This application is divided out of the Indian Patent Application no.: 165/KOLNP/2005
This invention relates to 1~heterocyclylalkyli-3-sulfonyl-indole or -indazole
derivatives useful as 5-hydroxytryptamine-6 ligands, to processes for their
preparation, methods of treatment using them and to pharmaceutical compositions
containing them.
Serotonin (5-Hydroxytryptamine)(5-HT) receptors play a critical role in many
physiological and behavioural functions in humans and animals. These functions are
mediated through various 5-HT receptors distributed throughout the body. There are
now approximately fifteen different human 5-HT receptor subtypes that have been
cloned, many with well-defined roles in humans. One of the most recently identified
5-HT receptor subtypes is the 5-HT6 receptor, first cloned from rat tissue in 1993
(Monsma, F. J.; Shen, Y.; Ward, R. P.; Hamblin, M. W. Molecular Pharmacology
1993, 43, 320-327) and subsequently from human tissue (Kohen, R.; Metcalf, M. A.;
Khan, N.; Druck, T.; Huebner, K.; Sibley, D. R. Journal of Neurochemistry 1996, 66,
47-56). The receptor is a G-protein coupled receptor (GPCR) positively coupled to
adenyiate cyclase (Ruat, M.; Traiffort, E.; Arrang, JM.; Tardivei-Lacombe, L; Diaz,
L; Leurs, R.; Schwartz, J-C. Biochemical Biophysical Research Communications
1993, 193, 268-276). The receptor is found almost exclusively in the central nervous
system (CNS) areas both in rat and in human. In situ hybridization studies of the
5-HT6 receptor in rat brain using mRNA indicate principal localization in the areas of
5-HT projection including striatum, nucleus accumbens, olfactory tubercle, and
hippocampal formation (Ward, R. P.; Hamblin, M. W.; Lachowicz, J. E.; Hoffman, B.
J.; Sibley, D. R.; Dorsa, D. M. Neuroscience 1995, 64, 1105-1111).
There are many potential therapeutic uses for 5-HT6 ligands in humans
based on direct effects and on indications from available scientific studies. These
studies include the localization of the receptor, the affinity of ligands with known in
vivo activity, and various animal studies conducted so far.
One potential therapeutic use of modulators of 5-HT6 receptor function is in
the enhancement of cognition and memory in human diseases such as Alzheimer's.
-1A-

The high levels of receptor found in important structures in the forebrain, including
the caudate/putamen, hippocampus, nucleus accumbens, and cortex suggest a role"
for the receptor in memory and cognition since these areas are known to play a vital
role in memory (Gerard, C; Martres, M.-P.; Lefevre, K.; Miquel, M.C.; Verge, D.;
Lanfumey, R.; Doucet, E.; Hamon, M,; El Mestikawy, S. Brain Research, 1997, 746,
207-219). The ability of known 5-HT6 receptor ligands to enhance cholinergic
transmission also supported the potential cognition use (Bentley, J. C; Boursson, A.;
Boess, F. G.; Kone, F. C; Marsden, C. A.; Petit, N.; Sleight, A. J. British Journal of
Pharmacology, 1999, 126(7), 1537-1542). Studies have found that a known 5-HT6
selective antagonist significantly increased glutamate and aspartate levels in the
frontal cortex without elevating levels of noradrenaline, dopamine, or 5-HT. This
selective elevation of neurochemicals known to be involved in memory and cognition
strongly suggests a role for 5-HT6 ligands in cognition (Dawson, L A.; Nguyen, H.
Q.; Li, P. British Journal of Pharmacology, 2000, 130(1), 23-26). Animal studies of
memory and learning with a known selective 5-HT6 antagonist found some positive
effects (Rogers, D. C; Hatcher, P. D.; Hagan, J. J. Society of Neuroscience,
Abstracts 2000, 26, 680).
A related potential therapeutic use for 5-HT6 ligands is the treatment of
attention deficit disorders (ADD, also known as Attention Deficit Hyperactivity
Disorder or ADHD) in both children and adults. Because 5-HT6 antagonists appear
to enhance the activity of the nigrostriatal dopamine pathway and because ADHD
has been linked to abnormalities in the caudate (Ernst, M; Zametkin, A. J.; Matochik,
J. H.; Jons, P. A..; Cohen, R. M. Journal of Neuroscience 1998, 18(15), 5901-5907),
5-HT6 antagonists may attenuate attention deficit disorders.
Early studies examining the affinity of various CNS ligands with known
therapeutic utility or a strong structural resemblance to known drugs suggests a role
for 5-HT6 ligands in the treatment of schizophrenia and depression. For example,
clozapine (an effective clinical antipsychotic) has high affinity for the 5-HT6 receptor
subtype. Also, several clinical antidepressants have high affinity for the receptor as
well and act as antagonists at this site (Branchek, T. A.; Blackburn, T. P. Annual
Reviews in Pharmacology and Toxicology 2000, 40, 319-334).
Further, recent in vivo studies in rats indicate 5-HT6 modulators may be
useful in the treatment of movement disorders including epilepsy (Stean, T.;
-2-

Routledge, C; Upton, N. British Journal of Pharmacology 1999, 127 Proc.
"Supplement 131P and Routledge, C; Bromidge, S. M.; Moss, S. F.; Price, G. W.;
Hirst, W.; Newman, H.; Riley, G.; Gager, T.; Stean, T.; Upton, N.; Clarke, S. E.;
Brown, A. M. British Journal of Pharmacology 2000, 130(7), 1606-1612).
Taken together, the above studies strongly suggest that compounds which are 5-
HT6 receptor modulators, i.e. ligands, may be useful for therapeutic indications
including: the treatment of diseases associated with a deficit in memory, cognition,
and learning such as Alzheimer's and attention deficit disorder; the treatment of
personality disorders such as schizophrenia; the treatment of behavioral disorders,
e.g., anxiety, depression and obsessive compulsive disorders; the treatment of
motion or motor disorders such as Parkinson's disease and epilepsy; the treatment of
diseases associated with neurodegeneration such as stroke and head trauma; or
withdrawal from drug addiction including addiction to nicotine, alcohol, and other
substances of abuse.
Therefore, it is an object of this invention to provide compounds which are
useful as therapeutic agents in the treatment of a variety of central nervous system
disorders related to or affected by the 5-HT6 receptor.
It is another object of this invention to provide therapeutic methods and
pharmaceutical compositions useful for the treatment of central nervous system
disorders related to or affected by the 5-HT6 receptor.
It is a feature of this invention that the compounds provided may also be used
to further study and elucidate the 5-HT6 receptor.
These and other objects and features of the invention will become more
apparent by the detailed description set forth hereinbelow.
SUMMARY OF THE INVENTION
The present invention provides a 1-heterocyclylalkyl-3-su!fonylindole or
-indazole compound of formula I


wherein
W is N or CR2;
R is halogen, CN, OCO2R9, CO2R10, CONR11R12, SOXR13, NR14R15, OR16,
COR17 or a C1C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, aryl
or heteroaryi group each optionally substituted;
R1 is an optionally substituted C1-C6alkyl, C3-C7cycloalkyl, aryl, or heteroaryi
group or an optionally substituted 8- to 13-membered bicyclic or tricyclic
ring system having a N atom at the bridgehead and optionally containing
1, 2 or 3 additional heteroatoms selected from N, O or S;
R2 is H, halogen, or a C1-C6alkyl, C1-C6alkoxy, C3-C7cycloa!kyl, aryl or
heteroaryi group each optionally substituted;
R3 and R4 are each independently H or an optionally substituted C1C6alkyl
group;
R5 is H or a C1C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl,
cycloheteroalkyl, aryl or heteroaryi group each optionally substituted;
R6is a C1-C6alkyI, C3-C7cycloalkyl, C2-C6alkenyl or C2-C6alkynyl group each
optionally substituted;
R7 and R8 are each independently H or a C1-C6alkyl, C3-C7cycloalkyl, C2-
C6alkenyl or C2-C6alkynyl group each optionally substituted;
m, n and p are each independently 0 or an integer of 1, 2 or 3;
q and x are each independently 0 or an integer of 1 or 2;
Rg, R10, R13 and R17 are each independently H or a C1-C6alkyl, C2-C6alkenyl,
C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl
group each optionally substituted;
R11 and R12 are each independently H or an optionally C1-Cealkyl group or R11
and R12 may be taken together with the atom to which they are
attached to form a 5- to 7-member ring optionally containing another
heteroatom selected from 0, N or S;
-4-

R14 and R15 are each independently H or an optionally substituted C1-C4alkyl
group or R-14and R15 may be taken together with the atom to which
they are attached to form a 5- to 7-membered ring optionally
containing another heteroatom selected from O, NR18 or SOX;
R16 is a C1C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally substituted
and;
R18 is H or a C1-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
or
the stereoisomers thereof or the pharmaceutically acceptable salts thereof.
The present invention also provides methods and compositions useful for the
therapeutic treatment of a central nervous system disorder related to or affected by
the 5-HT6 receptor.
DETAILED DESCRIPTION OF THE INVENTION
The 5-hydroxytryptamine-6 (5-HT6) receptor is one of the most recent
receptors to be identified by molecular cloning. Its ability to bind a wide range of
therapeutic compounds used in psychiatry, coupled with its intriguing distribution in
the brain has stimulated significant interest in new compounds which are capable of
interacting with or affecting said receptor. Significant efforts are being made to
understand the possible role of the 5-HT6 receptor in psychiatry, cognitive
dysfunction, motor function and control, memory, mood and the like. To that end,
compounds which demonstrate a binding affinity for the 5-HT6 receptor are earnestly
sought both as an aid in the study of the 5-HT6 receptor and as potential therapeutic
agents in the treatment of central nervous system disorders, for example see
C. Reavill and D. C. Rogers, Current Opinion in Investigational Drugs, 2001,
2(1): 104-109, Pharma Press Ltd.
Surprisingly, it has now been found that 1-heterocyclylalkyl-3-sulfonylindole
and -indazole derivatives of formula I demonstrate 5-HT6 affinity. Advantageously,
said indole and indazole derivatives may be used as effective therapeutic agents for
the treatment of central nervous system (CNS) disorders associated with' or affected
by the 5-HT6 receptor. Accordingly, the present invention provides 1 -
heterocyclylalkyl-3-sulfonylindole and -indazole derivatives of formula I
-5-


wherein
W is N or CR2;
R is halogen, CN, OCO2R9, CO2R10, CONR11R12, SOXR13, NR14R15, OR16,
COR17 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, aryl
or heteroaryl group each optionally substituted;
R1 is an optionally substituted C1-C6alkyl, C3-C7cycloalkyl, aryl, or heteroaryl
group or an optionally substituted 8- to 13-membered bicyclic or tricyclic
ring system having a N atom at the bridgehead and optionally containing
1,2 or 3 additional heteroatoms selected from N, O or S;
R2 is H, halogen, or a C1C6alkyl, C1-C6alkoxy, C3-C7cycloalkyl, aryl or
heteroaryl group each optionally substituted;
R3 and R4 are each independently H or an optionally substituted C1-C6alkyl
group;
R5 is H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R6 is a C1-C6alkyl, C3-C7cycloalkyl, C2-C6alkenyl or C2-C6alkynyl group each
optionally substituted;
R7 and R8 are each independently H or a C1-C6alkyl, C3-C7cycloalkyl, C2-
C6alkenyl or C2-C6alkynyl group each optionally substituted;
m, n and p are each independently 0 or an integer of 1, 2 or 3;
q and x are each independently 0 or an integer of 1 or 2;
R9, R10, R13 and R17 are each independently H or a C1-C6alkyl, C2-C6alkenyl,
C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl
group each optionally substituted;
R11and R12 are each independently H or an optionally C1-C6alkyl group or R11
and R-12 may be taken together with the atom to which they are
-6-

attached to form a 5- to 7-member ring optionally containing another
heteroatom selected from O, N or S;
R-I4 and R15 are each independently H or an optionally substituted CrC4alkyl
group or R14 and R15 may be taken together with the atom to which
they are attached to form a 5- to 7-membered ring optionally
containing another heteroatom selected from O, NR18 or SOX;
R16 is a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionaliy substituted;
and;
R16 is H or a CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
or
the stereoisomers thereof or the'pharmaceutically acceptable salts thereof.
As used in the specification and claims, the term halogen designates F, Cl, Br
or I and the term cycloheteroalkyl designates a five- to seven-membered cycloalkyl
ring system containing 1 or 2 heteroatoms, which may be the same or different,
selected from N, O or S and optionally containing one double bond. Exemplary of
the cycloheteroalkyl ring systems included in the term as designated herein are the
following rings wherein X is NR', O or S; and R' is H or an optional substituent as
described hereinbelow:

R'
Similarly, as used in the specification and claims, the term heteroaryl
designates a five- to ten-membered aromatic ring system containing 1,2 or 3
heteroatoms, which may be the same or different, selected from N, O or S. Such
heteroaryl ring systems include pyrrolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furyl,
thienyl, quinolinyl, isoquinolinyl, indolyl, benzothienyl, benzofuranyl, benzisoxazolyl or
the like. The term aryl designates a carbocyclic aromatic ring system e.g., of 6-14
carbon atoms such as phenyl, naphthyl, anthracenyl or the like. The term haloalkyl
-7-

as used herein designates a CnH2n+1 group having from one to 2n+1 halogen atoms
which may be the same or different and the term haloalkoxy as used herein -
designates an OCnH2n +1group having from one to 2n+1 halogen atoms which may be
the same or different.
Exemplary of the 8- to 13-membered bicyclic or tricyclic ring systems having a
N atom at a bridgehead and optionally containing 1, 2 or 3 additional heteroatoms
selected from N, O or S included in the term as designated herein are the following
ring systems wherein W2 is NR1, O or S; and R' is H or an optional substituent as
described hereinbelow:

In the specification and claims, when the terms such as C1C6alkyl, C2-
C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, cycloheteroalkyl, aryl, heteroaryl or 8- to 13-
membered bicyclic or tricyclic ring system having a N atom at a bridgehead are
designated as being optionally substituted, the substituent groups which are
-8-

optionally present may be one or more, e.g. two or three, the same or different, of
those customarily employed in the development of pharmaceutical compounds orthe
modification of such compounds to influence their structure/activity, persistence,
absorption, stability or other beneficial property. Specific examples of such
substituents include halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl,
alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl,
alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl,
carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heteroaryl,
cycloheteralkyl or cycloalkyl groups, preferably halogen atoms or lower alkyl or lower
alkoxy groups. Typically, 0-3 substituents, the same or different, may be present.
When any of the foregoing substituents represents or contains an alkyl substituent
group, e.g., alkoxy, alkanoyl, this may be linear or branched and may contain up to
12, preferably up io 6, more preferably up to 4 carbon atoms.
Pharmaceutically acceptable salts may be any acid addition sait formed by a
compound of formula I and a pharmaceutically acceptable acid such as phosphoric,
sulfuric, hydrochloric, hydrobromic, citric, maleic, malonic, mandelic, succinic,
fumaric, acetic, lactic, nitric, sulfonic, p-toluenesulfonic, methanesulfonic acid or the
like.
Compounds of the invention include esters, carbamates or other conventional
prodrug forms, which in general, are functional derivatives of the compounds of the
invention and which are readily converted to the inventive active moiety in vivo.
Correspondingly, the method of the invention embraces the treatment of the various
conditions described hereinabove with a compound of formula I or with a compound
which is not specifically disclosed but which, upon administration, converts to a
compound of formula I in vivo. Also included are metabolites of the compounds of
the present invention defined as active species produced upon introduction of these
compounds into a biological system.
Compounds of the invention may exist as one or more stereoisomers. The
various stereoisomers include enantiomers, diastereomers, atropisomers and
geometric isomers. One skilled in the art will appreciate that one stereoisomer may
be more active or may exhibit beneficial effects when enriched relative to the other
stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the
skilled artisan knows how to separate, enrich or selectively prepare said
-9-

stereoisomers. Accordingly, the present invention comprises compounds of Formula
I, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. The
compounds of the invention may be present as a mixture of stereoisomers, individual
stereoisomers, or as an optically active or enantiomerically pure form.
In the compounds of this invention:
An example of n is 0.
R5 may be for example H.
R1 is for example an optionally substituted phenyl group.
Examples of q are 0 and 1, e.g., where the piperidinyl or pyrrolidinyl group is
attached in the 3-position.
An example of p is 0.
An example of m is 0.
W may be for example N.
Preferred compounds of the invention are those compounds of formula I
wherein n is 0. Also preferred are those compounds of formula I wherein R5 is H.
Another group of preferred compounds of formula I are those compounds wherein R1
is an optionally substituted phenyl group.
More preferred compounds of the invention are those formula I compounds
wherein n is 0 and q is 0 or 1. Another group of more preferred compounds are
those formula I compounds wherein n, m and p are each 0. Further more preferred
formula I compounds are those compounds wherein n is 0; q is 0 or 1; and the
piperidinyl or pyrrolidinyl group is attached in the 3-position.
Examples of preferred compounds of formula I include:
6-chloro-3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1H-indole
6-fluoro-3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1H-indole;
5-chloro-3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1H-indole;
6-f luoro-3-(phenylsulf onyl)-1 -(piperidin-4-ylmethyl)-1 H-indole;
6-methoxy-3-(phenylsulfony!)-1-(piperidin-4-yImethyl)-1H-indole;
6-methyl-3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1 H-indole;
3-(4-methylphenylsu!fonyl)-1 -(piperidin-4-ylmethyl)-1 H-indole;
6-bromo-3-(phenylsulfonyl)-1 -(piperidin-4-ylmethyl)-1 H-indole;
4-chloro-3-(phenylsulfonyl)-1 -(piperidin-4-ylmethyl)-1 H-indole;
7-methoxy-3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1H-indoIe;
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6-hydroxy-3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1H-indole;
6-chloro-3-(4-fluorophenylsulfonyl)-1-(piperidin-4-ylmethyl)-1H-indoIe;
6-fluoro-3-(3-fluorophenylsulfonyI)-1-(piperidin-4-ylmethyl)-1 H-indole;
5-chloro-3-(3-chlorophenylsulfonyl)-1-(piperidin-4-ylmethyl)-1H-indole;
3-(2-chlorophenylsulfonyl)-6-fluoro-1-(piperidin-4-ylmethyl)-1 H-indole;
3-(2-fluorophenylsulfonyl)-6-methoxy-1-(piperidin-4-ylmethyl)-1 H-indole;
3-(4-methylphenylsulfonyl)-1 -(piperidin-3-ylmethyl)-1 H-indole;
6-bromo-3-(phenylsu!fonyl)-1-(piperidin-3-y!methyl)-1 H-indole;
4-chloro-3-(phenylsulfonyl)-1-(piperidin-3-ylmethyl)-1 H-indole;
7-methoxy-3-(phenylsulfonyl)-1-(piperidin-3-ylmethyl)-1 H-indole;
6-hydroxy-3-(phenylsulfonyl)-1-(piperidin-3-ylmethyl)-1 H-indole;
6-chloro-3-(4-fluorophenylsulfonyl)-1-(piperidin-2-ylmethyl)-1 H-indole;
6-fluoro-3-(3-fluorophenylsuifonyl)-1-(piperidin-2-yimethyl)-1 H-indole;
5-chIoro-3-(3-chlorophenylsulfonyl)-1-(piperidin-2-ylmethyi)-1 H-indole;
3-(2-chlorophenylsulfonyl)-6-fluoro-1-(piperidin-2-ylmethyl)-1 H-indole;
3-(2-fluorophenylsulfonyl)-6-methoxy-1-(piperidin-2-ylmethyl)-1 H-indole;
3-(phenylsulfonyl)-1 -(piperidin-4-ylmethyl)-1 H-indole;
3-(phenylsulfonyl)-1-(piperidin-3-ylmethyl)-1 H-indole;
3-(phenylsulfonyl)-1 -(piperidin-2-ylmethyl)-1 H-indole;
3-(phenylsulfonyl)-1 -(pyrrolidin-3-ylmethyl)-1 H-indole;
3-(phenylsulfonyl)-1 -(pyrrolidin-2-ylmethyl)-1 H-indole;
6-methyl-3-(phenylsulfonyl)-1-(pyrrolidin-3-ylmethyl)-1 H-indole;
3-(4-methylphenylsulfonyl)-1-(pyrrolidin-3-ylmethyl)-1 H-indole;
6-bromo-3-(phenylsulfonyl)-1-(pyrrolidin-3-ylmethyl)-1 H-indole;
4-chloro-2-methyl-3-(phenylsulfonyl)-1-(pyrrolidin-2-ylmethyl)-1 H-indole;
7-methoxy-3-(phenylsulfonyl)-1-(pyrrolidin-2-yImethyl)-1 H-indole;
6-hydroxy-3-(phenylsulfonyl)-1-(pyrrolidin-2-ylmethyl)-1 H-indole;
1 -(piperidin-2-ylmethyl)-3-(2-pyridinylsulfonyl)-1 H-indole;
1 -(piperidin-3-ylmethyl)-3-(2-pyridinylsulfonyl)-1 H-indole;
3-(2-pyridinylsulfonyl)-1 -(pyrrolidin-3-ylmethyl)-1 H-indole;
3-(2-pyridinylsulfonyl)-1 -(pyrrolidin-2-ylmethyl)-1 H-indole;
1 -(piperidin-4-ylmethyl)-3-(2-thienylsuIfonyl)-1 H-indole;
1 -(piperidin-3-ylmethyl)-3-(2-thienylsulfonyl)-1 H-indole;
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1 -(piperidin-2-ylmethy!)-3-(2-thieny!sulfony!)-1 H-indole;
1-(pyrrolidin-3-ylmethyl)-3-(3-thienylsulfonyl)-1 H-indole;
1-(pyrrolidin-2-ylmethyl)-3-(3-thienylsulfonyl)-1 H-indole;
3-(phenylsulfonyl)-1 -piperidin-4-yl-1 H-indole;
3-(phenylsulfonyl)-1 -pj peridi n-3-y I-1 H-indole;
3-(phenylsulfonyl)-1 -pyrrolidin-3-yl-1 H-indole;
1 -(1 -benzylpiperidin-4-yl)-3-(phenylsulfonyl)-1 H-indole;
1 -(1 -benzylpiperidin-3-y!)-3-(phenyisu!fonyl)-1 H-indole;
1 -(1 -benzylpyrrolidin-3-yl)-3-(phenylsulfonyl)-1 H-indole;
3-(3-chlorophenylsulfonyl)-1 -piperidin-4-yl-1 H-indole;
3-(4-f!uorophenylsu!fonyl)-1 -piperidin-3-yi-1 H-indole;
3-(2-f luorophenylsulfonyl)-1 -pyrrolidin-3-yl-1 H-indole;
1 -(1 -methylpiperidin-4-yl)-3-(phenylsulfonyl)-1 H-indole;
1 -(1 -ethylpiperidin-3-yl)-3-(phenylsulfonyl)-1 H-indole;
1 -(1 -phenethylpyrrolidin-3-yl)-3-(phenylsulfonyl)-1 H-indole;
1 -piperidin-4-yl-3-(2-pyridy!sulfonyl)-1 H-indole;
1 -piperidin-3-yl-3-(2-thienylsulfonyl)-1 H-indole;
1 -pyrrolidin-3-yl-3-(3-thienylsulfonyl)-1 H-indole;
3-(phenylsulfonyl)-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-indazole;
3-(phenylsulfonyl)-1-[(2S)-pyrrolidin-2-ylmethyl]-1H-indazole;
3-chloro-3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1H-indazole;
3-fluoro-3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1H-indazoIe;
5-chloro-3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1H-indazole;
3-fluoro-3-(phenylsulfonyl)-1 -(piperidin-4-ylmethyl)-1 H-indazole;
5-methoxy-3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1 H-indazole;
3-methyl-3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1 H-indazole;
3-(4-methylphenylsulfonyl)-1-(piperidin-3-ylmethyl)-1 H-indazole;
3-bromo-3-(phenylsulfonyl)-1-(piperidin-3-ylmethyl)-1H-inazdole;
3-methyl-3-(phenylsulfonyl)-1-(pyrrolidin-3-ylmethyl)-1 H-indazole;
3-(4-methylphenylsulfonyl)-1-(pyrrolidin-3-ylmethyl)-1H-indazoIe;
3-(2-pyridinylsulfonyl)-1-(pyrrolidin-2-ylmethyl)-1 H-indazole;
1-(piperidin-4-ylmethyl)-3-(2-thienylsulfonyl)-1 H-indazole;
1 -(pyrrolidin-3-ylmethyl)-3-(3-thienylsulfonyl)-1 H-indazole;
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1 -(pyrrolidin-2-ylmethyl)-3-(3-thienylsulfonyl)-1 H-indazole;
3-(phenylsulfonyl)"-1-(piperidin-4-yl)-1 H-indazole;
3-(phenylsulfonyl)-1 -(pyrrolidin-3-yl)-1 H-indazole;
1 -(1 -benzylpiperidin-4-yI)-3-(phenylsulfonyl)-1 H-indazole;
1 -(1 -benzylpiperidin-3-yl)-3-(phenylsulfonyl)-1 H-indazole;
1 -(1 -benzylpyrrolidin-3-yl)-3-(phenylsulfonyl)-1 H-indazole;
3-(3-chlorophenylsulfonyl)-1 -(piperidin-4-yl)-1 H-indazole;
3-(4-f luorophenylsulfonyl)-1 -(piperidin-3-yl)-1 H-indazole;
the stereoisomers thereof; or the pharmaceutically acceptable salts thereof.
This invention also provides processes for preparing compounds of formula
(I), which processes comprise one of the following:
(a) deprotecting a compound of forrnuia (IA):

wherein W, R, R1 R3, R4, R6, R7 and RB and m, n, p and q are as defined above and
P is a protecting group ; to give the free amine of formula I wherein R5 is H;
or
(b) alkylating a compound of formula I as defined above wherein R5 is H with an
alkylating agent of formula
R5-L
wherein L' is a leaving group and R5 is as defined above other than H;
(c) converting a basic compound of formula (I) to an acid addition salt or vice
versa;
or
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d) isolating an isomer of a compound of formula (1) from a mixture of isomers.
Compounds of formula I may also be conveniently prepared using
conventional synthetic methods and, if required, standard separation or isolation
echniques.
For example, compounds of formula I wherein n is 0; W is CR2; and R5 is H
(la) may be prepared by the reductive amination of the compound of formula II with a
Drotected azinone of formula III to give the intermediate of formula IV; reacting the
formula IV intermediate with an amide ketal of formula VII in the presence of an acid
such as p-toluenesu!fonic acid to give the enamine of formula V; cyclizing said
enamine in the presence of an acid such as aqueous HCL to give the compound of
VI; and deprotecting said formula VI compound to give the desired product of la.
Those compounds of formula I wherein n is 0; W is CR2 and R5 is other than H (Ib)
may be readily prepared by alkylating the formula la compound with an alkylating
agent of formula VII. The reactions are shown in flow diagram I wherein P
represents a protecting group and L' represents a leaving group.
-14-

Flow Diagram I

Compounds of formula I wherein R5 is H (la) may also be prepared by
reacting a compound of formula VIII with a protected azacyclic compound of formula
IX in the presence of a base to give the protected compound of formula X;
deprotection gives the desired compound of la. Alkylation of la as shown in flow
-15-

diagram 1 hereinabove gives the compound of formula I wherein R5 is other than H
(Ib). The reaction is shown in flow diagram II wherein P represents a protecting
group and L and L' represent a leaving group.
Flow Diagram II

Protecting groups suitable for use in the reactions shown hereinabove include
t-butylcarboxylate, benzyl, acetyl, benzyloxycarbonyl, or any conventional group
known to protect a basic nitrogen in standard synthetic procedures.
Conditions suitable for deprotecting compounds of formula VI or X may vary
depending upon the nature of the protecting group. For example, for a t-butyl-
carboxylate protecting group, deprotection may take place in the presence of an acid
such as trifluoroacetic acid or HCI and optionally an aprotic solvent such as dioxane;
for a benzyl protecting group, deprotection may take place via catalytic
hydrogenation.
Leaving groups suitable for use in the reactions shown hereinabove include
Cl, Br, I, OH, tosyl, mesyl or the like.
Compounds of formula VIII may be prepared using conventional synthetic
methods and, if required, standard separation and isolation techniques. For
-16-

xample, for compounds of formula VIII wherein W is CR2 (Villa), a nitrobenzene
ompound of formula XI may be reacted with a chloromethylsulfonyl compound of
Drmula XII in the presence of a strong base to give the intermediate of formula XIII;
said formula XIII intermediate may then be treated with a reducing agent such as Fe,
In or Sn in the presence of an acid to give the amine of formula II; said amine may
hen be reacted with the appropriate orthoester of formula XV to give the formula XVI
compound; and said formula XVI compound may be cyclized in the presence of a
Dase to give the desired formula Villa 3-sulfony!indole. The general synthetic
method is described by W. Wojciechowski and M. Makosza, Synthesis 1986. 651-
653. Similarly, the formula II amine may be reacted with NaNO2 in the presence of
an acid to give those compounds of formula VIII wherein W is N (Vlllb). The reaction
sequences are shown in flow diagram III.
-17-

Flow Diagram III

Compounds of formula VIII may also be prepared directly from an indole or
indazole of formula XVII by reacting the formula XVII substrate with iodine to give the
3-iodoindole or-indazole of formula XVIII; coupling the formula XVIII compound with
an appropriate thiol of formula XIX to give the 3-thioindole or-indazole of formula XX
and oxidizing said formula XX compound with a conventional oxidizing agent such as
H2O2, m-chloroperbenzoic acid, or the like to afford the desired formula VIII
intermediate. The reaction is shown in flow diagram IV.
-18-

Flow Diagram IV

Alternatively, the formuia XX 3-ihioincioie or -azazindoie compound may be
prepared in a single step from the formula XVII substrate by reacting the formuia XVil
compound with the formula XIX thiol in the presence of iodine, preferably in a polar
solvent such as aqueous alcohol. The thus-obtained formula XX compound may
then be oxidized as shown hereinabove to give the formula VIII intermediate. The
thus-obtained formula VIII intermediate may then be carried on to the desired
compounds of formula I via the alkylation of the basic indqle or indazole nitrogen
atom as shown in flow diagram II hereinabove.
Advantageously, the present invention provides another process for the
preparation of a compound of formula I which comprises reacting a compound of
formula VIII with a protected azacyclic compound of formula IX in the presence of a
first base to give the protected amine of formula X; and deprotecting said amine to
give the compound of formula I wherein R5 is H optionally alkylating said compound
with an alkylating agent, R5-L', wherein L' is a leaving group in the presence of a
second base to give the compound of formula I wherein R5 is other than H. The
process of the invention is illustrated in flow diagram II hereinabove.
-19-

Protecting groups suitable for use in the process of the invention include
t-butylcarboxylate, benzyl, acetyl, benzyloxycarbonyl, or any conventional group
known to protect a basic nitrogen.
Leaving groups suitable for use in the process of the invention include Cl, Br,
l,OH, tosyl, mesyl or the like.
Bases suitable for use as the first base in the process of the invention include
strong bases such as NaH, KOt-Bu, NaOH, or any conventional base capable of
removing a proton from an indole or indazole nitrogen atom.
Bases suitable for use as the second base in the inventive process include
weak bases such as K2CO3, Na2CO3, tertiary organic amines such as triethylamine or
the like.
Advantageously, the formula I compounds of the invention are useful for the
treatment of CNS disorders relating to or affected by 5-HT6 receptor including motor,
mood, personality, behavioral, psychiatric, cognitive, neurodegenerative, or the like
disorders, for example Alzheimer's disease, Parkinson's disease, attention deficit
disorder, anxiety, epilepsy, depression, obsessive compulsive disorder, sleep
disorders, neurodegenerative disorders (such as head trauma or stroke), feeding
disorders (such as anorexia or bulimia), schizophrenia, memory loss, disorders
associated with withdrawal from drug or nicotine abuse, or the like or certain
gastrointestinal disorders such as irritable bowel syndrome. Accordingly, the present
invention provides a method for the treatment of a disorder of the central nervous
system related to or affected by the 5-HT6 receptor in a patient in need thereof which
comprises providing said patient a therapeutically effective amount of a compound of
formula I as described hereinabove. The compounds may be provided by oral or
parenteral administration or in any common manner known to be an effective
administration of a therapeutic agent to a patient in need thereof.
The term "providing" as used herein with respect to providing a compound or
substance embraced by the invention, designates either directly administering such a
compound or substance, or administering a prodrug, derivative or analog which
forms an equivalent amount of the compound or substance within the body.
The therapeutically effective amount provided in the treatment of a specific
CNS disorder may vary according to the specific condition(s) being treated, the size,
age and response pattern of the patient, the severity of the disorder, the judgment of
-20-

the attending physician and the like. In general, effective amounts for daily oral
administration may be "about 0.01 to 1,000 mg/kg, "preferably about 0.5 to 500 "mg/kg
and effective amounts for parenteral administration may be about 0.1 to 100 mg/kg,
preferably about 0.5 to 50 mg/kg.
In actual practice, the compounds of the invention are provided by
administering the compound or a precursor thereof in a solid or liquid form, either
neat or in combination with one or more conventional pharmaceutical carriers or
excipients. Accordingly, the present invention provides a pharmaceutical
composition which comprises a pharmaceutically acceptable carrier and an effective
amount of a compound of formula I as described hereinabove.
Solid carriers suitable for use in the composition of the invention include one
or more substances which may also act as flavoring agents, lubricants, solubilizers,
suspending agents, fillers, glidants, compression aides, binders, tablet-disintegrating
agents or encapsulating materials. In powders, the carrier may be a finely divided
solid which is in admixture with a finely divided compound of formula I. In tablets, the
formula I compound may be mixed with a carrier having the necessary compression
properties in suitable proportions and compacted in the shape and size desired. Said
powders and tablets may contain up to 99% by weight of the formula I compound.
Solid carriers suitable for use in the composition of the invention include calcium
phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin,
cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low
melting waxes and ion exchange resins.
Any pharmaceutically acceptable liquid carrier suitable for preparing
solutions, suspensions, emulsions, syrups and elixirs may be employed in the
composition of the invention. Compounds of formula I may be dissolved or
suspended in a pharmaceutically acceptable liquid carrier such as water, an organic
solvent, or a pharmaceutically acceptable oil or fat, or a mixture thereof. Said liquid
composition may contain other suitable pharmaceutical additives such as
solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents,
suspending agents, thickening agents, coloring agents, viscosity regulators,
stabilizers, osmo-regulators, or the like. Examples of liquid carriers suitable for oral
and parenteral administration include water (particularly containing additives as
above, e.g., cellulose derivatives, preferably sodium carboxymethyl cellulose
-21-

solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g.,
glycols) or their derivatives, or oils (e.g., fractionated coconut oil and arachis oil). For
parenteral administration the carrier may also be an oily ester such as ethyl oleate or
isopropyl myristate.
Compositions of the invention which are sterile solutions or suspensions are
suitable for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions
may also be administered intravenously. Inventive compositions suitable for oral
administration may be in either liquid or solid composition form.
For a more clear understanding, and in order to illustrate the invention more
clearly, specific examples thereof are set forth hereinbelow. The following examples
are merely illustrative and are not to be understood as limiting the scope and
underlying principles of the invention in any way.
The term HNMR designates proton nuclear magnetic resonance. The terms
CH2CI2, THF and DMF designate methylene chloride, tetrahydrofuran and dimethyl
formamide, respectively. All chromatography is performed using SiO2 as support.
-22-

EXAMPLE 1
Preparation of 3-(Phenylthio)-1H-indole

A solution of methyl phenyl sulfoxide (4.0 g, 147 mmol) in CH2CI2 is cooled to
-78°C, treated dropwise with trifluoroacetic anhydride (4.0 mL, 5.99 g, 28.5 mmol),
stirred for 30 min at -78°C, treated with a solution of indole (1.82 g, 15.6 rnmol) in
CH2CI2l stirred for 30 min at -78°C, treated with triethylamine (20 mL, 145 mmol),
stirred for 4 days at ambient temperatures and diluted with water. The phases are
separated. The organic phase is dried over MgSO4 and concentrated in vacuo. The
resultant residue is chromatographed (1:99 methanol:CH2CI2) to give the title product
as a white solid, 3.08g (88% yield), mp 149-151 °C, characterized by mass spectral
and HNMR analyses.
EXAMPLE 2
Preparation of 3-(Phenylsulfonyl)-1H-indole

A stirred solution of 3-(phenylthio)-1 H-indole (12.0 g, 53.3 mmol) in CH2CI2
(800 mL) is chilled to 0°C, treated with 3-chloroperbenzoic acid (20.2 g, 117 mmol)
and stirred for 4h at ambient temperature. The reaction is washed sequentially with
water and saturated NaHCO3l dried over MgSO4 and concentrated in vacuo.
-23-

Chromatography (1:49 methanol:CH2CI2) of the resultant residue affords the title
compound as a white solid, 9.83 g (72% yield), mp 149-151°C, characterized by
nass spectral and HNMR analyses.
EXAMPLE 3
Preparation of t-Butyl 4-[3-(Phenvlsutfonyl)-1H-lndol-1-ylmethynpiperidine-1-
carboxylate

A stirred solution of 3-(phenylsulfonyl)-1 H-indole (700 mg, 2.72 mmol) in
anhydrous DMF is chilled to 0°C, treated with 60% sodium hydride in mineral oil (163
mg, 4.08 mmol) stirred for 2h at ambient temperature, treated with 4-(toiuene-4-
sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester1 (1.26 g, 3.40 mmol),
stirred for 16h at 55 °C, cooled to ambient temperature, diluted with water and
extracted with CH2CI2. The combined organic extracts are concentrated in vacua.
The resultant residue is triturated under hexanes and crystallized from
methanol/water to afford the title product as a light-yellow solid, 0.97 g, mp 181 -
182°C, identified by HNMR and mass spectral analyses.
1 Journal of Labeled Compound Radiopharm, 1999. 42, 1289-1300.
-24-

EXAMPLE 4
Preparation of 3-(Phenylsulfonyl)-1-(piperidin-4-vlmethyl)-1 H-indole
Hvdrochloride

A stirred solution of 4-[3-(phenylsulfonyl)-1H-indol-ylmethyl]-piperidine-1-
carboxylic acid tert-butyl ester (500 mg, 1.10 mmol) in dioxane is treated with 4N HCI
in dioxane (4.5 mL, 18 mmol), stirred for 5h at ambient temperature and concentrated
in vacuo. Crystallization of the resultant solid residue from ethanokether affords the
title compound as a white solid, 351 mg (82% yield), mp > 250°C, identified by
HNMR and mass spectral analyses.
EXAMPLE 5
Preparation of 2-(Phenylsulfonvlmethyl)-1-nitrobenzene

A solution of nitrobenzene (3.08 g, 25.0 mmol) and chloromethylphenylsulfone (4.76
g, 25.0 mmol) in dry THF is cooled to -50°C and treated with 1.0M KO'Bu/THF (55.0
mL, 55.0 mmol). The reaction is allowed to warm to -30°C over 1 h, treated with
glacial acetic acid (3.6 mL), warmed to 20°C, treated with water and extracted with
-25-

CH2CI2. The combined extracts are dried over MgSO4 and concentrated in vacuo.
Chromatography (1:1 ethyl acetate:hexanes) of the resultant residue give the title
product as a white solid, 5.62 g, (81 % yield), mp 106-108°C, identified by mass
spectral and HNMR analyses.
EXAMPLE 6
Preparation of 2-(Phenvlsulfonvlmethyl)aniline

A stirred mixture of 2-(phenylsulfonylmethyl)-1 -nitrobenzene (5.55 g, 20.0
mmol) and granular tin (10.4 g, 88 mmol) in methanol and concentrated HCI (60 mL)
is stirred under nitrogen at 45°C for 5h, cooled to ambient temperature over an 18h
period, poured onto NaHCO3 (80 g) with stirring, treated with water and extracted
with ethyl acetate. The combined extracts are washed with brine (2 x 100 mL). dried
over MgSO4, and concentrated in vacuo to afford the title product as an off-white
solid, 4.41 g (89%) mp 175-176°C, identified by HNMR and mass spectral analyses.
-26-

EXAMPLE 7
Reparation of 1-Benzvl-3-{[2-(phenylsulfonyl)methylaniline}piperidine

A mixture of 2-[(phenylsulfonyl)methyl]aniline (1.24 g, 5.00 mmoi), Na2SO4
(7.1 g, 50 mmol), and 1 -benzyl-3-piperidinone (2.26 g, 10.0 mmol) in glacial acetic
acid is stirred under nitrogen at ambient temperature for 45 min, treated with
NaBH(OC(O)CH3)3 (3.16 g, 15.0 mmol), stirred for 2.5h, poured slowly onto a stirred
mixture of NaHCO3 and water and extracted with ethyl acetate. The combined
extracts are washed with brine, dried over MgSO4, and concentrated in vacuo. The
resultant residue is chromatographed (1:1 ethyl acetate:hexanes) to afford the title
product as a viscous, pale yellow oil, 1.94 g (92% yield), identified by HNMR and
mass spectral analyses.
EXAMPLE 8
Preparation of 1-(1-Benzvlpiperidin-3-yl)-3-(phenvlsulfonyI)-1H-indole




A solution of 1-(1-benzylpiperidin-3-yl)-3-(phenylsulfonyl)-1H-indole (431 mg,
1.00 mmol) in dry 1,2-dichloroethane is treated with 1-chloroethyl chloroformate (0.27
mL, 2.50 mmol), heated at reflux temperature for 2.5h, cooled and concentrated in
vacuo (reconcentrated twice from CH2CI2). The resulting residue is heated at reflux
temperature in methanol for 3h, cooled and concentrated in vacuo to give an oil. The
oil is reconcentrated from ethanol and then from ether to give a tan solid. The solid is
triturated with ethanol and filtered. The filtercake is dried under vacuum to afford the
title product as an off-wh'ite solid, 322 mg (85% yield), mp 254-256°C, identified by
HNMR and mass spectral analyses.
-28-

EXAMPLES 10-13
Preparation of 1-Heterocvclvl-3-(phenvlsulfonyl)-1H-indole Derivatives

Using essentially the same procedures described in Examples 7 and 8
hereinabove and employing the appropriate protected piperidinone or pyrrolidinone
reagent, the compounds shown in Table I are obtained and identified by HNMR and
mass spectral analyses.

Ex.
No. q . R5 mp°C
10 0 benzyl 140 (foam)
11 0 H 209-211
12 1 benzyl 288-291
13 1 H 294-297
-29-

EXAMPLES 14-26
Preparation of 1-(3-Piperidinyl)-3-arvlsulfonyl-1H-indole Derivatives

Using essentially the same procedures described in Examples 5 through 9
hereinabove and employing the appropriately substituted nitrobenzene, arylsulfonyl
chloride and protected 3-piperidinbne, the compounds shown in Table II are obtained
and identified by HNMR and mass spectral analyses.

Ex
No R R1 R5 mp°C
H
14 H 1-naphthyl H > 180 (dec)
15 H 8-quinolinyl H > 195 (dec)
16 H 3-F-C6H4 H > 150 (dec)
17 H 3-CI- C6H4 H >150 (dec)
18 5-OCH3 3-F-C6H4 H 267-270
19 5-OCH3 3-F-C6H4 CH3 262-265
20 5-F 3-F-C6H4 H 275-278
21 5-F 3-F-C6H4 CH3 255-257
-30-

Table II. contd.

Ex.
No. R R1 R5 mp°C
22 5-CI 3-F-C6H4 H
23 5-CI 3-F-C6H4 CH3 242-245
24 5-OCH3 3-F-C6H4 C2H5 227-228
25 5-CI 3-F-C6H4 C2H5 225-226
26 H 8-quinolinyl CH3 >250 (dec)
EXAMPLE 27
Preparation of 3-(Phenylsulfonyl)-1 H-indazole

A stirred solution of 2-[(phenylsulfonyl)methyl]aniline (247 mg, 1.00 mmol) in
4N HCI (50 ml) is treated with a solution of NaNO2 (100 mg, 1.5 mmol) in water at
ice-bath temperatures, stirred for 30 min., neutralized with 10% NaOH and filtered.
The filtercake is dissolved in CH2CI2, dried over MgSO4 and concentrated in vacuo to
-31-

EXAMPLE 28
Preparation of 3-Phenvlsulfonyl-1-(pvrrolidin-2-vlmethyl)-1 H-indazole
hvdrochloride

A mixture of 3-phenylsulfonyl-1 H-indazole (258 mg, 1.00 mmol), N-t-BOC-D-
prolinol (402 mg, 2.00 mmol) and triphenylphosphine (524 mg, 2.00 mmol) in THF is
treated with diisopropyl azodicarboxylate (404 mg, 2.00 mmol) at room temperature,
stirred overnight and concentrated in vacuo. The resultant residue is
chromatographed (30/70 ethyl acetate/hexanes) to give the Boc-protected product
contaminated with diisopropyl azodicarboxylate-derived by-product. This product
mixture is treated with 4.0M HCI in dioxane (0.05 mL) in 5 mL methanol, stirred and
concentrated in vacuo. This residue is dispersec in ether and filtered. The white
solid filtercake is partitioned between ethyl acetate and saturated aqueous NaHCO3
The organic phase is washed with water, dried over MgSO4 and concentrated in
vacuo. The resultant residue is chromatographed (90/10 ethyl acetate/2% ethanolic
ammonia) to give the free amine of the title product. The amine is dissolved in
methanol and treated with 4.0M HCI in dioxane and concentrated in vacuo to afford
the title compound as a white solid, 65 mg (19% yield) mp: 225-227°C, identified by
HNMR and mass spectral analyses.
-32-

EXAMPLE 29
Comparative Evaluation of 5-HT6 Binding Affinity of Test Compounds
The affinity of test compounds for the serotonin 5-HT6 receptor is evaluated
in the following manner. Cultured Hela cells expressing human cloned 5-HT6
receptors are harvested and centrifuged at low speed (1,000 x g) for 10.0 min to
remove the culture media. The harvested cells are suspended in half volume of fresh
physiological phosphate buffered saline solution and recentrifuged at the same
speed. This operation is repeated. The collected cells are then homogenized in ten
volumes of 50 mM Tris.HCI (pH 7.4) and 0.5 mM EDTA. The homogenate is
centrifuged at 40,000 x g for 30.0 min and the precipitate is collected. The obtained
pellet is resuspended in 10 volumes of Tris.HCI buffer and recentrifuged at the same
speed. The final pellet is suspended in a small volume of Tris.HCI buffer and the
tissue protein content is determined in aliquots of iO-25 //I volumes. Bovine Serum
Albumin is used as the standard in the protein determination according to the method
described in Lowry et al., J. Biol. Chem., 193:265 (1951). The volume of the
suspended eel! membranes is adjusted to give a tissue protein concentration of 1.0
mg/mi of suspension. The prepared membrane suspension (iO times concentrated)
is aliquoted in 1.0 ml volumes and stored at -70° C until used in subsequent binding
experiments.
Binding experiments are performed in a 96 well microtiter plate format, in a
total volume of 200μl. To each well is added the following mixture: 80.0μI of
incubation buffer made in 50 mM Tris.HCI buffer (pH 7.4) containing 10.0 mM MgCI2
and 0.5 mM EDTA and 20μI of [3H]-LSD (S.A., 86.0 Ci/mmol, available from
Amersham Life Science), 3.0 nM. The dissociation constant, KD of the [3H]LSD at the
human serotonin 5-HT6 receptor is 2.9 nM, as determined by saturation binding with
increasing concentrations of [3H]LSD. The reaction is initiated by the final addition of
100.0μI of tissue suspension. Nonspecific binding is measured in the presence of
10.0 ΜM methiothepin. The test compounds are added in 20.0μl volume.
The reaction is allowed to proceed in the dark for 120 min at room
temperature, at which time, the bound ligand-receptor complex is filtered off on a 96
well unifilter with a Packard Filtermate® 196 Harvester. The bound complex caught
-33-

on the filter disk is allowed to air dry and the radioactivity is measured in a Packard
TopCount® equipped with sixphotomultiplier detectors, after the addition of 40.0μI
Microscint®-20 scintillant to each shallow well. The unifilter plate is heat-sealed and
counted in a PackardTopCount® with a tritium efficiency of 31.0%.
Specific binding to the 5-HT6 receptor is defined as the total radioactivity
bound less the amount bound in the presence of 10.0/yM unlabeled methiothepin.
Binding in the presence of varying concentrations of test compound is expressed as
a percentage of specific binding in the absence of test compound. The results are
plotted as log % bound versus log concentration of test compound. Nonlinear
regression analysis of data points with a computer assisted program Prism® yielded
both the IC50 and the K, values of test compounds with 95% confidence limits. A
linear regression line of data points is plotted, from which the IC50 value is
determined and the Ks value is determined based upon the following equation:
Ki =IC50/(1 + L/KD)
where L is the concentration of the radioactive ligand used and KD is the dissociation
constant of the ligand for the receptor, both expressed in nM.
Using this assay, the following Ki values are determined and compared to
those values obtained by representative compounds known to demonstrate binding
to the 5-HT6 receptor. The data are shown in Table !!!, below.
Table III
Test Compound 5-HT6 Binding Ki
(Ex. No.) (nM)
4 27
8 122
9 13
10 113
11 5
12 49
13 91
14 21
15 6
-34-

Table III, contd.
Test Compound(Ex. No.) 5-HT6 Binding Ki(nM)
17 5
18 11
19 68
20 4
22 29
23 62
5-HT6 Binding Ki
Comparative Examples (nM)
Clozapine 6.0
Loxapine 41.4
Bromocriptine 23.0
Methioihepin 8.3
Miansenn 44.2
Oianzepine 19.5
As can be seen from the data shown on Table III hereinabove, the
compounds of the invention demonstrate significant affinity for the 5-HT6 receptor.
-35-

WE CLAIM:
1. A compound of formula I

wherein
W is N or CR2;
R is halogen, CN, OCO2R9, CO2R10, CONRnR^, SOXR13, NR14R15, OR16,
COR17 or a C1C6alkyl, C2C6a!kenyl, C2-C6alkyny!, C3-C7cyc!oa!kyi, aryl
or heteroaryi group each optionally substituted;
R1 is an optionally substituted C1C6alkyl, C3-C7cycloalkyl, aryl, or heteroaryl
group or an optionally substituted 8- to 13-membered bicyclic or tricyclic
ring system having a N atom at the bridgehead and optionally containing
1, 2 or 3 additional heteroatoms selected from N, O or S;
R2 is H, halogen, or a C1C6alkyl, C1-C6alkoxy, C3-C7cycloalkyl, aryl or
heteroaryi group each optionally substituted;
R3 and R4 are each independently H or an optionally substituted CrC6alkyl
group;
R5 is H or a C1C5alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cyc!oalkyl,
cycloheteroalkyl, aryl or heteroaryi group each optionally substituted;
R6 is a C1-C6alkyl, C3-C7cycloalkyl, C2-C6alkenyl or C2-C6alkynyl group each
optionally substituted;
R7 and R8 are each independently H or a CrC6alkyl, C3-C7cycloalkyl, C2-
C6alkenyl or C2-C6alkynyl group each optionally substituted;
m, n and p are each independently 0 or an integer of 1,2 or 3;
q and x are each independently 0 or an- integer of 1 or 2;
-36-

Rg, R10, R13 and R17 are eadh independently H or a C1C6alkyl, C2-C6alkenyl,
C2-C6alkynyl, C3-C6qycloalkyl, cycloheteroalkyl, aryl or heteroaryl
group each optionally substituted;
R11 and R12 are each independently H or an optionally C1-C6alkyl group or R11
and R12 may be taken together with the atom to which they are
attached to form a 5- to 7-member ring optionally containing another
heteroatom selected from O, N or S;
R14 and R15 are each independently H or an optionally substituted CrC4alkyl
group or R14and R15 may be taken together with the atom to which
they are attached to form a 5- to 7-membered ring optionally
containing another heteroatom selected from O, NR18 or SOX;
R16 is a CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally substituted
and;
R18 is H or a C1C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
or
a stereoisomer thereof or a pharrnaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein n is 0.
3. A compound according to claim 1 or claim 2 wherein R5 is H.
4. A compound according to any one of claims 1 to 3 wherein R1, is an
optionally substituted phenyl group.
5. A compound according to any one of claims 1 to 4 wherein q is 0 or 1.
6. The compound according to claim 5 wherein the piperidinyl or
pyrrolidinyl group is attached in the 3-position.
7. A compound according to any one of claims 1 to 6 wherein p is 0.
8. A compound according to any one of claims 1 to 7 wherein m is 0.
-37-

9. A compound according to any one of claims 1 to 8 wherein W is N.
10. A compound according to claim 1 which is one of the following:
6-chloro-3-(phenylsulfonyl)-1 -(piperidin-4-ylmethyl)-1 H-indole;
6-fluoro-3-(phenylsulfonyl)-1-(piper|idin-4-ylmethyl)-1H-indol6;
5-chloro-3-(phenylsulfonyl)-1 -(piperidin-4-ylmethyl)-1 H-indole;
6-f luoro-3-(phenylsulfonyl)-l -(piperfidin-4-ylmethyl)-1 H-indole;
6-methoxy-3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1 H-indole;
6-methyl-3-(phenylsulfony!)-1 -(piperidin-4-ylmethyl)-1 H-indole;
3-(4-methyIphenylsulfonyl)-1-(piperidin-4-ylmethyl)-1 H-indole;
6-bromo-3-(phenylsulfonyl)-1 -(pipe!ridin-4-ylmethyl)-1 H-indole;
4-ch!oro-3-(pheny!sii!fonyl)-1 -(piperidin-4-ylmethyi)-1 H-indole;
7-methoxy-3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1 H-indole;
6-hydroxy-3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1 H-indole;
6-chloro-3-(4-fluorophenylsu!fonyl)-1-(piperidin-4-ylrnethyl)-1 H-indole;
6-fluoro-3-(3-fluorophenylsulfonyl)-1-(piperidin-4-ylmethyl)-1 H-indole;
5-chloro-3-(3-chlorophenylsulfonyi)-1 -(piperidin-4-ylmethyl)-1 H-indole;
3-(2-chlorophenylsuIfonyl)-6-fluoro-1-(piperidin-4-ylrnethyl)-1 H-indole;
3-(2-f!uorophenylsulfonyl)-6-methoxy-1 -(piperidin-4-ylmethyl)-1 H-indole;
3-(4-methylphenylsulfonyl)-1-(pipeitidin-3-ylmethyl)-'l H-indole;
6-bromo-3-(phenylsulfonyl)-1-(piperidin-3-ylmethyl)-1 H-indole;
4-chloro-3-(phenylsulfonyl)-1 -(piperidin-3-ylmethyl)-1 H-indo!e;
7-methoxy-3-(phenylsulfonyl)-1-(piperidin-3-ylmethyl)-1 H-indole;
6-hydroxy-3-(phenylsulfonyl)-1-(piperidin-3-ylmethyI)-1 H-indole;
6-chloro-3-(4-f luorophenylsulfonyl)-1 -(piperidin-2-ylrnethyl)-1 H-indole;
6-fluoro-3-(3-fluorophenylsulfonyl)-1-(piperidin-2-ylmethyl)-1 H-indole;
5-chloro-3-(3-chlorophenylsulfonyl)L1 -(piperidin-2-y!methyl)-1 H-indole;
3-(2-chlorophenylsulfonyl)-6-fluoro-1-(piperidin-2-ylmethyl)-1H-indole;
3-(2-fluorophenylsulfonyl)-6-methoxy-1-{piperidin-2-ylmethyl)-1 H-indole;
3-(phenyIsulfonyl)-1-(piperidin-4-yimethyl)-1H-indole;
3-(phenylsulfonyl)-1-(pip#eridin-3-yIrhethyl)-1 H-indole;
3-(phenylsulfonyl)-1 -(piperidin-2-ylrriethyl)-1 H-indole;
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3-(phenylsulfonyl)-1 -(pyrrolidin-3-ylrinethyl)-1 H-indole;
3-(phenylsulfonyI)-1 -(pyrrolidin-2-ylijnethyl)-1 H-indolo;
6-methyl-3-(phenyIsulfonyi)-1 -(pyrrolidin-3-ylmethyl)-1 H-indole;
3-(4-methylphenylsulfonyl)-1 -(pyrrolidin-3-yImethyl)-1 H-indole;
6-bromo-3-(phenylsulfonyl)-1-(pyrrd!id!n-3-ylmethy!)"1 H-indole;
4-chloro-2-methyl-3-(phenyIsuifonyl)-1-(pyrrolidin-2-ylmethyl)-1 H-indole;
7-methoxy-3-(phenylsulfony!)-1 -(pyrrolidin-2-ylmethyl)-1 H-indole;
6-hydroxy-3-(pheny!sulf onyl)-1 -(pyrro!idin-2-ylmethy!)-1 H-indo!e;
1 -(piperidin-2-ylmethyl)-3-(2-pyridinylsulfonyl)-1 H-inclole;
1-(piperidin-3-ylmethyl)-3-(2-pyridiriylsuIfonyl)-1H-inclole;
3-(2-pyridiny!su!fony!)-1 -(pyrro!idin-3-y!melhyl)-1 H-indole;
3-(2-pyridinylsulf onyl)-1-(pyrrolidin-2-ylmethyl)-1 H-indole;
1-(piperidin-4-yimethyi)-3-(2-thienytsulfonyl)-1 H-indole;
1 -(piperidin-3-yimethyl)-3-(2-thienyl;sulfonyl)-1 H-indole;
1 -{piperidin-2-ylmethyl)-3-(2-thienylsulfonyl)-1 H-indole;
1 -(pyrrolidin-3-ylmethyl)-3-(3-thienylsulf onyl)-1 H-indole;
1 -(pyrrolidin-2-ylmethyl)-3-(3-thienylsulfony!)-1 H-indole;
3-(phenylsulfonyl)-1-piperidin-4-yl-1 H-indole;
3-(phenylsulfonyl)-1 -piperidin-3-yl-1 H-indole;
3-(phenylsulfonyl)-1 -pyrrolidin-3-yl-1 H-indole;
1 -(1 -benzylpiperidin-4-yl)-3-(phenylsulfonyl)-1 H-indole;
1 -(1 -benzylpiperidin-3-yl)-3-(phenylsulfonyl)-1 H-indole;
1 -(1 -benzy!pyrro!idin-3-yl)-3-(phehylsulfonyl)-1 H-indole;
3-(3-chlorophenylsulfonyl)-1-piperidin-4-yl-1 H-indole;
3-(4-fluorophenylsulfonyl)-1 -piperidin-3-yl-1 H-indole;
3-(2-fluorophenylsulfonyl)-1 -pyrrolidin-3-yf-1 H-indole;
1 -(1 -methylpiperidin-4-yl)-3-(phenylsulfonyl)-1 H-indole;
1 -(1 -ethylpiperidin-3-yl)-3-(phenylsUlfonyI)-1 H-indole;
1 -(1 -phenethylpyrrolidin-3-yl)-3-(ph:enylsulfonyl)-1 H-indole;
1 -piperidin-4-yl-3-(2-pyridylsulfonyl)-1 H-indole;
1 -piperidin-3-yl-3-(2-thienylsulfonyl)-1 H-indole;
1 -pyrrolidin-3-yl-3-(3-thienylsulfonyl)-1 H-indole;
3-(pheny!sulfonyl)-1 -[(2R)-pyrrolidin-2-ylmethyl]-1 H-indazole;
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3-(phenylsulfonyl)-1 -[(2S)-pyrrolidin-2-ylmethyl]-1 H-indazole;
6-chloro-3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1 H-indazole;
6-fluoro-3-(phenyisuifonyl)-1-(pipeiridin-4-ylmethyl)-1 H-indazole;
5-chloro-3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1 H-indazole;
6-fluoro-3-(phenylsulfonyl)-1 -(piperidin-4-yimethy!)-1 H-indazole;
6-methoxy-3-(phenylsulfonyI)-1-(piperidin-4-ylmethyl)-1 H-indazole;
6-methyl-3-(phenylsulfonyl)-1-(piperidin-4-ylmethyl)-1 H-indazole;
3-(4-methylphenylsulfonyl)-1 -(pipeh'din-3-ylmethyl)-1 H-indazole;
6-bromo-3-(phenylsulfonyl)-1-(piperidin-3-ylmethyl)-1H-inazdole;
6-methyl-3-(phenylsulfonyl)-1 -(pyrrolidin-3-ylmethyl}-1 H-indazole;
3-(4-methylphenylsulfonyl)-1-(pyrroridin-3-yImethyl)-1 H-indazole;
3-(2-pyridinylsulfonyl)-1-(pyrrolidin-2-ylmethyl)-1H-indazole;
1 -(piperidin-4-y!methyi)-3-(2-thienyJsuifonyl)-1 H-indazole;
1 -(pyrrolidin-3-ylmethy!)-3-(3-thienylsuifonyl)-1 H-indazole;
1-(pyrrolidin-2-ylmethyl)-3-(3-thienyisulfonyl)-1 H-indazole;
3-(phenylsulfonyl)-1 -(piperidin-4-yI)-1 H-indazo!e;
3-(phenylsulfonyl)-1-(pyrrolidin-3-y!)-1 H-indazole;
1 -(1 -benzylpiperidin-4-yl)-3-(phenylSulfonyl)-1 H-indazole;
1 -(1 -benzylpiperidin-3-yl)-3-(phenylsulfonyl)-1 H-indazole;
1 -(1 -benzylpyrrolidin-3-yl)-3-(phenylsulfonyl)-1 H-indazole;
3-(3-chlorophenylsulfonyl)-1-(piperidin-4-yl)-1 H-indazole; or
3-(4-fluorophenylsulfonyl)-1 -(piperidin-3-yl)-1 H-indazole;
or a stereoisomer thereof; or a pharmaceutically acceptable salt thereof.
11. A method for the treatment of a central nervous system disorder
related to or affected by the 5-HT6 receptor in a patient in need thereof which
comprises providing to said patient a therapeutically effective amount of a
compound of formula I as defined in any one of claims 1 to 10 or a stereoisomer
thereof or a pharmaceutically acceptable salt thereof.
12. A method according to claim 11 wherein said disorder is a motor
disorder, anxiety disorder or cognitive disorder.
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13. A method according to claim 11 wherein said disorder is a
neurodegenerative disorder.
14. A method according to claim 11 wherein said disorder is attention
deficit disorder or obsessive compililsive disorder.
15. A method according to claim 13 wherein said disorder is stroke or
head trauma.
16. A pharmaceutical composition which comprises a pharmaceutically
acceptable carrier and a compound of formula I as defined in anyone of claims 1 to
10 or a stereoisomer thereof or a pharmaceuticaiiy acceptable salt thereof.
17. A process for the preparation of a compound of formula I as defined in
claim 1 which comprises one of the following:
(b) deprotecting a compound of formula (IA):

wherein W, R, R1 R3 R4 R6 R7 and R8 and m, n, p and q are as defined in claim 1
and P is a protecting group; to give the free amine of formula I wherein R5 is H;
or
(b) alkylating a compound of formula I as defined in Claim 1 wherein R5 is H with
an alkylating agent of formula
R5-L'
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wherein L' is a leaving group and R5 is other than HI;
(c) converting a basic compound of formula (I) to an acid addition satt or vice
versa;
or
(d) isolating an isomer of a compound of formula (1) from a mixture of isomers.
18. A process for the preparation of a compound of formula I as defined in claim 1
which comprises reacting a compound of formula Viii

wherein W, R, R, and rn are as defined in ciaim i with a protected azacyclic
compound of formula iX

wherein P is a protecting group; L is a leaving group; and R3, R4, R6, R7, R8 n, p and
are as described hereinabove in the presence of a first base to give the protected
ormula I compound; and deprotecting said compound to give the free amine of
ormula I wherein R5 is H; optionally alkylating said amine with an alkylating agent,
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R5-L', wherein L' is a leaving group in the presence of a second base.
19. A pharmaceutical composition, substantially as herein described,
particularly with reference to the examples.
20. A process for the preparation of a compound of formula i,
substantially as herein described, particularly with reference to the examples.

The present invention provides a compound of formula (I) and the use thereof for the
treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor.