THIS APPLICATION HAS BEEN DIVTDED OUT OF INDIAN
APPLICATION NO. 1583/KOLNP/2005
BACKGROUND OF THE INVENTION
Serotonin (5-Hydroxytryptamine)(5-HT) receptors play a critical role in many
physiological and behavioral 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
adenylate cyclase (Ruat, M.; Traiffort, E.; Arrang, J-M.; Tardivel-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.The high levels of receptor found in important structures in the forebrain,
including the caudate/putamen, hippocampus, nucleus accumbens, and cortex
-1A-

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). Further support for the role of a selective 5-HT6 ligand in
cognition can be found in Woolley, M. L; Marsden, C. A.; Sleight, A. J.; and Fone, K.
C. F., Psychopharmacology, 2003, 170(4), 358-367.
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.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula I
-3-


wherein
A is C, CR8 or N;
R1 is H, halogen, CN, COR9, OCO2R10, CO2R11, CONR12R13, SOxR14,
NR15R16, OR17 or a C1-C6alkyl, C3-C7cycloalkyl, aryl or heteroaryl
group each optionally substituted;
R2 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 ;
R3 is H or a C1-C6alkyl, C3-C7cycloalkyl, aryl or heteroaryl group each
optionally substituted;
R4 is H or a C1-C6alkyl or C3-C7cycloalkyl group each optionally substituted;
R5, R6 and R7 are each independently H or a CrC6alkyl or C3-C7cycloalkyl
group each optionally substituted;
m and p are each independently an integer of 1, 2 or 3;
n is an integer of 1 or 2;
R8 is H, OH or an optionally substituted C1-C6alkoxy group;
R9, R10, R11 and R17 are each independently H or a C1-C6alkyl, C2-C6alkenyl,
C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl
group each optionally substituted;
R12, R13, R15 and R16 are each independently H or an optionally substituted
C1-C4alkyl group or R12 and R13 or R15 and R16 may be taken together
with the atom to which they are attached to form a 5- to 7-membered
_4_

ring optionally containing another heteroatom selected from 0, NR18
or SOX;
R14 is a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R18 is H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl,
cycloheteroalkyl, aryl or heteraryl group each optionally substituted;
x is 0 or an integer of 1 or 2; and
— represents a single bond or a double bond; or
the stereoisomes thereof or the pharmaceutically acceptable salts thereof.
The present invention also provides methods and compositions useful in the
treatment of central nervous system disorders.
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 heterocyclyl-3-sulfonylindazoles of
formula I demonstrate 5-HT6 affinity along with significant sub-type selectivity.
Advantageously, said formula I indazoles are 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 -heterocyclyl-3-
sulfonylindazole compounds of formula I
-5-


wherein
A is C, CR8 or N;
R1 is H, halogen, CN, COR9, OCO2R10, CO2R11, CONR12R13, SOxR14,
NR15R16, OR17 or a C1-C6aIkyl, C3-C7cycloalkyl, aryl or heteroaryl
group each optionally substituted;
R2 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;
R3 is H or a C1-C6alkyl, C3-C7cycloalkyl, aryl or heteroaryl group each
optionally substituted;
R4 is H or a d-C6alkyl or C3-C7cycloalkyl group each optionally substituted;
R5, R6 and R7 are each independently H or a C1-C6alkyl or C3-C7cycloalkyl
group each optionally substituted;
m and p are each independently an integer of 1, 2 or 3;
n is an integer of 1 or 2;
R8 is H, OH or an optionally substituted C1-C6alkoxy group;
Rg, R10, R11 and R17 are each independently H or a C1-C6alkyl, C2-C6alkenyl,
C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl
group each optionally substituted;
R12, R13, R15 and R16 are each independently H or an optionally substituted
C1-C4alkyl group or R12 and R13 or R15and R16 may be taken together
with the atom to which they are attached to form a 5- to 7-membered
-6-

ring optionally containing another heteroatom selected from O, NR18
or SOX;
R14 is a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R18 is H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl,
cycloheteroalkyl, aryl or heteraryl group each optionally substituted;
x is 0 or an integer of 1 or 2; and
— represents a single bond or a double bond; or
the stereoisomes 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:

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 such as
phenyl, naphthyl, anthracenyl or the like. The term haloalkyl 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+1
group having from one to 2n+1 halogen atoms which may be the same or different.
-7-

Exemplary of the 8- to 13-membered bicyclic or tricyclic ring systems having a
N atom at the 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 NR, O or S; and R is H or an optional substituent as
described hereinbelow:

In the specification and claims, when the terms C1-C6alkyl, C2-C6alkenyl,
C2-C6alkynyl, C3-C7cycloalkyl, cycloheteroalkyl, aryl or heteroaryl are designated as
being optionally substituted, the substituent groups which are optionally present may
be one or more of those customarily employed in the development of pharmaceutical
compounds, or the 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,
-8-

alkylsuphinyl, alkylsulphonyl, carbamoyl, alkylaminocarbonyl, phenyl and substituted
phenyl (where the substituents are as defined herein), phenoxy, benzyl, benzyloxy,
heteroaryl, indolyl, heterocyclyl (e.g., heteroaryl, cycloheteroalkyl) or cycloalkyl
groups, preferably halogen atoms or lower alkyl or lower alkoxy groups. Typically, 0-
3 substituents may be present. When any of the foregoing substituents represents or
contains an alkyl substituent group, this may be linear or branched and may contain
up to 12, preferably up to 6, more preferably up to 4 carbon atoms.
Pharmaceutically acceptable salts may be any acid addition salt 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-toluene sulfonic, methane sulfonic 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
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.
-9-

Examples of R3 are hydrogen, phenyl and C1-C4alkyl which may be
substituted by optionally substituted phenyl, e.g., R3 is methyl, phenyl or 3-
chorobenzyl. An example of A is N. Examples of R2 are phenyl, 1-naphthyl, 2-
naphthyl, cyanophenyl, 2, 3, or 4-halophenyl, 2-phenethyl, 2-chloro-4-fluorophenyl,
aminophenyl and thienyl. Examples of R4 are H, methyl, ethyl, propyl and phenethyl.
Preferred compounds of the invention are those compounds of formula I
wherein n is 1. Another group of preferred compounds are those compounds of
formula I wherein R4 is H or an optionally substituted C1-C4alkyl group. A further
group of preferred compounds of the invention are those compounds of formula I
wherein R2 is an optionally substituted phenyl, naphthyl or heteroaryl group. Also
preferred are those compounds of formula I wherein R5, R6 and R7 are H.
More preferred compounds of the invention are those compounds of formula I
wherein A is N and R4 is H or an optionally substituted C1-C4alkyl group. Another
group of more preferred compounds are those compounds of formula I wherein A is
N; n is 1 and R2 is an optionally substituted phenyl, naphthyl or heteroaryl group.
Further more preferred compounds of the invention are those compounds of formula
I wherein the 6- or 7-membered azacyclic ring is attached to the indazole in the 5 or 7
position.
Among the preferred compounds of the invention are:
5-(4-methylpiperazin-1 -yl)-3-(1 -naphthylsulfonyl)-1H-indazole;
3-(1 -naphthylsulfonyl)-5-piperazin-1 -yl-1H-indazole;
1 -(3-chlorobenzyl)-5-(4-methylpiperazin-1 -yl)-3-(1-naphthylsulfonyl)-1H-indazole;
7-(4-methylpiperazin-1 -yl)-3-(phenylsulfonyl)-1H-indazole;
3-(phenylsulfonyl)-7-(4-propylpiperazin-1-yl)-1H-indazole;
3-(phenylsulfonyl)-7-piperazin-1-yl-1H-indazole;
5-(4-methylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-indazole;
3-(phenylsulfonyl)-5-(4-propylpiperazin-1-yl)-1H-indazole;
3-(phenylsulfonyl)-5-piperazin-1 -yl- 1H-indazole;
5-piperazin-1-yl-3-[(3-cyanophenyl)sulfonyl]-1H-indazole;
7-(4-methylpiperazin-1-yl)-3-[(2-phenethyl)sulfonyl]-1H-indazole;
3-(1-naphthylsulfonyl)-7-(4-propylpiperazin-1-yl)-1H-indazole;
5-(4-phenethylpiperazin-1-yl)-3-(1-naphthylsulfonyl)-1H-indazole;
5-(4-methylpiperazin-1-yl)-3-(2-naphthylsulfonyl)-1H-indazole;
-10-

3-[(2-chloro-4-fluorophenyl)sulfonyl]-5-piperazin-1-yl-1H-indazole;
1-methyl-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-indazole;
1-phenyl-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-indazole;
1-methyl-3-(phenylsulfonyl)-7-piperazin-1-yl - 1H-indazole;
1-phenyl-3-(phenylsulfonyl)-7-(piperazin-1 -yl)-1H-indazole;
7-piperazin-1-yl-3-[(3-fluorophenyl)sulfonyl]-1H-indazole;
3-[(4-fluorophenyl)sulfonyl]-7-(4-methylpiperazin-1-yl)-1H-indazole;
3-[(2-chlorophenyl)sulfonyl]-7-piperazin-1-yl-1H-indazole;
3-[(4-aminophenyl)sulfonyl]-7-(piperazin-1-yl)- 1H-indazole;
5-piperazin-1 -yl-3-[(3-fluorophenyl)sulfonyl]- 1H-indazole;
3-[(4-fluorophenyl)sulfonyl]-5-(4-methylpiperazin-1-yl)-1H-indazole;
3-[(2-chlorophenyl)sulfonyl]-5-(4-propylpiperazin-1-yl)-1H-indazole;
3-[(4-aminophenyl)sulfonyl]-5-piperazin-1-yi- 1H-indazole;
3-[(5-chlorothien-2-yl)sulfonyl]-5-piperazin-1-yl-1H-indazole;
3-[(5-chlorothien-2-yl)sulfonyl]-7-piperazin-1-yl-1H-indazole;
4-chloro-3-(phenylsulfonyl)-7-piperazin-1-yl- 1H-indazole;
5-fluoro-3-(phenylsulfonyl)-7-piperazin-1-yl- 1H-indazole;
6-fluoro-3-(phenyisulfonyl)-7-piperazin-1-yl- 1H-indazole;
4-chloro-3-(phenylsulfonyl)-5-piperazin-1-yl- 1H-indazole;
7-fluoro-3-(phenylsulfonyl)-5-piperazin-1-yl- 1H-indazole;
6-f luoro-3-(phenylsulfonyl)-5-piperazin-1-yl- 1H-indazole;
6-(4-phenethylpiperazin-1 -yl)-3-(phenylsulfonyl)- 1H-indazole;
6-(4-methylpiperazin-1-yl)-3-(phenylsulfonyl)- 1H-indazole;
6-(4-propylpiperazin-1-yl)-3-(phenylsulfonyl)- 1H-indazole;
3-(phenylsulfonyl)-6-piperazin-1-yl- 1H-indazole;
4-piperazin-1-yl-3-(phenylsulfonyl)- 1H-indazole;
4-(4-methylpiperazin-1-yl)-3-(phenylsulfonyl)- 1H-indazole;
4-(4-propylpiperazin-1-yl)-3-(phenylsulfonyl)- 1H-indazole;
3-(phenylsulfonyl)-4-piperazin-1-yl- 1H-indazole;
3-[(5-chlorothien-2-yl)sulfonyl]-5-piperidin-1-yl- 1H-indazole;
3-[(5-chlorothien-2-yl)sulfonyl]-7-piperidin-1 -yl- 1H-indazole;
1 -methyl-3-(phenylsulfonyl)-5-piperidin-1 -yl- 1H-indazole;
3-[(3-fluorophenyl)sulfonyl]-5-piperidin-1 -yl- 1H-indazole;
-11-

1 -methyl-3-(phenylsulfonyl)-7-(4-methylpiperidin-1 -yl)- 1H-indazole;
3-[(3-fluorophenyl)sulfonyl]-7-piperidin-1 -yl- 1H-indazole;
3-[(3"fluorophenyl)sulfonyl]-5-piperidin-1 -yl- 1H-indazole;
3-(phenylsulfonyl)-5-piperidin-1 -yl- 1H-indazole;
1 -methyl-3-[(3-fluorophenyl)sulfonyl]-7-piperidin-1 -yl- 1H-indazole;
3-(phenylsulfonyl)-7-piperidin-1 -yl-1H-indazole;
the stereoisomers thereof; or
the pharmaceutically acceptable salts thereof.
This invention also provides processes for preparing compounds of formula
(I) or salts thereof, which processes include one of the following
(a) diazotising and cyclising a compound of formula (VIIA):

wherein the dotted line, m, n, p, A, R1 R2, R4, R5, R6 and R7 are as defined herein,
e.g.with NaNO2/acid to give a compound of formula (I) wherein R3 is hydrogen,
or
(b) alkylating or arylating a protected compound of formula (IA)

-12-

wherein the dotted line, m, n, p, A, R1, R2, R5, R6 and R7 are as defined herein and P
is a protecting group or R4 where R4 is as defined herein excepting hydrogen, with an
alkylating or arylating agent of formula R3-LG where LG is a leaving group and R3 is
a C1-C6alkyl, C3-C7cycloalkyl, aryl or heteroaryl group each optionally substituted;
and if required removing the protecting group, to give a corresponding compound of
formula (I) where R3 is a C1-C6alkyl, C3-C7cycloalkyl, aryl or heteroaryl group each
optionally substituted;
or
(c) alkylating a compound of formula (IB)

wherein the dotted line, m, n, p, A, R1, R2, R3, R5, R6 and R7 are as defined herein,
with an alkylating agent of formula R4-LG where LG is a leaving group and R4 is a C1-
C6alkyl or C3-C7cycloalkyl group each optionally substituted, to give a corresponding
compound of formula (I) where R4 is a C1-C6alkyl or C3-C7cycloalkyl group each
optionally substituted;
or
(d) reacting a compound of formula (XII):

wherein m, R1, R2 and R3 are as defined herein, and LG' is a leaving group such as
Cl, Br, I or an activated hydroxyl group such as triflate, with a compound of formula
(V):
-13-


wherein n, p, R4, R5, R6 and R7 are as defined herein, in the presence of a catalyst,
e.g., a palladium or nickel catalyst, to give a corresponding compound of formula (I);
or
(e) reducing a compound of formula (XII):

wherein m, n, p, R1; R2, R5, R6 and R7 are as defined herein, P is a protecting group
or R4 as defined in claim 1 and P' is a protecting group or R3 as defined herein, if
required removing any protecting group, to give a corresponding compound of
formula (I) wherein A is CH;
or
(f) acidifying a compound of formula (XII):

wherein m, n, p, R1, R2, R5, R6 and R7 are as defined herein, P is a protecting group
or R4 as defined herein and P' is a protecting group or R3 as defined herein, if
-14-

required removing any protecting group, to give a corresponding compound of
formula (I) wherein A is C and = represents a double bond;
or
(g) converting a basic compound of formula (I) as defined herein to an
acid addition salt thereof or vice versa.
or
(h) separating a stereoisomer of a compound of formula (I) from a mixture
thereof.
In particular compounds of the invention may be conveniently prepared using
conventional synthetic methods and, if required, standard separation or isolation
techniques. For example, compounds of formula I wherein A is N; R3 is H; and =
represents a single bond (la) may be prepared by reacting a halonitrobenzene
compound of formula II with a chloromethylsulfone of formula III in the presence of
strong base, such as KO-t-Bu or KOH, to give the benzylsulfonyl compound of
formula IV; reacting said formula IV compound with a piperazine or homopiperazine
of formula V in the presence of a base such as K2CO3 to give the compound of
formula VI; reacting said formula VI compound with a reducing agent such as Sn, Fe
or Zn in the presence of an acid to give the corresponding amine of formula VII; and
reacting said amine with NaNO2 in the presence of an acid to give the desired
compound of formula la. The reaction is illustrated in flow diagram I wherein Hal
represents Cl or F.
-15-


Compounds of formula la wherein R3 is other than H may be prepared using
conventional alkylation/deprotection procedures. For example, compounds of
formula I wherein A is N; R3 is other than H; and = represents a single bond (Ib)
may be prepared by reacting a protected compound of formula VIII with an alkylating
agent of formula IX in the presence of a base and a solvent optionally in the
presence of a phase-transfer agent to give the protected alkylated compound of
formula X and deprotecting said formula X compound to give the desired compound
-16-

of formula Ib wherein R4 is H. Alternatively, for those compounds wherein R3 is an
aryl or heteroaryl group, the agent of formula IX may be an aryl or heteroaryl boronic
acid and may be coupled with the formula VIII indazole in the presence of a catalyst,
e.g., Cu(OCOCH3)2 to give the corresponding protected compound of formula X
wherein R3 is an aryl or heteroaryl group. Optionally the formula lb compound may
be reacted with an alkylating agent of formula XI under standard alkylation conditions
to give the compound of formula Ib wherein R4 is other than H. If desired, the
sequence may be reversed by deprotecting the formula VIII compound to give the
compound of formula la wherein R3 and R4 are H (Ic) and alkylating the formula Ic
compound with the formula XI alkylating agent to give the compound of formula Id.
Optionally, the formula Id compound may be reacted with a formula IX alkylating
agent, as described hereinabove, to give the compound of formula Ib. The reactions
are shown in flow diagram II wherein P is a protecting group and LG is a leaving
group such as Cl, Br, I, OH, B(OH)2, tosyl, mesyl or the like.
-17-

FLOW DIAGRAM II

Alternatively, compounds of formula Ib may be prepared directly from an
compound of formula XII by coupling said formula XII compound with the
appropriate piperazine or homopiperazine compound of formula V in the presence of
a catalyst such as a palladium or nickel catalyst. The reaction is shown in flow
diagram lll wherein LG' is a leaving group such as Cl, Br, I or an activated hydroxyl
group such as CF3SO3 (triflate).
-18-


FLOW DIAGRAM III
Compounds of formula VIII may also be prepared by reacting a protected 3-
iodoindazole of formula XIII with a sodium sulfinate of formula XIV in the presence of
copper iodide and dimethyl formamide (DMF) to give the desired compound of
formula VIII or by reacting the formula XIII compound with a thiol of formula XV in the
presence of copper iodide and a base, such as K2CO3, to give the thio ether of
formula XVI and oxidizing said formula XVI compound to give the desired compound
of formula VIII. The reactions are shown in flow diagram IV wherein P represents a
protecting group.


Compounds of formula XIII wherein R1, is H (Xllla) may be prepared by
reacting a dihalobenzaldehyde of formula XVII with the piperazine or homopiperazine
compound of formua V wherein R4 is a protecting group (Va) to give the ortho
halobenzaldehyde compound of formula XVIII, reacting the formula XVIII compound
with hydrazine hydrate to give the indazole of formula XIX and reacting the formula
XIX indazole with iodine in the presence of a base, such as KOH, to give the desired
formula Xllla compounds. The reactions are shown in flow diagram V wherein P is a
protecting group and Hal is F, Cl, Br, or I, preferably F.
FLOW DIAGRAM V

Compounds of formula XIII wherein n is 1 and R5, R6 and R7 are H (Xlllb) may
be prepared by reacting an indazole amine of formula XX with di(2-chloroethyl)amine
hydrochloride to give the corresponding piperazinyl indazole of formula XXI,
protecting said formula XXI compound and reacting the protected formula XXI
compound with iodine in the presence of a base, such as KOH, to give the desired
-20-

compound of formula Xlllb. The reactions are shown in flow diagram VI whereing P
epresents a protecting group.
FLOW DIAGRAM VI

Compounds of X!!!a and Xlllb may be converted to compounds of formula la,
Ib, or Ic as shown hereinabove in flow diagrams II and III.
Corresponding compounds of the invention wherein A is CR8 may be
obtained, for example, by lithiating a protected bromoindazole of formula XXII, and
reacting the lithiated compound in situ with an N-protected azacyclic ketone of
formula XXIII to give the protected hydroxy compound of formula XXIV, said hydroxy
compound may then be dehydrated to give the protected compound of formula XXV.
Catalytic hydrogenation and subsequent deprotection of said formula XXV compound
gives the desired compounds of formula I wherein A is CR8; R3 and R4 are H1 and =
represents a single bond (Id). The reaction sequence is shown in flow diagram VII
wherein P and P' each independently represent a protecting group.

FLOW DIAGRAM VII

Using the procedures shown in flow diagram II hereinabove, the compounds
of formulas XXIV, XXV and Id may be readily converted to compounds of formula I
wherein A is CR8 and R3 or R4 are other than H.
Alternatively, compounds of formula I wherein A is C or CR8 and R3 is H (le)
may be prepared by reacting a chloromethylsulfonyl compound of formula III with a
nitrobenzene derivative of formula XXVI in the presence of a strong base, such as
KO-t-Bu or KOH, to provide the compound of formula XXVII; reducing said formula
XVII compound with a reducing agent such as Sn, Fe or Zn in the presence of an
acid to give the corresponding amine of formula XXVIII; and reacting said amine with
NaNO2 in the presence of an acid to give the desired indazole compound of formula
le. The reactions are shown in flow diagram VIII.
-22-

FLOW DIAGRAM VIII

Compounds of formula le may be converted to the corresponding compounds
of formula I wherein A is C or CR8 and R3 is other than H by reacting said formula le
compound with an alkylating agent as shown hereinabove in flow diagram II.
Protecting groups suitable for use in the reactions shown hereinabove include
t-butyloxycarbonyl, benzyl, acetyl, benzyloxycarbonyl, or any conventional group
known to protect a basic nitrogen in standard synthetic procedures.
Advantageously, the formula I compounds of the invention are useful for the
treatment of CNS disorders relating 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
-23-

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
the attending physician or 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.
-24-

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
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.
Unless otherwise stated, all parts are parts by weight. The term NMR
designates proton nuclear magnetic resonance. The terms THF, DMF and DMSO
designate tetrahydrofuran, dimethyl formamide and dimethylsulfoxide, respectively.
In the chemical drawings, the term Ph represents a phenyl group.
-25-

EXAMPLE 1
Preparation of 1-Benzvl-4-(4-nitrophenyl)piperazine

A stirred solution of 1-benzylpiperazine (8.81 g, 50.0 mmol), 4-
fluoronitrobenzene (5.31 mL, 50.0 mmol), and K2CO3 (6.90 g, 50.0 mmol) in ethanol
is heated at reflux temperature under nitrogen for 18 h, cooled, diluted with water,
and extracted with CH2CI2. The combined extracts are dried over MgSO4 and
concentrated in vacuo to give a solid residue. The solid is triturated with 20:80 ethyl
acetate:hexanes and filtered. The filtercake is air-dried to afford the title compound
as orange crystals, 8.45 g (57% yield), mp 218-219°C, characterized by NMR and
mass spectral analyses.
EXAMPLE 2
Preparation of 1-Benzvl-4-{4-nitro-3-[(phenvlsulfonyl)methvl]phenvI}piperazine

A stirred solution of 1-benzyl-4-(4-nitrophenyl)piperazine (5.95 g, 20.0 mmol)
and chloromethylphenylsulfone (3.82 g, 20.0 mmol) in dry THF under nitrogen at
-60°C is treated with 1.0M KO-t-Bu in THF (44.0 mL, 44.0 mmol), warmed to -20°C
over a 1 h period, quenched with acetic acid and treated sequentially with water,
saturated aqueous NaHCO3 and ether. The phases are separated and the aqueous
phase is extracted with ether. The combined ethers are washed with water and
brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is
-26-

chromatographed (silica gel, 1:1 and 1:0 ethyl acetate:hexanes as eluent) to give the
title compound as a yellow solid, 7.52 g (83% yield), mp 145-146°C, characterized by
NMR and mass spectral analyses.
EXAMPLE 3
Preparation of 4-(4-Benzvlpiperazin-1-vl)-2-[(phenylsulfonvl)methyl]aniline

A mixture of 1-benzyl-4-{4-nitro-3-[(phenylsulfonyl)methyl]phenyl}piperazine
(6.77 g, 15.0 mmol) and granular tin (7.48 g, 63.0 mmol) in methanol and cone,
hydrochloric acid is heated at 45°C for 4 h, stirred at ambient temperature for 18 h,
carefully poured into saturated aqueous NaHCO3, treated with ether and stirred for
0.5 h. The phases are separated and the aqueous phase is extracted sequentially
with ether and CH2CI2. The extracts and organic phase are combined, dried over
MgSO4 and concentrated in vacuo. The resultant residue is dissolved in CH2CI2 and
filtered through Celite®. The filtrate is concentrated in vacuo to afford the title
compound as a pale yellow solid, 6.11 g (97% yield), mp 141-143°C, characterized
by NMR and mass spectral analyses
EXAMPLE 4
Preparation of 5-(4-Benzylpiperazin-1-yl)-3-(phenvlsuIfonyl)-1H-indazole
hydrochloride
-27-


A stirred solution of 4-(4-benzylpiperazin-1-yl)-2-[(phenylsulfonyl)methyl]-
aniline (0.371 g, 0.88 mmol) in 4.0 M aqueous hydrochloric acid is cooled in an ice
bath, treated dropwise with NaNO2 (91 mg, 1.32 mmol) in water, stirred for 40 min,
treated with 2.5 M aqueous NaOH to pH ~ 14 and filtered. The filtercake is dissolved
in CH2CI2, and chromatographed (silica gel, ethyl acetate as eluent) to afford the free
indazole of the title product as a yellow solid (276 mg, 64%). The solid is dissolved in
a mixture of ethanol and CH2CI2, treated with 4.0 M HCI in dioxane, and concentrated
in vacuo to give a solid residue. The residue is triturated with ethyl acetate to afford
the title product as an off-white solid, 278 mg (57% yield), mp 177-180°C, identified
by NMR and mass spectral analyses.
EXAMPLE 5
Preparation of 5-(4-Benzylpiperazin-1-yl)-3-r(3-fluorophenyl)sulfonyn-1H-
indazole hydrochloride

Using essentially the same procedures described hereinabove for Examples
2 - 4 and employing chloromethyl-(3-fluorophenyl)sulfone, the title compound is
obtained as an off-white solid, mp 157-160°C, identified by NMR and mass spectral
analyses.
-28-

EXAMPLE 6
Preparation of 1-Benzyl-4-(3-methoxy-4-nitrophenyl)piperazine

A stirred solution of 1-benzylpiperazine (3.53 g, 20.0 mmol), 4-chloro-3-
methoxy-nitrobenzene (3.75 g, 20.0 mmol), and K2CO3 (2.76 g, 20.0 mmol) in DMF is
heated at 85° to 100°C under nitrogen for 23 h, cooled to room temperature, treated
with 2M aqueous hydrochloric acid, diluted with water and extracted with ether. The
combined extracts are washed with brine, dried over MgSO4 and concentrated in
vacuo. The resultant residue is chromatographed (silica gel, 30:70 ethyl
acetate:hexanes and 50:50 ethyl acetate:hexanes as eluent) to afford the title
compound as a yellow-orange oil 2.64 g (57% yield), identified by NMR analysis.
EXAMPLE 7
Preparation of 5-(4-Benzylpiperazin-1-yl)-6-methoxy-3-(phenylsulfonyl)-1 H-indazole
hydrochloride

Using essentially the same procedures described hereinabove for Examples
2-4 and employing 1-benzyl-4-(2-methoxy-4-nitrophenyl)piperazine as starting
-29-

substrate, the title compound is obtained as a tan solid, 70 mg, mp 185-187°C,
identified by NMR and mass spectral analyses.
EXAMPLE 8
Preparation of 5-(4-Benzylpiperazin-1-yl)-6-methoxy-1-phenyl-3-(phenyl-
sulfonyl)-1H-indazole hydrochloride

A mixture of 5-(4-benzylpiperazin-1 -yl)-6-methoxy-3-(phenylsulfonyl)-1H-
indazole (448 mg, 0.97 mmol), phenylboronic acid (242 mg, 1.94 mmol), copper(ll)
acetate (271 mg, 1.50 mmol), pyridine (160 mg, 2.00 mmol) and 4A molecular sieves
(1.0 g) in methylene chloride is stirred at room temperature for 48 h and filtered. The
filtercake is washed with THF. The filtrates are combined and concentrated in vacuo.
The resultant residue is chromatographed (silica gel, 60:40 and 80:20 ethyl
acetate:hexanes as eluents) to afford the free amine of the title product as a white
solid, 130 mg (25% yield). The free amine is dissolved in ethanol, treated with 4.0 M
HCI in dioxane, and concentrated in vacuo to a solid residue. This solid is triturated
with ethyl acetate to afford the title product as a white solid, mp: 210-212°C,
identified by NMR and mass spectral analyses.
-30-

EXAMPLE 9
Preparation of 6-Methoxy-1 -phenyl 3-(phenylsulfonyl)--5-piperazin-1-vl-1H-indazole
hydrochloride

A mixture of 5-(4-benzylpiperazin-1-yl)-6-methoxy-1-phenyl-3-(phenyl-
sulfonyl)-1 H-indazole_(190 mg, 0.353 mmol) and 1 -chloroethylchloroformate (250 mg,
1.77 mmol) in 1,2-dichloroethane is heated at reflux temperature for 4 h, cooled to
room temperature and concentrated to dryness. The resultant residue is dissolved in
ethanol, heated at reflux temperature for 16 h and concentrated in vacuo to give the
title compound as a white solid, 130 mg, (82% yield). This compound is purified by
recrystalization from ethanol/ether to afford a white solid, mp 167-170°C, identified by
NMR and mass spectral analyses.
EXAMPLE 10
-31-
Preparation of 6-Methoxy-3-(phenylsulfonyl)-5-(piperazin-1 -yl)-1 -[4-
(trifluoromethyl)phenyl]-1H-indazole hydrochloride


Using essentially the same procedures described in Examples 8 and 9
hereinabove and employing 4-(trifluoromethyl)phenyl boronic acid, the title product is
obtained as a white solid, mp 175-177°C, identified by NMR and mass spectral
analyses.
EXAMPLE 11
Preparation of 5-(4-Benzylpiperazin-1-yl)-1-methvl-3-(phenvlsulfonyl)-1H-
indazole

A solution of 5-(4-benzylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-indazole (433
mg, 1.00 mmol) in THF at room temperature is treated with NaH (80 mg, 60% in
mineral oil, 2.00 mmol), stirred for 0.5 h, treated with methyl iodide (142 mg, 1.00
mmol), stirred for 16 h, and diluted with water and EtOAc. The organic phase is
separated, dried over MgSO4, and concentrated in vacuo. The resultant residue is
chromatographed (SiO2, 90:10 EtOAc:hexanes as eluent) to afford the title
compound as a white solid, 190 mg (43% yield), mp 195-197°C, identified by mass
spectral and NMR analyses.
EXAMPLE 12
Preparation of 5-(4-Benzylpiperazin-1-yl)-1-ethyl-3-(phenylsulfonyl)-1 H-indazole
dihydrochloride
-3:


A mixture of 5-(4-benzylpiperazin-1 -yl)-3-(phenylsulfonyl)-1H-indazole (400
mg, 0.92 mmol), bromoethane (108 mg, 1.00 mmol) and K2CO3 (276 mg, 2.00 mmol)
in DMF is stirred for 16 h at room temperature and diluted water and EtOAc. The
organic phase is separated, dried over MgSO4, and concentrated in vacuo. The
resultant residue is chromatographed (SiO2, 80:20, then 90:10 EtOAc:hexanes as
eluent) to afford the free amine of the title product as a white solid, 230 mg. A portion
of this solid (115 mg, 0.25 mmol) is dissolved in ethanol, treated with 4M HCI in
dioxane and concentrated in vacuo to give the title compound as a white solid, mp
>250°C, identified by mass spectral and NMR analyses.
EXAMPLES 13-93
Preparation of 3-Arylsulfonyl- -5-piperazinylindazole Derivatives

Using essentially the same procedures described in Examples 2-12
hereinabove and employing the appropriate 4-nitrophenylpiperazine as substrate and
suitable chloromethylarylsulfone as reactant, the compounds shown on Table I are
obtained and identified by HNMR and mass spectral analyses.
-33-

TABLE I

-34-

TABLE I, cont.

-35-

TABLE I. cont.

-36-

TABLE 1, cont.

-37-

EXAMPLE 94
Preparation of 1-(5-Chloro-2-nitrophenyl)-4-methylpiperazine

A mixture of 4-chloro-2-fluoro-nitrobenzene (28.5 mmol), 1-methylpiperazine
(28.5 mmol) and K2CO3 (37.0 mmol) in DMF is stirred at 100° C for 16 h and diluted
with water and EtOAc. The phases are separated and the aqueous phase is
extracted with EtOAc. The organic phase and the extracts are combined, washed
sequentially with water and brine, dried over Na2SO4 and dried in vacuo. The
resultant residue is chromatographed (SiO2, 10% methanol in EtOAc as eluent) to
afford the title product.
EXAMPLE 95
Preparation of 1-{5-Chloro-2-nitro-3-{[(4-fluorophenyl)sulfonyl]methvl}phenvl}-
4-methylpiperazine

A stirred mixture of 1-(5-chloro-2-nitrophenyl)-4-methylpiperazine (1.0 mmol)
and 4-fluorobenzylsulfonyl chloride (1.0 mmol) in THF is treated with 2.2 mL of a 1M
KOt-Bu (2.2 mmol) solution in THF at -78° C, warmed to room temperature over a 2 h
period, quenched with acetic acid and concentrated in vacuo. The resultant residue
is partitioned between EtOAc and aqueous Na2CO3. The phases are separated and
-38-

the aqueous phase is extracted with EtOAc. The organic phase is combined with the
extracts, dried over Na2SO4 and concentrated to dryness in vacuo to afford the title
product.
EXAMPLE 96
Preparation of 4-Chloro-2-{[(4-fluorophenvl)sulfonvl]methyl}-6-(4-
methylpiperazin-1-yl)aniline

A solution of 4-chloro-2-{[(4-fluorophenyl)sulfonyl]methyl}-6-(4-
methylpiperazin-1-yl)aniline (1.0 mmol) in methanol is treated with Sn foil (593.3 mg),
followed by 5.8 mL of 12 M HCI, heated at 60° C for 4 h (until reaction is complete by
thin layer chromatography), cooled to 0°C, treated with solid NaOH to pH >10 and
extracted with CH2CI2. The extracts are combined, washed with water and
concentrated to dryness in vacuo to give the title compound.
EXAMPLE 97
Preparation of 5-Chloro-3[(4-fluorophenvl)sulfonyl]-7-(4-methvlpiperazin-1-vl)-
1H-indazole
-39-


A solution of NaNO2 (2.0 mg) in water at 0° is treated dropwise with a solution
of 4-chloro-2-{[(4-fluorophenyl)sulfonyl]methyl}-6-(4-methylpiperazin-1-yl)aniline
(102.2 mg, 0.25 mmol) in 1M HCI, allowed to warm to room temperature over a 2 h
period, treated with saturated Na2CO3 to pH >10 and filtered. The filtercake is
washed with water and dried in vacuo to give the title compound, identified by mass
spectral and NMR analyses.
EXAMPLE 98-101
Preparation of 3 (Arylsulfonyl)-7-(4-methylpiperazin-1-yl)-1H-indazole
Derivatives

Using essentially the same procedures described hereinabove in Examples
95-97 and employing the appropriate arylsulfonyl chloride, the compounds shown in
Table II are obtained and identified by mass spectral and NMR analyses.
-40-


A stirred solution of 2,6-difIuorobenzaldehyde 5 (10.0 g, 70 mmol) in N,N-
dimethylformamide is treated with tert-butyl piperazine-1-carboxylate (Boc) 6 (14.4 g,
77.0 mmol) and potassium carbonate (11.7 g, 85.0 mmol), stirred at 80 °C for 16 h,
cooled to ambient temperature, diluted with water and extracted with methylene
chloride. The extracts are combined, washed sequentially with water and brine, dried
over sodium sulfate, and concentrated in vacuo to afford a crude oil. This oil is
purified by column chromatography (silica gel, 15:85 ethyl acetate/hexanes) to afford
-41-

the title compound as a yellow solid, 15.5g (71% yield), identified by NMR and mass
spectral analyses.
EXAMPLE 103
Preparation of 4-f4-(t-Butoxycarbonyl)piperazin-1 -yl]-1H-indazole

A solution of 7 (20.0 g, 64.9 mmol) and hydrazine monohydrate (30 mL) in
methyl sulfoxide is stirred at 95 °C for 96 h, cooled to room temperature, partitioned
between saturated sodium bicarbonate and ether. The phases are separated and
the aqueous phase is extracted with ether. The extracts are combined with the
organic phase, washed sequentially with water and brine, dried over sodium sulfate
and concentrated in vacuo to a crude residue. This residue is purified by column
chromatography (silica gel, 10:90 to 30:70 ethyl acetate/hexanes) to afford the title
compound as a light yellow solid, 12.3 g (57% yield), identified by NMR and mass
spectral analyses.
EXAMPLE 104
Preparation of 4-[4-(t-Butoxycarbonyl)piperazin-1-yl]--3-iodo-1H-indazole

A solution of 4-[4-(t-butoxycarbonyl)piperazin-1-yl]-1 H-indazole (5.00 g, 16.5
mmol) in N,N,-dimethylformamide is treated with powdered potassium hydroxide
-42-

(1.85 g, 33.07 mmol) and iodine (4.61 g, 18.2 mmol), stirred at room temperature for
16 h, diluted with ethyl acetate and quenched with 15% aqueous sodium
metabisulfite. The phases are separated and the aqueous phase is extracted with
ethyl acetate. The extracts and the organic phase are combined, washed with brine,
dried over sodium sulfate and concentrated in vacuo to afford a crude solid. This
solid is purified by column chromatography (silica gel, 10:90 to 15:85 to 20:80 ethyl
acetate/hexanes) to afford the title product as a yellow solid, 2.40 g (35% yield)
identified by HNMR and mass spectral analyses.
EXAMPLE 105
Preparation of 4-[4-(t-Butoxycarbonyl)piperazin-1-yl]--3-(phenylsulfonvl)-1H-indazole

A mixture of 4-[4-(t-butoxycarbonyl)piperazin-1-yl]--3-iodo-1H-indazole (0.110
g, 0.257 mmol), sodium benzene sulfinate (0.068 g, 0.411 mmol), copper(l) iodide
(0.073 g, 0.386 mmol) and /V,/V-dimethylformamide is added to a screw-capped test-
tube with Teflon-lined septum. The tube is evacuated and backfilled with argon. This
procedure is repeated twice, then the tube is heated to 125 °C for 4 h. The reaction
mixture is cooled, partitioned between ethyl acetate and water and filtered through a
pad of diatomaceous earth. The filtrate is separated. The organic phase is washed
with brine, dried over sodium sulfate and concentrated in vacuo. The resulting crude
material is purified by column chromatography (silica gel, 40:60 ethyl
acetate/hexanes) to afford the title compound as a pale yellow foam, 0.022 g (18%
yield), identified by NMR and mass spectral analyses.
-43-

EXAMPLE 106
Preparation of 3-(Phenylsulfonyl)-4-piperazin-1-vl-1H-indazole Hvdrochloride

A solution of 4-[4-(t-butoxycarbonyl)piperazin-1-yl]--3-(phenylsulfonyl)-1H-
indazole (0.022 g, 0.050 mmol) in methanol is treated with a 2 M solution of HCI in
ether (0.4 mL), heated at reflux temperature for 1 h, cooled to room temperature and
evaporated to dryness. The residue is re-dissolved in methanol and concentrated.
Repeating this procedure three more times affords the title product as a white solid,
0.009 g (40% yield), identified by NMR and mass spectral analyses.
EXAMPLE 107
Preparation of 4-r4-t-Butoxvcarbonvl)piperazin-1 -vl)-3-(1 -naphthylthio)-1H-indazole

A mixture of 4-[4-(t-butoxycarbonyl)piperazin-1 -yl]--3-iodo-1H-indazole (0.068
g, 0.159 mmol) copper(l) iodide (0.005 g, 0.024 mmol) and potassium carbonate
(0.044 g, 0.318 mmol) are added to a screw-capped test tube with a Teflon-lined
septum. The tube is evacuated and backfilled with argon and this procedure
repeated twice more. The reaction mixture is treated sequentially with 2-propanol
-44-

(1.5 mL), ethylene glycol (19 L, 0.318 mmol) and 1-naphthalenethiol (0.051 g,
0.318 mmol), heated at 130°-140° C for 8 h, cooled to room temperature, diluted with
ethyl acetate and filtered through diatomaceous earth. The filtrate is concentrated
under reduced pressure. The resultant crude material is purified by flash
chromatography (silica gel, 40:60 ethyl acetate/hexanes) to afford the title compound
as a colorless oil, 0.033 g (45% yield), identified by NMR and mass spectral
analyses.
EXAMPLE 108

10

Preparation of 4-[4-(t-Butoxycarbonyl)piperazin-1 -vl]--3-(1 -naphthylsulfonyl)-1 H-
indazole


15 A stirred solution of 4-[4-t-butoxycarbonyl)piperazin-1 -yl)-3-(1 -naphthylthio)-
1H-indazole (0.030 g, 0.065 mmol) in glacial acetic acid is treated with 35% aqueous
hydrogen peroxide (0.127 g, 1.30 mmol) stirred for 24 h, quenched with 10%
aqueous sodium metabisulfite solution (1 mL) and concentrated in vacuo. The
resulting solid is directly added to a suspension of 10% palladium-on-carbon (3 mg)
20 in methanol (10 mL) and the mixture is shaken on a Parr hydrogenator under a 40 psi
hydrogen atmosphere for 2 h and filtered through diatomaceous earth. The filtrate is
concentrated in vacuo. Purification of the resulting crude material by flash
chromatography (silica gel, 30:70 ethyl acetate/hexanes) affords the title compound
as a colorless oil, 0.011 g (35% yield), identified by NMR and mass spectral
5 analyses.
-45-

EXAMPLE 109
Preparation of 3-(1-Naphthylsulfonyn-4-piperazin-1-yl-1 H-indazole Hydrochloride

Using essentially the same procedure described in Example 106 hereinabove
and employing 4-[4-(t-butoxycarbonyl)piperazin-1 -yl]-3-(1-naphthylsulfonyl)-1 H-
indazole as substrate, the title product is obtained as a light yellow solid (74% yield),
mp 220°C dec, identified by NMR and mass spectral analyses.
EXAMPLES 110-114
Preparation of 3-(Arylsulfonyl)-4-piperazin-1-yl-1H-indazole Hvdrochloride
Derivatives

Using essentially the same procedures described in Examples 102-109
hereinabove and employing the appropriate arylthiol or arylsulfinate, the compounds
shown on Table III are obtained and identified by NMR and mass spectral analyses.
TABLE III
-46-


EXAMPLE 115
Preparation of 6-[4-t-Butoxycarbonyl)piperazin-1-yl]-1H-indazole

A stirred solution of 6-aminoindazole (13.3 g, 100 mmol) in n-butanol is
treated with bis(2-chloroethyl)amine hydrochloride (28.6 g, 160 mmol) and potassium
carbonate (34.6 g, 250 mmol), heated to reflux temperature for 72 h, cooled to room
temperature and concentrated in vacuo. A stirred solution of the resultant crude
material in 1,4-dioxane at 0° C is treated with 1 N sodium hydroxide solution (200 mL)
and di-tert-butyldicarbonate (34.9 g, 160 mmol), stirred at ambient temperature for
24 h and concentrated in vacuo to afford a crude oil. This oil is partitioned between
-47-

ethyl acetate and water. The organic layer is separated, washed with brine, dried
over sodium sulfate and concentrated in vacuo. Further purification of this resultant
residue by flash chromatography (silica gel, 40:60 ethyl acetate/hexanes) affords the
title compound as a colorless oil, 11.5 g (38% yield) identified by NMR and mass
spectral analyses.
EXAMPLE 116
Preparation of 6-[4-t-Butoxycarbonyl)piperazin-1-yl]-3-iodo-1H-indazole

A stirred solution of 6-[4-t-butoxycarbonyl)piperazin-1-yl]-1 H-indazole (7.20 g,
23.8 mmol) in N,N-dimethylformamide at 0°C is treated with powdered potassium
hydroxide (5.40 g, 95.4 mmol) followed by the dropwise addition of a solution of
iodine (10.9 g, 42.9 mmol) in N,N-dimethylformamide, stirred at ambient
temperatures for 16 h, diluted with ethyl acetate and quenched with 10% aqueous
sodium metabisulfite solution. The phases are separated. The aqueous phase is
extracted with ethyl acetate. The extracts are combined with the organic phase,
washed with brine, dried over sodium sulfate and concentrated in vacuo. The
resulting crude material is purified by flash chromatography (silica gel, 30:70 ethyl
acetate/hexanes) to afford the title compound as a yellow solid, 11.5 g (38% yield)
identified by NMR and mass spectral analyses.
-48-

EXAMPLE 117
Preparation of 6-[4-t-Butoxycarbonyl)piperazin-1-yl]-3-(phenylsulfunoyl)-1 H-indazole

Using essentially the same procedure described in Example 105 hereinabove
and employing of 6-[4-t-butoxycarbonyl)piperazin-1-yl]-3-iodo-1H-indazoIe and
sodium benzenesulfinate affords the title compound as a colorless foam (80% yield),
identified by NMR and mass spectral analyses.
EXAMPLE 118
Preparation of 3-(Phenylsulfonyl)- 6-piperazin-1-yl-1H-indazole Hydrochloride

Using essentially the same procedure described in Example 106 hereinabove
and employing 6-[4-t-butoxycarbonyl)piperazin-1-yl]-3-(phenylsulfonyl)-1 H-indazole
as substrate, the title compound is obtained as an off-white solid (81% yield),
identified by NMR and mass spectral analyses.
-49-

EXAMPLES 119-124
Preparation of 3-(Arylsulfunoyl)- 6-piperazin-1-yl-1H-indazole Hydrochloride
Compounds

-50-
Using essentially the same procedures described in Examples 117 and 118
hereinabove and employing the appropriate arylsulfinate, the compounds shown in
Table IV are obtained and identified by NMR and mass spectral analyses.


EXAMPLE 125
Preparation of 6-[4-t-Butoxycarbonyl)piperazin-1 -yl)-3-(1 -naphthylthio)-1 H-indazole

Using essentially the same procedure described in Example 107 hereinabove
and employing 6-[4-t-butoxycarbonyl)piperazin-1-yl)-3-iodo-1H-indazole as substrate,
the title compound is obtained as a colorless oil (78% yield), identified by NMR and
mass spectral analyses.
EXAMPLE 126
Preparation of 6-[4-t-Butoxycarbonyl)piperazin-1 -yl)-3-(1-naphthylsulfonyl)-1H-
indazole

A stirred solution of 6-[4-t-butoxycarbonyl)piperazin-1-yl)-3-(1-naphthylthio)-
1H-indazole (0.240 g, 0.521 mmol) in methylene chloride is treated with meta-
chloroperoxybenzoic acid (mcpba) (77% pure, 0.350 g, 1.56 mmol) and sodium
-51-

bicarbonate (0.219 g, 2.61 mmol), stirred at ambient temperatures for 16 h and
partitioned between ethyl acetate and water. The phases are separated and the
aqueous phase is extracted with methylene chloride. The extracts and the organic
phase are combined, washed sequentially with 10% aqueous sodium bicarbonate
solution and brine, dried over sodium sulfate and concentrated in vacuo to afford a
crude oil. This oil is added to a suspension of 10% palladium-on-carbon (40 mg) in
methanol and shaken on a Parr hydrogenator under a 40 psi hydrogen atmosphere
for 2 h and filtered through diatomaceous earth. The filtrate is concentrated in vacuo.
The resulting crude material is purified by flash chromatography (silica gel, 50:50
ethyl acetate/hexanes) to afford the title compound as a colorless oil, 0.106 g (41%
yield), identified by NMR and mass spectral analyses.
EXAMPLE 127
Preparation of 3-(1-Naphthylsulfonyl)- 6-piperazin-1-vl-1H-indazole Hydrochloride

Using essentially the same procedure described in Example 106 hereinablove
and employing of 6-[4-t-butoxycarbonyl)piperazin-1-yl)-3-(1-naphthylsulfonyl)-1H-
indazole as substrate, the title product is obtained as a white solid (98% yield), mp
205-210 °C, identified by NMR and mass spectral analyses.
-52-

EXAMPLE 128
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
centrif uged 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 10-25 μl 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 cell membranes is adjusted to give a tissue protein concentration of 1.0
mg/ml of suspension. The prepared membrane suspension (10 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 200 Μl. TO each well is added the following mixture: 80.0 μI of
incubation buffer made in 50 mM Tris.HCI buffer (pH 7.4) containing 10.0 mM MgCI2
and 0.5 mM EDTA and 20 μl 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
100.0 Μl of tissue suspension. Nonspecific binding is measured in the presence of
10.0 ΜM methiothepin. The test compounds are added in 20.0 μl 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
-53-

on the filter disk is allowed to air dry and the radioactivity is measured in a Packard
TopCount® equipped with six photomultiplier detectors, after the addition of 40.0μl
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 10.0μM 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® yields
both the IC50 and the Ki values of test compounds with 95% confidence limits.
The amount of displacement by the test compound is given in percent (%)
inhibition and is derived from the following equation:
BO-NSB
% inhibition = (1 ) 100
TB - NSB
where Bo is the amount of CPM bound in the presence of the testing agent. NSB
represents the CPM bound in the presence of a saturating concentration of a
displacer and TB represents the total amount of CPM bound at zero (0) concentration
of test compound.
Alternatively, a linear regression line of data points is plotted, from which the
IC50 value is determined and the Ki 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 % inhibition and 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 TableV, below.
-54-


-55-


-56-


-57-

WE CLAIM:

wherein
A is C, CR8 or N;
R1 is H, halogen, CN, COR9, OCO2R10, CO2R11, CONR12R13, SOXR14,
NR15R16, OR17 or a C1-C6alkyl, C3-C7cycloalkyl, aryi or heteroaryl
group each optionally substituted;
R2 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, 0 or S ;
R3 is H or a C1-C6alkyl, C3-C7cycloalkyl, aryl or heteroaryl group each
optionally substituted;
R4 is H or a C1-C6alkyl or C3-C7cycloalkyl group each optionally substituted;
R5, R6 and R7 are each independently H or a C1-C6alkyl or C3-C7cycloalkyl
group each optionally substituted;
m and p are each independently an integer of 1, 2 or 3;
n is an integer of 1 or 2;
R8 is H, OH or an optionally substituted C1-C6alkoxy group;
R9, R10, R11 and R17 are each independently H or a C1-C6alkyl, C2-C6alkenyl,
C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl
group each optionally substituted;
-58-

R12, R13, R15 and R16 are each independently H or an optionally substituted
C1-C4alkyl group or R12 and R13 or R15 and R16 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;
R14 is a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R18 is H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl,
cycloheteroalkyl, aryl or heteraryl group each optionally substituted;
x is 0 or an integer of 1 or 2; and
— represents a single bond or a double bond; or a
stereoisomer thereof or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein n is 1.
3. A compound according to claim 1 or claim 2 wherein R4 is H or an
optionally substituted C1-C4alkyl group.
4. Acompound according to any one of claims 1 to 3 wherein R2 is an
optionally substituted phenyl, naphthyl or heteroaryl group.
5. A compound according to any one of claims 1 to 4 wherein the 6- or 7-
membered azacyclic ring is attached to the indazole in the 5 or 7 position.
6. A compound according to any one of claims 1 to 5 wherein A is N.
7. A compound according to any one of claims 1 to 6 wherein R3 is
selected from hydrogen, phenyl and C1-C4alkyl which may be substituted by
optionally substituted phenyl.
8. A compound according to any one of claims 1 to 7 wherein m is 1 and
R1 is hydrogen or halogen.
-59-

9. A compound according to claim 1 which is one of the following:
5-(4-methyIpiperazin-1-yl)-3-(1-naphthylsulfonyl)-1H-indazole;
3-(1 -naphthylsulfonyl)-5-piperazin-1-yl-1 H-indazole;
1-(3-chloroben2yl)-5-(4-methylpiperazin-1-yl)-3-(1-naphthyIsulfonyl)-1H-indazole,-
5 7-(4-methylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-indazole;
3-(phenylsulfonyl)-7-(4-propylpiperazin-1 -yl)- 1H-indazole;
3-(phenylsulfonyl)-7-piperazin-1 -yl- /H-indazole;
5-(4-methylpiperazin-1-yl)-3-(phenylsulfonyl)- 1H-indazole;
3-(phenylsulfonyl)-5-(4-propylpiperazin-1-yl)- 1H-indazole;
0 3-(phenylsulfonyl)-5-piperazin-1 -yl- 1H-indazole;
5-piperazin-1-yl-3-[(3-cyanophenyl)sulfonyl]- 1H-indazole;
7-(4-methylpiperazin-1-yl)-3-[(2-ethylphenyl)sulfonyl]-1H-indazole;
3-(1-naphthylsulfonyl)-7-(4-propylpiperazin-1-yl)- 1H-indazole;
5-(4-phenethylpiperazin-1-yl)-3-(1-naphthylsulfonyl)- 1H-indazole;
5 5-(4-methylpiperazin-1-yl)-3-(2-naphthylsulfonyl)- 1H-indazole;
3-[(2-chloro-4-fluorophenyl)sulfonyl]-5-piperazin-1-yl- 1H-indazole;
1-methyl-3-(phenylsulfonyl)-5-piperazin-1-yl-1H-indazole;
1-phenyl-3-(phenylsulfonyl)-5-piperazin-1-yl- 1H-indazole;
1-methyl-3-(phenylsulfonyl)-7-piperazin-1-yl - 1H-indazole;
1-phenyl-3-(phenylsulfonyl)-7-(piperazin-1-yl)- 1H-indazole;
7-piperazin-1-yl-3-[(3-fluorophenyl)sulfonyl]- 1H-indazole;
3-[(4-fluorophenyl)sulfonyl]-7-(4-methylpiperazin-1-yl)- 1H-indazole;
3-[(2-chlorophenyl)sulfonylj-7-piperazin-1-yl- 1H-indazole;
3-[(4-aminophenyl)sulfonyl]-7-(piperazin-1 -yl)- 1H-indazole;
5-piperazin-1 -yl-3-[(3-fluorophenyI)sulfonyl]- 1H-indazole;
3-[(4-fluorophenyl)sulfonyl]-5-(4-methylpiperazin-1-yl)- 1H-indazole;
3-[(2-chlorophenyl)sulfonyl]-5-(4-propylpiperazin-1-yl)- 1H-indazole;
3-[(4-aminophenyl)sulfonyl]-5-piperazin-1-yl- 1H-indazole;
3-[(5-chlorothien-2-yl)sulfonyl]-5-piperazin-1-yl- 1H-indazole;
3-[(5-chlorothien-2-yl)sulfonyl]-7-piperazin-1-yl- 1H-indazole;
4-chloro-3-(phenylsulfonyl)-7-piperazin-1-yl- 1H-indazole;
5-fluoro-3-(phenylsulfonyl)-7-piperazin-1-yl- 1H-indazole;
6-fluoro-3-(phenylsulfonyl)-7-piperazin-1 -yl- 1H-indazole;
-60-

4-chloro-3-(phenylsulf onyl)-5-piperazin-1-yl-1H-indazole;
7-fluoro-3-(phenylsulfonyl)-5-piperazin-1-yl- 1H-indazole;
6-fluoro-3-(phenylsulfonyl)-5-piperazin-1-yl- 1H-indazole;
6-(4-phenethylpiperazin-1-yl)-3-(phenylsulfonyl)- 1H-indazole;
5 6-(4-methylpiperazin-1-yl)-3-(phenylsulfonyl)- 1H-indazole;
6-(4-propylpiperazin-1-yl)-3-(phenylsulfonyl)- 1H-indazole;
3-(phenylsulfonyl)-6-piperazin-1-yl- 1H-indazole;
4-piperazin-1-yl-3-(phenylsulfonyl)- 1H-indazole;
4-(4-methylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-indazole;
0 4-(4-propylpiperazin-1-yl)-3-(phenylsulfonyl)- 1H-indazole;
3-(phenylsulfonyl)-4-piperazin-1-yl- 1H-indazole;
3-[(5-chlorothien-2-yl)sulfonyl]-5-piperidin-1-yl- 1H-indazole;
3-[(5-chlorothien-2-yl)sulfonyl]-7-piperidin-1 -yl- 1H-indazole;
1-methyl-3-(phenylsulfonyl)-5-piperidin-1-yl- 1H-indazole;
5 3-[(3-fluorophenyl)sulfonyl]-5-piperidin-1-yl- 1H-indazole;
1-methyl-3-(phenylsulfonyI)-7-(4-methylpiperidin-1 -yl)-1H-indazole;
3-[(3-fluorophenyl)sulfonyl]-7-piperidin-1-yl-1H-indazole;
3-[(3-fluorophenyl)sulfonyl]-5-piperidin-1 -yl- 1H-indazole;
3-(phenylsulfonyl)-5-piperidin-1 -yl- 1H-indazole;
1 -methyl-3-[(3-fluorophenyl)sulfonyl]-7-piperidin-1 -yl- 1H-indazole;
3-(phenylsulfonyl)-7-piperidin-1 -yl-1H-indazole;
or a stereoisomer thereof; or a pharmaceutically acceptable salt thereof.
10. 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
claimed in any one of claims 1 to 9 or a stereoisomer thereof; or a pharmaceutically
acceptable salt thereof.
11. A method according to claim 10 wherein said disorder is a motor
disorder, anxiety disorder or cognitive disorder.
-61-

12. A method according to claim 10 wherein said disorder is a
neurodegenerative disorder.
13. A method according to claim 11 wherein said disorder is selected from
the group consisting of: attention deficit disorder; obsessive compulsive disorder;
withdrawal from drug, alcohol or nicotine addiction; schizophrenia; depression; and
Alzheimer's disease.
14. A method according to claim 12 wherein said disorder is selected from
the group consisting of: stroke; head trauma; and neuropathic pain.
15. A pharmaceutical composition which comprises a pharmaceutically
acceptable carrier and a compound of formula I as claimed in any one of claims 1 to
9 or a stereoisomer thereof; or a pharmaceutically acceptable salt thereof.
16. A process for preparing a compound of formula (I) according to claim
1 which comprises one of the following
(a) diazotising and cyclising a compound of formula (VIIA):

wherein the dotted line, m, n, p, A, R1, R2, R4, R5, R6 and R7 are as defined in claim 1,
e.g. with NaNO2/acid to give a compound of formula (I) wherein R3 is hydrogen,
or
(b) alkylating or arylating a protected compound of formula (IA)
-62-


wherein the dotted line, m, n, p, A, R1, R2, R5, R6 and R7 are as defined in claim 1
and P is a protecting group or R4 where R4 is as defined in claim 1 excepting
hydrogen, with an alkylating or arylating agent of formula R3-LG where LG is a
leaving group and R3 is a C1-C6alkyl, C3-C7cycloalkyl, aryl or heteroaryl group each
optionally substituted; and if required removing the protecting group, to give a
corresponding compound of formula (I) where R3 is a C1-C6alkyl, C3-C7cycloalkyl, aryl
or heteroaryl group each optionally substituted;
or
(c) alkylating a compound of formula (IB)

wherein the dotted line, m, n, p, A, R1, R2, R3, R5, R6 and R7 are as defined in claim 1,
with an alkylating agent of formula R4-LG where LG is a leaving group and R4 is a C1-
C6alkyl or C3-C7cycloalkyl group each optionally substituted, to give a corresponding
compound of formula (I) where R4 is a C1-C6alkyl or C3-C7cycloalkyl group each
optionally substituted;
or
-63-

(d) reacting a compound of formula (XII):

wherein m, R1, R2 and R3 are as defined in claim 1, and LG' is a leaving group such
as Cl, Br, I or an activated hydroxyl group such as triflate, with a compound of
formula (V):
wherein n, p, R4, R5, R6 and R7 are as defined in claim 1, in the presence of a
catalyst, e.g., a palladium or nickel catalyst, to give a corresponding compound of
formula (I);
or
(e) reducing a compound of formula (XII):

wherein m, n, p, R1, R2, R5, R6 and R7 are as defined in claim 1, P is a protecting
group or R4 as defined in claim 1 and P' is a protecting group or R3 as defined in
claim 1, if required removing any protecting group, to give a corresponding
compound of formula (I) wherein A is CH;
or
(f) acidifying a compound of formula (XII):
-64-


wherein m, n, p, R1, R2, R5, R6 and R7 are as defined in claim 1, P is a protecting
group or R4 as defined in claim 1 and P' is a protecting group or R3 as defined in
claim 1, if required removing any protecting group, to give a corresponding
compound of formula (I) wherein A is C and = represents a double bond;
or
(g) converting a basic compound of formula (I) as defined in claim 1 to an
acid addition salt thereof or vice versa.
or
-65-
(h) separating a stereoisomer of a compound of formula (I) from a mixture
thereof.

The invention provides compounds of formula
(I) and the use thereof in the therapeutic treatment of disorders related to or affected by the 5-HT6 receptor.