5'-y1)-amide trifluoroacetate and isovaleryl chloride.
LCMS calcd
for C27H30F3N503 (m/e) 529, obsd 530 (M+H).
Example 149
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-
(butyryl-
methyl-amino)-3,4,5,6-tetrahydro-2H-[1,21 bipyridiny1-5'-yl] -amide
F)e...._F
0 F
.
1/4_, -......N.::::-....N,--,....,
0
N)="L"'---..,
I
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid [4-(butyryl-methyl-
amino)-3,4,5,6-
tetrahydro-2H-[1,21bipyridiny1-5'-y1]-amide was prepared from 2-pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid (4-
methylamino -3 ,4,5 ,6-tetrahydro -2H-
[1,21bipyridiny1-5'-y1)-amide trifluoroacetate and butyryl chloride. LCMS
calcd for
C26H28F3N503 (m/e) 515, obsd 516 (M+H).
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Example 150
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid 14-[methyl-
(3,3,3-trifluoro-propiony1)-amino]-3,4,5,6-tetrahydro-2H-11,2,1bipyridiny1-5 '-
y1} -
amide
F
=N
0
N N 0 F
NF))<F
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic
acid {4- [methyl-(3 ,3 ,3 -trifluoro -
propiony1)-amino]-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-5'-y1} -amide was
prepared
from 2-phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid (4-methylamino -3
,4,5 ,6-
tetrahydro -2H-[1,21 bipyridiny1-5 '-y1)-amide trifluoro acetate and 3,3,3 -
trifluoropropionyl
chloride. LCMS calcd for C25H23F6N503 (m/e) 555, obsd 556 (M+H).
Example 151
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid 14-[methyl-
(4-
methyl-pentanoy1)-amino]-3,4,5,6-tetrahydro-2H-11,2,1bipyridiny1-5 '-y1} -
amide
=\N N
0 NN'0
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid {4- [methyl-(4-methyl-p
entano y1)-
amino]-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-5'-y1} -amide was prepared from
2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid (4-methylamino -3 ,4,5
,6-tetrahydro -
2H- [1,21bipyridiny1-5'-y1)-amide trifluoroacetate and 4-methyl-pentanoyl
chloride.
LCMS calcd for C28H32F3N503 (m/e) 543, obsd 544 (M+H).
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Example 152
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {44(2-
methoxy-acety1)-methyl-amino] -3,4,5,6-tetrahydro-2H- [1,2 '1bipyridiny1-5 '-
y1} -
amide
=
0
N
0
N N 0
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid }4-[(2-methoxy-acety1)-
methyl-
amino]-3,4,5,6-tetrahydro-2H-[1,21bipyridinyl-5'-y1}-amide was prepared from 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid (4-methylamino -3 ,4,5
,6-tetrahydro -
2H-[1,21bipyridinyl-5 '-y1)-amide trifluoroacetate and methoxyacetyl chloride.
LCMS
calcd for C25H26F3N504 (m/e) 517, obsd 518 (M+H).
Example 153
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[methyl-
(2,2,2-trifluoro-acety1)-amino]-3,4,5,6-tetrahydro-2H-[1,2,1bipyridiny1-5 '-
y1} -amide
\N
o N N 0
NYF
I F F
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid }4-[methyl-(2,2,2-
trifluoro-acety1)-
amino]-3,4,5,6-tetrahydro-2H-[1,21bipyridinyl-5'-y1}-amide was prepared from 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid (4-methylamino -3 ,4,5
,6-tetrahydro -
2H- [1,21bipyridiny1-5'-y1)-amide trifluoroacetate and trifluoroacetic
anhydride. LCMS
calcd for C24H21F6N503 (m/e) 541, obsd 542 (M+H).
Example 154
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Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
pyridin-2-y1}-piperazine-1-carboxylic acid isopropyl ester
F F
0
iik \ NFN
I
0 NN/
NO-
To a suspension of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-
piperazin-1 -
yl-pyridin-3-y1)-amide hydrochloride salt (50 mg, 0.102 mmol) in methylene
chloride (6
mL) was added triethylamine (0.1 mL). The clear solution was cooled in an ice
bath and
isopropylchloroformate (1M in toluene, 0.2 mL) was added. The mixture was
stirred at 0
C for 30 minutes and at room temperature for 1 hr. The solvents were
evaporated and
the residue was triturated with methanol. The precipitate was filtered and
dried to give 4-
{5 - [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino]-pyridin-2-y1} -
p ip erazine-1-
carboxylic acid isopropyl ester (32.4 mg). LC-MS calcd for C24H24F3N504 (m/e)
503.2, obsd 503.8 (M+H). The NMR spectrum obtained on the sample is compatible
with
its structure.
Example 155
Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
pyridin-2-y1}-piperazine-1-carboxylic acid ethyl ester
F F
0
. \NFN
I
0 N%N/
7Ny0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {5-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
pyridin-2-y1}-piperazine-1-carboxylic acid ethyl ester was prepared from 2-
pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid (6-
pip erazin-l-yl-pyridin-3 -y1)-amide
hydrochloride salt and ethyl chloroformate. LC-MS calcd for C23H22F3N504 (m/e)
489.2, obsd 490.0 (M+H). The NMR spectrum obtained on the sample is compatible
with its structure.
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Example 156
Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
pyridin-2-y1}-piperazine-1-carboxylic acid methyl ester
F F
0
.
N
N
I
0 e=Th\j/=
Ny0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {5-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
pyridin-2-y1} -piperazine- 1 -carboxylic acid methyl ester was prepared from 2-
pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid (6-pip erazin-l-yl-pyridin-3 -
y1)-amide
hydrochloride salt and methyl chloroformate. LC-MS calcd for C22H20F3N504
(m/e)
475.1, obsd 476.1 (M+H). The NMR spectrum obtained on the sample is compatible
with
its structure.
Example 157
Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
pyridin-2-y1}-piperazine-1-carboxylic acid propyl ester
F F
0--.F
=\ \ N
N
I
0 N%N/
.rNy0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {5-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
pyridin-2-y1} -piperazine- 1 -carboxylic acid propyl ester was prepared from 2-
pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid (6-pip erazin-l-yl-pyridin-3 -
y1)-amide
hydrochloride salt and propyl chloroformate. LC-MS calcd for C24H24F3N504
(m/e)
503.2, obsd 504.0 (M+H). The NMR spectrum obtained on the sample is compatible
with
its structure.
Example 158
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Preparation of 4-15-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
pyridin-2-y1}-piperazine-1-carboxylic acid isobutyl ester
F F
. \N \ N
I
0 NN
Ny0
0
With a method similar to that used for the preparation of 4- {5-[(2-phenyl-5-
trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {5-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
pyridin-2-y1} -piperazine- 1 -carboxylic acid isobutyl ester was prepared from
2-pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid (6-
pip erazin-l-yl-pyridin-3 -y1)-amide
hydrochloride salt and isobutyl chloroformate. LC-MS calcd for C25H26F3N504
(m/e)
517.2, obsd 518.1 (M+H). The NMR spectrum obtained on the sample is compatible
with
its structure.
Example 159
Preparation of 4-15-1(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-aminop
pyrimidin-2-y1}-piperazine-1-carboxylic acid methyl ester
F F
(:)--.F
.\ \
N NN
0 NLN
Ny0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {5-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
pyrimidin-2-y1} -piperazine- 1 -carboxylic acid methyl ester was prepared from
2-phenyl-
5 -trifluoromethyl-o xazo le-4-carboxylic acid (2-p ip erazin-l-yl-pyrimidin-5
-y1)-amide and
methyl chloroformate. LC-MS calcd for C21H19F3N604 (m/e) 476.1, obsd 477.0
(M+H). The NMR spectrum obtained on the sample is compatible with its
structure.
Example 160
Preparation of 4-14-1(2-phenyl-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
phenyll-piperidine-1-carboxylic acid methyl ester
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F F
= \N \ N
0 401
Ny0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
phenyl} -piperidine- 1 -carboxylic acid methyl ester was prepared from 2-
pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and
methyl
chloroformate. LC-MS calcd for C24H22F3N304 (m/e) 473.2, obsd 474.1 (M+H). The
NMR spectrum obtained on the sample is compatible with its structure.
Example 161
Preparation of 5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
3',4',5',6'-tetrahydro-2'H-[2,4,1bipyridinyl-1 '-carboxylic acid methyl ester
F F
4. \ \ N
N
I
0 N\/
Ny0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 5-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
3',4',5',6'-tetrahydro-2'H-[2,41bipyridinyl-1'-carboxylic acid methyl ester
was prepared
from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (1',2',3',4',5',6'-
hexahydro-
[2,41bipyridiny1-5-y1)-amide and methyl chloroformate. LC-MS calcd for
C23H21F3N404 (m/e) 474.2, obsd 475.1 (M+H). The NMR spectrum obtained on the
sample is compatible with its structure.
Example 162
Preparation of 4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-aminol-
phenylt-piperazine-1-carboxylic acid methyl ester
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F F
= \N \ N
0 401 N/
Ny0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
pheny1}-piperazine- 1-carboxylic acid methyl ester was prepared from 2-pheny1-
5-
trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-pheny1)-amide and
methyl
chloroformate. LC-MS calcd for C23H21F3N404 (m/e) 474.2, obsd 475.1 (M+H). The
NMR spectrum obtained on the sample is compatible with its structure.
Example 163
Preparation of 4-(5-111-(4-fluoro-pheny1)-3-trifluoromethyl-1H-pyrazole-4-
carbonylpamino}-pyridin-2-y1)-piperazine-1-carboxylic acid ethyl ester
F 40, F
N...\._-F
N'
\- F
N
0 0
N-
N----
C--N
,--0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4-(5- { [1-(4-fluoro-pheny1)-3-trifluoromethyl-1H-
pyrazo le-4-
carbonyl] -amino }-pyridin-2-y1)-piperazine- 1-carboxylic acid ethyl ester was
prepared
from 1-(4-fluoro-pheny1)-3-trifluoromethy1-1H-pyrazole-4-carboxylic acid (6-p
ip erazin-
1-yl-pyridin-3-y1)-amide and ethyl chloroformate. LCMS calcd for C23H22F4N603
(m/e) 506, obsd 507 (M+H). The NMR spectrum obtained on the sample is
compatible
with its structure.
Example 164
Preparation of 4-15-1(5-methy1-2-pheny1-2H-11,2,31triazole-4-carbony1)-aminop
pyridin-2-y1}-piperazine-1-carboxylic acid ethyl ester
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- 157 -OP 1,1µ,N
N-
N
0 0
N-
N
C--N
\-0
U \-
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {5- [(5-methy1-2-pheny1-2H- [1,2,3]triazo le-4-
carbonyl)-amino] -
pyridin-2-y1} -piperazine- 1 -carboxylic acid ethyl ester was prepared from 5-
methyl-2-
phenyl-2H- [1,2,3 acid (6-pip erazin-l-yl-pyridin-3 -y1)-
amide and
ethyl chloroformate. LCMS calcd for C22H25N703 (m/e) 435, obsd 436 (M+H). The
NMR spectrum obtained on the sample is compatible with its structure.
Example 165
Preparation of 4-14-[(1-phenyl-3-trifluoromethy1-1H-pyrazole-4-carbonyl)-
amino]-
phenylt-piperidine-1-carboxylic acid methyl ester
diN N
\- F
N
0=
N
,--0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {4- [(1-pheny1-3-trifluoromethy1-1H-pyrazo le-4-
carbonyl)-
amino]-phenyl} -piperidine-l-carboxylic acid methyl ester was prepared from 1-
phenyl-
3-trifluoromethy1-1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-
amide and
methyl chloroformate. LCMS calcd for C24H23F3N403 (m/e) 472, obsd 473 (M+H).
The NMR spectrum obtained on the sample is compatible with its structure.
Example 166
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Preparation of 4-14-[(1-phenyl-3-trifluoromethy1-1H-pyrazole-4-carbonyl)-
amino]-
phenyl}-piperidine-1-carboxylic acid ethyl ester
F
.,,,,,rF
\_ F
N
o,
N
0
With a method similar to that used for the preparation of 4- {5-[(2-phenyl-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {4-[(1-pheny1-3-trifluoromethy1-1H-pyrazole-4-
carbony1)-
amino]-phenyl} -piperidine-l-carboxylic acid ethyl ester was prepared from 1-
pheny1-3-
trifluoromethy1-1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide
and ethyl
chloroformate. LCMS calcd for C25H25F3N403 (m/e) 486, obsd 487 (M+H). The NMR
spectrum obtained on the sample is compatible with its structure.
Example 167
Preparation of 4-(5-1[2-(2-methoxy-ethyl)-5-phenyl-2H-pyrazole-3-carbony1]-
aminot-pyridin-2-y1)-piperazine-1-carboxylic acid ethyl ester
.
\
N
0 0
N ¨
N
--1\1
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4-(5- {[2-(2-methoxy-ethyl)-5-pheny1-2H-pyrazole-3-
carbonyl]-
amino 1 -pyridin-2-y1)-piperazine- 1 -carboxylic acid ethyl ester was prepared
from 2-(2-
metho xy-ethyl)-5 -p heny1-2H-pyrazo le-3 -carboxylic acid (6-p ip erazin-l-yl-
pyridin-3 -y1)-
amide and ethyl chloroformate. LCMS calcd for C25H30N604 (m/e) 478, obsd 479
(M+H).
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Example 168
Preparation of 4-15-[(5-methoxymethy1-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-
aminoppyridin-2-y1}-piperazine-1-carboxylic acid ethyl ester
.N,
N --
\ 0
N¨
N
0 0
N¨
N--\
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y4 -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {5 -[(5 -metho xymethy1-2-pheny1-2H41,2,3]triazo le-
4-carbony1)-
amino ] -pyridin-2-y4 -pip erazine- 1 -carboxylic acid ethyl ester was
prepared from 5-
metho xymethy1-2-p heny1-2H41,2,3]triazo le-4-carboxylic acid (6-p ip erazin-l-
yl-pyridin-
3-y1)-amide and ethyl chloroformate. LCMS calcd for C23H27N704 (m/e) 465, obsd
466 (M+H).
Example 169
Preparation of 4-14-[(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-aminop
phenyl}-piperidine-1-carboxylic acid ethyl ester
.,N
N
N¨
N
o,
N>--0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y4 -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {4-[(5-methy1-2-pheny1-2H-[1,2,3]triazole-4-
carbony1)-amino]-
phenyl} -piperidine-l-carboxylic acid ethyl ester was prepared from 5-methyl-2-
phenyl-
2H- [1,2,3]triazo le-4-carboxylic acid (4-p ip eridin-4-yl-p heny1)-amide and
ethyl
chloroformate. LCMS calcd for C24H27N503 (m/e) 433, obsd 434 (M+H). The NMR
spectrum obtained on the sample is compatible with its structure.
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Example 170
Preparation of 4-14-[(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-amino]-
phenylt-piperidine-1-carboxylic acid methyl ester
ill N-1,1-.
\
N¨
N
0 .
N
---$::
0 \
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {4-[(5-methy1-2-pheny1-2H-[1,2,3]triazole-4-
carbony1)-amino]-
pheny1}-piperidine-1-carboxylic acid methyl ester was prepared from 5-methy1-2-
pheny1-
2H-[1,2,3]triazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide and
methyl
chloroformate. LCMS calcd for C23H25N503 (m/e) 419, obsd 420 (M+H). (37660-298-
2)
Example 171
Preparation of 4-(4-1[1-(2-chloro-phenyl)-3-trifluoromethy1-1H-pyrazole-4-
carbonyl] -aminot-phenyl)-piperidine-1-carboxylic acid ethyl ester
* .--F
N F
\¨ F
CI N
o,
N
--0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4-(4- { [1-(2-chloro-pheny1)-3-trifluoromethyl-1H-
pyrazo le-4-
carbonyl]-amino}-pheny1)-piperidine-1-carboxylic acid ethyl ester was prepared
from 1-
(2-chloro -pheny1)-3 -trifluoromethy1-1H-pyrazo le-4-carbo xylic acid (4-p ip
eridin-4-yl-
pheny1)-amide and ethyl chloroformate. LCMS calcd for C25H24C1F3N403 (m/e)
520,
obsd 521 (M+H).
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Example 172
Preparation of (S)-3-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
pyridin-2-ylaminot-pyrrolidine-1-carboxylic acid ethyl ester
F
0-F
4. \ I F
N N
N
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, (S)-3- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbonyl)-
amino] -pyridin-2-ylamino } -pyrro lidine- 1 -carboxylic acid ethyl ester was
prepared from
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6((S)-pyrro lidin-3 -
ylamino)-
pyridin-3-y1]-amide and ethyl chloroformate. LCMS calcd for C23H22F3N504 (m/e)
489.45, obsd 490.17 (M+H).
Example 173
Preparation of (R)-3-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
aminop
pyridin-2-ylaminot-pyrrolidine-1-carboxylic acid ethyl ester
F
0----)\--F
4. \ I
NI N F"..)..
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, (R)-3- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbonyl)-
amino]-pyridin-2-ylamino}-pyrrolidine-l-carboxylic acid ethyl ester was
prepared from
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6((R)-pyrro lidin-3 -
ylamino)-
pyridin-3-y1]-amide and ethyl chloroformate. LCMS calcd for C23H22F3N504 (m/e)
489.45, obsd 490.17 (M+H).
Example 174
Preparation of (S)-3-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
aminol-
pyridin-2-ylaminot-pyrrolidine-1-carboxylic acid methyl ester
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F
OF
lit \ I F
N
N
0--
N
o
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, (S)-3- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbonyl)-
amino]-pyridin-2-ylamino}-pyrrolidine-l-carboxylic acid methyl ester was
prepared
from 2-phenyl-5-trifluoromethyl-oxazo le-4-carboxylic
acid [6((S)-pyrro lidin-3 -
ylamino)-pyridin-3-y1]-amide and methyl chloroformate. LCMS calcd for C22 H20
F3
N5 04 (m/e) 475.43, obsd 476.15 (M+H).
Example 175
Preparation of (S)-3-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
pyridin-2-ylaminot-pyrrolidine-1-carboxylic acid isopropyl ester
F
0---.)\--F
II \ I F
N-ThrNN/
C
I
0N-el--(
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, (S)-3- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbony1)-
amino]-pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid isopropyl ester was
prepared
from 2-phenyl-5-trifluoromethyl-oxazo le-4-carboxylic
acid [6((S)-pyrro lidin-3 -
ylamino)-pyridin-3 -yl] -amide and isopropyl chloro formate. LC MS calcd for
C24H24F3N504 (m/e) 503.48, obsd 504.19 (M+H).
Example 176
Preparation of (S)-3-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
pyridin-2-ylaminot-pyrrolidine-1-carboxylic acid benzyl ester
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F
0-F
*\ I F N
N
I 0
0
0 lip
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, (S)-3- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbonyl)-
amino]-pyridin-2-ylamino}-pyrrolidine-l-carboxylic acid benzyl ester was
prepared from
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6((S)-pyrro lidin-3 -
ylamino)-
pyridin-3-y1]-amide and benzyl chloroformate. LCMS calcd for C28H24F3N504
(m/e)
551.52, obsd 552.18 (M+H).
Example 177
Preparation of (S)-3-(methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-
amino] -pyridin-2-y1}-amino)-pyrrolidine-1-carboxylic acid ethyl ester
F
0----)\---F
0 N
N
I 0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, (S)-
3-(methyl- {5 - [(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbony1)-amino]-pyridin-2-y1} -amino)-pyrrolidine-l-carboxylic acid ethyl
ester was
prepared from 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [64(S)-
methyl-
pyrrolidin-3-yl-amino)-pyridin-3-y1]-amide and ethyl chloroformate. LCMS calcd
for
C24H24F3N504 (m/e) 503.48, obsd 504.19 (M+H).
Example 178
Preparation of rac-methyl-(1-15-[(2-phenyl-5-trffluoromethyl-oxazole-4-
carbonyl)-
amino] -pyridin-2-y1}-pyrrolidin-3-y1)-carbamic acid methyl ester
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F
0F
4. \ 1 F
N'ThiN
0 I
11--f
-
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, racemic methyl-(1- {5-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbonyl)-amino]-pyridin-2-y1}-pyrrolidin-3-y1)-carbamic acid methyl ester was
prepared
from racemic 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-
methylamino
-pyrrolidin-1-y1)-pyridin-3-y1]-amide and methyl chloroformate. LCMS calcd for
C23H22F3N504 (m/e) 489.45, obsd 490.17 (M+H).
Example 179
Preparation of (R)-(1-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
pyridin-2-y1}-pyrrolidin-3-y1)-carbamic acid methyl ester
F
0----)\--F
4. \ 1 F
N'ThrN
0 I
N-NR 0
N--f
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, (R)-(1- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbony1)-
amino ] -pyridin-2-y1} -pyrro lidin-3-y1)-carbamic acid methyl ester was
prepared from 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid [6-((R)-3 -amino -pyrro
lidin-l-y1)-
pyridin-3-y1]-amide and methyl chloroformate. LCMS calcd for C22H20F3N504
(m/e)
475.43, obsd 476.15 (M+H).
Example 180
Preparation of (S)-3-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
pyrimidin-2-ylaminot-pyrrolidine-1-carboxylic acid methyl ester
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=\ F
0
N N
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, (S)-3- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbonyl)-
amino]-pyrimidin-2-ylamino}-pyrrolidine-1-carboxylic acid methyl ester was
prepared
from 2-phenyl-5-trifluoromethyl-oxazo le-4-carboxylic
acid [2((S)-pyrro lidin-3 -
ylamino)-pyrimidin-5-y1]-amide and methyl chloroformate. LCMS calcd for
C21H19F3N604 (m/e) 476.41, obsd 477.15 (M+H).
Example 181
Preparation of (S)-3-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
aminol-
pyrimidin-2-ylaminot-pyrrolidine-1-carboxylic acid ethyl ester
F
N'ThrNN
0
Nr
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, (S)-3- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbony1)-
amino]-pyrimidin-2-ylamino}-pyrrolidine-1-carboxylic acid ethyl ester was
prepared
from 2-phenyl-5-trifluoromethyl-oxazo le-4-carboxylic
acid [2((S)-pyrro lidin-3 -
ylamino)-pyrimidin-5-y1]-amide and ethyl chloroformate. LCMS calcd for
C22H21F3N604 (m/e) 490.44, obsd 491.16 (M+H).
Example 182
Preparation of (S)-3-15-[(4-methyl-2-pyridin-2-yl-thiazole-5-carbonyl)-aminol-
pyridin-2-ylaminot-pyrrolidine-1-carboxylic acid ethyl ester
Sr
0 Nr
NN
0
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With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, (S)-3- {5 -[(4-methyl-2-pyridin-2-yl-thiazo le-5 -
carbonyl)-amino] -
pyridin-2-ylamino 1 -pyrrolidine- 1 -carboxylic acid ethyl ester was prepared
from 4-
methyl-2-pyridin-2-yl-thiazo le-5 -carbo xylic acid [64(S)-pyrro lidin-3 -
ylamino)-pyridin-
3-y1]-amide and ethyl chloro formate. LCMS calcd for C22H24N603S (m/e) 452.54,
obsd 453.17 (M+H).
Example 183
Preparation of 4-12-cyano-4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino] -phenylt-piperazine-1-carboxylic acid ethyl ester
F
F.......__F
0
0 \
/--\ 0
N N II N N-µ
11104 H
\\ 0
N
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {2-cyano-4-[(2-pheny1-5-trifluoromethyl-oxazo le-4-
carbonyl)-
amino]-phenyl} -piperazine-l-carboxylic acid ethyl ester was prepared from 2-
pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid (3 -cyano -4-pip erazin-l-yl-p
heny1)-amide and
ethyl chloroformate. LCMS for C25H22F3N504 (m/e) calc. 513, obsd 514 (M+H).
Example 184
Preparation of 4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
phenylt-piperazine-1-carboxylic acid butyl ester
F
F_ 0
0 _____________________________
F /--\
N * NN4
\
-- µ \- 0-\
\
N 0 \
*
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
phenyl} -piperazine- 1 -carboxylic acid butyl ester was prepared from 2-phenyl-
5-
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trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-pheny1)-amide and
butyl
chloroformate. LCMS calcd for C26H27F3N404 (m/e) 516, obsd. 517 (M+H).
Example 185
Preparation of 4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
pyridin-2-ylaminot-piperidine-1-carboxylic acid isobutyl ester
F
0--FF 0
\
. \N Ni NAO
I
0
N N
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {5-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
pyridin-2-ylamino}-piperidine-1-carboxylic acid isobutyl ester was prepared
from 2-
pheny1-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-
pyridin-3-
yl]-amide trifluoroacetate and isobutyl chloroformate. LCMS calcd for
C26H28F3N504
(m/e) 531, obsd 532 (M+H).
Example 186
Preparation of 4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
pyridin-2-ylaminot-piperidine-1-carboxylic acid methyl ester
o4FiFF 0
\
. \N Ni N)L0
I
0
N N
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {5-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
pyridin-2-ylamino}-piperidine-1-carboxylic acid methyl ester was prepared from
2-
pheny1-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-
pyridin-3-
y1]-amide trifluoroacetate and methyl chloroformate. LCMS calcd for
C23H22F3N504
(m/e) 489, obsd 490 (M+H).
Example 187
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Preparation of 4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
pyridin-2-ylaminot-piperidine-1-carboxylic acid ethyl ester
F
0- 0
\
= \N Ni NAO
I
0 -...... -;;;-=-..... .................õ--1
N N
With a method similar to that used for the preparation of 4- {5-[(2-phenyl-5-
trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-y4 -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {5-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
pyridin-2-ylamino}-piperidine-1-carboxylic acid ethyl ester was prepared from
2-phenyl-
5 -trifluoromethyl-o xazo le-4-carboxylic acid [6-
(pip eridin-4-ylamino)-pyridin-3 -yl] -
amide trifluoroacetate and ethyl chloroformate. LCMS calcd for C24H24F3N504
(m/e)
503, obsd 504 (M+H).
Example 188
Preparation of 4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
pyridin-2-ylaminot-piperidine-1-carboxylic acid 2,2-dimethyl-propyl ester
oF FF o
\
I
N N
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y4 -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {5-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
pyridin-2-ylamino}-piperidine-1-carboxylic acid 2,2-dimethyl-propyl ester was
prepared
from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-
ylamino)-
pyridin-3-y1]-amide trifluoroacetate and 2,2-dimethylpropyl chloroformate.
LCMS calcd
for C27H30F3N504 (m/e) 545, obsd 546 (M+H).
Example 189
Preparation of 4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
pyridin-2-ylaminot-piperidine-1-carboxylic acid isopropyl ester
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FF
0 F 0
0
N N
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {5-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
pyridin-2-ylamino}-piperidine-1-carboxylic acid isopropyl ester was prepared
from 2-
pheny1-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-
pyridin-3-
trifluoroacetate and isopropyl chloroformate. LCMS calcd for
C25H26F3N504 (m/e) 517, obsd 518 (M+H).
Example 190
Preparation of methyl-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-y1}-carbamic acid methyl ester
411
0
N N 0
NA0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, methyl- {5'-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-y1} -carbamic acid methyl
ester was
prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-
methylamino-
3,4,5,6-tetrahydro -2H- [1,21 bipyridiny1-5 '-y1)-amide trifluoro
acetate and methyl
chloroformate. LCMS calcd for C24H24F3N504 (m/e) 503, obsd 504 (M+H).
Example 191
Preparation of methyl-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-y1}-carbamic acid ethyl ester
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=0
0
N N 0
NAO
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, methyl- {5'-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-y1}-carbamic acid ethyl ester
was
prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-
methylamino-
3,4,5,6-tetrahydro -2H- [1,21 bipyridiny1-5 '-y1)-amide trifluoro
acetate and ethyl
chloroformate. LCMS calcd for C25H26F3N504 (m/e) 517, obsd 518 (M+H).
Example 192
Preparation of methyl-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-y1}-carbamic acid isobutyl ester
=
0
N N 0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, methyl- {5'-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-y1}-carbamic acid isobutyl
ester was
prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-
methylamino-
3,4,5,6-tetrahydro -2H- [1,21 bipyridiny1-5 '-y1)-amide trifluoro
acetate and isobutyl
chloroformate. LCMS calcd for C27H30F3N504 (m/e) 545, obsd 546 (M+H).
Example 193
Preparation of methyl-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-y1}-carbamic acid 2,2-dimethyl-propyl
ester
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=0
0
N 0
NAOX
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, methyl- {5'-[(2-pheny1-5-trifluoromethyl-oxazo le-4-
carbonyl)-
amino]-3,4,5,6-tetrahydro-2H41,21bipyridiny1-4-y1} -carbamic acid 2,2-dimethyl-
propyl
ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid
(4-
methylamino-3,4,5,6-tetrahydro-2H- [1,21bipyridiny1-5'-y1)-amide trifluoro
acetate and
2,2-dimethylpropyl chloroformate. LCMS calcd for C28H32F3N504 (m/e) 559, obsd
560 (M+H).
Example 194
Preparation of methyl-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-y1}-carbamic acid isopropenyl ester
0
=
0 0
NAO
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, methyl- {5'-[(2-pheny1-5-trifluoromethyl-oxazo le-4-
carbonyl)-
amino] -3,4,5,6-tetrahydro-2H- [1,21bipyridiny1-4-y1} -carbamic acid
isopropenyl ester
was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-
methylamino-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-5'-y1)-amide trifluoro
acetate and
isopropenyl chloro formate. LCMS calcd for C26H26F3N504 (m/e) 529, obsd 530
(M+H).
Example 195
Preparation of 4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-aminol-
phenylt-piperazine-1-carboxylic acid propylamide
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F
. \ ...F
0
N
Th
0 401 N
L,....,...õ. N ,Ii.... N ....,...õ,=¨....õ.õ.
0
To a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-
piperazin-l-yl-
pheny1)-amide hydrochloride (100 mg, 0.204 mmol) and triethylamine (57 ilL,
0.408
mmol) in 5 mL THF at 0 C was added n-propylisocyanate (21.6 mg, 0.255 mmol).
The
ice bath was removed and the reaction mixture was stirred at room temperature
for 1 hr.
The reaction mixture was diluted with ethyl acetate and washed with water. The
organic
layer was washed with saturated aqueous sodium bicarbonate solution, dried
over
magnesium sulfate, filtered, and evaporated under reduced pressure. The
residue was
crystallized from ethyl acetate/hexane to yield 4- }4-[(2-phenyl-5-
trifluoromethyl-
oxazole-4-carbonyl)-amino]-pheny1}-piperazine-1-carboxylic acid propylamide
(83 mg,
81%). ES-MS calcd for C25H26F3N503 (m/e) 501.51, obsd 502.1 (M+H).
Example 196
Preparation of 4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-aminoP
phenylt-piperazine-1-carboxylic acid isopropylamide
F
= \ ......F
0
t F
N
N
0I.1
N
1-.......,..,õ. N ,11,.. N .....s........
o
With a method similar to that used for the preparation of 4- }4-[(2-phenyl-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-
carboxylic acid
propylamide above, 4- }4- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbony1)-
amino ] -
pheny1}-piperazine-l-carboxylic acid isopropylamide was prepared from 2-pheny1-
5-
trifluoromethyl-oxazole-4-carboxylic acid (4-
pip erazin-l-yl-p heny1)-amide
hydrochloride and isopropylisocyanate. LC-MS calcd for C25H26F3N503 (m/e)
501.5,
obsd 502.1 (M+H). The NMR spectrum obtained on the sample is compatible with
its
structure.
Example 197
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Preparation of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
pyridin-2-y1}-piperazine-1-carboxylic acid propylamide
F
4. \ \ F
N N..,,,,,,=:.õ..,
I
0 ...,.N.--j-,..N.,..-.)
1...,,....õ..N.Ir.N....,........-,.....
0
With a method similar to that used for the preparation of 4- {4-[(2-phenyl-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-
carboxylic acid
propylamide above, 4- {5 - [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbony1)-
amino ] -
pyridin-2-y1}-piperazine-1-carboxylic acid propylamide was prepared from 2-
pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid (6-
pip erazin-l-yl-pyridin-3 -y1)-amide
hydrochloride and propylisocyanate. LC-MS calcd for C24H25F3N603 (m/e) 502.2,
obsd 503.1 (M+H). The NMR spectrum obtained on the sample is compatible with
its
structure.
Example 198
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-1-
tert-
butylcarbamoyl-pyrrolidin-3-ylamino)-pyridin-3-ylpamide
F
0-----.)\---F
N-Thrr,
0
N
0
With a method similar to that used for the preparation of 4-{4-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-
carboxylic acid
propylamide above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-
((S)-1-tert-
butylcarbamoyl-pyrrolidin-3-ylamino)-pyridin-3-y1]-amide was prepared from 2-
phenyl-
5 -trifluoromethyl-o xazo le-4-carboxylic acid [6((S)-pyrro lidin-3 -ylamino)-
pyridin-3 -yl] -
amide and tert-butyl isocyanate. LCMS calcd for C25H27F3N603 (m/e) 516.52,
obsd
517.2 (M+H).
Example 199
Preparation of 4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino-
pyridin-2-ylaminot-piperidine-1-carboxylic acid butylamide
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F
0--FF 0
\
. NNDI
0
N N
With a method similar to that used for the preparation of 4- {4-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-
carboxylic acid
propylamide above, 4-
{5 - [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbony1)-amino -
pyridin-2-ylamino}-piperidine-1-carboxylic acid butylamide was prepared from 2-
pheny1-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-
pyridin-3-
yl]-amide trifluoroacetate and butyl isocyanate. LCMS calcd for C26H29F3N603
(m/e)
530, obsd 531 (M+H).
Example 200
Preparation of 4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
pyridin-2-ylaminot-piperidine-1-carboxylic acid cyclohexylamide
F
\
iii \N N, NANO
I
0 -..., .--..--- -.... .....---õ,....-I
N N
With a method similar to that used for the preparation of 4- {4-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-
carboxylic acid
propylamide above, 4- {5 - [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbony1)-
amino ] -
pyridin-2-ylamino}-piperidine-1-carboxylic acid cyclohexylamide was prepared
from 2-
pheny1-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-
pyridin-3-
yl]-amide trifluoroacetate and cyclohexyl isocyanate. LCMS calcd for
C28H31F3N603
(m/e) 556, obsd 557 (M+H).
Example 201
Preparation of 4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
pyridin-2-ylaminot-piperidine-1-carboxylic acid benzylamide
o4iF FF o
\
I
1.1
0
N N
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With a method similar to that used for the preparation of 4- {4-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -piperazine-l-carboxylic
acid
propylamide above, 4- {5 - [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbony1)-
amino] -
pyridin-2-ylamino -piperidine- 1 -carboxylic acid benzylamide was prepared
from 2-
phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(piperidin-4-ylamino)-
pyridin-3-
trifluoroacetate and benzyl isocyanate. LCMS calcd for C29H27F3N603 (m/e)
564, obsd 565 (M+H).
Example 202
Preparation of 4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-aminol-
pyridin-2-ylaminot-piperidine-1-carboxylic acid methylamide
= FF
N NAN
0
N N
With a method similar to that used for the preparation of 4- {4-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -piperazine-l-carboxylic
acid
propylamide above, 4- {5 - [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbony1)-
amino] -
pyridin-2-ylamino -piperidine- 1 -carboxylic acid methylamide was prepared
from 2-
pheny1-5-trifluoromethyl-oxazo le-4-carboxylic acid [6-(piperidin-4-ylamino)-
pyridin-3-
trifluoroacetate and methyl isocyanate. LCMS calcd for C23H23F3N603
(m/e) 488, obsd 489 (M+H).
Example 203
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(3-
isopropyl-1-methyl-ureido)-3,4,5,6-tetrahydro-2H-[1,21 bipyridiny1-5'-yl] -
amide
FF
I
0
N N 0
NAN
With a method similar to that used for the preparation of 4- {4-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -piperazine-l-carboxylic
acid
propylamide above, 2-phenyl-5-trifluoromethyl-oxazo le-4-carboxylic acid [4-(3-
isopropy1-1-methyl-ureido)-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-5'-y1]-amide
was
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prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-
methylamino-
3,4,5,6-tetrahydro -2H- [1,21 bipyridiny1-5 '-y1)-amide trifluoro acetate and
isopropyl
isocyanate. LCMS calcd for C26H29F3N603 (m/e) 530, obsd 531 (M+H).
Example 204
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(3-
butyl-1-
methyl-ureido)-3,4,5,6-tetrahydro-2H-[1,21 bipyridiny1-5'-yl] -amide
0 F
. \NN
I
0 -...,N.f.::-...,N...---..., 0
NAN
I
With a method similar to that used for the preparation of 4- {4-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-
carboxylic acid
propylamide above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(3-
buty1-1-
methyl-ureido)-3,4,5,6-tetrahydro-2H-[1,21bipyridinyl-5'-y1]-amide was
prepared from
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-
methylamino -3 ,4,5 ,6-
tetrahydro-2H-[1,21bipyridiny1-5'-y1)-amide trifluoroacetate and butyl
isocyanate. LCMS
calcd for C27H31F3N603 (m/e) 544, obsd 545 (M+H).
Example 205
Preparation of 4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
pyridin-2-y1}-piperazine-1-carboxylic acid dimethylamide
F
= \ \ F
N
N
I
0 -....... ...-õ:--',., õ...--...1
N N
I
N N.i
o
With a method similar to that used for the preparation of 4- {4-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-
carboxylic acid
propylamide above, 4- {5 - [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbony1)-
amino ] -
pyridin-2-y1}-piperazine- 1-carboxylic acid dimethylamide was prepared from 2-
phenyl-
5 -trifluoromethyl-o xazo le-4-carboxylic acid (6-pip erazin-l-yl-
pyridin-3 -y1)-amide
hydrochloride and N,N-dimethylcarbamoyl chloride. LC-MS calcd for C23H23F3N603
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(m/e) 488.2, obsd 489.1 (M+H). The NMR spectrum obtained on the sample is
compatible with its structure.
Example 206
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [64(S)-1-
dimethylcarbamoyl-pyrrolidin-3-ylamino)-pyridin-3-y11-amide
F
0---)\--F
it \ I F
\
N----yN\
0
\N
0
With a method similar to that used for the preparation of 4- {4-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-
carboxylic acid
propylamide above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-
((S)-1-
dimethylcarbamoyl-pyrrolidin-3-ylamino)-pyridin-3-y1]-amide was prepared from
2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic
acid [6((S)-pyrro lidin-3 -ylamino)-
pyridin-3-y1]-amide and dimethyl carbamoyl chloride. LCMS calcd for
C23H23F3N603
(m/e) 488.47, obsd 489.18 (M+H).
Example 207
Preparation of 4-14-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
phenylt-piperazine-1-carboxylic acid (3-methyl-pyridin-2-y1)-amide
F
= \ \ F
N 0 N 401
N.
NyNN
I
0
To a solution of 2-amino-3-picoline (26 L, 0.204 mmol) and triethylamine (63
L,
0.448 mmol) in 5 mL methylene chloride at -40 C was slowly added a 20%
solution of
phosgene in THF (118 L, 0.224 mmol). The reaction mixture was stirred at -40
C for 1
hr and then a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid
(4-
piperazin-1-yl-pheny1)-amide hydrochloride (100 mg, 0.204 mmol) and
triethylamine (57
1, 0.408 mmol) in 8 ml of 1-methyl-2-pyrrolidinone was slowly added and
stirred at
room temperature overnight. The reaction mixture was diluted with ethyl
acetate and
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washed with saturated sodium bicarbonate solution and water. The organic layer
was
dried over magnesium sulfate, filtered and evaporated to dryness. The residue
was
purified by flash chromatography (eluting with ethyl acetate/hexane) to yield
4- {4-[(2-
phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -phenyl} -piperazine-l-
carboxylic
acid (3-methyl-pyridin-2-y1)-amide (18 mg, 16%). ES-MS calcd for C28H25F3N603
(m/e) 550.6, obsd 551.1 (M+H).
Example 208
Preparation of 4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
phenyl}-piperazine-l-carboxylic acid ethylamide
F
0--F
gi\ \ F N
N
0 01 N
NyN
0
With a method similar to that used for the preparation of 4- {4-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-
carboxylic acid (3 -
methyl-pyridin-2-y1)-amide above, 4-
{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid ethylamide was prepared
from 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid (4-p ip erazin-l-yl-p
heny1)-amide
hydrochloride and ethylamine. LC-MS calcd for C24H24F3N503 (m/e) 487.5, obsd
488.1 (M+H).
Example 209
Preparation of 4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
phenylt-piperazine-1-carboxylic acid ethyl-methyl-amide
F
. \ \ F
N 0 N 0
N
Nyll\I
0
With a method similar to that used for the preparation of 4- {4-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-
carboxylic acid (3 -
methyl-pyridin-2-y1)-amide above, 4-
{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-
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carbonyl)-amino] -phenyl} -piperazine-l-carboxylic
acid ethyl-methyl-amide was
prepared from 2-phenyl-5-trifluoromethyl-oxazo le-4-carboxylic acid (4-p ip
erazin-l-yl-
pheny1)-amide hydrochloride and N-ethylmethylamine. LC-MS calcd for
C25H26F3N503 (m/e) 501.51, obsd 502.1 (M+H).
Example 210
Preparation of 4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
phenylt-piperazine-1-carboxylic acid (5-methyl-isoxazol-3-y1)-amide
F
=\ \ F N
N
0 0 N
NõN N
1 1 T: 2K0
0 - - -
With a method similar to that used for the preparation of 4- {4-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-
carboxylic acid (3 -
methyl-pyridin-2-y1)-amide above, 4-
{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-amino ] -phenyl} -piperazine-l-carboxylic acid (5 -methyl-iso xazol-
3 -y1)-amide
was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-
piperazin-1-
yl-phenyl)-amide hydrochloride and 3-amino-5-methylisoxazole. LC-MS calcd for
C26H23F3N604 (m/e) 540.4, obsd 541.1 (M+H).
Example 211
Preparation of rac-2-[(4-14-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-phenylt-piperazine-1-carbony1)-aminoPcyclopentanecarboxylic acid methyl
ester
F
fat \ \ F N
N
.0c.3..0
0 1401 N
\
NyN
0
With a method similar to that used for the preparation of 4- {4-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-
carboxylic acid (3 -
methyl-pyridin-2-y1)-amide above, racemic 2-[(4- {4-[(2-pheny1-5-
trifluoromethyl-
o xazo le-4-carbony1)-amino ] -phenyl} -p ip erazine-l-carbony1)-amino ] -
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cyclopentanecarboxylic acid methyl ester was prepared from 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid (4-piperazin-1-yl-pheny1)-amide hydrochloride and
racemic
cis-2-aminocyclopentanecarboxylic acid methyl ester hydrochloride. LC-MS calcd
for
C29H30F3N505 (m/e) 585.6, obsd 586.1 (M+H).
Example 212
Preparation of rac-1-(4-14-[(2-phenyl-5-trffluoromethyl-oxazole-4-carbonyl)-
amino] -phenylt-piperazine-1-carbonyl)-pyrrolidine-3-carboxylic acid methyl
ester
F
41 \ \ F N
N
0 01 N
0
Nj---D--
[I o
/
o
With a method similar to that used for the preparation of 4- {4-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-
carboxylic acid (3 -
methyl-pyridin-2-y1)-amide above, racemic 1-(4-{4-[(2-pheny1-5-trifluoromethyl-
oxazole-4-carbony1)-amino]-phenyl} -piperazine-l-carbony1)-pyrrolidine-3-
carboxylic
acid methyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-
carboxylic
acid (4-piperazin-1-yl-pheny1)-amide hydrochloride and racemic pyrrolidine-3-
carboxylic acid methyl ester hydrochloride. LC-MS calcd for C28H28F3N505 (m/e)
571.6, obsd 572.1 (M+H).
Example 213
Preparation of 3-chloro-4-15-[(2-phenyl-5-trffluoromethyl-oxazole-4-carbonyl)-
amino] -pyridin-2-y1}-benzoic acid
0:F FF
\
1 CI
I
0
N Si
0
0
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo-
pyridin-3-
y1)-amide (600 mg, 1.46 mmol), (4-carboxy-2-chloro)benzeneboronic acid (437
mg, 2.18
MM01), tetrakis(triphenylphosphine)palladium(0) (84 mg, 0.07 mmol), and sodium
carbonate (2M, 1.5 mL) in ethanol (10 mL) was microwaved at 160 C for 30 min.
The
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reaction was filtered and the precipitates were washed with ethanol. The
combined
filtrates were concentrated and purified by flash chromatography (Merck silica
gel 60,
230-400 mesh, 0-25 % methanol in methylene chloride) to give 3-chloro-4-{5-[(2-
pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -benzoic
acid (506
mg, 71 %) as a light yellow solid. LCMS calcd for C23H13C1F3N304 (m/e) 487,
obsd
488 (M+H).
Example 214
Preparation of 4-15-1(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-aminop
pyridin-2-y1}-benzoic acid
F
. 0 ---)<FF
\ I
N
\
N-Th: I
NO0
0
With a method similar to that used for the preparation of 3-chloro-4-{5-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1}-benzoic acid above, 4-
{5-[(2-
pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -benzoic
acid was
prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo-
pyridin-
3-y1)-amide and 4-carboxyphenylboronic acid. LCMS calcd for C23H14F3N304 (m/e)
453, obsd 454 (M+H).
Example 215
Preparation of 2-chloro-4-15-1(2-pheny1-5-trffluoromethyl-oxazole-4-carbonyl)-
aminoppyridin-2-y1}-benzoic acid
F
.......)<F
afr 0 F
\ I
N-Th.rN
0 I
N
ill CI
0
0
With a method similar to that used for the preparation of 3-chloro-4-{5-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1}-benzoic acid above, 2-
chloro-
4- {5 - [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -pyridin-2-
y1} -benzoic
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acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-
bromo-
pyridin-3-y1)-amide and 4-carboxy-3-chlorophenylboronic acid. LCMS calcd for
C23H13C1F3N304 (m/e) 487, obsd 488 (M+H).
Example 216
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-
isobutylcarbamoyl-pheny1)-pyridin-3-ylpamide
F
F
=
F
N
NThi, I
N /401
N............====-...,,.
o
With a method similar to that used for the preparation of 3-chloro-4- {5-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-y1} -benzoic acid above,
2-phenyl-
5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-isobutylcarbamoyl-pheny1)-
pyridin-3-
yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic
acid (6-
bromo-pyridin-3-y1)-amide and 4-(isobutylaminocarbonyl)benzeneboronic acid.
LCMS
calcd for C27H23F3N403 (m/e) 508, obsd 509 (M+H).
Example 217
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4'-
isobutylcarbamoyl-bipheny1-4-y1)-amide
F
j<F
= 0
\ I F
N
NThOr lel
111 N............====-...,,.
0
With a method similar to that used for the preparation of 3-chloro-4- {5-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -benzoic acid above,
2-phenyl-
5-trifluoromethyl-oxazole-4-carboxylic acid (4'-isobutylcarbamoyl-biphenyl-4-
y1)-amide
was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-iodo-
pheny1)-amide and 4-(isobutylaminocarbonyl)benzeneboronic acid. LCMS calcd for
C28H24F3N303 (m/e) 507, obsd 508 (M+H).
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Example 218
Preparation of 4'-[(2-phenyl-5-trffluoromethyl-oxazole-4-carbonyl)-amino]-
biphenyl-4-carboxylic acid
F
F
40 0----)<F
\ I
SI0
401 0
0
With a method similar to that used for the preparation of 3-chloro-4- {5-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -benzoic acid above,
4'-[(2-
pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-biphenyl-4-carboxylic acid
was
prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-iodo-
pheny1)-
amide and 4-carboxyphenylboronic acid. LCMS calcd for C24H15F3N204 (m/e) 452,
obsd 453 (M+H).
Example 219
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-
cyclopentylcarbamoyl-phenyl)-pyridin-3-y1]-amide
F
F
441 \ I
N'ThiN
0 I
N 40
N
0 D
With a method similar to that used for the preparation of 3-chloro-4- {5-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -benzoic acid above,
2-phenyl-
5 -trifluoromethyl-o xazo le-4-carboxylic
acid [6-(4-cyc lop entylcarbamo yl-p heny1)-
pyridin-3 -yl] -amide was prepared from 2-phenyl-5 -trifluoromethyl-o xazo le-
4-carboxylic
acid (6-bromo-pyridin-3-y1)-amide and 4-
(cyclopentylaminocarbonyl)benzeneboronic
acid. LCMS calcd for C28H23F3N403 (m/e) 520, obsd 521 (M+H).
Example 220
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Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-
cyclop ropylca rb a moyl-p h eny1)-pyridin-3-yl] -amide
F
F
441 \ I
N----N.N
0 I õI
N__,
0 V
With a method similar to that used for the preparation of 3-chloro-4- {5-[(2-
phenyl-5-
trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-y1} -benzoic acid above,
2-phenyl-
5 -trifluoromethyl-o xazo le-4-carboxylic
acid [6-(4-cyc lopropylcarbamo yl-p heny1)-
pyridin-3 -yl] -amide was prepared from 2-phenyl-5 -trifluoromethyl-o xazo le-
4-carboxylic
acid (6-bromo-pyridin-3-y1)-amide and 4-(N-
cyclopropylaminocarbonyl)phenylboronic
acid. LCMS calcd for C26H19F3N403 (m/e) 492, obsd 493 (M+H).
Example 221
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4'-
cyclop ropylca rb a moyl-bip h eny1-4-y1)-amide
F
4.0---.)<FF __________________________________________ 15
1 \
N_Th.orN io
III N _______________________________________________ ,
0 V
With a method similar to that used for the preparation of 3-chloro-4- {5-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -benzoic acid above,
2-phenyl-
5-trifluoromethyl-oxazole-4-carboxylic acid (4'-cyclopropylcarbamoyl-bipheny1-
4-y1)-
amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid
(4-iodo-
pheny1)-amide and 4-(N-cyclopropylaminocarbonyl) phenylboronic acid. LCMS
calcd
for C27H20F3N303 (m/e) 491, obsd 492 (M+H).
Example 222
Preparation of (R)-1-(4-15-1(2-pheny1-5-trffluoromethyl-oxazole-4-carbony1)-
aminoppyridin-2-y1}-benzoy1)-pyrrolidine-2-carboxylic acid
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F
\
. \ N N \
I N 0
0
NO
0
A mixture of 4- {5-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
pyridin-2-
y1}-benzoic acid (45 mg, 0.1 mmol), D-proline t-butyl ester hydrochloride (31
mg, 0.15
mmol), triethylamine (50 ilL, 0.3 mmol), 1-hydroxy-7-azabenzotriazole (HOAT)
(20 mg,
.. 0.15 mmol), and 1-ethy1-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(30 mg,
0.15 mmol) in anhydrous dichloromethane (5 mL) and N,N-dimethylformamide (1.5
mL)
was stirred at room temperature overnight. The reaction mixture was
concentrated and
purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0%-100%
ethyl
acetate in hexane) to give (R)-1-(4- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo
le-4-carbonyl)-
.. amino]-pyridin-2-y1}-benzoy1)-pyrrolidine-2-carboxylic acid tert-butyl
ester (51 mg, 84
%) as a white solid.
(R)-1-(4- {5 - [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino]-
pyridin-2-y1} -
benzoy1)-pyrro lidine-2-carboxylic acid tert-butyl ester (37 mg) from above
was treated
.. with 2 mL of trifluoroacetic acid and stirred at room temperature for one
hour. The
reaction was concentrated and the product was lyophilized to give 27 mg of (R)-
1-(4- {5-
[(2-pheny1-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -pyridin-2-y1} -
benzo y1)-
pyrrolidine-2-carboxylic acid as a white powder. LCMS calcd for C28H21F3N405
(m/e)
550, obsd 551 (M+H).
Example 223
Preparation of (S)-1-(4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
aminol-
pyridin-2-y1}-benzoy1)-pyrrolidine-2-carboxylic acid
F
\
. \ N N \
I N
0
0
N
0
0L0
.. With a method similar to that used for the preparation of (R)-1-(4-{5-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -benzoy1)-pyrrolidine-
2-
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carboxylic acid above, (S)-1-(4- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbonyl)-
amino] -pyridin-2-y1} -benzoy1)-pyrrolidine-2-carboxylic acid was prepared
from 4- {5-
[(2-pheny1-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -pyridin-2-y1} -
benzoic acid and
L-proline t-butyl ester. LCMS calcd for C28H21F3N405 (m/e) 550, obsd 551
(M+H).
Example 224
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-
chloro-4-
cyclop ropylca rb a moyl-p h enyl)-pyridin-3-yl] -amide
F F
0--F
N
N CI
I
0
N ON /
V
0
With a method similar to that used for the preparation of (R)-1-(4- {5-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -benzo y1)-pyrro
lidine-2-
carboxylic acid above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-
(2-
chloro-4-cyclopropylcarbamoyl-pheny1)-pyridin-3-y1]-amide was prepared from 4-
{5-
[(2-pheny1-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -pyridin-2-y1} -
benzoic acid and
cyclopropylamine. LCMS calcd for C26H18C1F3N403 (m/e) 526, obsd 527 (M+H).
Example 225
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-
chloro-4-
isobutylcarbamoyl-phenyl)-pyridin-3-ylpamide
0-4F(FiF
\
. \NI N 01
IN si
0
N.,........
0
With a method similar to that used for the preparation of (R)-1-(4- {5-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -benzo y1)-pyrro
lidine-2-
carboxylic acid above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-
(2-
chloro-4-isobutylcarbamoyl-pheny1)-pyridin-3-y1]-amide was prepared from 3-
chloro-4-
{5 - [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -pyridin-2-y1}
-benzoic acid
and isobutylamine. LCMS calcd for C27H22C1F3N403 (m/e) 542, obsd 543 (M+H).
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Example 226
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-
chloro-4-
methanesulfonylaminocarbonyl-phenyl)-pyridin-3-yll-amide
o4rF FF
I
4116P \ N N
C I
I
0 401
N
N,
0 0
0
According to the procedures described in Tetrahedron Lett. 1998, 39, 5891 and
Org.
Proc. Res. Dev. 2004, 8, 952, 3-chloro -4- {5 - [(2-phenyl-5 -trifluoromethyl-
o xazo le-4-
carbony1)-amino]-pyridin-2-y1}-benzoic acid (30 mg, 0.06 mmol),
methanesulfonamide
(7 mg, 0.07 mmol), 4-dimethylaminopyridine (2 mg, 0.02 mmol) and 1-ethy1-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride (14 mg, 0.07 mmol) were
suspended
in 3 mL of dichloromethane and the mixture was refluxed for 3 h. The reaction
mixture
was cooled down to room temperature and filtered. The white precipitates were
washed
with ethyl acetate. The combined filtrate was stirred with 150 mg of Amberlyst-
15 at
room temperature for 2 h. The reaction was filtered to remove the resin, and
the filtrate
was concentrated and purified by flash chromatography (eluting with ethyl
acetate and
hexanes) to afford 12 mg of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic
acid [6-(2-
chloro-4-methanesulfonylaminocarbonyl-pheny1)-pyridin-3-y1]-amide as a light
yellow
solid. LCMS calcd for C24H16C1F3N405S (m/e) 564, obsd 565 (M+H).
Example 227
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {642-
chloro-4-
(methanesulfonyl-methyl-aminocarbony1)-phenylppyridin-3-y1}-amide
o4rF FF
I
4116P \ N N
CI
I
0 401
N
I
N
0 ,
0 0
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(2-chloro-4-
methanesulfonylamino carbonyl-pheny1)-
pyridin-3-y1]-amide above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic
acid {6-[2-
chloro -4-(methanesulfo nyl-methyl-amino carbony1)-phenyl] -pyridin-3 -y1} -
amide was
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prepared from 3 -chloro -4- {5- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbony1)-amino] -
pyridin-2-y1}-benzoic acid and N-methyl-methanesulfonamide. LCMS calcd for
C25H18C1F3N405S (m/e) 578, obsd 579 (M+H).
Example 228
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-12-
chloro-4-
(2-methyl-propane-2-sulfonylaminocarbonyll-phenylt-pyridin-3-y1)-amide
oF(FiF
CI
0
N,
0 0 0
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(2-chloro-4-methanesulfonylamino carbonyl-p
heny1)-
pyridin-3 -yl] -amide above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic
acid (6- {2-
chloro -4-(2-methyl-prop ane-2-sulfo nylamino carbonyl] -phenyl} -pyridin-3-
y1)-amide was
prepared from 3 -chloro -4- {5- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbony1)-amino] -
pyridin-2-y1}-benzoic acid and 2-methyl-propane-2-sulfonic acid amide. LCMS
calcd for
C27H22C1F3N405S (m/e) 606, obsd 607 (M+H).
Example 229
Preparation of rac-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid
{64443,4-
dihydroxy-cyclopentanecarbony1)-piperazin-l-ylppyridin-3-y1}-amide
F
0
0
To a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[4-
(cyclopent-
3 -enecarbony1)-p ip erazin-l-y1]-pyridin-3 -y1} -amide described previously
(50 mg, 0.0978
mmol) in acetone (10 mL) was added two drops of osmium tetroxide in butanol
(2.5%
wt) and 4-methylmorpholine N-oxide (15 mg). The mixture was stirred at room
temperature for 1 hr and the solvents were evaporated. The residue was
extracted with
methylene chloride and water. The organic layer was washed with citric acid
solution and
dried over sodium sulfate. The solvents were evaporated and the residue was
purified
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using flash chromatography (eluting with methylene chloride and methanol) to
give
racemic 2-phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid {6- [4-(3 ,4-
dihydro xy-
cyclopentanecarbony1)-piperazin-l-y1]-pyridin-3-y1} -amide (25.7 mg) as a
solid. LC-MS
calcd for C26H26F3N505 (m/e) 545.2, obsd 546.1 (M+H). The NMR spectrum
obtained
on the sample is compatible with its structure.
Example 230
Preparation of rac-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid
{44143,4-
dihydroxy-cyclopentanecarbony1)-piperidin-4-ylpphenylt-amide
F
0 --F
N
401 .0
0
yli)N -"C)
0
With a method similar to that used for the preparation of racemic 2-pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid {6- [4-(3 ,4-dihydro xy-cyc lop
entanecarbony1)-
p ip erazin-l-yl] -pyridin-3 -y1} -amide above, racemic 2-phenyl-5 -
trifluoromethyl-o xazo le-
4-carboxylic acid {4- [1-(3 ,4-dihydro xy- cyc lop entanecarbony1)-p ip eridin-
4-yl] -phenyl} -
amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid
{441-
(cyclopent-3-enecarbony1)-piperidin-4-y1]-phenyl} -amide and osmium tetroxide.
LC-MS
calcd for C28H28F3N305 (m/e) 543.2, obsd 544.1 (M+H). The NMR spectrum
obtained
on the sample is compatible with its structure.
Example 231
Preparation of (S)-3-(5-1[2-(2-bromo-phenyl)-5-propyl-oxazole-4-
carbonylPaminot-
pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl ester
Br
0
111. \N-ri,,, 0_7
I r\rõCN --
0
N 0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (S)-3 -(5- { [2-(2-bromo -pheny1)-5 -propyl-o xazo le-
4-carbonyl] -
amino } -pyridin-2-ylamino)-pyrrolidine- 1 -carboxylic acid ethyl ester was
prepared from
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- 190 -2-(2-bromo-pheny1)-5-propyl-oxazo le-4-carboxylic acid and (S)-3 -(5 -
amino -pyridin-2-
ylamino)-pyrrolidine- 1 -carboxylic acid ethyl ester. HRMS calcd for
C25H28BrN504
(M+H) 542.1398, obsd 542.1396.
Example 232
Preparation of (S)-3-(5-1[2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-
carbonyl] -aminot-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl ester
F
Br
0-..F
= \ \ F
N
0--/
N
0 ...... ..7.,
N 0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
__ trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (S)-3 -(5- { [2-(2-bromo-phenyl)-5-trifluoromethyl-
oxazo le-4-
carbonyl] -amino } -pyridin-2-ylamino)-pyrro lidine- 1-carboxylic acid ethyl
ester was
prepared from 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid
and (S)-
3-(5-amino-pyridin-2-ylamino)-pyrrolidine- 1 -carboxylic acid ethyl ester.
HRMS calcd
__ for C23H21BrF3N504 (M+H) 568.0802, obsd 568.0801.
Example 233
Preparation of (S)-3-15-[(1-phenyl-3-trifluoromethy1-1H-pyrazole-4-carbonyl)-
amino] -pyridin-2-ylaminot-pyrrolidine-1-carboxylic acid ethyl ester
F
F
0-7
= NI
.---- N
I Nr"CN--i
N 0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (S)-3- {5- [(1-pheny1-3 -trifluoromethy1-1H-pyrazo le-
4-carbonyl)-
amino] -pyridin-2-ylamino } -pyrro lidine- 1 -carboxylic acid ethyl ester was
prepared from
__ 1-pheny1-3-trifluoromethy1-1H-pyrazo le-4-carboxylic acid and (S)-3 -(5-
amino -pyridin-2-
ylamino)-pyrro lidine- 1 -carboxylic acid ethyl ester. HRMS calcd for
C23H23F3N603
(M+H) 489.1857, obsd 489.1853.
Example 234
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Preparation of (S)-3-15-[(1-Pyridin-2-y1-3-trifluoromethy1-1H-pyrazole-4-
carbonyl)-
amino] -pyridin-2-ylaminot-pyrrolidine-1-carboxylic acid ethyl ester
F
0-7
Nr"CN--i
0
0
With a method similar to that used for the preparation of 4- {5-[(2-phenyl-5-
trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (S)-3- {5- [(1-pyridin-2-y1-3-trifluoromethy1-1H-
pyrazo le-4-
carbonyl)-amino] -pyridin-2-ylamino} -pyrro lidine-l-carboxylic acid ethyl
ester was
prepared from 1-pyridin-2-y1-3-trifluoromethy1-1H-pyrazole-4-carboxylic acid
and (S)-3-
(5-amino-pyridin-2-ylamino)-pyrrolidine- 1 -carboxylic acid ethyl ester. HRMS
calcd for
C22H22F3N703 (M+H) 490.1809, obsd 490.1807.
Example 235
Preparation of (S)-3-(4-1[2-(2-Trifluoromethoxy-phenyl)-5-trifluoromethyl-
oxazole-
4-carbonyl] -aminot-phenylamino)-pyrrolidine-1-carboxylic acid tert butyl
ester
FF
F
0
0 N
=0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (S)-3-(4- { [2-(2-trifluoromethoxy-pheny1)-5-
trifluoromethyl-
o xazo le-4-carbonyl] -amino} -p henylamino)-pyrro lidine-1 -carboxylic acid
tert butyl ester
was prepared from 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-
oxazo le-4-
carboxylic acid and (S)-3-(4-amino-phenylamino)-pyrrolidine- 1 -carboxylic
acid tert
butyl ester. HRMS calcd for C27H26F6N405 (M+H) 601.188, obsd 601.1877.
Example 236
Preparation of (S)-3-(4-1[2-(2-Trifluoromethoxy-phenyl)-5-trifluoromethyl-
oxazole-
4-carbonyl] -aminot-phenylamino)-pyrrolidine-1-carboxylic acid ethyl ester
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F
F----(-"F F
0
0-.F
*\ \ F N
N
0 1101 vON-C-----\
0
With a method similar to that used for the preparation of (S)-3-(5- 4242-
trifluorometho xy-p heny1)-5 -trifluoromethyl-o xazo le-4-carbonyl] -amino} -
pyridin-2-
ylamino)-pyrro lidine-l-carboxylic acid ethyl ester
above, (S)-3-(4- {[2-(2-
trifluorometho xy-p heny1)-5 -trifluoromethyl-o xazo le-4-carbonyl] -amino} -
phenylamino)-
pyrro lidine- 1 -carboxylic acid ethyl ester was prepared from 2-(2-
trifluoromethoxy-
pheny1)-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-3-(4-amino-
phenylamino)-
pyrrolidine-1-carboxylic acid tert butyl ester, followed by deprotection with
tifluoroacetic acid and subsequent treatment with ethyl chloroformate. HRMS
calcd for
C25H22F6N405 (M+H) 573.1567, obsd 573.1565.
Example 237
Preparation of (8)-3444 (1-phenyl-3-trifluoromethy1-1H-pyrazole-4-carbonyl)-
aminopphenylaminot-pyrrolidine-1-carboxylic acid ethyl ester
F
0, N14--F
N
0 1.I eCN-C-----\
0
With a method similar to that used for the preparation of (S)-3-(5- 4242-
trifluorometho xy-p heny1)-5 -trifluoromethyl-o xazo le-4-carbonyl] -amino} -
pyridin-2-
ylamino)-pyrro lidine-l-carboxylic acid ethyl ester above, (S)-3- {4-[ (1-
pheny1-3-
trifluoromethy1-1H-pyrazo le-4-carbonyl)-amino]-phenylaminoI-pyrro lidine-l-
carboxylic
acid ethyl ester was prepared from 1-pheny1-3-trifluoromethy1-1H-pyrazole-4-
carboxylic
acid and (S)-3-(4-amino-phenylamino)-pyrrolidine-1-carboxylic acid tert butyl
ester,
followed by deprotection with tifluoroacetic acid and subsequent treatment
with ethyl
chloroformate. HRMS calcd for C24H24F3N503 (M+H) 488.1904, obsd 488.1904.
Example 238
Preparation of 1-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
phenylt-piperidine-4-carboxylic acid ethyl ester
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F
OF
0 N
0
0
With a method similar to that used for the preparation of 4-{5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 1-{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
phenyl}-piperidine-4-carboxylic acid ethyl ester was prepared from 2-pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid and
1-(4-amino -pheny1)-p ip eridine-4-
carboxylic acid ethyl ester. HRMS calcd for C25H24F3N304 (M+H) 488.1792, obsd
488.1792.
Example 239
Preparation of 1-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
pyrimidin-2-y1}-piperidine-4-carboxylic acid ethyl ester
OF
N N N
0
N N
0
0
With a method similar to that used for the preparation of 4-{5-[(2-pheny1-5-
1 5 trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-
l-carboxylic acid
tert-butyl ester above, 1-{5-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
pyrimidin-2-y1}-piperidine-4-carboxylic acid ethyl ester was prepared from 2-
pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid and 1-(5-amino-pyrimidin-2-y1)-
piperidine-4-
carboxylic acid ethyl ester. HRMS calcd for C23H22F3N504 (M+H) 490.1697, obsd
490.1695.
Example 240
Preparation of Methyl-[2-(methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-aminoppyridin-2-y1}-amino)-ethylpcarbamic acid ethyl ester
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F
. \ \ F
N
N
I
0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, methyl-[2-(methyl- {5-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbonyl)-amino]-pyridin-2-y1}-amino)-ethy1]-carbamic acid ethyl ester was
prepared
from 2-phenyl-5-trifluoromethyl-oxazo le-4-carboxylic acid and {2- [(5 -amino -
pyridin-2-
y1)-methyl-amino]-ethyl} -methyl-carbamic acid ethyl ester. HRMS calcd for
C23H24F3N504 (M+H) 492.1853, obsd 492.1855.
Example 241
Preparation of (S)-3-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)amino]-
pyridin-2-yloxyl-pyrrolidine-1-carboxylic acid tert butyl ester
F
0----)\--F
411 \ I F
N"--"y"m
0---
0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (S)-3- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbony1)-
amino]-pyridin-2-yloxy}-pyrrolidine-1-carboxylic acid tert butyl ester was
prepared from
2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-3 -(5 -amino -
pyridin-2-
yloxy)-pyrrolidine- 1 -carboxylic acid tert butyl ester. HRMS calcd for
C25H25F3N405
(M+Na) 541.1669, obsd 541.1664.
Example 242
Preparation of (S)-3-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)amino]-
pyridin-2-yloxyl-pyrrolidine-1-carboxylic acid ethyl ester
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F
0----)\--F
411 \ I F m
Nr--"y"
O--/
0 I
NNOCN---\K
0
With a method similar to that used for the preparation of (S)-3-(5-{[2-(2-
trifluorometho xy-p heny1)-5 -trifluoromethyl-o xazo le-4-carbonyl] -amino} -
pyridin-2-
ylamino)-pyrro lidine-l-carboxylic acid ethyl ester above, (S)-3-{5-[(2-pheny1-
5 -
trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yloxy} -pyrro lidine-l-
carboxylic
acid ethyl ester was prepared from (S)-3- {5-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbony1)-amino]-pyridin-2-yloxy}-pyrrolidine-1-carboxylic acid tert butyl
ester, by
deprotection with tifluoroacetic acid and subsequent treatment with ethyl
chloroformate.
HRMS calcd for C23H21F3N405 (M+H) 491.1537, obsd 491.1537.
Example 243
Preparation of (S)-3-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
phenoxyl-pyrrolidine-1-carboxylic acid tert butyl ester
F
0----)\--F
411 \ I F
y m
I.
0
oCN¨e7(
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (S)-3- {4-[(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbony1)-
amino ] -phenoxy} -pyrrolidine- 1 -carboxylic acid tert butyl ester was
prepared from 2-
phenyl-5 -trifluoromethyl-o xazo le-4-carboxylic acid and (S)-3 -(4-amino -
pheno xy)-
pyrrolidine-l-carboxylic acid tert butyl ester. HRMS calcd for C26H26F3N305
(M+Na)
540.1717, obsd 540.1716.
Example 244
Preparation of (S)-3-(4-{[(2-(2-Trifluoromethoxy-phenyl)-5-trifluoromethyl-
oxazole-4-carbonylpaminot-phenoxy)-pyrrolidine-1-carboxylic acid tert butyl
ester
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F
F-(---"F
F
0
NThrN
0 410 ....cN--*
0 o
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (S)-3-(4- {[(2-(2-trifluoromethoxy-pheny1)-5-
trifluoromethyl-
o xazo le-4-carbonyl] -amino} -p heno xy)-pyrro lidine-1 -carboxylic acid tert
butyl ester was
prepared from 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-
carboxylic
acid and (S)-3-(4-amino-phenoxy)-pyrrolidine-1-carboxylic acid tert butyl
ester. HRMS
calcd for C27H25F6N306 (M+Na) 624.154, obsd 624.1539.
Example 245
Preparation of (S)-3-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
aminol-
phenoxyl-pyrrolidine-1-carboxylic acid ethyl ester
F
0----)\--F
411 \ I F
y m
I.
0 N--\K
0 0
With a method similar to that used for the preparation of (S)-3-(5- 4242-
trifluorometho xy-p heny1)-5 -trifluoromethyl-o xazo le-4-carbonyl] -amino} -
pyridin-2-
ylamino)-pyrro lidine-l-carboxylic acid ethyl ester above, (S)-3- {4-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pheno xy} -pyrro lidine-l-
carboxylic acid
ethyl ester was prepared from (S)-3- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbonyl)-amino]-phenoxy} -pyrrolidine-l-carboxylic acid tert butyl ester, by
deprotection with trifluoro acetic acid and subsequent treatment with ethyl
chloroformate.
HRMS calcd for C24H22F3N305 (M+H) 490.1585, obsd 490.1585.
Example 246
Preparation of (S)-3-(4-{[(2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-
oxazole-
4-carbonyll-aminot-phenoxy)-pyrrolidine-1-carboxylic acid ethyl ester
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F
F----kF F
0
0---..)\--F
411 \ I F N
or IS
With a method similar to that used for the preparation of (S)-3-(5- 4242-
trifluorometho xy-p heny1)-5 -trifluoromethyl-o xazo le-4-carbonyl] -amino} -
pyridin-2-
ylamino)-pyrro lidine-l-carboxylic acid ethyl
ester above, (S)-3-(4- { [(2-(2-
trifluorometho xy-p heny1)-5 -trifluoromethyl-o xazo le-4-carbonyl] -amino} -
pheno xy)-
pyrrolidine-l-carboxylic acid ethyl ester was prepared from (S)-3-(4- { [(2-(2-
trifluorometho xy-p heny1)-5 -trifluoromethyl-o xazo le-4-carbonyl] -amino} -
pheno xy)-
pyrrolidine- 1 -carboxylic acid tert butyl ester, by deprotection with
trifluoro acetic acid
and subsequent treatment with ethyl chloroformate. HRMS calcd for C25H21F6N306
(M+Na) 596.1227, obsd 596.1223.
Example 247
Preparation of (S)-3-(5-{[(2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-
oxazole-
4-carbonyl]-aminot-pyrimidin-2-yloxy)-pyrrolidine-1-carboxylic acid tert butyl
ester
F
F¨(--"F
F
0
0----)\--F
lit \ I F
N1---"yNN
N o 0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, (S)-3-(5- {[(2-(2-trifluoromethoxy-pheny1)-5-
trifluoromethyl-
o xazo le-4-carbonyl] -amino} -pyrimidin-2-ylo xy)-pyrro lidine-l-carboxylic
acid tert butyl
ester was prepared from 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxaxo
le-4-
carboxylic acid and (S)-3 -(5 -amino -pyrimidin-2-ylo xy)-pyrro lidine-l-
carboxylic acid
tert butyl ester. HRMS calcd for C25H23F6N506 (M+Na) 626.1445, obsd 626.1447.
Example 248
Preparation of (S)-3-(5-{[(2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-
oxazole-
4-carbonylpaminot-pyrimidin-2-yloxy)-pyrrolidine-1-carboxylic acid ethyl ester
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F
F---kF F
0
0 ----.)\--F
4I \ I F
N
0 ¨/
0 \No.....,CN--i
0
With a method similar to that used for the preparation of (S)-3-(5- 4242-
trifluorometho xy-p heny1)-5 -trifluoromethyl-o xazo le-4-carbonyl] -amino} -
pyridin-2-
ylamino)-pyrro lidine-l-carboxylic acid ethyl ester above, (S)-
3-(5- { [(2-(2-
trifluorometho xy-p heny1)-5 -trifluoromethyl-o xazo le-4-carbonyl] -amino} -
pyrimidin-2-
yloxy)-pyrrolidine-1-carboxylic acid ethyl ester was prepared from (S)-3-(5-
{[(2-(2-
trifluoromethoxy-pheny1)-5-trifluoromethyl-oxazole-4-carbonyl] amino} -
pyrimidin-2-
ylo xy)-pyrro lidine- 1 -carboxylic acid ten' butyl ester, by deprotection
with tifluoroacetic
acid and subsequent treatment with ethyl chloroformate. HRMS calcd for
C23H19F6N506 (M+Na) 576.1313, obsd 576.1314.
Example 249
Preparation of (S)-3-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
aminol-
pyrimidin-2-yloxyl-pyrrolidine-1-carboxylic acid ethyl ester
F
0----)\--F
411 \ I F m
N'Thr-N
O--/
0 (
(DCI\j-i
0
With a method similar to that used for the preparation of (S)-3-(5- 4242-
trifluorometho xy-p heny1)-5 -trifluoromethyl-o xazo le-4-carbonyl] -amino} -
pyridin-2-
ylamino)-pyrro lidine-l-carboxylic acid ethyl ester above, (S)-3- {5-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyrimidin-2-ylo xy} -pyrro
lidine-1-
carboxylic acid ethyl ester was prepared from (S)-3-{5-[(2-pheny1-5-
trifluoromethyl-
oxazole-4-carbony1)-amino]-pyrimidin-2-yloxy} -pyrrolidine-l-carboxylic acid
ten' butyl
ester, by deprotection with trifluoro acetic acid and subsequent treatment
with ethyl
chloroformate. HRMS calcd for C22H20F3N505 (M+H) 492.149, obsd 492.149.
Example 250
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Preparation of (1R,2R)-2-0S)-3-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-aminopphenylaminot-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic
acid
F N
0 01 .CN---A-OH
0 0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 2-((S)-3- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino ] -phenylaminoI-pyrro lidine-l-carbony1)-cyc lop entane carbo xylic
acid was
prepared as a mixture of diastereomers. The diastereomeric mixture was
purified by
chiral supercritical fluid chromatography (the first eluting peak) to yield
(1R,2R)-2-((S)-
3 - {4- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbony1)-amino]-
phenylaminoI-
pyrrolidine- 1 -carbony1)-cyclopentanecarboxylic acid as a yellow oil. HRMS
calcd for
C28H27F3N405 (M+H) 557.2007, obsd 557.2004
Example 251
Preparation of (1S,2S)-2-0S)-3-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-aminopphenylaminot-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic
acid
= F N
0
0 0
From the above chiral supercritical fluid chromatography of racemic 24(S)-3-
{4-[(2-
phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -phenylaminoI-pyrro
lidine-1-
carbony1)-cyclopentanecarboxylic acid, the second eluting peak was isolated to
yield
(1S ,2S)-2-((S)-3 - {4- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbony1)-
amino] -
phenylamino}-pyrro lidine-l-carbony1)-cyc lop entanec arbo xylic acid as a
yellow oil.
HRMS calcd for C28H27F3N405 (M+H) 557.2007, obsd 557.2004.
Example 252
Preparation of 4-0S)-3-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
aminol-
pyridin-2-ylaminot-pyrrolidine-1-carbonyl)-cyclohexanecarboxylic acid
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F 0
0---)\---F
= \ I F
NThrN
0
NN 0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 4-((S)-3- {5-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino] -pyridin-2ylaminoI -pyrro lidine-l-carbony1)-cyclohexanecarboxylic acid
was
prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-
pyrrolidine-
3-yl-amino)-pyridin-3-y1]-amide and cis-cyclohexane-1,4-dicarboxylic acid.
HRMS
calcd for C28H28F3N505 (M+H) 572.2116, obsd 572.2113.
Example 253
Preparation of 4-14-[(1-pyridin-2-y1-3-trifluoromethy1-1H-pyrazole-4-carbonyl)-
amino] -phenylt-piperidine-1-carboxylic acid ethyl ester
F F
IN-__-_-_-)<F
0N-N
-
.-\õThN Is
0
Ny0
0
With a similar method to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {4- [(1-pyridin-2-y1-3 -trifluoromethy1-1H-pyrazo le-
4-carbonyl)-
amino]-phenyl} -piperidine-l-carboxylic acid ethyl ester was prepared from 1-
pyridin-2-
y1-3 -trifluoromethy1-1H-pyrazo le-4-carboxylic acid (4-p ip eridin-4-yl-p
heny1)-amide
hydrochloride and ethyl chloroformate. LCMS calcd for C24H24F3N503(m/e)
487.18,
obsd 488 (M+H).
Example 254
Preparation of 4-14-[(1-pyridin-2-y1-3-trifluoromethy1-1H-pyrazole-4-carbonyl)-
amino] -phenylt-piperidine-1-carboxylic acid isopropyl ester
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F\rF
N__-_-_..F
-N
G-NI
\:....---ThrN 0
0
NyOr0
With a similar method to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester above, 4- {4- [(1-pyridin-2-y1-3 -trifluoromethy1-1H-pyrazo le-
4-carbonyl)-
amino]-phenyl} -piperidine-l-carboxylic acid isopropyl ester was prepared from
1-
pyridin-2-yl-trifluoromethy1-1H-pyrazole-4-carboxylic acid (4-piperidin-4-yl-
pheny1)-
amide hydrochloride and isopropyl chloroformate. LCMS calcd for C25H26F3N503
(m/e) 501.2, obsd 502 ( M+H).
Example 255
Preparation of 1-pyridin-2-y1-3-trinuoromethyl-1H-pyrazole-4-carboxylic acid
[4-
(1-cyclopropanecarbonyl-piperidin-4-y1)-phenylpamide
F F
IN4Fr
--N
0 0
NA
0
With a similar method to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-p ip erazin-l-y1)-pyridin-3 -yl] -amide
from above,
1-pyridin-2-y1-3 -trifluoromethy1-1H-pyrazo le-4-carboxylic acid [4-
(1-
cyclopropanecarbonyl-piperidin-4-y1)-phenyl]-amide was prepared from 1-pyridin-
2-yl-
3 -trifluoromethy1-1H-pyrazo le-4-carbo xylic
acid (4-p ip eridin-4-yl-p heny1)-amide
hydrochloride and cyclopropanecarbonyl chloride. LCMS calcd for C25H24F3N502
(m/e) 483.2, obsd 484 ( M+H).
Example 256
Preparation of 1-pyridin-2-y1-3-trinuoromethyl-1H-pyrazole-4-carboxylic acid
[4-
(1-cyclopentanecarbonyl-piperidin-4-y1)-phenylpamide
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F F
(-----NI
---- N 0
\-7---N
0
NrC)
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 1-pyridin-2-y1-3-trifluoromethy1-1H-pyrazole-4-
carboxylic acid
[4-(1-cyclopentanecarbonyl-piperidin-4-y1)-pheny1]-amide was prepared from 1-
pyridin-
2-y1-3 -trifluoromethy1-1H-pyrazo le-4-carboxylic acid (4-p ip eridin-4-yl-p
heny1)-amide
and cyclopentanecarboxylic acid. LC-MS calcd for C27H28F3N502 (m/e) 511.2,
obsd
512 (M+H). The NMR spectrum obtained on the sample is compatible with its
structure.
Example 257
Preparation of 4-14-[(1-pyridin-2-y1-3-trifluoromethy1-1H-pyrazole-4-carbonyl)-
amino] -phenylt-piperidine-1-carboxylic acid propylamide
F F
N\I......
0--NI
-N
0
y
o
With a method similar to that used for the preparation of 4- {4-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-
carboxylic acid
propylamide above, 4- {4- [(1-pyridin-2-y1-3 -trifluoromethy1-1H-pyrazo le-4-
carbonyl)-
amino] -phenyl} -piperidine-l-carboxylic acid propylamide was prepared from 1-
pyridin-
2-y1-3 -trifluoromethy1-1H-pyrazo le-4-carboxylic acid (4-p ip eridin-4-yl-p
heny1)-amide
and propylisocyanate. LC-MS calcd for C25H27F3N602 (m/e) 500.2, obsd 501
(M+H).
The NMR spectrum obtained on the sample is compatible with its structure.
Example 258
Preparation of 4-14-[(5-Methyl-2-phenyl-2H-[1,2,3]-triazole-4-carbonyl)-amino]-
phenylt-piperidine-1-carboxylic acid propylamide
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N--./
=
NN......,_,..-...õ.
11
o
With a method similar to that used for the preparation of 4- {4-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -piperazine-l-
carboxylic acid
propylamide above, 4- {4-[(5-Methy1-2-pheny1-2H-[1,2,3]-triazo le-4-carbonyl)-
amino] -
phenyl} -piperidine-l-carboxylic acid propylamide was prepared from 5-Methy1-2-
pheny1-2H-[1,2,3]triazole-4-carboxylic acid (4-
pip eridin-4-yl-p heny1)-amide and
propylisocyanate. LCMS calcd for C25H30N602 (m/e) 446.24, obsd 447 (M+H).
Example 259
Preparation of 444-(4-1[1-(4-fluoro-phenyl)-3-trifluoromethy1-1H-pyrazole-4-
carbonyl] -aminot-phenyl)-piperidine-1-carbonylPbenzoic acid
F F
F. NIN; F N
0 0 0
N 0 0
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y4 -piperazine-l-
carboxylic acid
tert-butyl ester above, 4- [4-(4- { [1-(4-fluoro-pheny1)-3-trifluoromethyl-1H-
pyrazo le-4-
carbonyl] -amino } -p heny1)-p ip eridine-l-carbonyl] -benzoic acid was
prepared from 1-(4-
fluoro-pheny1)-3-trifluoromethy1-1H-pyrazo le-4-carboxylic
acid (4-p ip eridin-4-yl-
pheny1)-amide and terephthalic acid monomethyl ester, followed by basic
hydrolysis.
LC-MS calcd for C30H24F4N404 (m/e) 580.2, obsd 581 (M+H). The NMR spectrum
obtained on the sample is compatible with its structure.
Example 260
Preparation of 3-chloro-4-(5-1[1-(4-fluoro-phenyl)-3-trifluoromethy1-1H-
pyrazole-4-
carbonyl] -aminot-pyridin-2-y1)-benzoic acid
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F F
N_ F
At N __
/
N
CI
0
0
0
With a method similar to that used for the preparation of 3-chloro-4- {5-[(2-
pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -benzoic acid
above, 3 -chloro -
4-(5 - { [1-(4-fluoro-pheny1)-3-trifluoromethyl-1H-pyrazo le-4-carbonyl] -
amino} -pyridin-
2-y1)-benzoic acid was prepared from 1-(4-fluoro-pheny1)-3-trifluoromethy1-1H-
pyrazole-4-carboxylic acid (6-bromo-pyridin-3-y1)-amide and 2-chloro-4-
carboxyphenylboronic acid. LCMS calcd for C23H13F4N403 (m/e) 504, obsd 505
(M+H). The NMR spectrum obtained on the sample is compatible with its
structure.
Example 261
Preparation of (1R,2R)-2-(4-14-[(5-phenyl-2-trifluoromethyl-furan-3-carbonyl)-
amino] -phenylt-piperazine-1-carbonyl)-cyclopentanecarboxylic acid
0 0 F N 0
JN 1:3 0
401 o
With a similar procedure as above (1R,2R)-2-(4- {44(5-pheny1-2-trifluoromethyl-
furan-
3 -carbonyl)-amino] -phenyl} -p ip erazine-l-carbony1)-cyc lop entanecarbo
xylic acid was
prepared from (1R,2R)-2-(4- {4-[(5-pheny1-2-trifluoromethyl-furan-3-carbony1)-
amino]-
phenyl} -piperazine- 1 -carbonyl)-cyclopentanecarboxylic acid benzyl ester.
The product
was isolated as an off-white solid (183 mg, 99 % yield). HRMS m/z calcd. for
C29H29F3N305 [M+Fl] 556.2054; found: 556.2054.
Example 262
Preparation of 2-fluoro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino] -pyridin-2-y1}-benzoic acid
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F
F
0---)<
=F
\ I
N-ThrN
I
0
ill F
N
0
0
With a method similar to that used for the preparation of 3-chloro-4- {5-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -benzoic acid above,
2-fluoro-
4- {5 - [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino]-pyridin-2-
y1} -benzoic
acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-
bromo-
pyridin-3-y1)-amide and 4-carboxy-3-fluorophenylboronic acid. LCMS calcd for
C23H13F4N304 (m/e) 471, obsd 472 (M+H).
Example 263
Preparation of (S)-2-(3-chloro-4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-aminoPpyridin-2-y1}-benzoylamino)-3-methyl-butyric acid methyl ester
F
...
0 F
N CI
I
0 0
N
Nj0
0
A mixture of 3 -chloro -4- {5- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-
carbony1)-amino ] -
pyridin-2-y1}-benzoic acid (50 mg, 0.1 mmol), (S)-2-amino-3-methyl-butyric
acid methyl
ester (17 mg, 0.1 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (21 mg, 0.15
mmol),
and 1-ethy1-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (30 mg, 0.15
mmol)
in anhydrous dichloromethane (3 mL) was stirred at room temperature for 3 h.
The
reaction mixture was concentrated and partitioned between water and ethyl
acetate. The
organic layer was washed with brine, dried and concentrated to give a solid.
The solid
was purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0%-
100%
ethyl acetate in hexane) to give 2-(3-chloro-4-{5-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbony1)-amino]-pyridin-2-y1}-benzoylamino)-3-methyl-butyric acid methyl
ester (41
mg, 66 %) as a white solid. LCMS calcd for C29H24C1F3N405 (m/e) 600, obsd 601
(M+H).
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Example 264
Preparation of (S)-2-(3-chloro-4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-amino] -pyridin-2-y1}-benzoylamino)-3-methyl-butyric acid
o4rF FF
\
= \N N
, 1
I
0 0
N 0
Nj-Lo
0
A solution of (S)-2-(3 -chloro-4- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo
le-4-carbony1)-
amino]-pyridin-2-y1}-benzoylamino)-3-methyl-butyric acid methyl ester (30 mg,
0.05
mmol) in a mixture of tetrahydrofuran, methanol and water (3:1:1, 2 mL) was
treated
with lithium hydroxide monohydrate (6 mg, 0.15 mmol) at 50 C for an hour. The
reaction mixture was concentrated, diluted with water and the pH was adjusted
to 1-2
with dilute hydrochloric acid (1N). The white precipitate was collected by
centrifugation,
and then was dried under vacuum to give 2-(3-chloro-4-{5-[(2-pheny1-5-
trifluoromethyl-
oxazole-4-carbony1)-amino]-pyridin-2-y1}-benzoylamino)-3-methyl-butyric acid
(27 mg,
93%) as a white solid. LCMS calcd for C28H22C1F3N405 (m/e) 586, obsd 587
(M+H).
Example 265
Preparation of 1-(3-chloro-4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-
amino] -pyridin-2-y1}-benzoy1)-piperidine-4-carboxylic acid
o4rF FF
\
= \N N , CI 0
I
0
N 40/ HL 0
N
0
With a method similar to that used for the preparation of (S)-2-(3-chloro-4-
{54(2-
phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -pyridin-2-y1} -benzo
ylamino)-3 -
methyl-butyric acid above, 1-(3 -chloro -4- {5 - [(2-phenyl-5 -trifluoromethyl-
o xazo le-4-
carbony1)-amino]-pyridin-2-y1} -benzoy1)-piperidine-4-carboxylic acid was
prepared
from 3 -chloro -4- {5 -[(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbony1)-
amino ] -pyridin-2-
y1}-benzoic acid and piperidine-4-carboxylic acid ethyl ester. LCMS calcd for
C29H22C1F3N405 (m/e) 598, obsd 599 (M+H).
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Example 266
Preparation of 1-(14'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
biphenyl-4-carbonylt-amino)-cyclopropanecarboxylic acid
F
0 F
. \ -4:
N
N 401
0
401 N \)L 0
0 __
With a method similar to that used for the preparation of (S)-2-(3-chloro-4-
{5-[(2-
phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -pyridin-2-y1} -benzo
ylamino)-3 -
methyl-butyric acid above, 1-( {4'-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-bipheny1-4-carbonyl} -amino)-cyclopropanecarboxylic acid was prepared
from 4'-
[(2-phenyl-5-trifluoromethyl-oxazo le-4-carbonyl)-amino] -biphenyl-4-
carboxylic acid
and 1-amino-cyclopropanecarboxylic acid ethyl ester. LCMS calcd for
C28H20F3N305
(m/e) 535, obsd 536 (M+H).
Example 267
Preparation of 1-(14'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
biphenyl-4-carbonylt-amino)-cyclobutanecarboxylic acid
F
_.
0 F
= \ \
0 N 401
N
0
401 N
eL 0
0
With a method similar to that used for the preparation of (S)-2-(3-chloro-4-
{5-[(2-
phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -pyridin-2-y1} -
benzoylamino)-3 -
methyl-butyric acid above, 1-( {4'-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-bipheny1-4-carbonyl} -amino)-cyclobutanecarboxylic acid was prepared
from 4'-
[(2-pheny1-5-trifluoromethyl-oxazo le-4-carbonyl)-amino] -biphenyl-4-
carboxylic acid
and 1-amino-cyclobutanecarboxylic acid ethyl ester. LCMS calcd for
C29H22F3N305
(m/e) 549, obsd 550 (M+H).
Example 268
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Preparation of 1-(14'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
biphenyl-4-carbonylt-amino)-cyclopentanecarboxylic acid
0 F
i file \ ...<F
0 N 401
N
0
401 N
,'L 0
0
With a method similar to that used for the preparation of (S)-2-(3-chloro-4-
{54(2-
phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -pyridin-2-y1} -benzo
ylamino)-3 -
methyl-butyric acid above, 1-( {4'-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-bipheny1-4-carbonyl} -amino)-cyclopentanecarboxylic acid was prepared
from 4'-
[(2-pheny1-5-trifluoromethyl-oxazo le-4-carbonyl)-amino] -biphenyl-4-
carboxylic acid
and 1-amino-cyclopentanecarboxylic acid methyl ester. LCMS calcd for
C30H24F3N305 (m/e) 563, obsd 564 (M+H).
Example 269
Preparation of (S)-3,3-dimethy1-2-(14'-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-amino]-biphenyl-4-carbonylt-amino)-butyric acid
F
0 F
al. N
4N
0 401 0
0
N j-L o
0
1 5
With a method similar to that used for the preparation of (S)-2-(3-chloro-4-
{5-[(2-
phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -pyridin-2-y1} -benzo
ylamino)-3 -
methyl-butyric acid above, (S)-
3,3-dimethy1-2-( {4'-[(2-pheny1-5-trifluoromethyl-
oxazole-4-carbony1)-amino]-bipheny1-4-carbonyl} -amino)-butyric acid was
prepared
from 4'-[(2-pheny1-5-trifluoromethyl-oxazo le-4-carbonyl)-amino] -biphenyl-4-
carboxylic
acid and (S)-2-Amino-3,3-dimethyl-butyric acid tert-butyl ester. LCMS calcd
for
C30H26F3N305 (m/e) 565, obsd 566 (M+H).
Example 270
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Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-
fluoro-4-
isobutylcarbamoyl-phenyl)-pyridin-3-ylpamide
o4rF FF
\
I
0 0 F
N
N
0
With a method similar to that used for the preparation of (S)-2-(3-chloro-4-
{54(2-
phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino]-pyridin-2-y1} -benzo
ylamino)-3 -
methyl-butyric acid above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic
acid [6-(3-
fluoro-4-isobutylcarbamoyl-pheny1)-pyridin-3-y1]-amide was prepared from 2-
fluoro-4-
{5 - [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino]-pyridin-2-y1} -
benzoic acid
and isobutylamine. LCMS calcd for C27H22F4N403 (m/e) 526, obsd 527 (M+H).
Example 271
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-
chloro-4-
methylcarbamoyl-phenyl)-pyridin-3-y1]-amide
o4rF FF
\
=
I
o lei
N
N \
0
With a method similar to that used for the preparation of (S)-2-(3-chloro-4-
{5-[(2-
phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino]-pyridin-2-y1} -benzo
ylamino)-3 -
methyl-butyric acid above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic
acid [6-(2-
chloro-4-methylcarbamoyl-pheny1)-pyridin-3-y1]-amide was prepared from 3-
chloro-4-
{5 - [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino]-pyridin-2-y1} -
benzoic acid
and methylamine. LCMS calcd for C24H16C1F3N403 (m/e) 500, obsd 501 (M+H).
Example 272
Preparation of (S)-3-methyl-2-(14'-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-aminol-biphenyl-4-carbonylt-amino)-butyric acid
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orF FF
\
. \N4 N1.1
0
401 N jo
0
With a method similar to that used for the preparation of (S)-2-(3-chloro-4-
{5-[(2-
phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -pyridin-2-y1} -benzo
ylamino)-3 -
methyl-butyric acid above, (S)-3-methy1-2-( {4'- [(2-phenyl-5 -trifluoromethyl-
o xazo le-4-
carbonyl)-amino]-bipheny1-4-carbony1}-amino)-butyric acid was prepared from
4'4(2-
pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-biphenyl-4-carboxylic acid
and
(S)-2-amino-3-methyl-butyric acid methyl ester. LCMS calcd for C29H24F3N305
(m/e)
551, obsd 552 (M+H).
Example 273
Preparation of racemic trans-2-15-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-amino]-[2,3,1bipyridiny1-6'-ylcarbamoy1}-cyclopentanecarboxylic acid
o(FiFF
\
0
N 1
I 0
N N 0
With a method similar to that used for the preparation of (S)-2-(3-chloro-4-
{54(2-
phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -pyridin-2-y1} -benzo
ylamino)-3 -
methyl-butyric acid above, racemic trans-2- {5-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbony1)-amino]-[2,31bipyridinyl-6'-ylcarbamoyl} -cyclopentanecarboxylic acid
was
prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo-
pyridin-
3-y1)-amide, 2-tert-butyloxycarbonylaminopyridine-5-boronic acid pinacol ester
and
racemic trans-cyclopentane-1,2-dicarboxylic acid monobenzyl ester. LCMS calcd
for
C28H22F3N505 (m/e) 565, obsd 566 (M+H).
Example 274
Preparation of (1R,2R)-2-14'-[(2-pheny1-5-trilluoromethyl-oxazole-4-carbony1)-
amino] bipheny1-4-ylcarbamoy1}-cyclopentanecarboxylic acid (or enantiomer)
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\
= \N N
0
01 N0
With a method similar to that used for the preparation of (S)-2-(3-chloro-4-
{5-[(2-
phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -pyridin-2-y1} -benzo
ylamino)-3 -
methyl-butyric acid above, racemic trans-2- {4'-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbonyl)-amino]-bipheny1-4-ylcarbamoy1}-cyclopentanecarboxylic acid was
prepared
from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-iodo-phenyl)-
amide, 4-
(4,4,5,5 -tetramethyl-1,3 ,2-dio xaboro lan-2-y1) aniline and cyc lop entane-
1,2-dicarbo xylic
acid monobenzyl ester. The benzyl ester was then removed by hydrogenolysis.
The
racemic mixture was separated by chiral SFC to afford (1R,2R)-2-{4'-[(2-pheny1-
5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -biphenyl-4-carbonyl} -
cyclopentanecarboxylic acid (or enantiomer). LCMS calcd for C30H24F3N305 (m/e)
563, obsd 564 (M+H).
Example 275
Preparation of (1S,2S)-2-14'-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-biphenyl-4-ylcarbamoyll-cyclopentanecarboxylic acid (or enantiomer)
oiFFF
\
= \N4 N
0 lel 0
N 0
With a method similar to that used for the preparation of (1R,2R)-2-{4'-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-biphenyl-4-carbonyl} -
cyc lop entanecarbo xylic acid above, (1 S ,2S)-2- {4'- [(2-phenyl-5 -
trifluoromethyl-o xazo le-
4-carbonyl)-amino] -biphenyl-4-carbonyl} -cyclopentanecarboxylic acid (or
enantiomer)
was obtained by chiral SFC separation. LCMS calcd for C30H24F3N305 (m/e) 563,
obsd 564 (M+H).
Example 276
Preparation of racemic trans-2-(methyl-{4'-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbony1)-amino]-biphenyl-4-y1}-carbamoy1)-cyclopentanecarboxylic acid
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F(FiF
0
N 0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester, racemic trans-2-(methyl- {4'-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbonyl)-amino]-bipheny1-4-y1}-carbamoy1)-cyclopentanecarboxylic acid was
prepared
from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic trans-2-
[(4'-
amino-bipheny1-4-y1)-methyl-carbamoy1]-cyclopentanecarboxylic acid. LCMS calcd
for
C31H26F3N305 (m/e) 577, obsd 578 (M+H).
Example 277
Preparation of 2-pyridin-2-y1-4-trffluoromethyl-oxazole-5-carboxylic acid [6-
(4-
isobutylcarbamoyl-phenyl)-pyridin-3-y1Pamide
N N
0-<0
0
N
0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-y1} -piperazine-l-
carboxylic acid
tert-butyl ester above, 2-pyridin-2-y1-4-trifluoromethyl-oxazole-5-carboxylic
acid [6-(4-
isobutylcarbamoyl-pheny1)-pyridin-3-y1]-amide was prepared from 2-pyridin-2-y1-
4-
trifluoromethyl-oxazole-5-carboxylic acid and 4-(5-amino-pyridin-2-y1)-N-
isobutyl-
benzamide. LCMS calcd for C26H22F3N503 (m/e) 509, obsd 510 (M+H).
Example 278
Preparation of methyl-(1-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino] -pyrimidin-2-y1}-piperidin-4-y1)-carbamic acid ethyl ester
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F F
0 --F
.\ \ N,
N --1 N
0
N N ` 0
NAO
I
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino ] -pyridin-2-y1} -piperazine-l-
carboxylic acid
isopropyl ester, methyl-(1- {5-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-amino]-
pyrimidin-2-y1}-piperidin-4-y1)-carbamic acid ethyl ester was prepared from 2-
pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid [2-(4-methylamino-piperidin-1-y1)-
pyrimidin-
5-y1]-amide and ethyl chloroformate. LC-MS calcd for C24H25F3N604 (m/e) 518,
obsd
519 (M+H). The NMR spectrum obtained on the sample is compatible with its
structure.
Example 279
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-14-
[methyl-
(2,2,2-trifluoro-acetyl)-aminoppiperidin-1-y1}-pyrimidin-5-y1)-amide
F F
0 -.F
. \N\ N IV
0
N N ` 0
NH<F
I F F
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-y1)-pyridin-3-y1]-amide
above, 2-
pheny1-5-trifluoromethyl-oxazole-4-carboxylic
acid (2- {4-[methyl-(2,2,2-trifluoro-
acety1)-amino]-piperidin-1-y1}-pyrimidin-5-y1)-amide was prepared from 2-
pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid [2-(4-methylamino-piperidin-1-y1)-
pyrimidin-
5-y1]-amide hydrochloride salt and trifluoroacetic anhydride. LCMS calcd for
C23H20F6N603 (m/e) 542, obsd 543 (M+H).
Example 280
Preparation of (1R,2R)-2-[methyl-(1-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-amino]-pyrimidin-2-y1}-piperidin-4-y1)-carbamoy1]-
cyclopentanecarboxylic acid (or enantiomer)
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F
= 0
\ N N \I
0 0 o()
)L6
With a method similar to that used for the preparation of (1R,2R)-2-{4'-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-biphenyl-4-carbonyl} -
cyclopentanecarboxylic acid above,
(1R,2R)-2-[methyl-(1-{5-[(2-pheny1-5 -
trifluoromethyl-oxazole-4-carbonyl)-amino]-pyrimidin-2-y1} -piperidin-4-y1)-
carbamoy1]-
cyclopentanecarboxylic acid (or enantiomer) was prepared from 2-pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid [2-(4-methylamino-piperidin- 1 -y1)-
pyrimidin-
5-y1]-amide hydrochloride salt and racemic trans-1,2-cyclopentanedicarboxylic
acid,
followed by chiral SFC. LCMS calcd for C28H29F3N605 (m/e) 586, obsd 587 (M+H).
Example 281
Preparation of (18,28)-2-[methyl-(1-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-aminol-pyrimidin-2-y1}-piperidin-4-y1)-carbamoyll-
cyclopentanecarboxylic acid (or enantiomer)
= FF
\ N N \I
0 4, 0 0 0
N N
N '
With a method similar to that used for the preparation of (1R,2R)-2-{4'-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-biphenyl-4-carbonyl} -
cyclopentanecarboxylic acid above,
(1S,2S)-2-[methyl-(1-{5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyrimidin-2-y1} -p ip eridin-4-y1)-
carbamo yl] -
cyclopentanecarboxylic acid (or enantiomer) was prepared from 2-pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid [2-(4-methylamino-piperidin- 1 -y1)-
pyrimidin-
5-y1]-amide hydrochloride salt and racemic trans-1,2-cyclopentanedicarboxylic
acid,
followed by chiral SFC. LCMS calcd for C28H29F3N605 (m/e) 586, obsd 587 (M+H).
Example 282
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Preparation of (R)-2-(4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino] -phenylt-piperazine-1-carbonyl)-pyrrolidine-1-carboxylic acid benzyl
ester
F F
0
\N N 0
0/
0 01
With a method similar to that used for the preparation of (1R,2R)-2- {4'-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbonyl)-amino]-bipheny1-4-carbonyl} -
cyclopentanecarboxylic acid above, (R)-2-(4- {4- [(2-phenyl-5 -trifluoromethyl-
oxazo le-4-
carbony1)-amino ] -phenyl} -p ip erazine-l-carbony1)-pyrro lidine-l-carboxylic
acid benzyl
ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid
(4-
piperazin-1-yl-pheny1)-amide hydrochloride salt and (R)-pyrrolidine-1,2-
dicarboxylic
acid 1-benzyl ester. LCMS calcd for C34H32F3N505 (m/e) 647, obsd 648 (M+H).
Example 283
Preparation of (R)-2-(4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino] -phenylt-piperazine-1-carbonyl)-pyrrolidine-1-carboxylic acid ethyl
ester
=FF
\N N
0 01
11'
0
With a method similar to that used for the preparation of (1R,2R)-2- {4'-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-bipheny1-4-carbonyl} -
cyclopentanecarboxylic acid above, (R)-2-(4- {4- [(2-phenyl-5 -trifluoromethyl-
oxazo le-4-
carbony1)-amino ] -phenyl} -p ip erazine-l-carbony1)-pyrro lidine-l-carboxylic
acid ethyl
ester was prepared by hydrogenolysis of (R)-2-(4- {4-[(2-pheny1-5-
trifluoromethyl-
o xazo le-4-carbony1)-amino] -phenyl} -p ip erazine-l-carbony1)-pyrro lidine-l-
carboxylic
acid benzyl ester followed by reaction with ethyl chloroformate. LCMS calcd
for
C29H30F3N505 (m/e) 585, obsd 586 (M+H).
Example 284
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Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-
methanesulfonylaminocarbony1-3,4,5,6-tetrahydro-2H-11,21 bipyridiny1-5 '-y1)-
amide
F
F........--F
0
/
0 \
N-S ----0
00/ ---N N-C -1\1/ ) ______________________________ ( c
- N \ 0
To a suspension of 5 '-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
3,4,5,6-
tetrahydro-2H-[1,2']bipyridiny1-4-carboxylic acid (39.4 mg, 0.085 mmol) in
methylene
chloride (5 mL) was added methanesulfonamide (8.2 mg, 0.086 mmol). Then 4-
dimethylaminopyridine (10.45 mg, 0.085 mmol) and EDCI (16.4 mg, 0.085 mmol)
was
added. The mixture was stirred at room temperature overnight. Solvents were
evaporated
and the residue was purified by flash column chromatography using a linear
gradient of
ethyl acetate containing 1% acetic acid in hexanes (20% to 100% in 15 minutes)
to give
the desired compound as a pale yellow solid (16.5 mg). 11-I-NMR is consistent
with the
desired structure. LRMS for C23H22F3N5055 (m/e) calcd 537.13, obsd 538.1
(M+1).
Example 285
Preparation of 1-14-1(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
phenylt-piperidine-4-carboxylic acid methyl ester
F F
F
0
401 N
0 0
To a solution of 4-fluoronitrobenzene (0.70g, 4.96 mmol) in THF (8 mL) was
added
piperadine-4-carboxylic acid methyl ester (0.71g, 4.96 mmol) and
diisopropylethylamine
(0.66 g, 5.11 mmol). The mixture was heated in a microwave oven at 150 C for
1.5 hr.
The resulting mixture was extracted with ethyl acetate and hydrochloric acid
(0.2 N). The
organic layer was washed with brine and concentrated sodium bicarbonate
solution. After
the evaporation of solvents, the residue was purified through a Biotage flash
column
chromatography using ethyl acetate and hexanes (1:1 ratio) to give a yellow
solid as 1-(4-
nitropheny1)-piperidine-4-carboxylic acid methyl ester (490 mg). 11-I-NMR is
consistent
with the structure.
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The yellow solid prepared above (463 mg, 1.75 mmol) was dissolved into
methanol (25
ml) and THF (5 mL). To this solution was added 10% palladium on carbon (100
mg) and
the mixture was hydrogenated at 50 psi for 2 hrs. The mixture was filtered and
solvents
were evaporated to give a purple residue. This material was dissolved in
methylene
chloride (5 mL) containing triethyl amine (0.4 mL) and the solution was added
to a
methylene chloride solution of 2-phenyl-5-trifluoromethyloxazole-4-carbonyl
chloride
which was prepared from 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid
(450.7
mg, 1.753 mmol) and oxalyl chloride. The mixture was stirred at r.t for 3 hrs
and solvents
were evaporated. The residue was extracted with ethyl acetate and diluted
hydrochloric
acid and solvents were evaporated. The resulting mixture was purified through
a flash
column chromatography using ethyl acetate and hexanes (1:1 ratio) to give a
white solid
as 1-
{4- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbony1)-amino] -phenyl} -p ip
eridine-4-
carboxylic acid methyl ester (650 mg). 11-1-NMR is consistent with the
structure. LC-MS
indicated a single peak (Rf=3.85 min). LRMS for C24H22F3N304 (m/e) calcd
473.16, obsd
474.3 (M+1).
Example 286
1-14-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-aminoPphenylt-piperidine-
4-
carboxylic acid
F F
. -, NO.........\<0
N
0
0
The above 1-
{4- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbony1)-amino ] -phenyl} -
piperidine-4-carboxylic acid methyl ester (470 mg, 1 mmol) was dissolved in a
mixture
of methanol (7 mL) and THF (2 mL). To this solution was added 1N sodium
hydroxide
solution (3 mL). The mixture was stirred at room temperature for 4 hrs until
all starting
material was consumed. Solvents were evaporated and the residue was diluted
with water
(8 mL). The solution was filtered and the filtrate was acidified with 1N
hydrochloric acid
(3.5 mL). The yellow precipitate was filtered and dried in the air to give 1-
{4-[(2-phenyl-
5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -phenyl} -p ip eridine-4-carbo
xylic acid (395
mg). 11-1-NMR is consistent with the desired structure. LC-MS indicated a
single peak
(Rf=3.23 min). LRMS for C23H20F3N304 (m/e) calcd 459.14, obsd 460.2 (M+1).
Example 287
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Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(4-
methanesulfonylaminocarbonyl-piperidin-1-y1)-phenylpamide
F
F
0 F----......\c\ N 11
/
. Na.....e-sz__,
N
0 II "1
0
0
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid (4-methanesulfo nylamino carbony1-3 ,4,5 ,6-
tetrahydro -2H-
[1,21bipyridiny1-5'-y1)-amide, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic
acid [4-
(4-methanesulfonylaminocarbonyl-piperidin-1-y1)-pheny1]-amide was prepared
from 1-
{4- [(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -phenyl} -p ip
eridine-4-
carboxylic acid and methanesulfonamide. LRMS for C24H23F3N405S (m/e) calcd
536.13,
obsd 537.1 (M+1). The 11-1-NMR obtained on the sample is consistent with the
desired
structure.
Example 288
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(4-
ethanesulfonylaminocarbonyl-piperidin-l-y1)-phenylpamide
F F
F
0
= \N-4N 0 NaN /--_____
1-s,
'0
0
0
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid (4-methanesulfo nylamino carbony1-3 ,4,5 ,6-
tetrahydro -2H-
[1,21bipyridiny1-5'-y1)-amide, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic
acid [4-
(4-ethanesulfonylaminocarbonyl-piperidin-1-y1)-pheny1]-amide was prepared from
1- {4-
[(2-phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -phenyl} -p ip
eridine-4-
carboxylic acid and ethanesulfonamide. LRMS for C25H25F3N405S (m/e) calcd
550.15,
obsd 551.1 (M+H). The 11-1-NMR obtained on the sample is consistent with the
desired
structure.
Example 289
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {44442-
methyl-propane-2-sulfonylaminocarbony1)-piperidin-l-ylpphenylt-amide
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F F
F
0"--- i
_________________________________________________ 0
N \N 411 N( ) ________ -l'i' 0
NS----
)----
With a method similar to that used for the preparation of 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid (4-methanesulfonylaminocarbony1-3,4,5,6-tetrahydro-
2H-
[1,21bipyridiny1-5'-y1)-amide, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic
acid {4-
5 [4-(2-
methyl-propane-2-sulfonylaminocarbony1)-piperidin-l-y1]-phenyl} -amide was
prepared from 1- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
phenyl}-
piperidine-4-carboxylic acid and tert-butylsulfonamide. LRMS for C27H29F3N405S
(m/e)
calcd 578.18, obsd 579.2 (M+H). The 11-1-NMR obtained on the sample is
consistent with
the desired structure.
Example 290
Preparation of (S)-3-14-[(1-Phenyl-3-trifluoromethy1-1H-pyrazole-4-carbonyl)-
amino] -phenoxyl-pyrrolidine-1-carboxylic acid ethyl ester
F
/NI_ F F
faN ..---- N
0 lel CN----e---1
0 0
With a method similar to that used for the preparation of 4- {5-[(2-pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1}-piperazine-1-
carboxylic acid
tert-butyl ester, (S)-3- {4-[(1-Pheny1-3-trifluoromethy1-1H-pyrazole-4-
carbony1)-amino]-
phenoxy}-pyrrolidine-1-carboxylic acid t-butyl ester was prepared from 2-
pheny1-5-
trifluoromethy1-1H-pyrazole-4-carboxylic acid and (S)-3-(5-amino-phenoxy)-
pyrrolidine-l-carboxylic acid ten' butyl ester. LRMS calcd for C26H28F3N503 (M-
1)
516.56, obsd 515.1
With a method similar to that used for the preparation of (S)-3-(5- {[2-(2-
trifluorometho xy-p heny1)-5 -trifluoromethyl-o xazo le-4-carbonyl] -aminoI-
pyridin-2-
ylamino)-pyrrolidine-l-carboxylic acid ethyl ester, (S)-3- {4 -[(1-Pheny1-3-
trifluoromethy1-1H-pyrazo le-4-carbonyl)-amino]-phenoxy} -pyrrolidine-l-
carboxylic
acid ethyl ester was prepared from (S)-3- {4-[(1-Pheny1-3-trifluoromethyl-1H-
pyrazole-4-
carbony1)-amino]-phenoxy} -pyrrolidine-l-carboxylic acid t-butyl ester, by
deprotection
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with tifluoroacetic acid and subsequent treatment with ethyl chloroformate.
HRMS calcd
for C24H23F3N404 (M+H) 489.1745, obsd 489.1744.
Example 291
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-1444-
(1H-
tetrazol-5-y1)-cyclohexanecarbonylPpiperazin-1-y1}-phenyl)-amide
0
=
F r\NAD
0 N
H
110
H1ON 1\1/
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-
1-yl-
pheny1)-amide (130 mg, 0.31 mmol), 4-(1H-tetrazol-5-y1)-cyclohexanecarboxylic
acid
(61 mg, 0.31 mmol), DMAP (2 mg, .016 mmol), and 1-ethy1-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride (71 mg, 0.37 mmol) in anhydrous
DMF (2 mL) was stirred at room temperature for 2.5 days. The reaction was
diluted in
water (100 mL) and extracted with dichloromethane (2 x 100 mL) and ethyl
acetate (1 x
100 mL), the organic layers combined, dried over sodium sulfate and purified
by flash
chromato graph with increasing concentrations of methanol in dichloromethane
(0 to 10
% over 20 min) to give 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-
{4-[4-
(1H-tetrazol-5-y1)-cyclohexanecarbony1]-piperazin-1-y1}-pheny1)-amide (90 mg,
49 %)
as a light yellow solid. LCMS calcd for C29H29F3N803 (m/e) 594, obsd 595(M+H).
Example 292
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-1144-
(1H-
tetrazol-5-y1)-cyclohexanecarbonylPpiperidin-4-y1}-phenyl)-amide
0
F __________________________ F
0
Njb.
H
N
HONN
With a procedure similar to example 1, 2-phenyl-5-trifluoromethyl-oxazole-4-
carboxylic
acid (4- {1-[4-(1H-tetrazol-5-y1)-cyclohexanecarbony1]-piperidin-4-y1}-pheny1)-
amide
was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-
piperidin-4-
yl-pheny1)-amide (212 mg, 0.51 mmol) and 4-(1H-tetrazol-5-y1)-
cyclohexanecarboxylic
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acid (100 mg, 0.51 mmol) as an off white solid (147 mg, 49 %). LCMS calcd for
C30H30F3N703 (m/e) 593, obsd 594 (M+H).
Example 293
Preparation 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-1144-(5-
oxo-
4,5-dihydro-1,2,41oxadiazol-3-y1)-cyclohexanecarbonylPpiperidin-4-y1}-pheny1)-
amide
0
F ___________________________ F 0
-N
11
0
With a procedure similar to example 1, 2-phenyl-5-trifluoromethyl-oxazole-4-
carboxylic
acid (4- {1-[4-(5-oxo-4,5-dihydro-1,2,4]oxadiazol-3-y1)-cyclohexanecarbony1]-
piperidin-
4-y1}-pheny1)-amide was prepared from 2-pheny1-5-trifluoromethyl-oxazole-4-
carboxylic acid (4-piperidin-4-yl-phenyl)-amide (202 mg, 0.49 mmol) and 4-(5-
0xo-4,5-
dihydro-[1,2,4]oxadiazo1-3-y1)-cyclohexanecarboxylic acid (104 mg, 0.49 mmol)
as an
off white solid (13 mg, 4 %). LCMS calcd for C31H30F3N505 (m/e) 609, obsd 610
(M+H).
Example 294
Preparation of 5'-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
3,4,5,6-
tetrahydro-2H-1,2]bipyridinyl-4-carboxylic acid amide
FJ
401
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3.42 g,
12.6 mmol),
5'-amino-3,4,5,6-tetrahydro-2H-[1,21bipyridiny1-4-carboxylic acid amide (which
was the
product from the catalytic hydrogenation of 5'-nitro-3,4,5,6-tetrahydro-2H-
[1,21bipyridiny1-4-carboxylic acid amide: 2.93 g, 12.6 mmol, 200 mL
Et0H/THF/Et0Ac
mixture, 50 psi H2, 7 hr, with 300 mg of Pd/C 10 %), 1-ethy1-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride (2.89 g, 15.1 mmol) and DMAP
(catalytic) in anhydrous DMF (25 mL) was stirred at room temperature
overnight. The
reaction was diluted with ethyl acetate (400 mL) and washed with aqueous
ammonium
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chloride (saturated, 200 mL), sodium bicarbonate (saturated, 200 mL with
addition of
brine to clear emulsion) and brine (100 mL). The aqueous ammonium chloride was
extracted with ethyl acetate (200 mL) which was subsequently washed with brine
(100
mL). The organic layers were combined, dried over sodium sulfate,
concentrated, and
tritrated from boiling ethyl acetate to give 5'-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbony1)-amino]-3,4,5,6-tetrahydro-2H-1,21bipyridinyl-4-carboxylic acid amide
(1.5 g,
26 %) as a light brown solid. LCMS calcd for C22H20F3N503 (m/e) 459, obsd 460
(M+H).
Example 295
Preparation of [1-(4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
aminol-
phenylt-piperidine-1-carbonyl)-piperidin-4-y1Pacetic acid
F
0.F
S\ 1 FN
N
0 101
Nyo
N
--- -.,
--.....,...--
c)
0
To a mixture of 4- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
phenyl} -
piperidine-l-carboxylic acid 4-nitro-phenyl ester (150 mg, 0.26 mmol) in 1-
methyl-
pyrrolidin-2-one (10 mL) at room temperature was added piperidin-4-yl-acetic
acid
methyl ester (0.04 g, 0.25 mmol) followed by N,N-diisopropylethylamine (0.14
mL, 0.8
mmol). The mixture was stirred in a 90 C oil bath overnight. The mixture was
blown to
dryness and the crude was purified by flash chromatography (Merck silica gel
60, 230-
400 mesh, gradient elution with 0%-60% ethyl acetate in hexane) to give [1-(4-
{4-[(2-
pheny1-5-trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} -piperidine-l-
carbony1)-
piperidin-4-y1]-acetic acid methyl ester (70 mg). LCMS calcd for C31H33F3N405
(m/e)
598, obsd 599 (M+H).
To a mixture of [1-(4- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
phenyl} -piperidine-l-carbony1)-piperidin-4-y1]-acetic acid methyl ester (70
mg, 0.117
mmol) in dioxane (3 mL) and water (3 mL) at room temperature was added lithium
hydroxide (0.01 g, 0.24 mmol). The mixture was stirred at room temperature for
about an
hour. The mixture was acidified to pH of about 2 and then blown to dryness.
Purification
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by reversed-phase HPLC gave [1-(4- {4-[(2-pheny1-5-trifluoromethyl-oxazole-
4-
carbony1)-amino] -phenyl} -piperidine-l-carbony1)-piperidin-4-y1]-acetic acid.
LCMS
calcd for C30H31F3N405 (m/e) 584, obsd 585 (M+H). The NMR spectrum obtained on
the sample is compatible with its structure.
Example 296
Preparation of 1-(4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
phenylt-piperidine-1-carbonyl)-piperidine-4-carboxylic acid
F
0 V
N
o,
N
0
9
o
o
With a procedure similar to above, 1-(4- {4-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbony1)-amino]-phenyl} -piperidine-l-carbony1)-piperidine-4-carboxylic acid
was
prepared from 4- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
phenyl}-
piperidine-1-carboxylic acid 4-nitro-phenyl ester and piperidine-4-carboxylic
acid ethyl
ester. LCMS calcd for C29H29F3N405 (m/e) 570, obsd 571 (M+H). The NMR
spectrum obtained on the sample is compatible with its structure.
Example 297
Preparation of 1-(4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
phenylt-piperidine-1-carbonyl)-pyrrolidine-3-carboxylic acid
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F
F
N
N
a,
N
0
¨N
-----0
0
With a procedure similar to above, 1-(4-{4-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbony1)-amino]-phenylI-piperidine-1-carbonyl)-pyrrolidine-3-carboxylic acid
was
prepared from 4- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
phenyl} -
piperidine-l-carboxylic acid 4-nitro-phenyl ester and pyrrolidine-3-carboxylic
acid
methyl ester. LCMS calcd for C28H27F3N405 (m/e) 556, obsd 557 (M+H). The NMR
spectrum obtained on the sample is compatible with its structure.
Example 298
Preparation of 341-(4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
phenylt-piperidine-1-carbonyl)-piperidin-4-ylPpropionic acid
F
. VF
\ / F
N
N
0 .
N
---NO----\__4
0 0
With a procedure similar to above, 3-[1-(4-{4-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbony1)-amino]-phenyl}-piperidine-l-carbony1)-piperidin-4-y1]-propionic acid
was
prepared from 4- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
phenyl}-
piperidine-1-carboxylic acid 4-nitro-phenyl ester and 3-piperidin-4-yl-
propionic acid
methyl ester. LCMS calcd for C31H33F3N405 (m/e) 598, obsd 599 (M+H). The NMR
spectrum obtained on the sample is compatible with its structure.
Example 299
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Preparation of 441-(4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
phenylt-piperidine-1-carbonyl)-piperidin-4-y1]-butyric acid
F
F
N
N
o,
N
---N
0 0
0
With a procedure similar to above, 4-[1-(4- {4-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbonyl)-amino]-phenyl}-piperidine-l-carbony1)-piperidin-4-y1]-butyric acid
was
prepared from 4- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
phenyl}-
piperidine-1-carboxylic acid 4-nitro-phenyl ester and 3-piperidin-4-yl-butyric
acid
methyl ester. LCMS calcd for C32H35F3N405 (m/e) 612, obsd 613 (M+H). The NMR
spectrum obtained on the sample is compatible with its structure.
Example 300
Preparation of (R)-3-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
pyrimidin-2-yloxyl-pyrrolidine-1-carboxylic acid ethyl ester
F F
.....-0
. 0
N
N \ NN
I .c31
0 %L
N 0
This compound was prepared using the same method described in the preparation
of(S)-
3- {5-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-pyrimidin-2-
yloxy}-
pyrrolidine-1-carboxylic acid ethyl ester. LC-MS showed a single peak with
retention
time of 4.09 min. LRMS calcd for C22H20F3N505 (M+H) 492.14, obsd 492.1
Example 301
Preparation of 1-(1-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
phenylt-piperidine-4-carbonyl)-piperidine-4-carboxylic acid ethyl ester
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F F
0
0¨.1Fr
N = 0
41,\
N
Noõ....lre z------
0
o
To a solution of 1- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-
phenyl} -
piperidine-4-carboxylic acid (229.5 mg, 0.5 mmol) in DMF (4 mL) was added
piperidine-4-carboxylic acid ethyl ester (79 mg, 0.5 mmol), PyBrop (233.1 mg,
0.5
MM01) and triethylamine (0.1 mL). The mixture was stirred overnight and
solvents were
evaporated. The residue was extracted with ethyl acetate and water. After the
evaporation
of solvents, the residue was purified through flash column chromatography
using ethyl
acetate and hexanes. The desired fraction was evaporated and triturated with
ether and
petroleum ether (2:1) to give a yellow solid as 1-(1- {4-[(2-pheny1-5-
trifluoromethyl-
oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carbony1)-piperidine-4-
carboxylic acid
ethyl ester. LC-MS showed a single peak with a retention time of 3.54 min.
LRMS calcd
for C31H33F3N405 (M+H) 599.24, obsd 599.3
Example 302
Preparation of 1-(1-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
phenylt-piperidine-4-carbonyl)-piperidine-4-carboxylic acid
F F
,
______IFc 0
0
\ N . NO. s0
N ..1
Ne
0
0
This compound was prepared from the hydrolysis of the corresponding ethyl
ester. LC-
MS showed a single peak with a retention time of 3.09 min. LRMS calcd for
C29H29F3N405 (M+H) 571.21, obsd 571.2
Example 303
Preparation of 1-(1-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
phenylt-piperidine-4-carbonyl)-piperidine-3-carboxylic acid ethyl ester
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F
0--/F
410 \ \
N----irN
0 0 N3lNa0--../l
0
0
This compound was prepared from 1- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-amino]-phenyl} -piperidine-4-carboxylic acid and piperidine-3-
carboxylic acid
ethyl ester using the same method describer in earlier example. LC-MS showed a
single
peak with a retention time of 3.62 min. LRMS calcd for C31H33F3N405 (M+H)
599.24,
obsd 599.2
Example 304
Preparation of 1-(1-14-[(2-phenyl-5-trilluoromethyl-oxazole-4-carbonyl)-aminoP
phenyl}-piperidine-4-carbonyl)-piperidine-3-carboxylic acid
F F
F
1\7.1(46 N o
0 ,
\ N
0 NO.......py
0
0
This compound was prepared from the hydrolysis of the corresponding ethyl
ester. LC-
MS showed a single peak with a retention time of 3.12 min. LRMS calcd for
C29H29F3N405 (M+H) 571.21, obsd 571.2
Example 305
Preparation of 2,2-dimethy1-4-oxo-4-(4-14-[(2-phenyl-5-trifluoromethyl-oxazole-
4-
carbonyl)-aminoPphenoxyl-piperidin-1-y1)-butyric acid
F
0/1<F
\ I F 0
.
N----/N 0
0 0
0
To a solution of 4-fluoronitrobenzene (1.41g, 10 mmol) in THF (50 mL) was
added N-
Boc-4-hydroxypiperidine (2.01g, 10 mmol) and sodium hydride (60% in mineral
oil,
583mg, 14.5 mmol). The mixture was stirred at room temperature for 14 hrs.
After
purification through flash column chromatography, 4-(4-nitro-phenoxy)-
piperidine-1-
carboxylic acid tert-butyl ester (2.51g, 78% yield) was obtained as a solid.
This nitro
compound was hydrogenated to the corresponding amine and coupled with 2-phenyl-
5-
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trifluoromethyloxazole-4-carboxylic acid to give 4- {4-[(2-pheny1-5-
trifluoromethyl-
oxazole-4-carbony1)-amino]-phenoxy}-piperidine-1-carboxylic acid tert-butyl
ester. LC-
MS showed a single peak with a retention time of 4.08 min. LRMS calcd for
C27H28F3N305 (M+1) 532.20, obsd 532.1
The above compound (1.89g, 3.56 mmol) was dissolved in methylene chloride (6
mL)
and treated with gaseous hydrogen chloride in ether (3.8M, 10 mL). The mixture
was
stirred at room temperature for 4 hrs and then diluted with ether (20 mL). The
white solid
was filtered to give 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-
(piperidin-
4-yloxy)-phenyl]-amide hydrochloride. LC-MS showed a single peak with a
retention
time of 3.03 min. LRMS calcd for C22H20F3N303 (M+1) 432.15, obsd 432.1
The above hydrochloride salt (101 mg, 0.2 mmol) was dissolved in methylene
chloride (5
mL) and triethylamine (0.12 mL) was added followed by the addition of 2,2-
dimethylsuccinic anhydride (38.4 mg, 0.3 mmol). The mixture was stirred at
room
temperature overnight. Solvents were evaporated and the residue was extracted
with
ethyl acetate and 1N hydrochloric acid. The organic layer was washed with
brine and
solvents were evaporated. The residue was triturated with ether and the white
solid was
filtered to give 2,2-dimethy1-4-oxo-4-(4- {4-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbony1)-amino]-phenoxy}-piperidin-1-y1)-butyric acid (97 mg). LC-MS showed a
single peak with a retention time of 4.14 min. LRMS calcd for C28H28F3N306
(M+1)
560.19, obsd 560.4
Example 306
Preparation of 2,2-dimethy1-4-oxo-4-0S)-3-14-[(2-phenyl-5-trifluoromethyl-
oxazole-
4-carbonyl)-aminol-phenoxyl-pyrrolidin-1-y1)-butyric acid
F
F
\O___
40 F
N N o
0, ) ________________________________________________ µ
II _________________________________________________ 0
0 = 0
This compound was prepared using the same method as the preparation of 2,2-
dimethy1-
4-oxo-4-(4-{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-phenoxy}
-
piperidin-1-y1)-butyric acid. LC-MS showed a single peak with a retention time
of 4.02
min. LRMS calcd for C27H26F3N306 (M+1) 546.18, obsd 546.2
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Example 307
Preparation of 4-08)-3-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
phenoxyl-pyrrolidine-1-carbonyl)-trans-cyclohexanecarboxylic acid
0
F
F
41' \ I
N¨rN 0N\
0
o '..--1
This compound was prepared by the hydrogenation of the corresponding benzyl
ester.
The benzyl ester was synthesized by coupling 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid [4((S)-pyrrolidin-3-yloxy)-pheny1]-amide with trans-1,4-
cyclohexane-
dicarboxylic acid mono-benzyl ester through an acid chloride intermediate.
After the
lo hydrogenation and evaporation of solvents, the residue was triturated
with ether to give a
white solid. LC-MS showed a single peak with a retention time of 3.75 min.
LRMS calcd
for C29H28F3N306 (M+1) 572.19, obsd 572.3
Example 308
Preparation of 142-oxo-2-08)-3-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-aminol-phenoxyl-pyrrolidin-1-y1)-ethyll-cyclopentanecarboxylic acid
F
F
it 01,,kF
0
\N"--N
0 0
This compound was prepared with the same method described previously by
treating the
amine hydrochloride salt with an anhydride in the presence of triethylamine.
LC-MS
showed a single peak with a retention time of 4.17 min. LRMS calcd for
C29H28F3N306 (M+1) 572.19, obsd 572.4
Example 309
Preparation of 2,2-dimethy1-4-(4-14-[(5-methyl-2-phenyl-oxazole-4-carbonyl)-
amino]-phenylt-piperidin-l-y1)-4-oxo-butyric acid
o o
4. \NIN 10 o
0 N
0
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This compound was prepared with the same method described in previous
examples. LC-
MS showed a single peak with a retention time of 4.05 min. LRMS calcd for
C28H31N305 (M+1) 490.23, obsd 490.5
Example 310
Preparation of (1R,2R)-2-0S)-3-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-aminoPphenoxyl-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid
0
F F OyO
F
0 \
Ot 1\7,r1\1 0 ,,DN
0 0
This compound was prepared through the hydrogenation of the corresponding
benzyl
ester. The benzyl ester was synthesized through the coupling of 2-pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid [4((S)-pyrrolidin-3-yloxy)-pheny1]-
amide
with (1R, 2R)-2-benzyloxycarbonyl-cyclopantane carboxylic acid. LC-MS showed a
single peak with a retention time of 3.93 min. LRMS calcd for C28H26F3N306
(M+1)
558.18, obsd 558.4
Example 311
Preparation of 1-(1-14-[(2-phenyl-5-trffluoromethyl-oxazole-4-carbonyl)-amino]-
phenylt-piperidine-4-carbonyl)-pyrrolidine-3-carboxylic acid methyl ester;
hydrochloride
F
0
4. \NF 10 0
N
Nala-1(0--
0
0
H-Cl
With a method similar to that used for the preparation of compounds in
previous
examples. LRMS calcd for C29H29F3N405 (M+H) 571.21, obsd 571.1
Example 312
Preparation of (S)-1-(1-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
phenylt-piperidine-4-carbonyl)-pyrrolidine-2-carboxylic acid methyl ester;
hydrochloride
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,0--F F Ni lp
\
Na..8._ /
0 N 0
0
0 0
H-Cl
With a method similar to that used for the preparation of compounds in
previous
examples. LRMS calcd for C29H29F3N405 (M+H) 571.21, obsd 571.1
Example 313
Preparation of (S)-1-(1-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
phenylt-piperidine-4-carbonyl)-pyrrolidine-2-carboxylic acid
F
0-F(F N =
401 N Nalr\li-
0
0
0 0
With a method similar to that used for the preparation of compounds in
previous
examples. LRMS calcd for C28H27F3N405 (M+H) 557.19, obsd 557.2
Example 314
Preparation of 1-(1-14-[(2-phenyl-5-trffluoromethyl-oxazole-4-carbonyl)-amino]-
phenylt-piperidine-4-carbonyl)-piperidine-2-carboxylic acid; hydrochloride
F F
F
0 \
* NI:1<N II Na\R
0 0
0 0
H-Cl
With a method similar to that used for the preparation of compounds in
previous
examples. LRMS calcd for C29H29F3N405 (M+H) 571.21, obsd 571.2
Example 315
Preparation of (1S,2S)-2-(4-14-[(2-tert-butyl-5-methyl-oxazole-4-carbonyl)-
amino]-
phenylt-piperazine-1-carbonyl)-cyclopentanecarboxylic acid; hydrochloride
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=Nr--\
0 0
0 of/
H¨Cl
With a method similar to that used for the preparation of compounds in
previous
examples. The 2-tert-butyl-5-methyl-oxazole-4-carboxylic acid was prepared
from (L)-
threonine methyl ester according to known procedure in literature. LRMS calcd
for
C26H34N405 (M+H) 483.25, obsd 483.2
Example 316
Preparation of 4-08)-3-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-
amino]-
phenoxyl-pyrrolidine-1-carbonyl)-cis-cyclohexanecarboxylic acid
\ 0
1\1 \NI
0
With a method similar to that used for the preparation of compounds in
previous
examples. LRMS calcd for C29H28F3N306 (M+H) 572.19, obsd 572.30
Example 317
Preparation of 2-phenyl-thiazole-4-carboxylic acid (4-1442-(2,4-dioxo-
thiazolidin-5-
y1)-acetylppiperazin-1-y1}-phenyl)-amide; hydrochloride
= 0
NZ
N
0
0
0
H¨Cl
With a method similar to that used for the preparation of compounds in
previous
examples. LRMS calcd for C25H23N504S2 (M+H) 522.12, obsd 522.2
Example 318
Preparation of (18,28)-2-(4-13-fluoro-4-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-aminoPphenylt-piperazine-1-carbonyl)-cyclopentanecarboxylic acid
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F F
0
\4H
OH
0FNTh
0
'
0
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-fluoro-4-
piperazin-1-yl-pheny1)-amide (0.22 g, 0.5 mmol) prepared from 2-pheny1-5-
trifluoromethyl-oxazole-4-carboxylic acid and 4-(4-amino-3-fluoro-pheny1)-
piperazine
using a procedure similar to the one described above, (1S,2S)-cyclopentane-1,2-
dicarboxylic acid monobenzyl ester (0.26 g, 0.5 mmol), N-hydroxybenzotriazole
(0.1 g,
0.74 mmol), and 1-ethy1-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(0.14 g,
0.74 mmol), N,N-diisopropylethylamine (0.26 mL, 1.5 mmol) in anhydrous
dichloromethane (4 mL) was stirred at room temperature for overnight. After
the
reaction, solvent was evaporated. The resulted mixture was mixed with water
and
extracted with ethyl acetate twice. The organic layers were collected,
combined, washed
with brine before dried over sodium sulfate, and then concentrated to give a
solid. The
crude product was purified by reverse phase HPLC (10%-80% acetonitrile in
water) to
gave (1S,2S)-2-(4- {3-fluoro-4-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-amino]-
pheny1}-piperazine-1-carbony1)-cyclopentanecarboxylic acid benzyl ester as a
yellow
solid. LCMS calcd for C35H32F4N405 (m/e) 664, obsd 665 (M+H)
To the solution of (1S,25)-2-(4-{3-fluoro-4-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbony1)-amino]-pheny1}-piperazine-1-carbony1)-cyclopentanecarboxylic acid
benzyl
ester in methanol, lithium hydroxide and water were added. The so formed
mixture was
stirred at 25 C overnight. Solvent was removed and the residue was
resuspended in ethyl
acetate and water. Citric acid was added to acidify the mixture. Organic layer
was
concentrated and the residue was purified on a reverse phase HPLC system to
give
(1S,2S)-2-(4- {3-fluoro-4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
pheny1}-piperazine-1-carbony1)-cyclopentanecarboxylic acid as a white solid.
LCMS
calcd for C28H26F4N405 (m/e) 574, obsd 575 (M+H).
Example 319
Preparation of trans-4-(4-{3-fluoro-4-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-aminol-phenylt-piperazine-1-carbonyl)-cyclohexanecarboxylic acid
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F F
0
\NI-1-1\11
0
0
('OH
0
With a procedure similar to the one described above, trans-4-(4- {3-fluoro-4-
[(2-phenyl-
5-trifluoromethyl-o xazo le-4-carbonyl)-amino] -phenyl} -pip erazine-l-
carbony1)-
cyclohexanecarboxylic acid methyl ester was prepared from 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid (2-fluoro-4-piperazin-1-yl-pheny1)-amide and trans-
cyclohexane-1,4-dicarboxylic acid monomethyl ester. LC-MS calcd for
C30H30F4N405
(m/e) 602, obsd 603 (M+H).
trans-4-(4- {3-fluoro-4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
pheny1}-piperazine-1-carbony1)-cyclohexanecarboxylic acid methyl ester was
hydrolized
using a procedure similar to the one described above to give trans-4-(4- {3-
fluoro-4-[(2-
pheny1-5 -trifluoromethyl-oxazo le-4-carbonyl)-amino] -phenyl} -pip erazine-l-
carbony1)-
cyclo hexanecarboxylic acid as a white solid. LC-MS calcd for C29H28F4N405
(m/e)
588, obsd 589 (M+H).
Example 320
Preparation of trans-2-[methyl-(1-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-aminopphenylt-piperidin-4-y1)-carbamoyll-cyclopentanecarboxylic acid
OF
0 lel
0 I C)
With a similar coupling procedure as described above, trans-2-[methyl-(1-{4-
[(2-phenyl-
5-trifluoromethyl-o xazo le-4-carbonyl)-amino] -phenyl} -pip eridin-4-y1)-
carbamo yl] -
cyclopentanecarboxylic acid benzyl ester was prepared from 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid [4-(4-methylamino-piperidin-1-y1)-pheny1]-amide and
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cyclopentane-trans-1,2-dicarboxylic acid monobenzyl ester. LCMS calcd for
C37H37F3N405 (m/e) 674, obsd 675 (M+H).
Trans-2-[methyl-(1- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]
-
pheny1}-piperidin-4-y1)-carbamoyl]-cyclopentanecarboxylic acid benzyl ester
was
hydrolyzed with lithium hydroxide in methanol and water. The resulted crude
mixture
was concentrated and the residue was dissolved in ethyl acetate and water with
citric acid
as acidifying agent. The organic layer then was concentrated and purified by
reverse
phase HPLC. The mixture of isomers was obtained as a yellow solid. LCMS calcd
for
C30 H31 F3 N4 05 (m/e) 584, obsd 585 (M+H).
Example 321
Preparation of (1R,2R)-2-[methyl-(1-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-aminopphenylt-piperidin-4-y1)-carbamoyll-cyclopentanecarboxylic acid
O
,F
\ H
II \N N
0 lel N 0 0.......OH
N)LIC)
I
(1R,2R)-2-[methyl-(1-{4-[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-
amino]-
pheny1}-piperidin-4-y1)-carbamoy1]-cyclopentanecarboxylic acid was obtained
from SFC
chiral purification of trans-2- [methyl-(1- {4-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbony1)-amino]-phenyl} -piperidin-4-y1)-carbamoy1]-cyclopentanecarboxylic
acid
LCMS calcd for C30 H31 F3 N4 05 (m/e) 584, obsd 585 (M+H).
Example 322
Preparation of (1S,2S)-2-[methyl-(1-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-aminopphenylt-piperidin-4-y1)-carbamoyll-cyclopentanecarboxylic acid
F
F
0 F
46,
N
N
0 0 N 0 OH
0
)1--
N -=1
I
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(15 ,25)-2-[methyl-(1- {4- [(2-phenyl-5-trifluoromethyl-oxazo le-4-carbonyl)-
amino] -
phenyl} -piperidin-4-y1)-carbamoy1]-cyclopentanecarboxylic acid was obtained
from SFC
chiral purification of trans-2- [methyl-(1- {4-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbony1)-amino]-pheny1}-piperidin-4-y1)-carbamoy1]-cyclopentanecarboxylic
acid
LCMS calcd for C30 H31 F3 N4 05 (m/e) 584, obsd 585 (M+H).
Example 323
Preparation of (1S,2S)-2-(methyl-{5'-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-amino]-3,4,5,6-tetrahydro-2H-[1,21 bipyridiny1-4-y1}-carbamoy1)-
cyclopentanecarboxylic acid
F
0-.FiF
\
I
0 0 0 0
NN
I
With a similar coupling procedure as described above, (15,25)-2-(methyl- {5'-
[(2-phenyl-
5-trifluoromethyl-oxazole-4-carbony1)-amino]-3,4,5,6-tetrahydro-2H-
[1,21bipyridiny1-4-
y1}-carbamoy1)-cyclopentanecarboxylic acid benzyl ester was prepared from 2-
phenyl-5-
trifluoromethyl-oxazole-4-carboxylic acid (4-methylamino-3,4,5,6-tetrahydro-2H-
[1,21bipyridiny1-5'-y1)-amide and (15, 25)-cyclopentane-dicarboxylic acid
monobenzyl
ester. LCMS calcd for C36H36F3N505 (m/e) 675, obsd 676 (M+H).
With a similar procedure as described above, (15,25)-2-(methyl- {5'-[(2-pheny1-
5-
trifluoromethyl-oxazole-4-carbony1)-amino]-3,4,5,6-tetrahydro-2H-
[1,21bipyridiny1-4-
y1}-carbamoy1)-cyclopentanecarboxylic acid was prepared from (15,25)-2-(methyl-
{5'-
[(2-pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-3,4,5,6-tetrahydro-2H-
[1,21bipyridinyl-4-y1}-carbamoy1)-cyclopentanecarboxylic acid benzyl ester.
LCMS
calcd for C29H30F3N505 (m/e) 585, obsd 586 (M+H).
Example 324
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4- [4-
((R)- 1-
methanesulfonyl-pyrrolidine-2-carbonyl)-piperazin- l-ylJ -phenyl}-amide
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F F
0
0,õ 0
0 lel S
N
N
0
With a similar coupling procedure as described above, 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid {4- [4((R)-pyrro lidine-2-carbony1)-pip erazin-l-yl]
-phenyl} -
amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid
(4-
piperazin-l-yl-pheny1)-amide and (R)-pyrrolidine-1,2-dicarboxylic acid 1-tert-
butyl ester.
LCMS calcd for C26 H26 F3 N5 03 (m/e) 513, obsd 514 (M+H).
With a similar procedure as described above, 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid {4- [4-((R)-1-methanesulfonyl-pyrro lidine-2-carbony1)-pip
erazin-l-y1]-
phenyl} -amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-
carboxylic acid
{4[4-((R)-pyrro lidine-2-carbony1)-pip erazin-l-yl] -phenyl} -amide and
methanesulfonyl
chloride. LCMS calcd for C27 H28 F3 N5 05 S (m/e) 591, obsd 592 (M+H).
Example 325
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4- [4-
((R)- 1-
dimethylsulfamoyl-pyrrolidine-2-carbonyl)-piperazin- l-ylJ -phenyl}-amide
FF
= \N
0 N 1101
0 ¨
õ
, S
N 0
0
With a similar procedure as described above, 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid {4- [4-((R)-1-dimethylsulfamo yl-pyrro lidine-2-carbony1)-pip
erazin-l-y1]-
phenyl} -amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-
carboxylic acid
{4[4-((R)-pyrro lidine-2-carbony1)-pip erazin-l-yl] -phenyl} -amide and
dimethylsulfamoyl chloride. LCMS calcd for C28 H31 F3 N6 05 S (m/e) 620, obsd
621(M+H).
Example 326
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Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4- [4-
((S)- 1-
methanesulfonyl-pyrrolidine-2-carbonyl)-piperazin- l-ylj -phenyl}-amide
0-4<iF FF
N
0 40 A
Nyl..,D
0
With a similar coupling procedure as described above, 2-pheny1-5-
trifluoromethyl-
oxazole-4-carboxylic acid {4- [4-((S)-pyrro lidine-2-carbonyl)-pip erazin-l-
yl] -phenyl} -
amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid
(4-
piperazin-1-yl-pheny1)-amide and (S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-
butyl ester.
LCMS calcd for C26 H26 F3 N5 03 (m/e) 513, obsd 514 (M+H).
With a similar procedure as described above, 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid {4- [4-((S)-1-methanesulfonyl-pyrro lidine-2-carbony1)-pip
erazin-l-y1]-
phenyl} -amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-
carboxylic acid
{4[4-((S)-pyrro lidine-2-carbony1)-pip erazin-l-y1]-phenyl} -amide and
methanesulfonyl
chloride. LCMS calcd for C27 H28 F3 N5 05 S (m/e) 591, obsd 592 (M+H).
Example 327
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4- [4-
((S)- 1-
dimethylsulfamoyl-pyrrolidine-2-carbonyl)-piperazin- l-ylJ -phenyl}-amide
F
0 -4<rFF
= \
N \
\N
0N -
N 0' \N
0
With a similar procedure as described above, 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid {4- [4-((S)-1-dimethylsulfamo yl-pyrro lidine-2-carbony1)-pip
erazin-l-y1]-
phenyl} -amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-
carboxylic acid
{4[4-((R)-pyrro lidine-2-carbony1)-pip erazin-l-yl] -phenyl} -amide and
dimethylsulfamoyl chloride. LCMS calcd for C28 H31 F3 N6 05 S (m/e) 620, obsd
621
(M+H).
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Example 328
Preparation of 2-(4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
pyridin-2-y1}-benzoy1)-cyclopentanecarboxylic acid methyl ester
F
0- - FF
. \ \
N
N 0-
N
I 0
0
o
2-(4-{5-[(2-Pheny1-5-trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1}-
benzoy1)-cyclopentanecarboxylic acid methyl ester was prepared through a
standard
Suzuki coupling procedure by mixing 2-phenyl-5-trifluoromethyl-oxazole-4-
carboxylic
acid (6-bromo-pyridin-3-y1)-amide (prepared using a similar coupling procedure
as
described above from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and
6-
bromo-pyridin-3-ylamine.), 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-
benzoy1]-cyclopentanecarboxylic acid methyl ester, palladium
tetrakis(triphenylphosphine) and aquous sodium bicarbonate solution in toluene
and
ethanol, and heating this mixture to 160 C under microwave condition for 20
min.
Aqueous workup followed by silica gel chromatography separation gave 2-(4-{5-
[(2-
pheny1-5-trifluoromethyl-oxazo le-4-carbonyl)-amino] -pyridin-2-y1} -benzo y1)-
cyclopentanecarboxylic acid methyl ester as light yellow solid. LCMS calcd for
C30 H24
F3 N3 05 (m/e) 563, obsd 564 (M+H).
Example 329
Preparation of 2-(4-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
pyridin-2-y1}-benzoy1)-cyclopentanecarboxylic acid
F
0 --FF
. \ \
N
N 0
I 0
0
o
With a similar hydrolysis procedure as described above, 2-(4- {5-[(2-Pheny1-5-
trifluoromethyl-o xazo le-4-carbony1)-amino] -pyridin-2-y1} -benzo y1)-
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cyclopentanecarboxylic acid was obtained by a hydrolysis of 2-(4-{5-[(2-pheny1-
5-
trifluoromethyl-oxazole-4-carbony1)-amino]-pyridin-2-y1} -benzo y1)-
cyclopentanecarboxylic acid methyl ester with lithium hydroxide in THF,
methanol and
water. LCMS calcd for C29 H22 F3 N3 05 (m/e) 549, obsd 550 (M+H).
Example 330
Preparation of 3-15-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-
pyridin-2-yloxyl-piperidine-1-carboxylic acid ethyl ester
F F
0 --F Oy 0
N
I
0 .., ,....1.:=-..õ
.......,............,
N 0
With a similar procedure to that used for the preparation of 3- {4-[(2-pheny1-
5-
trifluoromethyl-oxazole-4-carbony1)-amino]-phenoxy}-pyrrolidine-l-carboxylic
acid
ethyl ester (example in the application), 3- {5-[(2-pheny1-5-trifluoromethyl-
oxazole-4-
carbony1)-amino]-pyridin-2-yloxy}-piperidine-1-carboxylic acid ethyl ester was
prepared
from 5-ethy1-2-phenyl-oxazole-4-carboxylic acid, 2-chloro-5-nitro-pyridine, 3-
hydroxy-
piperidine-l-carboxylic acid tert-butyl ester and ethyl chloroformate. LCMS
calcd for
C24H23F3N405 (m/e) 504, obsd 505 (M+H).
Example 331
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {44443-
propy1-1-methyl-ureido)-piperidin-1-y1]-phenylt-amide
F
0-FF
\ 1 H
(10
N 0
N)LN
I "
With a similar procedure as described above, 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid {4-[4-(3-propy1-1-methyl-ureido)-piperidin-1-y1]-pheny1}-amide
was
prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(4-
methylamino-
piperidin-1-y1)-pheny1]-amide and propylisocyanate. LCMS calcd for
C27H30F3N503
(m/e) 529, obsd 530 (M+H).
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Example 332
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {44443-
ethyl-
1-methyl-ureido)-piperidin-l-y1]-phenylt-amide
F
\ \ H
= N N
0 lel
N 0
)L N
11 H
With a similar procedure as described above, 2-pheny1-5-trifluoromethyl-
oxazole-4-
carboxylic acid {4-[4-(3-ethyl-1-methyl-ureido)-piperidin-1-y1]-pheny1}-amide
was
prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(4-
methylamino-
piperidin-1-y1)-pheny1]-amide and ethylisocyanate. LCMS calcd for C26H28F3N503
(m/e) 515, obsd 516 (M+H).
Example 333
Preparation of 2,2,N-trimethyl-N-(1-14-[(2-phenyl-5-trilluoromethyl-oxazole-4-
carbonyl)-aminoPphenylt-piperidin-4-y1)-succinamic acid
F F
0-F
4. \N 1 N
OS
N 0
I 0
With a similar procedure as described above, 2,2,N-trimethyl-N-(1- {4-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbonyl)-amino]-pheny1}-piperidin-4-y1)-succinamic
acid
was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(4-
methylamino-piperidin-1-y1)-pheny1]-amide and 2,2-dimethyl-succinic acid. LCMS
calcd
for C29H31F3N405 (m/e) 572, obsd 573 (M+H).
Example 334
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4- [4-(2-
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F
0-F
fi \ 1 F
N 0
N
0
N.
N1r-frN,
N
0 N-4/
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-pheny1)-
amide,
hydrochloride (53 mg, 0.117 mmol), (1H-tetrazol-5-y1)-acetic acid (15 mg,
0.117 mmol),
and triethylamine (49 uL, 0.351 mmol) were dissolved in 1.5 mL of DMF and
chilled in
an ice bath. To this solution was added BOP (52 mg, 0.122 mmol) in one
portion. The
mixture was stirred at room temperature for 30 minutes and then diluted with
30 ml
CH2C12. The organic phase was washed with 1N citric acid (1 x 8 mL), water (3
x 8 mL)
and saturated sodium chloride (10 mL). The organic layer was dried over MgSO4,
filtered and evaporated to dryness under vacuum. The residue was crystallized
from
acetonitrile to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-
[4-(2-1H-
tetrazol-5-yl-acety1)-piperazin-1-y1]-pheny1}-amide as light yellow crystals
(26 mg,
42%). ES-MS calcd for C24H21F3N803 (m/e) 526.48, obsd 527 (M+H).
Example 335
Preparation of 3-(4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-aminol-
phenylt-piperazine-1-carbonyl)-adamantane-1-carboxylic acid
F
fii \ 1 F
N 0
N
0
N 1.04
N
0
0
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-pheny1)-
amide,
hydrochloride (51.5 mg, 0.113 mmol), adamantane-1,3-dicarboxylic acid (51 mg,
0.227
mmol), and triethylamine (48 uL, 0.341 mmol) were dissolved in 1 mL of DMF. To
this
solution was added BOP (52 mg, 0.122 mmol) in one portion. The mixture was
stirred at
room temperature overnight. 4-N,N-dimethylamino-pyridine (5 mg) was added and
the
reaction was stirred for an additional 72 hours and then diluted with 30 ml
ethyl acetate.
The organic phase was washed with saturated ammonium chloride (1 x 5 mL), 2.5%
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KHSO4 (3 x 5 mL), water (2 x 5 mL) and saturated sodium chloride. The organic
layer
was dried over MgSO4, filtered, passed through a plug of silica gel and
evaporated to
dryness under vacuum to a light brown solid. The residue was purified by flash
chromatography to yield 3-(4- {4-[(2-pheny1-5-trifluoromethyl-oxazole-4-
carbony1)-
amino]-phenyl}-piperazine-1-carbony1)-adamantane-1-carboxylic acid as light
yellow
crystals (9.4 mg, 13%). ES-MS calcd for C33H33F3N405 (m/e) 622.65, obsd 623
(M+H).
Example 336
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {441-(2-1H-
tetrazol-5-yl-acetyl)-piperidin-4-yll-phenyl}-amide
F
0 F
.\ \ F
N
0 N is
N ,..,.. NJ,
1 /NI
0 N-N/
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-
amide
(50.7 mg, 0.122 mmol), (1H-tetrazol-5-y1)-acetic acid (15.6 mg, 0.122 mmol),
triethylamine (51 uL, 0.366 mmol) and BOP (54 mg, 0.128 mmol) in 1 mL DMF were
reacted as above to give a clear oil. The crude product was crystallized from
methanol/acetonitrile to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic
acid {4-
[1-(2-1H-tetrazol-5-yl-acety1)-piperidin-4-y1]-pheny1}-amide as off-white
crystals (11
mg, 17%). ES-MS calcd for C25H22F3N703 (m/e) 525.49, obsd 526 (M+H).
Example 337
Preparation of 1-methyl-4-(4-14-[(2-phenyl-5-trifluoromethyl-oxazole-4-
carbonyl)-
amino] -phenylt-piperidine-1-carbonyl)-cyclohexanecarboxylic acid
F
0 --F
N 0 N 0
N = 0
0
0
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Methyl-cyclohexane-1,4-dicarboxylic acid (34.1 mg, 0.183 mmol) in dry CH2C12
(3 mL)
was treated with phosgene (2M in CH2C12, 366 uL, 0.732 mmol) for 30 minutes.
THF
(0.5 mL) was added and stirred for an additional 30 minutes. The reaction was
evaporated and re-evaporated from toluene three times and re-dissolved in 5 mL
CH2C12.
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-
amide
(76.2 mg, 0.183 mmol) and triethylamine (77 uL, 0.549 mmol) in 3 mL of CH2C12
were
added dropwise over 15 minutes to the above solution. The mixture was stirred
at room
temperature for 90 minutes and then diluted with 10 mL CH2C12. Following work-
up, the
crude residue was purified by flash chromatography to yield 1-methyl-4-(4-{4-
[(2-
phenyl-5 -trifluoromethyl-o xazo le-4-carbonyl)-amino] -phenyl} -piperidine-l-
carbony1)-
cyclohexanecarboxylic acid as a white solid (26 mg, 24%). ES-MS calcd for
C31H32F3N305 (m/e) 583.61, obsd 584 (M+H).
Example 338
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-
114242,4-
dioxo-thiazolidin-5-y1)-acetyll-piperidin-4-y1}-phenyl)-amide
F
0
= \ N 0
N
0
0
NI.r.r.A
N
0 S-i
0
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-
amide
(60.1 mg, 0.149 mmol), (2,4-dioxo-thiazolidin-5-y1)-acetic acid (26.2 mg,
0.149 mmol),
triethylamine (63 uL, 0.448 mmol) and BOP (63.2 mg, 0.149 mmol) in 1 mL DMF
were
reacted as above. The crude product was purified by flash chromatography to
yield 2-
pheny1-5-trifluoromethyl-oxazole-4-carboxylic acid (4- {1-[2-(2,4-dioxo-
thiazolidin-5-
y1)-acety1]-piperidin-4-y1}-pheny1)-amide as a white solid (76.9 mg, 90%). ES-
MS calcd
for C27H23F3N4055 (m/e) 572.57, obsd 573 (M+H).
Example 339
Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-114343-
hydroxy-isoxazol-5-y1)-propionyll-piperidin-4-y1}-phenyl)-amide
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F
0 F
40 \ , F
N 40
N
0
0-N
\
N ----... 0
0
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-
amide
(46.8 mg, 0.112 mmol), 3-(3-hydroxy-isoxazol-5-y1)-propionic acid (17.7 mg,
0.112
mmol), triethylamine (47 uL, 0.337 mmol) and BOP (47.6 mg, 0.112 mmol) in 1 mL
DMF were reacted as above. The crude product was purified by flash
chromatography to
yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4- {1-[3-(3-
hydroxy-
isoxazol-5-y1)-propiony1]-piperidin-4-y1}-pheny1)-amide as a white solid (15.5
mg,
25%). ES-MS calcd for C28H25F3N405 (m/e) 554.53, obsd 555 (M+H).
Example 340
Preparation of 2,2-dimethy1-4-oxo-4-(3-14-[(2-phenyl-5-trifluoromethyl-oxazole-
4-
carbonyl)-aminoPphenoxyl-piperidin-1-y1)-butyric acid
F
0 F
. \ \ F
N 40
N õõ...-----........... 0
0
0 N 0
0
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(piperidin-3-yloxy)-
pheny1]-
amide (52.3 mg, 0.121 mmol), 3,3-dimethyl-dihydro-furan-2,5-dione (17 mg,
0.133
mmol) and triethylamine (34 uL, 0.242 mmol) in 1 mL DMSO were stirred at room
temperature for 30 minutes and then diluted with 30 ml ethyl acetate. The
organic phase
was washed with 2.5% KHSO4 (5 mL) and saturated sodium chloride (2 x 5 mL),
dried
over Mg504, filtered and evaporated to dryness under vacuum. The crude product
was
purified by flash chromatography to yield 2,2-dimethy1-4-oxo-4-(3- {4-[(2-
pheny1-5-
trifluoromethyl-oxazole-4-carbony1)-amino]-phenoxy}-piperidin-1-y1)-butyric
acid as a
white solid (46.4 mg, 68%). ES-MS calcd for C28H28F3N306 (m/e) 559.55, obsd
560
(M+H).
Example 341
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Preparation of 2,2-dimethy1-5-oxo-5-(3-14-[(2-phenyl-5-trifluoromethyl-oxazole-
4-
carbonyl)-aminopphenoxyl-piperidin-1-y1)-pentanoic acid
F
ii \ ..F
0
\ F
N N 0
0 ON'ro
0 0
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(piperidin-3-yloxy)-
pheny1]-
amide (44.1 mg, 0.102 mmol), 3,3-dimethyl-dihydro-pyran-2,6-dione (17.5 mg,
0.122
mmol) and triethylamine (28.5 uL, 0.204 mmol) in 1 mL DMSO were treated as
above.
The crude product was purified by flash chromatography to yield 2,2-dimethy1-5-
oxo-5-
(3- {4- [(2-phenyl-5-trifluoromethyl-o xazo le-4-carbonyl)-amino] -pheno xy} -
piperidin-l-
y1)-pentanoic acid as a white solid (33 mg, 56%). ES-MS calcd for C29H30F3N306
(m/e) 573.57, obsd 574 (M+H).
Example 342
Preparation of 3,3-dimethy1-5-oxo-5-(3-14-[(2-phenyl-5-trifluoromethyl-oxazole-
4-
carbonyl)-aminopphenoxyl-piperidin-1-y1)-pentanoic acid
F
OF
ili \\ F
N N 0
0 ON=r'ro
0 0
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(piperidin-3-yloxy)-
pheny1]-
amide (46.2 mg, 0.107 mmol), 4,4-dimethyl-dihydro-pyran-2,6-dione (18.3 mg,
0.128
mmol) and triethylamine (30 uL, 0.214 mmol) in 1 mL DMSO were treated as
above.
The crude product was purified by flash chromatography to yield 3,3-dimethy1-5-
oxo-5-
(3- {4- [(2-phenyl-5-trifluoromethyl-o xazo le-4-carbonyl)-amino] -pheno xy} -
piperidin-l-
y1)-pentanoic acid as a white solid (34 mg, 55%). ES-MS calcd for C29H30F3N306
(m/e) 573.57, obsd 574 (M+H).
Example 343
DGAT Phospholipid FlashPlate Assay
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Materials for the assay were: PL-FlashPlate: Phospholipid FlashPlates from
PerkinElmer,
catalog number SMP108; DAG (1,2-Dioleoyl-sn-glycerol) 10 mM suspended in water
containing 0.1% Triton X-100; "C-Pal-CoA (palmitoyl coenzyme A, [palmitoy1-1-
'4C])
from PerkinElmer, catalog number NEC-555 with a specific activity of 55
mCi/mmol;
and DGAT pellet, with a protein concentration of 9.85 mg/ml.
Aqueous buffers were prepared or purchased as follows: The coating buffer (CB)
was
purchased from PerkinElmer, catalog number SMP900A; the reaction buffer (RB)
was
50 mM Tris-HC1, pH 7.5, 100 mM NaC1, 0.01 % BSA in water; the washing buffer
(WB)
is 50 mM Tris-HC1, pH 7.5, 100 mM NaC1, 0.05 % deoxycholic acid sodium salt in
water; the dilution buffer (DB) was 50 mM Tris-HC1, pH 7.5, 100 mM NaC1, 1 mM
EDTA, 0.2 % Triton X-100 in water.
1,2-Dioleoyl-sn-glycerol (DAG, 10 mmoles) was diluted to 500 ILLM with coating
buffer
(CB). The diluted DAG solution was then added to 384-well PL-FlashPlates at 60
glper
well, and incubated at room temperature for 2 days. The coated plates were
then washed
twice with washing buffer (WB) before use. Test compounds were serial diluted
to 2000,
666.7, 222.2, 74.1, 24.7, 8.2, 2.7 and 0.9 ILLM in 100 % DMSO. Diluted
compound were
further diluted 10 fold with reaction buffer (RB). 14C -Pal-CoA was diluted to
8.3 ILLM
with RB. The DGAT pellet was diluted to 0.13 mg protein/ml with dilution
buffer (DB)
immediately before it was added to the PL-FlashPlates to start the reaction.
20 1 of the
RB-diluted compounds (or 10% DMSO in RB for Total and Blank), 15 1 of RB
diluted
14C-Pal-CoA and 15 1 of DB diluted DGAT pellet (DB without DGAT for Blanks)
were transferred to each well of the PL-FlashPlates. The reaction mixtures
were
incubated at 37 C for 1 hour. The reactions were stopped by washing 3 times
with WB.
Plates were sealed with Top-seal and read on a Topcount instrument.
Calculation of 1050: The IC50 values for each compound were generated using an
Excel
template. The Topcount rpm readings of Total and Blank were used as 0 % and
100 %
inhibition. The percent inhibition values of reactions in the presence of
compounds were
calculated, and plotted against compound concentrations. All data were fitted
into a Dose
Response One Site model (4 parameter logistic model) as the following:
(A+((B-A)/(1+((x/C)AD)))),
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with A and B as the bottom and top of the curve (highest and lowest
inhibition),
respectively, and C as 1050 and D as Hill Coefficient of the compound. The
results are
summarized in Table 1 below:
Table 1
Compound in Activity in DGAT Phospholipid FlashPlate Assay
(104)
Example 1 0.055
Example 2 0.034
Example 3 0.034
Example 4 0.193
Example 5 0.085
Example 6 0.082
Example 7 0.065
Example 8 0.123
Example 9 0.098
Example 10 0.103
Example 11 0.091
Example 12 0.081
Example 13 0.092
Example 14 0.150
Example 15 0.122
Example 16 0.167
Example 17 0.164
Example 18 0.083
Example 19 0.272
Example 20 0.057
Example 21 0.142
Example 22 0.185
Example 23 0.218
Example 24 0.065
Example 25 0.148
Example 26 0.094
Example 27 0.911
Example 28 0.128
Example 29 0.035
Example 30 0.147
Example 31 0.049
Example 32 0.080
Example 33 0.088
Example 34 0.059
Example 35 0.056
Example 36 0.145
Example 37 0.236
Example 38 0.202
Example 39 0.131
Example 40 0.083
Example 41 0.137
Example 42 0.122
DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.
CECI EST LE TOME 1 DE 2
NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des
Brevets.
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