WO 2006/107661 PCT/US2006/011320
2
HISTAMINE H3 RECEPTOR AGENTS, PREPARATION AND
THERAPEUTIC USES
This patent application claims the benefit of United States Provisional Patent
Application No. 60/667,582 filed April 1, 2005.
The present invention relates to novel substituted aryl-methanone-pyrrolidinyl-
methyl-pyrrolidinyl 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-
pecific peripheral consequences. By this mechanism, they 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 Alzheimer disease, mood and attention adjustments, cognitive
deficiencies, obesity, dizziness, schizophrenia, epilepsy, sleeping disorders, narcolepsy
and motion sickness.

WO 2006/107661 PCT/US2006/011320
3
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 GPRv53. GPRv53 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 WO96/38142. 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,
such as those in WO2002076925. 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 substituted aryl-methanone-pyrrolidinyl-
methyl-pyrrolidinyl 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.

WO 2006/107661 PCT/US2006/011320

4
SUMMARY OF THE INVENTION
The present invention provides a compound structurally represented by Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
Y independently represents carbon or nitrogen;
X independently represents carbon or nitrogen, provided that at least one of Y or X is
carbon;
Rl is independently
-halogen, -CN, -NO2, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens),
-(C3-C8) cycloalkyl, -(C1-C7) alkyl-S(O)2-(C1-C3) alkyl,
-(C1-C7) alkyl-C(O)-O-R3, -(C1-C7) alkyl-S(O)2-phenyl(R2)(R2)(R2),
-(C1-C7) alkyl-S-(C1-C7) alkyl, -(C1-C7) alkyl-(C3-C8) cycloalkyl,
-(C1-C7) alkyl-phenyl(R2)(R2)(R2), -C(O)-phenyl(R2)(R2)(R2),
-C(O)-(C1-C7) alkyl, -C(O)-(C3-C8) cycloalkyl,
-(C1-C7) alkyl-C(O)-phenyl(R2)(R2)(R2), -S-(C1-C7) alkyl,
-S-(C1-C7) alkyl-phenyl(R2)(R2)(R2), -S-(C3-C8) cycloalkyl-(C1-C7) alkyl,
-S-(C3-C8) cycloalkyl, -S-(C2-C7) alkenyl, -S-phenyl(R2)(R2)(R2),
-SO2-phenyl(R2)(R2)(R2), -SO2R7, -S(O)R7, -(C2-C7) alkenyl,
-(C3-C8) cycloalkenyl, -(C2-C7) alkenyl-S(O)(C1-C3) alkyl,
-(C2-C7) alkenyl-C(O)-O-R3, -(C2-C7) alkenyl-S(O)2-phenyl(R2)(R2)(R2),
-(C2-C7) alkenyl-S-(C1-C7) alkyl, -(C2-C7) alkenyl-(C3-C8) cycloalkyl, or
-(C2-C7)alkenyl-phenyl(R2)(R2)(R2);
R2 is independently at each occurrence
-H, -halogen, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens),
-C(O)R7, -C(O)OR7, -C(O)(C3-C8)cycloalkyl, -OCF3, -OR7, -SR7, -SO2R7,
-SO2CF3, or -S(O)R7;
R3 is independently at each occurrence

WO 2006/107661 PCT/US2006/011320
5
-H, or -(C1-C3) alkyl(optionally substituted with 1 to 3 halogens);
R4 and R5 are independently at each occurrence
-H, -halogen, -(C1-C3) alkyl(optionally substituted with 1 to 3 halogens), or -OR3,
provided that when Y is nitrogen, then R4 or R5 are not attached to Y, and
provided that when X is nitrogen, then R4 or R5 are not attached to X;
R6 is independently at each occurrence
-H, -halogen, -CF3, -(C1-C3) alkyl(optionally substituted with 1 to 3 halogens), or
-OR3; and
R7 is independently at each occurrence
-H, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens), or -(C2-C7)
alkenyl.
. 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
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.
In a preferred embodiment the present invention provides a compound structurally
represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein:
Y independently represents carbon; X independently represents carbon;
Rl is independently
-halogen, -CN, -NO2, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens),

WO 2006/107661 PCT/US2006/011320

6
-(C3-C8) cycloalkyl, -(C1-C7) alkyl-S(O)2-(C1-C3) alkyl,
-(C1-C7) alkyl-C(O)-O-R3, -(C1-C7) alkyl-S(O)2-phenyl(R2)(R2XR2,
-(C1-C7) alkyl-S-(C1-C7) alkyl, -(C1-C7) alkyl-(C3-C8) cycloalkyl,
-(C1-C7) alkyl-phenyl(R2)(R2)(R2), -C(O)-phenyl(R2)(R2)(R2),
-C(O)-(C1-C7) alkyl, -C(O)-(C3-C8) cycloalkyl,
-(C1-C7) alkyl-C(O)-phenyl(R2)(R2)(R2), -S-(C1-C7) alkyl,
-S-(C1-C7) alkyl-phenyl(R2)(R2)(R2), -S-(C3-C8) cycloalkyl-(C1-C7) alkyl,
-S-(C3-C8) cycloalkyl, -S-(C2-C7) alkenyl, -S-phenyl(R2)(R2)(R2),
-SO2-phenyl(R2)(R2)(R2), -SO2R7, -S(O)R7, -(C2-C7) alkenyl,
-(C3-C8) cycloalkenyl, -(C2-C7) alkenyl-S(O)2-(C1-C3) alkyl,
-(C2-C7) alkenyl-C(O)-O-R3, -(C2-C7) alkenyl-S(O)2-phenyl(R2)(R2)(R2),
-(C2-C7) alkenyl-S-(C1-C7) alkyl, -(C2-C7) alkenyl-(C3-C8) cycloalkyl, or
-(C2-C7)alkenyl-phenyl(R2)(R2)(R2);
R2 is independently at each occurrence
- H, -halogen, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens),
-C(O)R7, -C(O)OR7, -C(O)(C3-C8)cycIoalkyl, -OCF3, -OR7, -SR7, -SO2R7,
-SO2CF3, or -S(O)R7;
R3 is independently at each occurrence
-H, or -(C1-C3) alkyl(optionally substituted with 1 to 3 halogens);
R4 and R5 are independently at each occurrence
-H, -halogen, -(C1-C3) alkyl(optionally substituted with 1 to 3 halogens), or -OR3,
provided that when Y is nitrogen, then R4 or R5 are not attached to Y, and
provided that when X is nitrogen, then R4 or R5 are not attached to X;
R6 is independently at each occurrence
-H, -halogen, -CF3, -(C1-C3) alkyl(optionally substituted with 1 to 3 halogens), or
-OR3; and
R7 is independently at each occurrence
-H, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens), or
-(C2-C7) alkenyl.
In a preferred embodiment the present invention provides a compound structurally
represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein:
Y independently nitrogen; X independently represents carbon;

WO2006/10766I PCT/US2006/01I320

7
Rl is independently
-halogen, -CN, -NO2, -(C1-C7) alkyl(optionally substituted with I to 3 halogens),
-(C3-C8) cycloalkyl, -(C1-C7) alkyl-S(O)2-(C1-C3) alkyl,
-(C1-C7) alkyl-C(O)-O-R3, -(C1-C7) alkyl-S(O)2-phenyl(R2)(R2)(R2),
-(C1-C7) alkyl-S-(C1-C7) alkyl, -(C1-C7) alkyl-(C3-C8) cycloalkyl,
-(C1-C7) alkyl-phenyl(R2)(R2)(R2), -C(O)-phenyl(R2)(R2)(R2),
-C(O)-(C1-C7) alkyl, -C(O)-C3-C8) cycloalkyl,
-(C1-C7) alkyl-C(O)-phenyl(R2)(R2)(R2), -S-(C1-C7) alkyl,
-S-(C1-C7) alkyl-phenyl(R2)(R2)(R2), -S-(C3-C8) cycloalkyl-(C1-C7) alkyl,
-S-(C3-C8) cycloalkyl, -S-(C2-C7) alkenyl, -S-phenyl(R2)(R2)(R2),
-SO2-phenyl(R2)(R2)(R2), -SO2R7, -S(O)R7, -(C2-C7) alkenyl,
.-(C3-C8) cycloalkenyl, -(C2-C7) alkenyl-S(O)2-(C1-C3) alkyl,
-(C2-C7) alkenyl-C(O)-O-R3, -(C2-C7) alkenyl-S(O)2-phenyl(R2)(R2)(R2),
-(C2-C7) alkenyl-S-(C1-C7) alkyl, -(C2-C7) alkenyHC3-C8) cycloalkyl, or
-(C2-C7) alkenyl-phenyl(R2)(R2)(R2);
R2 is independently at each occurrence
- H, -halogen, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens),
-C(0)R7, -C(O)OR7, -C(O)(C3-C8)cycloalkyl, -OCF3, -OR7, -SR7, -SO2R7,
-SO2CF3, or -S(O)R7;
R3 is independently at each occurrence
-H, or -(C1-C3) alkyl(optionally substituted with 1 to 3 halogens);
R4 and R5 are independently at each occurrence
-H, -halogen, -(C1-C3) alkyl(optionally substituted with I to 3 halogens),or -OR3,
provided that when Y is nitrogen, then R4 or R5 are not attached to Y, and
provided that when X is nitrogen, then R4 or R5 are not attached to X;
R6 is independently at each occurrence
-H, -halogen, -CF3, -(C1-C3) alkyl(optionally substituted with 1 to 3 halogens), or
-OR3; and
R7 is independently at each occurrence
-H, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens), or
-(C2-C7) alkenyl.

WO 2006/107661 PCT/US2006/011320

8
In a preferred embodiment the present invention provides a compound structurally
represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein:
Y independently carbon; X independently represents nitrogen;
Rl is independently
-halogen, -CN, -NO2, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens),
-(C3-C8) cycloalkyl,-(C1-C7) alkyl-S(O)2-(C1-C3) alkyl,
-(C1-C7) alkyl-C(O)-O-R3, -(C1-C7) alkyl-S(O)2-phenyl(R2)(R2)(R2),
-(C1-C7) alkyl-S-(C1-C7) alkyl, -(C1-C7) alkyl-(C3-C8) cycloalkyl,
-(C1-C7) alkyl-phenyl(R2)(R2)(R2), -C(O)-phenyl(R2)(R2)(R2),
-C(O)-(C1-C7) alkyl, -C(O)-(C3-C8) cycloalkyl,
-(C1-C7) alkyl-C(O)-phenyl(R2)(R2)(R2), -S-(C1-C7) alkyl,
-S-(C1-C7) alkyl-phenyl(R2)(R2)(R2), -S-(C3-C8) cycloalkyl-(C1-C7) alkyl,
-S-(C3-C8) cycloalkyl, -S-(C2-C7) alkenyl, -S-phenyl(R2)(R2)(R2),
-SO2-phenyl(R2)(R2)(R2), -SO2R7, -S(O)R7, -(C2-C7) alkenyl,
-(C3-C8) cycloalkenyl, -(C2-C7) alkenyl-S(O)2-(C1-C3) alkyl,
-(C2-C7) alkenyl-C(O)-O-R3, -(C2-C7) alkenyl-S(O)2-phenyl(R2)(R2)(R2),
-(C2-C7) alkenyl-S-(C1-C7) alkyl, -(C2-C7) alkenyl-(C3-C8) cycloalkyl, or
-(C2-C7)alkenyl-phenyl(R2)(R2)(R2);
R2 is independently at each occurrence
- H, -halogen, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens),
-C(O)R7, -C(O)OR7, -C(O)(C3-C8)cycloalkyl, -OCF3, -OR7, -SR7, -SO2R7,
-SO2CF3, or -S(O)R7;
R3 is independently at each occurrence
-H, or -(C1-C3) alkyl(optionally substituted with 1 to 3 halogens);
R4 and R5 are independently at each occurrence
-H, -halogen, -(C1-C3) alkyl(optionally substituted with 1 to 3 halogens), or -OR3,
provided that when Y is nitrogen, then R4 or R5 are not attached to Y, and
provided that when X is nitrogen, then R4 or R5 are not attached to X;
R6 is independently at each occurrence
-H, -halogen, -CF3, -(C1-C3) alkyl(optionally substituted with 1 to 3 halogens), or
-OR3; and
R7 is independently at each occurrence

WO 2006/107661 PCT/US2006/011320

9
-H, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens), or
-(C2-C7) alkenyl.
In a preferred embodiment the present invention provides a compound structurally
represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein:
Y independently represents carbon or nitrogen; X independently represents carbon or
nitrogen, provided that at least one of Y or X is carbon;
Rl is independently
-halogen, -CN, -NO2, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens),
-(C3-C8) cycloalkyl, -(C1-C7) alkyl-S(O)(C1-C3) alkyl,
-(C1-C7) alkyl-phenyl(R2)(R2)(R2), -C(O)-phenyl(R2)(R2)(R2),
-C(O)-(C1-C7) alkyl, -C(O)-(C3-C8) cycloalkyl,
-(C1-C7) alkyl-C(O)-phenyl(R2)(R2)(R2), -S-(C1-C7) alkyl,
-S-(C1-C7) alkyl-phenyl(R2)(R2)(R2), -S-(C3-C8) cycloalkyl-(C1-C7) alkyl,
-S-(C3-C8) cycloalkyl, -S-phenyl(R2)(R2)(R2), -SO2-phenyl(R2)(R2)(R2),
-SO2R7, or -S(O)R7;
R2 is independently at each occurrence
-H, -halogen, -(C1-C3) alkyl(optionally substituted with 1 to 3 halogens),
-C(O)R7, -C(O)OR7, -OCF3, -OR7, -SR7, -SO2R7, -SO2CF3, or -S(O)R7;
R3 is independently at each occurrence
-H, or -(C1-C3) alkyl(optionally substituted with 1 to 3 halogens);
R4 is -H or -halogen; R5 is -H or -halogen,
provided that when Y is nitrogen, then R4 or R5 are not attached to Y, and
provided that when X is nitrogen, then R4 or R5 are not attached to X;
R6 is -H at one occurrence, and R6 is -CH3 at the second occurrence; and
R7 is independently at each occurrence
-H or -(C1-C3) alkyl(optionally substituted with 1 to 3 halogens).
Other embodiments of the invention are provided wherein each of the
embodiments described herein above is further narrowed as described in the following
preferences. Specifically, each of the preferences below is independently combined with
each of the embodiments above, and the particular combination provides another
embodiment in which the variable indicated in the preference is narrowed according to
the preference. Further, the invention provides a pharmaceutical composition comprising

WO 2006/107661 PCT/US2006/011320
10
the compounds of the new embodiments created by the combinations of the embodiments
described herein above with the narrowing preferences below, and a pharmaceutically
acceptable carrier.
Preferably Y is carbon. Preferably Y is nitrogen. Preferably X is carbon.
Preferably X is nitrogen.
Preferably Rl is -halogen, -(C1-C7) alkyl(optionally substituted with 1 to 3
halogens), -(C3-C8) cycloalkyl, -(C1-C7) alkyl-S(O)2-(C1-C3) alkyl,
-(C1-C7) alkyl-C(O)-O-R3, -(C1-C7) alkyl-S-(C1-C7) alkyl,
-(C1-C7) alkyl-(C3-C8) cycloalkyl, -C(O)-(C1-C7) alkyl, -S-(C1-C7) alkyl, -S(O)R7,
-C(O)-(C3-C8) cycloalkyl, -S-(C3-C8) cycloalkyl-(C1-C7) alkyl, or -S-(C3-C8) cycloalkyl.
Preferably Rl is -(C1-C7) alkyl-S(O)2-phenyl(R2)(R2)(R2),
-(C1-C7) alkyl-phenyl(R2)(R2)(R2), -C(O)-phenyl(R2)(R2)(R2),
-(C1-C7)alkyl-C(O)-phenyl(R2)(R2)(R2),
-S-(C1-C7) alkyl-phenyl(R2)(R2)(R2), -S-phenyl(R2)(R2)(R2),
-SO2-phenyl(R2)(R2)(R2), or -SO2R7.
Preferably Rl is -halogen. Preferably Rl is -(C1-C7) alkyl(optionally substituted
with 1 to 3 halogens), -(C3-C8) cycloalkyl, or -(C1-C7) alkyl-(C3-C8) cycloalkyl.
Preferably R2 is independently at each occurrence -H, -halogen,
-(C1-C7) alkyl(optionally substituted with 1 to 3 halogens), -C(O)R7, -C(O)OR7, -OCF3,
-OR7, -SR7, -SO2R7, -SO2CF3, or -S(O)R7.
Preferably R2 is independently at each occurrence -H, -halogen, or -(C1-C3)alkyl
(optionally substituted with 1 to 3 halogens). Preferably R2 is independently at each
occurrence -H.
Preferably R4 and R5 are independently at each occurrence -H. Preferably R4 and
R5 are independently at each occurrence -H or -halogen. Preferably R4 and R5 are
independently at each occurrence -halogen or -(C1-C3) (alkyl optionally substituted with
1 to 3 halogens). Preferably R4 is hydrogen and R5 is -halogen.
Preferably R6 is independently at each occurrence -H. Preferably R6 is
independently at each occurrence -H or -(C1-C3) alkyl (optionally substituted with 1 to 3
halogens). Preferably R6 is independently at each occurrence -H or -CH3(optionally
substituted with 1 to 3 halogens). Preferably one occurrence of R6 is -H and the second

WO 2006/107661 PCT/US2006/011320

11
occurrence of R6 is -CH3(optionally substituted with 1 to 3 halogens). Preferably one
occurrence of R6 is -H and the second occurrence of R6 is -CH3.
Preferably R7 is independently at each occurrence -H, or -(C1-C3) alkyl(optionally
substituted with 1 to 3 halogens).
In another embodiment, the present invention is a compound structurally
represented by Formula I:

or a pharmaceutically acceptable salt thereof wherein:
Y independently represents carbon or nitrogen,
X independently represents carbon or nitrogen, provided that at least one of Y or X is
carbon,
Rl is independently
-halogen, -CN, -NO2, -(C1-C7) alkyl, -(C3-C8) cycloalkyl,
-(C1-C7) alkyl-S(O)2-(C1-C3) alkyl, -(C1-C7) alkyl-C(O)-O-R3,
-(C1-C7) aIkyl-S(O)2-phenyl(R2)(R2)(R2), -(C1-C7) alkyI-S-(C1-C7) alkyl,
-(C1-C7) aIkyl-(C3-C8) cycloalkyl, -(C1-C7) alkyl-phenyl(R2)(R2)(R2),
-C(O)-phenyl(R2)(R2)(R2), -C(O)-(C1-C7) alkyl, -C(O)-(C3-C8) cycloalkyl,
-(C1-C7) alkyl-C(O)-phenyl(R2)(R2)(R2),-S-(C1-C7) alkyl,
-S-(C1-C7) alkyl-phenyl(R2)(R2)(R2), -S-(C3-C8) cycloalkyl-(C1-C7) alkyl,
-S-(C3-C8) cycloalkyl, -S-(C2-C7) alkenyl, -S-phenyl(R2)(R2)(R2),
-SO2-phenyl(R2)(R2)(R2), -SO2R7, -S(O)R7, -(C2-C7) alkenyl,
-(C3-C8) cycloalkenyl, -(C2-C7) alkenyl-S(O)2-(C1-C3) alkyl,
-(C2-C7) alkenyl-C(O)-O-R3, -(C2-C7) alkenyl-S(O)2-phenyl(R2)(R2)(R2),
-(C2-C7) alkenyl-S-(C1-C7) alkyl, -(C2-C7) alkenyl-(C3-C8) cycloalkyl, or
-(C2-C7)alkenyl-phenyl(R2)(R2)(R2),
R2 is independently at each occurrence
- H, -halogen, -(C1-C7) alkyl, -C(O)R7, -C(O)OR7, -C(O)(C3-C8)cycloalkyl,

WO 2006/107661 PCT/US2006/011320

12
-OCF3, -OR7, -SR7, -SO2R7, -SO2CF3, or -S(O)R7,
R3 is independently at each occurrence;
-H, or -(C1-C3) alkyl,
R4 and R5 are independently at each occurrence
-H, -halogen, -(C1-C3) alkyl, or -OR3,
provided that when Y is nitrogen, then R4 or R5 are not attached to Y, and
provided that when X is nitrogen, then R4 or R5 are not attached to X,
R6 is independently at each occurrence
-H, -halogen, -CF3, -(C1-C3) alkyl, or -OR3,
R7 is independently at each occurrence
-H, -(C1-C7) alkyl, or -(C2-C7) alkenyl.
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
listing sets out several groups of preferred compounds. It will be understood that each of
the listings may be combined with other listings to create additional groups of preferred
embodiments. Other embodiments are,
1. wherein Y is carbon,
2. wherein Y is nitrogen,
3. wherein X is carbon,
4. wherein X is nitrogen,
5. wherein both Y and X are carbon,
6. wherein Rl is -halogen, -CN, -NO2, -(C1-C7) alkyl, -(C3-C8) cycloalkyl, -(C1-C7)
alkyl-S(O)2-(C1-C3) alkyl, -(C1-C7) alkyl-C(O)-O-R3, -(C1-C7) alkyl-S(O)2-
phenyl(R2)(R2)(R2), -(C1-C7) alkyl-S-(C1-C7) alkyl, -(C1-C7) alkyl-(C3-C8)
cycloalkyl, -(C1-C7) alkyl-phenyl(R2)(R2)(R2), -C(O)-phenyl(R2)(R2)(R2),
-C(O)-(C1-C7) alkyl, -C(O)-(C3-C8) cycloalkyl, -(C1-C7) alkyl-C(O)-
phenyl(R2)(R2)(R2), -S-(C1-C7) alkyl, -S-(C1-C7) alkyl-phenyl(R2)(R2)(R2),
-S-(C3-C8) cycloalkyl-(C1-C7) alkyl, -S-(C3-C8) cycloalkyl, -S-(C2-C7) alkenyl,
-S-phenyl(R2)(R2)(R2), -SO2-phenyl(R2)(R2)(R2), -SO2R7, -S(O)R7, -(C2-C7)
alkenyl, -(C3-C8) cycloalkenyl, -(C2-C7) alkenyl-S(O)2-(C1-C3) alkyl,
-(C2-C7) alkenyl-C(O)-O-R3, -(C2-C7) alkenyl-S(O)2-phenyl(R2)(R2)(R2),

WO 2006/107661 PCX/US2006/011320

13
-(C2-C7) alkenyl-S-(C1-C7) alkyl, -(C2-C7) aIkenyl-(C3-C8) cycloalkyl, or -(C2-C7)
alkenyl-phenyl(R2)(R2)(R2),
7. wherein Rl is -halogen, -CN, -NO2, -(C1-C7) alkyl, -(C3-C8) cycloalkyl, -(C1-C7)
alkyl-S(O)2-(C1-C3) alkyl, -(C1-C7) alkyl-C(O)-O-R3, -(C1-C7) alkyl-S(O)2-
phenyl(R2)(R2)(R2), -(C1-C7) alkyl-S-(C1-C7) alkyl, -(C1-C7) alkyl-(C3-C8)
cycloalkyl, -(C1-C7) alkyl-phenyl(R2)(R2)(R2), -C(O)-phenyl(R2)(R2)(R2), -
C(O)-(C1-C7) alkyl, -C(O)-(C3-C8) cycloalkyl, -(C1-C7) alkyl-C(O)-
phenyl(R2)(R2)(R2), -S-(C1-C7) alkyl, -S-(C1-C7) alkyl-phenyl(R2)(R2)(R2), -S-
(C3-C8) cycloalkyI-(C1-C7) alkyl, -S-(C3-C8) cycloalkyl, -S-(C2-C7) alkenyl, -S-
phenyl(R2)(R2)(R2), -SO2-phenyl(R2)(R2)(R2), -SO2R7, or -S(O)R7,
8. wherein Rl is -halogen, -CN, -NO2, -(C1-C7) alkyl, -(C3-C8) cycloalkyl, -(C1-C7)
alkyl-S(O)2-(C1-C3) alkyl, -(C1-C7) alkyl-C(O)-O-R3, -(C1-C7) alkyl-S(O)2-
phenyl(R2)(R2)(R2), -(C1-C7) alkyl-S-(C1-C7) alkyl, -(C1-C7) alkyl-(C3-C8)
cycloalkyl, -(C1-C7) alkyl-phenyl(R2)(R2)(R2), -C(O)-phenyl(R2)(R2)(R2), -
C(O)-(C1-C7) alkyl, -C(O)-(C3-C8) cycloalkyl, or -(C1-C7) alkyl-C(O)-
phenyl(R2)(R2)(R2),
9. wherein Rl is -S-(C1-C7) alkyl, -S-(C1-C7) alkyl-phenyl(R2)(R2)(R2), -S-(C3-Cg)
cycloalkyl-(C1-C7) alkyl, -S-(C3-C8) cycloalkyl, -S-(C2-C7) alkenyl, -S-
phenyl(R2)(R2)(R2), -SO2-phenyl(R2)(R2)(R2), -SO2R7, or -S(O)R7,
10. wherein Rl is -(C2-C7) alkenyl, -(C3-C8) cycloalkenyl, -(C2-C7) alkenyl-S(O)2-
(C1-C3) alkyl, -(C2-C7) alkenyl-C(O)-O-R3, -(C2-C7) alkenyl-5(O)2-
phenyl(R2)(R2)(R2), -(C2-C7) alkenyl-S-(C1-C7) alkyl, -(C2-C7) alkenyl-(C3-C8)
cycloalkyl, or-(C1-C7) aikenyl-phenyl(R2)(R2)(R2),
11. wherein R2 is - H, - halogen, -(C1-C7) alkyl, -C(O)R7, -C(O)OR7,
-C(O)(C3-C8)cycloalkyl, -OCF3, -OR7, -SR7, -SO2R7, -SO2CF3, or
-S(O)R7,
12. wherein one independent occurrence of R2 is - H, - halogen, -(C1-C7) alkyl, -
C(O)R7, -C(O)OR7, -C(O)(C3-C8)cycloalkyl, -OCF3, -OR7, -SR7, -SO2R7, -
SO2CF3) or -S(O)R7, and a second independent occurrence of R2 is - H, -
halogen, or -(C1-C7) alkyl, and a third independent occurrence of R2 is -H or -
halogen,

WO 2006/107661 PCT/US2006/011320

14
13. wherein one independent occurrence of R2 is -SO2R7, -SO2CF3, or -S(O)R7, and
a second independent occurrence of R2 is - H, - halogen, or -(C1-C7) alkyl, and a
third independent occurrence of R2 is -H or -halogen,
14. wherein R3 is -H, or -(C1-C3) alkyl,
15. wherein R3 is -(C1-C3) alkyl,
16. wherein R4 and R5 are independently H, - halogen, -(C1-C3) alkyl, or, -OR3,
provided that when Y is nitrogen, then R4 or R5 are not attached to Y, and
provided that when X is nitrogen, then R4 or R5 are not attached to X,
17. wherein R4 is independently -halogen,
18. wherein R4 is independently halogen and R5 is halogen,
19. wherein R6 is independently at each occurrence -H, -halogen, -CF3, -(C1-C3)
alkyl, or -OR3,
20. wherein one independent occurrence of R6 is -(C4-C3) alkyl,
21. wherein one independent occurrence of R6 is -CH3,
22. whereinR7 is independently at each occurrence -H, -(C1-C7) alkyl, or -(C2-C7)
alkenyl,
23. wherein R7 is independently at each occurrence -(C1-C7) alkyl.
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. The present invention also
provides a pharmaceutical composition which comprises a compound of Formula I or a
pharmaceutical salt thereof, and a pharmaceutically acceptable carrier, diluent, or
excipient. The present invention further provides an antagonist or inverse agonist of
Formula I which is characterized by having little or no binding affinity for the histamine
receptor GPRv53. The present invention further provides an antagonist or inverse agonist
of Formula I 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. The
uses and methods of this invention encompass a prophylactic and therapeutic
administration of a compound of Formula I, or pharmaceutical composition which
comprises a compound of Formula I or a pharmaceutical salt thereof. In addition the
embodiments of the present invention include the synthesis of the examples named herein

WO 2006/107661 PCT/US2006/011320

15
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.
Thus, the invention provides a compound of Formula I, or a pharmaceutical salt
thereof, or a pharmaceutical composition which comprises a compound of Formula I, or a
pharmaceutical salt thereof, for use to prevent, treat and/or alleviate diseases or
conditions, for example, 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, eating disorders, 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, 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. In addition, the compounds of Formula I, or a pharmaceutical salts
thereof, or a pharmaceutical composition which comprises a compound of Formula I, or a
pharmaceutical salt thereof, 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. 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.

WO 2006/107661 PCT/US2006/011320

16
In addition, the present invention provides a compound of Formula I, or a
pharmaceutical salt thereof, or a pharmaceutical composition which comprises a
compound of Formula I, or a pharmaceutical salt thereof, and a pharmaceutically
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 neurotransmitters in a mammal; for
use in treating a disease arising from excessive histamine H3 receptor activity.
The present invention is further related to the use of a compound of Formula I, or
a pharmaceutical salt thereof, or a pharmaceutical composition which comprises a
compound of Formula I, 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.
In addition, the present invention 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

WO2006/I07661 PCT/US2006/011320
17
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 1,01
a pharmaceutically acceptable salt thereof, or a pharmaceutical composition which
comprises a compound of Formula I, or a pharmaceutical salt thereof, and a
pharmaceutically acceptable carrier, diluent, or excipient.
A pharmaceutical composition of the present invention comprising a
compound such as herein described and a pharmaceutically acceptable carrier showed
surprising and enhanced effects. Therefore, the said composition is synergistic in nature.
The invention further provides 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 a pharmaceutical composition
comprising a compound of Formula I, or a pharmaceutical salt thereof, and a
pharmaceutically acceptable carrier, diluent, or excipient. 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 a pharmaceutical salt thereof, and a
pharmaceutically acceptable carrier, diluent, or excipient. In addition, a compound of
Formula I, or a pharmaceutical composition comprising a compound of Formula I, or a
pharmaceutical salt thereof, 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.
General terms used in the description of compounds, compositions, and methods
herein described, bear their 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.

WO 2006/107661 PCT/US2006/011320
18
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;
The terms "C1-C3 alkyl" and "C1-C7 alky!" mean hydrocarbon chains of the
indicated number of carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl,
heptyl, and the like, and branched or isomeric forms thereof, and as herein defined,
optionally may be substituted with up to four halogens, such as trifluoromethyl and the
like.
"(C3-C8) cycloalkyl" means a ring of the indicated number of carbon atoms, with
three to eight carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,
cycloheptyl, and the like, and as herein defined optionally may be substituted with up to
four halogens.
"(C2-C7) alkenyl" means hydrocarbon chains of the indicated number of carbon
atoms, of either a straight or branched configuration, having at least one carbon-carbon
double bond which may occur at any point along the chain, such as ethenyl, propenyl,
butenyl, pentenyl, vinyl, 2-butenyl and the like, and may be optionally substituted with up
to four halogens.
The term "(C3-C8) cycloalkenyl" refers to a partially saturated carbocycle
containing one or more rings of from 3 to 8 carbon atoms, such as cyclopropenyl,
cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like,
optionally substituted with up to four halogens.
The substituent "-phenyl(R2)(R2)(R2)" represents a phenyl ring which is itself
independently substituted three times with R2, each at any open position around the
phenyl ring, and in any order.
"Boc" or "BOC" refer to r-butyl carbamate. "HOBt" is 1-hydrobenzotriazole.
"PS-Trisamine" is Tris-(2-aminoethyl)amine polystyrene. "PS-Carbodiimide" or "PS-
CDI" is N-Cyclohexylcarbodiimide-N'-propyloxymethyl polystyrene. "PS-DIEA" is

WO 2006/107661 PCT/US2006/011320

19
N,N-(Diisopropyl)aminomethylpolystyrene (1% inorganic antistatic agent). "PS-DMAP"
is N-(methylpolystyrene)-4-(raethylamino) pyridine.
"Halogen" or "halo" means fluoro, chloro, bromo, and iodo.
"Composition" means a pharmaceutical composition and is intended to encompass
a pharmaceutical product comprising the active ingredient(s) of Formula I, or X1 to X34,
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 "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.
The terms "treating" and "treat", as used herein, include their generally accepted
meanings, i.e., preventing, prohibiting, restraining, alleviating, ameliorating, slowing,
stopping, or reversing the progression or severity of a pathological condition, described
herein.
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 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" or "racemic
modification" refer to a mixture of equal parts of enantiomers.

WO 2006/10766, PCT/US2006/011320

20
The term "enantiomeric enrichment" as used herein refers to the 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:
ee = E1 - E2 X 100
E1+E2
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 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-
838448, published April 29,1998. Examples of resolutions include recrystallization
techniques or chiral chromatography.
Some of the compounds of the present invention have one or more chiral centers
and may exist in a variety of stereoisomeric configurations. As a consequence of these
chiral centers, the compounds of the present invention occur as racemates, mixtures of
enantiomers and as individual enantiomers, as well as diastereomers and mixtures of
diastereomers. All such racemates, enantiomers, and diastereomers are within the scope
of the present 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

WO 2006/107661 PCT/US2006/011320
21
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.
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 which are substantially
non-toxic to living organisms. See, e.g., Berge, S.M, Bighley, L.D., and Monkhouse,
D.C., "Pharmaceutical Salts," J. Pharm. Sci, 66:1, 1977. Typical pharmaceutical salts
include those salts prepared by reaction of the compounds of Formula I 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 prepared
by reaction of a compound of Formula I 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., J. 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 pharmaceutical acid addition salts of the invention are typically formed by
reacting the compound of Formula I with an equimolar or excess amount of acid. The
reactants are generally combined in a mutual solvent such as diethylether,
tetrahydrofuran, methanol, ethanol, isopropanol, benzene, and the like. The salts

WO 2006/107661 PCT/US2006/011320
22
normally precipitate out of solution within about one hour to about ten days and can be
isolated by filtration or other conventional methods.
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 acids commonly employed to form such 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, methanesulfonic acid, oxalic
acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid,
acetic acid and the like. 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,
-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate,
naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.
The term "base addition salt" refers to a salt of a compound of Formula I prepared
by reaction of a compound of Formula I 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. The present invention also
contemplates pharmaceutical base addition salts of compounds of Formula I. The skilled
artisan would appreciate that some compounds of Formula I may be acidic in nature and
accordingly react with any of a number of inorganic and organic bases to form
pharmaceutical base addition salts. Examples of pharmaceutical base addition salts are
the ammonium, lithium, potassium, sodium, calcium, magnesium, methylamino,
diethylamino, ethylene diamino, cyclohexylamino, and ethanolamino salts, and the like of
a compound of Formula I.
The compounds of Formula I, 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

WO 2006/107661 PCT/US2006/011320

23
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 may be
obtained by stereospecific synthesis using optically pure starting materials or reagents of
known configuration or through enantioselective synthesis.
The compounds of Formula I 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 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 identifiable and 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 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 in the instant Preparations and Examples have
their normal meanings unless otherwise designated. For example, as used herein, the
following terms have the meanings indicated: "eq" refers to equivalents; "N" refers to
normal or normality, "M" refers to molar or molarity, "g" refers to gram or grams, "mg"
refers to milligrams; "L" refers to liters; "mL" refers to milliliters; "µL" refers to
microliters; "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; "HPLC" refers to high performance
liquid chromatography; "Rf" refers to retention factor; "Rt" refers to retention time;
"δ"refers to part per million down-field from tetramethylsilane; "MS" refers to mass
spectrometry, Observed Mass indicates (M+ 1) unless indicated otherwise. "MS(FD)"
refers to field desorption mass spectrometry, "MS(IS)" refers to ion spray mass

WO 2006/107661 PCT/US2006/011320

24
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, "1H NMR" refers to proton nuclear magnetic
resonance spectrometry. In addition, "IR" refers to infra red 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 Preparations:
SCHEME A

In Scheme A, Ra and Ra ,are each independently but not limited to F, Cl, CF3,
alkyl and can include disubstituted compounds; Rb is H, or the corresponding carboxylic
acids salts; Rc and Rc- are each independently but not limited to alkyl, amino, hydroxy,
and Rl is, but not limited to a halogen, cyano, sulfone, nitro, acetyl, or an alkyl, branched
alkyl group, cycloalkyl group which substituted with other functional groups not limited
to sulfones, trifluoromethyl, halo, methoxy, ester, acid, phenyl etc. In Scheme A, Step 1
aryl carboxylic acids or the lithium, sodium or potassium salt of the acid where Rb can be
H, Li, Na or K are 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, 4-pentylbenzoic acid or the corresponding lithium or sodium salt is
suspended a suitable organic solvent such as dichloromethane, DMF or mixtures thereof.
A suitable amide coupling agent i.e EDC, DCC, TBTU, PS-carbodiimide etc., is added
followed by HOBt, HATU, etc., at room temperature. Diisopropylethyl amine and
suitable amine in this case, (S)(+)-l-(2-pyrrolidinylmethyl)pyrrolidine are added to the
mixture. The mixture, is stirred or shaken at room temperature for a period of 8-48 hours.

WO 2006/107661 PCT/US2006/011320

25
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.
Alternatively the corresponding acid chloride can be formed from the
corresponding acid or salt thereof using thionyl chloride or oxalyl chloride and a few
drops DMF, and treated with a suitable amine to give the desired amide. For example 4-
bromo-2-fluorobenzoic acid and oxalyl chloride are combined in a suitable solvent such
as dichloromethane, pyridine or mixtures thereof, and 2 drops of dimethylformamide are
added as a catalyst. The reaction is stirred at room temperature for a period of 1-8 hours.
After this time, the reaction is concentrated in vacuo. Total conversion to the acid
chloride is assumed.
Alternatively the ether can be formed by a Mitsunobu or related reaction using an
alkyl alcohol and a coupling agent such as DEAD, DIAD etc. with triphenyl phosphine in
a suitable solvent such as THF or CH2CI2. The reaction is quenched with water, and the
resulting mixture may be extracted, concentrated, and purified according to techniques
well known in the art.
Intermediate 1
4-(3-Oxo-3-phenyl-propenyl)-benzoicacid

Sodium hydroxide (128.0 g, 3.2 mol) is dissolved in water (1400 mL) and ethanol (675
mL). The mixture is cooled to 20 °C and acetophenone (120 g, 0.5 mol) is added with
mechanical stirring. 4-Carboxybenzaldehyde (75 g, 0.5 mol) and the reaction stirred at
room temperature for 6 h. The reaction is acidified with concentrated HC1 (300 mL) and
extracted with ethyl acetate (3x). The combined organic portions are washed with water,
staturated brine, dried, and evaporated in vacuo. The material is recrystillized from
isopropanol with a small amount of methanol to obtain 48 g (38%) of the titled
compound, m.p. = 197 - 200 °C; Anal. Calcd for C16H12O3: C, 76.18; H, 4.79. Found:
C, 76.03; H, 5.05.

PCT/US2006/011320
WO 2006/107661

26
Intermediate 2
4-(3-Oxo-3-phenyl-propyl)-benzoic acid

4-(3-Oxo-3-phenyl-propenyl)-benzoic acid (7.64 g, 30 mmol) is combined with Raney
nickel (2 g) in ethanol (140 mL). The mixture is hydrogenated at room temperature and
50 psi for 1.5 h. The reaction is filtered evaporated in vacuo. The resulting residue is
recrystillized from ethyl acetate to obtain 4.57 g (59%) of the titled compound, m.p. =
145 _ 147 °C; Anal. Calcd for C16H14O3: C, 75.58; H, 5.55. Found: C, 75.60; H, 5.32.
Intermediate 3
4-(5-Oxo-5-phenyI-penta-l,3-dienyI)-benzoicadd

Sodium hydroxide (128.0 g, 3.2 mol) is dissolved in water (1400 mL) and ethanol (675
mL). Cinnamaldehyde (66.1 g, 0.5 mol) and 4-acetylbenzoic acid (82.1 g, 0.5 mol) are
added and the mixture stirred for about 5 min. A thick precipitate is formed and the thick
mixture is diluted with water (750 mL) and ethanol (750 mL). Stir at room temperature
for 18 h. The reaction is cooled and acidified with concentrated HC1 (270 mL). The
mixture is extracted with ethyl acetate (3x). The combined organic portions are washed
with water (2x), dried over Na2SO4, filtered and evaporated. The resulting solid is
recrystillized from 2-methoxyethanol and washed with diethyl ether to obtain 36.1 g
(26%) of yellow crystals, m.p. = 210 - 214 °C; Anal. Calcd for C18H14O3: C, 77.68; H,
5.07. Found: C, 77.47; H, 5.09.

WO 2006/107661 PCT/US2006/011320

27
Intermediate 4
4-(5-Phenyl-pentyl)-benzoic acid

4-(5-Oxo-5-phenyl-penta-l,3-dienyl)-benzoic acid (13.9 g, 50 mmol) is dissolved in
ethanol (280 mL). Concentrated H2SO4 (1 mL) and 5% palladium on carbon (2.8 g) are
added and the mixture hydrogenated at 50 °C and 60 psi for 4 h. The reaction is filtered,
diluted with water (1000 mL), and extracted several times with diethyl ether. The
combined organic extracts are washed with 2 N NaOH. The aqueous portion is acidified
with concentrated hydrochloric acid and extracted with diethyl ether. The ether extracts
are washed with water, dried over Na2SO4, and evaporated to obtain a solid. The solid is
recrystillized from hexanes to obtain 7.2 g (54%) of white crystals. m.p. = 80 - 80.5 °C;
Anal. Calcd for C18H20O2: C, 80.56; H, 7.51. Found: C, 80.75; H, 7.34.
Intermediate 5
2-(R)-Methyl-l-(2-(S)-pyrrolidinylmethyI)pyrroIidine

Equimolar amounts of (S) BOC proline (CAS 15761-39-4) and 2-(R)-methyl-pyrrolidine
hydrochloride (CAS 135324-85-5) are coupled in a manner substantially analogous to
Procedure D in dichloromethane to give 2(S)-(2(R)-methyl-pyrrolidine-l-carbonyl)-
pyrrolidine-1-carboxylic acid tert-butyl ester. The material is deprotected by stirring in
dichloromethane at 5-10 °C while trifluoroacetic acid (10 eq,) is added and then stirred at
room temperature for 18 h. The reaction is concentrated, dissolved in H2O, and the pH is
adjusted to 8-9 with K2CO3. The mixture is extracted several times with CH2C12. The
extracts are combined, dried (Na2SO4), filtered, and concentrated in vacuo to give (2(R)-
methyl-pyrrolidin-l-yl)-pyrrolidin-2-yl-methanone. AIM lithium aluminum hydride/
THF solution (3 eq.) is diluted with an equal volume of THF and stirred under N2 as a
THF solution of (2(R)-methyl-pyrrolidin-l-yI)-pyrrolidin-2-yl-methanone is added

WO 2006/107661 PCT/US2006/011320
28
dropwise, allowing the reaction to mildly exotherm. The reaction mixture is stirred at 40
°C for 45 min, and then at room temperature 18 h. The mixture is cooled in an ice bath
and quenched with H2O (3 eq.), 4 N NaOH (3 eq.), then H2O (9 eq.) while keeping the
reaction temperature less than 15 °C. The mixture is stirred overnight, filtered, and the
precipitate is washed three times with THF. The filtrate and washes are combined and
concentrated to give 2-(R)-methyl-1- (2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+)
169.3 (M+ H)+. The title compound is used as such or is purified by SCX
chromatography or distillation.
Intermediate 6
4-Bromo-2-fluorobenzoic acid chloride

4-Bromo-2-fluorobenzoic acid (l.0mmol) and oxalyl chloride (2.0 mmol) are combined
in dichloromethane (0.10 M), and 2 drops of dimethylformamide are added as a catalyst.
The reaction is stirred at room temperature for 3 h. After this time, the reaction is
concentrated in vacuo. Total conversion to the acid chloride is assumed.
Intermediate 7
6-(4-Trifluoromethoxy-phenylsuIfanyI)-nicotinic acid methyl ester

Procedure: To a stirring solution of methyl-6-chloronicotinate (200mg, 1.17mrnol) and
potassium carbonate (483mg, 3.5mmol) in N,N-dimethylformamide (6mL), add 4-
trifluoromethoxy-benzenethiol (340mg, 1.75mmol) and heat to 100°C for two hours.
After this time, remove the heat and wash the reaction with water while extracting with
dichloromethane. Dry the organics with sodium sulfate, filter and concentrate in vacuo.
Purify via radial chromatography eluting with ethyl acetate and hexane.

PCT/US2006/011320
WO 2006/107661
29

MS (m/e): 330.1 (M+l).
Intermediate 8
6-(4-TrifIuoromethoxy-phenyIsulfanyl)-nicotinic acid sodium salt

Procedure: To a stirring solution of 6-(4-trifluoromethoxy-phenylsulfanyl)-nicotinic
acid methyl ester (See Intermediate 7) (52mg, 0.158mmol) in methanol/tetrahydrofuran
(1:1) (0.15M), add 2N sodium hydroxide (0.08mL, 0.161mmol) and heat to reflux for one
hour. After this time, remove the heat and concentrate in vacuo.
MS (m/e): 316.0 (M+l).
Example 1
(S)-(4-Pentyl-phenyl)-(2-pyrrolidin-l-yImethyl-pyrrolidin-l-yl)-methanone

Procedure A: 4-Pentylbenzoic acid (62 mg, 0.32mmol) and PS-carbodiimide
(mmol/g=1.32, 484 mg, 0.64mmol) are combined in 5.0 ml of 5% DMF in
Dichloromethane and mixed well in a vial. (S)(+)-l-(2-Pyrrolidinylmethyl)pyrrolidine
(50 mg) is added to this mixture and the vial is capped with a Teflon cap. The vial is
shaken at room temperature overnight. The mixture is filtered and the resin is washed
with dichloromethane. The Filtrate is concentrated under N2 gas and applied to silica-gel
column chromatography (CH2CI2 followed by CH2CI2: 2M NH3 in MeOH=45:1) to
give the product. Observed mass: 329 (M+l).
Example 2
(S)-(4-Methylsulfanyl-phenyl)-(2-pyrroIidin-l-ylmethyl-pyrrolidin-l-yl)-methanone


WO 2006/107661 PCT/US2006/01I320
30
(S)-(4-Methylsulfanyl-phenyl)-(2-pyrrolidin-1 -ylmethyl-pyrrolidin-1 -yl)-methanone is
prepared from 4-(methylthio)benzoic acid in a manner substantially similar Procedure A.
Observed mass 305.
Example 3
(S)-[4-(4-Methyl-cyclohexyIsuIfanyl)-phenyl]-(2-pyrrolidin-l-ylmethyl-pyrrolidia-l-
yl)-methanone

(S)-[4-(4-Methyl-cyclohexylsulfanyl)-phenyl]-(2-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-
methanone is prepared from 4-(4-methyl-cyclohexylsulfanyl )-benzoic acid in a manner
substantially similar Procedure A. Observed mass 387.
Example 4
(S)-(4-Methanesulfonyl-phenyl)-(2-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-
methanone

(S)-(4-Methanesulfonyl-phenyl)-(2-pyrrolidin-1 -ylmethyl-pyrrolidin-l-yl)-methanone is
prepared from 4-methanesulfonyl benzoic acid in a manner substantially similar
Procedure A. Observed mass 337.

The title compound is prepared from p-toluic acid in a manner substantially similar
Procedure A. Observed mass 273.
Example 5
(S)-(2-PyrroIidin-l-ylmethyI-pyrroIidin-l-yl)-p-toIyl-methanone

WO 2006/107661 PCT/US2006/011320
31

Example 6
(S)-(4-Ethyl-phenyl)-(2-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-methanone
The title compound is prepared from 4-ethylbenzoic acid in a manner substantially similar
Procedure A. Observed mass 287.
Example 7
(S)-(4-Propyl-phenyl)-(2-pyrroIidin-l-ylmethyl-pyrroIidin-l-yl)-methanone

The title compound is prepared from 4-N-propylbenzoic acid in a manner substantially
similar Procedure A. Observed mass 301.
Example 8
(S)-(4-Butyl-phenyl)-(2-pyrro!idin-l-ylmethyl-pyrrolidin-l-yl)-methanone

The title compound is prepared from 4-N-butylbenzoic acid in a manner substantially
similar Procedure A. Observed mass 315.
Example 9
(S)-(4-Benzyl-phenyl)-(2-pyrrolidin-l-yImethyl-pyrrolidin-l-yl)-methanone

The title compound is prepared from diphenylmethane-4carboxylic acid in a manner
substantially similar Procedure A. Observed mass 349.

WO 2006,107661 PCT/US2006/011320

32
Example 10
(S)-(3,4-Ditnethyl-phenyl)-(2-pyrroIidin-l-ylmethyl-pyrrolidin-l-yI)-methanone

The title compound is prepared from 3,4-dimethylbenzoic acid in a manner substantially
similar Procedure A. Observed mass 287.
Example 11
(S)-(4-tert-Butyl-phenyl)-(2-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-methanone

The title compound is prepared from 4-tert-butylbenzoic acid in a manner substantially
similar Procedure A. Observed mass 315.
Example 12
(S)-(4-BenzoyI-phenyl)-(2-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-methanone

The title compound is prepared from 4-benzoylbenzoic acid in a manner substantially
similar Procedure A. Observed mass 363.
Example 13
(S)-(4-Cyclohexyl-phenyl)-(2-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-methanone


WO 2006/107661 PCT/US2006/011320

33
The title compound is prepared from 4-cyclohexylbenzoic acid in a manner substantially
similar Procedure A. Observed mass 341.
Example 14
l-Phenyl-3-[4-(2-(S)-pyrrolidin-l-ylmethyl-pyrrolidine-l-carbonyi)-phenyl]-propan-
1-one

The title compound is prepared from 4-(3-oxo-3-phenyl-propyl)-benzoic acid
(Intermediate 2), in a manner substantially similar Procedure A. Observed mass 391.
Example 15
[4-(5-Phenyl-pentyl)-phenyl]-(2-(S)-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-
methanone

The title compound is prepared from 4-(5-phenyl-pentyl)-benzoic acid (Intermediate 4),
in a manner substantially similar to Procedure A. Observed mass 405.
Example 16
(S)-[4-(2-Chloro-ethyl)-phenyl]-(2-pyrrolidin-l-ylmethyl-pyrroIidin-l-yl)-methanone

Add thionylchloride (6mL) to 4-(2-chIoroethyl)benzoic acid (l.OOg, 5.4mmol) and stir at
50°C for 30min. Remove the excess thionylchloride in vacuo and dissolve the reside to
dichloromethane (2mL). Add this acid chloride solution to the mixture of triethylamine
(656mg, 6.5mmol) and (S)(+)-l-(2-pyrrolidinylmethyl)pyrrolidine (l.OOg, 6.5mmol) in
dichloromethane (30mL) at 0°C and stir it at room temperature for 2h. Dilute the reaction
mixture and wash with brine, dry over sodium sulfate and remove the solvent. Purify the

WO 2006/107661 PCT/US2006/011320
34
crude product by a silica-gel column chromatography (dichloromethane : 2M ammonia in
methanol = 40:1) to give the title compound. 1.35g (80%). Observed Mass 321.
Example 17
(4-Bromo-2-fluoro-phenyl)-(2-(S)-pyrroHdin-l-ylmethyl-pyrrolidin-yl)methanone

To a stirring solution of (S)-(+)-l-(2-pyrrolidinylmethyl)pyrrolidine (l.Ommol) and N-
methylmorpholine (l.Ommol) in dichloromethane (0.10M), slowly add 4-Bromo-2-
fluorobenzoic acid chloride (l.Ommol) diluted in dichloromethane. Stir reaction at room
temperature for one hour. After this time wash the reaction with saturated aqueous
sodium bicarbonate while extracting with dichloromethane. Dry the organic layer with
sodium sulfate, filter and concentrate in vacuo to give the title compound. MS (m/e):
355.1/357.1 (M+l).
Example 18
(4-Fluoro-phenyl)-(2-(S)-pyrrolidin-l-ylmethyI-pyrrolidin-l-yl)-methanone

Procedure B: (S)(+)-l-(2-Pyrrolidinylmethyl)pyrrolidine (1.07 g, 6.93 mmol) and
triethylamine (763 mg, 7.56 mmol) are dissolved in dichloromethane (20 mL) and cooled
to 0 °C. 4-Fluorobenzoyl chloride (1.00 g, 6.3 mmol) in dichloromethane (2.0 mL) is
added to the mixture at 0 °C and stirred at room temperature for 3 h. The reaction
mixture is washed with brine, dried over Na2SO4, filtered and evaporated. The residue is
purified using silica-gel column chromatography (CH2Cl2:2M NH3 in MeOH=40:l) to
give 1.45 g (83%) of the title compound. Observed mass: 277(M+1).

WO 2006/107661 PCT/US2006/011320
35

Example 19
(4-Bromo-2-fluoro-phenyI)-[2-(S)-(2-(R)-methyl-pyrroIidin-l-ylmethyl)-pyrrolidin-
l-yl]-methanone

The title compound is prepared in a manner substantially analogous to Procedure C (see
example 32) from 4-bromo-2-fluoro-benzoic acid (CAS 112704-79-7) and 2-(R)-Methyl-
1- (2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (HA) 369/371 (MH*).
Example 20
(S)-(2-Pyrrolidin-l-yImethyl-pyrrolidin-l-yl)-(4-trifluoromethyl-phenyI)-methanone

The title compound is prepared from 4-trifluoromethyl benzoic acid in a manner
substantially similar to Procedure A. Observed mass 327.
Example 21
(4-Bromo-phenyl)-(2-(S)-pyrrolidin-l-ylmethyl-pyrroIidin-yI)methanone

To a stirring solution of 4-bromobenzoic acid-2,5-dioxo-pyrrolidin-l-yl ester (3.5 g, 11:7
mmol), [which can be prepared from 4-bromobenzoic acid and N-hydroxy succinamide
by the method of C. Mitsos, Chem Pharm Bull 48(2),211-214(2000), or purchased from
Ambinter, CAS# 80586-82-9], in tetrahydrofuran (0.15 M), add (S)-(+)-l-(2-
pyrrolidinylmethyl)pyrrolidine and heat to reflux for 4 h. After this time, remove the heat
and wash the reaction with water while extracting with 10% isopropanol
/dichloromethane. Dry the organic portion with sodium sulfate, filter and concentrate in

WO 2006/107661 PCT/US2006/011320

36
vacuo. Purify the resulting residue on a silica column eluting with 2 M ammonia in
methanol and dichloromethane to give (4-bromo-phenyl)-(2-(S)-pyrrolidin-l-ylmethyl-
pyrrolidin-yl)methanone (93% yield with 80% purity). MS (m/e): 337.1 (M+l).
Example 22
(S)-(4-Chloro-phenyl)-(2-(S)-pyrrolidin-l-yImethyl-pyrrolidin-l-yl)-methanone

The title compound is prepared from 4-chlorobenzoic acid in a manner substantially
similar to Procedure A. Observed mass 293.
Example 23
4-(2-(S)-Pyrrolidin-l-ylmethyl-pyrrolidine-l-carbonyl)-benzonitrile

The title compound is prepared from 4-cyanobenzoic acid in a manner substantially
similar to Procedure A. Observed mass 391.
Example 24
(4-Nitro-phenyl)-(2-(S)-pyrrolidin-l-yImethyl-pyrrolidin-l-yl)-methanone

The title compound is prepared from 4-nitrobenzoic acid in a manner substantially similar
to Procedure A. Observed mass: 304(M+l).

WO 2006/107661 PCT/US2006/011320

37
Example 25
(4-Bromo-2-trifluoromethyl-phenyl)-(2-(S)-pyrrolidin-l-ylmethyl-pyrroIidin-l-yI)-
methanone

Procedure D: 4-Bromo-2-trifluoromethylbenzoic acid (CAS 320-31-0) (0.46g, 1.7mmol)
is dissolved in dimethylformamide (5ml) with stirring at room temperature. TBTU
(0.558g, 1.8mmol), triethylamine (lml) and (S)(+)-l-(2-pyrrolidinylmethyl)pyrrolidine
(0.26g, 1.7mmol) are added and this mixture is stirred at room temperature overnight.
Water and ethyl acetate are added to the mixture. The aqueous layer is extracted several
times with ethyl acetate. The combined organic layers are dried over MgSO4 and
evaporated. The crude product is purified by silica-gel column chromatography (gradient:
100% CH2C12 to 8% 2M NH3 in MeOH/ CH2C12) give the title compound. MS (HA)
405/407 (MH+).
Example 26
(4-Bromo-2,6-difluoro-phenyl)-(2-(S)-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-
methanone

The title compound is prepared in a manner substantially analogous to Procedure D from
2,6-difluoro-4-bromobenzoic acid (CAS 183065-68-1). MS (FIA) 405/407 (MH+).
Example 27
l-[4-(2-(S)-PyrroHdin-l-ylmethyl-pyrrolidine-l-carbonyl)-phenyl]-ethanone
hydrochloride salt

WO 2006/107661 PCT/US2006/011320
38

Procedure E: 4-Acetylbenzoic acid (Aldrich) (CAS# 586-89-0) (295 mg, 1.8mmol) is
suspended in dichloromethane (9 mL) and DMF (1 mL). EDC (344 mg, 1.8 mmol) and
HOBt (243 mg, 1.8 mmol) are added at room temperature in that order. DIEA (0.63 mL,
3.6 mmol) and (S)(+)-l-(2-pyrrolidinylmethyl)pyrrolidine (185 mg, 1.2 mmol) are added
to the mixture. The mixture is stirred at room temperature for overnight. Brine is added to
the mixture. The aqueous layer is extracted with dichlormethane (2X), the combined
organic layers are washed with aq. NaHCO3, then brine (3X), dried over Na2SO4 and
evaporated. The crude product is purified by an SCX column (MeOH wash, then elute
with 2M NH3 in MeOH ). The product is then further purified by silica-gel column
chromatography (gradient: 100% CH2C12 to 10% 2M NH3 in MeOH/CH2Cl2) give the
free base. The free base (312 mg, 1.04 mmol) is stirred in anhyd. MeOH (5 mL) and 1 N
HC1/ Et2O (1.22 mL, 1.22 mmol) is added, stirred 10 minutes, evaporated, dissolved in
anhyd. MeOH, evaporated, and the material is triturated in Et2O, filtered, and dried in
vacuo to the HC1 salt as a white solid (350 mg, 87% yld). MS (ES+) 301.2 (free base).
Example 28
(4-CycIopropanecarbonyl-phenyl)-(2-(S)-pyrroIidin-l-ylmethyl-pyrrolidin-l-yl)-
methanone hydrochloride salt

The title compound is prepared in a manner substantially analogous to Procedure E
starting from 4-cyclopropanecarbonyl-benzoic acid (CAS# 303021-37-6; Dorwald, F et
al. WO 2000063208) and (S)(+)-l-(2-pyrrolidinylmethyl)pyrrolidine MS (ES+) 327.2
(M+H)+.

PCT/US2006/011320
WO 2006/107661
39
Example 29
(2-(S)-Pyrrolidin-l-ylmethyl-pyrrolidin-l-yI)-[6-(4-trifIuoromethoxy-
phenylsulfanyl)-pyridin-3-yl]-methanone dihydrochloride salt

To a stirring solution of 6-(4-trifluoromethoxy-phenylsulfanyl)-nicotinic acid sodium salt
(54mg, 0.158mmol) (see Intermediate 8) and n-methyl morpholine (0.02rnL, 0.158mmol)
in dichloromethane (2.0mL) in a 0°C ice bath, add 2-chloro-4,6-dimethoxy-l,3,5-triazine
(28mg, 0.158mmol). Remove the ice bath and stir for 45 minutes. After this time, add
(S)-(+)-l-(2-pyrrolidinylmethyl)pyrrolidine (24mg, 0.158mmol) and stir at room
temperature for 2 hours. After this time, wash the reaction with saturated aqueous sodium
bicarbonate while extracting with 10%isopropanol/dichloromethane. Dry the organic
layer with sodium sulfate, filter and concentrate in vacuo. Purify via chromatography
eluting with 2M ammonia in methanol and dichloromethane. Dissolve the purified free
base in minimal dichloromethane and add 1M HC1 in ether in slight excess followed by
hexane. Concentrate in vacuo to give the titled compound. MS (m/e): 452.2 (M+l).
Example 30
(4-BenzenesuIfonyI-phenyI)-(2-(S)-pyrrolidin-l-yImethyl-pyrrolidin-l-yl)-methanone

The title compound is prepared in a manner substantially analogous to the procedures
found in Intermediate 6 and Example 17 using 4-(phenylsulfonyl)-benzoic acid [CAS#
5361-54-6] and (S)-(+)-l-(2-pyrrolidinylmethyl)pyrroIidine.
MS (m/e): 399.2 (M+l).

WO 2006/10766, PCT/US2006/011320
40
Example 31
(5-Benzylsulfanyl-pyridin-2-yl)-(2-(S)-pyrrolidin-l-yImethyl-pyrrolidin-l-yI)-
methanone: bis-trifluoroacetic acid salt

To a stirring solution of 5-Benzylsulfanyl-pyridine-2-carboxylic acid (0.045g, 0.183
mmol)(which can be prepared from Butyl 6-methyl-3-pyridyl sulfoxide by the method of
N. Finch, J. Med Chem., 21(12), 1269-1274,1978.) in DMF (2ml), add EDC (O.O36g,
0.188 mmol), (S)(+)-l-(2-PyrrolidinylmethyI)pyrrolidine (0.028g, 0.183 mmol) and the
mixture is stirred at room temperature for 15 hours. The mixture is diluted with ethyl
acetate and washed successively with a saturated sodium bicarbonate solution and brine.
The organic layers are separated, dried with anhydrous sodium sulfate, filtered, and
concentrated to a crude residue. The residue is purified by well known reverse phase
techniques using TFA / water as the mobile phase. The desired fractions are concentrated
to give pure titled compound. MS (m/e): 382.2 M+l (free base).
Example 32
(2-(S)-Pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-(-4-bromo-3-fluoro-phenyl-4-yl)-
tnethanone

Procedure C: 4-Bromo-3-fluorobenzoic acid (CAS 153556-42-4) (0.5g, 2.28mmol) is
dissolved in dichloromethane (25ml) containing dimethylformamide (200 µl) with
stirring at room temperature. Oxalyl chloride (0.5ml, 5.7mmol) is added and the reaction
is left to stir overnight. The solvent is removed under reduced pressure and the residue is
taken up in dichloromethane (15ml) and added dropwise to a solution of triethylamine
(lml) and (S)(+)-l-(2-pyrrolidinylmethyl)pyrrolidine (0.36g, 2.3mmol) and this mixture
is stirred at room temperature for two hours. Aqueous sodium hydroxide solution is added

WO 2006/107661 PCT/US2006/011320
41
to the mixture and the organic layer is collected, dried over MgSO4 and evaporated to
give the product. MS (FIA) 354/356 (MH+).
Example 33
(4-Bromo-phenyl)-[2-(S)-(2-(R)-Methyl-pyrrolidin-l-ylmethyl)-pyrrolidin-l-yl]-
methanone

The title compound is prepared in a manner substantially analogous to Procedure C
using commercially available 4-bromo benzoic acid, 2-(R)-methyl-l-(2-(S)-
pyrrolidinylmethyl)pyrrolidine, and thionyl chloride in place of oxalyl chloride. (MS
(ES+) 352.3 (M+H)+
Example 34
(4-Bromo-2,6-difluoro-phenyl)-(2-(R)-methyl-l-(2-(S)-
pyrrolidinylmethyl)pyrrolidin-l-yl)-methanone

The title compound is prepared in a manner substantially analogous to Procedure
D from 2,6-difluoro-4-bromobenzoic acid (CAS 183065-68-1) and 2-(R)-Methyl-l- (2-
(S)-pyrrolidinylmethyl)pyrrolidine. MS (FIA) 387/389 (MH+).

WO 2006/107661 PCT/US2006/011320
42
Further embodiments of the invention include the compounds of formulae X1 to
X34. A further embodiment of the invention are any novel intermediate preparations
described herein which are useful for preparing the histamine H3 receptor antagonists or
inverse agonists of formulae I, or X1 to X34.
Table 1:


WO 2006/107661 PCT/US2006/011320
43


WO 2006/10766l PCT/US2006/011320
44


WO 2006/107661 PCT/US2006/011320
45


WO 2006/107661 PCT/US2006/011320
46


WO 2006/107661 PCT/US2006/011320
47

The pharmaceutical salts of the invention are typically formed by reacting a
compound of Formula I 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 widiin about one hour to
about ten days and can be isolated by filtration or other conventional methods.
Acids commonly employed to form pharmaceutical 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,
methanesulfonic acid, ethanesulfonic acid, oxalic acid, p-bromophenylsulfonic 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.
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 like. 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. The potassium and sodium salt
forms are particularly preferred.
The optimal time for performing the reactions of the Schemes, Preparations, and
Procedures can be determined by monitoring the progress of the reaction via conventional

WO 2006/107661 PCT/US2006/011320

48
chromatographic techniques. Furthermore, it is preferred to conduct the reactions of the
invention under an inert atmosphere, such as, for example, argon, or, particularly,
nitrogen. Choice of solvent is generally not critical so long as the solvent employed is
inert to the ongoing reaction and sufficiently solubilizes the reactants to effect the desired
reaction. 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 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 a convenient point
in the synthesis by methods well known in the art.
The compound of Formula I is preferably formulated in a unit dosage form prior
to administration. Therefore, yet another embodiment of the present invention is a
pharmaceutical composition comprising a compound of Formula I and one or more
pharmaceutically acceptable carriers, diluents or excipients, and can be administered by a
variety of routes. Such pharmaceutical compositions and processes for preparing same are
well known in the art. See, e.g. REMININGTON: THE SCIENCE AND PRACTICE OF
PHARMACY (A. Gennaro, et al, eds., 19th ed., Mack Publishing Co., 1995).
Preferably the compound is administered orally. Preferably, the pharmaceutical
preparation 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.

WO 2006/107661 PCT/US2006/011320
49
Compounds of Formula I 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
Formula I are useful in the treatment of diseases, disorders, or conditions responsive to
the inactivation of the histamine H3 receptor, including but not limited to obesity and
other eating-related disorders, and cognitive disorders. Selective antagonists or inverse
agonists of H3R are understood to 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 the 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 [3H] a methylhistamine 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) are used in a [35S]GTPχS functional assay. Binding of [35S]GTPχS to
membranes indicates agonist activity. Compounds of the invention of Formula I or

WO 2006/107661 PCT/US2006/011320
50
Formula II are tested for their ability to inhibit binding in the presence of agonists.
Alternately, the same transfected cell lines are used for a cAMP assay wherein H3R
agonists inhibit forskolin-activated synthesis of cAMP. Compounds of Formula I or
Formula II are 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) is 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 are selected using G418 (500 µ/ml).
Colonies that survived selection are 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, are 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% CO2). Growth media is
removed and wells are rinsed two times with PBS (minus Ca2+ or Mg2+). For total
binding, cells are 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 0.8nM3H-pyrilamine (Net-594, NEN) (total volume per well = 200µl).
Astemizole (10µM, Sigma #A6424) is added to appropriate wells to determine non-
specific binding. Plates are covered with FasCal and incubated at room temperature for
120 minutes. Following incubation, plates are centrifuged at l,000rpm (~800g) for 10
minutes at room temperature. Plates are counted in a Wallac Trilux 1450 Microbeta
scintillation counter. Several clones are selected as positive for binding, and a single
clone (H1R40) is used to prepare membranes for binding studies. Cell pellets,
representing -10 grams, are resuspended in 30ml assay buffer, mixed by vortexing, and
centrifuged (40,000g at 4°C) for 10 minutes. The pellet resuspension, vortexing, and
centrifugation is repeated 2 more times. The final cell pellet is resuspended in 30ml and
homogenized with a Polytron Tissue Homogenizer. Protein determinations are done

WO 2006/107661 PCT/US2006/011320
51
using the Coomassie Plus Protein Assay Reagent (Pierce). Five micrograms of protein is
used per well in the SPA receptor-binding assay.
B. Preparation H2R membranes
cDNA for the human histamine 2 receptor is cloned, expressed and transfected
into HEK 293 cells as described above. Histamine binding to cells is assayed by SPA
described above. For total binding, cells are 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 6.2nM3H-tiotidine (Net-688, NEN) (total volume
per well = 200µl). Cimetidine (l0µM, Sigma #C4522) is added to appropriate wells to
determine non-specific binding.
Several clones are selected as positive for binding, and a single clone (H2R10) is
used to prepare membranes for binding studies. Five micrograms of protein is used per
well in the SPA receptor-binding assay.
C. Preparation of H3R membranes
cDNA for the human histamine 3 receptor is cloned and expressed as described in
(A. Preparation H1R membranes), above. Transfected cells are selected using G418 (500
µ/ml), grown, and tested for histamine binding by the SPA described above. For total
binding, cells are 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 lnM (3H)-n-alpha-methylhistamine (NEN, NET1027) (total
volume per well = 200µ1). Thioperimide is added to determine non-specific binding.
Several clones are selected as positive for binding, and a single clone (H3R8) is used to
prepare membranes for binding studies described above. Five micrograms of protein is
used per well in the SPA receptor-binding assay.
All compounds set forth in the examples exhibit affinity for the H3 receptor
greater than 1 uM. Preferred compounds of the invention exhibit affinity for the H3
receptor greater than 200 nM. Most preferred compounds of the invention exhibit affinity
for the H3 receptor greater than 20 nM.
D. Preparation of GPRv53 Membranes

WO 2006/107661 PCT/US2006/011320
52
cDNA for the human GPRv53 receptor is cloned and expressed as described in
(A. Preparation H1R membranes), above. Transfected cells are selected, tested for
histamine binding, and selected. HEK293 GPRv53 50 cells are 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 are homogenized with a
Polytron tissuemizer in binding buffer, 50 mM Tris pH 7.5. Cell lysates, 50 ug, are
incubated in 96 well dishes with 3 nM (3H) Histamine and compounds in binding buffer
for 2 hours at room temperature. Lysates are filtered through glass fiber filters (Perkin
Elmer) with a Tomtec cell harverster. Filters are counted with melt-on scintillator sheets
(Perkin Elmer) in a Wallac Trilux 1450 Microbeta Scintillation counter for 5 minutes.
Pharmacological Results
cAMP ELISA
HEK293 H3R8 cells prepared as described above are 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 is 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 are added in 50 µl cell
culture medium and incubated for 20 minutes at room temperature. Agonist
R (-) methylhistamine (RBI) at a dose response from 1x10-10 to lx10-5 M is 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) is
added to each well and incubated for 20 minutes at room temperature. Tissue culture
medium is removed and cells are lysed in 0.1 M HC1 and cAMP is measured by ELISA
(Assay Designs, Inc.).
[35S] GTP γ [S] Binding Assay
Antagonist activity of selected compounds is tested for inhibition of [35S] GTP γ
[S] binding to H3R membranes in the presence of agonists. Assays are 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-

WO 2006/107661 PCT/US2006/011320
53
expressing HEK293 cell line (20 ug/well) and GDP are added to each well in a volume of
50 µl assay buffer. Antagonist is then added to the wells in a volume of 50 µ1 assay
buffer and incubated for 15 minutes at room temperature. Agonist R(-)alpha
methylhistamine (RBI) at either a dose response from lxlO-10 to lxl0-5 M or fixed
concentration of 100 nM are then added to the wells in a volume of 50µ1 assay buffer
and incubated for 5 minutes at room temperature. GTP γ [35S] is 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 are counted in Wallac
Trilux 1450 Microbeta scintillation counter for 1 minute. Compounds that inhibit more
than 50% of the specific binding of radioactive ligand to the receptor are serially diluted
to determine a K[i ](nM). The results are given below for the indicated compound.

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
various usages and conditions. Thus, other embodiments are also within the claims.

WO 2006/107661 PCT/US2006/011320
54
WHAT IS CLAIMED IS:
1. A compound structurally represented by Formula I

or a pharmaceutically acceptable salt thereof, wherein:
Y independently represents carbon or nitrogen;
X independently represents carbon or nitrogen,
provided that at least one of Y or X is carbon;
Rl is independently
-halogen, -CN, -NO2, -(C1-C7) alkyl(optionally substituted with 1 to 3
halogens), -(C3-C8) cycloalkyl, -(C1-C7) alkyl-S(O)2-(C1-C3) alkyl,
-(C1-C7)alkyI-C(O)-O-R3,--(C1-C7)alkyI-S(O)2-phenyI(R2)(R2)(R2),
-(C1-C7) alkyl-S-(C1-C7) alkyl, -(C1-C7) alkyl-(C3-C8) cycloalkyl,
-(C1-C7) alkyl-phenyl(R2)(R2)(R2), -C(O)-phenyl(R2)(R2)(R2),
-C(O)-(C1-C7) alkyl, -C(O)-(C3-C8) cycloalkyl,
-(C1-C7) alkyl-C(O)-phenyl(R2)(R2)(R2), -S-(C1-C7) alkyl,
-S-(C1-C7) alkyl-phenyl(R2)(R2)(R2), -S-(C3-C8) cycloalkyl-(C1-C7) alkyl,
-S-(C3-C8) cycloalkyl, -S-(C2-C7) alkenyl, -S-phenyl(R2)(R2)(R2),
-SO2-phenyl(R2)(R2)(R2), -SO2R7, -S(O)R7, -(C2-C7) alkenyl,
-(C3-C8) cycloalkenyl, -(C2-C7) alkenyl-S(O)2-(C1-C3) alkyl,
-(C2-C7) alkenyl-C(O)-O-R3, -(C2-C7) alkenyl-S(O)2-phenyl(R2)(R2)(R2),
-(C2-C7) alkenyl-S-(C1-C7) alkyl, -(C2-C7) alkenyl-(C3-C8) cycloalkyl, or
-(C2-C7)alkenyl-phenyl(R2)(R2)(R2);
R2 is independently at each occurrence
-H, -halogen, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens),
-C(O)R7, -C(O)0R7, -C(O)(C3-C8)cycloalkyl, -OCF3, -OR7, -SR7,
-SO2R7, -SO2CF3, or -S(O)R7;
R3 is independently at each occurrence

WO 2006/107661 PCT/US2006/011320
55
-H, or -(C1-C3) alkyl(optionally substituted with 1 to 3 halogens);
R4 and R5 are independently at each occurrence
-H, -halogen, -(C1-C3) alkyl(optionally substituted with 1 to 3 halogens),
or -OR3, provided that when Y is nitrogen, then R4 or R5 are not attached
to Y, and provided that when X is nitrogen, then R4 or R5 are not attached
toX;
R6 is independently at each occurrence
-H, -halogen, -CF3, -(C1-C3) alkyl(optionally substituted with 1 to 3
halogens), or -OR3; and
R7 is independently at each occurrence
-H, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens), or
-(C2-C7) alkenyl.
2. The compound of claim 1 wherein Y and X are carbon.
3. The compound of claim 1 wherein X is nitrogen.
4. The compound of claim 1 wherein Y is nitrogen.
5. The compound of any of claims 1 to 4 wherein Rl is -halogen, -CN, -NO2,
-(C1-C7) alkyl, -(C3-C8) cycloalkyl, -(C1-C7) alkyl-S(O)2-(C1-C3) alkyl,
-(C1-C7) alkyl-C(O)-O-R3, -(C1-C7) alkyl-S(O)2-phenyl(R2)(R2)(R2),
-(C1-C7) alkyl-S-C1-C7) alkyl, -(C1-C7) alkyI-(C3-C8) cycloalkyl,
-(C1-C7) alkyl-phenyl(R2)(R2)(R2), -C(O)-phenyl(R2)(R2)(R2),
-C(O)-(C1-C7) alkyl, -C(O)-(C3-C8) cycloalkyl,
-(C1-C7) alkyl-C(O)-phenyl(R2)(R2)(R2), -S-(C1-C7) alkyl,
-S-(C1-C7) alkyl-phenyl(R2)(R2XR2), -S-(C3-C8) cycloalkyl-(C1-C7) alkyl,
-S-(C3-C8) cycloalkyl, -S-(C2-C7) alkenyl, -S-phenyl(R2)(R2)(R2),
-SO2-phenyl(R2)(R2)(R2), -SO2R7, or -S(O)R7.
6. The compound of any of claims 1 to 4 wherein Rl is -halogen, -CN, -NO2,
-(C1-C7) alkyl, -(C3-C8) cycloalkyl, -(C1-C7) alkyl-S(O)2-(C1-C3) alkyl,
-(C1-C7) alkyl-C(O)-O-R3, -(C1-C7) alkyl-S(O)2-phenyl(R2)(R2)(R2),
-(C1-C7) alkyl-S-(C1-C7) alkyl, -(C1-C7) alkyl-(C3-C8) cycloalkyl,
-(C1-C7) alkyl-phenyl(R2)(R2)(R2), -C(O)-phenyl(R2)(R2)(R2),
-C(O)-(C1-C7) alkyl, -C(O)-(C1-C8) cycloalkyl, or
-(C1-C7)alkyl-C(O)-phenyl(R2)(R2)(R2).

WO 2006/107661 PCT/US2006/011320
56
7. The compound of any of claims 1 to 4 wherein Rl -S-(C1-C7) alkyl,
-S-(C1-C7) alkyl-phenyl(R2)(R2)(R2), -S-(C3-C8) cycloalkyl-(C1-C7) alkyl,
-S-(C3-C8) cycloalkyl, -S-(C2-C7) alkenyl, -S-phenyl(R2)(R2)(R2),
-SO2-phenyl(R2)(R2)(R2), -SO2R7, or -S(O)R7.
8. The compound of any of claims 1 to 7 wherein one independent occurrence of
R2 is - H, -halogen, -(C1-C7) alkyl, -C(O)R7, -C(O)OR7,
-C(O)(C3-C8)cycloalkyl, -OCF3, -OR7, -SR7, -SO2R7, -SO2CF3) or -S(O)R7,
and a second independent occurrence of R2 is - H, - halogen, or -(C1-C7) alkyl,
and a third independent occurrence of R2 is -H or -halogen.
9. The compound of any of claims 1 to 7 wherein one independent occurrence of
R2 is SO2R7, -SO2CFs, or -S(O)R7, and a second independent occurrence of
R2 is -H, halogen, or -(C1-C7) alkyl, and a third independent occurrence of R2
is -H or halogen.
10. The compound of any of claims 1 to 9 wherein R4 is -halogen.
11. The compound of any of claims 1 to 9 wherein one independent occurrence of
R6 is -CH3 and the second independent occurrence of R6 is -H.
12. The compound of claim 1 selected from the group consisting of formulae X1 to


WO 2006/107661 PCT/US2006/011320
57


WO 2006/107661 PCT/US2006/011320
58


WO 2006/107661 PCT/US2006/011320
59


WO 2006/107661 PCT/US2006/011320
60


WO 2006/107661 PCT/US2006/011320
61

or a pharmaceutically acceptable salt or solvate thereof.
13. The compound of claim 1, selected from the group consisting of
(S)-(4-Pentyl-phenyl)-(2-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-methanone,
(S)-(4-Methylsulfanyl-phenyl)-(2-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-
methanone,
(S)-[4-(4-Methyl-cycIohexylsulfanyl)-phenyl]-(2-pyrrolidin-l-ylmethyl-
pyrrolidin-1 -yl)-methanone,
(S)-(4-Methanesulfonyl-phenyl)-(2-pyrrolidin- 1-ylmethyl-pyrrolidin- 1-yl)-
methanone,
(S)-(2-Pyrrolidin- 1-ylmethyl-pyrrolidin- l-yl)-p-tolyl-methanone,
(S)-(4-Ethyl-phenyl)-(2-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-methanone,
(S)-(4-Propyl-phenyl)-(2-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-methanone,
(S)-(4-Butyl-phenyl)-(2-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-methanone,
(S)-(4-Benzyl-phenyl)-(2-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-methanone,

WO 2006/107661 PCT/US2006/011320
62
(S)-(3,4-Dimethyl-phenyl)-(2-pynrrolidin-l-ylmethyl-pyrrolidin-l-yl)-methanone,
(S)-(4-tert-Butyl-phenyl)-(2-pyrrolidin-1 -ylmethyl-pyrrolidin-1 -yl)-methanone,
(S)-(4-Benzoyl-phenyl)-(2-pynolidin-l-ylmethyl-pyrrolidin-l-yl)-methanone,
(S)-(4-Cyclohexyl-phenyl)-(2-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-methanone,
l-Phenyl-3-[4-(2-(S)-pyrrolidin-l-ylmethyl-pyrrolidine-l-carbonyl)-phenyl]-
propan-1-one,
[4-(5-Phenyl-pentyl)-phenyl]-(2-(S)-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-
methanone,
(S)-[4-(2-Chloro-ethyl)-phenyl]-(2-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-
methanone,
(4-Bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-l-ylmethyl-pyrrolidin-
yl)methanone,
(4-Fluoro-phenyl)-(2-(S)-pyrrolidin-l-yltnethyl-pyrrolidin-l-yl)-methanone,
(4-Bromo-2-fluoro-phenyl)-[2-(S)-(2-(R)-methyl-pyrrolidin-l-ylmethyl)-
pyrrolidin-1 -yl]-methanone,
(S)-(2-Pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-(4-trifluoromethyl-phenyl)-
methanone,
(4-Bromo-phenyl)-(2-(S)-pyrrolidin-l-yImethyl-pyrrolidin-yl)methanone,
(S)-(4-Chloro-phenyl)-(2-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-methanone,
4-(2-(S)-Pyrrolidin-l-ylmethyl-pyrrolidine-l-carbonyl)-benzonitrile,
(4-Nitro-phenyl)-(2-(S)-pyrrolidin-1 -ylmethyl-pyrrolidin-1 -yl)-methanone,
(4-Bromo-2-txifluoromethyl-phenyl)-(2-(S)-pyrrolidin-l-ylmethyl-pyrrolidin-l-
yl)-methanone,
(4-Bromo-2,6-difluoro-phenyl)-(2-(S)-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-
methanone,
l-[4-(2-(S)-Pyrrolidin-l-ylmethyl-pyrrolidine-l-carbonyl)-phenyl]-ethanone
hydrochloride salt,
(4-Cyclopropanecarbonyl-phenyl)-(2-(S)-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-
methanone hydrochloride salt,
(2-(S)-Pyrrolidin- 1-ylmethyl-pyrrolidin- l-yl)-[6-(4-trifluoromethoxy-
phenylsulfanyl)-pyridin-3-yl]-methanone dihydrochloride salt,

WO 2006/107661 PCT/US2006/011320
63
(4-Benzenesulfonyl-phenyl)-(2-(S)-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl)-
methanone,
(5-Benzylsulfanyl-pyridin-2-yl)-(2-(S)-pyrrolidin-l-ylmethyl-pyrrolidin-l-yl>
methanone: bis-trifluoroacetic acid salt,
(2-(S)-Pyrrolidin- l-ylmethyl-pyrrolidin- l-yl)-(-4-broino-3-fluoro-phenyl-4-yl)-
methanone,
(4-Bromo-phenyl)-[2-(S)-(2-(R)-Methyl-pynolidin-l-ylmethyl)-pynolidin-l-yl]-
methanone, and
(4-Bromo-2,6-difluoro-phenyL)-(2-(R)-methyl- l-(2-(S)-
pyrrolidinylmethyl)pyrrolidin- l-yl)-methanone,
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition which comprises a compound of any of claims 1 to
13 and a pharmaceutically acceptable carrier.
15. A method of treating conditions associated with histamine H3 receptor activity in
a mammal comprising administering to a mammal in need thereof a histamine H3
receptor inhibiting dose of a compound of any of claims 1 to 12.
16. A method for treatment or prevention of a nervous system disorder which
comprises administering to a mammal in need of such treatment or prevention an
effective amount of a compound of any of claims lto 12.
17. The method of Claim 16 wherein the antagonist or inverse agonist is a
pharmaceutical composition of claim 14
18. A method for treatment or prevention of obesity which comprises administering to
a mammal in need of such treatment or prevention an effective amount of a
compound of any of Claims 1 to 12.
19. The method of Claim 18 wherein the antagonist is a pharmaceutical composition
of claim 14.
20. The use of a compound of formula I, or a salt thereof, as claimed in any one of
claims 1 to 13, for the manufacture of a medicament for treatment of a nervous
system disorder.

WO 2006/107661 PCT/US2006/011320
64
21. A compound and/or a pharmaceutical composition and/or a method of treating and/or
the use of a compound substantially as herein described with reference to the given
examples.
Dated this the 22nd day of August, 2007.

The present invention discloses novel compounds of Formula (I) or pharmaceutically
acceptable salts thereof which have histamine-H3 receptor antagonist or inverse agonist
activity, as well as methods and intermediates for preparing such compounds. In another
embodiment, the invention discloses pharmaceutical compositions comprising compound of
Formula (I) as well as methods of using these compositions to treat obesity, cognitive
deficiencies, narcolepsy, and other histamine H3 receptor-related diseases.