Title of Invention "OXAZOLE DERIVATIVES AS HISTAMINE H3 RECEPTOR AGENTS, PREPARATION AND THERAPEUTIC USES"
Abstract The present invention discloses novel aryl oxizole compounds of Formula I (I), or pharmaceutically acceptable salts thereof, which have histamin:-H3 receptor antagonist or inverse agonist activity, as well as methods for preparing and using such compounds. In another embodiment, the invention disclose pharmaceutical compositions comprising compounds of Formula I as well as methods of using these compositions to treat obesity, cognitive deficiencies, narcolepsy, and other histamine H3 receptor related diseases. Formula 1 (I) or a pharmaceutically acceptable salt thereof, wherein: m is independently at each occurrence 1, 2, or 3 Z independently represents carbon (substituted with hydrogen or the optional substituents indicated herein) or nitrogen, provided that when Z is nitrogen then R6 is not attached to Z; R1 and R2 are independently -(C1-C7) alkyl(optionally substituted with one to three halogens), or R1 and R2 and the nitrogen to which they are attached form an azetidinyl ring, a pyrrolidinyl ring, or a piperidinyl zing, wherein further the azetidinyl, pyrrolidinyl, or piperidinyl ring so formed may be optionally substituted one to three times with R5; R6 is independently to each occurrence -H, -halogen, or-CH3
Full Text This patent application claims the benefit of United States Provisional Patent
Application No. 60/591,191 filed July 26,2004.
The present invention relates to novel aryl oxazole compounds, and to the use of
these compounds as pharmaceutical compositions, to pharmaceutical compositions
comprising the compounds, to methods of treatment employing these compounds and
compositions, and to intermediates and methods for making these compounds.
The histamine H3 receptor is relatively neuron specific and inhibits the release of
a number of monoamines, including histamine. The histamine H3 receptor is a
presynaptic autoreceptor and hetero-receptor located both in the central and the peripheral
nervous system. The histamine H3 receptor regulates the release of histamine and other
neurotransmitters, such as serotonin and acetylcholine. These are examples of histamine
H3 receptor mediated responses. Recent evidence suggests that the H3 receptor shows
intrinsic, constitutive activity, in vitro as well as in vivo (i.e. it is active in the absence of
an agonist). Compounds acting as inverse agonists can inhibit this activity. A histamine
H3 receptor antagonist or inverse agonist would therefore be expected to increase the
release of H3 receptor-regulated neurotransmitters in the brain. A histamine H3 receptor
agonist, on the contrary, leads to an inhibition of the biosynthesis of histamine and an
inhibition of the release of histamine and also of other neurotransmitters such as serotonin
and acetylcholine. These findings suggest that histamine H3 receptor agonists, inverse
agonists, and antagonists could be important mediators of neuronal activity, and the
activities of other cells that may express this receptor. Inverse agonism or selective
antagonism of the histamine H3 receptor raises brain levels of histamine, and other
monoamines, and inhibits activities such as food consumption while minimizing non-
specific peripheral consequences. By this mechanism, H3R inverse agonists or
antagonists induce a prolonged wakefulness, improved cognitive function, reduction in
food intake and normalization of vestibular reflexes. Accordingly, the histamine H3
receptor is an important target for new therapeutics in Alzheimers disease, mood and
attention adjustments, cognitive deficiencies, obesity, dizziness, schizophrenia, epilepsy,
sleeping disorders, narcolepsy and motion sickness.
Histamine mediates its activity via four receptor subtypes, H1R, H2R, H3R and a
newly identified receptor designated GPRv53 [(Oda T., et al., J.Biol.Chem. 275 (47):
36781-6 (2000)], and alternative names for this receptor are PORT3 or H4R. Although
relatively selective ligands have been developed for H1R, H2R and H3R, few specific
ligands have been developed that can distinguish H3R from H4R. H4R is a widely
distributed receptor found at high levels in human leukocytes. Activation or inhibition of
this receptor could result in undesirable side effects when targeting antagonism of the
H3R receptor. The identification of the H4R receptor has fundamentally changed
histamine biology and must be considered in the development of histamine H3 receptor
antagonists.
Some histamine H3 receptor antagonists were created which resembled histamine
in possessing an imidazole ring generally substituted in the 4(5) position (Ganellin et al.,
Ars Pharmaceutica, 1995, 36:3,455-468). A variety of patents and patent applications
directed to antagonists and agonists having such structures include EP 197840, EP
494010, WO 97/29092, WO 96/38141, and W096/38142. These imidazole-containing
compounds have the disadvantage of poor blood-brain barrier penetration, interaction
with cytochrome P-450 proteins, and hepatic and ocular toxicities. Recently, other
imidazole and non-imidazole ligands of the histamine H3 receptor have been described.
The compounds of the present invention differ in structure from the compounds described
in the art.
There remains a need for improved treatments using alternative or improved
pharmaceutical agents that act as histamine H3 receptor agonists, inverse agonists, or
antagonists, to modulate H3 receptor activity, and treat the diseases that could benefit
from H3 receptor modulation. The present invention provides such a contribution to the
art based on the finding that a novel class of aryl oxazole compounds; has a high affinity,
selective, and potent activity at the histamine H3 receptor. The subject invention is
distinct in the particular structures and their activities.
SUMMARY OF THE INVENTION
The present invention provides a compound structurally represented by Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
m is independently at each occurrence 1,2, or 3,
wherein optionally one or two of the hydrogens of the -CH2-, -CH2-CH2-, or
-CH2-CH2-CH2- so formed may independently be replaced by halogen, or
optionally on a carbon not adjacent to nitrogen one of the hydrogens of the
-CH2-CH2-, or -CH2-CH2-CH2- so formed may independently be replaced by
-OH, -O-(C1-C4) alkyl(optionally substituted with one to three halogens), or
-(C1-C3)alkyl(optionally substituted with one to three halogens);
Z independently represents carbon (substituted with hydrogen or the optional substituents
indicated herein) or nitrogen, provided that when Z is nitrogen then R6 is not attached to
Z;
Rl and R2 are independently
-(C1-C7) alkyl(optionally substituted with one to three halogens), or
Rl and R2 and the nitrogen to which they are attached form an azetidinyl ring, a
pyrrolidinyl ring, or a piperidinyl ring, wherein further the azetidinyl, pyrrolidinyl,
or piperidinyl ring so formed may be optionally substituted one to three times with
R5;
R3 is independently
-H, -halogen, -(C1-C4) alkyl(optionally substituted with one to three halogens), or
-0-(C1-C3) alkyl(optionally substituted with one to three halogens);
R4 is independently
-halogen, -(C1-C7) alkyl(optionally substituted with one to three halogens), -CN,
-C(0)R7, -C(0)(C3-C7)cycloalkyl(optionally substituted with one to three
halogens), -C(0)NR7R8, -OR7, -O-phenyl(R10)(Rll), -N02, -NR7R8, -NR7S02
R7, -NR7C(0)R7, -NR7C02R7, -NR7C(0)NR7R8, -SR7, -S02R7, -S02NR7R8,
-S(0)R7, -0(CH2)mNR7R8, -heteroaryl-R9, -OCH2-heteroaryI-R9, or
wherein the zig-zag lines represent the point of attachment,
and wherein Q, T, D, X, and Y independently represent carbon (substituted with
hydrogen or the optional substituents indicated herein) or nitrogen, provided that
no more than two of Q, T, D, X, and Y are nitrogen; and provided however that
wherein D is nitrogen, then R10, R11, and R12 are not attached to D, and
provided that wherein X is nitrogen, then R10, Rl1, and R12 are not attached to
X, and provided that wherein T is nitrogen, then R10, R11, and R12 are not
attached to T, and provided that wherein Q is nitrogen, then R10, R11, and R12
are not attached to Q, and provided that wherein Y is nitrogen, then R10, R11, and
R12 are not attached to Y; or
;rein the zig-zag lines represent the point of
attachment, and wherein Q, T, D, X, and Y independently represent carbon
(substituted with hydrogen or the optional substituents indicated herein) or
nitrogen, provided that no more than two of Q, T, D, X, and Y are nitrogen;
provided however that wherein D is nitrogen, then R10, Rl1, and R12 are not
attached to D, and provided that wherein X is nitrogen, then R10, R11, and R12
are not attached to X, and provided that wherein T is nitrogen, then R10, R11,
and R12 are not attached to T, and provided that wherein Q is nitrogen, then R10,
R11, and R12 are not attached to Q, and provided that wherein Y is nitrogen, then
R10, R11, and R12 are not attached to Y;
-H, -OH, -halogen, -(C1-C4) alkyl(optionally substituted with one to three
halogens), -0-(C1-C3) alkyl(optionally substituted with one to three halogens), or
-(C1-C3) alkyl-0-(C1-C3)alkyl(optionally substituted with one to three halogens);
R6 is independently at each occurrence
-H,-halogen, or-CH3;
R7 and R8 are independently at each occurrence
-H, or -(C1-C7) alkyl(optionally substituted with one to three halogens), or NR7R8
combine to form a four to seven membered ring;
R9 is independently at each occurrence
-H, -CN, or -(C1-C3) alkyl(optionally substituted with one to three halogens);
R10, Rll, and R12 are independently at each occurrence
-H, -halogen, -(C1-C7) alkyl(optionally substituted with one to three halogens),
-(C1-C7) alkyl-OH(optionally substituted with one to three halogens), -CN,
-C(O)-(C1-C7) alkyl(optionally substituted with one to three halogens), -C(0)OR7,
-C(0)(C3-C7)cycloalkyl(optionally substituted with one to three halogens),
-C(0)NR7R8, -OR7, -NR7R8, -NR9SOz R7, -NR9C(0)R7, -NR9C02R7,
-NR9C(0)NR7R8, -SR7, -S02R7, -S02NR7R8, -S(0)R7, -heteroaryl-R9,
or when R10 and R11 are adjacent to each other they may combine along with the
respective atoms to which they are attached to form a five membered or six
membered heterocarbon ring containing at least one but not more than two atoms
selected from O, S, or N, provided the heteroatoms are not adjacent to each other,
and wherein optionally said five membered or six membered heterocarbon ring
may contain one to three double bonds.
The present invention provides compounds that show a selective and high affinity
binding for the histamine H3 receptor, and thus the compounds are useful as histamine
H3 receptor antagonists or inverse agonists. In another aspect, the present invention
provides compounds that are useful as selective antagonists or inverse agonists of the
histamine H3 receptor but have little or no binding affinity of GPRv53. In addition, the
present invention provides a method for the treatment of a nervous system disorder,
which comprises administering to a patient in need thereof an effective amount of a
compound of formula I. The present invention further provides a method for the treatment
of obesity or cognitive disorders, which comprises administering to a patient in need
thereof an effective amount of a compound of formula I. In yet another aspect, the present
invention provides pharmaceutical compositions comprising antagonists or inverse
agonists of the histamine H3 receptor.
DETAILED DESCRIPTION OF THE INVENTION
General terms used in the description of compounds, compositions, and methods
herein described, bear dieir usual meanings. Throughout the instant application, the
following terms have the indicated meanings:
The term "GPRv53" means a recently identified novel histamine receptor as
described in Oda, et al., supra. Alternative names for this receptor are PORT3 or H4R.
The term "H3R" means the histamine H3 receptor that inhibits; the release of a
number of monoamines, including histamine.
The term "H1R" means the histamine H1 receptor subtype.
The term "H2R" means the histamine H2 receptor subtype.
The term "H3R antagonists" is defined as a compound with the ability to block
forskolin-stimulated cAMP production in response to agonist R-(-) methylhistamine.
The term "H3R inverse agonist" is defined as a compound with the ability to inhibit the
constitutive activity of H3R. "Selective H3R antagonists or inverse agonists" means a
compound of the present invention having a greater affinity for H3 histamine receptor
than for GPRv53 histamine receptor.
In the general formulae of the present document, the general chemical terms have
their usual meanings. For example;
"(C1-C3) Alkyl" are one to three carbon atoms such as methyl, ethyl, propyl, and
the like, optionally substituted with one to three halogens, and "(C1-C4) alkyl" are one to
four carbon atoms such as methyl, ethyl, propyl, butyl and the like, optionally substituted
with one to three halogens, and "(C1-C7) Alkyl" are one to seven carbon atoms such as
methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and the like, optionally substituted with
one to three halogens, and as defined herein "alkyl" includes branched or isomeric forms.
"Cycloalkyl" means a ring with three to seven carbon atoms such as cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl, cycloheptyl, and the like.
"Heteroaryl" means a monocyclic aromatic ring containing live atoms, and
containing at least one ring heteroatom selected from N, 0 and S (including SO and SO2).
Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl,
oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl,
thiophenyl, and the like.
"Halogen" or "halo" means fluoro, chloro, bromo and iodo.
The term "optionally substituted" as used herein means that the groups in question
are either unsubstituted or substituted with one or more of the substituents specified.
When the groups in question are substituted with more than one substituent, the
substituents may be the same or different.
Furthermore, when using the terms "independently", "independently are", and
"independently selected from" it should be understood that the groups in question may be
the same or different.
The term "patient" includes human and non-human animals such as companion
animals (dogs and cats and the like) and livestock animals. Livestock animals are
animals raised for food production. Ruminants or "cud-chewing" animals such as cows,
bulls, heifers, steers, sheep, buffalo, bison, goats and antelopes are examples of livestock.
Other examples of livestock include pigs and avians (poultry) such as chickens, ducks,
turkeys and geese. Yet other examples of livestock include fish, shellfish and crustaceans
raised in aquaculture. Also included are exotic animals used in food production such as
alligators, water buffalo and ratites (e.g., emu, rheas or ostriches). The patient to be
treated is preferably a mammal, in particular a human being.
The terms "treatment", "treating" and "treat", as used herein, include their
generally accepted meanings, i.e., the management and care of a patient for the purpose of
preventing, prohibiting, restraining, alleviating, ameliorating, slowing, stopping, delaying,
or reversing the progression or severity of a disease, disorder, or pathological condition,
described herein, including the alleviation or relief of symptoms or complications, or the
cure or elimination of the disease, disorder, or condition.
"Composition" means a pharmaceutical composition and is intended to encompass
a pharmaceutical product comprising the active ingredient(s) including compound(s) of
Formula I and the inert ingredient(s) that make up the carrier. Accordingly, the
pharmaceutical compositions of the present invention encompass any composition made
by admixing a compound of the present invention and a pharmaceutically acceptable
carrier.
The term "suitable solvent" refers to any solvent, or mixture of solvents, inert to
the ongoing reaction that sufficiently solubilizes the reactants to afford a medium within
which to effect the desired reaction.
The term "unit dosage form" means physically discrete units suitable as unitary
dosages for human subjects and other non-human animals, each unit containing a
predetermined quantity of active material calculated to produce the desired therapeutic
effect, in association with a suitable pharmaceutical carrier.
Certain of the above defined terms may occur more than once in the structural
formulae, and upon such occurrence each term shall be defined independently of the
other.
In one embodiment, the present invention provides compounds of Formula I as
described in detail above. While all of the compounds of the present invention are useful,
certain of the compounds are particularly interesting and are preferred. The following
listings set out several groups of preferred compounds. It will be understood that each of
the listings may be combined with other listings to create additional gproups of preferred
embodiments.
In a preferred embodiment the invention provides a compound structurally
represented by Formula I, or a pharmaceutically acceptable salt thereof wherein:
m is independently at each occurrence 1 or 2, wherein optionally one or two of the
hydrogens of the -CH2-, or -CH2-CH2- so formed may independently be replaced
by halogen, or optionally on the carbon not adjacent to nitrogen one of the
hydrogens of the -CH2-CH2- so formed may independently be replaced by -OH,
-0-(C1-C4) alkyl(optionally substituted with one to three halogens), or
-(C1-C3)alkyl(optionally substituted with one to three halogens);
Z independently represents carbon (substituted with hydrogen or the optional substituents
indicated herein);
Rl and R2 are independently
-(C1-C7) alkyl(optionally substituted with one to three halogens), or
Rl and R2 and the nitrogen to which they are attached form an azetidinyl ring, a
pyrrolidinyl ring, or a piperidinyl ring, wherein further the azetidinyl, pyrrolidinyl,
or piperidinyl ring so formed may be optionally substituted once with R5;
R3 is independently -H, or -CH3 (optionally substituted with one to three halogens);
R5 is independently -H, -CH3 (optionally substituted with one to three halogens);
R6 is independently at each occurrence -H, -halogen, or -CH3;
R7 and R8 are independently at each occurrence
-H, or -(C1-C7) alkyl(optionally substituted with one to three halogens), or NR7R8
combine to form a four to seven membered ring;
R9 is independently at each occurrence
-H, -CN, or -(C1-C3) alkyl(optionally substituted with one to three halogens);
R10, Rll, and R12 are independently at each occurrence
-H, -halogen, -(C1-C7) alkyl(optionally substituted with one to three halogens),
-(C1-C7) alkyl-OH(optionally substituted with one to three halogens), -CN,
-C(0)-(C1-C7) alkyl(optionally substituted with one to three halogens), -CO(0)R7,
-C(O)(C3-C7)cycloalkyl(optionally substituted with one to three halogens),
-C(0)NR7R8, -OR7, -NR7R8, -NR9S02 R7, -NR9C(0)R7, -NR9C02R7,
-NR9C(0)NR7R8, -SR7, -SOzR7, -SO2NR7R8, -S(0)R7, -heteroaryl-R9,
or when R10 and R11 are adjacent to each other they may combine along with the
respective atoms to which they are attached to form a five membered or six
membered heterocarbon ring containing at least one but not more than two atoms
selected from O, S, or N, provided the heteroatoms are not adjacent to each other,
and wherein optionally said five membered or six membered heterocarbon ring
may contain one to three double bonds.
In another preferred embodiment the invention provides a compound structurally
represented by Formula I, or a pharmaceutically acceptable salt thereof wherein:
m is independently at each occurrence 2, wherein optionally one or two of the hydrogens
of the -CH2-CH2- so formed may independently be replaced by halogen, or optionally on
the carbon not adjacent to nitrogen one of the hydrogens of the -CH2-CH2- so formed may
independently be replaced by -OH, -0-(C1-C4) alkyl(optionally substituted with one to
three halogens), or -(C1-C3)alkyl(optionally substituted with one to three halogens);
Z independently represents carbon (substituted with hydrogen);
Rl and R2 and the nitrogen to which they are attached form a pyrrolidinyl ring, or a
piperidinyl ring, wherein further the pyrrolidinyl or piperidinyl ring so formed may be
optionally substituted once with R5;
R3 is independently -H, or -CH3 (optionally substituted with one to three halogens);
R5 is independently -H, or -CH3 (optionally substituted with one to three halogens);
R6 is independently at each occurrence -H, or -halogen, provided that at least one of R6
is-H;
R7 and R8 are independently at each occurrence
-H, or -(C1-C7) alkyl(optionally substituted with one to three halogens), or NR7R8
combine to form a four to seven membered ring;
R9 is independently at each occurrence -H, -CN, or -(C1-C3) alkyl(optionally substituted
with one to three halogens);
R10, Rll, and R12 are independently at each occurrence
-H, -halogen, -(C1-C7) alkyl(optionally substituted with one to three halogens),
-(C1-C7) alkyl-OH(optionally substituted with one to three halogens), -CN, -C(O)
-(C1-C7) alkyl(optionally substituted with one to three halogens), -C(0)OR7,-C(0)(C3-C7)cycloalkyl(optionally
substituted with one to three halogens),
-C(0)NR7R8, -OR7, -NR7R8, -NR9S02 R7, -NR9C(0)R7, -NR9CO2R7,
-NR9C(0)NR7R8, -SR7, -S02R7, -S02NR7R8, -S(0)R7, -heteroaryl-R9,
provided that not more than one of R10, R11, and R12 are -heteroaryl-R9.
In another preferred embodiment the invention provides a compound structurally
represented by Formula I, or a pharmaceutical^ acceptable salt thereof wherein:
m is independently at each occurrence 2; Z independently represents carbon (substituted
with hydrogen); Rl and R2 and the nitrogen to which they are attached form a
pyrrolidinyl ring, wherein further the pyrrolidinyl ring so formed may be optionally
substituted once with R5; R3 is independently -CH3 (optionally substituted with one to
three halogens); R5 is independently -H, or -CH3 (optionally substituted with one to three
halogens); R6 is independently at each occurrence -H; R7 and R8 are independently at
each occurrence -H, or -(C1-C7) alkyl(optionally substituted with one to three halogens);
R9 is independently at each occurrence -H, -CN, or -(C1-C3) alkyl(optionally substituted
with one to three halogens); R10, Rll, and R12 are independently at each occurrence -H,
-halogen, -(C1-C7) alkyl(optionally substituted with one to three halogens),
-(C1-C7)alkyl-OH(optionally substituted with one to three halogens), -CN,
-C(0)-(C1-C7)alkyl(optionally substituted with one to three halogens), -C(0)0R7,
-C(0)(C3-C7)cycloalkyl(optionally substituted with one to three halogens), -C(0)NR7R8,
-OR7, -NR7R8, -NR9S02 R7, -NR9C(0)R7, -NR9C02R7, -NR9C(0)NR7R8, -SR7,
-S02R7, -S02NR7R8, -S(0)R7, -heteroaryl-R9, provided that not more than one of R10,
Rll, and R12 are -heteroaryl-R9.
In another preferred embodiment the invention provides a compound structurally
represented by Formula I, or a pharmaceutically acceptable salt thereof wherein:
R4 is independently
-O-phenyl(R10)(Rll), -heteroaryl-R9, -0-CH2-heteroaryl-R9, or
therein the zig-zag lines represent the point of attachment,
and wherein Q, T, D, X, and Y independently represent carbon (substituted with
hydrogen or the optional substituents indicated herein) or nitrogen, provided that
no more than two of Q, T, D, X, and Y are nitrogen; and provided however that
wherein D is nitrogen, then R10, Rl1, and R12 are not attached to D, and
provided that wherein X is nitrogen, then R10, R11, and R12 are not attached to
X, and provided that wherein T is nitrogen, then R10, R11, and R12 are not
attached to T, and provided that wherein Q is nitrogen, then R10, Rll, and R12
are not attached to Q, and provided that wherein Y is nitrogen, then R10, Rll, and
R12 are not attached to Y; or
wherein the zig-zag lines represent the point of
attachment, and wherein Q, T, D, X, and Y independently represent carbon
(substituted with hydrogen or the optional substituents indicated herein) or
nitrogen, provided that no more than two of Q, T, D, X, and Y are nitrogen;
provided however that wherein D is nitrogen, then R10, Rl1, and R12 are not
attached to D, and provided that wherein X is nitrogen, then R10, Rll, and R12
are not attached to X, and provided that wherein T is nitrogen, then R10, Rll,
and R12 are not attached to T, and provided that wherein Q is nitrogen, then R10,
Rll, and R12 are not attached to Q, and provided that wherein Y is nitrogen, then
R10, R11, and R12 are not attached to Y.
In another embodiment the invention provides a compound structurally
represented by Formula I, or a pharmaceutically acceptable salt thereo wherein: -(CH2)m-
is -CH2-, -CH2CH2-, or -CH2-CH2-CH2-, wherein one of the hydrogens on a carbon not
adjacent to a nitrogen may be replaced by -OH or -OCH3; Z is carbon (substituted with
hydrogen or optionally substituted with fluorine) or nitrogen, provided that when Z is
nitrogen then R6 is not attached to Z; Rl and R2 are independently -CH3 -CH2CH3, or -
CH(CH3)2, wherein Rl and R2 and the nitrogen to which they are attached may
optionally from an azetidinyl ring, a piperidinyl ring, or a pyrrolidinyl ring, wherein
further the azetidinyl, piperidinyl, or pyrrolidinyl ring so formed may, independently, be
optionally substituted once with -F, -OH, -OCH3 -CH3 -CH2-CH3, -CH2-F, or -CH2-0-
CH3; R3 is hydrogen or -CH3; R4 is -Br, -OH, -OCH2CH2CH2CH3, -O-phenyl, -2-
pyridinyl, -3-pyridinyl, -4-pyridinyl, -pyrimidinyl, -OCH2-R14, -pyridazinyl, -lH-indolyl,
-phenyl, -2-thiophenyl, or -benzo[l,3]dioxolyl, wherein further the -2-pyridinyl,
-3-pyridinyl, -4-pyridinyl, -pyrimidinyl, -pyridazinyl, -lH-indolyl, -phenyl, or
-2-thiophenyl, may be optionally substituted one to two times with R7 provided that R7 is
not directly attached to the nitrogen of -2-pyridinyl, -3-pyridinyl, -4- ayridinyl,
-pyrimidinyl, -pyridazinyl, -lH-indolyl, or the sulfur of-2-thiophenjl; R6 is hydrogen or
-F; R7 is -S(0)2-R9, -N-S(0)2-CH3, -S(0)CH3) 2-methyl-[l,3,4]oxadiazolyl, -CN, -
C(0)N(CH3)2, -F, -CH3, -CH2-OH, -OCH3, -CF3, -OCF3, -C(0)-CH:;, -C(0)-pyrrolidinyl,
or -C(0)NH2; R14 is -2-pyridinyl, -3-pyridinyl, -4-pyridinyl, -Phenyl, -thiazolyl,
4-methanesulfonyl-phenyl, -5-thiophenyl-2-carbonitrile, -2-methylthiazol-4-yl,
-2-methoxy-pyridin-5-yl, 2-methyl-pyridin-6-yl; and R9 is -CH3, -CH2CH3, -CH2-CH2-
CH3 -CF3, -CH2-CH2-CH2-F, or -N(CH3)2.
In another preferred embodiment R4 is -Br, -OH, -OCH2CH2CH2CH3, -O-phenyl,
-2-pyridinyl, -3-pyridinyl, -4-pyridinyl, -pyrimidinyl,-2-oxymethylpyridmyl,
-3-oxymethylpyridinyl, -4-oxymethylpyridinyl, -oxymethylbenzene;,
-4-oxymethyl-2-methylthiazoIyl, -4-oxymethylthiazolyl, -benzyloxy-4-methanesulfonyl,
-5-oxymethyl-thiophene-2-carbonitrile, -5-oxymethyl-2-methoxy-Fyridyl,
-2-oxymethyl-6-methyl-pyridinyl -pyridazinyl, -lH-indolyl, -phenyl, -2-thiophenyl, or -
benzo[l,3]dioxolyl, wherein further the -2-pyridinyl, -3-pyridinyl, -4-pyridinyl, -
pyrimidinyl, -pyridazinyl, -lH-indolyl, -phenyl, -2-thiophenyl, may be optionally
substituted one to two times with R7 provided that R7 is not directly attached to the
nitrogen of -2-pyridinyl, -3-pyridinyl, -4-pyridinyl, -pyrimidinyl, -pyridazinyl, -1H-
indolyl, or the sulfur of -2-thiophenyl.
In another preferred embodiment the invention provides a compound of formula I
or a pharmaceutically acceptable salt wherein Z is nitrogen and R6 is not attached to Z.
Other preferred embodiments of the invention include;
1. wherein m is 1,
2. wherein m is 2,
3. wherein mis 3,
4. wherein Rl and R2 and the nitrogen to which they are attached form an
azetidinyl ring, and wherein the azetidinyl ring so formed may be optionally
substituted once with R5,
5. wherein Rl and R2 and the nitrogen to which they are attached form a
pyrrolidinyl ring, and wherein the pyrrolidinyl ring so formed may be optionally
substituted once with R5,
6. wherein Rl and R2 and the nitrogen to which they are attached form a
piperidinyl ring, and wherein further the piperidinyl ring so formed may be
optionally substituted once with R5,
7. wherein R5 is H,
8. wherein R5 is -(C1-C4) alkyl (optionally substituted with one to three halogens),
9. wherein R5 is -CH3,
10. wherein R5 is halogen,
11. wherein R3 is -(C1-C4) alkyl(optionally substituted with one to three halogens),
12. wherein R3 is-CH3,
13. wherein R3 is halogen,
14. wherein Z is carbon(substituted with hydrogen or the optional substituents
indicated herein),
15. wherein Z is nitrogen,
16. wherein R6 is halogen,
17. wherein R6 is hydrogen,
18. wherein R6 is -CH3,
19. wherein R4 is -halogen, -(C1-C7) alkyl(optionally substituted with one to three
halogens), -CN, -C(0)R7, -C(0)(C3-C7)cycloalkyl(optionally substituted with
one to three halogens), -C(0)NR7R8, -OR7, -N02, -NR7R8, -NR7S02 R7,
-NR7C(0)R7, -NR7C02R7, -NR7C(0)NR7R8, -SR7, -S02R7, -S02NR7R8,
-S(0)R7, or-0(CH2)mNR7R8,
, 20. wherein R4 is-O-phenyl(R10)(R11),
21. wherein R4 is -heteroaryl-R9, •
22. wherein R4 is -0-CH2-heteroaryl-R9,
23. wherein R4 is wherein the zig-zag lines represent the point
of attachment, and wherein Q, T, D, X, and Y independently represent
carbon(substituted with hydrogen or the optional substituenti indicated herein),
or nitrogen, provided that no more than two of Q, T, D, X, and Y are nitrogen;
and provided however that wherein D is nitrogen, then R10 or R11 or R12 are
not attached to D, and provided that wherein X is nitrogen, then R10 or R11 or
R12 are not attached to X, and provided that wherein T is nitrogen, then R10 or
Rll or R12 are not attached to T, and provided that wherein Q is nitrogen, then
R10 or R11 or R12 are not attached to Q, and provided that wherein Y is
nitrogen, then R10 or R11 or R12 are not attached to Y;
24. wherein R4 is wherein the zig-zag lines represent
the point of attachment, and wherein Q, T, D, X, and Y independently represent
carbon(substituted with hydrogen or the optional substituents indicated herein),
or nitrogen, provided that no more than two of Q, T, D, X, and Y are nitrogen;
provided however that wherein D is nitrogen, then R10 or Rll or R12 are not
attached to D, and provided that wherein X is nitrogen, then R10 or R11 or R12
are not attached to X, and provided that wherein T is nitrogen, then R10 or R11
or R12 are not attached to T, and provided that wherein Q is nitrogen, then R10
or Rll or R12 are not attached to Q, and provided that wherein Y is nitrogen,
then R10 or R11 or R12 are not attached to Y;
25. wherein Q, T, D, X, and Y are carbon(substituted with hydrogen or the optional
substituents indicated herein),
26. wherein X is carbon and R10 is attached to X,
27. wherein D is carbon and R10 is attached to D,
28. wherein T is carbon and R10 is attached to T,
29. wherein D is carbon and R10 is attached to D and R10 is selected from the group
consisting of -NR9SO2 R7, -S02R7, -S02NR7R8, and -S(0)R7,
30. wherein one of Q, T, D, X, or Y is nitrogen,
31. wherein Q is nitrogen,
32. wherein T is nitrogen,
33. wherein D is nitrogen,
34. wherein X is nitrogen,
35. wherein Y is nitrogen,
36. wherein two of Q, T, D, X, or Y are nitrogen,
37. wherein D and Q are nitrogen,
38. wherein T and X are nitrogen,
39. wherein D and Y are nitrogen,
40. wherein D and Q are nitrogen,
41. wherein Q and Y are nitrogen,
42. wherein R10 is selected from the group consisting of - halogen, -(C1-C7) alkyl
optionally substituted with one to three halogens), -(C1-C7) alkyl-OH optionally
substituted with one to three halogens), -CN, -C(0)-(C3-C7)cycloalkyl(optionally
substituted with one to three halogens), -C(0)OR7, -C(0)(C3-C7)cycloalkyl,
-C(0)NR7R8, -OR7, -NR7R8, -NR9S02 R7, -NR9C(0)R7, -NR9C02R7,
-NR9C(0)NR7R8, -SR7, -S02R7, -S02CF3, -S02 NR7R8, and -S(0)R7,
43. wherein R10 is -heteroaryl-R9,
44. wherein when R10 and Rl1 are adjacent to each other they may combine along
with the respective atoms to which they are attached to form a saturated or
unsaturated five membered or six membered ring containing at least one but not
more than two atoms selected from O, S, and N,
In another embodiment according to the invention there is provided a compound
structurally represented by Formula I, or pharmaceutical^ acceptable salts thereof
wherein:
m is 1,2, or 3, wherein one or two of the hydrogens of the -CH2-, -CH2-CH2-, or
-CH2-CH2-CH2- so formed may be replaced by halogen, or -OH, or -(C1-C3)alkyl;
Z independenty represents carbon or nitrogen, provided that when Z if nitrogen then R6 is
not attached to Z;
Rl and R2 are independently
-(C1-C7) alkyl,
wherein Rl and R2 and the nitrogen to which they are attached may optionally
form an azetidinyl ring, a pyrrolidinyl ring, or a piperidinyl ring, provided the
combination of Rl and R2 represent a suffcieint number of carbon atoms to form
the azetidinyl, pyrrolidinyl, or piperidinyl ring, wherein further the azetidinyl,
pyrrolidinyl, or piperidinyl ring so formed may be optionally substituted one to
three times with R5;
R3 is independently
- H, -halogen, -CF3, -(C1-C4) alkyl, or -0-(C1-C3) alkyl;
R4 is independently
- H, -halogen, -(C1-C7) alkyl, -CN, -C(0)R7, -C(0)(C3-C7)cycloalkyl,
-C(0)NR7R8, -OCF3, -OR7, -N02, -NR7R8, -NR7S02 R7, -NR7C(0)R7,
-NR7C02R7, -NR7C(0)NR7R8, -SR7, -S02R7, -SO2CF3, -S02 NR7R8,
-S(0)R7, -0(CH2)mNR7R8, - heteroaryl-R9,
, wherein the zig-zag lines represent the point of attachment,
and wherein Q, T, D, X, and Y independently represent carbon or nitrogen,
provided that no more than two of Q, T, D, X, and Y are nitrogen; and provided
however that wherein D is nitrogen, then R10 or Rl1 or R12 are not attached to D,
and provided that wherein X is nitrogen, then R10 or R11 or R12 are not attached
to X, and provided that wherein T is nitrogen, then R10 or R11 or R12 are not
attached to T, and provided that wherein Q is nitrogen, then R10 or Rll or R12
are not attached to Q, and provided that wherein Y is nitrogen, then R10 or Rll or
R12 are not attached to Y; or
wherein the zig-zag lines represent the point of
attachment, and wherein Q, T, D, X, and Y independently represent carbon or
nitrogen, provided that no more than two of Q, T, D, X, and Y are nitrogen;
provided however that wherein D is nitrogen, then R10 or R11 or R12 are not
attached to D, and provided that wherein X is nitrogen, then R10 or Rll or R12
are not attached to X, and provided that wherein T is nitrogen, then R10 or Rl1
or R12 are not attached to T, and provided that wherein Q is nitrogen, then R10 or
R11 or R12 are not attached to Q, and provided that wherein Y is nitrogen, then
R10 or R11 or R12 are not attached to Y;
R5 is independently
- H, -OH, -halogen, -(C1-C4) alkyl, -0-(C1-C3) alkyl, or
-(C1-C3) arkyl-0(C1-C3)alkyl;
R6 is independently at each occurrence
-halogen or -CH3;
R7 and R8 are independently at each occurrence
- H, or -(C1-C7) alkyl, wherein R7 and R8 can combine with the atom to which
they are attached to form a three to seven membered ring, provided that R7 and
R8 are attached to the same atom;
R9 is independently at each occurrence
-H.-CN, or-(C1-C3) alkyl;
R10, Rll, and R12 are independently at each occurrence
r
- H, -halogen, -(C1-C7) alfcyl, -(C1-C7) alkyl-OH, -CF3, -CN, -C(0)R14,
-CO(0)R7, -CO(0)Li, -C(0)(C3-C7)cycloaIkyI, -C(0)NR7R8, -0CF3,
-OR7, -NR7R8, -NH2S02R7, -NR9S02 R7, -NR9C(0)R7, -NR9C02R7,
-NR9C(0)NR7R8, -SR7, -S02R7, -S02CF3, -S02NR7R8, -S(0)R7,
- CH2S02R14, -heteroaryl-R9, -pyridyl, or -pyrimidyl,
wherein R10 and R11 may combine along with the respective adorns to which they
are attached to form a saturated or unsaturated five membered or six membered
ring containing at least one but not more than two atoms selected from O, S, or N;
R14 is
- H, -(C1-C7) alkyl, or -phenyl
In another embodiment, the invention provides a compound of Formula (IT),

or a pharmaceutically acceptable salt thereof, wherein:
m is 1 or 2,
wherein one or two of the hydrogens of the -CH2- or -CH2-CH2- so formed
may be replaced by halogen;
Rl' and R2' are independently
-(C1-C7) alkyl,
wherein Rl' and R2' and the nitrogen to which they are attached may optionally
form an azetidinyl ring, a pyrrolidinyl ring, or a piperidinyl ring, provided the
combination of Rl' and R2' represent a suffcieint number of carbon atoms to
form the azetidinyl, pyrrolidinyl, or piperidinyl ring, wherein further the
azetidinyl, pyrrolidinyl, or piperidinyl ring so formed may be optionally
substituted one to three times with R5';
R3' is independently
- H, or-(C1-C4) alkyl;
R4' is independently
- H, -halogen, -(C1-C7) alkyl, -CN, -C(0)R7; -C(0)(C3-C7)cycloalkyl,
-C(0)NR7'R8; -OCF3, -0R7', -NC2, -NR7;R8', -NR7'S02 R7',
-NR7,C(0)R7', -NR7'C02R7\ -NR7'C(0)NR7'R8', -SR7\ -S02R7-S02CF3) -S02NR7'R8; -S(0)R7', -0(CH2)mNR7'R8\ -heteroaryl-R9;
wherein the zig-zag lines represent the point of attachment,
and wherein Q; T, D', X', and Y' independently represent carbon or nitrogen,
provided that no more than two of Q', T;, D', X', and Y' are nitrogen; and
provided however that wherein D' is nitrogen, then R10' or R11' or R12' are not
attached to D', and provided that wherein X' is nitrogen, then R10' or Rll' or
R12' are not attached to X', and provided that wherein T' is nitrogen, then R10'
or Rll' or R12' are not attached to T", and provided that wherein Q' is nitrogen,
then R10' or Rll' or R12' are not attached to Q', and provided that wherein Y' is
nitrogen, then R10' or Rll' orR12' are not attached to Y'; or
wherein the zig-zag lines represent the point of
attachment, and wherein Q' T' D', X', and Y' independently represent carbon or
nitrogen, provided that no more than two of Q', T", D', X', and Y' are nitrogen;
provided however that wherein D' is nitrogen, then R10' or Rll' or R12' are not
attached to D', and provided that wherein X' is nitrogen, then R10' or Rll' or
R12' are not attached to X', and provided that wherein T' is nitrogen, then R10'
or R11' or R12' are not attached to T' and provided that wherein Q' is nitrogen,
then R10' or Rll' or R12' are not attached to Q', and provided that wherein Y' is
nitrogen, then R10' or R11' or R12' are not attached to Y';
R5' is independently
- H, -OH, -halogen, -(C1-C4) alkyl, -0-(Ci-C3) alkyl, or
-(C1-C3) alkyl-0-(C1 -C3) alkyl,
R7' and R8' are independently at each occurence
-H,or-(C1-C7)alkyl,
wherein R7' and R8' can combine with the atom to which they are attached to
form a three to seven membered ring, provided that R7' and R8' are attached to
the same atom;
R9' is independently at each occurence
- H, -CN, or -(C1-C3) alkyl;
R10' Rll', and R12' are independently at each occurrence
- H, -halogen, -(C1-C7) alkyl, -(C1-C7) alkyl-OH, -CF3, -CN, -C(0)R14',
-CO(0)R7', -CO(0)Li, -C(0)(C3-C7)cycloalkyl, -C(0)NR7'R8-OCF3, -OR7', -NR7'R8', -NH2S02R7', -NR9'SO2 R7', -1SR9'C(0)R7'
-NR9'C02R7', -NR9'C(0)NR7'R8' -SR7' -S02R7' -SO2:CF3,
-SO2NR7'R8', -S(0)R7', -CH2S02R14', -heteroaryl-R9', -pyridinyl,
- pyrimidinyl,
wherein R10' and Rll' may combine along with the respective atoms to which
they are attached to form a saturated or unsaturated five membered or six
membered ring containing at least one but not more than two atoms selected from
O, S, or N;
R14' is
- H, -(C1-C7) alkyl, or -phenyl.
Due to their interaction with the histamine H3 receptor, the present compounds
are useful in the treatment of a wide range of conditions and disorders in which an
interaction with the histamine H3 receptor is beneficial. Thus, the compounds may find
use for example to prevent, treat and/or alleviate diseases or conditions of the central
nervous system, the peripheral nervous system, the cardiovascular system, the pulmonary
system, the gastrointestinal system and the endocrinological system, while reducing and
or eliminating one or more of the unwanted side effects associated with the current
treatments. Such diseases or conditions include those responsive to the modulation of
histamine H3 receptors, such as nervous system disorders which include but are not
limited to obesity, cognitive disorders, attention deficit disorders, memory processes;
dementia and cognition disorders such as Alzheimer's disease arid attention-deficit
hyperactivity disorder; bipolar disorder, cognitive enhancement, cognitive deficits in
psychiatric disorders, deficits of memory, deficits of learning, dementia, mild cognitive
impairment, migraine, mood and attention alteration, motion sickness, narcolepsy,
neurogenic inflammation, obsessive compulsive disorder, Parkinson's disease,
schizophrenia, depression, epilepsy, and seizures or convulsions; sleep disorders such as
narcolepsy; vestibular dysfunction such as Meniere's disease, migraine, motion sickness,
pain, drug abuse, depression, epilepsy, jet lag, wakefulness, Tourette's syndrome, vertigo,
and the like, as well as cardiovascular disorders such as acute myocardial infarction;
cancer such as cutaneous carcinoma, medullary thyroid carcinoma and melanoma;
respiratory disorders such as asthma; gastrointestinal disorders, inflammation, and septic
shock, diabetes, type II diabetes, insulin resistance syndrome, metabolic syndrome,
polycystic ovary syndrome, Syndrome X, and the like.
The present invention also provides a pharmaceutical composition which
comprises a compound of Formula I or Formula II and a pharmaceutically acceptable
earner. Pharmaceutical formulations of Formula I or Formula II can provide a method of
selectively increasing histamine levels in cells, or increasing histamine release by cells,
by contacting the cells with an antagonist or inverse agonist of the histamine H3 receptor,
the antagonist or inverse agonist being a compound of Formula I or Formula II. Thus, the
methods of this invention encompass a prophylactic and therapeutic administration of a
compound of Formula I or Formula II.
The present invention further provides an antagonist or inverse agonist of Formula
I or Formula II which is characterized by having little or no binding affinity for the
histamine receptor GPRv53.
Thus, a pharmaceutical preparation of Formula I or Formula II can be useful in the
treatment or prevention of obesity, cognitive disorders, attention deficit disorders,
memory processes, dementia and cognition disorders such as Alzheimer's disease and
attention-deficit hyperactivity disorder; bipolar disorder, cognitive enhancement,
cognitive deficits in psychiatric disorders, deficits of memory, deficits of learning,
dementia, mild cognitive impairment, migraine, mood and attention alteration, motion
sickness, narcolepsy, neurogenic inflammation, obsessive compulsive disorder,
Parkinson's disease, schizophrenia, depression, epilepsy, and seizures or convulsions;
sleep disorders such as narcolepsy; vestibular dysfunction such as Meniere's disease,
migraine, motion sickness, pain, drug abuse, depression, epilepsy, jet h.g, wakefulness,
Tourette's syndrome, vertigo, and the like, which comprises administering to a subject in
need of such treatment or prevention an effective amount of a compound of Formula I or
Formula II. In addition, a pharmaceutical preparation of Formula I or Formula II can be
useful in the treatment or prevention of a disorder or disease in which modulation of
histamine H3 receptor activity has a beneficial effect or the treatment or prevention of
eating disorders which comprises administering to a subject in need of such treatment or
prevention an effective amount of a compound of Formula I or Formula II. In yet another
aspect, the present invention provides compounds, pharmaceutical compositions, and
methods useful in the treatment of nervous system and other disorders; associated with
histamine H3 receptor.
In addition, the present invention relates to a compound of Formula I or II, or a
pharmaceutical salt thereof, or a pharmaceutical composition which comprises a
compound of Formula I or II, or a pharmaceutical salt thereof, and a iAarmaceutically
acceptable carrier, diluent, or excipient; for use in inhibiting the histamine H3 receptor;
for use in inhibiting a histamine H3 receptor mediated cellular response in a mammal; for
use to increase the release of H3 receptor-regulated neurotransmitter> in a mammal; for
use in treating a disease arising from excessive histamine H3 receptor activity; and for use
in treating nervous system disorders in a mammal including but not limited to obesity,
cognitive disorders, attention deficit disorders, memory processes, dementia and
cognition disorders such as Alzheimer's disease and attention-defici: hyperactivity
disorder; bipolar disorder, cognitive enhancement, cognitive deficits in psychiatric
disorders, deficits of memory, deficits of learning, dementia, mild cognitive impairment,
migraine, mood and attention alteration, motion sickness, narcolepsy, neurogenic
inflammation, obsessive compulsive disorder, Parkinson's disease, schizophrenia,
depression, epilepsy, and seizures or convulsions; sleep disorders such as narcolepsy;
vestibular dysfunction such as Meniere's disease, migraine, motion sickness, pain, drug
abuse, depression, epilepsy, jet lag, wakefulness, Tourette's syndrome, and vertigo. Thus,
the uses and methods of this invention encompass a prophylactic and therapeutic
administration of a compound of Formula I or II.
The present invention is further related to the use of a compound of Formula I or
II, or a pharmaceutical salt thereof, or a pharmaceutical composition which comprises a
compound of Formula I or II, or a pharmaceutical salt thereof, and a pharmaceutically
acceptable carrier, diluent, or excipient; for the manufacture of a medicament for
inhibiting the histamine H3 receptor; for the manufacture of a medicament for inhibiting a
histamine H3 receptor mediated cellular response in a mammal; for the manufacture of a
medicament to increase the release of H3 receptor-regulated neurotransmitters in the
brain of a mammal; for the manufacture of a medicament for treating a disease arising
from excessive histamine H3 receptor activity; for the manufacture of a medicament for
treating cognitive disorders in a mammal; and for the manufacture of a medicament for
treating nervous system disorders in a mammal including but not limited to obesity,
cognitive disorders, attention deficit disorders, memory processes, dementia and
cognition disorders such as Alzheimer's disease and attention-deficit hyperactivity
disorder; bipolar disorder, cognitive enhancement, cognitive deficits in psychiatric
disorders, deficits of memory, deficits of learning, dementia, mild cognitive impairment,
migraine, mood and attention alteration, motion sickness, narcolepsy, neurogenic
inflammation, obsessive compulsive disorder, Parkinson's disease, schizophrenia,
depression, epilepsy, and seizures or convulsions; sleep disorders such as narcolepsy;
vestibular dysfunction such as Meniere's disease, migraine, motion sickness, pain, drug
abuse, depression, epilepsy, jet lag, Wakefulness, Tourette's syndrome, and vertigo.
The present invention further provides; a method of treating conditions resulting
from excessive histamine H3 receptor activity in a mammal; a method of inhibiting the
histamine H3 receptor activity in a mammal; a method of inhibiting a histamine H3
receptor mediated cellular response in a mammal; a method to increase the release of H3
receptor-regulated neurotransmitters in the brain of a mammal; a method of treating
cognitive disorders in a mammal; a method of treating nervous system disorders in a
mammal including but not limited to obesity, cognitive disorders, attention and attention
deficit disorders, memory processes, learning, dementia, Alzheimer's disease, attention-
deficit hyperactivity disorder, Parkinson's disease, schizophrenia, depression, epilepsy,
and seizures or convulsions; comprising administering to a mammal in need of such
treatment a histamine H3 receptor-inhibiting amount of a compound of Formula I or II or
a pharmaceutically acceptable salt thereof, or a pharmaceutical composition which
comprises a compound of Formula I or n, or a pharmaceutical salt thereof, and a
pharmaceutically acceptable carrier, diluent, or excipient.
A pharmaceutical composition of the present invention comprises a compound as described
herein along with a pharmaceutically acceptable carrier showed surprising effects. Therefore the said
composition is synergistic in nature.
The present invention further provides a method of treating conditions resulting
from excessive histamine H3 receptor activity in a mammal comprising administering to a
mammal in need of such treatment a histamine H3 receptor inhibiting amount of a
pharmaceutical composition which comprises a compound of Formula I or II, or a
pharmaceutical salt thereof, and a pharmaceutically acceptable carrier, diluent, or
excipient. In addition, a pharmaceutical composition of Formula I or II can be useful in
the treatment or prevention of a disorder or disease in which modulation of histamine H3
receptor activity has a beneficial effect. The present invention further provides an
antagonist or inverse agonist of Formula I or II which is characterized by having greater
affinity for the histamine H3 receptor as compared to the affinity for the histamine H1R,
H2R, or H4R receptors. In addition the embodiments of the present invention include the
synthesis of the examples named herein by methods included herein, and supplemented
by methods known in the art, to create positron emission topography (PET) ligands that
bind to histamine H3 receptors and are useful for PET imaging.
The invention includes tautomers, enantiomers and other stereoisomers of the
compounds also. Thus, as one skilled in the art knows, certain aryls may exist in
tautomeric forms. Such variations are contemplated to be within the scope of the
invention. It will be understood that, as used herein, references to the compounds of
Formula I or Formula II are meant to also include the pharmaceutical salts, its
enantiomers and racemic mixtures thereof.
As used herein, the term "stereoisomer" refers to a compound, made up of the
same atoms bonded by the same bonds but having different three-dimensional structures
which are not interchangeable. The three-dimensional structures are called
configurations. As used herein, the term "enantiomer" refers to two stereoisomers whose
molecules are nonsuperimposable mirror images of one another. The term "chiral center"
refers to a carbon atom to which four different groups are attached. As used herein, the
term "diastereomers" refers to stereoisomers which are not enantiomers. In addition, two
diastereomers which have a different configuration at only one chiral center are referred
to herein as "epimers." The terms "racemate," "racemic mixture" 01 "racemic
modification" refer to a mixture of equal parts of enantiomers.
The compounds of the present invention may be chiral, and it is intended that any
enantiomers, as separated, pure or partially purified enantiomers or racemic mixtures
thereof are included within the scope of the invention. Furthermore, when a double bond
or a fully or partially saturated ring system or more than one center of asymmetry or a
bond with restricted rotatability is present in the molecule diastereomers may be formed.
It is intended that any diastereomers, as separated, pure or partially purified diastereomers
or mixtures thereof are included within the scope of the invention. Furthermore, some of
the compounds of the present invention may exist in different tautomeric forms and it is
intended that any tautomeric forms, which the compounds are able to form, are included
within the scope of the present invention. Thus, as one skilled in the art knows, certain
aryls may exist in tautomeric forms. The invention also includes tautomers, enantiomers
and other stereoisomers of the compounds of Formula I or Formula n. Such variations are
contemplated to be within the scope of the invention.
The terms "R" and "S" are used herein as commonly used in organic chemistry to
denote specific configuration of a chiral center. The term "R" (rectus) refers to that
configuration of a chiral center with a clockwise relationship of group priorities (highest
to second lowest) when viewed along the bond toward the lowest priority group. The
term "S" (sinister) refers to that configuration of a chiral center with a counterclockwise
relationship of group priorities (highest to second lowest) when viewed along the bond
toward the lowest priority group. The priority of groups is based upon their atomic
number (in order of decreasing atomic number). A partial list of priorities and a
discussion of stereochemistry is contained in "Nomenclature of Organic Compounds:
Principles and Practice", (J.H. Fletcher, et al., eds., 1974) at pages 103-120.
The designation "- " refers to a bond that protrudes forward out of the plane
of the page. The designation..........' refers to a bond that protrudes backward out of the
plane of the page. The designation " ~~** " refers to a bond wherein the stereochemistry
is not defined.
The compounds of Formula I or Formula II, when existing as a diastereomeric
mixture, may be separated into diastereomeric pairs of enantiomers by, for example,
fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or
a mixture thereof. The pair of enantiomers thus obtained may be separated into
individual stereoisomers by conventional means, for example by the use of an optically
active acid as a resolving agent. Alternatively, any enantiomer of a compound of
Formula I or Formula II may be obtained by stereospecific synthesis using optically pure
starting materials or reagents of known configuration or through enantioselective
synthesis.
The term "enantiomeric enrichment" as used herein refers to th3 increase in the
amount of one enantiomer as compared to the other. A convenient method of expressing
the enantiomeric enrichment achieved is the concept of enantiomeric excess, or "ee,"
which is found using the following equation:

wherein E1 is the amount of the first enantiomer and E2 is the amount of the
second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is
present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final
ratio of 70:30 is achieved, the ee with respect to the first enantiomer is 40%. However, if
the final ratio is 90:10, the ee with respect to the first enantiomer is 80%. An ee of
greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of
greater than 99% is most especially preferred. Enantiomeric enrichment is readily
determined by one of ordinary skill in the art using standard techniques and procedures,
such as gas or high performance liquid chromatography with a chiral column. Choice of
the appropriate chiral column, eluent and conditions necessary to effect separation of the
enantiomeric pair is well within the knowledge of one of ordinary skill in the art. In
addition, the specific stereoisomers and enantiomers of compounds of Formula I or
Formula II can be prepared by one of ordinary skill in the art utilizing well known
techniques and processes, such as those disclosed by J. Jacques, et al, "Enantiomers.
Racemates, and Resolutions," John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H.
Wilen," Stereochemistry of Organic Compounds," (Wiley-Interscience 1994), and
European Patent Application No. EP-A-S38448, published April 29.1998. Examples of
resolutions include recrystallization techniques or chiral chromatography.
In general, the term "pharmaceutical" when used as an adjective means
substantially non-toxic to living organisms. For example, the term 'pharmaceutical salt"
as used herein, refers to salts of the compounds of Formula I or Formula II which are
substantially non-toxic to living organisms. See, e.g., Berge, S.M, Bighley, L.D., and
Monkhouse, D.C., "Pharmaceutical Salts," /. Pharm. Sci, 66:1, 1977. The present
invention also encompasses pharmaceutically acceptable salts of the present compounds.
Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically
acceptable metal salts, ammonium and alkylated ammonium salts. Also intended as
pharmaceutically acceptable acid addition salts are any hydrates that the present
compounds are able to form. Furthermore, the pharmaceutically acceptable salts comprise
basic amino acid salts such as lysine, arginine and ornithine. Typical pharmaceutical salts
include those salts prepared by reaction of the compounds of Formula I or Formula II
with an inorganic or organic acid or base. Such salts are known as acid addition or base
addition salts respectively. These pharmaceutical salts frequently have enhanced
solubility characteristics compared to the compound from which they are derived, and
thus are often more amenable to formulation as liquids or emulsions.
The term "acid addition salt" refers to a salt of a compound of Formula I or
Formula II prepared by reaction of a compound of Formula I or Formula II with a mineral
or organic acid. For exemplification of pharmaceutical acid addition salts see, e.g.,
Berge, S.M, Bighley, L.D., and Monkhouse, D.C., /. Pharm. Sci, 66:1,1977. Since
compounds of this invention can be basic in nature, they accordingly react with any of a
number of inorganic and organic acids to form pharmaceutical acid addition salts.
The acid addition salts may be obtained as the direct products of compound
synthesis. In the alternative, the free base may be dissolved in a suitable solvent
containing the appropriate acid, and the salt isolated by evaporating the solvent or
otherwise separating the salt and solvent.
Acids commonly employed to form acid addition salts are inorganic acids such as
hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and
the like, and organic acids, such as p-toluenesulfonic acid, ethanesulfonic acid,
methanesulfonic acid, oxalic acid, p-bromophenylsutfonic acid, carbonic acid, succinic
acid, citric acid, tartaric acid, benzoic acid, acetic acid and the like. Preferred
pharmaceutical acid addition salts are those formed with mineral acids such as
hydrochloric acid, hydrobromic acid, and sulfuric acid, and those formed with organic
acids such as maleic acid, tartaric acid, and methanesulfonic acid. Examples of such
pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite,
bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate,
acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,
succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate,
benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate,
methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate,
phenylbutyrate, citrate, lactate, |3-hydroxybutyrate, glycollate, tartrate, methanesulfonate,
propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the
like.
The skilled artisan would appreciate that some compounds of Formula I or
Formula II may be acidic in nature and accordingly react with any of a number of
inorganic and organic bases to form pharmaceutical base addition salts. The term "base
addition salt" refers to a salt of a compound of Formula I or Formula 13 prepared by
reaction of a compound of Formula I or Formula II with a mineral or organic base. For
exemplification of pharmaceutical base addition salts see, e.g., Berge, S.M, Bighley, L.D.,
and Monkhouse, D.C., J. Pharm. Sci., 66:1,1977. Bases commonly employed to form
pharmaceutical base addition salts are inorganic bases, such as ammonium or alkali or
alkaline earth metal hydroxides, carbonates, bicarbonates, and the lite. Such bases useful
in preparing the salts of this invention thus include sodium hydroxide, potassium
hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium
bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
Examples of pharmaceutical base addition salts are the ammonium, lithium, potassium,
sodium, calcium, magnesium, methylamino, diethylamino, ethylene diamino,
cyclohexylamino, and efhanolamino salts, and the like of a compound of Formula I or
Formula II. The potassium and sodium salt forms are particularly preferred. The present
invention also contemplates pharmaceutical base addition salts of compounds of Formula
I or Formula II.
The pharmaceutical salts of the invention are typically formed by reacting a
compound of Formula I or Formula II with an equimolar or excess amount of acid or
base. The reactants are generally combined in a mutual solvent such as diethylether,
tetrahydrofuran, methanol, ethanol, isopropanol, benzene, and the like for acid addition
salts, or water, an alcohol or a chlorinated solvent such as dichloromethane for base
addition salts. The salts normally precipitate out of solution within about one hour to
about ten days and can be isolated by filtration or other conventional methods.
The compounds of the present invention may form solvates with standard low
molecular weight solvents using methods well known to the person skilled in the art.
Such solvates are also contemplated as being within the scope of the present invention.
The invention also encompasses prodrugs of the present compounds, which on
administration undergo chemical conversion by metabolic processes before becoming
pharmacologically active substances. In general, such prodrugs will be functional
derivatives of present compounds, which are readily convertible in vivo into a compound
of the present invention. Conventional procedures for the selection and preparation of
suitable prodrug derivatives are described, for example in "Design of Prodrugs", ed. H.
Bundgaard, Elsevier, 1985.
Furthermore, they may be applicable as diagnostic agents for identifying patients
having a defect in the histamine H3 receptor. Furthermore, the invention relates to the use
of a compound of the general formula I as well as any diastereomer or enantiomer or
tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt
thereof for the preparation of a medioament for the treatment of disorders or diseases,
wherein a histamine H3 receptor antagonistic action is beneficial.
The invention also relates to a method for the treatment of disorders or diseases,
wherein a histamine H3 receptor antagonistic action is beneficial the method comprising
administering to a subject in need thereof an effective amount of a compound according
to the invention. In another embodiment of the invention the present compounds are used
for the preparation of a medicament for the treatment of any histamine H3 receptor -
mediated conditions and diseases. In still another embodiment of the invention the present
compounds are used for the preparation of a pharmaceutical composition for the treatment
of an appetite regulation or energy expenditure disorder. In a further embodiment of the
invention, treatment of a patient with the present compounds is combined with diet and/or
exercise. In another embodiment the intermediate compounds are useful for preparing
final compounds of the invention, or may themselves possess H3 antagonist or inverse
agonist activity.
The compounds of Formula I or Formula II can be prepared by one of ordinary
skill in the art following a variety of procedures, some of which are illustrated in the
procedures and schemes set forth below. The particular order of steps required to produce
the compounds of Formula I or Formula II is dependent upon the particular compound to
being synthesized, the starting compound, and the relative liability of the substituted
moieties. The reagents or starting materials are readily available to one of skill in the art,
and to the extent not commercially available, are readily synthesized by one of ordinary
skill in the art following standard procedures commonly employed in the art, along with
the various procedures and schemes set forth below.
The following Schemes, Procedures, Preparations and Examples are provided to
better elucidate the practice of the present invention and should not be interpreted in any
way as to limit the scope of the same. Those skilled in the art will recognize that various
modifications may be made while not departing from the spirit and scope of the
invention. All publications mentioned in the specification are indicative of the level of
those skilled in the art to which this invention pertains.
The terms and abbreviations used herein have their normal meanings unless
otherwise designated. For example, as used herein, the following terras have the
meanings indicated:
"Boc" or "BOC" refer to f-butyl carbonyl. "HOBt" is 1-hydrobenzotriazole.
"HATU" is 0-(7-azabenzotriazol-l-yl)-N-N-N-N'-tetrarnethyluroniuni
hexafluorophosphate. "DCC" is dicyclohexylcarbodiirnide. "EDC" i s
l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. "Red-Al®" is 65+
weight % solution of sodium bis(2-methoxyethoxy)aluminum hydride. "DMAP" is
4-dimethylaminopyridine. "DIPEA" is diisopropylethylamine. "DDBAL-H" is
diisobutylaluminum hydride. "NBS" is Af-bromosuccinimide. "DMEA" is
dimethylethylamine. "THF" is tetrahydrofuran. "DMF" is dimethylxormamide.
"EtOAc" is ethyl acetate. "EtOH" is ethyl alcohol or ethanol. "MeOH" is methyl alcohol
or methanol. "DMSO" is dimethylsulfoxide. "TBAF" is tetrabutylammonium fluoride.
"DME" is ethylene glycol dimethyl ether.
"PS-Trisamine" is Tris-(2-aminoethyl)amine polystyrene. "FS-Carbodiimide" or
"PS-CDI" is N-Cyclohexylcarbodiimide-N'-propyloxymethyl polystyrene. "PS-DEA" is
N,N-(Diisopropyl)aminomethylpolystyrene (1% inorganic antistatic agent). "PS-DMAP"
is N-(memylpolystyrene)^-(methylamino) pyridine.
"Rpm" refers to revolutions per minute; "W" refers to watts; "mmHg" refers to
millimeters of mercury; "CAS" or "CAS#" refers to Chemical Abstract Service number;
"SCX" refers to strong cation exchange; "eq" refers to equivalents; "N" refers to normal
or normality, "M" refers to molar or molarity, "mol" refers to moles; "mmol" refers to
millimoles; "psi" refers to pounds per square inch; "min" refers to minutes; "h" or "hr"
refers to hours; "°C" refers to degrees Celsius; "TLC" refers to thin layer chromatography;
"Rf" refers to retention factor; "HPLC" refers to high performance liquid chromatography;
"Rt" refers to retention time; "MS" refers to mass spectrometry, Observed Mass indicates
(M+l) unless indicated otherwise, "m/e" refers to mass to charge ratio. "MS(FD)"
refers to field desorption mass spectrometry, "MS(IS)" refers to ion spray mass
spectrometry, "MS(FIA)" refers to flow injection analysis mass spectrometry,
"MS(FAB)" refers to fast atom bombardment mass spectrometry, "MS(EI)" refers to
electron impact mass spectrometry, "MS(ES)" refers to electron spray mass spectrometry;
"UV" refers to ultraviolet spectrometry; "'H NMR" refers to proton nuclear magnetic
resonance spectrometry. "5"refers to part per million down-field from tetramethylsilane.
"s", "d", "t", "q", "dd", and, "m" refer to singlet, doublet, triplet, quartet, doublet of
doublets, and multiplex, respectively; In addition, "IR" refers to infrared spectrometry,
and the absorption maxima listed for the IR spectra are only those of interest and not all
of the maxima observed. "RT" refers to room temperature.
GENERAL SCHEMES:
Compounds of the present invention have been formed as specifically described in
the examples. Further, many compounds are prepared using the general schemes
described below. Unless otherwise indicated, all variables are defined as in the summary
of the invention and as otherwise defined herein. Alternative synthesis methods may also
be effective and known to the skilled artisan

phenyl, pyridine, pyrimidine, pyrazine, pyridazine, and Z independently represents carbon
(substituted with hydrogen or the optional substituents indicated herein), or nitrogen. In
(step 1) the hydroxyl group of compound i [obtained by the method of D. Brooks, J.
Med. Chem., 2001, 44, 2061-2064 or the patent WO 0116120] is converted to a suitable
leaving group i.e. mesylate, tosylate, iodide (Ra = OMs, OTs, I) etc:, using standard
literature procedures. For example, a mixture of 2-[2-(4-Bromo-phenyI)-5-methyl-
oxazol-4-yl]-ethanol and a sutable base in this case triethylamine in an aprotic solvent
such as dichloromethane is cooled to 0°C and treated with methanesulfonyl chloride. The
mixture is allowed to stir at room temperature for l-4h. The reaction is concentrated and
purified according to techniques well known in the art or used crude in the next reaction.
In Scheme A (step 2), mis activated alcohol is treated with excess amine (Rb =
pyrrolidine, 2-methylpyrrolidine, piperidine, 2-methylpiperidine, utc.) in a suitable
solvent to provide the desired amines. For example, the crude methanesulfonic acid
Methanesulfonic acid 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester is
dissolved in a suitable solvent such as THF and 2-10 equivalents of 2-methylpyrrolidine
is added. The mixture is stirred at room temperature or heated for a period of 8 - 48h at
70 °C. The reaction is concentrated and purified according to techniques well known in
the art. In step 3, the amine from step 2 substituted with halogen X, where X can be CI,
Br, I combined with an aryl boronic acid (Rc = H) or ester (Rc = pinacol) are converted to
the corresponding triaryls. The triaryls can be achieved by a variety of palladium
catalyzed Suzuki reaction memods as described in Section rV-14 of the following review
(Hassan, Jwanro; Sevignon, Marc; Gozzi, Christel; Schulz, Emmanuelle; Lemaire, Marc.
Aryl-Aryl Bond Formation One Century after the Discovery of the Ullmann Reaction.
Chemical Reviews (Washington, D. C.) (2002), 102(5), 1359-1469). For example, 2-
(4-Bromo-phenyl)-5-methyl-4-(2-pyiTolidin-l-yl-etliyl)-oxazoleand4-
methylsulfonylphenylboronic acid are dissolved in a suitable orgjinic solvent such as
dioxane, acetonitrile, DME, THF, EtOH, or mixtures thereof. A suitable palladium
catalyst such as tetrakis-(triphen3'lphosphine) palladium (0), palh.dium(II) dichloride
(dppf) complex with dichloromethane, dichloropalladium di-triphitnylphosphine etc. is
added followed by a suitable base such as aqueous sodium or potassium carbonate,
anhydrous cesium or potassium fluoride, anhydrous potassium or cesium carbonate etc.
The reaction is heated within a temperature range of 70 to 100 °C for a period of 4-24
hours. The reaction is concentrated and purified according to techniques well known in
the art.
Alternatively, the triaryl formation (step 3) can also be performed using
microwave assisted Suzuki couplings. For example, 2-(4-Brorno-phenyl)-5-methyI-4-(2-
pyrrolidin-l-yl-ethyl)-oxazole and pyridine 3-boronic acid are dissolved in a suitable
organic solvent such as dioxane, acetonitrile, DME, THF, EtOH, or mixtures thereof. A
suitable palladium catalyst such as tetrakis-(triphenylphosphine) palladium (0),
palladium(II) dichloride (dppf) complex with dichloromethane, dichloropalladium di-
triphenylphosphine etc. is added followed by a suitable base such as aqueous sodium or
potassium carbonate, anhydrous cesium or potassium fluoride, anhydrous potassium or
cesium carbonate etc. The reaction is run in a CEM or MARS microwave reactor for 10-
40 minutes, at 90-120 °C, with 75W power and cooling control on to maintain
temperature range. The reaction is concentrated and purified according to techniques
well known in the art.

In Scheme B, compound 1, Ra, Rb, Rc, X and Ar are previously defined. In
Scheme B (step 1), compound i is combined with an aryl boronic acid (Rc = H) or ester
(Rc = pinacol) is converted to the corresponding triaryl alcohols. The triaryl alcohols can
be achieved by the methods of the Review previously described for Scheme A (step 3).
For example, 2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-ethanol and 4-
methylsulfonylphenylboronic acid are dissolved in a suitable organic solvent such as
dioxane, acetonitrile, DME, THF, EtOH, or mixtures thereof. A suitable palladium
catalyst such as tetrakis-(triphenylphosphine) palladium (0), palladium(II) dichloride
(dppf) complex with dichloromethane, dichloropalladium di-triphenylphosphine etc. is
added followed by a suitable base such as aqueous sodium or potassium carbonate,
anhydrous cesium or potassium fluoride, anhydrous potassium or cesium carbonate etc.
The reaction is heated within a temperature range of 70 to 100 °C for a period of 4-24
hours. The reaction is concentrated and purified according to techniques well known in
the art.
Alternatively in Scheme B (stepl), aryl chlorides, bromides, or: iodides can be
combined with compound 2 [which is obtained by the methods of T. Ishiyama,
Tetrahedron, 57, 9813-9816, 2001 using compound (I) to give the corresponding triaryl
alcohols. For example, 2-{5-Methyl-2-[4-(4,4,5,5-tetramethyI-[l,3,2]dioxaborolan-2-yl)-
phenyl]-oxazol-4-yl}-ethanol and 2-(4-Chloro-phenyl)-5-methyl-[l,3,4]oxadiazole are
dissolved in a suitable organic solvent such as dioxane, acetonitrile, PME, THF, EtOH, or
mixtures thereof. A suitable palladium catalyst such as tetrakis-(triph.eny}phosphine)
palladium (0), pal]adium(II) dichloride (dppf) complex with dichloromethane,
dichloropalladium di-triphenylphosphine etc. is added followed by a suitable base such as
aqueous sodium or potassium carbonate, anhydrous cesium or potassium fluoride,
anhydrous potassium or cesium carbonate etc. The reaction is run in a CEM or MARS
microwave reactor for 2-4 hours, at 90-120 °C, with 75W power and cooling control on to
maintain temperature range. The reaction is concentrated and purified according to
techniques well known in the art.
In Scheme B (step 2), the resulting triaryl alcohol can be converted to a leaving
group i.e. mesylate, tosylate, iodide (Ra = OMs, OTs, I) etc. using standard literature
procedures. For example, a mixture of 2-[2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-
methyl-oxazol-4-yl]-ethanol and a suitable base in this case triethylamine in an aprotic
solvent such as dichloromethane is cooled to 0°C and treated with methanesulfonyl
chloride. The mixture is allowed to stir at room temperature for l-4h. The reaction is
concentrated and purified according to techniques well known in the art or used crude in
the next reaction.
In Scheme B (step 3), this activated alcohol is treated with excess amine in a
suitable solvent to provide the desired triaryl amine.

In Scheme C, Rb, Rc, X and Ar are previously defined. In Scheme C (step 1),
compound 3 [CAS# 478540-95-3] is combined with an aryl boronic acid (Rc = H) or ester
(Rc = pinacol) under the previously described Suzuki conditions to provide the
corresponding triaryl carboxylate. For example, [2-(6-CbJoro-pyridin-3-yl)-5-methy]-
oxazol-4-yl]-acetic acid methyl ester and 4-methylsulfonylphenylboronic acid are
dissolved in a suitable organic solvent such as dioxane, acetonitrile, DME, THF, EtOH, or
mixtures thereof. A suitable palladium catalyst such as tetrakis-(triphenylphosphine)
palladium (0), palladium(II) dichloride (dppf) complex with dichloromethane,
dichloropalladium di-triphenylphosphine etc. is added followed by a suitable base such as
aqueous sodium or potassium carbonate, anhydrous cesium or potassium fluoride,
anhydrous potassium or cesium carbonate etc. The reaction is heated within a
temperature range of 70 to 100 °C for a period of 4-24 hours. The reaction is
concentrated and purified according to techniques well known in the art.
In Scheme C (step 2), the ester can be saponified using standard conditions to
yield the corresponding triaryl carboxylic acid or the lithium, sodium or potassium salt of
the acid where Rd can be H, Li, Na or K. For example, [2-(6-Chloro-pyridin-3-yl)-5-
methy]-oxazol-4-yl]-acetic acid methyl ester and NaOH are combined in methanol /
tetrahydrofuran and heated to reflux for 1 hour. The reaction is concentrated and the
resulting sodium salt is washed with dichloromethane and dried to purify.
In Scheme C (step 3) the triaryl carboxylic acid or the lithium, sodium or
potassium salt of me acid where Rd can be H, Li, Na or K are converted to me
corresponding amides using a number of different methods known in Ihe literature. Some
of these methods can be found described in a review of coupling reagents in peptide
synthesis by Klausner & Bodansky, Synthesis, 1972, 9, 453-463. For example, Sodium
{2-[6-(4-methanesulfonyl-phenyl)-pyridin-3-yl]-5-methyl-oxazol-4-y]}-acetate, oxalyl
chloride, and catalytic dimethylformamide are dissolved in a suitable solvent such as
dioxane or acetonitrile and heated to reflux for or a period of 0.5-1.0 hours. After solvent
exchange to dichloromethane the resulting acid chloride is combined with a suitable acid
scavenger such as n-methylmorpholine, triethylamine, pyridine etc. and a cyclic or
dialkylated amine such as pyrrolidine, 2-methylpyrrolidine, piperidine, etc. and the
mixture is stirred for a period of 1-4 hours. The reaction is concentrated and purified
according to techniques well known in the art.
In Scheme C (step 4) the resulting triaryl carboxamides are converted to the
corresponding amines using standard literature reduction methods. For example, 2-{2-[6-
(4-Methanesulfonyl-phenyl)-pyridin-3-yl]-5-methyl-oxazol-4-yl}-l-(2-(R)-methyl-
pyrrolidin-l-yl)-ethanone is combined with a suitable reducing agent such as LAH or
Red-Al® in a suitable solvent such as tetrahydrofuran or diethyl ether at a temperature of
-78-0°C and warming to room temperature for a period of 4-8 hours. The reaction is
quenched according to standard literature procedures (Fieser and Fieser) and after
concentration is purified according to techniques well known in the art.

In Scheme D, Ra, Rb, and Ar are previously defined. In Scheme D (step 1), the
hydroxyl group of compound 4 [CAS# 403611-91-6, 2-[2-(4-Benzyloxy-phenyl)-5-
methyI-oxazol-4-yl]-ethanol] is protected by a silyl group using standard literature
procedures. For example, 2-[2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethanol is
combined with a suitable base such as triethylamine, imidazole, dimeuiylaminopyridine
etc., in a suitable solvent such as dichloromethane or dimetliyformamide and treated with
a silylating reagent such as tert-butylchlorodiphenylsilane or tert-
butylchlorodimethylsilane at 0°C to room tmeprature for a period of 6-18 hours. The
crude material extracted from an acidic aqueous work up is purified according to
techniques well known in the art.
In Scheme D (step 2), the benzyl protecting is removed by catalytic hydrogenation
using standard literature procedures. For example, 2-(4-Benzyloxy-phenyl)-4-[2-(tert-
butyl-diphenyl-silanyloxy)-ethyl]-5-methyl-oxazole is combined with 5-10% palladium
on carbon and dissolved in a suitable solvent such as ethyl acetate, terrahydrofuran,
ethanol or a mixture thereof under an atmosphere of 1-60 mmHg of hydrogen for 24-48
hours. After filtration, the reaction is concentrated and purified according to techniques
well known in the art.
In Scheme D (step 3), the resulting phenol is alkylated with a variety of aryl
chlorides, bromides and iodides under standard literature conditions. For example, 4-{4-
[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-5-methyl-oxazol-2-yl}-pheriol and 2-
bromomethylpyridine hydrobromide is combined with a suitable base such as potassium
carbonate, cesium carbonate, sodium carbonate etc., in a suitable solvent such as acetone,
dimethylformamide, acetonitrile or a mixture thereof at a temperature of 20-100°C for a
period of 12-24 hours. The crude material extracted from an aqueous work up is purified
according to techniques well known in the art.
In Scheme D (step 4), the silyl- protecting group of the resulting aryl ether is
removed using standard literature procedures. For example, 2-(4-{4-[2-(tert-Butyl-
diphenyl-silanyloxy)-ethyl]-5-methyl-oxazol-2-yl}-phenoxymethyI)-pyridineand
tetrabutylammonium fluoride are combined in a suitable solvent such as tetrahydrofuran,
dioxane or a mixture thereof at a temperature of -10-40°C for a period of 2-8 hours. The
crude material extracted from an aqueous work up is purified according to techniques
well known in the art.
In Scheme D (step 5), the resulting alcohol can be converted to a leaving group
i.e. mesylate, tosylate, iodide (Ra = OMs, OTs, I) etc. using standard literature
procedures. For example, a mixture of 2- {5-Methyl-2-[4-(pyridin-2-ylmethoxy)-phenyl]-
oxazol-4-yl }-ethanol and a suitable base in this case triethylamine in an aprotic solvent
such as dichloromefhane is cooled to 0°C and treated with methanesulfonyl chloride. The
mixture is allowed to stir at room temperature for l-4h. The reaction is concentrated and
purified according to techniques well known in the art or used crude in the next reaction.
In Scheme D (step 6), this activated alcohol is treated with excess amine in a suitable
solvent to provide the desired triaryl amine.

In Scheme E, Rb and Ar are previously defined. In Scheme E (step 1), the
carboxylic acid of compound 5 [CAS 403611-89-2, [2-(4-Benzyloxy-phenyl)-5-methyl-
oxazoI-4-yl]-acetic acid] is converted to the corresponding amides using a number of
different methods known in the literature. Some of these methods can be found described
in a review of coupling reagents in peptide synthesis by Klausner & Bodansky, Synthesis,
1972, 9, 453-463. For example, [2-(4-Benzyloxy-phenyl)-5-methyl-oxazoI-4-yl]-acetic
acid is suspended in a suitable organic solvent such as dichloromethane, DMF or mixtures
thereof. A suitable amide coupling agent i.e EDC, DCC, etc. is added followed by HOBt,
HATU, etc. at room temperature. Diisopropylethyl amine and suitable amine in this case,
pyrrolidine or (2R)-methylpyrrolidine for example are added to the mixture. The mixture
is stirred at room temperature for a period of 8-48 hours. The reaction is quenched by
addition of water. The resulting mixture may be extracted, concentrated and purified
according to techniques well known in the art.
In Scheme E (step 2), the amide is reduced to the corresponding amine using
procedures analogous to Scheme C (step 4). For example, 2-[2-(4-Benzyloxy-phenyl)-5-
methyl-oxazol-4-yl]-l-(2-(R)-methyl-pyrrolidin-l-yl)-ethanone is combined with a
suitable reducing agent such as LAHor Red-Al® in a suitable solvent such as
tetrahydrofuran or diethyl ether at a temperature of-78-0°C and warming to room
temperature for a period of 4-8 hours. The reaction is quenched according to standard
literature procedures (Fieser and Fieser) and after concentration is purified according to
techniques well known in the art.
In Scheme E (step 3), the resulting amine is deprotected to the corresponding
phenol using procedures analogous to the procedure of Scheme D (step 2). For example,
2-(4-BenzyIoxy-phenyl)-5-methyI-4-[2-(2-(R)-methyl-pyrrolidin- l-yl)-ethyl]-oxazoIe is
combined with 5-10% palladium on carbon and dissolved in a suitable solvent such as
ethyl acetate, tetrahydrofuran, ethanol or a mixture thereof under an atmosphere of 1-60
mm of hydrogen for 24-48 hours. After filtration, the reaction is concentrated and
purified according to techniques well known in the art.
In Scheme E (step 4), the resulting phenol is alkylated using procedures analogous
to the procedure of Scheme D (step 3). For example, 2-[2-(4-Hydroxy-phenyl)-5-methyl-
oxazol-4-ylJ-l-(2-(R)-methyl-pyrrolidin-l-yl)-ethanone and 2-bromomethylpyridine
hydrobromide is combined with a suitable base such as potassium carbonate, cesium
carbonate, sodium carbonate etc., in a suitable solvent such as acetone,
dimethylformamide, acetonitrile or a mixture thereof at a temperature of 20-100°C for a
period of 12-24 hours. The crude material extracted from an aqueous work up is purified
according to techniques well known in the art.

In Scheme F, Rb, X and Ar are previously defined. In Scheme F (step 1), halo
substituted phenylcarboxamides are condensed with dihalo ketones to form halo
methyloxazoles. For example, 4-bromo-benzamide and 1,3 dichloro or dibromo acetone
is dissolved in a suitable solvent such as isopropanol, ethanol, or a mixture thereof and
heated to temperature of 60-80 °C for a period of 5-10 hours. The reaction is
concentrated and used crude or purified according to techniques well known in the art.
In Scheme F (step 2), the resulting halo methyloxazoles are converted to an amino methyl
oxazole by procedures analogous to Scheme A (step 2). For example, 2-(4-Bromo-
phenyl)-4-cbJoromethyl-oxazole is dissolved in a suitable solvent such as THF and 2-10
equivalents of pyrrolidine is added. The mixture is stirred at room temperature or heated
for a period of 8 - 48h at 70 °C. The reaction is concentrated and purified according to
techniques well known in the art.
In Scheme F (step 3), the resulting amino methyloxazole can be converted to the
triaryl amine using procedures analogous to those of Scheme A 9step 3). For example, 2-
(4-Bromo-phenyl)-4-pyrrolidin-l-ylmethyl-oxazole and pyridine 3-boronic acid are
dissolved in a suitable organic solvent such as dioxane, acetonitrile, DME, THF, EtOH, or
mixtures thereof. A suitable palladium catalyst such as tetrakis-(triphenylphosphine)
palladium (0), palladium(II) dichloride (dppf) complex with dichloromethane,
dichloropalladium di-triphenylphosphine etc. is added followed by a suitable base such as
aqueous sodium or potassium carbonate, anhydrous cesium or potassium fluoride,
anhydrous potassium or cesium carbonate etc. The reaction is run in a CEM or MARS
microwave reactor for 10-40 minutes, at 90-120 °C, with 75W power and cooling control
on to maintain temperature range. The reaction is concentrated and purified according to
techniques well known in the art.

4-brorno-benzamide (4.03 g, 20.11 mmol), and 1,3-dichloro-acetone (3.83 g,
30.17 mmol) are placed in a 250 mL flask and dissolved in 150 mL of isopropyl alcohol.
The mixture is heated to reflux for 5 hours and cooled to ambient temperature. The
reaction is concentrated to dryness. The resulting solid is triturated with diethyl ether and
filtered to remove unreacted 4-bromo-benzamide. The Filtrate is concentrated to the title
compound as an oily solid (3.1 g) and is used without further purification. MS (m/e)
273.9 (M+l)
Intermediate 2
2-[5-MetbyI-2-(4-pyridin-3-yl-phenyl)-oxazol-4-yl}-ethanoI

2-(4-Chlorophenyl)-5-methyl-oxazoleethanol (0.4 g, 1.68 mmol) [which is
obtained by the method of D. Brooks, J. Med. Chem., 2001,44, 2061-2064 or see WO
0116120], 3-pyridylboronic acid (0.516 g, 4.2 mmol), tricyclohexylphosphine (0.0235 g,
0.084 mmol), palladium (II) acetate (0.0094 g, 0.042 mmol), and potassium carbonate
(1.16 g, 8.4 mmol) are placed in a 10 mL CEM microwave tube. To this mixture is added
8.0 mL of ethanol. The tube is capped and placed in a CEM microwave reactor for 4
hours at 90 °C, 65 psi, applying 70 W of power with cooling to maintain temperature.
The reaction is cooled and concentrated to a dark residue which is dissolved in 30 mL of
IN HCI and washed with ethyl acetate. The aqueous layer is adjusted to pH 9 with
sodium carbonate and extracted with 15% isopropyl alcohol / 85% dichloromethane. The
organics are separated, dried with sodium sulfate, filtered, and concentrated to give pure
title compound (0.377 g, 71.5% yield). MS (m/e) 281.1 (M+l)
Intermediate 3
2-{5-Methyl-244-(4,4,5-tetramethyl-(1,3;2]dioxaborolan-2-yI)plienyl]-oxazoI-4-yl}-
ethanol

To a stirring solution of 2-(4-bromophenyl)-5-methyl-oxazoIeethanol (CAS#
328918-84-9) (1.0 mmol), potassium acetate (1.5 mmol), and bis(pinacolato)diboron (1.1
mmol) in dioxane (0.15 M), add [1,1 bis(diphenylphosphino)ferrocerje]di-
chloropalladium(II) complex with CH2CI2 (1:1) (0.03 mmol) and heat to reflux for 1.5
hours. After this time, cool the reaction to room temperature and concentrate in vacuo.
Wash the crude mixture with water while extracting with dichloromethane. Dry the
organics with sodium sulfate, filter and concentrate in vacuo. Purify on an Isco
CombiFlasb® chromatography system eluting with ethyl acetate and hexane. MS (m/e)
330.2 (M+l)
2-{5-MethyJ-2-f4,-(5-methy]-[1,3,4JoxadiazoI-2-yI)-biphenyl-4-ylJ-oxazoI-4-yl}-
ethanol

To a 10 mL CEM microwave tube is placed 2-{5-Methyl-2-[4-(4,4,5,5-
tetramemyl-[l,3,2]dioxaboroIan-2-yl)phenyl]-oxazol-4-yI}-ethanol (See Intermediate 3)
(0.125 g, 0.38 mmol), 2-(4-Chloro-phenyl)-5-methyl-[l,3,4]oxadiazole (0.061 g, 0.317
mmol) [obtained by the method B. Rigo.Synthetic Comm, 19, 2321-2335, 1989,
CAS#22815-98-l], tricyclohexylphosphine (0.0044 g, 0.016 mmol), palladium acetate
(0.0018 g, 0.008 mmol), and potassium carbonate (0.105 g, 0.76 mmol) and 8.0 mL of
ethanol. The mixture is placed in a CEM microwave reactor for 4 hours at 90 °C, 65 psi,
applying 70 W of power with cooling to maintain temperature. Reaction is cooled and all
solids are collected by filtration. The solids are washed with 15% methanol /
dichloromethane and the washes are concentrated to provide 49 mg of pure titled
compound. MS (m/e) 362.2 (M+l)
Intermediate 5
2S-MethanesuIfonyloxymethyl-pyrrolidine-l-carboxylic acid tert-butyl ester

(S)-(-)-l-(tert-Butoxycarbonyl)-2-pyrrolidinemethanol (Aldrich) (11.49 g, 57.09
mmol), and triethylamine (8.64 mL, 62 mmol) is placed in a 1 L flask and dissolved in
150 mL of dichJoromethane. Methanesulfonyl chloride (4.8 mL, 62 mmol) is added and
the mixture is stirred for 2 hours. The reaction mixture is diluted with ethyl acetate and
water and the organics are separated. The organics are washed with 0.1 N HCI, saturated
sodium bicarbonate solution, separated and dried over sodium sulfate, filtered and
concentrated to pure title compound (-15.95 g, 100% yield). MS (m/e) 224.1 (M+l, -t-
butyl)
2R-Methyl-pyrrolidine-l-carboxylic acid tert-butyl ester

To a 1000 mL flask is placed 2S-Methanesulfonyloxymethyl-pyrrolidine-1-
carboxylic acid tert-butyl ester (see Intermediate 5) (8.13 g, 29.1 mmol) in 15 mL of
tetrahydrofuran and cooled to 0 °C. Lithium triethylborohydride (1M, 90 mL) is added to
the flask over 20 minutes. The mixture is warmed to ambient temperature and allowed to
stir for 16 hours. The mixture is diluted with ethyl acetate and washed successively with
0.1N HC1, saturated sodium bicarbonate solution, and brine. The organics phase is
separated, dried over sodium sulfate, filtered and concentrated to an oil. The oil is
dissolved indiethyl ether and any particulate is removed by filtration. The filtrate is
concentrated to give 5.4g of pure title compound. MS (m/e) 130.1 (M+l -t-butyl). 400
MHz NMR (CDC13) 5 3.83 (m, 1H), 3.38 (m, 2H), 1.92 (m, 3H), 1.58 (m, 1H), 1.48 (s,
9H), and 1.2 (d, J = 8Hz, 3H)
Intermediate 7
2R-Methyl-pyrrolidine; hydrochloride

To a 500 mL flask is placed 2R-Methyl-pyrrolidine-l-carboxylic acid tert-butyl
ester (see Intermediate 6) (5.4 g, 29.1 mmol) and HC1 / acetic acid (1M, 45 mL) at
ambient temperature. The mixture is stirred for 1 hour and men concentrated to an oily
solid. The solid is triturated with 2:1 diethyl ether / hexane and dried to give 3.02 g of
pure titled compound. 400 MHz NMR (Methanol- d4) 3.67 (m, 1H), 3.35 (m, 2H), 2.25
(rn, 1H) 2.1 (m, 2H), 1.66 (m, 1H), and 1.43 (d, J = 8Hz, 3H)
5-MethyI-4-(2-pyrroIidin-l-yI-ethyI)-2-[4-(4,4,5,5-tetramethyl-[l,3,2xaborolan-2-
yI)-phenyl]-oxazoIe

The titled compound is prepared substantially in accordance with the procedure of
2-{5-Methyl-2-[4-(4,4,5,5-tetramethyl-[l,3,2)dioxaborolan-2-yl)phenyl]-oxazol-4-yl}-
ethanol (see Intermediate 3) using 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrroLidin-l-yl-
ethyl)-oxazoIe (See Example 8). MS (m/e) 383.3 (M+l)
Intermediate 9
2-[2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyI-oxazoI-4-yl]-ethanol

2-(4-Bromophenyl)-5-methyl-oxazoleethanol (4.0 g, 14.18 mmol) [which is
obtained by the method of D. Brooks, J. Med. Chem., 2001,44,2061-2064 or see WO
0116120], 4-methylsulfonylphenylboronic acid (3.97 g, 19.85 mmol), [1,1
bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2CI2 (1:1)
(0.347 g, 0.425 mmol), and aqueous sodium carbonate (2M, 22.15 mL) is placed in a 500
mL flask with 150 mL dioxane and heated to reflux for 2 hours. The reaction is
concentrated to about 100 mL and cooled in an ice bath. The solids are filtered and the
filtrate is set aside. The solids are then stirred with 200 mL of 15 % methanol /
dichloromethane. This slurry is filtered and the filtrate is concentrated to give 4.0 g of
pure titled compound. MS (m/e) 358.1 (M+l)
Intermediate 10
(l-{2-[2-(4-Bromo-enyl)-5-methyl-oxazol-4-yl]-ethyl}-pyrrolidin-3-yl)-methyl-
carbamic acid tert-butyl ester

The titled compound is prepared significantly in accordance with the procedure of
Example 8 using 2-(4-Bromophenyl)-5-methyl-oxazoleethanol [which is obtained by the
method of D. Brooks, J. Med. Chem., 2001,44,2061-2064 or see WO 0116120], and 3-
(Boc-methylamino)pyrrolidine. Purification via radial chromatography eluting with
methanol and dichloromethane gives the titled compound. MS (m/e) (79 Br/81'Br):
464.1/466.0 (M+l)
Intermediate 11
(l-{2-[2-(4-Bromo-phenyl)-5-methyI-oxazol-4-yl]-ethyl}-pyrroIidin-3-yl)-methyl-

Stir (1- {2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl} -pyrrolidin-3-yl)-
metliyl-carbamic acid tert-butyl ester (see Interniediate 10) with a 1:1 solution of
trifluoroacetic acid and dichloromethane (0.30M) for 30 minutes at room temperature.
After this time, quench the reaction with 1N sodium hydroxide and extract with
dichloromethane. Extract from the organic layer with 1N hydrochloric acid. Basify the
aqueous layer with 1N sodium hydroxide and extract with dichloromethane. Dry the
organics with sodium sulfate, decant and concentrate in vacuo to yield the pure title
compound- MS (m/e) (79Br/slBr): 364.1/366.0 (M+l)
(The present case does not have an intermediate 12)
Intermediate 13
Methanesulfonic acid 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester

To a stirring solution of 2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-ethanol
(1 .Ommol) [which is obtained by the method of D. Brooks, J. Med. Chem., 2001,44,
2061-2064 or see WO 0116120], and triediylamine (1.25mmoI) in dichloromethane
(0.25M) in a 0°C ice bath, add methylsulfonyl chloride (1.05mmol) and remove the ice
bath. Stir at room temperature for 1 hour and then concentrate in vacuo to yield the title
compound. MS (m/e) (81Br): 362.3 (M+l)
Intermediate 14
2-(4-Benzyloxy-phenyl)-4-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-methyl-oxazole

To a mixture of 2-[2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethanol [CAS
403611-91-6] (4.04 g, 13.0 mmol), triethylamine (3.6 mL, 25 mmol, and DMAP (0.16 g,
1.3 mmol) in CH2C12 (80 mL) at 0 °C is added a solution of tert-
burylchlorodipbenylsilane (3.95 g, 14.4 mmol) in CH2CI2 (10 mL) drop wise. The
mixture is warmed to room temperature and stirred for 6 h. The mixture is washed with
0.5 N HC1 (80 mL), and the organic phase is dried (MgSO4). After the solvent is
removed in vacuo, the residue is purified by flash chromatography (elute 2:1 hexanes :
EtOAc) to yield 7.09 g of the title compound as a white solid. MS (ES+) 548
Intermediate 15
4-{4-[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-S-methyl-oxazol-2-yl}-phenol

A mixture of 2-(4-Benzyloxy-phenyl)-4-[2-(tert-butyl-diphenyl-silanyloxy)-
ethyl]-5-methyl-oxazole (7.0 g, 12.8 mmol) and 5% Pd/C (1.75 g) in EtOAc (105 mL) is
stirred under a hydrogen atmosphere (balloon) for 18 h. The mixture is filtered and
concentrated. The residue is resubjected to the reaction conditions of 5% Pd/C (1.75 g) in
a mixture of THF and EtOH for an additional 24 h. The mixture is filtered and
concentrated. After the solvent is removed, the residue is purified by flash
chromatography (elute 4:1 hexanes.EtOAc) to obtain 3.25 g of the title- compound. 'H
NMR (400 MHz, CDC13) 5 7.8 (d, 2 H), 7.6 (m, 4 H), 7.3 (m, 6 H), 6.S (d, 2 H), 3.9 (t, 2
H), 2.7 (t, 2 H), 2.2 (s, 3 H), 1.0 (s, 9 H)
Intermediate 16
2-(4-{4-[2-(tert-ButyI-diphenyl-silanyloxy)-ethyl]-5-methyl-oxazol-2-yl}-
phenoxymethyl)-pyridine

A ;mixture of 4- {4-[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-5-methyl-oxazol-2-
yl}-phenol (1.0 g, 2.25 mmol), 2-bromomethylpyridine hydrobromide (0.85 g, 3.4 mmol),
and K2CO3 (1.1 g, 7.9 mmol) in acetone (20 mL) is heated at reflux for 12 h. The mixture
is filtered, and the solvent is removed in vacuo. The residue is partitioned between
EtO Ac and water. The organic phase is washed with water and brine, dried (Na2SC4),
and concentrated. The residue is purified by flash chromatography (90 g SiO2,
elute 10% to 50% EtOAc/hexane) to yield 0.97 g of the title compound. MS (ES+) 549.3
Intermediate 17
2-{5'Methyl-2-[4-(pyridin-2-ylmethoxy)-phenyl]-oxazol-4-yl}-ethanol

To a mixture of 2-(4-{4-[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-5-methyl-
oxazol-2-yl}-phenoxymethyl)-pyridine (0.97 g, 1.76 mmol) in THF (20 mL) at 0 °C is
add ed a solution of TBAF in THF (1.0 M, 1.76 mL). The mixture is warmed to room
temperature and stirred for 2 h. The mixture is partitioned between EtOAc and water.
The aqueous phase is extracted with EtO Ac (3x). The combined organic phase is washed
with brine (2x), dried (Na2S04), and concentrated. The residue is purified by flash
chromatography (SiCh, elute 0% to 10% MeOH/CH2Cl2) to yield 0.53 g of the title
compound. 1H NMR (400 MHz, DMSO-d6) 5 8.6 (dd, 1 H), 7.8 (m, 3 H), 7.6 (d, 1 H), 7.4
(dd, 1 H), 7.2 (d, 2 H), 5.2 (s, 2 H), 3.6 (t, 2 H), 2.6 (t, 2 H), 2.2 (s, 3 H). MS (m/e) 311.1
(M+l)
Intermediate 18
2-[2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-yI]-l-(2-(R)-methyI-pyrrolidin-l-yl)-
ethanone

To a mixture of [2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-acetic acid [CAS
403611-89-2] (2.2 g, 6.8 mmol) in CH2C12 (40 mL) is added EDC (1.57 g, 8.2 mmol) and
HOBT (1.11 g, 8.2 mmol). After a few minutes, (R)-2-methylpyrrolidine hydrochloride
[CAS 41720-98-3] (1.0 g, 8.2 mmol) and DIPEA (2.5 mL, 13.6 mmol) are added. The
mixture is stirred at room temperature overnight. The mixture is partitioned between
EtOAc and water. The aqueous phase is extracted with EtOAc (2x), and the combined
organic phase is washed with brine, dried (Na2S04), and concentrated. The residue is
purified by flash chromatography [120 g Si02, elute gradient 30% EtOAc/hexane to 80%
EtOAc/hexane) to yield 1.25 g of the title compound as a yellow oil. MS (m/e):. 391.2
(M+l)
Intermediate 19
{2-[6-(4-Methanesulfonyl-phenyl)-pyridin-3-yl]-5-methyl-oxazol-4-yl}-aceticacid
methyl ester

The titled compound is prepared substantially in accordance with the procedure of
Example 4 using 4-(methanesulfonyl)benzene boronic acid and [2-(6-Chloro-pyridin-3-
yl)-5-methyl-oxazol-4-yl]-acetic acid'methyl ester [CAS 478540-95-3].
MS(m/e): 387.3 (M+l)
Intermediate 20
Sodium {2-[6-(4-methanesulfonyl-phenyI)-pyridin-3-yl]-5-methyl-oxazol-4-yl}-
acetate

To a stirring solution of {2-[6-(4-MethanesuLfonyl-phenyl)-pyridin-3-yl]-5-
methyl-oxazol-4-yl}-acetic acid methyl ester (See Intermediate 19) (l.Ommol) in 1:1
methanol/tetrahydrofuran (0.10M), add 2N sodium hydroxide (1.2mmol) and heat to
reflux for 1 hour. After this time, concentrate the reaction in vacuo. Wash die resulting
solid twice with dichloromethane to rinse away any impurities. MS (m/e): 373.3 (M+l)
Intermediate 21
2-{2-[6-(4-Methanesulfonyl-pbenyI)-pyridin-3-yl]-5-methyl-oxazol-4-yl}-l-(2-(R)-
methyl-pyrrolidin-l-yl)-ethanone

To a stirring solution of Sodium {2-[6-(4-methanesulfonyl-phenyl)-pyridin-3-yl]-
5-methyl-oxazol-4-yl}-acetate (See Intermediate 20) (1.0 mmol) and oxalyl chloride (3.0
rnmol) in dioxane (0.10M), add a catalytic amount of dimethylformamide and heat to
reflux for 30 minutes. After this time, remove the heat and concentrate in vacuo. Take
the resulting solid into dichloromethane (0.10M) and slowly add a solution of (R)-methyl-
p yrrolidine hydrochloride (1.0 mmol) and n-methylmorpholine (2.0 mmol) in
dichloromethane. Stir at room temperature for 1 hour. After this time, the reaction
appears complete. Wash the reaction with 1N hydrochloric acid while extracting with
dichloromethane. Concentrate the organic layer in vacuo and purify via radial
chromatography eluting with methanol and dichloromethane. MS (m/e): 440.2(M+1)
Intermediate 22
2-Ethanesulfonyl-5-iodo-pyridine

To a solution of 2-chloro-5-iodopyridine (1.0 mmol) in ethanol (0.33M), add
sodium ethanethiolate (0.95 mmol) and heat reaction to reflux for 24 hours. After this
time, remove the heat and concentrate in vacuo. Wash with water and saturated aqueous
sodium bicarbonate while extracting with dichloromethane. Dry the organic layer with
sodium sulfate, filter and concentrate in vacuo to a crude residue. To a portion of dais
crude material (1.0 mmol) in ethanol (0.2M), add m-chloroperoxybenzoic acid
(2.95mmol) and stir at room temperature for 18 hours. After this time, concentrate the
reaction in vacuo. Dilute in ethyl acetate and wash with IN sodium hydroxide.
Concentrate the organic layer in vacuo and purify on a silica column eluting with ethyl
acetate and hexane. 400 MHz NMR (CDC13) 5 8.98 (d, J = 2.2 Hz, 1H), 8.34 (q, J = 3.4
Hz, 1H),7.89 (d,J = 7.9 Hz, 1H), 3.43 (q,J = 7.5 Hz, 2H), 1.34 (t, J = 7.5 Hz, 3H)
Intermediate 23
2-{2-[4-(6-Ethanesulfonyl-pyridin-3-yl)-phenyl]-5-methyl-oxazol-4-yl}-ethanol
The titled compound is prepared substantially in accordance with the procedure of
Intermediate 9 using 2-{ 5-Methyl-2-[4-(4,4,5,5-tetramefhyl-[l,3,2]dioxaborolan-2-
yl)phenyl]-oxazol-4-yl} -ethanol (See Intermediate 3) and 2-Ethanesulfonyl-5-iodo-
pyridine (See Intermediate 22). MS (m/e) 373.3 (M+l)
Intermediate 24
2S-Fluoromethyl-pyrrolidine hydrochloride

2S-Fluoromethyl-pyrrolidine hydrochloride is prepared by the method of M.
Cowart (See WO 2002074758).
Intermediate 25
2R-Ethyl-pyrroIidirie-l-carboxylic acid tert-butyl ester


Add methanesulfonyl chloride (2.30 mL, 29.7 mmpl) over five minutes to a cold
(0 °C) stirred solution of 2S-hydroxymethyl-pyrroIidine-l-carboxylic acid tert-butyl ester
(5.04 g, 25.0 mmol) and triethylamine (4.60 mL, 32.8 mraol) in dry dichloromethane (100
mL) and stir at 0°C for 90 minutes before adding saturated aqueous sodium bicarbonate.
Separate the layers, wash the organic layer one time with water, dry over anhydrous
magnesium sulfate, and concentrate under reduced pressure to afford the crude mesylate
which is used in the next step without further purification.
In a separate flask, add enough methyllithium (1.4-1.6 M in diethyl ether, -250
mmol) to a cold (-20 °C) stirred suspension of copper(I)iodide (23.84 g, 125.2 mmol) in
dry diediyl ether and until the bright yellow suspension gives way to a pale yellow
homogeneous mixture. Add to this mixture the crude mesylate prepared as described
above as a solution using dry diethyl ether (45 mL). Store the reaction mixture in a
freezer at -15 °C overnight, and then add saturated aqueous ammonium chloride (adjusted
to pH 8 with ammonium hydroxide) and warm to room temperature with vigorous stirring
until the aqueous layer is deep blue. Filter the mixture through Celite© and wash the
filter cake with diethyl ether and water. Separate the layers, extract the aqueous layer
with diethyl ether, wash the combined organic extracts successively with brine, and 20%
aqueous sodium thiosulfate, dry over anhydrous magnesium sulfate, and concentrate
under reduced pressure. The residue is purified by flash chromatography (SiOj, elute 0%
to 20% EtOAc/hexanes) to yield 2.445 g of the title compound as a colorless oil. 'H NMR
(400 MHz, CDC13) 8 3.65-3.75 (m, 1H), 3.29-3.45 (m, 2H), 1.62-1.98 (m, 5H), 1.49 (s,
9H), 1.28-1.41 (m, 1H), 0.89 (dd, 7 = 7.6,7.6 Hz, 3H).
Intermediate 26
2R-Ethyl-pyrrolidine hydrochloride

Add HCl (23 mL, 4N in 1,4-dioxane, 92 mmol) to a stirred solution of 2R-ethyl-
pyrrolidine-1-carboxylic acid tert-butyl ester (2.4 g, 12 mmol) and stir at room
temperature for 3 days. Concentrate under reduced pressure to afford the title compound
as a colorless solid (1.6 g). *H NMR (CDC13) 5 9.81 (br s, 1H), 9.18 (br s, 1H), 3.25-3.53
(m, 3H), 1.90-2.21 (m, 6H), 1.03-1.10 (m, 3H).
Intermediate 27
l-Bromo-4-propyisuJfanyl-benzene

Add sodium hydride (625 mg, 60% in oil, 15.6 mmol) to a stirred solution of 4-
bromo-benzenethiol (2.305 g, 12.2 mmol) in dry DMF (40 mL) and then rinse the sides of
the flask down with DMF (5 mL). Stir at room temperature for 1 hr and then add 1-
iodopropane and stir at room temperature for 2.5 h. Add water, IN sodium hydroxide,
and ethyl acetate, and separate the layers. Extract the aqueous layer twice with ethyl
acetate, wash the organic layer successively, once with IN sodium hydroxide, and three
times with brine, dry over anhydrous magnesium sulfate, and concentrate under reduced
pressure. The residue is purified by flash chromatography (SiQj, elute 0% to 5%
EtOAc/hexanes) to yield 2.53 g of the title compound as a colorless oil. *H NMR (400
MHz, CDC13) 5 7.42 (d, J = 6.8 Hz, 2H), 7.21 (d, / = 6.4 Hz, 2H), 2.91 (dd, J - 6.8,6.8
Hz, 2H), 1.70 (ddddd, J = 7.2, 7.2,7.2,6.8,6.8 Hz, 2H), 1.05 (dd, J = 7.2, 7.2 Hz, 3H).
Intermediate 28
l-Bromo-4-(propane-l-sulfonyI)-benzene

Add oxone (potassium mono persulfate, 15.03 g, 24.4 mmol) in one portion to a
cold (0 °C) stirred solution of l-bromo-4-propylsulfanyl-benzene (1.881 g, 8.14 mmol) in
THF (20 mL), methanol (10 mL), and water (10 mL) and slowly warm to room
temperature overnight. Remove the solvents under reduced pressure and add
dichloromethane and water to the residue. Separate the layers, extract the aqueous layer
twice with dichloromethane, wash the organic layer with saturated aqueous sodium
bicarbonate, dry over anhydrous magnesium sulfate, and concentrate under reduced
pressure. Purify the residue by flash chromatography (Si02, elute 0% to 30%
EtOAc/hexanes) to yield 1.96 g of the title compound as a colorless oil. *H NMR (400
MHz, CDCI3) 5 7.80 (d, J = 9.2 Hz, 2H), 7.74 (d, J = 8.8 Hz, 2H), 3.06-3.11 (m, 2H),
1.72-1.83 (m, 2H), 1.04 (dd, J = 7.2,7.2 Hz, 3H).
Intermediate 29
4,4^^-Tetramethyl-2-[4-(propane-l-sulfonyl)-phenyl]-[l,3^]dioxaborolane

Add dichloro [l,r-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (37 mg, 0.045 mmol) to a solution of l-bromo-4-(propane-l-
sulfonyl)-benzene (238 mg, 0.904 mmol), potassium acetate (270 mg, 2.15 mmol) and
bis(pinacolato)diboron(II) (355 mg, 1.40 mmol) in DMSO (5 mL) anc. heat at 10O°C
overnight Cool to room temperature and add ethyl acetate, water, and saturate aqueous
sodium bicarbonate and separate the layers. Extract the aqueous layer twice with ethyl
acetate, wash the organic layer four times with water, dry over anhydrous magnesium
sulfate, and concentrate under reduced pressure. Heat the residue under vacuum to
approximately 240°C to remove some of the unreacted bis(pinacolato)diboron(II) via
sublimation. Dissolve the residue in ethyl acetate and dichloromethane, add decolorizing
charcoal, filter through Celite®, and concentrate the filtrate under reduced pressure to
afford 256 mg of the title compound as a brown solid. 'H NMR (400 MHz, CDCI3) 8 8.02
(d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 3.06-3.11 (m, 2H), 1.70-1.80 (m, 2H), 1.39
(s, 12H), 1.01 (dd, 7= 6.8,6.8 Hz, 3H).
Intermediate 30
2-(4-Bromo-phenyl)-4-(2-iodo-ethyl)-5-methyl-ox£izole

Add iodine (1.90 g, 7.49 mmol) to a stirred mixture of 2-[2-(4-bromo-phenyl)-5-
methyl-oxazol-4-yl]-ethanol (1.503 g, 5.33 mmol), triphenylphosphine (2.101 g, 8.01 i
mmol), and pyridine (1.4 mL, 17 mmol) in toluene (48 mL) and heat at 100°C for 45 min.
Cool to room temperature, add ethyl acetate and water, and separate the layers. Extract
the aqueous layer twice with ethyl acetate, wash the organic layer with 0.1N HC1, dry
over anhydrous magnesium sulfate, and concentrate under reduced pressure. Purify the
residue by flash chromatography (Si02, elute 0% to 10% EtOAc/hexanes) to yield 1.804
g of the title compound as a colorless solid. *H NMR (400 MHz, CDC13) 5 7.89 (d, J =
8.4 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 3.49 (dd, / = 7.2,7.2 Hz, 2H), 3.11 (dd, J= 7.2,7.2
Hz, 2H), 2.39 (s, 3H).
Intermediate 31
2-{2-t6-(4-MethanesuIfonyl-phenyl)-pyridin-3-yl]-5-methyl-oxazol-4-yl}-NJN-
dimethyl-acetamide

The reaction which produces Intermediate 21 also produces Intermediate 31. MS
(m/e): 400.3 (M+l)
Intermediate 32
Methanesulfonicacid 2-{2-[4-(6-raethoxy-pyridazin-3-yl)-phenyl]-5-methyl-oxazol-4-
yl}-ethyl ester

The titled compound is prepared substantially in accordance with the procedures
of Example 4 and Intermediate 13 using 2-{5-Methyl-2-[4-(4,4,5,5-tetramethyl-
tl,3,2Jdioxaborolan-2-yI)phenyl]-oxazol-4-yl}-ethanol (see Intermediate 3) and 3-Chloro-
6-methoxy-pyridazine [CAS: 1722-10-7]. MS (m/e): 390.3 (M+l)
Intermediate 33
2-Methanesulfonyl-5-iodo-pyridine

The titled compound is prepared substantially in accordance with the procedure of
Intermediate 22 using sodium methanethiolate in place of sodium ethanethiolate.
MS(m/e): 284.0 (M+l)
Intermediate 34
2-Amino-4-benzyloxy-butyric acid hydrochloride salt

In a round bottom flask containing 4-benzyloxy-2-tert-butoxycarbonylamino-
butyric acid (1.0 mmol), add 1M hydrochloric acid in ether (1.7 mmol) and stir at room
temperature for two days. The product precipitates out as the hydrochloride salt. Collect
by centrifugation in which the mother liquor is decanted off of the product. Rinse two
times with ether, transfer solid to a flask and concentrate in vacuo.
MS(m/e): 210.2 (M+l)
Intermediate 35
4-Benzyloxy-2-(4-bromo-2-fluoro-betizoylamino)-butyricacid

To a stirring solution of 2-amino-4-benzyloxy-butyric acid hydrochloride salt (1.0
mmol) (See Intermediate 34) and sodium carbonate (3.0 mmol) in 1:1 acetone / water
(0.5M) in a 0 °C ice bath, slowly add 4-bromo-2-fluoro-benzoyl chloride (1.2mmol)
diluted in acetone (prepared from 4-bronio-2-fluoro-benzoic acid (1.0 mmol) and oxalyl
chloride (1.0 mmol) in dichloromethane using catalytic dimethylformamide). Stir for 30
minutes at 0 °C. After this time, wash the reaction with IN hydrochloric acid while
extracting with ethyl acetate. Concentrate the organics in vacuo. Purify on an Isco
CombiFlash® chromatography system eluting with 1% acetic acid in ethyl acetate and
hexane. MS (m/e) (^Br/^Br): 410.3/412.3 (M+l)
Intermediate 36
N-[l-(2-BenzyIoxy-ethyl)-2-oxo-propyI]-4-bromo-2-fluorc>-benzamide

Add acetic anhydride (0.97mmol) and pyridine (0.58mmol) to a round bottom
flask containing 4-benzyloxy-2-(4-bromo-2-fluoro-benzoylamino)-biityric acid
(1 .Ommol) (See Intermediate 35) and heat to 90°C for two hours. After this time, remove
the heat and concentrate in vacuo. Wash crude with IN hydrochloric acid and water
while extracting with diethyl ether. Concentrate the organics in vacuo and purify on an
Is co CombiFlash® chromatography system eluting with ethyl acetate: and hexane.
MS (m/e) (^r/^Br): 4083/410.3 (M+l)
Intermediate 37
4-(2-Benzyloxy-ethyl)-2-(4-bromo-2-fluoro-phenyl)-5-methyl-oxazrile

To a stirring solution of N-[l-(2-benzyloxy-ethyl)-2-oxo-propyl]-4-bromo-2-
fluoro-benzamide (1.0 mmol) (See Intermediate 36) in dimethylformamide (0.25M),
slowly add phosphorus oxychloride (3.0 mmol) and heat to 90 °C for 2.5 hours. After this
time, remove the heat and carefully add water (same amount as DMF) and allow the
reaction to cool to room temperature before extracting with ether. Wash organics with
water and brine. Dry the organics with sodium sulfate, filter and concentrate in vacuo.
Purify via radial chromatography eluting with ethyl acetate and hexane.
MS (m/e) (79Br/81Br): 390.2/392.2 (M+l)
2-[2-(3-Fluoro-4'-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethanoI

Using 4-(2-benzyloxy-ethyl)-2-(4-bromo-2-fluoro-phenyI)-5-methyl-oxazole (see
Intermediate 37) and 4-methylsulfonylphenylboronic acid, follow a procedure in
substantial accordance with that found in Example 4. Take this product and hydrogenate
using 20% palladium hydroxide on carbon in tetrahydrofuran for 36 hours at 40 °C and 60
psi. After this time, filter die reaction and concentrate in vacuo. Purify via radial
chromatography eluting with methanol and dichloromethane. MS (m/e): 376.2 (M+l)
Intermediate 39
2-[4-(3-Fiuoro-propane-l-sulfonyl)-phenyl]-4,4^^-tetramethyI-[13^]dioxaborolane

Charge a flame dried round bottom flask with l-bromo-4-(3-fluoro-propane-l-
sulfonyl)-benzene (0.330 g, 1.17 mmol), bis(pinocolato)diboron (0.318 g, 1.25 mrnoi),
Pd(dppf)2Cl2-CH2Cl2 (0.045 g, 0.054 mmol), potassium acetate (0.346 g, 3.53 mmol), and
dry DMSO (6 mL). Heat at 80-100 °C overnight. Cool, add ethyl acetate and water, and
separate the layers. Wash the crude organic extracts with water, dry over MgSC»4, add
decolorizing charcoal, filter through Celite® and concentrate the filtrate to give the title
compound. *H NMR (400 Hz): (CDC13) 5 8.03 (d, 2H, / = 8 Hz), 7.93 (d, 2H, / = 8 Hz),
4.51 (ddd, 2H, J = 47, 5, 5 Hz), 3.26 (dd, 2H, /= 8, 8 Hz), 2.04-2.22 (m, 2H), 1.40 (s,
6H), 1.30 (s, 6H).
Intermediate 40
4,4^,5-Tetramethyl-2-(4-trifluoromethanesuIfonyl-phenyl)-[l,3,2]dioxaborolane

Charge a flame dried round bottom flask wiui l-bromo-4-
trifluoromethanesulfonyl-benzene (1.01 g, 3.50 mmol), bis(pinocolato)diboron (1.33 g,
5.23 mmol), Pd(dppf)2Cl2-CH2Cl2 (0.147 g, 0.180 mmol), potassium acetate (1.08 g, 11.0
mmol), and dry DMSO (18 mL). Heat at 80-100°C overnight. Cool, add ethyl acetate
and water, and separate the layers. Wash the crude organic material with water, dry over
MgSO and purify on silica gel (0-100% EtOAc/Hexanes, then 0-20% EtOAc/Hexanes) to give
the title compound (0.416 g, 35%). 'H NMR (400 Hz): (CDC13) 5 8.11 (d, 2H, / = 8 Hz),
8.05 (d, 2H, J = 8 Hz), 1.40 (s, 12H).
Intermediate 41
3-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-propan-l-ol

a) Add a cold (-78 °C) solution of 2-(4-bromo-phenyl>4-(2-iodo-ethyl)-5-methyl-
oxazole (See Intermediate 30) (1.05 g, 2.67 mmol) in 15 mL THF to a cold (-78 °C)
solution of dithiane anion [Preparation: Add n-BuLi (7.5 mL, 12 mmol, 1.6M in hexanes)
to a -20 °C solution of 1,3-dithiane (1.92 g, 15.9 mmol) in 25 mL THF. Stir 20 min at -
78 °C and add 13-dimemyl-3,4,5,6-tetrahydro-2(lH>pyrimidinone (DMPU, 4.03 g, 31.4
rnmol).] Stir the reaction mixture at -78 °C for 15 min. Add water arid warm to room
temperature. Add dichloromethane, and separate the layers. Dry the crude organic
extracts over MgSCv, filter and concentrate. Purify on silica gel 0-10% EtOAc/Hexanes
to give 2-(4-bromo-phenyl)-4-(2-[l,3]difhian-2-yl-ethyl)-5-methyl-oxazole (0.672 g,
66%). MS (m/e): 384 (M+l).
b) Add HgC104-4H20 (1.49 g, 4.00 mmol) to a solution of 2-(4-bromo-phenyl)-4-
(2-[l,3]dithian-2-yI-ethyl)-5-methyl-oxazole (0.672 g, 1.75 mmol) in 1:1 THF:CH2C12
(16 mL) and water (1.6 mL). After 6 hours, filter and wash the solids with
dichloromethane. Concentrate to give 3-[2-(4-bromo-phenyI)-5-methyl-oxazol-4-yl]-
propionaldehyde (0.445 g, 86%). MS (m/e): 294 (M+l).
d) Add DIB AL-H (1M in THF, 2.0 mL, 2.0 mmol) to a 0 °C solution of 3-[2-(4-
bromo-phenyl)-5-methyl-oxazol-4-yl]-propionaldehyde (0.395 g, 1.39 mmol) in
dichloromethane. After 15 min add IN HC1 and warm to room temperature. Add 5N
HC1 and stir until two clear, homogeneous layers are formed. Separate the layers and
extract the aqueous layer with dichloromethane. Dry the crude organic extracts over
MgS04, filter, and concentrate. Purify on silica gel (0-70% EtOAc/Hexanes) to give the
title compound (0.315 g, 79%): MS (m/e): 296 (M+l).
Intermediate 42
2-Bromo-l-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethanoI

a) Add 2,8,9-trimethyl-2,5,8,9-tetraaza-l-phosphabicyclo[3.3.3]undecane (3.17 g,
14.7 mmol) as a solution using acetonitrile (10 mL) to a solution of 2-(4-bromo-phenyl)-
4-(2-iodo-ethyl)-5-methyl-oxazole (See Intermediate 30) (4.38 g, 11.1 mmol) in 2.8:1
acetonitrile:THF (190 mL). After 4 hrs, concentrate under reduced pressure and add
EtOAc and water to the residue. Separate the layers and extract the aqueous material with
EtOAc. Wash the crude organic extract with water, dry over MgS04, filter and
concentrate. Purify on silica gel eluting with 7% EtOAc to give 2-(4-bromo-phenyl)-5-
methyl-4-vinyl-oxazole (2.31 g, 83%): 'H NMR (400 Hz): (CDC13) 5 7.89 (d, 2H, / = 8
Hz), 7.57 (d, 2H, J = 8 Hz), 6.54 (dd, 1H, /= 17,11 Hz), 5.93 (dd, 1H, J=11,2 Hz),
5.29 (dd, 1H, J = 11, 2 Hz), 2.40 (s, 3H).
b) Add NBS (1.44 g, 8.08 mmol) to a solution of 2-(4-bromo-phenyl)-5-methyl-4-
vinyl-oxazole (1.01 g, 4.02 mmol) in water (0.180 mL) and DMSO (30 mL). After 10
min add water and EtOAc. Separate the layers, extract aqueous material with EtOAc, and
wash the crude organic extracts with water. Dry over MgS04, filter and concentrate.
Purify on silica gel eluting with 20% EtOAc/Hexanes to give the title compound (1.08 g,
74%): MS (m/e): 362 (M+l).
Intermediate 43
(R)-(+)- 2-HydroxymethyI-pyrrolidine-l-carboxylic acid tert-butyl ester

Add di-tert-butyldicarbonate (5.2 g, 24 mmol) to a 10% triethylaminermethanol
(15 mL) solution containing pyrrolidin-2-yl-metb.anol (1.20 g, 11.9 mmol). Heat the
reaction mixture for 30 min at reflux, then remove the solvent under reduced pressure to
give the title compound (2.96 g, quant.): MS (m/e): 146 (M+2, -tert-butyl).
2R-Methanesulfonyloxymethyl-pyrrolidine-l-carboxylicacicl tert-butylester

Add methanesulfonyl chloride (0.937 g, 6.46 mmol) to a cold (0°C) solution of
(R)-(+)- 2-hydroxymethyl-pyrrolidine-l-carboxylic acid tert-butyl ester (1.0 g, 5.0 mmol)
and triethylamine (1.0 niL, 7.5 mmol.) in dichloromethane (10 mL). Warm the reaction
mixture slowly to room temperature and stir overnight. The reaction mixture is diluted
with dichloromethane and saturated aqueous sodium chloride and the layers are separated.
Dry the crude organic extracts over MgSCU, filter, and concentrated to give crude title
compound (1.55 g, quantitative): MS (m/e): 224.1 (M+2 -tert-butyl).
Intermediate 45
2S-Methyl-pyrrolidine-l-carboxylic acid tert-butyl ester

Slowly add lithium triethylborohydride (1M in THF, 17 mL, 17. mmol) to a 0 °C
solution of 2R-methanesulfonyloxymethyl-pyrrolidiiie-l-carboxylic acid tert-butyl ester
CI.6 g, 5.73 mmol) in 10 mL of tetrahydrofuran. Warm the reaction mixture to ambient
temperature and stir for 16 hours. Dilute the reaction mixture with ethyl acetate and
^water and wash successively with 0.1N HC1 and brine. Dry the crude organic extracts
over MgSC>4, filter and concentrate to afford the title compound as a clear oil (0.930 g,
88%). 400 MHz NMR (CDC13) 8 3.83 (m, 1H), 3.38 (m, 2H), 1.92 (m, 3H), 1.58 (m,
1H), 1.48 (s, 9H), and 1.2 (d, J = 8 Hz, 3H).
Intermediate 46
2S-Methyl-pyrroIidine; hydrochloride

Add IN HC1 in ether to neat 2S-methyl-pyrrolidine-l-carboxylic acid tert-butyl ester
(0.930 g, 5.02 mmol) at ambient temperature. The mixture is stirred for 1 hour and then
concentrated to afford an oily solid. The solid is triturated with diethyl ether and dried to
give (0.109 g, 18%) of the title compound. 400 MHz NMR (Methanol-dL,) 8 3.67 (m,
1H), 3.35 (m, 2H), 2.25 (m, 1H) 2.1 (m, 2H), 1.66 (m, 1H), and 1.43 (d, 7= 8Hz, 3H).
Intermediate 47
2-{5-Methyl-2-[4-(6-methyl-pyridazin-3-yl)-phenyI]-oxazol-4-yl}-ethanol

To a stirring solution of 2-{5-Methyl-2-[4-(4,4,5,5-tetramethyl-
[l,3,2]dioxaborolan-2-yl)phenyl]-oxazol-4-yl}-ethanol (0.314 g, 0.952 mmol) (See
Intermediate 3), 3-Iodo-6-memyl-pyridazine (0.178 g, 0.810 mmol) [CAS# 1618-47-9]
and [1,1 bi&(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2CI2
(1:1) (0.02 g, 0.024 mmol) in 10 mL dioxane is added aqueous sodium carbonate (2M,
1.22 mL) and the reaction is carried out substantially in accordance with the procedure of
Example 9 to provide after purification by radial chromatography pure titled compound
(0.208 g, 87%). MS (m/e): 296.3 (M+l).
Intermediate 48
tert-Butyl (3S)-3-fluoropyrrolidine-l-carboxylate

Slowly add [bis(2-memoxyemyl)amino]sulfur trifluoride (2.40 mL, 13.03 mmol)
to a solution of Ar-Boc-(i?)-(-)-3-pyrrolidinoI (2.00 g, 10.86 mmol) in anhydrous
dichloromethane (10 mL), at -78 °C and under nitrogen. Allow the reaction mixture to
warm to room temperature and stir overnight. Carefully add an aqueous solution of
sodium hydrogen carbonate (saturated, 20 mL) and extract with dichloromethane.
Concentrate the combined organic extracts under vacuum then purify using automated
flash chromatography (ISCO® System, 120 g Redisep® Si02 column; 0 - 40% ethyl
acetate in cyclohexane gradient elution over 30 minutes at 85 mL/min) to give the title
compound as a pale yellow liquid (1.67 g): MS (m/e): 212 (M+23).
Intermediate 49
(3S)-3-FluoropyrroHdine 4-methylbenzenesulfonate (salt)

Add p-toluenesulfonic acid monohydrate (0.50 g, 2.64 mmol) to tert-butyl (3S)-3-
fluoropyrrolidine-1-carboxylate (See Intermediate 48) (0.50 g, 2.64 nimol) in ethanol (5
mL) at room temperature. Stir the resulting solution overnight. Concentrate the reaction
mixture in vacuo to remove solvent and bi-products to give the title compound as an off-
white solid (0.65g): MS (m/e): 90(M+1).
Intermediate 50
tert-Butyl (3J?)-3-fluoropyrrolidine-l-carboxylate

Prepare using the method of Intermediate 48 with /V"-Boc-(S)-(+)-3-pyrrolidinol
(0.50 g, 2.67 mmol), [bis(2-metlioxyethyl)ammo]sulfur trifluoride (0.59 mL, 3.20 mmol)
and anhydrous dichloromethane (4 mL) to give the title compound as a colourless oil
(0.36 g): MS (m/e): 212(M+23).
Intermediate 51
(3/f )-3-FluoropyrroIidine 4-methylbenzenesuifonate (salt)

Prepare using the method of Intermediate 49 with p-toluenesulfonic acid
monohydrate (0.356 g, 1.87 mmol), tert-bntyl (3/?)-3-fluoropyrrolidins-l-carboxylate
(See Intermediate50) (0.353 g, 1.87 mmol) and ethanol (2 mL) to give the title compound
as a white solid (0.478 g): MS (m/e): 90(M+1).
(3#)-Pyrrolidin-3-ol 4-methyIbenzenesulfonate (salt)

Prepare using the method of Intermediate 49 with p-toluenesulfonic acid
monohydrate (0.255 g, 1.34 mmol), N-Boc-(/?)-(-)-3-pyrrolidinol (0.251 g, 1.34 mmol)
and ethanol (5 mL) to give the title cbmpound as a pale yellow oil (0.34 g): MS (m/e):
88(M+1).
Intermediate 53
(3S)-Pyrrolidin-3-ol 4-methylbenzenesulfonate (salt)

Prepare using the method of Intermediate 49 with p-toluenesulfonic acid
monohydrate (0.254 g, 1.34 mmol), W-Boc-(SM+)-3-pyrrolidinol (0.250 g, 1.34 mmol)
and ethanol (2 mL) to give the title compound as a white solid (0.35 g): MS (m/e):
88(M+1).
Intermediate 54
tert-Butyl (3S)-3-(fluoromethyl)pyrrolidine-l-carboxylate

Prepare using the method of Intermediate 48 with (5)-AT-Boc-(5)-pyrrolidine-3-
methanol (0.50 g, 2.48 mmol), [bis(2-memoxyethyl)amino]sulfur trifluoride (0.55 mL,
2.98 mmol) and anhydrous dichloromethane (2.5 mL) to give the title compound as a
colourless oil (0.17 g): MS (m/e): 226(M+23).
(3S)-3-(FIuoromethyI)pyrrolidine 4-methylbenzenesulfonate (salt)

Prepare using the method of Intermediate 49 with /?-toluenesulfonic acid
monohydrate (0.14 g, 0.74 mmol), terr-butyl (3S)-3-(fluoromethyl)p>irolidine-l-
carboxylate (See Intermediate 54) (0.15 g, 0.74 mmol) and ethanol (2 mL) to give the title
compound as a white solid (0.20 g): MS (m/e): 104(M+1).
Intermediate 56
tert-Butyl(3JR)-3-(fluoromethyl)pyrrolidine-l-carboxylate

Prepare using the method of Intermediate 48 with (/?)-AT-Boc- pyrrolidine-3-
methanol (0.50 g, 2.48 mmol), [bis(2-methoxyethyl)amino]sulfur trifiuoride (0.55 mL,
2.98 mmol) and anhydrous dichloromefhane (2.5 mL) to give the title compound as a
colourless oil (0.34 g): MS (m/e): 226(M+23).
Intermediate 57
(3if)-3-(FluoromethyI)pyrrolidine 4-methylbenzenesulfcnate (salt)

Prepare using the method of Intermediate 49 with p-toluenesulfonic acid
monohydrate (0.304 g, 1.87 mmol), terr-butyl (3J?)-3-(fluoromethyI)pyrrolidine-l-
carboxylate (See Intermediate 56) (0.325 g, 1.87 mmol) and ethanol (2 mL) to give the
title compound as a white solid (0.421 g): MS (m/e): 104(M+1).
tert-Butyl (3/f)-3-methoxypyrrolidine-l-carboxylate and (3l?)-3-MethoxypyrroUdine

Add sodium hydride (60% dispersion in oil, 0.048 g, 1.20 mmol) to a solution of
AT-Boc-(R)-(-)-3-pyrrolidinol (0.20 g, 1.09 mmol), under nitrogen. Leave to stir at room
temperature for 10 minutes then add methyl iodide (0.10 mL, 1.64 mmol). Stir the
mixture for 2 days then add methanol (10 mL). Load the methanol solution onto an
Isolute® SCX-2 (5 g) column. Wash the column with methanol then concentrate this
methanol fraction in vacuo to give an orange/red oil (0.42 g) containing oil from the
sodium hydride dispersion and the title compounds: MS (m/e): 102(M+1).
Intermediate 59
(3R)-3-MethoxypyrroIidine 4-methylbenzenesulfonate (salt)

Prepare using the method of Intermediate 49 with />-toluenesulfonic acid
monohydrate (0.207 g, 1.09 mmol), crude tert-butyl (3/?)-3-methoxypyrrolidine-l-
carboxylate and (3i?)-3-methoxypyrrolidine (See Intermediate 58) (0.42 g, 1.09 mmol)
and ethanol (2 mL) to give the title compound as a red solid (0.42 g): MS (m/e):
102(M+1).
Intermediate 60
&rf-Butyl (3S)-3-methoxypyrrolidine-l-carboxylate and (3S)-3-Methoxypyrrolidine

Prepare using the method of Intermediate 58 using sodium hydride (60%
Taethyl iodide (0.10 mL, 1.64 mmol) to give an dark orange oil (0.50 g) containing oil
torn the sodium hydride dispersion and the title componds: MS (m/e): 102(M+1).
(3S)-3-Methoxypyrrolidine 4-methylbenzenesulfonate (salt)

Prepare using the method of Intermediate 49 with p-toluenesulfonic acid
monohydrate (0.207 g, 1.09 mmol), crude fert-butyl (3S)-3-methoxypyrrolidine-l-
carboxylate (See Intermediate 60) (0.50 g, 1.09 mmol) and ethanol (2 mL) to give the title
compound as a dark orange coloured oil (0.42 g): MS (m/e): 102(M+1).
Intermediate 62
2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-l-(2-(R)-methyl-pyrrolidin-l-yl)-
ethanone

The title compound is prepared in a manner substantially similar to Example 56
from2-[2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-l-(2-(R)-methyl-pyrrolidin-l-yl)-
ethanone (See Intermediate 18). MS (ES+) 301.2
Intermediate 63
l-(2-(R)-Methyl-pyrrolidin-l-yl)-2-{5-methyl-2-[4-(thiazol-4-ylmethoxy)-phenyl]-
oxazol-4-yl}-ethanone

The title compound is prepared in a manner substantially similar to Intermediate
.6 from 2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-l-(2-(R)-methyl-pyrrolidin-1-
yl)-ethanone (See Intermediate 62) and 4-(chloromethyl)thiazole hydrochloride except KI
(1.5 eq.) is also added. MS (ES+) 398.3
Intermediate 64
[2-(4-Hydroxy-phenyl)-oxazol-4-yl]-acetic acid ethyl ester
HO
A mixture of 4-hydroxybenzamide (25.2 g, 0.18 mol) and ethyl chloroacetoacetate
(90 mL) is heated to 110 °C. After 1 h, more ethyl chloroacetoacetate (30 mL) is added,
and continue to heat for 3 h more. The mixture is cooled to approximately 60 °C, and
MeOH is added. The mixture is filtered and dried to yield the title compound (36.6 g,
80%) as an off-white solid. MS (m/e): 248.3 (M+l)
Intermediate 65

The title compound is prepared in a manner substantially similar to Intermediate
16 from [2-(4-Hydroxy-phenyl)-oxazol-4-yl]-acetic acid ethyl ester (See Intermediate 64)
and 2-(bromomethyl)pyridine hydrobromide. MS (m/e): 339.2 (M+l)
Intermediate 66

HO
The title compound is prepared in a manner substantially similar to Example 55
from {2-[4-(Pyridin-2-ylmethoxy)-phenyl]-oxazol-4-yl}-acetic acid uthyl ester (See
Intermediate 65). The crude material was purified by flash chromatography (40 g SiC>2,
elute 1% to 10% MeOH/CH2Cl2). MS (m/e): 297.2 (M+l)
Intermediate 67

The title compound is prepared in a manner substantially similar to Intermediate
16 from [2-(4-Hydroxy-phenyl>oxazol-4-yl]-acetic acid ethyl ester (See Intermediate 64)
and 4-(chloromethyl)tbiazole hydrochloride except KI (2 eq.) is also added. MS (m/e):
345.2 (M+l)
Intermediate 68

The title compound is prepared in a manner substantially similar to Example 55
from {2-[4-(Thiazol-4-ylmethoxy)-phenyl]-oxazol-4-yl}-acetic acid ethyl ester (See
Intermediate 67). The crude material was purified by flash chromatography (12 g Si02,
elute 1% to 10% MeOH/CH2Cl2). MS (m/e): 303.2 (M+l)
Intermediate 69
[2-(4-Trifluoromethanesulfonyloxy-phenyl)-oxazol-4-yl]-acetic acid ethyl ester
-JV- II

To a mixture of [2-(4-Hydroxy-phenyl)-oxazol-4-yl]-acetic acid ethyl ester (See
Intermediate 64) (1.0 g, 4 mmol) and triethylamine (0.61 mL, 4.4 mmol) in CH2C12 (20
mL) at 0 °C is added trifluoromethane'sulfonic anhydride (0.71 mL, 4.2 mmol). The
cooling bath is removed, and the mixture is stirred at room temperature overnight. The
mixture is partitioned between EtOAc and Sat. NaHC03. The aqueous phase is extracted
with EtOAc, and the combined organic phase is washed with brine, dried (Na2S04), and
concentrated. The residue is purified by flash chromatography (40 g SiC>2, elute 5% to
50% EtOAc/hexane to yield 0.83 g (55%) of the title compound. MS (m/e): 380.2 (M+l)
Intermediate 70
[2-(4'-MethanesaIfonyI-biphenyi-4-yi)-oxaz(ri-4-yl]-acetic acid ethyl ester

A suspension of [2-(4-Trifluoromethanesulfonyloxy-phenyl)-oxazol-4-yl]-acetic
acid ethyl ester (See Intermediate 69) (0.83 g, 2.2 mmol), 4-(methanesulfonyl)phenyl
boronic acid (0.48 g, 2.4 mmol), triphenylphosphine (69 mg, 0.26 mmol), cesium fluoride
(0.67 g, 4.4 mmol) and palladium acetate (15 mg, 0.066 mmol) in DMF (10 mL) is heated
at 110 °C for 24 h. The suspension is cooled to room temperature and filtered. The
filtrate is partitioned between EtOAc and water. The aqueous phase is extracted with
EtOAc. The combined organic phase is washed with brine, dried (Na2S04), and
concentrated. The residue is purified by flash chromatography (40 g SiOa, elute 20% to
80% EtOAC/hexane) to yield the title compound (0.10 g, 12%). MS (m/e): 386.2 (M+l)
Intermediate 71

The title compound is prepared in a manner substantially similar to Example 55 from [2-
(4'-Methanesulfonyl-biphenyl-4-yl)-oxazol-4-yl]-acetic acid ethyl ester (See Intermediate
70). MS (m/e): 344.3 (M+l)
Example 1

2-(4-Bromo-phenyl)-4-chloromethyl-oxazole (See Intermediate 1) (0.321 g, 1.18
mrnol), and pyrrolidine (0.639 g, 9.0 mmol) are dissolved in 20 mL tstrahydrofuran and
stirred at ambient temperature for 1.5 hours. The reaction is concentrated to an oil and
redissolved in diethyl ether which is washed with aqueous sodium bicarbonate, water,
separated and dried over sodium sulfate, filtered and concentrated to a dark oil. The oil is
purified by flash silica gel chromatography (2% 2M NH3 in MeOH / dichloromethane) to
give 0.185 g of the titled compound. MS (m/e) (81Br): 309.1 (M+l)
Example 2
2-(4-Bromo-pbenyl-4-pyrrolidin-l-ylmethyl-oxazole; hydrochloride

The free base of the titled compound is prepared substantially in accordance the
procedure of Example 1 without chromatography. The crude free base is treated with
1M HC1 in diethyl ether and the resulting solids are dissolved a minimum amount of
d ichloromethane. Diethyl ether is added and the brown precipitate is; removed by
filtration. To the filtrate is added 1:1 diethyl ether / hexane to precipitate the titled
compound as a light tan solid. MS (m/e) (81Br): 309.1 (M+l)
Example 3

Step A: 2-(4-Bromo-phenyl)-4-pyrrolidin-l-ylmethyl-oxazoIe (See Example 1)
(0.174 g, 0.57 mmol), 3-pyridylboronic acid (0.184 g, 1.5 mmol), dichloropalladium di-
triphenylphosphine (0.060 g, 0.086 mmol), cesium fluoride (0.866 g, 5.7 mmol) and 6 mL
acetonitrile are placed in a 10 mL CEM microwave tube. The tube is placed in a CEM
microwave reactor for 30 minutes at 140 °C, 125 psi, and 75 watts of power. The mixture
is cooled and concentrated to a dark residue which is purified by radial silica gel
chromatography (1% 2M NH3 in MeOH / dichloromethane) to give 0.015 g of the free
base of the titled compound.
Step B: The free base is dissolved in 1 mL of dichloromethane and 0.20 mL of a
1M HC1 in diethyl ether solution is added to precipitate 0.018 g of the pure titled
compound. MS (m/e): 306.1 (M+l)
Example 4

2-(4-Bromo-phenyl-4-pyrrolidin-l-ylmethyl-oxazole hydrochloride (See Example
2) (0.151 g, 0.439 mmol), 4-methylsulfonylphenylboronic acid (0.132 g, 0.66 mmol),
tetrakis-(triphenylphosphine) palladium (0.010 g, 0.009 mmol), aqueous sodium
carbonate (2M, 0.88 mL, 1.76 mmol) and 7 mL of dioxane is placed in a 10 mL CEM
microwave-tube. The tube is placed in a CEM microwave reactor for 30 minutes at 90
°C, 25 psi, and 45 watts of power. The mixture is cooled and concentrated to a dark
residue which is purified by radial silica gel chromatography (1% 2M NH3 in MeOH /
dichloromethane) to give 0.125 g of the titled compound. MS (m/e): 383.1 (M+l)
Example 5

The titled compound is prepared substantially in accordance with the procedures
of Examples 1 and 2 using 2-(4-Bromo-phenyl)-4-chloromethyl-oxazole (See
Intermediate 1) and racemic 2-methylpyrrolidine [CAS# 765-38-8]. MS (m/e) (81Br):
323.1 (M+l)
Example 6
(+/-)-2-(4'-MethanesulfonyI-biphenyl-4-yI)-4-(2-methyl-pyrrolidiji-l-ylmethyl)-
oxazole

The tided compound is prepared substantially in accordance with the procedure of
Example 4 using 4-methylsulfonylphenylboronic acid and (+/-)-2-(4-Bromo-phenyl)-4-
(2-methyl-pyrrolidin-l-ylmethyl)-oxazole; hydrochloride (See Example 5). MS (m/e)
397.1 (M+l)
Example 7
Ar-[4'-(4-Pyrrolidin-l-ylmeUiyl-oxazol-2-yl)-biphenyl-4-yl]-methaaesttlfonamide

The titled compound is prepared substantially in accordance with the procedure of
Example 4 using 4-(methylsulfonylamino)phenylboronic acid and 2-(4-Bromo-phenyl-4-
pyrrolidin-1-ylmethyl-oxazole; hydrochloride (See Example 2). MS (m/e) 39S.2 (M+l)
Example 8
2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazole

2-(4-Bromophenyl)-5-methyl-oxazoleethanol (10.0 g, 35.44 mmol) [which is
obtained by the method of D. Brooks, I. Med. Chem., 2001,44,2061-2064 or see WO
0116120], triethylamine (5.4 mL, 38.6 mmol), and methanesulfonyl chloride (3.0 mL,
38.6 mmol) is dissolved in 200 mL of dichloromethane and stirred at ambient temperature
for 1 hour. The mixture is then concentrated to an tan residue and redissolved in 100 mL
of tetrahydrofuran. Pyrrolidine (32.2 mL, 386 mmol) is added and the mixture is heated
to reflux for 4 hours. The reaction is concentrated and redissolved in ethyl acetate and
washed successively with water and aqueous sodium bicarbonate. The organics phase is
separated, dried over sodium sulfate, filtered and concentrated to provide the titled
compound (11.87 g, 99.9% yield). MS (m/e) (81Br): 337.0 (M+l)
Example 9
4-{4-[5-Methyl-4-(2-pyrrolidin-l-yl-ethyI)-oxazol-2-yl]-phenyl}-pyridine

2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1 -yl-ethyl)-oxazole (See Example
8) (7.23 g, 21.57 mmol), 4-pyridylboronic acid (3.98 g, 32.35 mmol), [1,1
bis(diphenylphosphino)ferrocene]dich]oropalladium(II) complex with CH2CI2 (1:1)
(0.616 g, 0.755 mmol), and aqueous sodium carbonate (2M, 40 mL) are dissolved in 200
xeL of dioxane and heated to reflux for 1.5 hours. The mixture is concentrated to a dark
residue and purified by flash silica gel chromatography (gradient: 3-6% 2M NH3 in
ISleOH / dichloromethane) to provide the titled compound (5.94 g, 82.5% yield). MS
(m/e): 334.2 (M+l)
Example 10

The titled compound is prepared substantially in accordance with the procedure of
Example 3, Step B using 4-{4-[5-Methyl-4-(2-pyrrolidin-l-yl-efhyl)-oxazol-2-yl]-
phenyl}-pyridine (See Example 9). MS (m/e): 334.2 (M+l)
Example 11
3-{4-[5-MethyI-4-(2-pyrrolidin-l-yl-ethyI)-oxazol-2-yl]-phenyl}-pyridine

The titled compound is prepared by either of the following methods:
Method A: Using 2-[5-Methyl-2-(4-pyridin-3-yl-phenyl)-oxazol-4-y] }-ethanol (See
Intermediate 2), the titled compound is prepared substantially in accordance with the
procedure of Example 8. MS (m/e): 334.2 (M+l)
Method B: The titled compound is prepared substantially in accordance with the
procedure of Example 9 using 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-l-yl-ethyl)-
oxazole (See Example 8) and 3-pyridylboronic acid. MS (m/e): 334.2 (M+l)
Example 12
3-{4-[5-MethyI-4-(2-pyrroUdin-l-yl-ethyl)-oxazol-2-yl]-phenyl}-pyridine:
dibyrdochloride

The titled compound is prepared substantially in accordance with the procedure of
Example 3, Step B using 3-{4-[5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazol-2-yl]-
phenyl}-pyridine (See Example 11). MS (m/e): 334.2 (M+l)
Example 13
(+/-)-2-(4-Bromo-phenyl)-5-methyl-4-t2-(2-methyl-pyrrolidin-l-yl)-etliyl]-oxazole

The titled compound is prepared substantially in accordance with the procedure of
Example 8 using racemic 2-methylpyrrolidine. MS (m/e): 334.2 (M+l)
Example 14
(+/-)-4-(4-{5-Methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-phenyI)-
pyridine: dihydrochloride

The free base of the titled compound is prepared substantially in accordance with
the procedure of Example 4 using (+/-)-2-(4-Bromo-phenyl)-5-meth yl-4-[2-(2-methyl-
¦cvrrolidin-l-yl)-ethyl]-oxazole (See Example 13) and 4-pyridylboroiuc acid. The free
base is converted to the dihydrochloride salt according to the procedure of Example 3,
Step B to provide the titled compound. MS (m/e): 348.3 (M+l)
Example 15
2-Methyl-5-{4'-[5-methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxa2ol-2-yl]-biphenyl-4-yl}-
[l,3,4]oxadiazole

The titled compound is prepared substantially in accordance with the procedure of
Example 8 using 2-{5-Methyl-2-[4-(5-methyI-[l,3,4]oxadiazol-2-yl)-phenyl]-oxazol-4-
yl }-ethanol (See Intermediate 4). MS (m/e): 415.3 (M+l)
Example 16
2-(4-Bromo-phenyl)-5-methyl-4-[2-(2R-methyl-pyrrolidin-l-yl)-ethyl]-oxa2ole;
hydrochloride

2-(4-Bromophenyl)-5-methyl-oxazoleethanol (0.592 g, 2.1 mmol) [which is
obtained by the method of D. Brooks," J. Med. Chem., 2001,44, 2061-2064 or see WO
0116120], triethylamine (0.316 mL, 2.27 mmol), and methanesulfonyl chloride (0.176
mL, 2.27 mmol) are dissolved in 12 mL of dichloromethane and stirred at ambient
temperature for 1 hour. The mixture is concentrated to a tan residue and redissolved in 4
rnL of tetrahydrofuran. Triethylamine (0.585 mL, 4.2 mmol), and 2R-Methyl-
pyrrolidine; hydrochloride (See Intermediate 7) (0.510 g, 4.2 mmol) are added and the
mixture is heated to reflux for 40 hours. The reaction is concentrated and redissolved in
dichloromethane and washed successively with water and aqueous sodium bicarbonate.
The organics phase is separated, dried over sodium sulfate, filtered and concentrated to
provide the free base of the titled compound (0.586 g) which is converted to the titled
compound substantially in accordance with the procedure of Example 2. MS (m/e):
349.1 (M+l)
4-(4-{5-MethyI-4-[2-(2R-methyl-pyrroIidin-l-yl)-ethyl]-oxaz(»l-2-yl}-phenyI)-
pyridine: dihydrochloride

The free base of the titled compound is prepared substantial!) in accordance with
the procedure of Example 4 using 2-(4-Bromo-phenyl)-5-methyl-4-[2-(2R-methyl-
pyrrolidin-l-yl)-ethyl]-oxazole; hydrochloride (See Example 16) and 4-pyridylboronic
acid. The free base is converted to the dihydrochloride salt according to the procedure of
Example 3, Step B to provide the titled compound. MS (m/e): 348.3 (M+l)
Example 18
6-{4-[5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazol-2-yl]-pbenyl}-n»cotinontrUe:
dihydrochloride

The free base of the titled compound is prepared substantially in accordance witii
the procedure of Example 4 using 5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-2-[4-(4,4,5,5-
tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-oxazole (See Intermediate 8) and 6-
chloronicotinonitrile (Alfa Aesar, CAS# 33252-28-7). The free base is converted to the
dihydrochloride salt according to the procedure of Example 3, Step B to provide the
titled compound. MS (m/e): 359.2 (M+l)
Example 19
2-(4'-Methanesulfonyl-biphenyl-4-yI)-5-methyl-4-[2-(2R-methyl-]5yrrolidin-l-yl)-
ethyI]-oxazo!e
The titled compound is prepared by either of the following methods:
Method A: Using 2-[2-(4'-MethanesulfonyI-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-
ethanol (See Intermediate 9) the titled compound is prepared substantially in accordance
with the procedure of Example 16. MS (m/e) 425.2 (M+l)
Method B: The titled compound is prepared substantially in accordance with the
procedure from Example 4 using 2-(4-Bromo-phenyl)-5-methyl-4-[2-(2R-methyl-
pyrrolidin-l-yl)-ethyl]-oxazole; hydrochloride (see Example 16) and 4-
methylsulfonylphenylboronic acid. MS (m/e): 425.2 (M+l)
Example 20
3-(4-{5-Methyl-4-[2-(2R-methyl-pyrroIidin-l-yl)-ethyl]-oxazol-2-yl}-phenyl)-
pyridine: dihydrochloride

The free base of the titled compound is prepared substantially in accordance with
the procedure of Example 9 using (+/-)-2-(4-Bromo-phenyl)-5-mefhyl-4-[2-(2-methyl-
pyrrolidin-l-yl)-ethyl}-oxazole (See Example 13) and 3-pyridyIboronic acid. The free
base is converted to the dihydrochloride salt according to the procedure of Example 3,
Step B to provide the titled compound. MS (m/e): 348.3 (M+l)
Example 21
(+/-)-l-[2-(4-Bromo-phenyl)-oxazoI-4-ylmethyl]-2-methyl-piperidine

The titled compound is prepared substantially in accordance with the procedure of
Example 16 using 2-(4-Bromo-phenyl)-4-chloromethyl-oxazole (See Intermediate 1) and
2-methylpiperidine. MS (m/e): 336.2 (M+l)
Example 22
(+/-)-3-{4-[4-(2-Methyl-piperidin-l-ylmethyl)-oxazol-2-yl]-phenyl}-pyridine

l-[2-(4-Bromo-phenyl)-oxazol-4-ylmemyl]-2-methyl-piperidine (See Example
21) (1.0 mmol; N96-A03858-154), 3-pyridyl boronic acid (1.2 mmol), tetrakis-
triphenylphosphine)paIladium (0.044 mmol), 2M aqueous sodium carbonate (3 mmol)
and dioxane (0.1M) is placed in a microwave reactor vessel with a stirbar. Run the
reaction in a CEM microwave reactor at 90 °C with 30 W power and cooling for 30
minutes. After this time, perform an aqueous workup and purify via radial
chromatography eluting with 2M ammonia in methanol and dichloromethane to provide
the titled compound. MS (m/e): 334.2 (M+l)
. Example 23
(+/-)-3-{4-[4-(2-Methyl-piperidin-l-yImethyl)-oxazol-2-yl]-phenyI}-pyridine
dihydrochloride salt

Dissolve 3-{4-[4-(2-Methyl-piperidin-l-ylmethyl)-oxazol-2-yl]-phenyl} -pyridine
(See Example 22) in minimal dichloromethane and add 1M hydrochloric acid in diethyl
ether until the solution is cloudy. Add hexane and concentrate in vacuo to yield the titled
compound. MS (m/e): 334.1 (M+l)
Example 24
2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazole

Starting with 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-l-yl-ethyi)-oxazole
(SeeExample 8) and 4-methylsulfonylphenylboronic acid, follow a procedure
significantly analogous to that found in Example 22 to give the titled compound. MS
(m/e): 411.2 (M+l)
Example 25
4'-[5-Methyl-4-(2-pyrroIidin-l-yl-ethyl)-oxazol-2-yl]-biphenyl-4-carboxylicacid
dimethylamide

Starting with 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazole
(See Example 8) and 4-(N,N-dimethylcarbamoyl)phenylboronic acid, follow a procedure
significantly analogous to that found in Example 22 to give the titled compound. MS
(m/e): 404.3 (M+l)
Example 26
5-{4-[5-Methyl-4-(2-pyrroIidin-l-yl-ethyl)-oxazol-2-yl]-phenyl}-thiophene-2-
carbonitrile

Starting with 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazole
(See Example 8) and 4-cyanothiophene boronic acid, follow a procedure significantly
analogous to that found in Example 22 to give the titled compound. MS (m/e): 364.2
(M+l)
Example 27
2-{4-Bromo-phenyl)-4-[2-(SH+)- oxazole

The titled compound is prepared significantly in accordance with the procedure of
Example 8 using 2-(4-Bromophenyl)-5-methyl-oxazoleethanoi [which is obtained by the
method of D. Brooks, J. Med. Chem., 2001,44, 2061-2064 or the see WO 0116120] and
(S)-(+)-2-methoxymethylpyrrolidine. MS (m/e) (79Br/ 8lBr): 379.2/381.2 (M+l)
Example 28
2-(4'-Methanesulfonyl-biphenyl-4-yl)-4-[2-(S)-(+)-(2-methoxymethyl-pyrrolidin-l-
yl)-ethyI]-5-methyI-oxazole

Starting with 2-(4-Bromo-phenyl)-4-[2-(S)-(+)-(2-methoxymethyl-pyrrolidin-l-
yl)-ethyl]-5-methyl-oxazole (See Example 27) and 4-methylsulfonylphenylboronic acid,
follow a procedure significantly analogous to Example 22 to give the titled compound.
MS(m/e): 455.2 (M+l)
Example 29
J.(4-{4-[2-(S)-(+)-(2-Methoxymethyl-pyrrolidin-l-yl)-ethyl]-5-methyl-oxazol-2-yl}-
phenyl)-pyridine dihydrochloride salt

Starting with 2-(4-Bromo-phenyl)^[2-(S)-(+)-(2-methoxymethyl-pyrrolidin-l-
yl>ethyl]-5-methyl-oxazole (See Example 27) and 3-pyridylboronic acid, follow
procedures significantly analogous to those found in Example 22 to give the free base of
the titled compound. The free base is converted to the titled compound significantly in
accordance with the procedure of Example 23. MS (m/e): 378.3 (M+l)
Example 30
4.(4-{4.[2-(S)-(+)-(2-Methoxymethyl-pyrrolidin-l-yl)-ethyI].5-niethyl-oxazol-2-yl}-
phenyl)-pyridine dihydrochloride salt

Starting with 2-(4-Bromo-phenyl)-4-[2-(S)-(+)-(2-medioxymethyl-pyrrolidin-l-
y.)-ethyl]-5-methyl-oxazole (See Example 27) and 4-pyridylboronic acid, follow
procedures significantly analogous to Example 22 to give the free base of the titled
compound. The free base is converted to the titled compound significantly in accordance
with the procedure of Example 23. MS (m/e): 378.3 (M+l)
2-(4-Bromo-phenyI)-4-[2-(R)-(+)-(2-methoxymethyl-pyrrolidin-l-yI)-ethyl]-5-methyl-
oxazole

The titled compound is prepared significantly in accordance with the procedure of
Example 8 using 2-(4-Bromophenyl)-5-mefhyl-oxazoleethanoI [which is obtained by the
method of D. Brooks, J. Med. Chem., 2001,44,2061-2064 or see WO 0116120] and (R)-
(-)-2-methoxymethylpyn:olidine. MS (m/e) (79Br/ 81Br): 379.2/381.2 (M+l)
Example 32
2^4*-Metbanesulfonyl-bipbcnyl-4-yl)-4-[2-(RH+H2-i»ethoxyi»etbyl-pyrrolidiii-l-
yl)-ethyl]-5-methyl-oxazole

Starting with 2-(4-Bromo-phenyl)-4-[2-(R)-(+)-(2-methoxymethyl-pyrrolidin-l-
yl)-ethyl]-5-methyl-oxazole (See Example 31) and 4-methylsulfonylphenylboronic acid,
follow a procedure significantly analogous to drat found in Example 22 to give the titled
compound. MS (m/e): 455.2 (M+l)
Example 33
(+/-)-2-(4-Butoxy-phenyI)-5-methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyI]-oxazole
hydrocholoride salt

Starting with Toluene-4-sulfonic acid 2-[2-(4-butoxy-phenyl)-5-methyl-oxazol-4-
yl)-ethyl ester [CAS 478540-91-9] and racemic 2-methylpyrrolidine, follow procedures
significantly analogous to Example 8 to provide the free base of the titled compound.
The free base is converted to the titled compound significantly in accordance with the
procedure of Example 23. MS (m/e): 343.3 (M+l)
Example 34
l-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-piperidine

a) Add piperidine (3.04 g, 36.11 mmol) to a solution of Methsinesulfonic acid 2-
[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yI]-ethyI ester (See Intermediate 13) (1.3 g, 3.61
mmol) in anhydrous THF (15 mL). Reflux the reaction overnight and cool. Wash
organic material with IN HC1 (50 mL) and extract aqueous layer with diethyl ether (2 x
50 mL). Add 5N NaOH to aqueous layer (pH >10) and extract with dichoromethane (2 x
50 mL). Dry organics over Na2S04, filter and concentrate. Purify crude on silica gel,
eluting with 5% 2N NH3 in methanol/dichloromethane to give l-{2-[2-(4-bromo-phenyl>
5-memyl-oxazpl-4-yl]-ethyl}-piperidine (0.944 g, 75%).
Example 35
5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-2-(3'-trifluoromethyl-biphetiyl-4-yl)-oxa2ole

To a stirred solution of 2-(4-Bromo-phenyl)-5-methyl-4-(2-p>Trolidin-l-yl-ethyl)-
oxazole (100 mg, 0.299 mmol), sodium carbonate (94.9 mg, 0.895 mmol) and 3-
Trifluoromethylbenzene boronic acid (284mg, 1.49mmol) in toluene [5 mL), water (1
mL) and ethanol (1.5 mL) under nitrogen was added Tetrakis(triphenylphosphine)
-palladium (0) (34.5 mg, 0.030 mmol), The reaction was then heated to reflux for 48 h.
The reaction was allowed to cool and bound to a SCX-2 cartridge (5 g). The cartridge was
washed with one cartridge volume of dimethylformamide and two volumes of methanol.
The product was eluted using 2M ammonia in methanol. The ammonia/methanol solution
nie resulting acetonitrile/water fractions were combined and evaporated using a
Genevac® HT4 to give 77.7 mg of a colourless oil (65%). MS (m/e): 401.2 (M+l)
Example 36
2-(3',4'-Dimethoxy-biphenyl-4-yl)-5-methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazole

The title compound is prepared in a manner substantially analogous to Example
35 starting from 3,4-Dimethoxybenzene boronic acid and 2-(4-Bromo-phenyl)-5-methyl-
4-(2-pyrrolidin-l-yl-ethyl)-oxazole. MS (m/e): 393.2 (M+l)
Example 37
5-MethyI-4-(2-pyrrolidiD-l-yl-ethyl)-2-(3'-trinuoromethoxy-biphenyl-4-yl)-oxazole

The title compound is prepared in a manner substantially analogous to Example
35 starting from 3-Trifluorometb.oxybenzene boronic acid and 2-(4-Bromo-phenyl)-5-
rnethyl-4-(2-pyrrolidin.-l-yl-ethyl)-oxazole. MS (m/e): 417.1 (M+l)
Example 38
5-Methyl-4-(2-pyrrolidin-l-yI-ethyI)-2-(4,-trifluoromethoxy-biphenyl-4-yl)-oxazole

The title compound is prepared in a manner substantially analogous to Example
35 starting from 4-Trifluoromethoxybenezene boronic acid and 2-(4-Bromo-phenyl)-5-
methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazole. MS (m/e): 417.1 (M+l)
Example 39
2-(4'-Methoxy-biphenyI-4-yl)-5-methyI-4-(2-pyrroIidin-l-yl»ethyI)-oxazole

The title compound is prepared in a manner substantially analogous to Example
35 starting from 4-Methoxybenzene boronic acid and 2-(4-Bromo-pher»yl)-5-methyl-4-(2-
pyrrolidin-l-yl-ethyl)-oxazole. MS (m/e): 363.2 (M+l)
Example 40
2-(4-Benzo[lr3]dioxol-5-yl-phenyl)-5-methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazole

The title compound is prepared in a manner substantially analogous to Example
35 starting from 3,4-Methylenedioxybenzene boronic acid and 2-(4-Bromo-phenyl)-5-
methyI-4-(2-pyrrolidin-l-yl-ethyI)-oxazole. MS (m/e): 377.1 (M+l)
Example 41
2-(2',4'-Dimethoxy-biphenyl-4-yl)-5-methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazole

The title compound is prepared in a manner substantially analogous to Example
35 starting from 2,4-Dimethoxybenzene boronic acid and 2-(4-Bromo-phenyl)-5-methyl-
4-(2-pyrrolidin-l-yl-ethyl)-oxazole. MS (m/e): 393.2 (M+l)
Example 42
3-Methoxy-5-{4-t5-methyl-4-(2-py,rrolidin-l-yl-ethyl)-oxazol-2-yl]-phenyl}-pyridine

The title compound is prepared in a manner substantially analogous to Example
35 starting from 3-Methoxypyridine-5-boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-
(2-pyrrolidin-l-yl-ethyl>oxazole. MS (m/e): 364.2 (M+l)
Example 43
2-(3'-MethanesaIfonyl-biphenyl-4-yl)-5-methyI-4-(2-pyrr«lidin-l-yl-ethyl)-oxazole

The title compound is prepared in a manner substantially analogous to Example
35 starting from 3-Methylsulfonylbenzene boronic acid and 2-(4-Bromo-phenyl)-5-
raethyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazole. MS (m/e): 411.1 (M+l)
Example 44
2-(4'-Ethanesulfonyl-biphenyl-4-yl)-5-methyl-4-(2-pyrrolidin-l-yl-ethyI)-oxazoIe

The title compound is prepared in a manner substantially analogous to Example
35 starting from 4-Ethylsulfonylbenzene boronic acid and 2-(4-Bromo-phenyl)-5-methyl-
4-(2-pyrrolidin-l-yl-ethyI)-oxazole. MS (m/e): 425.1 (M+I)
Example 45
2-(4'-Methanesulfinyl-biphenyl-4-yl)-5-metbyl-4-(2-pyrrolidin-l-yI-ethyl)-oxazole

To a stirred solution of 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-l-yl-ethyl)-
oxazole (50 mg, 0.149 mmol), sodium carbonate (47.5 mg, 0.448 mmol) and 4-
Methylsulfinylbenzene boronic acid (137.3 mg, 0.75 mmol) in toluene (2.5 mL), water
(0.75 mL) and ethanol (1 mL) under nitrogen was added Tetrakis(triphenylphosphine)
palladium (0) (17.2mg, 0.015 mmol). The reaction was then heated to reflux for 48 h.
The reaction was allowed to cool and bound to a SCX-2 cartridge (5 g). The cartridge was
washed with one cartridge volume of dimemytformamide and two volumes of methanol.
The product was eluted using 2M ammonia in methanol. The ammonia/methanol solution
was evaporated on a Genevac® HT4. The sample was further purified by prep-LCMS.
The resulting acetonitrile/water fractions were combined and evaporated using a
Genevac® HT4 to give 17.8 mg of a colourless oil (30%). MS (m/e): 395.2 (M+l)
Example 46
5-{4-[5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazol-2-yl]-phenyI}-pyrimidiiie

The title compound is prepared in a manner substantially analogous to Example
-.3 starting from 5-Pyrimidine boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-
pyrrolidin-l-yl-ethyl)-oxazole. MS (m/e): 335.2 (M+l)
Example 47
2-Methoxy-5-{4-[5-methyI-4-(2-pyrroHdin-l-yl-ethyl)-oxazoI-2-yl]-phenyl}-
pyrimidine

The title compound is prepared in a manner substantially analogous to Example
45 starting from 2-Methoxy-5-pyriraidirje boronic acid and 2-(4-Bromo-phenyl)-5-
rnethyl-4-(2-pyrrolidin-l-yl-ethyl)-oxa2ole. MS (m/e): 365.2 (M+l)
Example 48
5-{4-[5-Metbyl-4-(2-pyrroHdin-l-yl-ethyl)-oxazol-2-yl]-phenyl}-lH-indole

The title compound is prepared in a manner substantially analogous to Example
45 starting from 5-Indole boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-
l-yl-ethyl)-oxazole. MS (m/e): 372.2 (M+l)
Example 49
5-Methyl-4-(2-pyrrolidin-l-yI-ethyl)-2-(4-thiophen-2-yl-phenyI)-oxazole

The title compound is prepared in a manner substantially analogous to Example
45 starting from 2-Thiophene boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-
pyrrolidin-l-yl-ethyl)-oxazole. MS (m/e): 339.1 (M+l)
Example 50
l-{2-[2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl}-piperidine
hydrochloride

b) Add l-{2-[2-(4-bromo-phenyl)-5-methyl-oxa2ol-4-yI]-etbyl}-piperidine (See
Example 34) (0.290 g, 0.830 mmol), PdOPhs)* (0.043 g, 0.037 mmol), 4-
methanesulfonylphenylboronic acid (0.249 g, 1.25 mmol), 2N Na2C03 (2.1 mL), and 1,4-
dioxane (1 mL) to a microwave vessel. Microwave at 30 W, 90 °C for 30-45 minutes.
Concentrate and purify on silica gel eluting with 10% 2N NH3 in methanol /
dichloromethane to give l-{2-[2-(4'-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-
yl]-ethyl}-piperidine (0.323 g, 92%).
c) Treat the recovered material (0.211 g, 0.499 mmol) with IN HC1 (523 uL, 0.523
mmol) in ether and lyophilize to give the title compound: MS (m/e): 351 (M+2).
• Example 51
(+/-)-l-{2-[2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl}-2-
methyl-piperidine hydrochloride

a) Add 2-methylpiperidine (3.55 g, 36.1 mmol) to a solution of Methanesulfonic
acid 2~[2-(4-bromo-phenyl)-5-methyl-oxazoI-4-yl]-ethyl ester (See Intermediate 13) (1.3
g, 3.61 mmol) in anhydrous THF (15, mL). Reflux the reaction overnight and cool. Wash
organic material with IN HC1 (50 mL) and extract aqueous layer with diethyl ether (2 x
50 mL). Add 5N NaOH to aqueous layer (pH > 10) and extract with dichoromethane (2 x
50 mL). Dry organics over Na2SC>4, filter and concentrate to give l-{2-[2-(4-bromo-
phenyl)-5-methyl-oxazol-4-yl]-ethyl}-2-methylpiperidine (1.32 g, quant).
b) Add l-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-2-methylpiperidine
(0.290 g, 0.798 mmol), Pd(Ph3)4 (0.041 g, 0.035 mmol), 4-methanesulfonylphenylboronic
acid (0.240 g, 1.20 mmol), 2N Na2C03 (1.98 mL), and 1,4-dioxane (1 mL) to a
microwave vessel. Microwave at 30 W, 90 °C for 30-45 minutes. Concentrate and purify
on silica gel eluting with 10% 2N NH3 in methanol/dichloromethane to give l-{2-[2-(4'-
metbanesulfonyl-biphenyl-4-yl)-5-me&yl-oxazol-4-yl]-ethyl}-2-methylpiperidine (0.120
g.34%).
c) Treat the recovered material (0.095 g, 0.218 mmol) with IN HC1 (228 |JL, 0.288
mmol) in ether and lyopholize to give the title compound: MS (m/e): 365(M+2).
Example 52
l-{2-[2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl}-25-methyl-
piperidine hydrochloride
a) Add ^-2-methylpiperidine (1.0 g, 10.19 mmol) to a solution of Methanesulfonic
acid 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester (See Intermediate 13) (1.28
g, 3.55 mmol) in anhydrous THF (15 mL). Reflux the reaction overnight and cool. Wash
organic material with IN HC1 (50 mL) and extract aqueous layer wirn diethyl emer (2 x
50 mL). Add 5N NaOH to aqueous layer (pH > 10) and extract with dichoromethane (2 x
50 mL). Dry organics over Na2S04, filter and concentrate to give l-{2-[2-(4-bromo-
phenyl)-5-methyl-oxazol-4-yl]-ethyl}-5-2-methylpiperidine (0.315 g, 25%).
b) Add 1 - {2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl} -.S-2-methylpiperidine
(0.315 g, 0.867 mmol), Pd(Ph3)4 (0.044 g, 0.038 mmol), 4-methanesulfonylphenylboronic
acid (0.260 g, 1.30 mmol), 2N Na2C03 (2.20 mL), and 1,4-dioxane (1.5 mL) to a
microwave vessel. Microwave at 30 W, 90 °C for 30-45 minutes. Add dichloromethane
(10 niL) and water (5 mL). Extract aqueous with dichloromethane (15 mL). Wash
organics with saturated sodium chloride. Dry over Na2SC>4, filter and concentrate.
Precipitate from ethyl acetate/hexanes to give l-{2-[2-(4'-methanesu!lfonyl-biphenyl-4-
yl)-5-methyl-oxazol-4-yl]-ethyl}-5-2-methylpiperidine (0.264 g, 69%).
c) Treat the recovered material (0.264 g, 0.605 mmol) with IN HC1 (635 ^L, 0.635
mmol) in ether and lyophilize to give'the title compound: MS (m/e): 365 (M+2).
Example 53
2-{4-[5-Methyl-4-(2-pyrrolidin-l-yl-ethyI)-oxazol-2-yl]-phenoxymethyI}-pyridine

To a mixture of 2-{5-Mediyl-2-[4^pyiidm-2-ylmethoxy)-phenyl]-oxazol-4-yl}-
ethanol (0.264 g, 0.85 mmol) and triethylamine (0.154 mL, 1.1 mmol) in CH2C12 (4 mL)
at 0 °C is added methanesutfonyl chloride (0.077 mL, 1.0 mmol). Tbe mixture is
warmed to room temperature and stirred for 2 h. The mixture is concentrated to provide
medianesulfonic acid 2- {5-methyl-2-[4-(pyridin-2-ylmethoxy)-phenyl]-oxazol-4-yl} -
ethyl ester, which is used without purification. MS (m/e): 389 (M+l)
A mixture of methanesulfonic acid 2-{5-methyl-2-[4-(pyridin-2-ylmethoxy)-
phenyl]-oxazol-4-yl} -ethyl ester (0.85 mmol) and pyrrolidine (0.71 mL, 8.5 mmol) in
THF (4 mL) is heated at reflux overnight. The mixture is partitioned between EtOAc and
water. The aqueous phase is extracted with EtOAc (2x), and the combined organic phase
is washed witih brine and dried (NaSCU). After the solvent is removed, the residue is
purified by flash chromatography chromatography [40 g Si02, elute 20% (10% 2 M NH3
in MeOH/90% CH2C12) : 80 % CH2C12 to 70% (10% 2 M NH3 in MeOH/90% CH2C12) :
30 % CH2C12] to yield the title compound. MS (m/e): 364.2 (M+l)
Example 54
(+/-)-2-(4-{5-Methyl-4-[2-(2-methyI-pyrrolidin-l-yI)-ethyl]-oxazol-2-yl}-
phenoxymethyl)-pyridine

2-(4- {5-Methyl-4-[2-(2-methyl-pyrTolidin- l-yI)-ethyl]-oxazol-2-yl} -
phenoxymethyl)-pyridine is prepared in a manner substantially similar to Example 53
from 2-{5-Methyl-2-[4-(pyridin-2-ylmethoxy)-phenyl]-oxazol-4-yl}-ethanol and 2-
methylpyrrolidine. MS (m/e): 378.3 (M+l)
Example 55
2-(4-Benzyloxy-phenyl)-5-methyl-4-[2-(2-(R)-methyl-pyrrolidin-l-yl)-ethyl]-oxazole

To a solution of 2-[2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-l-(2-(R)-
melhyl-pyrrolidm-l-yl)-ethanone (See Intermediate 18) (0.62 g, 1.6 mmol) in THF (5
mL) at 0 °C is added a solution of lithium aluminum hydride in THF (1 M, 1.6 mL, 1.6
mmol). The cooling bath is removed, and the reaction mixture is allowed to warm to
room temperature and stirred for 3.5 h. The reaction is quenched by the sequential
addition of water (0.06 mL), 5 N NaOH (0.06 mL), and water (0.18 mL). The mixture is
stirred at room temperature overnight and filtered. The solvent is removed in vacuo, and
the crude product is obtained (0.49 g, 81%) and used without purification. MS (m/e):
377.2 (M+l)
Example 56
2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-l-(2-(R)-methyl-pyrrolidin-l-yl)-
ethanone

A mixture of 2-(4-Benzyloxy-phenyl)-5-methyl-4-[2-(2-(R)-methyl-pyrrolidin-l-
yl)-ethyl]-oxazole (See Example 55) (0.48 g, 1.3 mmol) and 5% Pd/C (0.046 g) in
absolute ethanol (25 mL) is shaken under a hydrogen atmosphere (65 psi) for 18 h. The
mixture is filtered and concentrated to provide the title compound (0.35 g, 94%) as a
yellow oil, which was used without purification. MS (m/e): 287.3 (M+l)
Example 57
2-(4-{5-Methyl-4-[2-(2-(R)-methyl-pyrrolidin-l-yI)-ethyl]-oxazol-2-yI}-
phenoxymethyI)-pyridine

A mixture of 2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-l-(2-(R)-methyl-
pynolidui-l-yl)-ethanone (See Example 56) (0.35 g, 1.2 mmol), 2-bromomethylpyridine
hydrobromide (0.40 g, 1.6 mmol), and Cs2C03 (1.4 g, 4.3 mmol) in DMF (5 mL) is
stirred at room temperature overnighti The mixture is partitioned between EtOAc and
water. The aqueous phase is extracted with EtOAc (2x), and the combined organic phase
is washed with brine, dried (Na2SC>4), and concentrated. The residue is purified by flash
chromatography [40 g SiOo, dkate 20% (10% 2 M NH3 »n MeOH/90% CH2C12): 80 %
CH2a2 to 70% (10% 2 M NH3 in MeOH/90% CKfeCfe) : 30 % CH2CJ2] to yield the title
compound MS (m/e): 378.3 (M+l)
Example 58
2-[4^4-Methanesulfonyi-benzyloxy)-phenyl]-5-nieUiyl-4-[2-(2-CR)-methyl-
pyrrolidin-l-yl)-etbyl]-oxazole

A mixture of 2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-l-(2-(R)-methyl-
pyrrolidin-l-yl)-ethanone (See Example 56) (0.32 g, 1.1 mmol), 4-methylsulfonylbenzyl
chloride (0.29 g, 1.4 mmol), Cs2C03 (0.9 g, 2.75 mmol), and potassium iodide (0.24 g,
1.4 mmol) in DMF (5 mL) is stirred at room temperature overnight. The mixture is
partitioned between EtOAc and water. The aqueous phase is extracted with EtOAc (2x),
and the combined organic phase is washed with brine, dried (Na2S04), and concentrated.
The residue is purified by flash chromatography [40 g Si02l elute 20% (10% 2 M NH3 in
MeOH/90% CH2C12): 80 % CH2C12 to 70% (10% 2 M NH3 in MeOH/90% CH2C12) : 30
% CH2C12] to yield the title compound. MS (m/e): 455.3 (M+l)
2-(4-MethanesuIfonyl-phenyl)-5-{5-methyl-4-[2-(2-(R)-methyl-pyrrolidin-l-yl)-
ethyl]-oxazol-2-yl}-pyridine

To a stirring solution of 2-{2-[6-(4-Methanesulfonyl-phenyl)-pyridin-3-yl]-5-
methyl-oxazol-4-yl}-l-(2-(R)-methy]-pyrrolidin-l-yl)-ethanone (See Intermediate 21)
(l.Ommol) in tetrahydrofuran (0.10M) in a 0 °C ice bath, slowly add 1M lithium
aluminum hydride in tetrahydrofuran (2.0 mmol). Remove the ice bath and stir for four
hours. After this time, perform a Fieser and Fieser work up by adding water (1 mL per
gram of LAH used) followed by 5N sodium hydroxide (1 mL per gram of LAH used) and
then water again (3 mL per gram of LAH used). Stir this for 18 hours and then filter the
reaction through Celite®. Wash the filtrate with dichloromethane while extracting with
IN hydrochloric acid. Basify the aqueous layer with 2N sodium hydroxide and extract
with dichloromethane. Concentrate the organic layer and purify via radial
chromatography eluting with 2M ammonia in methanol and dichloromethane. MS (m/e):
426.2 (M+l)
Example 60
2-Ethanesulfonyl-5-(4-{5-methyl-4-[2-(2-(R)-methyl-pyrrolidin-l-yl)-ethyI]-oxazol-2-
yl}-phenyl)-pyridine

The titled compound is prepared substantially in accordance with the procedure of
Example 16 using 2-{2-[4-(6-Emanesulfonyl-pyridm-3-yl)-phenyl]-5-memyl-oxazol-4-
yl}-ethanol (See Intermediate 23). MS (m/e) 440.2 (M+l)
Example 61
4-(2-Azetidin-l-yl-ethyl)-2-(4-bromo-pheny!)-5-methyl-oxazole

Add methanesulfonyl chloride (0.745 g, 6.50 mmol) to a cool (0 °C) solution of 2-
t2-(4-bromo-phenyl)-5-raethyl-oxazol-4-yl]-ethanol (1.4 g, 5.0 mmol) and triethylamme
(1.26 g, 12.5 mmol) in dichloromethane (20 mL). Warm to room temperature and stir for
1 hour. Remove solvents, transfer crude of methanesulfonic acid 2-[2-(4-bromo-phenyl)-
5-methyl-oxazol-4-yl]-ethyl ester residue to a sealed tube, add tetrahydrofuran (30 mL),
azetidine (2.0 g, 35.5 mmol), and heat at 60 °C overnight. Wash the crude organic
material with IN HC1. Separate layers and add 5N NaOH to the aqueous layer until it is
basic. Extract the aqueous layer with diethyl ether (2 x 50 mL), dry the organic extracts
over Na2S04, filter, and concentrate. Purify on silica gel eluting with 10% ammoniated
methanol in dichloromethane to give 4-(2-azetidin"l-yl-ethyl)-2-(4-bromo-phenyl)-5-
methyl-oxazole (l-22g> 72%): mass spectrum (m/e): 323 (M +1).
Example 62
l-{2-[2-(4-Bromo-phenyl)-5-methyl-«xazol-4-yl]-elhyI}-piperidine

Add piperidine (1.3 g, 15 mmol) to a solution of methanesulfonic acid 2-[2-(4-
bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester (0.531 g, 1.47 mmol) in tetrahydrofuran
(5 mL) in a sealed tube, and heat at 60 °C overnight. Cool to room temperature and add
dichloromethane. Wash the crude organic material with saturated sodium chloride
solution. Dry the organic layer over Na2SC>4, filter, and concentrate. Purify on silica gel
eluting with 10% ammoniated methanol in dichloromethane to give 1 {2-[2-(4-bromo-
phenyl)-5-methyl-oxazol-4-yl]-ethyl} -piperidine (0.421 g, 82%): MS (m/e): 349 (M +1).
Example 63
(+/-)-l-{2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-2-niethyl-piperidine

Add 2-methyl piperidine (0.871 g, 8.77 mmol) to a solution of methanesulfonic
acid 2-[2-(4-bromo-phenyI)-5-mediyl-oxazol-4-yl]-ethyl ester (0.316 g, 0.877 mmol) in
tetrahydrofuran (5 mL) in a sealed tube, and heat at 60 °C overnight. Cool to room
temperature and add dichloromethane. Wash the crude organic material with saturated
sodium chloride solution. Dry the organic layer over Na2SC>4, filter, and concentrate.
Purify on silica gel eluting with 10% ammoniated methanol in dichloromethane to give
(+/-)-l-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-piperidine (0.215 g, 67%):
MS (m/e): 363 (M +1).
Example 64
l-{2-[2-(4-Bromo-phenyl)-5-roethyl-oxazol-4-yl)-ethyl}-2S-methyl-piperidine

Add 2-S-methyl piperidine (0.734 g, 7.4 mmol) to a solution of methanesulfonic
acid 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester (0.261 g, 0.74 mmol) in
tetrahydrofuran (5 mL) in a sealed tube, and heat at 60 °C overnight. Cool and add
dichloromethane. Wash crude organic material with saturated sodium chloride solution.
Dry organic layer over Na2S04, Filter, and concentrate. Purify on silica gel eluting with
10% ammoniated memanol in dichloromethane to give l-{2-[2-(4-bromo-phenyl)-5-
methyl-oxazol-4-yl]-ethyl}-2S-methyl-piperidine (0.166 g, 62%): MS (m/e): 363 (M
+1).
Example 65
^(Z-Azetidin-l-yl-ethyO-Z^'-methanesulfonyl-biphenyl^-yO-S-methyl-oxazole
hydrochloride

Add 4-(2-azetidin-l-yl-ethyl)-2-(4-bromo-phenyl)-5-methyI-oxazole (0.606 g, 1.88
mmol), Pd(Ph3P)4 (0.083 g, 0.096 mmol), 4-methanesulfonyl boronic acid (0.566 g, 2.83
mmol), 2N Na2C03 (4.7 mL), and 1,4-dioxane (3 mL) to a microwave vessel. Microwave
at 30 W, 90 °C for 60 minutes. Add dichloromethane and water. Wash the organic layer
with saturated sodium chloride solution. Dry the organic layer over Na^SO^ filter, and
concentrate. Purify on silica gel eluting with 10% ammoniated methanol in
dichloromethane to give 4-(2-azetidin-l-yl-ethyl)-2-(4'-methanesulfonyl-biphenyl-4-yl)-
5-methyl-oxazole (0.350 g, 47%): MS (m/e): 397 (M+l). Treat the recovered material
(0.350 g, 0.883 mmol) with IN HC1 (971 uL, 0.971 mmol) in ether, concentrate, and
lyophilize to give the title compound: MS (m/e): 397 (M+l).
Example 66
2-(4'-Ethanesulftmyl-biphenyl-4-y!)-5-methyl-4-[2-(2/{-methyl-pyrrolidin-l-yl)-
ethytj-oxazole hydrochloride

Add2^4-bromo-phenyl)-5-methyl^[2-(2i?-nieAyl-pvrrolidm-l-yl)^thyl]-oxazole
(0.221 g, 0.634 mmol), Pd(Ph3P)4 (0.032 g, 0.029 mmol), 4-ethanesulfonyl boronic acid
(0.203 g, 0.950 mmol), 2N Na2C03 (1.6 mL), and 1,4-dioxane (2 mL) to a microwave
vessel. Microwave at 30 W, 90 °C for 60 minutes. Add dichloromethane and water.
Wash the organic layer with saturated sodium chloride solution. Dry ihe organic layer
over Na2SC>4, filter, and concentrate. Purify on silica gel eluting with 10% ammoniated
methanol in dichloromethane to give 2-(4'-emanesulfonyl-biphenyl-4-yl)-5-niethyl-4-[2-
(2/?-methyl-pyrrolidin-l-yl)-ethyl]-oxazole (0.235 g, 85%): MS (m/e): 439 (M+l).
Treat the recovered material (0.235 g, 0.536 mmol) with IN HC1 (589 uL, 0.589
mmol) in ether, concentrate, and lyophilize to give the title compound (221 mg): MS
(m/e): 439 (M+l).
Example 67
4-[2-(2R-Ethyl-pyrrolidin-l-yl)-ethyl]-2-(4'-methanesulfonyl-biphenyl-4-yl)-5-
methyl-oxazole hydrochloride

Charge a sealed tube with 2-(4-bromo-phenyl)-4-(2-iodo-ethyl)-5-methyl-oxazole
(0.3S5 g, 0.983 mmol) (see intermediate 30), 2/?-ethyl-pyrrolidine hydrochloride (0.400 g,
2.95 mmol) (see intermediate 26), triethylamine (0.329 g, 3.24 mmol), and
tetrahydrofuran (5 mL). Seal and heat at 60 °C overnight. Wash the crude organic
material with IN HC1. Separate layers and add 5N NaOH to the aqueous layer until
basic. Extract the aqueous layer with diethyl ether (2 x 50 mL), dry the organic extracts
over NaiSO/j, filter, and concentrate. Purify on silica gel eluting with 5% ammoniated
methanol in dichloromethane to give 2-(4-bromo-phenyl)-4-[2-(2i?-ethyl-pyrrolidin-l-yl)-
ethyl]-5-methyl-oxazole (0.249 g, 70%): MS (m/e): 365 (M+2).
Add 2^4-broroo-phenyl>^[2^2if-ethyl-pvrrolidin-l-yl)-emyl]-5-methyl-oxazole
(0.249 g, 0.685 mmol), PoXPh^P)* (0.030 g, 0.035 mmol), 4-methanesulfonyl boronic acid
(0.206 g, 1.03 mmol), 2N Na^COa (1.7 mL), and 1,4-dioxane (2 mL) to a microwave
vessel. Microwave at 30 W, 90 °C for 60 minutes. Add dichloromethane and water.
Wash the organic layer with saturated sodium chloride solution. Dry the organic layer
over Na2SC>4, filter, and concentrate. Purify on silica gel eluting with 10% ammoniated
methanol in dichloromethane to give 4-[2-(2i?-ethyl-pynolidin-l-yl)-ethyl]-2-(4'-
methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazole (0.170 g, 55%): MS (m/e): 439 (M+l).
Treat the recovered material (0.170 g, 0.387 mmol) with IN HC1 (426 jjL, 0.426
mmol) in ether, concentrate, and lyophilize to give the title compound (174 mg): MS
(m/e): 439 (M+l).
Example 68
(4'-{5-Methyl-4-[2-(2i{-methyl-pyrrolidm-l-yl)-ethyl]-oxazol-2-yl}-biphenyl-4-yl)-
methanol hydrochloride

Add methanesulfonyl chloride (0.742 g, 5.14 mmol) to a cool (0 °C) solution of 2-
[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethanol (1.1 g, 3.95 mmol) and triethylamine
(0.999 g, 9.88 mniol) in dichloromethane (10 mL). Warai to room temperature and stir
for 1 hour. Remove solvents, transfer residue to a sealed tube, add tetrahydrofuran (30
mL) and 2#-methyl pyrrolidine hydrochloride (2.4 g, 20 mmol), triethylamine (2.2 g, 22
mmol), and heat at 60°C overnight. Add dichloromethane and wash the crude organic
material with saturated sodium chloride solution. Dry the organic layer over Na2S04,
filter, and concentrate. Purify on silica gel eluting with 2% ammoniated methanol in
dichloromethane to give 2-(4-bromo-phenyl)-5-methyl-4-[2-(2/?-methyl-pyrrolidin-l-yl)-
ethyl]-oxazole (0.471 g, 34%): MS (m/e): 349 (M +1).
Add2-(4-bromo-phenyl)-5-methyl-4-[2-(2/?-methyl-pyrrolidin-l-yl>ethyl]-
oxazole (0.200 g, 0.573 mmol), Pd(Ph3P)4 (0.025 g, 0.029 mmol), 4-hydroxymethyl
boronic acid (0.131 g, 0.859 mmol), 2N Na2C03 (1.4 mL), and 1,4-dioxane (2 mL) to a
microwave vessel. Microwave at 30 W, 90 °C for 60 minutes. Add dichloromethane and
water. Wash the organic layer with saturated sodium chloride solution. Dry the organic
layer over NajSO^ filter, and concentrate. Purify on silica gel eluting with 10%
ammoniated methanol in dichloromethane to give (4'-{5-methyl-4-[2-(2i?-memyl-
pyrrolidin-l-yl)-emyI]-oxazol-2-yl}-biphenyl-4-yl)-methanol (0.181 g, 84%): MS (m/e):
377 (M+l).
Treat the recovered material (0.170 g, 0.387 mmol) with IN HC1 (426 nL, 0.426
mmol) in ether, concentrate, and lyophilize to give the title compound (173 mg): MS
(m/e): 377 (M+l).
Example 69
(4'-{5-Methyl-4-[2-(2R-methyl-pyrrolidin-l-yl)-ethyl)-oxazol-2-yl}-biphenyl-3-yl)-
methanol hydrochloride

Add2-(4-bromo-phenyl)-5-methyl-4-[2-(2/?-methyl-pyrrolidirL-l-yl)-ediyl]-
oxazole (0.200 g, 0.573 mmol), Pd(Ph3P)4 (0.025 g, 0.029 mmol), 3-hydroxymethyl
boronic acid (0.131 g, 0.859 mmol), 2N Na2C03 (1.4 mL), and 1,4-dioxane (2 mL) to a
microwave vessel. Microwave at 30 W, 90 °C for 60 minutes. Add dichloromethane and
water. Wash the organic layer with saturated sodium chloride solution. Dry the organic
layer over Na2S04, filter, and concentrate. Purify on silica gel eluting with 10%
ammoniated methanol in dichloromethane to give (4'-{5-methyl-4-[2-(2J?-methyl-
pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-biphenyl-3-yl)-methanol (0.131 g, 61%): MS (m/e):
377 (M+l).
Treat the recovered material (0.131 g, 0.348 mmol) with IN HC1 (383 uL, 0.383
mmol) in ether, concentrate, and lyophilize to give the title compound (143 mg): MS
(m/e): 377 (M+l).
Example 70
5-Methyl-4-[2-(2K-methyl-pyrrolidin-l-yl)-ethyl]-2-[4'-(propane-l-sulfonyl)-
biphenyI-4-yl]-oxazole hydrochloride

Add2^4-bromc>-phenyl>5-rnfAyl^[2^2/?-iiKthyl-pvrix»lidin-l-yl)-ethyl]-
oxazole (0.070 g, 0.20 mmol), Pd(Ph3P>t (0.008 g, 0.005 mmol), 4,4,5,5-tetramethyl-2-[4-
(propane-l-sulfonyl)-pheiiyl]-[l,3,2)dioxaborolarie (0.093 g, 0.30 mmol) (see
intermediate 29), 2N Na2CC>3 (0.50 mL), and 1,4-dioxane (2 mL) to a microwave vessel.
Microwave at 30 W, 90 °C for 60 minutes. Add dichloromethane and water. Wash the
organic layer with saturated sodium chloride solution. Dry the organic layer over
Na2S04, filter, and concentrate. Purify on silica gel eluting with 10% ammoniated
methanol in dichloromethane to give 5-methyl-4-[2-(2/?-methyl-pyrrolidin-l-yl)-ethyl]-2-
[4'-(propane-l-sulfonyl)-biphenyl-4-yI]-oxazole (0.075 g, 83%): MS (m/e): 453 (M+l).
Treat the recovered material (0.036 g, 0.078 mmol) with IN HC1 (86 uL, 0.086
mmol) in ether, concentrate, and lyophilize to give the title compound (35 mg): MS (m/e):
453 (M+l).
Example 71
4-[2-(2S-FIuoromethyl-pyrrolidin-l-yl)-ethyl]-2-(4'-methanesulfonyl-biphenyl-4-yI)-
5-methyl-oxazole hydrochloride

Add 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yI]-ethanol (0.200 g, 0.709
mmol), Pd(Ph3P)4 (0.031 g, 0.036 mmol), 4-methanesulfonyl boronic acid (0.213 g, 1.06
mmol), 2N Na2C03 (0.251 mL), and 1,4-dioxane (1 mL) to a microwave vessel.
Microwave at 30 W, 90 °C for 60 minutes. Add dichloromethane and water. Wash the
organic layer with saturated sodium chloride solution. Dry the organic layer over
Na2S04. filter, and concentrate. Purify on silica gel eluting with 10%' ammoniated
methanol in dichloromethane to give 2-[2-(4'-methanesulfonyl-biphenyl-4-yl)-5-methyl-
oxazol-4-y]]-ethanol (0.167 g, 66%).
Add methanesulfonyl chloride (0.088 g, 0.607 mmol) to a cool (0°C) solution of
2-[2-(4'-ntethanesuMbnyl-bird»enyl^yl)-5-ine&yl-o]«izol^yl]-ethaDol (0.167 g, 0.467
mmol) and triethylamine (0.118 g, 1.17 mmol) in dichloromethane (5 mL). Warm to
room temperature and stir for 1 hour. Remove the solvents, transfer the residue to a
sealed tube, add tetrahydrofuran (5 mL) and 25-fluoromethyl-pyrrolidine hydrochloride
(lit. prep. M. Cowart, WO 2002074758) (0.326 g, 2.34 mmol), triethylamine (0.280 g,
2.57 mmol), and heat at 60 °C overnight. Add dichloromethane and v/ash the crude
organic material with saturated sodium chloride solution. Dry the organics over Na2S04,
filter, and concentrate. Purify on silica gel eluting with 5% ammoniated methanol in
dichloromethane to give 4-[2-(25-fluoromethyl-pyrrolidin-l-yl)-ethyl]-2-(4'-
methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazole (0.077 g, 37%): MS (m/e): 443 (M
+1).
Treat the recovered material (0.077 g, 0.174 mmol) with IN HC1 (192 \lL, 0.192
mmol) in ether, concentrate, and lyophilize to give the title compound (79 mg): MS (m/e):
443 (M+l).
Example 72
Isopropyl-{2-[2-(4'-methanesulfonyl-biphenyl-4-yl)-5-methyl-ox;azol-4-yI]-ethyI}-
methyl-amine hydrochloride

Add methanesulfonyl chloride (0.135 g, 0.935 mmol) to a cool (0 °C) solution of
2-[2-(4-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yI]-ethanol (0.257 g, 0.719
mmol) and triethylamine (0.182 g, 1.80 mmol) in dichloromethane (5 mL). Warm to
room temperature and stir for 1 hour. Remove the solvents, transfer the residue to a
sealed tube, add tetrahydrofuran (5 mL) and N-methyl-isopropylamine (0.526 g, 7.19
mmol), and heat at 60 °C overnight. Add dichloromethane and wash the crude organic
material with saturated sodium chloride solution. Dry the organic layer over Na2S04,
filter, and concentrate. Purify on silica gel eluting with 5% ammoniated methanol in
dichloromethane to give isopropyl-{2-[2-(4'-methanesulfonyl-biphenyl-4-yl)-5-memyl-
oxazoI-4-yl]-ethyl}-me&yl-aniine (0.056 g, 18%): mass spectrum (m/e): 413 (M +1).
Treat the recovered material (0.056 g, 0.131 mmol) with IN HC1 (144 pJL, 0.144 mmol)
in ether, concentrate, and lyophilize to give the title compound (12.8 tag): MS (m/e): 413
(M+l).
Example 73
4'-{5-Methyl-4-[2-(2-(K)-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yI}-biphenyl-4-
' carbonitrile

The titled compound is prepared substantially in accordance with the procedure of
Example 4 using 2-(4-Bromo-phenyl)-5-methyl-4-[2-(2R-methyl-pyrrolidin-l-yl)-ethyl]-
oxazole; hydrochloride (See Example 16) and 4-cyanobenzeneboronic acid.
MS (m/e): 472.4 (M+l)
Example 74
(2-{2-[6-(4-Methanesulfonyl-phenyl)-pyridin-3-yl]-5-methyl-oxazol-4-yl}-ethyl)-
dimethyl-amine

The titled compound is prepared substantially in accordance with the procedure of
Example 59 using 2-{2-[6-(4-Methantsulfonyl-phenyl)-pyridm-3-yl]-5-methyl-oxazol-4-
yl}-N,N-dirnethyl-acetamide (See Intermediate 31). MS (m/e): 386.2 (M+l)
Example 75
3-Methoxy-6-(4-{5-methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-etIiyl]-oxazol-2-yl}-
phenyl)-pyridazine

To a stirring solution of methanesulfonic acid 2-{2-[4-(6-methoxy-pyridazin-3-
yl)-phenvl]-5-methyI-oxazol-4-yl}-ethyl ester (l.Ommol) (see Intermediate 32),
potassium carbonate (3.5mmoI), potassium iodide (O.lmmol) in acetonitrile (0.1M), add
2R-methyIpyrrolidine hydrochloride (1.8mmol) (see Intermediate 7). The reaction is
heated to a light reflux, for 18 hours. After mis time, the heat is removed and the product
is extracted into IN HC1 while washing with dichloromethane. The aqueous layer is then
made basic with 2N NaOH and extracted with dichloromethane. The organic layer is
concentrated in vacuo and purified via radial chromatography eluting with 2M ammonia
in methanol and dichloromethane. MS (m/e): 379.2 (M+l)
Example 76
3-Ethanesulfonyl-6-(4-{5-methyl-4-[2-(2-methyl-pyrroIidin-l-yl)-ethyl]-oxazol-2-yI}-
phenyl)-pyridazine

The titled compound is prepared in substantial accordance with the procedures
found in Example 4, Intermediate 22, Intermediate 13, and Example 75 using 2-{5-
Methyl-2-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl]-oxazol-4-yl)-ethanol
(see Intermediate 3) and 3,6-Dichloro-pyridazine. MS (m/e): 441.3 (M+l)
2-(4-{5-Methyl-4-[2-(2-methyl-pyrrolidia-l-yl)-ethyl]-oxazol-2-yl}-phenyl)-pyridine

The titled compound is prepared in substantial accordance with the procedures
found in Example 4, Intermediate 13, and Example 75 using 2-{5-Methyl-2-[4-(4,4,5,5-
tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl]-oxazol-4-yl}-ethanol (see Intermediate 3)
and 2-bromopyridine. MS (m/e): 348.3 (M+l)
Example 78
3-Methanesulfonyl-6-(4-{5-methyl-4-[2-(2-methyl-pyrroIidin-l-yl)-ethyl]-oxazol-2-
yl}-phenyl)-pyridazine

The titled compound is prepared in substantial accordance with the procedures
found in Example 4, Intermediate 33, Intermediate 13, and Example 75 using 2-{5-
Methyl-2-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl]-oxazol-4-yl}-ethanol
(see Intermediate 3) and 3,6-Dichloro-pyridazine. MS (m/e): 427.3 (M+l)
Example 19
2-EthanesuIfonyl-5-(4-{S-methyl-4-[2-(2-(R)-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-
yl}-phenyl)-pyridine dihydrochloride salt

The titled compound is prepared substantially in accordance with the procedure of
Example 23 using 2-ethanesulfonyl-5-(4-{5-methyl-4-[2-(2-(R)-methyl-pyrrolidin-l-yl)-
ethyl]-oxazol-2-yl}-phenyl)-pyridine (see Example 60). MS (m/e): 440.4 (M+l)
2-Methanesulfonyl-5-(4-{5-methyI-4-[2-(2-CR)-methyl-pyrrolidin-l-yI)-ethyl]-oxazoI-
2-yl}-phenyl)-pyridine

The titled compound is prepared substantially in accordance with the procedures
of Example 4, Intermediate 13, and Example 75 using 2-{5-methyl-2-[4-(4,4,5,5-
tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl]-oxazol-4-yl}-ethanol (see Intermediate 3)
and 2-methanesulfonyl-5-iodo-pyridine (see Intermediate 33). MS (m/e): 426.3 (M+l)
Example 81
2-MethanesuIfonyl-5-(4-{5-methyl-4-[2-(2-(R)-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-
2-yl}-phenyl)-pyridine dihydrochloride salt

The titled compound is prepared substantially in accordance witii the procedure of
Example 23 using 2-medianesulfonyl-5-(4-{5-methyl-4-[2-(2-(R)-memyl-pyrroIidin-l-
yl>ethyl]-oxazol-2-yl}-phenyl)-pyridine (see Example 80). MS (m/e): 426.3 (M+l)
Example 82
2-(3-Fluoro-4'-methanesulfonyl-biphenyl-4-yI)-5-methyl-4-[2-(2-methyl-pyrrolldin-
l-yl)-ethyl]-oxazole

The titled compound is prepared in substantial accordance with the procedures
found in Intermediate 13 and Example 75 using 2-[2-(3-Fluoro-4'-melhanesulfonyl-
biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethanol (see Intermediate 38). MS (m/e): 443.3
(M+l)
2-(3-Fluoro-4*-methanesulfonyl-biphenyI-4-yl)-5-methyl-4-[2-(2-methyI-pyrrolidin-
l-yI)-ethyl]-oxazole hydrochloride salt
c

The titled compound is prepared substantially in accordance with the procedure of
Example 23 using 2-(3-Fluoro-4'-methanesulfonyl-biphenyl-4-yl)-5-methyl-4-[2-(2-
methyl-pyrrolidin-l-yl)-ethyl]-oxazole (see Example 82). MS (m/e): 443.3 (M+l)
, Example 84
5-Methanesulfonyl-2-(4-{5-methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyI]-oxazol-2-
yl}-phenyl)-pyrimidine

The titled compound is prepared in substantial accordance with the procedures
found in Example 4, Intermediate 33, Intermediate 13, and Example 75 using 2-{5-
Methyl-2-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyl]-oxazol-4-yl}-ethanol
(see Intermediate 3) and 5-bromo-2-iodo-pyrimidine. MS (m/e): 427.3 (M+l)
Example 85
5-Methanesulfonyl-2-(4-{5-methyl-4-[2-(2-methyl-pyrroIidin-l-yI)-ethyI]-oxazol-2-
yl}-phenyl)-pyrimidine hydrochloride salt

The titled compound is prepared substantially in accordance with the procedure of
Example 23 using 5-methanesulfonyl-2-(4-{5-meuiyl-4-[2-(2-methyl-pyrrolidm-l-yl)-
emyl]-oxazol-2-yl}-phenyl)-pyrimidine (See Example 84). MS (m/e): 427.3 (M+l)
Example 86
N^f-DimethyI-6-(4-{5-methyl-4-[2-(2-methyI-pyrrolidin-l-yl)-ethyI]-oxazol-2-yl}-
phenyI)-nicotinamide

The titled compound is prepared substantially in accordance with the procedures
of Example 4, Intermediate 13, and Example 75 using 2-{5-methyl-2-[4-(4,4,5,5-
tetramethyl-[l,3,2]dioxaborolan-2-yl)phenyI]-oxazol-4-yl)-ethanol (see Intermediate 3)
and 6-chloro-N,N-dimethyl-nicotinamide [CAS: 54864-83-4].
MS (m/e): 419.3 (M+l)
Example 87
4^4^5-Methyi^[2-(2-methyl-piperidin-l-yI)-ethyl]-oxazol-2-yI}-phenyl)-pyridine
hydrochloride

a) Add 2-metiiylpiperidine (3.55 g, 36.1 mmol) to a solution of methanesulfonic
acid 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyI ester (See Intermediate 13) (1.3
g, 3.6 mmol) in anhydrous THF (15 mL). Heat the reaction mixture at reflux overnight
and cool to room temperature. Wash the organic material with IN HC1 (50 mL) and
extract die aqueous layer with diethyl ether (2 x 50 mL). Add 5N NaOH to the aqueous
layer (pH > 10) and extract with dichoromethane (2 x 50 mL). Dry the organic extracts
over Na2SC>4, filter and concentrate to give l-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-
yl]-ethyl}-2-metbylpiperidine (1.32 g, quantitative).
b) Add l-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-2-
methylpiperidine (0.724 g, 1.99 mmol), Pd(Ph3)4 (0.101 g, 0.088 mmol), 4-pyridylboronic
acid (0.367 g, 2.99 mmol), 2N Na2C03 (5 mL), and 1,4-dioxane (1.5 mL) to a microwave
vessel. Subject the reaction mixture to microwave irradiation at 30 W, 90 °C for 30-45
minutes. Concentrate and purify on silica gel eluting with 10% 2N NH3 in
methanol/dichloromethane to give 4-(4-{5-methyl-4-[2-(2-methyl-piperidin-l-yl)-ethyl]-
oxazoI-2-yl}-phenyl)-pyridine (0.059 g, 10%).
c) Treat the recovered material (0.059 g, 0.164 mmol) with IN HC1 (173 jjL,
0.173 mmol) in ether and freeze dry to give the title compound (0.070 g, quantitative):
MS (m/e): 362(M+1).
Example 88
DiethyI-{2-[2-(4,-methanesulfonyl-biphenyl-4-yI)-5-methyI-oxazol-4-yl]-ethyl}-amine
trifluoroacetate

a) Add diethyl amine (0.488 g, 6.68 mmol) to a solution of methanesulfonic acid
2^2^4-bromo-phenyl)-5-inetiiylH)xazol-4-yl]-emyl ester (See Intermediate 13) (0.240 g,
0.668 mmol) in anhydrous THF (5 mL) in a sealed tube, and heat at 60°C overnight. Add
dichloromethane and wash the crude organic layer with saturated sodium chloride
solution. Dry the organic extracts over Na2S04, filter, and concentrate. Purify on silica
gel eluting with 5% ammoniated methanol in dichloromethane to give {2-[2-(4-bromo-
phenyl)-5-methyl-oxazol-4-yl]-ethyl)-diethyl-amine (0.150 g, 67%): MS (m/e): 337 (M
+1).
b) Add {2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-diethyl-amine
(0.150 g, 0.445 mmol), Pd(Ph3)4 (0.023 g, 0.020 mmol), 4-methylsulfonylphenylboronic
acid (0.133 g, 0.667 mmol), 2N Na2C03 (2.0 mL), and 1,4-dioxane (1.1 mL) to a
microwave vessel. Microwave at 30 W, 90 °C for 30-45 minutes. Concentrate and purify
on reversed phase HPLC (20-70%MeCN, 0.1%TFA; 100 mL/min, 30 min, 50x250
Symmetry C18,7|im) to give the title compound (0.092 g, 50%): MS (m/e): 413 (M+l).
Example 89
l-(4'-{5-Methyl-4-[2-(2R-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-biphenyl-3-yl)-
ethanone hydrochloride

a) Add 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethanol (0.200 g, 709 mmol)
[which is obtained by the method of D. Brooks, J. Med. Chem., 2001, 44, 2061-2064 or
see WO 0116120], Pd(Ph3)4 (0.036 g, 0.031 mmol), 3-acetylphenylboronic acid (0.174 g,
1.06 mmol), 2N Na2CC>3 (1.8 mL), and 1,4-dioxane (1.5 mL) to a microwave vessel.
Subject the reaction mixture to microwave irradiation at 30 W, 90 °C for 30-45 minutes.
Concentrate and purify on silica gel eluting with 10% 2N NH3 in
methanol/dichloromethane to give l-{4'-[4-(2-hydroxy-ethyl)-5-rnethyl-oxazol-2-yl]-
biphenyl-3-yl}-ethanone (0.188 g, 83%).
b) Add methanesulfonyl chloride (0.110 g, 0.760 mmol) to a cool (0°C) solution of 1-
{4'-[4-(2-hydroxy-ethyl)-5-methyl-oxazol-2-yl]-biphenyl-3-yl}-ethanone (0.188 g, 0.584
mmol) and triethylamine (0.089 g, 0.88 mmol) in dichloromethane (5 mL). Warm the
reaction mixture to room temperature and stir for 1 hour. Add dichloromethane and wash
the crude organic layer with saturated sodium chloride solution. Dry the organic extracts
over Na2SC>4, filter, and concentrate to give crude merhanesulfonic acid 2-[2-(3'-acetyl-
b^*ienyl-4-yl)-5-metf»yl-oxazol-4-yl]-emyl ester (0.256 g, >10O%).
c) Add a solution of methanesulfonic acid 2-[2-(3'-acetyl-biphenyl-4-yl>-5-methyl-
oxazol-4-yl]-emyl ester (0.233 g, 0.583 mmol) in 3 mL acetonitrile to a sealed tube
containing 2R-methylpyrrolidine hydrochloride (See Intermediate 7) (0.142 g, 1.17
mmol), K2CO3 (0.282 g, 2.04 mmol), and KI (0.010 g, 0.058 mmol), and heat at 60°C
overnight. Add dichloromethane and wash the crude organic layer with saturated sodium
chloride solution. Dry the organic extracts over Na2SC>4, filter, and concentrate. Purify on
silica gel eluting with 8% ammoniated methanol in dichloromethane to give to give l-(4'-
{5-methyl-4-[2-(2R-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-biphenyl-3-yl)-ethanone
(0.201 g, 89%).
d) Treat the recovered material (0.201 g, 0.517 mmol) with IN HC1 (569 uL. 0.569
mmol) in ether and freeze dry to give the title compound (0.207 g, 94%): MS (m/e):
389(M+1).
Example 90
2-[4'-(3-Fluoro-propane-l-sulfonyl)-biphenyI-4-yl]-5-methyl-4-[2-(2R-raethyl-
pyrrolidin-l-yl)-ethyl]-oxazole hydrochloride

The free base of the title compound is prepared in a manner similar to that
described in Example 89 using 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethanol and
2-[4-(3-fluoro-propane-1 -sulfonyl)-phenyl]-4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolane (See
Intermediate 39). The free base is converted to the hydrochloride salt according to the
procedure of example 89 to provide the title compound: MS (m/e): 471(M+1).
Example 91
5-Methyl-4-[2-(2R-meth3'l-pyrrolidin-l-yl)-ethyl]-2-(4'-trifluororoethanesulfonyI-
biphenyl-4-yl)-oxazole hydrochloride

The free base of the title compound is prepared in a manner similar to that
described in Example 89 using 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethanol
(See Example 13) and 4,4,5,5-tetrainethyl-2-(4-trifluoromethanesulfonyl-phenyI)-
[l,3,2]dioxaborolane (See Intermediate 40). The free base is converted to the
hydrochloride salt according to the procedure of Example 89 to provide the title
compound: MS (m/e): 479(M+1).
Example 92
2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyl-4-[3-(2R-methyl-pyrrolidin-l-yl)-
propylj-oxazole hydrochloride

a) Add 3-[2-(4-bromo-phenyl)-5-mediyl-oxazol-4-yl]-propan-l-ol (See Intermediate
41) (0.189 g, 0.638 mmol), Pd(Ph3)4 (0.038 g, 0.032 mmol), 4-
methylsulfonylphenylboronic acid (0.192 g, 0.957 mmol), 2N Na2C03 (1.6 mL), and 1,4-
dioxane (2.0 mL) to a microwave vessel. Subject the reaction mixture to microwave
irradiation at 30 W, 90 °C for 30-45 minutes. Concentrate and purify on silica gel eluting
with 8% 2N NH3 in methanol/dichloromethane to give 3-[2-(4'-methanesuIfonyl-
biphenyl-4-yl)-5-methyl-oxazol-4-yl]-propan-l-ol (0.170 g, 72%): MS (m/e): 372(M+1).
b) Add methanesulfonyl chloride (0.086 g, 0.60 mmol) to a cool (0°C) solution of 3-
[2-(4'-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-propan-l-ol (0.170 g, 0.458
mmol) and triethylamine (0.070 g, 0.69 mmol) in dichloromethane (3 mL). Warm the
reaction mixture to room temperature and stir for 1 hour. Add dichloromethane and wash
the crude organic material with saturated sodium chloride solution. Dry the organic
extracts over Na2SC>4, filter, and concentrate to give crude methanesulfonic acid 3-[2-(4'-
methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-propyl ester (0.206 g, 100%): MS
(m/e): 450(M+1).
c) Add a solution of methanesulfonic acid 3-[2-(4'-methanesulfonyl-biphenyl-4-yl)-5-
rnemyl-oxazoI-4-yi]-propyl ester (0.206 g, 0.458 mmol) in 3 mL acetonitrile to a sealed
tube containing 2R-methyl-pyrrohdine hydrochloride (See Intermediate 7) (0.111 g, 0.916
mmol), K2CO3 (0.221 g, 1.60 mmol), and KI (0.008 g, 0.05 mmol), and heat at 60 °C
overnight. Add dichloromethane and wash the crude organic layer with saturated sodium
chloride solution. Dry the organic extracts over N^SQt, filter, and concentrate. Purify on
silica gel eluting with 8% ammoniated methanol in dichloromethane to give to give 2-(4'-
memanesulfonyl-biphenyl^-yl)-5-memyl-4-[3-(2/?-methyl-pyiTolidm-l-yl)-propyl]-
oxazole (0.130 g, 65%): MS (m/e): 439(M+1).
d) Treat the recovered material (0.130 g, 0.296 mmol) with IN HC1 (326 |iL, 0.326
mmol) in ether and freeze dry to give the title compound (0.144 g, 100%): MS (m/e):
439(M+1).
Example 93
l-{2-[2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazoI-4-yr|-ethyI}-2R-methyl-
piperidine hydrochloride

a) l-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-2-methylpiperidine
was separated into its isomers on 0.46x15 cm Chiralpak® AD-H column with MeOH w/
0.2% DMEA (Flow: 0.6 rnL/min, UV: 290 nm). The isomers were assigned by
comparison to a standard l-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-2S-
methylpiperidine prepared from enantiomerically pure commercially available 2S-
methylpiperidine.
b) Add l-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-2R-
metiiylpiperidine (0.094 g, 0.26 rnmol), Pd(Ph3)4 (0.013 g, 0.011 mmol), 4-
methylsulfonylphenylboronic acid (0.072 g, 0.36 mmol), 2N Na2C03 (0.64 mL), and 1,4-
dioxane (1 mL) to a microwave vessel. Subject the reaction mixture to microwave
irradiation at 30 W, 90 °C for 30-45 minutes. Add dichloromethane and wash the crude
organic layer with saturated sodium chloride solution. Dry the organic extracts over
Na2S(>4, filter, and concentrate. Purify on silica gel eluting with 8% ammoniated
methanol in dichloromethane to give l-{2-[2-(4'-methanesulfonyl-biphenyl-4-yl)-5-
inemyl-oxazol-4-yl]-ediyl}-2Il-rjM;thyl-piperidine (0.094 g, 84%): MS (m/e): 439(M+1).
c) Treat the recovered material (0.094 g, 0.22 mmol) with IN HC1 (237 uJL, 0.237
mmol) in ether and freeze dry to give the title compound (79 mg, 77%): MS (m/e): 439
(M+l).
Example 94
2-(4'-MetbanesnIfonyI-biphenyI-4-yl)-S-metbyl-4-(3-pyrroKdin-l-yl-propyI)-oxazole
hydrochloride

The free base of the title compound is prepared in a manner similar to that
described in Example 92 using 3-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-propan-l-ol
and pyrrolidine. The free base is converted to the hydrochloride salt according to the
procedure described for Example 92 to provide the title compound: MS (m/e): 425
(M+l).
Example 95
l-[2-(4'-MethanesulfonyI-biphenyl-4-yI)-5-methyI-oxazol-4-yl]-2-(2R-methyl-
pyrrolidin-l-yl)-ethanol hydrochloride

a) Add a solution of 2-bromo-l-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-
ethanol (0.500 g, 0.139 mmol) in 8 mL acetonitrile to a sealed tube containing 2R-
methyl-pyrrolidine hydrochloride (See Intermediate 7) (0.507 g, 4.1(5 mmol), K2C03
(0.959 g, 6.95 mmol), and KI (0.002 g, 0.01 mmol), and heat at 60 °C overnight. Add
dichloromethane and wash die crude organic layer with saturated sodium chloride
solution. Dry the organic extracts over Na2SC>4, filter, and concentrate. Purify on silica
gel eluting with 5% ammoniated methanol in dichloromethane to give l-[2-(4-bromo-
phenyl)-5-methyl-oxazol-4-yl]-2-(2R-methyl-pyrrolidin-l-yl)-ethanol (0.221 g, 44%):
mass spectrum (m/e): 365 (M+l).
b) Add l-[2^4-bromo-phenyl)-5-methyI^xazol^yl]-2-(2R-attemyl-pyrro]idin-l-
yl)-ethanol (0.220 g, 0.580 mmol) to a solution of Pd(Ph3)4 (0.034 g, 0.029 mmol), 4-
methylsulfonylphenylboronic acid (0.104 g, 0.522 mmol), Na2C03 (0.123 g, 1.16 mL) in
acetonitrile (5 mL) and water (5 mL). Heat the reaction mixture at reflux for 3 hrs. Add
dichloromethane and wash the crude organic material with saturated sodium chloride
solution. Dry the organic extracts over Na2SO gel eluting with 8% ammoniated methanol in dichloromethane to give l-[2-(4'-
memanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-2-(2R-methyl-pyrrolidin-l-yl)-
ethanol (0.189 g, 72%): mass spectrum (m/e): 441(M+1).
c) Treat the recovered material (0.100 g, 0.227 mmol) with IN HCl (250 ^iL,
0.250 mmol) in ether and freeze dry to give the title compound (0.101 g): mass spectrum
(m/e): 441(M+1).
Example 96
2-(4'-Methanesulfonyl-biphenyl-4-yl)-4-[l-methoxy-2-(2R-methyl-pyrrolidin-l-yl)-
ethylJ-5-methyl-oxazole hydrochloride

a) Add Mel (0.035 g, 0.25 mmol) and NaH (60%, 0.006 g, 0.2 mmol) to a cold (0
°C) solution of l-[2-(4'-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-2-(2R-
methyl-pyrrolidin-l-yl)-ethanol (See Example 95) (0.078 g, 0.18 mmol) in THF and stir
at this temperature for 2 hi. Add several drops of saturated NH4CI and dichloromethane.
Wash the crude organic extracts with saturated NaCl, dry over MgSCXi, filter, and
concentrate. Purify on silica gel eluting with 7% ammoniated methanol in
dichloromethane to give 2-(4'-methanesulfonyl-biphenyl-4-yl)-4-[l-methoxy-2-(2R-
methyl-pyrrolidin-l-yl)-ethyl]-5-methyl-oxazole (0.010 g, 13%): mass spectrum (m/e):
455(M+1).
b) Treat the recovered material (0.010 g, 0.023 mmol) with IN HC1 (24 (JL, 0.024
mmol) in ether and freeze dry to give the title compound (11.2 mg): mass spectrum (m/e):
455(M+1).
Example 97
2-(4^MethaDesuIfonyl-biphenyl-4-yl)-5-niethyl-4-[2-(2S-niethyl-pyrroIidin-l-yl)-
ethyI]-oxazole hydrochloride

a) Add methanesulfonic acid 2-[2-(4'-methanesulfonyl-biphenyl-4-yl)-5-methyl-
oxazoI-4-yl]-ethyl ester (TP1-A07475-04) (0.139 g, 0.299 mmol) to a solution of 2S-
methyl-pyrrolidine hydrochloride (See Intermediate 46) (0.109 g, 0.896 mmol), K2CO3
(0.206 g, 1.49 mmol), and KI (0.0005 g, 0.003 mmol), and heat the reaction mixture at
reflux for 6 hrs. Add dichloromethane and wash the crude organic layer with saturated
sodium chloride solution. Dry the organic extracts over Na2SC>4, filter, and concentrate.
Purify on silica gel eluting with 5% ammoniated methanol in dichloromethane to give _2-
(4'-methanesulfonyl-biphenyl-4-yl)-5-methyl-4-[2-(2S-methyl-pyrrolidin-l-yl)-ethyl]-
oxazole (0.140 g, quantatative): mass spectrum (m/e): 425 (M+l).
b) Treat the recovered material (0.100 g, 0.227 mmol) with IN HC1 (250 (XL,
0.250 mmol) in ether and freeze dry to give the title compound (115 mg): mass spectrum
(m/e): 425 (M+l).
3-Methyl-6-(4-{5-methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-phenyl)-
pyridazine

The titled compound is prepared substantially in accordance with the procedures
of Intermediate 13 and Example 75 using 2-{5-Methyl-2-[4-(6-mediyl-pyridazin-3-yl)-
phenyl]-oxazol-4-yl}-ethanol (See Intermediate 47) and 2R-methylpyrroIidine
hydrochloride (see Intermediate 7). MS (m/e) 363.3 (M+l).
Example 99
2-(4-Bromo-phenyl>-5-methyl-4-(2-n»ethyl-pyrrolidin-l-ylmethyI)-oxazole

The titled compound is prepared substantially in accordance with the procedure of
Example 75 using die 2^4-Broino-phenyl)-4-chloromethyl-oxazole (See Intermediate 1)
and 2R-methylpyrrolidine hydrochloride (see Intermediate 7). MS (m/e) 337.0 (M+l).
Example 100
2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyl-4-(2-methyI-pyrrolidin-l-yImethyl)-
oxazole

The titled compound is prepared substantially in accordance with the procedure of
Example 9 using 2-(4-Bromo-phenyl)-5-methyl-4-(2-methyl-pyrrolidin-l-ylmethyl)-
oxazole (See Example 99) and 4-methylsulfonylphenylboronic acid. MS (m/e) 411.2
(M+l).
Example 101
5-{5-Methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-2-phenoxy-pyridine

The titled compound is prepared substantially in accordance with the procedure of
Example 75 using Toluene-4-sulfonic acid 2-[5-methyl-2-(6-phenoxy-pyridin-3-yl)-
oxazol-4-yl]-ethyl ester [prepared by the method of S.E.Connor, WO 2003072102] and
2R-methylpyrrolidine hydrochloride (see Intermediate 7). MS (m/e) 364.2 (M+l).
Example 102
2-(4-Bromophenyi)-4-{2-[(3S)-3-fluoropyrrolidin-l-yl]ethyl}-5-methyI-l,3-oxazole

To a solution of 2-[2^4-bromopheiiyl)-5-methyl-13-oxazol-4-yi}ethyl
rnethanesulfonate (See intermediate 13) (0.16 g, 0.44 mmole) in anhydrous acetonitrile (2
mL) add potassium carbonate (0.21 g, 1.54 mmol) and potassium iodide (0.007 g, 0.04
mmol), followed by (35)-3-fluoropyrrolidiQe 4-methylbenzenesulfonate (salt) (See
Intermediate 49) (0.21 g, 0.79 mmol). Heat the reaction mixture to 60 °C (oil bath
temperature) overnight. Add water and extract with dichloromethane. Dry the combined
extracts over sodium sulfate then concentrate in vacuo to give an orange oil (0.15 g).
Load the oil onto a 5 g Isolute® SCX-2 column (preconditioned with methanol). Wash
the SCX-2 with methanol then elute the target compound with 2N ammonia in methanol
solution. Concentrate of the ammonia solution in vacuo to give the title compound as an
orange oil (0.14 g): MS (m/e) (79Br/81Br): 353,355 (M+l)
Example 103
4-{[(3S)-3-fluoropyrrolidin-l-yl]ethyl}-2-[4,-(methylsulfonyl)biphenyl-4-yl]-S-
methyl-l,3-oxazole

To a solution of palladium (II) acetate (0.002 g, 0.008 mmol) in anhydrous
acetonitrile (4 mL), add triphenylphosphine (0.008 g, 0.032 mmol), under nitrogen and at
room temperature. Stir for 15 minutes then add distilled water (1 mL), 4-
(methanesulfonyl)benzeneboronic acid (0.089 g, 0.416 mmol), 2-(4-bromophenyl)-4-{2-
[(35)-3-fluoropyrrolidin-l-yl]ethyl)-5-methyl-l,3-oxazole (0.140 g, 0.396 mmol) (see
example 102) and potassium carbonate (0.164 g, 1.19 mmol). Heat the reaction mixture
at 70 °C overnight.
Cool to room temperature then pour into water. Extract with dichloromethane
then concentrate the combined extracts in vacuo. Load onto a 5 g Isolute® SCX-2
column (preconditioned with methanol). Wash the SCX-2 with methanol then elute the
target compound with 2N ammonia in methanol solution followed by 7N ammonia in
methanol. Concentrate the combined ammonia solutions in vacuo to give a pale yellow
solid (0.16 g). Purify using automated flash chromatography (ISCO® System, 12 g
Redisep® SiO? column; 0 - 30% methanol in ethyl acetate gradient elutkra over 20
minutes at 30 rnL/rnin) to give the title compound as a pale yellow solid (0.133 g): MS
(m/e):429(M+l).
Example 104
2-(4-BronMq>henyI)-4-{2-[(3/f)-3-fluoropyrrolidin-l-yI]ethyl}-5-methyl-l^-oxazoIe

Prepare using the method of Example 102 with 2-[2-(4-bromophenyl)-5-methyl-
l,3-oxazol-4-yl]ethyl methanesulfonate (See Intermediate 13) (0.16 g, 0.44 mmole),
anhydrous acetonitrile (2 mL), potassium carbonate (0.21 g, 1.54 mmol), potassium
iodide (0.007 g, 0.04 mmol) and (3J?)-3-fluoropyrrolidine 4-methylbenzenesulfonate
(salt) (See Intermediate 51) (0.21 g, 0.79 mmol) to give the title compound as a pale
orange oil (0.16 g): MS (m/e) (79Br/81Br): 353, 355(M+1)
Example 105
4-{[(3*)-3-FluoropyrroIidin-l-yl]ethyl}-2-t4'-(methylsulfonyl)biphenyl-4-yl]-5-
methyl-l^-oxazole

Prepare using the method of Example 103 with palladium (II) acetate (0.002 g,
0.008 mmol), anhydrous acetonitrile (4 mL), triphenylphosphine (0.009 g, 0.034 mmol),
distilled water (1 mL), 4-(methanesulfonyl)benzenehoronic acid (0.096 g, 0.45 mmol), 2-
(4-bromophenyl)-4-{2-[(35)-3-fluoropyrrolidin-l-yl]ethyl}-5-methyl-l,3-oxazole(See
Example 104) (0.150 g, 0.42 mmol) and potassium carbonate (0.176 g, 1.27 mmol) to
give the title compound as a cream coloured solid (0.133 g): MS (m/e): 429(M+1).
Example 106
(3i!!)-l-{2-[2-(4-Broinophenyl)-5-methyI-13-oxazol-4-yI]ethyl}pyrroIidiii-3-ol

Prepare using the method of Example 102 with 2-[2-(4-broniophenyl)-5-methy]-
l,3-oxazol-4-yl]ethyl methanesulfonate (See Intermediate 13) (0.16 g, 0.44 mmole),
anhydrous acetonitrile (2 mL), potassium carbonate (0.21 g, 1.54 mmol), potassium
iodide (0.007 g, 0.04 mmol) and (3/?)-pyrrolidin-3-ol 4-methylbenzenesuIfonate (salt)
(See Intermediate 52) (0.13 g, 0.51 mmol) to give the title compound as a pale orange oil
(0.15 g): MS (m/e) (79Br/81Br): 351, 353(M+1)
Example 107
4-{[(3/?)-3-Hydroxypyrrolidin-l-yl]ethyl}-2-[4*-(methyIsulfonyl)biphenyl-4-yl]-5-
methyl-l,3-oxazoIe acetate (salt)

Prepare using the method of Example 103 with palladium (II) acetate (0.002 g,
0.008 mmol), anhydrous acetonitrile (4 mL), triphenylphosphine (0.009 g, 0.034 mmol),
distilled water (1 mL), 4-(methanesulfonyI)benzeneboronic acid (0.096 g, 0.45 mmol),
(3/?)-1 -{2-[2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yI]ethyl}pyrrolidin-3-ol (See
Example 106) (0.150 g, 0.43 mmol) and potassium carbonate (0.177 g, 1.28 mmol).
Additionally purify using mass guided HPLC to give the title compound as a cream
coloured solid (0.034 g): MS (m/e): 427(M+1).
Example 108
(35)-l-{2-[2-(4-BromophenyI)-5-methyM^-oxa2ol-4-yI]ethyI}pyrrolidin-3-ol

Prepare using the method of Example 102 with 2-[2-(4-bromophenyl)-5-methyl-
l,3-oxazol-4-yI]ethyl methanesulfonate (See Intermediate 13) (0.16 g, 0.44 mmole),
anhydrous acetonitrile (2 mL), potassium carbonate (0.21 g, 1.54 mmol), potassium
iodide (0.007 g, 0.04 mmol) and (3S)-pyrrolidin-3-ol 4-mediylbenzenesulfonate (salt)
(See Intermediate 53) (0.21 g, 0.80 mmol) to give the title compound as a pale orange oil
(0.15 g): MS (m/e) C'W'Br): 351,353(M+1)
Example 109
4^[(3S)-3-HydroxypyiTolidin-l-yl]^
methyl-l^-oxazole acetate (salt)

Prepare using the method of Example 103 with palladium (II) acetate (0.002 g,
0.008 mmol), anhydrous acetonitrile (4 mL), triphenylphosphine (0.009 g, 0.034 mmol),
distilled water (1 mL), 4-(rnethanesulfonyl)benzeneboronic acid (0.096 g, 0.45 mmol),
(3S)-l-{2-[2-(4-bromophenyl)-5-methyl-l,3-oxazoI-4-yl]ethyl}pyrrolidin-3-ol(See
Example 108) (0.150 g, 0.43 mmol) and potassium carbonate (0.177 g, 1.28 mmol).
Additionally purify using mass guided HPLC to give the title compound as a cream
coloured solid (0.035 g): MS (m/e): 427(M+1).
Example 110
2-(4-BromophenyI)-4-{2-[(35)-3-(fluoromethyl)pyrrolidin-l-yI]ethyl}-5-methyl-l,3-
oxazole

Prepare using the method of Example 102 with 2-[2-(4-bromophenyl)-5-methyl-
l,3-oxazol-4-yl]ethyl methanesulfonate (See Intermediate 13) (0.17 g, 0.46 mmole),
anhydrous acetonitrile (2 mL), potassium carbonate (0.25 g, 1.84 mmol), potassium
iodide (0.008 g, 0.05 mmol) and (35)-3-(fluoromethyl)pyrrolidine 4-
methylbenzenesulfonate (salt) (See Intermediate 55) (0.19 g, 0.69 mmol) to give the title
compound as a pale orange oil (0.17 g): MS (m/e): 367, 369(M+1)
Example 111
4-{2-f(3S)-3-(Fluo^omethyl)py^rolidin-l-yl]ethyl}-5-methyl.2-[4,-
(metbylsutfonyl)biphenyl-4-yl]-l,3-oxazole

Prepare using the method of Example 103 with palladium (II) acetate (0.002 g,
0.01 mmol), anhydrous acetonitrile (4 mL), triphenylphosphine (0.010 g, 0.04 mmol),
distilled water (1 mL), 4-(methanesulfonyl)benzeneboronic acid (0.10 g, 0.49 mmol), 2-
(4-bromophenyl)-4-{2-[(35)-3-(fluoromethyl)pyiTolidin-l-yl]ethyI}-5-methyl-I,3-oxazole
(See Example 110) (0.17 g, 0.46 mmol) and potassium carbonate (0.19 g, 1.39 mmol).
Additionally triturate the resulting solid with 2:1 diethyl ether : ethyl acetate to give the
title compound as a yellow coloured solid (0.07 g): MS (m/e): 443(M+1).
Example 112
2-(4-Broraophenyl)-4-{2-[(3/?)-3-(fluoromethyl)pyrroIidin-l-yl]ethyI}-5-methyl-l^-

Prepare using the method of Example 102 with 2-[2-(4-bromophenyl)-5-methyl-
l,3-oxazol-4-ylJethyl methanesulfonate (See Intermediate 13) (0.36 g, 0.99 mmole),
anhydrous acetonitrile (2 mL), potassium carbonate (0.55 g, 3.98 ramol), potassium
iodide (0.016 g, 0.10 mmol) and (3/?)-3-(fluoromethyl)pyrrolidine 4-
methylbenzenesulfonate (salt) (See Intermediate 57) (0.41 g, 1.49 mmol) to give the title
compound as a pale orange oil (0.34 g): MS (m/e) (79Br/8lBr): 367, 369(M+1)
Example 113
4-{2-[(3i^)-3-(Fluoromethyl)pyrrolidin-l-yl]ethyl}-5-methyI-2.[4,-
(methylsuIfonyl)biphenyl-4-yl]-l,3-oxazole

Prepare using the method of Example 103 with palladium (II) acetate (0.003 g,
0.01 mmol), anhydrous acetonitrile (4 mL), triphenylphosphine (0.014 g, 0.05 mmol),
distilled water (1 mL), 4-(methanesulfonyl)benzeneboroiuc acid (0.15 g, 0.71 mmol), 2-
(4-bromophenyl)^{2-[(3i?>3KfliK)rornetbyl)pyrrolidm-l-yl]emyl}-5-methyl-l,3^
oxazole (See Example 112) (0.25 g, 0.68 mmol) and potassium carbonate (0.28 g, 2.04
mmol). Additionally triturate the resulting solid with 2:1 diethyl etfier : ethyl acetate to
give the title compound as a pale yellow coloured solid (0.11 g): MS (m/e): 443 (M+l).
Example 114
3-[4-(5-{2-[(3R)-3-(FluoromethyI)pyrrolidin-l-y[]ethyl}-4-methyl-ly3-oxazol-2-
yl)phenyl]pyridine L-tartrate

Prepare using the method of Example 103 with palladium (II) acetate (0.001 g,
0.005 mmol), anhydrous acetonitrile (4 mL), triphenylphosphine (0.006 g, 0.02 mmol),
distilled water (1 mL), 3-pyridylboronic acid (0.035 g, 0.29 mmol), 2-(4-bromophenyl)-4-
{2-[(3/?)-3-fluoropyrrolidin-l-yl]ethyl}-5-methyl-l,3-oxazole (See Example 112) (0.09 g,
0.25 ramol) and potassium carbonate (0.11 g, 0.82 mmol) to give a pale orange oil (0.061
g). Dissolve the oil in ethyl acetate. Add L-tartaric acid (0.025 g, 0.17 mmole) as a
solution in ethanol. Remove the solvent under vacuum. Add dichloromethane and
concentrate under vacuum to give the title compound as a pale yellow coloured foam
(0.086 g): MS (m/e): 366(M+1).
Example 115
2-(4-Bromophenyl)-4-{2-[(3/f)-3-methoxypyrroIidin-l-yl]ethyl}-S-methyI-l,3-oxazole

Prepare using the method of Example 102 with 2-[2-(4-bromophenyl)-5-methyl-
l,3-oxazol-4-yl]ethyl methanesulfonate (See Intermediate 13) (0.32 g, 0.89 mmole),
anhydrous acetonitrile (4 mL), potassium carbonate (0.43 g, 3.11 mmol), potassium
iodide (0.015 g, 0.09 mmol) and (3/?)-3-methoxypyrrolidine 4-methylbenzenesulfonate
(salt) (See Intermediate 59) (0.25 g, 0.91 mmol) to give the title compound as a pale
orange oil (0.25 g): MS (m/e) (^r/^Br): 365, 367(M+1)
Example 116
4-{2-t(3«)-3-methoxypyrrolidin-l-yl]ethyl}-5-methyI-2-[4'-(methylsulfonyl)biphenyl-
4-yl]-l,3-oxazole

Prepare using the method of Example 103 with palladium (II) acetate (0.003 g,
0.014 mmol), anhydrous acetonitrile (4 mL), triphenylphosphine (0.014 g, 0.055 mmol),
distilled water (1 mL), 4-(methanesulfonyl)benzeneboronic acid (0.22 g, 1.03 mmol), 2-
(4-bromophenyl)-4- {2-[(3/?)-3-methoxypyrrolidin-l-yl]ethyl }-5-methyl-1,3-oxazole (See
Example 115) (0.25 g, 0.68 mmol) and potassium carbonate (0.28 g, 2.05 mmol) to give
the title compound as a white solid (0.17 g): MS (m/e): 441(M+1).
Example 117
2-(4-Bromophenyl)-4-{2-[(35)-3-methoxypyrrolidin-l-yl]ethyI}-5-methyl-l,3-oxazole

Prepare using the method of Example 102 with 2-[2-(4-bromophenyl)-5-methyl-
l,3-oxazol-4-yl]ethyl methanesulfonate (See Intermediate 13) (0.16 g, 0.44 mmole),
anhydrous acetonitrile (2 mL), potassium carbonate (0.21 g, 1.54 mmol), potassium
iodide (0.007 g, 0.04 mmol) and (3S)-3-methoxypyrrolidine 4-rnethylbenzenesulfonate
(salt) (See Intermediate 61) (0.22 g, 0.79 mmol) to give the title compound as a pale
orange oil (0.10 g): MS (m/e) (79Br/8,Br): 371, 373(M+1)
Example 118
4-{2-[(3S)-3-Methoxypyrrolidin-l-ylJethyI}-5-methyl-2-[4'-(methy!sulfonyl)biphenyl-
4iyl]-ly3-oxa«ole

Prepare using the method of Example 103 with palladium (II) acetate (0.003 g,
0.015 mmol), anhydrous acetonitrile (4 mL), triphenylphosphine (0.016 g, 0.059 mmol),
distilled water (1 mL), 4-(methanesulfonyl)benzeneboronic acid (0.24 g, 1.11 mmol), 2-
(4-bromophenyl)-4-{2-[(35)-3-methoxypyrrolidin-l-yl]ethyl}-5-methyl-l,3-oxazole(See
Example 117) (0.27 g, 0.74 mmol) and potassium carbonate (0.31 g, 2.22 mmol) to give
the title compound as a white solid (0.12 g): MS (m/e): 441(M+1).
Example 119
2-(4-Bromophenyl)-4-{2-[(2/?)-2-methylpyrrolidin-l-yl]ethyI}-5-methyI-l,3-oxazole

Prepare using the method of Example 102 with 2-[2-(4-bromophenyI)-5-methyl-
l,3-oxazol-4-yl]ethyl methanesulfonate (See Intermediate 13) (0.65 g, 1.80 mmole),
anhydrous acetonitrile (6 mL), potassium carbonate (0.87 g, 6.32 mmol), potassium
iodide (0.03 g, 0.18 ramol) and (2/?)-2-methylpyrrolidine hydrochloride (salt) (See
Intermediate 7) (0.25 g, 2.08 mmol) to give the title compound as a pale orange oil (0.65
g): MS (m/e) (79Br/81Br): 349, 351(M+1)
Example 120
3-Methoxy-5-[4-(5-methyl-4-{2-[(2/?)-2-methylpyrrolidin-l-yI]ethyI}-l>3-oxazol-2-
yl)phenyl]pyridine

To a solution of palladium (II) acetate (0.004 g, 0.02 mmol) in anhydrous toluene
(5 mL), add triphenylphosphine (0.019 g, 0.07 mmol), under nitrogen and at room
temperature. Stir for 15 minutes then add distilled water (1.5 mL), ethanol (1 mL), 3-
methoxypyridine-5-boronic acid pinacol ester (0.26 g, 1.10 mmol), 2-(4-bromophenyl)-4-
{2-[(2J?>2-methylpyrrolidin-l-yl)ethyl}-5-methyl-l,3-oxazole (See Intermediate 73)
(0.32 g, 0.92 mmol) and potassium carbonate (0.38 g, 2.75 mmol). Heat the reaction
mixture at 110 °C overnight Cool to room temperature then pour into water. Extract
with dichloromethane then concentrate the combined extracts in vacuo. Load onto a 10 g
Isolute® SCX-2 column (preconditioned with methanol). Wash the SCX-2 with
methanol then elute the target compound with 2N ammonia in methanol solution followed
by 7N ammonia in methanol. Concentrate the combined ammonia solutions in vacuo to
give a pale yellow solid (0.16 g). Purify using automated flash chromatography (ISCO®
System, 12 g Redisep® Si02 column; 0 - 30% methanol in ethyl acetate gradient elution
over 20 minutes at 30 mL/rnin) to give the title compound as a pale yellow solid (0.23 g):
MS (m/e): 378(M+1).
Example 121
5-[4-(5-Methyl-4-{2-[(2/?)-2-methylpyrrolidin-l-yl]ethyl}-l,3-oxazol-2-
yI)phenyl]thiophene-2-carbonitrile

Prepare using the method of Example 120 with palladium (II) acetate (0.008 g,
0.04 mmol), anhydrous toluene (5 mL), triphenylphosphine (0.038 g, 0.15 mmol),
distilled water (1.5 mL), ethanol (1 mL), 5-cyanothiophene-2-boronic acid (0.21 g, 1.37
mmol), 2-(4-bromophenyl)-4-{2-[(2/?)-2-methylpyn-olidin-l-yl]ethyl}-5-me%l-l,3-
oxazole (See Intermediate 73) (0.32 g, 0.92 mmol) and potassium carbonate (0.38 g, 2.75
mmol). Additionally purify by trituration with ethyl acetate to give the title compound as
a cream coloured solid (0.03 g): MS (m/e): 378(M+1).
Example 122
2-Methoxy-5-[4-(5-methyl-4-{2-[(2i?)-2.niethylpyrroIidin-l-yl]ethyI}-l^-oxazol-2.
yl )pheny l]py rimidin e

Prepare using the method of Example 103 with palladium (II) acetate (0.011 g,
0.05 mmol), anhydrous acetonitrile (8 mL), triphenylphosphine (0.051 g, 0.19 mmol),
distilled water (2 mL), 2-methoxy-5-pyrimidineboronic acid (0.75 g, 4.87 mmol), 2-(4-
bromophenyI>4- {2-[(2J?)-2-methylpyrrolidin-1 -yl]ethyl} -5-methyl-1,3-oxazole (See
Intermediate 73) (0.85 g, 2.43 mmol) and potassium carbonate (0.1.01 g, 7.30 mmol).
Additionally recrystallise from acetonitrile / ethyl acetate to give the title compound as a
cream coloured solid (0.016 g): MS (m/e): 379(M+1).
Example 123
5-(4-{5-Methyl-4-[2-(2-(R)-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yI}-
phenoxymethyl)-thiophene-2-carbonitrile

The title compound is prepared in a manner substantially similar to Example 57
from2-[2-(4-Hydroxy-phenyl)-5-metliyl-oxazol-4-yl]-l-(2-(R)-methyl-pyn"olidb-l-yl)-
ethanone (See Example 56) and 5-bromomethyl-thiophene-2-carbonitrile [CAS 134135-
41-4]. MS (m/e): 408.3 (M+l)
5-MethyI-4-[2-(2-(R)-methyl-pyrrolidin-l-yl)-ethyl]-2-[4-(2-methyl-thiazol-4-
ylmethoxy)-phenyI]-oxazole

The title compound is prepared in a manner substantially similar to Example 58 from 2-
[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-l-(2-(R)-methyl-pyrrolidin-l-yl)-emanone
(See Example 56) and 4-(chloromethyl)-2-methylthiazole hydrochloride. MS (m/e):
398.3 (M+l)
Example 125
3-(4^5-Methyl-4-{2-(2-{R)-methyl-pyrroUdin-l-yl)-ethyl]-oxazoI-2-yl}-
phenoxymethyl)-pyridine

The title compound is prepared in a manner substantially similar to Example 57
from2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazo]-4-yl]-l-(2-(R)-methyl-pyrroIidin-l-yl)-
ethanone (See Example 56) and 3-(bromomethyl)pyridine hydrobromide. MS (m/e):
378.3 (M+l)
Example 126
4-(4-{5-Methyl-4-[2-(2-(R)-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-
phenoxymethyl)-pyridine

The title compound is prepared in a manner substantially similar to Example 57
from 2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yI]- l-(2-(R)-methyl-pyrroIidin-l-yl)-
ethanone (See Example 56) and 4-(bromomethyl)pyridine hydrobromide. MS (m/e):
378.3 (M+I)
Example 127
2-Methoxy-5-(4-{5-methyI-4-[2-(2-(R)-methyl-pyrroIidin-l-yI)-ethyl]-oxazol-2-yl}-
phenoxymethyl)-pyridine

The title compound is prepared in a manner substantially similar to Example 58
from2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-l-(2-(R)-methyl-pyrrolidin-l-yl)-
ethanone (See Example 56) and 5-chloro-2-methoxypyridine hydrochloride [CAS
120276-36-0]. MS (m/e): 408.3 (M+l)
Example 128
2-Methyl- phenoxymethyl)-pyridine

The title compound is prepared in a manner substantially similar to Example 58 from 2-
[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-l-(2-(R)-methyl-pyrrolidin-l-yl)-ethanone
(See Example 56) and 2-chloromethyl-6-methyl-pyridine hydrochloride [CAS 3099-30-
7]. MS (m/e): 392.3 (M+l)
Example 129
5-Methyl-4-[2-(2-(R)-methyl-pyrroIidin-l-yl)-ethyI]-2-[4-(thiazol-4-ylmethoxy)-
phenylj-oxazole

The title compound is prepared in a manner substantially similar to Example 55
from 1 -(2-(R)-Methyl-pyrrolidin-1 -yl)-2- {5-methyl-2-[4-(thiazol-4-ylmethoxy)-phenyl3-
oxazol-4-yl}-ethanone (See Intermediate 63). The crude material is purified by flash
chromatography (12 g Si02, elute elute 20% (10% 2 M NH3 in MeOH/90% CH2Cl2)/80
% CH2Cl2 to 80% (10% 2 M NH3 in MeOH/90% CH2Cl2)/20% CH2C12). MS (m/e):
384.2 (M+l)
Example 130
2-(4-{4-[2-(2-(R)-Methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yI}-phenoxymethyl)-
pyridine

The title compound is prepared in a manner substantially similar to Example 53
from 2-{2-[4-(Pyridrn-2-ylme*hoxy)-phenyll-oxazol-4-yl}-ethanol (See Intermediate 66)
and (R>2-methylpynolidine hydrochloride [CAS 41720-98-3]. MS (m/e): 364.2 (M+l)
Example 131
4-[2^2-(R)-Methyl-pyTrolidin-l-yl)-ethyl)-2-[4-(thiazol-4-ylmethoxy)-phenyl]-
oxazole

The title compound is prepared in a manner substantially similar to Example 53
from 2-{2-[4-(Thiazol-4-ylmethoxy)-phenyl]-oxazol-4-yl}-euianol (See Intermediate 68)
and (R)-2-methylpyrrolidine hydrochloride [CAS 41720-98-3]. MS (m/e): 370.2 (M+l)
Example 132
2-(4'-MethanesulfonyI-biphenyl-4-yl)-4-[2-(2-(R)-methyl-pyrrolidin-l-yl)-ethyI]-
oxazole

The title compound is prepared in a manner substantially similar to Example 53
from 2-[2-(4'-Memanesulfonyl-biphenyl-4-yl)-oxazol-4-yl]-ethanol (See Intermediate 71)
and (R)-2-methylpyrrolidine hydrochloride [CAS 41720-98-3]. MS (m/e): 411.2 (M+l)
Example 133
l-(4'-{5-Methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yI}-biphenyl-4-
yl)-ethanone

To a stirred solution of 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-l-
yl)-ethyl]-oxazole (100 mg, 0.287 mmol), sodium carbonate (91 mg, 0.860 mmol) and 4-
acetylphenyl boronic acid (235 mg, 1.43 mmol) in toluene (5 mL), water (1 mL) and
ethanol (1.5 mL) under nitrogen is added Tetrakis (triphenylphosphine) palladium (0)
(33.1 mg, 0.029 mmol). The reaction is heated at reflux for 48 h. The reaction is allowed
to cool and bound to a SCX-2 cartridge (10 g). The cartridge is washed with one cartridge
volumes of dimemylformamide and two volume of methanol. The product is eluted using
2M ammonia in methanol. The anunonia/methanol solution is evaporated on a Genevac®
HT4. The sample is further purified by prep-LCMS. The resulting acetonitrile/water
fractions are combined and evaporated using a Genevac® HT4 to give 62 mg of a
colourless oil (56 %). MS (m/e) 389.2 (M+l)
Example 134
l-(4'-{5-Methyl-4-[2-((R)-2-methyl-pyrroUdin-l-yl)-ethyl]-oxazol-2-yl}-biphenyI-2-
yl)-ethanone

The title compound is prepared in a manner substantially analogous to example 133
starting from 2-acetylphenyl boronic acid (235 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-
5-methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to
give 94 mg (85%). MS (m/e) 389.2 (M+l)
Example 135
4,-{5-MethyI.4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-oxazoi-2-yl}-biphenyl-3-
carbonitrile

The title compound is prepared in a manner substantially analogous to example 133
starting from 3-Cyanobenzene boronic acid (211 mg, 1.43 mmol) and 2-(4-Bromo-
phenyl)-5-methyl-4-[2-((R)"2-methyl-pyrrolidin-l-yl)-ethyl]-oxazole (100 mg, 0.287
mmol) to give 50 mg (47%). MS (m/e) 372.2 (M+l)
Example 136
4M5-Methy]^[2^(R)-2-methyl-pyrrriidin-l-yI)-ethyl]^>xazol-2-yl}-btphenyl-2-
carbonitriie

The title compound is prepared in a manner substantially analogous to example 133
starting from 2-Cyanobenzene boronic acid (211 mg, 1.43 mmol) and 2-(4-Bromo-
phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-oxazole (100 mg, 0.287
mmol) to give 70 mg (66%). MS (m/e) 372.2 (M+l)
Example 137
2-(4'-FIuoro-biphenyl-4-yl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-
oxazole

The title compound is prepared in a manner substantially aniilogous to example
133 starting from 4-fluorobenzene boronic acid (201 mg, 1.43 mmol) and 2-(4-Bromo-
phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-oxazole (100 mg, 0.287
mmol) to give 10 mg (10%). MS (m/e) 365.2 (M+l)
Example 138
2-(3,-Fluoro-biphenyl-4-yl)-5-methyl-4-[2-((R)-2-methyl-pyrroIidin-l-yl)-ethyl]-
oxazole

The title compound is prepared in a manner substantially analogous to example
133 starting from 3-fluorobenzene boronic acid (201mg, 1.43 mmol) and 2-(4-Bromo-
pheoyl)-5-methyl-4-[2K(R)-2-mediyl-pyirolidin-l-yl)-ethyI]-oxazole (100 mg, 0.287
mmol) to give 70 mg (67%). MS (m/e) 365J2 (M+l)
Example 139
2^2'-Fluoro4)iphenyM-ylV5-methvl-^[2- oxazoie

The title compound is prepared in a manner substantially analogous to example
133 starting from 2-fluorobenzene boronic acid (201 mg, 1.43 mmol) and 2-(4-Bromo-
phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-etliyl]-oxazole (100 mg, 0.287
mmol) to give 61 mg (59%). MS (m/e) 365.2 (M+l)
Example 140
2-(4'-Methoxy-biphenyl-4-yI)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyI]-
oxazole

The title compound is prepared in a manner substantially analogous to example 133
starting from 4-methoxybenzene boronic acid (218 mg, 1.43 mmol) and 2-(4-Bromo-
phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-oxazole (100 mg, 0.287
mmol) to give 61 mg (56%). MS (m/e) 377.2 (M+l)
Example 141
2-(3-Methoxy-biphenyl-4-yI)-5-methyl-4-[2-((R)-2-methyl-pyrroIidin-l-yI)-ethyI]-
oxazole

The title compound is prepared in a manner substantially analogous to example
133 starting from 3-methoxybenzene boronic acid (218 mg, 1.43 mmol) and 2-(4-Bromo-
pheayl)-5-inediyl-4-[2^(R)-2-inethyl-pyrrolidin-l-yl>eaiyl]-oxazole (100 mg, 0.287
mmol) to give 21 mg (19%). MS (m/e) 377.2 (M+l)
Example 142
Z^Z'-Methoxy-biph^yM-ylVS-meftyl^^W-Z-methyl-pyrrolidin-l-y^-ethyl]-
oxazole
The title compound is prepared in a manner substantially analogous to example
133 starting from 2-methoxybenzene boronic acid (218 mg, 1.43 mmol) and 2-(4-Bromo-
phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-oxazole (100 mg, 0.287
mmol) to give 67 mg (62%). MS (m/e) 377.2 (M+l)
Example 143
4'-[5-Methyl-4-(2-pyrroIidin-l-yl-ethyl)-oxazol-2-yI]-biphenyl-3-carbonitrile

The title compound is prepared in a manner substantially analogous to example
133 starting from 3-cyanobenzene boronic acid (219 mg, 1.49 rnmol) and 2-(4-Bromo-
phenyl)-5-methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazole (100 mg, 0.30 mmol) to give 21 mg
(20%). MS (m/e) 358.2 (M+l)
Example 144
2-BiphenyI-4-yl-5-methyl-4-[2-((R)-2-methyI-pyrroIidin-l-yI)-ethyl]-oxazoIe

The title compound is prepared in a manner substantially analogous to example
133 starting from phenyl boronic acid (174 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-
methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give
16 mg (16%). MS (m/e) 347.3 (M+l)
Example 145
5-Methyl-2-(4*Hiietfayl-biphenyt-^yl)-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-
etbyi]oxazole

The title compound is prepared in a manner substantially analogous to example
133 starting from tolyl boronic acid (195 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-
methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give
33 mg (32%). MS (m/e) 361.3 (M+l)
Example 146
3-(4-{5-Methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-oxa2ol-2-yl}-phenyl)-
pyridine

The title compound is prepared in a manner substantially analogous to example
133 starting from 3-pyridyl boronic acid (176 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-
5-methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to
give 49 mg (49%). MS (m/e) 348.3 (M+l)
Example 147
5-(4-{S-Methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yI}-phenyl)-
pyrimidine

The title compound is prepared in a manner substantially analogous to example
133 starting from 5-pyrimidine boronic acid (178 mg, 1.43 mmol) and 2-(4-Bromo-
phenyl)-5-niethyl^[2^(R)-2-inemyl-pyrrolidin-l-yl)-ethyl]-oxazole (100 mg, 0.287
mmol) to give 40 mg (40%). MS (m/e) 349.3 (M+l)
Example 148
4-{5-Methyl-4-[2- carboxylic acid dimethylamide

The title compound is prepared in a manner substantially analogous to example
133 starting from 4-(N,N)-dimethylaminocarbonyl phenyl boronic acid (277 mg, 1.43
mmol) and 2-(4-Bromo-phenyl)-5-memyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-
oxazole (100 mg, 0.287 mmol) to give 26 mg (22%). MS (m/e) 418.5 (M+l)
Example 149
(4'-{5-Methyl-4-[2-((R)-2-methy]-pyrrolidin-l-yl)-ethyl]-oxa2ol-2-yl}-
biphenyl-4-yl)-pyrrolidin-l-yl-methanone

The title compound is prepared in a manner substantially analogous to example
133 starting from 4-pyrrolidine-l-carbonyl phenyl boronic acid (314 mg, 1.43 mmol) and
2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-oxazole(100
mg, 0.2S7 mmol) to give 55 mg (43%). MS (m/e) 444.4 (M+l)
Example 150
4'-{5-Methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyI]-oxazol-2-yl}-biphenyl-4-
carboxylic acid amide

The title compound is prepared in a manner substantially analogous to example
133 starting from 4-arninocarbonyl phenyl boronic acid (236 mg, 1.43 mmol) and 2-(4-
Bromo-phenyl)-5-memyl-4-[2-((R)-2-memyl-pyrrolidin- l-yl)-ethyl] -oxazole (100 mg,
0.287 mmol) to give 17 mg (15%). MS (m/e) 390.3 (M+l)
Example 151
4'-{5-Methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-biphenyl-4-
sulfonic acid diethylamide

The title compound is prepared in a manner substantially analogous to example 133
starting from 4-dihydroxy borane pinocol ester dimethyl sulfonamide (446 mg, 1.43
mmol) and2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ettiyl]-
oxazole (100 mg, 0.287 mmol) to give 45 mg (35%). MS (m/e) 454.3 (M+l)
Example 152
5-Methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-2-(4'-trifluororaethoxy-
biphenyI-4-yl)-oxazole

The title compound is prepared in a manner substantially analogous to example
133 starting from 4-triflouromethoxy phenyl boronic acid (295 mg, 1.43 mmol) and 2-(4-
Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-oxazole(100mg,
0.287 mmol) to give 63 mg (51%). MS (m/e) 431.2 (M+l)
Embodiments of the invention include compounds of the following formulae,
including racemates and stereoisomers, and pharmaceutically acceptable salts thereof:
2^4-Bromo-phenyl)^pyrrolidin-l-ylmethyl-oxazole;
3-[4-(4-Pyrrolidin-1 -ylmethyl-oxazol-2-yl)-phenyl]-pyridine;
2-(4' -Methanesulfonyl-biphenyl-4-yl)-4-pyrrolidin-1 -ylmethyl-oxazole;
2K4-Brorno-pheoyl)-4-(2-methyl-pyrrolidin-1 -ylmethyl)-oxazole;
2-(4'-Methanesulfonyl-biphenyl^ylMK2-memyI-pyrrolidin-l-ylmethyI)-
oxazole;
N-[4'-(4-Pyrrolidin-l-ylmethyl-oxazol-2-yl)-biphenyl-4-yl]-methanesulfonamide;
2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-l-yI-ethyl)-oxazole;
4- {4-[5-Methyl-4-(2-pyrrolidin-l-yl-ethyI)-oxazol-2-yl]-phenyl) -pyridine;
3- {4-[5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazol-2-yl]-phenyl} -pyridine;
2-(4-Bromo-phenyl)-5-methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazole;
4-(4-{5-Methyl-4-t2-(2-metliyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-phenyl)-
pyridine;
2-Methyl-5-{4'-[5-methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazol-2-yl]-biphenyl-4-
yl} - [ 1,3,4] oxadiazole;
2-(4-Bromo-phenyl)-5-memyl-4-[2-(2-methyl-pyrrolidin-l-yl)-emyl]-oxazole;
4-(4-{5-Mefhyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-phenyl)-
pyridine;
6-{4-[5-Memyl-4-(2-pyirolidm-l-yl-emyl)-oxazol-2-yl]-phenyl}-nicotinontrile;
2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-raethyl-4-[2-(2-metliyl-pyrrolidin-l-yl)-
ethylj-oxazole;
3 -(4- {5-Methyl-4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-oxazol-2-yl} -phenyl-
pyridine;
l-[2-(4-Bromo-phenyl)-oxazol-4-yImediyl]-2-methyl-piperidine;
3-{4-[4-(2-Methyl-piperidin-l-ylmethyl)-oxazol-2-yl]-phenyl}-pyridine;
3-{4-[4-(2-Methyl-piperidin-l-ylmethyl)-oxazol-2-yI]-phenyl}-pyridine;
2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyl-4-(2-pyrrolidin-l-yI-ethyl)-
oxazole;
4'-[5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazol-2-yl]-biphenyl-4-carboxylicacid
dimethylamide;
5-{4-[5-MethyI-4-(2-pyrrolidiQ-l-yl-ethyl)-oxazol-2-ylj-phenyl}-thiophene-2-
carbonitrile;
2-(4-Bromo-phoiyl)-4-[2-(2-metiboxymetliyl-pyrrolidin-1 -yI)-ethyI]-5-methyl-
oxazole;
2-(4'-Methatiesulfc>nyl-biphenyl-4-yl>-4-[2-(2-methoxymetiiyl-pyrrolidin-l-yl)-
ethyl]-5-methyl-oxazoIe;
3-(4-(4-[2-(2-MethoxymethyI-pyrrolidiii-l-yl)-ethyl]-5-methyl-oxazoI-2-yl}-
phenyl)-pyridine;
4-(4-{4-[2-(2-MethoxymethyI-pyrrolidin-l-yl)-ediyl]-5-metib.yl-oxazol-2-yl}-
phenyl)-pyridine;
2-(4-Bromo-phenyl)-4-[2-(2-methoxymethyl-pyrrolidin-l-yl)-ediyl]-5-methyl-
oxazole;
2-(4'-Methanesulfonyl-biphenyl-4-yl)-4-[2-(2-methoxymethy]-pyrrolidin-l-yl)-
ethyl]-5-methyl-oxazole;
2-(4-Butoxy-phenyl)-5-methyl-4-[2-(2-methyl-pyrrolidin-l-y])-ethyl]-oxazole;
1 - {2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl }-piperidine;
5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-2-(3'-trifluoromethyl-biphenyl-4-yl)-
oxazole;
2-(3')4'-Dimethoxy-biphenyl-4-yl)-5-methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazole;
5-Methyl-4-(2-pyrrolidin-1 -yI-ethyl)-2-(3 '-trifluoromethoxy-biphenyl-4-yl)-
oxazole;
5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-2-(4'-trifluoromethoxy-biphenyl-4-yl)-
oxazole;
2-(4'-Methoxy-biphenyl-4-yl)-5-methyI-4-(2-pyrrolidin-l-yl-ethyl)-oxazole;
2-(4-Benzo[l,3]dioxoI-5-yl-phenyl)-5-methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazole;
2-(2',4'-Dimethoxy-biphenyl-4-yl)-5-methyl-4-(2-pyrrolidin-l-yJ-ethyl)-oxazole;
3-Methoxy-5-{4-f5-methyl-4-(2-pyrroIidin-l-yl-ethyl)-oxazol-2-yl]-phenyI}-
pyridine;
2-(3 '-Methanesulfonyl-biphenyl-4- yl)-5-methyl-4-(2-pyrrolidin-1 -yl -ethyl)-
oxazole;
2-(4'-Ethanesulfonyl-biphenyl-4-yl)-5-methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazole;
2-(4'-Methanesulfinyl-biphenyl-4-yl)-5-med-iyl-4-(2-pyirolidin-l-yl-ethyl)-
oxazole;
5- {4-[5-Me*hyl-4-(2-pyrrolidin- l-yl-ediyl)-oxazol-2-yl]-phemyl) -pyrimidine;
2-Methoxy-5-{4-[5-methyI-4-(2-pyrrolidin-l-yl-ethyl)-oxazol-2-yl]-phenyl}-
pyrimidine;
5-{ 4-[5-Me&yl-4- 5-Methyl-4-(2-pynolidia-l-yl-ethyl>-2-(4-thiophen-2-yl-pheDyl)-oxazole;
l-{2-[2-(4'-Methanesulfony]-biphenyl-4-yl)-5-mediyl-oxazol-4-yl]-ethyl}-
piperidine;
l-{2-[2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl}-2-
methyl-piperidine;
l-{2-[2-(4'-Medianesulfonyl-bipheny]-4-yl)-5-methyl-oxazol-4-yl]-ethyl}-2-
methyl-piperidine;
2-{4-[5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazol-2-yl]-phenoxymethyl}-
pyridine;
2-(4-{ 5-Methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl }-
phenoxymethyl)-pyridine;
2-(4-Benzyloxy-phenyl)-5-methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazole;
2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-l-(2-methyl-pyrrolidin-l-yl)-
ethanone;
2-(4- {5-Methyl-4-[2-(2-methyl-pyrrolidiQ-l-yl)-ethyl3-oxazol-2-yl }-
phenoxymethyl)-pyridine;
2-[4-(4-Methanesulfonyl-beiizyloxy)-phenyl]-5-methyl-4-[2-(2-methyl-pyrrolidin-
1 yl)-ethyl]-oxazole;
i
2-(4-Methanesulfonyl-phenyI)-5-{5-methyl-4-[2-(2-metl"iyl-pyrrolidin-1-yl)-
ethyl]-oxazol-2-yl}-pyridine;
2-EthanesulfonyI-5-(4- {5-methyl-4-[2-(2-methyl-pyrrolidin- l-yl)-etliyl]-oxazol-2-
yl} -phenyl)-pyridine;
4-(2-Azetidin-l-yl-ethyl)-2-(4-bromo-phenyl)-5-methyl-oxazole;
1 - {2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yI]-ethyl} -piperidine;
1 - {2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl} -2-methyl-piperidine;
1 - {2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl} -2S-methyl-piperidine;
i
4-(2-Azetidin-l-yl-ethyl)-2-(4'-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazole;
2-(4'-Ethanesulfonyl-biphenyl-4-yl)-5-methyl-4-[2-(2R-methyl-pyrrolidin-l-yl)-
ethyl]-oxazole; !
4-[2-(2R-Ethyl-pyrrolidin-1 -yl)-e&yl]-2-(4'-methanesulfonyl-biphenyl-4-yl)-5-
methyl-oxazole;;
(4'- {5-Methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl} -biphenyl-4yl)-
methanol;
(4'-{5-Methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-biphenyl-3-yl)-
methanol;
5-Methyl-4-[2-(2-metiiyl-pyrrolidin-l-yl)-ethyl]-2-[4'-(propane-l-sulfonyl)-
biphenyl-4-yl]-oxazole;
4-[2-(2-Fluorometliyl-pyrrolidin-l-yl)-ethyl]-2-(4'-methanesulfonyl-biphenyl-4-
yl)-5-methyl-oxazole;
Isopropyl-{2-[2-(4'-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yI]-
ethyl} -methyl-amine;
i
4'-{5-Methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-etbyl]-oxazol-2-yl}-biphenyl-4-
carbonitrile;
(2-{2-[6-(4-Methanesulfonyl-phenyl)-pyridiii-3-yl]-5-methy]-oxazol-4-yl}-ethyI)-
dimethyl-amine; '
3-Metlioxy-6-(4- {5-methyl-4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyI]-oxazol-2-yl} -
phenyl)-pyridazine;
3-Ethanesulfonyl-6-(4- {5-methyl-4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-oxazol-2-
yl}-phenyl)-pyridazine;
2-(4-{5-Methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-phenyl)-
pyridine;
3-Methanesulfonyl-6-(4-{5-methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazbl-
2-yl}-phenyl)-pyridazine;
2-Ethanesulfonyl-5-(4- {5-methyl-4-[2-(2-methyl-pyrrolidin-1 -yI)-ethyl]-oxazol-2-
yl) -phenyl)-pyridine;
2-Methanesulfonyl-5-(4- {5-mediyl-4-[2-(2-mediyl-pyrrolidin-1 -yI)-ethyl]-oxazol-
2-yl} -pheny])-pyridine;
2-Methanesulfonyl-5-(4-{5-mediyl-4-[2-(2-methyl-pyirolidin-l-yl)-ethyl]-oxazol-
2-yl} -phenyl)-pyridine;
2-(3-Fluoro-4'-inethanesulfonyl-biphenyl-4-yl)-5-metiiyl-4-[2-(2-methyl-
pyrrolidin-l-yl)-etbyl)-oxazole;
5-Metbanesulfonyl-2-(4- {5-methyl-4-[2-(2-methyl-pyrrolidin- l-yl)-ethyl]-oxazol-
2-yl}-phenyl>pyrimidine;
NrN-DimethyI-6-(4- {5-methyl-4-[2-(2-methyl-pyrroIidin-1 -yI)-ethyI]-oxazol-2-
y] }-phenyl)-iiicotinamide;
4-(4- {5-Methyl-4-[2-(2-methyl-piperidin- l-yl)-ethyl] -oxazol-2-yl} -phenyl-
pyridine;
DiethyI-{2-[2-(4'-methanesulfonyl-biphenyl-4-yl)-5-mettiyl-oxazol-4-yl]-ethy]}-
amine;
l-(4'-{5.Mediyl-4-[2-(2-methyl-pyrrolidin-l-yI)-ethyl]-oxazol-2-yl}-biphenyl-3-
yl)-ethanone hydrochloride;
2-[4'-(3-nuoro-propane-l-sulfonyl)-biphenyl-4-yl]-5-methyl-4-[2-(2-methyl-
pyrrolidin-1-yl)-ethyl]-oxazole;
5-Metiiyl-4-[2--(2-methyl-pyrrolidin-l-yl)-ethyl]-2-(4'-trifluoroniethanesulfonyl-
biphenyI-4-yl)-oxazole;
2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyl-4-[3-(2-methyl-pyrrolidin-l-yl)-
propyl]-oxazole;
l-{2-[2-(4'-Methanesulfonyl-biphenyI-4-yl)-5-methyl-oxazol-4-yl]-ethyl}-2-
methyl-piperidine;
2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methy]-4-(3-pyrroli.din-l-yl-propyl)-
oxazole;
l-[2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyI-oxazol-4-yl]-2-(2-methyl-
pyrrolidin-1 -yl)-ethanol;
2-(4'-Methanesulfonyl-biphenyl-4-yl)-4-[l-metlioxy-2-(2-methyl-pyrrolidin-l-yl)-
ethyl]-5-methyI-oxazole;
2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyl-4-[2-(2-mediyl-pyrrolidin-l-y])-
ediyI]-oxazole;
3-Methyl-6-(4- {5-methyl-4~[2-(2-methyl-pyrrolidin-1 -yl)-ethyl] -oxazol-2-yl} -
phenyl)-pyridazine;
2-(4-Bromo-phenyl)-5-methyl-4-(2-metbyl-pyrrolidin-l-ylmethyl)-oxazole;
2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-rQethyl-4-(2-methyl- pyrrolidin-1 -
ylmethyl)-oxazole;
5- {5-M^hyl-4-[2-(2-methyl-pyrroIidin-1 -yl)-ethyl ]-oxazol-2-yl} -2-phenoxy-
pyridine;
2-(4-Bromophenyl)-4-{2-[(3)-3-fluoropyiTolidin-l-yl]ethyl}-5-methyl-l,3-
oxazole;
4- {[(3)-3-fluoropyrrolidin-1 -yl]ethyl} -2-[4'-(methylsulfonyl)biphenyl-4-yl]-5-
methyl-1,3-oxazole;
2-(4-Bromophenyl)-4- {2-[(3)-3-fluoropyrrolidin-1 -yl]ethyl} -5-methyl-1,3-
oxazole;
4-{[(3)-3-FIuoropyrrolidin-l-y]]ethyl}-2-[4'-(methylsulfonyl)biphenyl-4-yl]-5-
methyl-1,3-oxazole;
(3)-1- {2-[2-(4-Bromophenyl)-5-methyl-1,3-oxazol-4-yl]ethyl }pyrrolidin-3-ol;
4-{[(3)-3-Hydroxypyrrolidin-l-yl]ethyl}'2-[4'-(methylsulfonyl)biphenyl-4-yl]-5-
methyl-1,3-oxazole;
(3)-l-{2-[2-(4-Bromophenyl)-5-methyl-l,3-oxazol-4-yl]etiiyl}pyrrolidin-3-ol;
4-{[(3)-3-Hydroxypyrrolidin-l-yl]ethyl}-2-[4'-(methylsulfonyl)biphenyl-4-yl]-5-
methyl-1,3-oxazole;
2-(4-Bromophenyl)-4-{2-[(3)-3-(fluorometb.yl)pyrrolidin-l-y].]ethyl}-5-methyl-
1,3-oxazole;
4-{2-[(3)-3-(Fluoromethyl)pyrrolidin-l-y]]ethyl}-5-methyl-2-[4'
(methylsulfonyl)biphenyl-4-yl]-1,3-oxazole;
2-(4-Bromophenyl)-4-{2-[(3)-3-(fluororaethyl)pyrrolidin-l-yl]ethyl}-5-methyl-
l,3oxazole;
4-{2-[(3)-3-(Fluoromethyl)pyrrolidin-l-yl]ethyl}-5-methyl-2-[4'-
(methylsulfonyl)biphenyl-4~yl]-1,3-oxazole;
3-[4-C5-{2-[(3)-3-(FIuoromethyI)pyrroIidin-l-yl]ethyl}-4-methyl-l,3-oxazol-2-
yl)phenyl]pyridine;
2-(4-Bromophenyl)-4-{2-[(3)-3-methoxypyrrolidin-l-yl]ethyl}-5-methyl-l,3-
oxazole;
4-{2-[(3)-3-methoxypyrrolidin-l-ylJethyl}-5-methyl-2-[4'-
(methylsulfonyl)biphenyl-4-yl]-1,3-oxazole;
2-(4-Bromophenyl)-4-{ 2-[(3)-3-me£hoxypyrrolidin-1 -yljethyl} -5-methyl-1,3-
oxazole;
4-{2-[(3)-3-Methoxypyrrolidin-l-yl]ethyl}-5-methyl-2-[4'-
(methylsulfonyl)biphenyI-4-yl]-l,3-oxazole;
2-(4-Broniophenyl)-4-{2-[(2)-2-methylpyrrolidin-l-yl]ethyl} -5-methyl-1,3-
oxazole;
3-Methoxy-5-[4-(5-methyI-4- {2-[(2)-2-methylpyrrolidin-1 -yljediyl} -1,3-oxazol-
2-yl)phenyl]pyridine;
5-[4-(5-Methyl-4- {2-[(2)-2-methylpyrrolidin-l-yl]ethyl} -1,3-oxazol-2-
yl)phenyl]thiophene-2-carbonitrile;
2-Methoxy-5-[4-(5-methyl-4-{2-[(2)-2-methylpyrrolidin-l-yl]ethyl}-l,3-oxazol-
2-yl)phenyl]pyrimidine;
5-(4-{5-Methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-
phenoxymetfiyl)-thiophene-2-carbonitrile;
5-Methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-2-[4-(2-methyl-thiazol-4-
ylmethoxy)-phenyl]-oxazole;
3-(4-{5-Methyl-4-t2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-r2-yl}-
phenoxymethyl)-pyridine;
4-(4-(5-Methyl-4-[2-(2-methyI-pyrroIidin-l-yl)-e%l]-oxazol-2-yl}-
phenoxymethyl)-pyridine;
2-Methoxy-5-(4-{5-methylr4-t2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2--yl}-
phenoxymethyl)-pyridine;
2-MethyI-6-(4-{5-methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-etIiyI]-oxazol-2-yl}-
phenoxymethyl)-pyridine;
5-Methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyI]-2-[4-(thiazol-4-ylmethoxy)-
phenylj-oxazole;
2-(4- {4-f 2-(2-Methyl-pyrrolidin- l-yl)-ethyl]-oxazol-2-yl} -phenoxymethyl)-
pyridine;
4-[2-(2-Methyl-pyrrolidin-l-yl)-ethyl]-2-[4-(thiazol-4-ylmetlioxy)-phenyl]-
oxazole;
2-(4'-Methanesulfonyl-biphenyl-4-yl)-4-[2-(2-mediyl-pyrrolidin-l-yl)-ethyl]-
oxazole;
l-(4'- {5-Metbyl-4-[2K2-methyl-pyrrolidin- l-yl)-ethyl] -oxazol-2-yl} -biphenyl-4-
yl>ethanone;
H4'-{5-Meaiy]-4-[2-(2-methyI-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-biphenyl-2-
yl)-ethanooe;
4'- {5-Methyl-4-(2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-oxazol-2-yl} -biphenyl-3 -
carbonitrile;
4'- {5-Methyl-4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-oxazol-2-yl} -biphenyl-2-
carbonitrile;
2-(4'-Fluoro-biphenyl-4-yl)-5-methyl-4-[2-(2-methyl-pyrrolid in- l-yl)-ethyl]-
oxazole;
2-(3 '-Fluoro-biphenyl-4-yl)-5-methyl-4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-
oxazole;
2-(2'-Fluoro-biphenyl-4-yl)-5-metbyl-4-[2-(2-methyl-pyrrolidm-l-yl)-ethyl]-
oxazole;
2-(4'-Methoxy-biphenyl-4-yl)-5-methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-
oxazole;
2-(3'-Methoxy-biphenyl-4'yl)-5-metliyl-4-[2-(2-methyl-pyrro]idin-l-yl)-ethylj-
oxazole;
2-(2'-Metlioxy-biphenyl-4-yl)-5-methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-
oxazole;
4'-[5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazol-2-yl]-biphenyl-3-carbonitrile;
2-Biphenyl-4-yl-5-methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyI]-oxazole;
5-Methyl-2-(4'-methyl-biphenyl-4-yl)-4-[2-(2-methyl-pyrrolidin-l-yl)-
ethyl]oxazole;
3-(4-{5-Methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-phenyl)-
pyridine;
5-(4-{5-Methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-phenyl)-
pyrimidine;
4'- {5-Methyl-4-[2-(2-methyl-pynx)lidin-1 -yl)-ethyl]-oxazol-2-yl} -biphenyl-4-
carboxylic acid dimethylamide;
(4'- {5-Methyl-4-[2-(2-methyl-pyrrolidin- l-yl)-ethyl]-oxazol-2-yl} -
biphenyl-4-yl)-pyrrolidin-l-yl-methanone;
4'-{5-Methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-biphenyl-4-
carboxylic acid amide;
4,-{5-Metfayl-4-[2-(2-mediyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-biphenyl-4-
sulfonic acid dimethylamide; and
5-Metbyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-2-(4'-trifluoromethoxy-biphenyl'
4-yl)-oxazole.
The optimal time for performing the reactions of the Schemes, Preparations, and
Procedures can be determined by monitoring the progress of die reaction via conventional
chromatographic techniques. Furthermore, it is preferred to conduct the reactions of the
invention under an inert atmosphere, such as, for example, argon, or, particularly,
ni nogen. Choice of solvent is generally not critical so long as the solvent employed is
in ert to the ongoing reaction and sufficiently solubilizes the reactants to effect the desired
re-action. The compounds are preferably isolated and purified before their use in
subsequent reactions. Some compounds may crystallize out of the reaction solution
during their formation and then collected by filtration, or the reaction solvent may be
removed by extraction, evaporation, or decantation. The intermediates and final products
of Formula I or Formula IT may be further purified, if desired by common techniques such
as recrystallization or chromatography over solid supports such as silica gel or alumina.
The skilled artisan will appreciate that not all substituents are compatible with all
reaction conditions. These compounds may be protected or modified at aiconvenient point
in the synthesis by methods well known in the art. '
i
The compound of Formula I or Formula II is preferably formulated in a unit
dosage form prior to administration. Therefore, yet another embodiment of die present
invention is a pharmaceutical composition comprising a compound of Formula I or
Formula n and one or more pharmaceutically acceptable carriers, diluents or excipients.
The present pharmaceutical compositions are prepared by known procedures using well-
known and readily available ingredients. Preferably the compound is administered orally.
Preferably, the pharmaceutical composition is in a unit dosage form. In such form, the
preparation is subdivided into suitably sized unit doses containing appropriate quantities
of the active components, e.g., an effective amount to achieve the desired purpose.
The quantity of the inventive active composition in a unit dose of preparation may
be generally varied or adjusted from about 0.01 milligrams to about 1,000 milligrams,
preferably from about 0.01 to about 950 milligrams, more preferably from about 0.01 to
about 500 milligrams, and typically from about 1 to about 250 milligrams) according to
the particular application. The actual dosage employed may be varied depending upon
the patient's age, sex, weight and severity of the condition being treated. Such techniques
are well known to those skilled in the art. Generally, the human oral dosage form
containing the active ingredients can be administered 1 or 2 times per day.
Compounds of Formula I or Formula n are effective as antagonists or inverse
agonists of the histamine H3 receptor, and thus inhibit the activity of the H3 receptor.
More particularly, these compounds are selective antagonists or inverse agonists of the
histamine H3 receptor. As selective antagonists or inverse agonists, the compounds of
i
Formula I or Formula II are useful in the treatment of diseases, disorders, or conditions
responsive to the inactivation of the histamine H3 receptor, including but riot limited to
obesity and other eating-related disorders, and cognitive disorders. It is postulated that
selective antagonists or inverse agonists of H3R will raise brain histamine levels and
possibly that of other monoamines resulting in inhibition of food consumption while
minimizing peripheral consequences. Although a number of H3R antagonists are known
in the art, none have proven to be satisfactory obesity or cognitive drugs. There is
increasing evidence that histamine plays an important role in energy homeostasis.
Histamine, acting as a neurotransmitter in the hypothalamus, suppressed appetite.
Histamine is an almost ubiquitous amine found in many cell types and it binds to a family
of G protein-coupled receptors (GPCRs). This family provides a mechanism by which
histamine can elicit distinct cellular responses based on receptor distribution. Both the
H1R and H2R are widely distributed. H3R is primarily expressed in the brain, notably in
die thalamus and caudate nucleus. High density of expression of H3R was found in
feeding center of the brain. A novel histamine receptor GPRv53 has been recently
identified. GPRv53 is found in high levels in peripheral white blood cells; only low
levels have been identified in the brain by some investigators while others cannot detect it
in the brain. However, any drug discovery effort initiated around H3R must consider
GPRv53 as well as the other subtypes.
The compounds of the present invention can readily be evaluated by using a
competitive inhibition Scintillation Proximity Assay (SPA) based on a H3R binding assay
using R-[3H] a methyihistamine as ligand. Stable cell lines, including but not limited to
HEK can be transfected with cDNA coding for H3R to prepare membranes used for the
binding assay. The technique is illustrated below (Preparation of Histamine Receptor
Subtype Membranes) for the histamine receptor subtypes.
Membranes isolated as described in (Preparation of Histamine Receptor Subtype
Membranes) were used in a T35S1GTPy.S functional assay. Binding of [35S]GTPxS to
membranes indicates agonist activity. Compounds of the invention of Formula I or
Formula II were tested for their ability to inhibit binding in the presence of agonists.
Alternately, the same transfected cell lines were used for a cAMP assay wherein H3R
agonists inhibited forskolin-activated synthesis of cAMP. Compounds of Formula I or
Formula II were tested for their ability to permit forskolin -stimulated cAMP synthesis in
the presence of agonist.
Preparation of Histamine Receptor Subtype Membranes
A. Preparation H1R membranes
cDNA for the human histamine 1 receptor (H1R) was cloned into a mammalian
expression vector containing the CMV promoter (pcDNA3.1(+), Invitogen) and
transfected into HEK293 cells using the FuGENE Tranfection Reagent (Roche
Diagnostics Corporation). Transfected cells were selected using G418 (500 fi/mL).
Colonies that survived selection were grown and tested for histamine binding to cells
grown in 96-well dishes using a scintillation proximity assay (SPA) based radioligand
binding assay. Briefly, cells, representing individual selected clones, were grown as
confluent monolayers in 96-well dishes (Costar Clear Bottom Plates, #3632) by seeding
wells with 25,000 cells and growing for 48 hours (37°C, 5% C02). Growth media was
removed and wells were rinsed two times with PBS (minus Ca2+ or Mg2+). For total
binding, cells were assayed in a SPA reaction containing 50mM Tris-HCL (assay buffer),
pH 7.6, lmg wheat germ agglutinin SPA beads (Amersham Pharmacia Biotech,
#RPNQ0001), and 0.8nM 3H-pyrilamine (Net-594, NEN) (total volume per well = 200(0.1).
Astemizole (lOuM, Sigma #A6424) was added to appropriate wells to determine non-
specific binding. Plates were covered with FasCal and incubated at room temperature for
120 minutes. Following incubation, plates were centrifuged at l.OOOrpm (~800g) for 10
minutes at room temperature. Plates were counted in a Wallac Trilux 1450 Microbeta
scintillation counter. Several clones were selected as positive for binding, and a single
clone (H1R40) was used to prepare membranes for binding studies. Cell pellets,
lepresenting -10 grams, were resuspended in 30mL assay buffer, mixed by vortexing, and
centrifuged (40,000g at 4°C) for 10 minutes. The pellet resuspension, vortexing, and
centrifugation was repeated 2 more times. The final cell pellet was resuspended in 30mL
and homogenized with a Polytron Tissue Homogenizer. Protein determinations were
done using, the Coomassie Plus Protein Assay Reagent (Pierce). Five micrograms of
protein was used per well in the SPA receptor-binding assay.
B. Preparation H2R membranes
cDNA for the human histamine 2 receptor was cloned, expressed and transfected
into HEK 293 cells as described above. Histamine binding to cells was assayed by SPA
described above. For total binding, cells were assayed in a SPA reaction containing
50mM Tris-HCl (assay buffer), pH 7.6, lmg wheat germ agglutinin SPA beads
(Amersham Pharmacia Biotech, #RPNQ0001), and 6.2nM 3H-tiotidine (Net-688, NEN)
(total volume per well = 200ul). Cimetidine (lOuM, Sigma #C4522) was added to
appropriate wells to determine non-specific binding.
Several clones were selected as positive for binding, and a single clone (H2R10)
was used to prepare membranes for binding studies. Five micrograms of protein was
used per well in the SPA receptor-binding assay.
C. Preparation of H3R membranes
cDNA for the human histamine 3 receptor was cloned and expressed as described
in (A. Preparation H1R membranes), above. Transfected cells were selected using G418
(500 |i/mL), grown, and tested for histeurtine binding by the SPA described herein. For
total binding, cells were assayed in a SPA reaction described above (containing 50mM
Tris-HCL (assay buffer), pH 7.6, lmg wheat germ agglutinin SPA beads (Amersham
Pharmacia Biotech, #RPNQ0001), and InM (3H)-n-alpha-metaylhist^miine (NEN,
NET1027) (total volume per well = 200ul). Thioperimide was added to determine non-
specific binding. Several clones were selected as positive for binding, and a single clone
(H3R8) was used to prepare membranes for binding studies described herein. Five
micrograms of protein was used per well in the SPA receptor-binding assay.
D. Preparation of GPRv53 Membranes
cDNA for the human GPRv53 receptor was cloned and expressed as described in
(A. Preparation H1R membranes), above. Transfected cells were selected, tested for
histamine binding, and selected. HEK293 GPRv53 50 cells were grown to confluency in
DMEM/F12 (Gibco) supplemented with 5 % FBS and 500 ug/mL G418 and washed with
Delbecco's PBS (Gibco) and harvested by scraping. Whole cells were homogenized with
a Polytron tissuemizer in binding buffer, 50 mM Tris pH 7.5. Cell lysates, 50 ug, were
incubated in 96 well dishes with 3 nM (3H) ffistarnine and compounds in binding buff er
for 2 hours at room temperature. Lysates were filtered through glass fiber filters (Perkin
Elmer) with a Tomtec cell harverster. Filters were counted with melt-on scintillator
sheets (Perkin Elmer) in a Wallac Trilux 1450 Microbeta Scintillation counter for 5
minutes.
Pharmacological Assays
cAMPELISA
HEK293 H3R8 cells prepared as described above were seeded at a density of
50,000 cells/well and grown overnight in DMEM/F12 (Gibco) supplemented with 5 %
FBS and 500 ug/mL G418. The next day tissue culture medium was removed and
replaced with 50 µl cell culture medium containing 4 mM 3-isobutyl-l-methylxanthine
(Sigma) and incubated for 20 minutes at room temperature. Antagonist were added in 50
µl cell culture medium and incubated for 20 minutes at room temperature. Agonist
R (-)a methylhistamine (RBI) at a dose response from lxl0"10 to lxl0-5 M was then
added to the wells in 50 µl cell culture medium and incubated for 5 minutes at room
temperature. Then 50 µl of cell culture medium containing 20 |µM Forskolin (Sigma) was
added to each well and incubated for 20 minutes at room temperature. Tissue culture
medium was removed and cells were lysed in 0.1M HC1 and cAMP was measured by
ELISA (Assay Designs, Inc.).
[35S] GTP ? [S] Binding Assay
Antagonist activity of selected compounds was tested for inhibition of [35SJ GTP
?[S] binding to H3R membranes in the presence of agonists. Assays were run at room
temperature in 20 mM HEPES, 100 mM NaCl, 5 mM MgCl2 and 10 uM GDP at pH 7.4
in a final volume of 200 ul in 96-well Costar plates. Membranes isolated from H3R8-
expressing HEK293 cell line (20 ug/well) and GDP were added to each well in a volume
of 50 µl assay buffer. Antagonist was then added to the wells in a volume of 50 ul assay
buffer and incubated for 15 minutes at room temperature. Agonist R(-)alpha
methylhistamine (RBI) at either a dose response from lxl0-10 to 1x10-5 M or fixed
concentration of 100 nM were then added to the wells in a volume of 50 µl assay buffer
and incubated for 5 minutes at room temperature. GTP ? [35S] was added to each well in
a volume of 50 µl assay buffer at a final concentration of 200 pM, followed by the
addition of 50 µl
of 20 mg/mL WGA coated SPA beads (Amersham). Plates were
counted in Wallac Trilux 1450 Microbeta scintillation counter for 1 minute. Compounds
that inhibited more than 50% of the specific binding of radioactive ligand to the receptor
were serially diluted to determine a K[i ](nM).
The compounds according to the invention preferably have a Ki value of no
greater than 5µM as determined by the Histamine H3 Receptor Binding Assay disclosed
herein. More preferably, the compounds according to the invention have a Ki value of
less than µM, and preferably of less than 500 nM, and even more preferred of less than
100 nM as determined by the Histamine H3 Receptor Binding Assay disclosed herein.
Most preferred compounds of the invention exhibit affinity for the H3 receptor greater
than 20 nM. Furthermore, the compounds according to the invention preferably have a
higher binding affinity to the histamine H3 receptor than to the GPRv53 receptor.All
compounds set forth in the examples exhibit affinity for the H3 receptor greater than 1
uM.

From the above description, one skilled in the art can ascertain the essential
characteristics of the present invention, and without departing from the spirit and scope
thereof, can make various changes and modifications of the invention to adapt it to
va rious usages and conditions. Thus, other embodiments are also within the claims.
WE CLAIM:

or a pharmaceutically acceptable salt thereof, wherein:
m is independently at each occurrence 1, 2, or 3,
wherein optionally one or two c f the hydrogens of the -CH2-, -CH2-CH2-, or
-CH2-CH2-CH2- so formed may independently be replaced by halogen, or
optionally on a carbon not adjacent to nitrogen one of the hydrogens of the
-CH2-CH2-, or -CH2-CH2-CH2- so formed may independently be replaced by
-OH, -0-(C1-C4) alkyl(optionaI y substituted with one to three halogens), or
-(C1-C3)alkyl(optionally substituted with one to three halogens);
Z independently represents carbon (sub stituted with hydrogen or the optional substituents
indicated herein) or nitrogen, provided that when Z is nitrogen then R6 is not attached to
Z;
R t and R2 are independently
-(C1-C7) alkyl(optionally substiiuted with one to three halogens), or
Rl and R2 and the nitrogen to which they are attached form an azetidinyl ring, a
pyrrolidinyl ring, or a piperidinyl ring, wherein further the azetidinyl, pyrrolidinyl,
or piperidinyl ring so formed m ly be optionally substituted one to three times with
R5;
R3 is independently
-H, -halogen, -(C1-C4) alkyl(optionally substituted with one to three halogens), or -
0-(C1-C3) alkyl(optionally substituted with one to three halogens);
R4 is independently
-halogen, -(C1-C7) alkyl(optional!y substituted with one to three halogens), -CN,
-C(0)R7, -C(0)(C3-C7)cycloallyl(optionaIly substituted with one to three
halogens), -C(0)NR7R8, -OR7, -O-phenyl(R10)(R11), -N02) -NR7R8, -NR7S02
R7, -NR7C(0)R7, -NR7C02R7, -NR7C(0)NR7R8, -SR7, -S02R7, -S02NR7R8,
-S(0)R7, -0(CH2)mNR7R8, -hcteroaryI-R9, -0-CH2-heteroaryl-R9, or
, wherein the zig-zag lines represent the point of attachment,
and wherein Q, T, D, X, and Y independently represent carbon (substituted with
hydrogen or the optional substiiuents indicated herein) or nitrogen, provided that
no more than two of Q, T, D, X, and Y are nitrogen; and provided however that
wherein D is nitrogen, then R10, Rl1, and R12 are not attached to D, and
provided that wherein X is nitrogen, then R10, R11, and R12 are not attached to X,
and provided that wherein T is nitrogen, then R10, R11, and R12 are not attached
to T, and provided that wherein Q is nitrogen, then R10, Rl I, and R12 are not
attached to Q, and provided tha wherein Y is nitrogen, then R10, R11, and R12
are not attached to Y; or
wherein the zig-zag lines represent the point of
attachment, and wherein Q, T, I), X, and Y independently represent carbon
(substituted with hydrogen or the optional substituents indicated herein) or
nitrogen, provided that no more than two of Q, T, D, X, and Y are nitrogen;
provided however that wherein D is nitrogen, then R10, R11, and R12 are not
attached to D, and provided that wherein X is nitrogen, then R10, R11, and R12
are not attached to X, and prov ded that wherein T is nitrogen, then R10, R11, and
R12 are not attached to T, and provided that wherein Q is nitrogen, then R10,
R11, and R12 are not attached t) Q, and provided that wherein Y is nitrogen, then
R10, R11, and R12 are not attached to Y;
R5 is independently
- H, -OH, -halogen, -(C1-C4) alkyl(optionally substituted with one to three
halogens), -O-(C1-C3) alkyl(opt onally substituted with one to three halogens), or
-(C1-C3) alkyl-0-(C1-C3)alkyl(optionally substituted with one to three halogens);
R6 is independently at each occurrence
-H, -halogen, or -CH;
R7 and R8 are independently at each occurrence
- H, or -(C1-C7) alkyl(optionally substituted with one to three halogens), or NR7R8
combine to form a four to seven membered ring;
R9 is independently at each occurrence
- H, -CN, or -(C1-C3) alkyl(optianally substituted with one to three halogens);
R10, R11, and R12 are independently a each occurrence
- H, -halogen, -(C1-C7) alkyl(optionally substituted with one to three halogens),
-(C1-C7) alkyl-OH(optionally substituted with one to three halogens), -CN,
-C(0)-(C1C7) alkyl(optionally substituted with one to three halogens), -CO(0)R7,
-C(0)(C3-C7)cycloalkyl(optionally substituted with one to three halogens),
-C(0)NR7R8, -OR7, -NR7R8, -NR9S02 R7, -NR9C(0)R7, -NR9C02R7,
-NR9C(0)NR7R8, -SR7, -S02R7, -S02NR7R8, -S(0)R7, -heteroaryl-R9,
or when R10 and R11 are adjacent to each other they may combine along with the
respective atoms to which they are attached to form a Five membered or six
membered heterocarbon ring containing at least one but not more than two atoms
selected from O, S, or N, provided the heteroatoms are not adjacent to each other,
and wherein optionally said five membered or six membered heterocarbon ring
may contain one to three double bonds.
2. The compound as claimed in claim 1, wherein Z is nitrogen and R6 is not attached to Z.
3. The compound as claimed in claim 1, wherein Z is carbon (substituted with hydrogen
or the optional substituents indicated herein).
4. The compound as claimed in claim 1, wherein:
m is independently at each occi rrence 1 or 2, wherein optionally one or two of the
hydrogens of the -CH2-, or -CH2-CH2- so formed may independently be replaced
by halogen, or optionally on the carbon not adjacent to nitrogen one of the
hydrogens of the -CH2-CH2- so formed may independently be replaced by -OH,
-0-(C1C4) alkyl(optionally substituted with one to three halogens), or
-(C1-C3)alkyl(optionally substit Jted with one to three halogens);
Z independently represents carbon (substituted with hydrogen or the optional
substituents indicated herein);
Rl and R2 are independently
-(C1-C7) alkyl(optionally substituted with one to three halogens), or
Rl and R2 and the nitrogen to which they are attached form an azetidinyl
ring, a pyrrolidinyl ring, or apiperidinyl ring, wherein further the
azetidinyl, pyrrolidinyl, or piperidinyl ring so formed may be optionally
substituted once with R5;
R3 is independently -H, or -CH3 (optionally substituted with one to three
halogens);
R5 is independently -H, -CH3 (optionally substituted with one to three halogens);
R6 is independently at each occurence -H, -halogen, or -CH3;
R7 and R8 are independently at each occurrence
-H, or -(C1-C7) alkyl(optionally substituted with one to three halogens), or
NR7R8 combine to forrr a four to seven membered ring;
R9 is independently at each occarrence
-H, -CN, or -(C1-C3) alk/l(optionally substituted with one to three
halogens);
R10, R11, and R12 are independently at each occurrence
-H, -halogen, -(C1-C7) alkyl(optionally substituted with one to three
halogens), -(C1-C7) alky -OH(optionally substituted with one to three
halogens), -CN, -C(0)-(C1-C7) alkyl(optionally substituted with one to
three halogens), -CO(0)R7, -C(0)(C3-C7)cycloalkyl(optionally substituted
with one to three halogens), -C(0)NR7R8, -OR7, -NR7R8, -NR9S02R7,
-NR9C(0)R7, -NR9CO;R7, -NR9C(0)NR7R8, -SR7, -S02R7, -S02
NR7R8, -S(0)R7, -heteioaryl-R9,
or when R10 and Rl1 are adjacent to each other they may combine along
with the respective atoms to which they are attached to form a five
membered or six membered heterocarbon ring containing at least one but
not more than two atom;; selected from O, S, or N, provided the
heteroatoms are not adjacent to each other, and wherein optionally said five
membered or six membered heterocarbon ring may contain one to three
double bonds.
5. The compound as claimed in claim 1, wherein:
m is independently at each occurrence 2, wherein optionally one or two of the
hydrogens of the -CH2-CH2- so formed may independently be replaced by halogen,
or optionally on the carbon not adjacent to nitrogen one of the hydrogens of the
-CH2-CH2- so formed may independently be replaced by -OH,
-0-(C1-C4)alkyl(optionally substituted with one to three halogens), or
-(C1-C3)alkyl(optionally substiluted with one to three halogens);
Z independently represents carbon (substituted with hydrogen);
Rl and R2 and the nitrogen to which they are attached form a pyrrolidinyl ring, or
a piperidinyl ring, wherein further the pyrrolidinyl or piperidinyl ring so formed
may be optionally substituted once with R5;
R3 is independently -H, or -CH3 (optionally substituted with one to three
halogens);
R5 is independently -H, or -CH3 (optionally substituted with one to three
halogens);
R6 is independently at each occurrence -H, or -halogen, provided that at least one
of R6 is-H;
R7 and R8 are independently a' each occurrence
-H, or -(C1-C7) alkyl(optionally substituted with one to three halogens), or
NR7R8 combine to form a four to seven membered ring;
R9 is independently at each occurrence -H, -CN, or -(C1-C3) alkyl(optionally
substituted with one to three halogens);
R10, R11, and R12 are indeper dently at each occurrence
-H, -halogen, -(C1-C7)alkyl(optionally substituted with one to three
halogens), -(C1-C7) alkyl-OH(optionally substituted with one to three
halogens), -CN, -C(O) (C1-C7) alkyl(optionally substituted with one to
three halogens), -CO(0)R7, -C(0)(C3-C7)cycloalkyl(optionally substituted
with one to three halogens), -C(0)NR7R8, -OR7, -NR7R8, -NR9S02R7,
-NR9C(0)R7, -NR9CC2R7, -NR9C(0)NR7R8, -SR7, -S02R7, -S02
NR7R8, -S(0)R7, -hete roaryl-R9, provided that not more than one of R10,
R11, and R12 are -hete oaryl-R9.
6. The compound as claimed in claim 1, wherein:
m is independently at each occurrence 2; Z independently represents carbon
(substituted with hydrogen); Rl and R2 and the nitrogen to which they are attached
form a pyrrolidinyl ring, when in further the pyrrolidinyl ring so formed may be
optionally substituted once with R5; R3 is independently -CH3 (optionally
substituted with one to three halogens); R5 is independently -H, or -CH3
(optionally substituted with on: to three halogens); R6 is independently at each
occurrence -H; R7 and R8 are independently at each occurrence -H, or -(C1-C7)
alkyl(optionally substituted with one to three halogens); R9 is independently at
each occurrence -H, -CN, or -(C1 -C3) alkyl(optionally substituted with one to three
halogens); R10, R11, and R12 an; independently at each occurrence -H, -halogen, -
(C1-C7) alkyl(optionally substitutad with one to three halogens), -(C1C7) alkyl-
OH(optionally substituted with one to three halogens), -CN, -C(0)-(C1-C7)
alkyl(optionally substituted with Dne to three halogens), -CO(0)R7, -C(0)(C3-
C7)cycloalkyl(optionally substituted with one to three halogens), -C(0)NR7R8, -
OR7, -NR7R8, -NR9S02 R7, -NR9C(0)R7, -NR9C02R7, -NR9C(0)NR7R8, -
SR7, -S02R7, -S02NR7R8, -S(C)R7, -heteroaryI-R9, provided that not more than
one of R10, R11, and R12 are -heroaryl-R9.
7. A compound as claimed in any of claims 1-5 wherein R4 is independently:
-O-phenyl(R10)(R11), -heteroary 1-R9, -0-CH2-heteroaryl-R9, or
wherein the zig-zag lines represent the point of attachment,
and wherein Q, T, D, X, and Y irdependently represent carbon (substituted with
hydrogen or the optional substitujnts indicated herein) or nitrogen, provided that
no more than two of Q, T, D, X, ind Y are nitrogen; and provided however that
wherein D is nitrogen, then R10, R11, and R12 are not attached to D, and
provided that wherein X is nitrogen, then R10 R11, and R12 are not attached to X,
and provided that wherein T is nitrogen, then R10, R11, and R12 are not attached
to T, and provided that wherein Q is nitrogen, then R10, R11, and R12 are not
attached to Q, and provided that wherein Y is nitrogen, then R10, R11, and R12
are not attached to Y; or
wherein the zig-zag lines represent the point of
attachment, and wherein Q, T, D. X, and Y independently represent carbon
(substituted with hydrogen or th; optional substituents indicated herein) or
nitrogen, provided that no more than two of Q, T, D, X, and Y are nitrogen;
provided however that wherein is nitrogen, then R10, R11, and R12 are not
attached to D, and provided tha: wherein X is nitrogen, then R10, Rl I, and R12
are not attached to X, and provided that wherein T is nitrogen, then R10 R11, and
R12 are not attached to T, and povided that wherein Q is nitrogen, then R10,
R11, and R12 are not attached to Q, and provided that wherein Y is nitrogen, then
R10, R11, and R12 are not attacied to Y.
8. A compound as claimed in any of claims 1-7 wherein R3 is independently -CH3 and R5 is -
CH3.
9. A compound as claimed in any of claims 1-8 wherein T is nitrogen, and Q, D, X and Y are
carbon substituted with hydrogen or the optional substituents indicated herein.
10. A compound as claimed in any of claims 1-8 wherein Q and T are nitrogen and D, X and Y
are carbon substituted with hydrogen or the optional substituents indicated herein.
11. A compound as claimed in any of claims 1-8 wherein T and X and Q, D, and Y are carbon
substituted with hydrogen or the optional substituents indicated herein.
12. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein: -
(CH2)m- is -CH2-, -CH2CH2-, or -CH2-CH2-CH2-, wherein one of the hydrogens on
a carbon not adjacent to a nitrogen may be replaced by -OH or -OCH3; Z is carbon
(substituted with hydrogen or optionally substituted with fluorine) or nitrogen,
provided that when Z is nitroger then R6 is not attached to Z; Rl and R2 are
independently -CH3, -CH2CH3, or -CH(CH3)2) wherein Rl and R2 and the nitrogen
to which they are attached may optionally from an azetidinyl ring, a piperidinyl
ring, or a pyrrolidinyl ring, wherein further the azetidinyl, piperidinyl, or
pyrrolidinyl ring so formed may, independently, be optionally substituted once
with -F, -OH, -OCH3, -CH3, -CH2-CH3, -CH2-F, or -CH2-0-CH3; R3 is hydrogen
or -CH3; R4 is -Br, -OH, -0CH2CH2CH2CH3, -O-phenyl, -2-pyridinyl,
-3-pyridinyl, -4-pyridinyI, -pyrimidinyl, -OCH2-R14, -pyridazinyl, -lH-indolyl,
-phenyl, -2-thiophenyI, or -benzo[l,3]dioxolyl, wherein further the -2-pyridinyl,
-3-pyridinyl, -4-pyridinyl, -pyrimidinyl, -pyridazinyl, -lH-indolyl, -phenyl, or
-2-thiophenyl, may be optionally substituted one to two times with R7 provided
that R7 is not directly attached O the nitrogen of-2-pyridinyl, -3-pyridinyl,
-4-pyridinyl, -pyrimidinyl, -pyridazinyl, -lH-indolyl, or the sulfur of
-2-thiophenyl; R6 is hydrogen or-F; R7 is-S(0)2-R9, -N-S(0)2-CH3, -S(0)CH3,
2-methyl-[l,3,4)oxadiazolyl, -CM, -C(0)N(CH3)2, -F, -CH3, -CH2-OH, -OCH3,
-CF3, -OCF3, -C(0)-CH3, -C(0)-pyrrolidinyl, or -C(0)NH2; R14 is -2-pyridinyl,
-3-pyridinyI, -4-pyridinyl, -Phery], -thiazolyl, 4-methanesulfonyl-phenyl,
-5-thiophenyl-2-carbonitrile, -2-meth'ylthiazol-4-yl, -2-methoxy-pyridin-5-yl,
2-methyl-pyridin-6-yl; and R9 is -CH3, -CH2CH3, -CH2-CH2-CH3, -CF3 -CH2-
CH2-CH2-F, or -N(CH3)2.
13. The compound as claimed in claim 12, or a pharmaceutically acceptable salt thereof, wherein:
R4 is -Br, -OH, -OCH2CH2CH2OH3, -O-phenyl, -2-pyridinyl, -3-pyridinyl, -4-
pyridinyl, -pyrimidinyl,-2-oxymsthylpyridinyl, -3-oxymethy!pyridinyl, -4-
oxymethylpyridinyl, -oxymethy benzene, -4-oxymethyl-2-methylthiazolyl, -4-
oxymethylthiazolyl, -benzyloxy-4-methanesulfonyl, -5-oxymethyl-thiophene-2-
carbonitrile, -5-oxymethyl-2-methoxy-pyridyl, -2-oxymethyl-6-methyl-pyridinyl -
pyridazinyl, -lH-indolyl, -phenjl, -2-thiophenyl, or-benzo[l,3]dioxolyl, wherein
further the -2-pyridinyl, -3-pyricinyl, -4-pyridinyl, -pyrimidinyl, -pyridazinyl, -1H-
indolyl, -phenyl, -2-thiophenyl, nay be optionally substituted one to two times
with R7 provided that R7 is not iirectly attached to the nitrogen of-2-pyridinyl, -
3-pyridinyl, -4-pyridinyl, -pyrirr idinyl, -pyridazinyl, -lH-indolyl, or the sulfur of-
2-thiophenyl.
14. A compound of formula I selected from the group consisting of:
2-(4-Bromo-phenyl)-4-pyrrolidh-l-y!methyl-oxazole;
2-(4-Bromo-phenyl-4-pyrrolidin-l-ylmethyl-oxazole hydrochloride;
3-[4-(4-Pyrrolidin-l-ylmethyl-o:cazol-2-yl)-phenyl]-pyridine dihydrochloride;
2-(4'-Methanesulfonyl-biphenyl-4-yl)-4-pyrrolidin-l-ylmethyl-oxazole;
(+/-)-2-(4-Bromo-phenyl)-4-(2-methyl-pyrrolidin-l-ylmethyl)-oxazole
hydrochloride;
(+/-)-2-(4'-Methanesulfonyl-biphenyl-4-yl)-4-(2-methyl-pyrrolidin-l-ylmethyl)-
oxazole;
N-[4'-(4-Pyrrolidin-l-ylmethyI-3xazol-2-yl)-biphenyl-4-yl]-methanesulfonamide;
2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-I-yl-ethyl)-oxazole;
4- {4-[5-Methyl-4-(2-pyrrolidin-1 -yI-ethyl)-oxazol-2-yl]-phenyl} -pyridine;
4-{4-[5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazol-2-yl]-phenyl}-pyridine
dihydrochloride;
3-{4-[5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazol-2-yl]-phenyl}-pyridine;
3-{4-[5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazol-2-yl]-phenyl}-pyridine
dihyrdochloride;
(+/-)-2-(4-Bromo-phenyl)-5-me;hyi-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-
oxazole;
(+/-)-4-(4-{5-Methyi-4-[2-(2-mcthyl-pyrrolidin-l-yl)-ethy!]-oxazol-2-yl}-phenyl)-
pyridine dihydrochloride;
2-Methyl-5-{4'-[5-methyl-4-(2-3yrrolidin-l-yl-ethyl)-oxazol-2-yl]-biphenyl-4-yl}-
[l,3,4]oxadiazole;
2-(4-Bromo-phenyl)-5-methyl-4-[2-(2R-methyl-pyrrolidin-l-yl)-ethyl]-oxazole
hydrochloride;
4-(4-{5-Methyl-4-[2-(2R-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-phenyl)-
pyridine dihydrochloride;
6-{4-[5-Methyl-4-(2-pyrrolidin-l-yI-ethyl)-oxazoI-2-yl]-phenyl}-nicotinontrile
dihydrochloride;
2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyl-4-[2-(2R-methyl-pyrrolidin-l-yl)-
ethyl]-oxazole;
3-(4-{5-Methyl-4-[2-(2R-methyl-pyrrolidin-t-yl)-ethyl]-oxazol-2-yl}-phenyl)-
pyridine dihydrochloride;
(+/-)- l-[2-(4-Bromo-phenyl)-oxizoI-4-ylmethyl]-2-methyl-piperidine;
(+/-)-3-{4-[4-(2-Methyl-piperidin-l-ylmethyl)-oxazol-2-yl]-phenyl}-pyridine;
(+/-)-3-{4-[4-(2-Methyl-piperidin-l-ylmethyl)-oxazol-2-yl]-phenyl}-pyridine
dihydrochloride salt;
2-(4'-Methanesulfonyl-biphenyl 4-yl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-
oxazole;
4'-[5-Methyl-4-(2-pyrrolidin-l-)l-ethyl)-oxazol-2-yl]-biphenyl-4-carboxylic acid
dimethylamide;
5-{4-[5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazol-2-yl]-phenyl}-thiophene-2-
carbonitrile;
2-(4-Bromo-phenyl)-4-[2-(S)-(+)-(2-methoxymethyl-pyrrolidin-l-yl)-ethyl]-5-
methyl-oxazole;
2-(4'-Methanesulfonyl-biphenyl4-yl)-4-[2-(S)-(+)-(2-methoxymethyl-pyrroiidin-
l -yl)-ethyl]-5-methyl-oxazole;
3-(4-{4-[2-(S)-(+)-(2-Methoxyniethyl-pyrrolidin-l-yl)-ethyl]-5-methyl-oxazol-2-
yl}-phenyl)-pyridine dihydrochloride salt;
4-(4-{4-[2-(S)-(+)-(2-MethoxynethyI-pyrrolidin-l-y!)-ethyl]-5-methyl -oxazo1-2-
yl}-phenyl)-pyridine dihydroch oride salt;
2-(4-Bromo-phenyl)-4-[2-(R)-(--)-(2-methoxymethyl-pyrrolidin-l-yl)-ethyl]-5-
methyl-oxazole;
2-(4'-Methanesu)fonyl-biphenyl-4-yl)-4-[2-(R)-(+)-(2-methoxymethyI-pyrrolidin-
I -yl)-ethyl]-5-methyl-oxazole;
(+/-)-2-(4-Butoxy-phenyl)-5-m£thyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-
oxazole hydrocholoride salt;
l-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-piperidine;
5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-2-(3'-trifluorotnethyl-biphenyl-4-yl)-oxazole;
2-(3\4'-Dimethoxy-biphenyl-4-yl)-5-methyl-4-(2-pyrrolidin-l-yI-ethyl)-oxazole;
5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-2-(3'-trifluoromethoxy-biphenyl-4-yl)-
oxazole;
5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-2-(4'-trifluoromethoxy-biphenyl-4-yl)-
oxazole;
2-(4'-Methoxy-biphenyl-4-yl)-5-methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazole;
2-(4-Benzo[ 1,3]dioxol-5-yl-pheiyl)-5-methyl-4-(2-pyrroIidin-1-yl-ethyl)-oxazole;
2-(2',4'-Dimethoxy-biphenyl-4-yl)-5-methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazoIe;
3-Methoxy-5-{4-[5-methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazol-2-yl]-phenyl}-
pyridine;
2-(3'-MethanesulfonyI-biphenyl-4-yl)-5-methyI-4-(2-pyrrolidin-l-yl-ethyl)-
oxazole;
2-(4'-Ethanesulfonyl-biphenyl-4-yl)-5-methyl-4-(2-pyrrolidin-l-yI-ethyl)-oxazole;
2-(4'-Methanesulfinyl-biphenyl-4-yl)-5-methyi-4-(2-pyrrolidin-l-y!-ethyl)-
oxazole;
5-{4-[5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazol-2-yl]-phenyl}-pyrimidine;
2-Methoxy-5- {4-[5 -methy l-4-(2 -pyrrolidin-1 -yl-ethy l)-oxazol-2-y 1] -phenyl} -
pyrimidine;
5-{4-[5-Methyl-4-(2 -pyrrolidin- l-yl-ethyl)-oxazol-2-yl]-phenyl}-lH-indole;
5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-2-(4-thiophen-2-yl-phenyl)-oxazole;
l-{2-[2-(4'-Methanesulfonyl-bi3henyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl}-
piperidine hydrochloride;
(+/-)-l-{2-[2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl}-2-
methyl-piperidine hydrochloride;
l-{2-[2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl}-2S-
methyl-piperidine hydrochloride;
2-{4-[5-Methyl-4-(2-pyrrolidin- l-yi-ethyl)-oxazol-2-yl]-phenoxymethyl}-pyridine;
(+/-)-2-(4-{5-Methyl-4-[2-(2-m;thyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yi}-
phenoxymethyl)-pyridine;
2-(4-Benzyloxy-phenyl)-5-metryl-4-[2-(2-(R)-methyl-pyrrolidin-l-yl)-ethyl]-
oxazole; 2-[2-(4-Hydroxy-phen /l)-5-methyl-oxazol-4-yI]-l -(2-(R)-methyl-
pyrrolidin-l-yl)-ethanone;
2-(4-{5-Methyl-4-[2-(2-(R)-meihy!-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-
phenoxymethyI)-pyridine;
2-[4-(4-Methanesulfonyl-benzy oxy)-phenyl]-5-methyl-4-[2-(2-(R)-methyl-
pyrrol idin-1 -yl)-ethyl]-oxazole;
2-(4-Methanesulfonyl-phenyl)-'i-{5-methyl-4-f2-(2-(R)-methyl-pyrrolidin-l-yl)-
ethyl]-oxazol-2-yl} -pyrid ine;
2-Ethanesulfonyl-5-(4-{5-methy!-4-[2-(2-(R)-methyl-pyrrolidin-l-yl)-ethyl]-
oxazol-2-yl}-phenyl)-pyridine;
4-(2-Azetidin-1 -y l-ethyl)-2-(4-t romo-phenyl)-5 -methy 1-oxazole;
]-{2-[2-(4-Bromo-phenyl)-5-mcthyl-oxazol-4-yl]-ethyl}-piperidine;
(+/-)-1 - {2-[2-(4-Bromo-phenyl] -5-methyl-oxazol-4-yl]-ethyl} -2-methy 1-
piperidine;
l-{2-[2-(4-Bromo-phenyl)-5-mi;thyl-oxazol-4-yl]-ethyl}-2S-methyl-piperidine;
4-(2-Azetidin-l-yl-ethyl)-2-(4'-inethanesulfonyl-biphenyl-4-yl)-5-methyI-oxazole
hydrochloride;
2-(4'-EthanesuIfonyl-biphenyl-^-yl)-5-methyl-4-[2-(2R-methyl-pyrrolidin-l-yl)-
ethyl]-oxazole hydrochloride;
4-[2-(2R-Ethyl-pyrrolidin-l-yl>ethyl]-2-(4'-methanesuIfonyl-biphenyl-4-yl)-5-
methyl-oxazole hydrochloride;
(4'-{5-Methyl-4-[2-(2R-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-biphenyl-4-
yl)-rnethanol hydrochloride;
(41. {5-MethyI-4-[2-(2R-methyl- pyrrolidin-1 -yl)-ethy l]-oxazol-2-yl }-biphenyl-3-
yl)-methanol hydrochloride;
5-Methyl-4-[2-(2R-methyl-pyrrDlidin-l-yl)-ethyl]-2-[4'-(propane-l-sulfonyl)-
biphenyl-4-yl]-oxazole hydrochloride;
4-[2-(2S-Fluoromethyl-pyrrolidin-l-yl)-ethyl]-2-(4'-methanesulfonyl-biphenyl-4-
yl)-5-methyl-oxazole hydrochloride;
Isopropyl-{2-[2-(4'-methanesuironyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl}-
methyl-amine hydrochloride;
4'-{5-Methyl-4-[2-(2-(R)-meth>l-pyrrolidin-l-yl)-ethyl]-oxazoI-2-yl}-biphenyl-4-
carbonitrile;
(2- {2-[6-(4-Methanesulfonyl-phenyl)-pyrid in-3-yl]-5-methyl-oxazol-4-y I} -ethyl)-
dimethyl-amine;
3-Methoxy-6-(4-{5-methyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-y!}-
phenyl)-pyridazine;
3-Ethanesulfonyl-6-(4-{5-methy|-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-
yl}-phenyl)-pyridazine;
2-(4-{5-MethyI-4-[2-(2-methyl-pyrrolidin-l-yI)-ethyl]-oxazol-2~y]}-phenyl)-
pyridine;
3-MethanesulfonyI-6-(4-{5-metiyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazoI-
2-y 1} -pheny l)-pyridazine;
2-Ethanesulfonyl-5-(4-{5-methyl-4-[2-{2-(R)-methyl-pyrrolidin-l-yl)-ethyl]-
oxazol-2-yl}-pheny!)-pyridJne dihydrochloride salt;
2-Methanesulfonyl-5-(4-{5-metiyl-4-[2-(2-(R)-methyl-pyrrolidin-l-yl)-ethyl]-
oxazol-2-yl}-pheny l)-pyridine;
2-Methanesuifonyl-5-{4-{5-metiyl-4-[2-(2-(R)-methyl-pyiTolidin-l-yI)-ethy]]-
oxazol-2-yl}-phenyl)-pyridine dihydrochloride salt;
2-(3-Fluoro-4'-methanesulfonyl biphenyl-4-yl)-5-methyl-4-[2-(2-methyl-
pyrrolidin-1 -y l)-ethyl]-oxazole;
2-(3-Fluoro-4'-methanesulfonyI biphenyl-4-yl)-5-methyl-4-[2-(2-methyl-
pyrrolidin-l-yl)-ethy!]-oxazole hydrochloride salt;
5-Methanesulfonyl-2-(4-{5-metiyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-
2-yl}-phenyl)-pyrimidine;
5-Methanesulfonyl-2-(4-{5-metnyl-4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-
2-yl}-phenyl)-pyrimidine hydrochloride salt;
N,N-Dimethyl-6-(4-{5-methyl-^-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-
y 1} -phenyl)-nicotinamide;
4-(4-{5-Methyl-4-[2-(2-methyl-piperidin-l-yl)-ethyl]-oxazol-2-yl}-phenyl)-
pyridine hydrochloride;
Diethyl-{2-[2-(4,-methanesulfonyl-biphenyl-4-yl)-5-methyI-oxazol-4-yl]-ethyl}-
amine trifluoroacetate;
l-(4'-{5-Methyl-4-[2-(2R-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-biphenyl-3-
yl)-ethanone hydrochloride;
2-[4'-(3-Fluoro-propane-l-sulfonyI)-biphenyl-4-yl]-5-methyl-4-[2-(2R-methyl-
pyrrolidin-l-yI)-ethyI]-oxazole hydrochloride;
5-Methyl-4-[2-(2R-methyl-pyrrolidin-l-yl)-ethyl]-2-(4,-trifluoromethanesulfonyl-
biphenyl-4-yl)-oxazole hydroch oride;
2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyl-4-[3-(2R-methyl-pyrrolidin-l-yl)-
propyl]-oxazole hydrochloride;
l-{2-[2-(4'-Methanesulfonyl-bi|)henyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl}-2R-
methyl-piperidine hydrochloride;
2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyl-4-(3-pyrrolidin-l-yl-propyl)-
oxazole hydrochloride;
l-[2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-2-(2R-methyl-
pyrrolidin-1 -yl)-ethanol hydrochloride;
2-(4'-Methanesulfonyl-biphenyl -4-yl)-4-[ 1 -methoxy-2-(2R-methy l-pyrrolidin-1 -
yl)-ethyl]-5-methy!-oxazole hydrochloride;
2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyl-4-[2-(2S-methyl-pyrrolidin-l-yl)-
ethyl]-oxazole hydrochloride;
3-MethyI-6-(4-{5-methyl-4-[2-(2-methyl-pyiTolidin-l-yl)-ethyl]-oxazol-2-yl}-
phenyl)-pyridazine;
2-(4-Bromo-phenyl)-5-methyl-4-(2-methyl-pyrrolidin-l-ylmethyl)-oxazole;
2-(4'-Methanesulfonyl-biphenyl-4-yl)-5-methyl-4-(2-methyl-pyrrolidin-l-
ylmethyl)-oxazole;
5-{5-Methyl-4-[2-(2-methyl-pyirolidin-l-yl)-ethyl]-oxazol-2-yl}-2-phenoxy-
pyridine;2-(4-Bromophenyl)-4-'2-[(3S)-3-fluoropyrrolidin-l-yl]ethyl}-5-methyl-
1,3-oxazole;
4-{[(3S)-3-fluoropyrrolidin-l-y ]ethyl}-2-[4'-(methylsulfonyI)biphenyl-4-yl]-5-
methyl-l,3-oxazole;
2-(4-Bromophenyl)-4-{2-[(3R)-3-fluoropyrrolidin-l-yl]ethyl}-5-methyl-l,3-
oxazole;
4-{[(3R)-3-Fluoropyrrolidin-l-yl]ethyl}-2-[4'-(methylsulfonyl)biphenyl-4-yl]-5-
methyl-l,3-oxazole;
(3R)-1 -{2-[2-(4-Bromophenyl)-5-methyl-1,3-oxazol-4-y!]ethyl} pyrrolidin-3-ol;
4-{[(3R)-3-Hydroxypyrrolidin- -y!]ethyl}-2-[4'-(methylsulfonyl)biphenyl-4-yl]-5-
methyl-l,3-oxazoIe acetate (salt);
(3S)-l-{2-[2-(4-Bromophenyl)-5-methyl-l,3-oxazol-4-yl]ethyl}pyrrolidin-3-ol;
4-{[(3S)-3-Hydroxypyrrolidin-l-yI]ethyl}-2-[4'-(methy!sulfonyl)biphenyl-4-yl]-5-
methyl-1,3-oxazole acetate (salt);
2-(4-Bromophenyl)-4-{2-[(3S)-5-(fluoromethyl)pyrrolidin-l-yi]ethyl}-5-methyl-
1,3-oxazole;
4-{2-[(3S)-3-(Fluoromethyl)pyrrolidin-l-yl]ethyl}-5-methyl-2-[4*-
(methylsulfonyI)biphenyI-4-yI]-1,3-oxazole;
2-(4-Bromophenyl)-4-{2-[(3R)-3-(fluoromethyl)pyrroIidin-l-yl]ethyl}-5-methyl-
1,3-oxazole;
4-{2-[(3R)-3-(Fluoromethyl)pyirolidin-l-yl]ethyl}-5-methyI-2-[4'-
(methy lsulfonyl)biphenyl-4-yl]-1,3-oxazole;
3-[4-(5-{2-[(3R)-3-(Fluoromethyl)pyrrolidin-l-yl]ethyl}-4-methyl-l,3-oxazol-2-
yl)phenyl]pyridine L-tartrate;
2-(4-Bromophenyl)-4-{2-[(3R)-3-methoxypyrrolidin-l-yl]ethyl}-5-methyl-l,3-
oxazole;
4-{2-[(3R)-3-methoxypyrrolidir!-l-yl]ethyI}-5-methyl-2-[4'-
(methylsulfonyl)biphenyl-4-yl]-l,3-oxazole;
2-(4-Bromophenyl)-4-{2-[(3S)-5-methoxypyrrolidin-l-yl]ethyl}-5-methyl-l,3-
oxazole;
4- {2-[(3 S)-3-Methoxypyrrol idir i-1 -yl]ethyl} -5-methy l-2-[4'-
(methylsulfonyl)biphenyl-4-yl]-l,3-oxazo!e;
2-(4-Bromophenyl)-4-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-5-methyl-l,3-
oxazole;
3-Methoxy-5-[4-(5-methyl-4-{2-[(2R)-2-methylpyrroIidin-l-yi]ethyl}-l,3-oxazol-
2-yl)phenyl]pyridine;
5-[4-(5-Methyl-4- {2-[(2R)-2-m.jthylpyrrolidin-1 -yl]ethyl} -1,3-oxazol-2-
yl)phenyl]thiophene-2-carbonitrile;
2-Methoxy-5-[4-(5-methyl-4-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l,3-oxazol-
2-yl)phenyl]pyrimidine;
5-(4-{5-Methyl-4-[2-(2-(R)-mehyl-pyrrolidin-l-yl)-ethyI]-oxazol-2-yl}-
phenoxymethyl)-thiophene-2-ci:rbonitrile;
5-Methyl-4-[2-(2-(R)-methyl-pyrro!idin-l-yl)-ethyl]-2-[4-(2-methyl-thiazo!-4-
ylmethoxy)-phenyl]-oxazole;
3-(4-{5-Methyl-4-[2-(2-(R)-metiyI-pyrrolidin-l-yl)-ethyl]-oxazoI-2-yl}-
phenoxymethyl)-pyridine;
4-(4-{5-Methyl-4-f2-(2-(R)-metiyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-y!}-
phenoxymethyl)-pyridine;
2-Methoxy-5-(4-{5-methyl-4-[2-(2-(R)-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-
yl} -phenoxymethyl)-pyridine;
2-Methyl-6-(4-{5-methyl-4-[2-(2-(R)-methyl-pyrrolidin-l-yI)-ethyl]-oxazol-2-yl}-
phenoxymethyl)-pyridine;
5-Methyl-4-[2-(2-(R)-methyl-p>rrolidin-l-yl)-ethyl]-2-[4-(thiazol-4-ylmethoxy)-
phenyl]-oxazole;
2-(4-{4-[2-(2-(R)-Methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-phenoxymethyl)-
pyridine;
4-[2-(2-(R)-Methyl-pyrrolidin-l-yl)-ethyl]-2-[4-(thiazol-4-yimethoxy)-phenyl]-
oxazole;
2-(4'-MethanesuIfonyl-biphenyl -4-yl)-4-[2-(2-(R)-niethyl-pyrrolidin-1 -yl)-ethyl]-
oxazole;
l-(4'-{5-Methyl-4-[2-((R)-2-mehyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-biphenyl-
4-yl)-ethanone;
l-(4'-{5-Methyl-4-[2-((R)-2-me:hyl-pyiTolidin-l-yl)-ethyl]-oxazol-2-yl}-biphenyl-
2-yl)-ethanone;
4'-{5-Methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-biphenyl-3-
carbonitrile;
4'- {5-Methyl-4-[2-((R)-2-meth> l-pyrrolidin-1 -yl)-ethyl]-oxazol-2-yl} -biphenyi-2-
carbonitrile;
2-(4'-Fluoro-biphenyl-4-yl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-l-y!)-ethyl]-
oxazole;
2-(3'-Fluoro-biphenyl-4-yl)-5-n-ethyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-
oxazole;
2-(2'-Fluoro-biphenyl-4-yl)-5-irethyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-
oxazole;
2-(4'-Methoxy-biphenyl-4-yl)-5-methyl-4-[2-((R)-2-tnethyl-pyrrolidin-l-yl)-ethyl]-
oxazole;
2-(3'-Methoxy-biphenyl-4-yl)-5 -methyl-4-[2-((R)-2-methyl-pyrrolidin-1 -yl)-ethyl]-
oxazole;
2-(2'-Methoxy-biphenyl-4-yl)-5 methyl-4-[2-((R)-2-methyl-pyrrolidin-1 -yl)-ethyI]-
oxazole;
4'-[5-Methyl-4-(2-pyrrolidin-l-yl-ethyl)-oxazol-2-yl]-biphenyl-3-carbonitrile;
2-Biphenyl-4-yl-5-methyl-4-[2- (R)-2-methyI-pyrrolidin-l-yl)-ethyl]-oxazole;
5-Methyl-2-(4'-methyl-biphenyl-4-yI)-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-
ethyl]oxazole;
3-(4-{5-Methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-y!}-phenyl)-
pyridine;
5-(4-{5-Methyl-4-[2-((R)-2-methyl-pyrroIidin-l-yl)-ethyl]-oxazol-2-yl}-phenyl)-
pyrimidine;
4'-{5-Methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-biphenyl-4-
carboxylic acid dimethylamide;
(4'-{5-Methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-oxazol-2-yl}-
biphenyl-4-yl)-pyrrolidin-l-yl-niethanone;
4'-{5-MethyI-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyI]-oxazol-2-yl}-biphenyl-4-
carboxylic acid amide;
4'-{5-Methyl-4-[2-((R)-2-methyl-pyiTolidin-l-yI)-ethyl]-oxazol-2-yI}-biphenyl-4-
sulfonic acid dimethylamide; and
5-Methyl-4-[2-((R)-2-methyl-pyrrolidin-l-yl)-ethyl]-2-(4'-trifluoromethoxy-
biphenyl-4-yl)-oxazole.
15. A pharmaceutical composition which comprises a compound as claimed in any of claims 1-14
and a pharmaceutically acceptable carrier.
16. A compound of formula I, or a salt thereof, as claimed in any one of
claims 1-14, for use in treating a nervous system disorder.



The present invention discloses novel aryl oxizole compounds of Formula I (I), or pharmaceutically
acceptable salts thereof, which have histamin:-H3 receptor antagonist or inverse agonist activity, as
well as methods for preparing and using such compounds. In another embodiment, the invention
disclose pharmaceutical compositions comprising compounds of Formula I as well as methods of
using these compositions to treat obesity, cognitive deficiencies, narcolepsy, and other histamine H3
receptor related diseases. Formula 1 (I) or a pharmaceutically acceptable salt thereof, wherein: m is
independently at each occurrence 1, 2, or 3 Z independently represents carbon (substituted with
hydrogen or the optional substituents indicated herein) or nitrogen, provided that when Z is nitrogen
then R6 is not attached to Z; R1 and R2 are independently -(C1-C7) alkyl(optionally substituted with
one to three halogens), or R1 and R2 and the nitrogen to which they are attached form an azetidinyl
ring, a pyrrolidinyl ring, or a piperidinyl zing, wherein further the azetidinyl, pyrrolidinyl, or
piperidinyl ring so formed may be optionally substituted one to three times with R5; R6 is
independently to each occurrence -H, -halogen, or-CH3

Documents:

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/00099-kolnp-2007%20abstract.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/00099-kolnp-2007%20assignment.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/00099-kolnp-2007%20claims.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/00099-kolnp-2007%20correspondence%20others.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/00099-kolnp-2007%20description%20(complete).pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/00099-kolnp-2007%20form-1.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/00099-kolnp-2007%20form-2.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/00099-kolnp-2007%20form-26.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/00099-kolnp-2007%20form-3.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/00099-kolnp-2007%20form-5.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/00099-kolnp-2007%20international%20publication.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/00099-kolnp-2007%20international%20search%20authority%20report.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/00099-kolnp-2007%20pct%20form.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/00099-kolnp-2007%20priority%20document.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/00099-kolnp-2007-correspondence-1.1.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/00099-kolnp-2007-correspondence-1.2.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/00099-kolnp-2007-form-1-1.1.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/00099-kolnp-2007-form-18.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/00099-kolnp-2007-form-3-1.1.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/99-KOLNP-2007-(27-01-2012)-CORRESPONDENCE.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/99-KOLNP-2007-(27-01-2012)-FORM%2027.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/99-KOLNP-2007-ABSTRACT%201.1.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/99-KOLNP-2007-AMANDED%20CLAIMS.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/99-kolnp-2007-assignment.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/99-kolnp-2007-correspondence.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/99-KOLNP-2007-DESCRIPTION%20(COMPLETE)%201.1.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/99-KOLNP-2007-EXAMINATION%20REPORT%20REPLY%20RECIEVED.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/99-kolnp-2007-examination%20report.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/99-KOLNP-2007-FORM%201%201.1.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/99-kolnp-2007-form%2018.pdf

http://ipindiaonline.gov.in/documentkol/99-KOLNP-2007/99-KOLNP-2007-FORM%202%201.1.pdf

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Patent Number 245570
Indian Patent Application Number 99/KOLNP/2007
PG Journal Number 04/2011
Publication Date 28-Jan-2011
Grant Date 25-Jan-2011
Date of Filing 09-Jan-2007
Name of Patentee ELI LILLY AND COMPANY
Applicant Address A CORPORATION OF THE STATE OF INDIANA, HAVING A PRINCIPAL PLACE OF BUSINESS AT LILLY CORPORATE CENTER, CITY OF INDIANAPOLIS, STATE OF INDIANA 46285
Inventors:
# Inventor's Name Inventor's Address
1 LISA SELSAM BEAVERS 74 NORTH EDWARDS STREET, FRANKLIN, INDIANA 46131
2 FINN TERRY PATRICK ADDEX PHARMACEUTICALS SA, 12 CHEMIN DES AULX, 1228 PLAN-LES-OUATES/GE, GENEVA
3 ROBERT ALAN GADSKI 4431 NORTH ILLINOIS, INDIANAPOLIS, INDIANA 46208
4 WILLIAM JOSEPH HORNBACK 10063 BENT TREE LANE, FISHERS, INDIANA 46038
5 RICHARD TODD PICKARD 20980 PRAIRIE BAPTIST ROAD, NOBLESVILLE, INDIANA 46060
6 FREDDIE CRAIG STEVENS 8039 PAINTED PONY DRIVE, INDIANAPOLIS, INDIANA 46217
7 CYNTHIA DARSHINI JESUDASON 1090 FLEETWOOD DRIVE, INDIANAPOLIS, INDIANA 46228
8 GRANT MATHEWS VAUGHT 7352 TARRAGON LANE, INDIANAPOLIS, INDIANA 46237
9 SERGE LOUIS BOULET 10813 WINDEMERE BOULEVARD, FISHERS, INDIANA 46037
PCT International Classification Number C07D 263/32
PCT International Application Number PCT/US2005/024883
PCT International Filing date 2005-07-14
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/591,191 2004-07-26 U.S.A.