AU2008203389A1 - Heterocyclyloxy-, -thioxy- and - aminobenzazole derivatives as 5- hydroxytryptamine-6 ligands - Google Patents

Description

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: 00 00

O

Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Wyeth Actual Inventor(s): Boyd Lynn Harrison, Yanfang Li, Ping Zhou Address for Service and Correspondence: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: HETEROCYCLYLOXY-, -THIOXY- AND AMINOBENZAZOLE DERIVATIVES AS HYDROXYTRYPTAMINE-6 LIGANDS Our Ref: 834861 POF Code: 460048/460161 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1- 60065 00

O

N HETEROCYCLYLOXY-, -THIOXY- AND -AMINOBENZAZOLE N DERIVATIVES AS 5-HYDROXYTRYPTAMINE-6 LIGANDS SThe present application is a divisional application from Australian patent 00 c 5 application number 2002307424, the entire disclosure of which is incorporated O herein by reference.

00 SThis invention relates to heterocyclyloxy-, -thioxy- and -aminobenzazole c derivatives as 5-hydroxytryptamine-6 ligands, to processes for preparing them, to methods of using them and to pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION Various central nervous system disorders such as anxiety, depression, motor disorders, etc., are believed to involve a disturbance of the neurotransmitter 5-hydroxytryptamine (5-HT) or serotonin. Serotonin is localized in the central and peripheral nervous systems and is known to affect many types of conditions including psychiatric disorders, motor activity, feeding behavior, sexual activity, and neuroendocrine regulation among others.

The effects of serotonin are regulated by the various 5-HT receptor subtypes.

Known 5-HT receptors include the 5-HTI family 5-HTIA), the 5-HT2 family 5-HT2A), 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 subtypes.

The recently identified human 5-hydroxytryptamine-6 (5-HT6) receptor subtype has been cloned, and the extensive distribution of its mRNA has been reported. Highest levels of 5-HT6 receptor mRNA have been observed in the olfactory tubercle, the striatum, nucleus accumbens, dentate gyrus and CA1, CA2 and CA3 regions of the hippocampus. Lower levels of 5-HT6 receptor mRNA were seen in the granular layer of the cerebellum, 00 c several diencephalic nuclei, amygdala and in the cortex.

Northern blots have revealed that 5-HT6 receptor mRNA appears to be exclusively present in the brain, with Cl little evidence for its presence in peripheral tissues.

The high affinity of a number of antipsychotic agents for h the 5-HT6 receptor, in addition to its mRNA localization 00 c in striatum, olfactory tubercle and nucleus accumbens C suggests that some of the clinical actions of these C compounds may be mediated through this receptor.

00 Therefore, 5-HT6 receptor ligands are believed to be of C) potential use in the treatment of certain CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, attention deficit disorder, migraine, cognitive memory enhancement for the treatment of Alzheimer's disease), sleep disorders, feeding disorders anorexia and bulimia), panic attacks, withdrawal from drug abuse cocaine, ethanol, nicotine and benzodiazepines), schizophrenia, or the like; or in the treatment of certain gastrointestinal disorders such as irritable bowel syndrome.

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.

SUM~hARY OF THE INVENTION~ The present invention provides compounds of formula

II

Y

~Z

00 M(RI)m

"R

10 00 wherein W is S0 2 CO, CONE, CSNH or X is 0, SO. orNR, Y is CR 2 or N; Z is CR,, or N with the proviso that when Y is N then Z must be CR 13 m and x are each independently 0 or an integer of 1, 2 or 3; Q is R8NR NVRR 2 or R5 R 28 R2 R is halogen, CN, C0 2

CONR.,R

17

CNR,,NR

9

R

2

SO

2

.NR-,R

22

SO,,R

23 or a C 1 C~alkyl, C,-C~alkenyl, C 2 Calkynyl, C,-C~cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted;

R

2 i s H, CNR 4

,NR

5 or a C,-C~alkyl, C, -C~alkenyl, C,-

C

6 a lkynyl, c -C 6 cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;

R

3

R

4 1 R 5

R

6 1 P- 7 Ra, and are each independently H or an optionally substituted C,- C~a ikyl group; 00 is an optionally substituted C-C,alkyl, aryl or heteroaryl group; h n and p are each independently 0 or an integer of 1 or 2; R, is H or a C,-Calkyl, C,-Calkenyl, C,-Calkynyl, C,- 00 Ccycloalkyl or cycloheteroalkyl group each c r optionally substituted; 0 R 1 2 and R, are each independently H, halogen or a C,- 00 Calkyl, aryl, heteroaryl or C-C 6 alkoxy group each optionally substituted; (C R, 1 is H, COR, or a C,-C,alkyl, C,-Calkenyl, C,- Calkynyl, aryl or heteroaryl group each optionally substituted; R, and are each independently H or a C,-Calkyl,

C

2 -Calkenyl, C,-Calkynyl, C,-Ccycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; Rs, R,7, Ro, ,R 2

R

2 and are each independently H or an optionally substituted C,-

C

6 alkyl group; R, and are each independently H or a C,-Calkyl, aryl or heteroaryl group each optionally substituted; and R, is an optionally substituted C,-C 6 alkyl, aryl, or heteroaryl group; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.

The present invention also provides methods and compositions useful for the therapeutic treatment of central nervous system disorders related to or affected by the 5-HT6 receptor.

I

00 C<K 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 O\ distribution in the brain has stimulated significant 00 M iinterest in new compounds which are capable of n interacting with or affecting said receptor. At present, CN there are no known fully selective agonists. Significant efforts are being made to understand the possible role of O 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.

Surprisingly, it has now been found that heterocyclyloxy-, -thioxy- or -aminobenzazole derivatives of formula I demonstrate 5-HT6 affinity. Advantageously, said benzazole 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 heterocyclyloxy-, -thioxy- or -aminobenzazole derivatives of formula I

X

IQ

Y\\z N (Ri)m WRIo wherein 00 W is SO 2 CO, CONI, CSNH or (CHJ.; n ~X is 0, SO. or R; Y is CR,, or N; Z is CR 3 or N with the proviso that when Y is N then Z must be CR 3 00 m and x are each independently 0 or an integer of 1, 2 or 3;

RR

7

R

8 6R 7

R

8 -R 3 4-R 9 Qis 1 R28 gR

R

5 1 N R 5 N R or R R4 R 2 R R3 R 3

R

2

'R

3 R2 R, is halogen, CN, OR 14 C0 2

P

1 CONR,.R,,,

SO,R

2

SO,,R

23 or a C,-C~alkyl, C,-C~alkenyl, C 2 C,a ikynyl, C -C~cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted; R, is H, CNR 4 NRSR,, or a C,-C~alkyl, C,-C~alkenyl, C,- C~a lkynyl, C,-C~cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; and are each independently H or an optionally substituted C 1 Calkyl group; is an optionally substituted C,-C,alkyl, aryl. or heteroaryl group; n and p are each independently 0 or an integer of 1 or 2; R, is H or a C,-C,alkyl, C,-C~alkenyl, C-C~a1kyyl, C,- Ccycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; and R, are each independently H, halogen or a C,-

C

6 alkyl, aryl, heteroaryl or C,-C~alkoxy group each optionally substituted; -6- 00 is H, COR 2 or a C-Calkyl, C,-Calkenyl, C,-

SC

6 alkynyl, aryl or heteroaryl group each optionally substituted; CI and are each independently H or a C,-C,alkyl,

C

2 -Calkenyl, C,-C 6 alkynyl, C,-C,cycloalkyl, h cycloheteroalkyl, aryl or heteroaryl group each 00 M optionally substituted; R, 7, R R 2, R 2 PR, RPs and are each CI independently H or an optionally substituted C,- 00 Calkyl group; ci R, and R 22 are each independently H or a C.-Calkyl, aryl or heteroaryl group each optionally substituted; and is an optionally substituted C,-Calkyl, aryl, or heteroaryl group; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.

As used in the specification and claims, the term halogen designates Br, Cl, I or F and the term cycloheteroalkyl designates a Cs-C,cycloalkyl ring system containing 1, 2 or 3 heteroatoms, which may be the same or different, selected from N, 0 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, 0 or S and R is H or an optional substituent as defined hereinbelow.

N XI X, X, I X, L, XO X 1 N NR

R

00 CI Similarly, as used in the specification and claims, the term heteroaryl designates a 5- to aromatic ring system containing 1, 2 or 3 heteroatoms, which may be the same or different, selected from N, 0 or S. Such heteroaryl ring systems include pyrrolyl, h azolyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, 00 00 quinolinyl, isoquinolinyl, indolinyl, benzothienyl, C) benzofuranyl, benzisoxazolyl or the like. The term CI haloalkyl as used herein designates a group having from one to 2n+l halogen atoms which may be the same or different and the term haloalkoxy as used herein designates an OCH,., group having from one to 2n+l halogen atoms which may be the same or different.

In the specification and claims, when the terms C.-Calkyl, C,-Calkenyl, C 2 -Calkynyl, C 3 -Ccycloalkyl, cycloheteroalkyl, phenyl 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, alkylsuphinyl, alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl heteroaryl and cycloheteroalkyl) or cycloalkyl groups, preferably halogen atoms or lower alkyl 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.

00 CI Pharmaceutically acceptable salts may be any acid addition salt formed by a compound of formula I and a pharmaceutically acceptable acid such as phosphoric, Cq sulfuric, hydrochloric, hydrobromic, citric, maleic, malonic, mandelic, succinic, fumaric, acetic, lactic, 0 nitric, sulfonic, p-toluene sulfonic, methane sulfonic 0 0 acid or the like.

C Compounds of the invention may exist as one or more N- stereoisomers. The various stereoisomers include 0 0 10 enantiomers, diastereomers, atropisomers and geometric Sisomers. 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 steroisomer(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.

Preferred compounds of the invention are those compounds of formula I wherein W is SO, or CO. Also preferred are those compounds of formula I wherein X is O. Another group of preferred compounds of the invention are those compounds of formula I wherein Y is CRy.

Further preferred compounds of the invention are those compounds of formula I wherein R, is an aryl or heteroaryl group each optionally substituted. Preferably Q is an optionally substituted 3-pyrrolidinyl group. Z may be for example N.

Examples of R, are aryl e.g. phenyl or naphthyl, or heteroaryl e.g.,pyrazolyl (such as pyrazol-4-yl) thienyl (such as thien-2-yl) or quinolyl (such as quinolin-8-yl); 00 CI said aryl and heteroaryl groups being unsubstituted or Z optionally substituted by one or more 1 to 3) substituents the same or different as described herein.

CI Such substituents include halo, nitro, cyano, thiocyanato, cyanato, hydroxcyl, alkyl of 1-6 carbon atoms, halo (C 1 -C,)alkyl, (C,-C 6 )alkoxy, halo (C.-C,)alkoxy, 00amino, (C -Calymno d- (C 1 Calkyl) amino, formyl, (CL- M Calkoxy)carbonyl, carboxyl, (C 1 -_C)alkanoyl, N0 C 6 alkylthio, (C, 1

-C

6 alkylsuphinyl, alkyl-sulphonyl, 00 10 carbainoyl, (C,-C)alkylaxnido, phenyl, phenoxy, benzyl, benzyloxy, heteroaryl and cycloheteroalkyl or cycloalkyl groups.

More preferred compounds of the invention are those compounds of formula I wherein W is X is 0; and R 1 0 is an aryl or heteroaryl group each optionally substituted.

Another group of more preferred compounds of the invention are those compounds of formula I wherein W is SO,; X is 0; Y is CR.; and Q is a 3-pyrrolidinyl group.

Among the preferred compounds of the invention are: l-(phenylsulfonyl) (3-pyrrolidinyloxy) -lH-indole; 4- (3-pyrrolidinyloxy)1- (thien-2-ylsulfonyl) -1H-indole; 4 (4 -pyrrolidinyloxy) -lH-indol-l-yl Isul fonyl) aniline; 1- (l-naphthylsulfonyl) (3-pyrrolidinyloxy) -lH-indole; 1- ((5-chloro-l, 3-dimethyl-lH-pyrazol-4-yl) sulfonyl] (3pyrrolidinylox-y) -1H-indole; 1- (phenylsulf onyl) (3-pyrrolidinyloxy) -lH-indazole; 1- (l-naphthylsulf onyl) (3-pyrrolidinyloxy) -lH-indazole; 1- (2-chlorophenyl) sulf onyl] (3-pyrrolidinyloxy) -lHindazole; 1- (2-f luorophenyl) sulf onyl] (3-pyrrolidinyloxy) -lHindazole; 1- 4 -dime thoxyphenyl) sulfonyl] (3-pyrrolidinyloxy) 1H-indazole; 1- C (5-chlorothien-2-yl) sulfonyl] (3-pyrrolidinyloxy) 1H-indazole; 00 N- (2-chloro-4- (3-pyrrolidinyloxy) -1H-ildazol-l- Z ~yl ]sul fonyl phenyl) acetaide; N- (3-pyrrolidinyloxy) -lH-indazol- Cl ly} (sulfonyl] phenyl) acetamide; 8- (3-pyrrolidinyloxy) -lH-indazol-1yl] sulfonyllquinoline; 00 M 1- (1-naphthylsulf onyl) (piper idin- 4-yloxy) -1H-indazole; 1- (l-naphthylsulfolyl) (piperidin-3-yloxy) -lH-indazole; Cl 1- (5-chlorothien-2-yl)sulfol1 (piperidin-4-yloxy)- 00 1H-indazole; 1- (5-chlorothien-2-yl) sulfonyl 1-4- (piperidin-3-yloxy) lH-indazole; 1- (phenylsulfonyl) (piperidin-3-yloxy) -1H-indole; 4- (piperidin-3-yloxy) -1H-indol-l-yl]I sulfonyllaniline; 1- (1-naphthylsulfony-) (piperidin-3-yloxy) -lH-ildole; 1- (phenylsulfonyl) (piperidin-4-yloxy) -lH--indole; 4- (piperidin-4-yloxy) -lH-indol-l-yl]I sulfonyl} aniline; 1- (l-naphthylsulf onyl) (piperidin-4-yloxy) -lH-indole; 1- (phenylsulfonyl) (pyrrolidin-3-yloxy) -lH-indole; 1- (phenylsulf onyl) (pyrrolidin-3 -yloxy) -lH-indole; 1- (phenylsulfonyl) (pyrrolidin-3-yloxy) -lH-indazole; 1- (phenylsulfonyl) (pyrrolidin-3-yloxy) -lH-indazole; or the stereoisomers thereof or pharmaceutically acceptable salts thereof.

This invention also provides a process for the preparation of a compound of formula I which comprises one of the following: a) reacting a compound of formula (B) (RI)m H

(B)

-11- 00 Z wherein m, Q, X, Y, Z and R are as defined herein, with an appropriate sulphonylating, acylating, carbamoylating, (1 thiocarbamoylating, arylating or alkylating agent containing the group:

RI

0

-W-

00 Mc where R, is as defined above and W is SO,, CO, CONH, CSNH or (CH,) x said reactants protected on reactive sites 00 and/or on reactive substituent groups as required, and 00 removing any protecting groups, to give a corresponding C- compound of formula or b) removing a protecting group from a compound of formula

XQI

N

(RI)m WRo

(C)

wherein m, W, X, Y, Z, R, and R, are as defined herein and S R R 7

R

8 R7 Q,is R 28

N-P

R

5 NF RN or R 5

R

R3 RR3 P R R3 K 29 where P is a protecting group to give a corresponding compound of formula wherein R, is H; or c) alkylating a compound of formula as defined herein wherein R, is hydrogen with an alkylating agent of formula R 2 -L wherein L is a leaving group, such as -12c halogen, and R, is as defined herein excepting hydrogen to Sgive a corresponding compound of formula or CI d) converting a compound of formula having a reactive substituent group to a different compound of Sformula I; 00 M or M e) converting a basic compound of formula to an C acid addition salt or vice versa.

00 Q 10 Compounds of the invention may be conveniently Sprepared using conventional synthetic methods and, if required, standard separation and isolation techniques.

For example, compounds of formula I wherein W is SO 2 X is O; Y is CR,; Z is Q is an optionally substituted 3pyrrolidinyl group; and R, is H (Ia) may be prepared by reacting an hydroxyindole of formula II with a protected 3-hydroxypyrrolidine of formula III in the presence of triphenylphosphine and diethyl azodicarboxylate to give the pyrrolidinyloxyindole of formula IV. Sulfonylation followed by deprotection gives the desired compound of formula Ia. The reaction is shown in flow diagram I wherein P is a protecting group.

-13- Flow Diagram I HO R8RR R6 17 "R9 R 13

N-P

/Z N R 5 R3ii (RI)m HHOR a) base b) RIOS0 2

CI

deprotection

(R

1 )m (Rj)r Commonly used protecting groups include t-butylcarboxylate, benzyl, acetyl, benzyloxycarbonyl, or any conventional group known to protect a basic nitrogen in standard synthetic procedures.

Compounds of formula I wherein W is SO,; X is 0; Y is CH; Z is N; and Q is optionally substituted 3pyrrolidiny. group (1b) may be prepared by reacting a nitrornethylphenol of formula VI with a protected 3hydroxypyrrol idine of formula III in the presence of -14- 00 triphenylphosphine and diethyl azodicarboxylate to give n the corresponding pyrrolidinyloxybenzene of formula VII, reducing the nitro group, for example via catalytic C hydrogenation, to give the amine of formula VIII, reacting the formula VIII amine with isoamylnitrite in 00 the presence of potassium acetate and acetic anhydride to

O

M give the pyrrolidinyl-oxyindazole of formula IX.

0 Sulfonylation and deprotection of said formula IX 00 compound gives the desired compound of formula Ib.

Subsequent reaction of the formula Ib compound with a (1 suitable alkylating reagent such as an alkyl or aryl halide, R.-Hal, gives those compounds of formula Ib' wherein R, is other than H. The reaction sequence is shown in flow diagram II wherein P is a protecting group and Hal is Cl, Br or I.

00 Flow Diagram II

HO

(RI)m NO 2

N-P

R

(R

1 )m N2 R

RII

Ia) base lb) RIOS0 2 C1 2) deprotection

R

2 -HaI

(R

1 )rfi -16-- C Similarly, compounds of formula I wherein X is S and SW is SO, may be prepared by employing the appropriate indolylthiol or thiophenol and utilizing the reactions shown in flow diagrams I and II, respectively. Oxidation of the thus-formed heterocyclylthiobenzazole derivatives C of formula I gives those compounds of formula I wherein X 00 C is SO, and n is 1 or 2.

Compounds of formula I wherein W is SO,; X is NH; Y c is CR Z is CRu,; Q is an optionally substituted 3- 00 pyrrolidinyl group; and R, and R, are H(Ic) may be prepared by hydrogenating a nitroindole of formula X to give the corresponding aminoindole of formula XI and reacting the formula XI aminoindole with a protected 3pyrrolidinone of formula XII to give the protected pyrrolidinylaminoindole of formula XIII. Subsequent sulfonylation and deprotection afford the desired compound of formula Ic. The reaction sequence is shown in flow diagram III.

-17- 00 C Flow Diagram III

RH

S

N 2 R12 R12 I N

R,

N N- (Ri)m H (Rl)m

H

00 M) MX)

S

R 8 00R 3 b) RN-SOCI (xn) I4NH la) base N-P ^-R3 1b) R,oS02Cl R3 NH R NH R R SR12 2) deprotection H R 4

R

(Ri)m S (Ri)m H S02RIo (Ic) (XIM) Compounds of formula I wherein W is SO,; X is NR,; Y is CH; Z is N; and Q is an optionally substituted 3pyrrolidinyl group (Id) may be prepared by reacting the nitromethylphenol compound of formula VI with trifluoromethanesulfonic anhydride in the presence of a base to give the compound of formula XIV, coupling the formula XIV compound with a protected 3-aminopyrrolidine compound of formula XV in the presence of a palladium catalyst to give the pyrrolidinylaminobenzene of formula XVI, reducing the nitro group to give the amine of formula XVII and reacting the formula XVII amine with isoamylnitrite in the presence of potassium acetate and acetic anhydride to give the pyrrolidinylaminoindazole of formula XVIII. Subsequent sulfonylation and deprotection -18-

I

as described hereinabove give the desired compound of formula Id. The reaction sequence is shown in flow diagram IV wherein Tf designates a trifluoromethaflesulfonyl group.

Flow Diagram IV

(CF

3

SO

2 2 0 TfO 1: CH3

(R

1 )m NO (Rj)a{

(XIV

(XV)

R

7 R r CH 3

(R

1 )m 2

(XVMI

IM

(X-V)

1a) base i1b) RI 0 S0 2 C1 2) deprotection

(XVII)

-19- 00 SCorresponding compounds of formula I wherein Q is an optionally substituted 3- or 4-piperidinyl group may be C prepared by utilizing the reaction sequences described hereinabove and illustrated in flow diagrams I, II, III Sand IV and by employing the appropriate protected 00 M piperidinylhydroxy, piperidinone or piperidinylamine, Mc respectively, in place of the corresponding pyrrolidinyl C starting materials of formulas III, XII or XV.

00 0 10 Compounds of formula I wherein W is CO may be C prepared by reacting the benzazole precursor, for example a compound of formula IV, IX, XIII or XVIII, with the appropriate isocyanate, carbonyl halide or carbamoyl halide in the presence of a base. Similarly, compounds of formula I wherein W is (CHl) x and x is an integer of 1, 2 or 3 may be prepared by reacting the appropriately substituted alkylhalide with a compound of formula IV, IX, XIII or XVIII in the presence of a base. Compounds of formula I wherein W is and x is 0 may be prepared via a palladium-catalyzed N-arylation such as that described by D. W. Old et al., Organic Letters, 2000 pp 1403-1406. Using these and other conventional methods, compounds of formula I may be prepared from readily available starting materials.

Advantageously, the inventive compound of formula I may be utilized in the treatment of central nervous system disorders relating to or affected by the 5-HT6 receptor such as motor, mood, psychiatric, cognitive, neurodegenerative, or the like disorders, for example, Alzheimer's disease, Parkinson's disease, attention deficit disorder, anxiety, epilepsy, depression, obsessive compulsive disorder, migraine, sleep disorders, feeding disorders (such as anorexia or bulimia), schizophrenia, memory loss, disorders associated with withdrawl from drug abuse, or the like or certain 00 gastrointestinal disorders such as irritable bowel syndrome. Accordingly, the present invention provides a c method for the treatment of a disorder of the central nervous system (CNS) related to or affected by the 5-HT6 receptor in a patient in need thereof which comprises providing said patient a therapeutically effective amount 00 M of a compound of formula I as described hereinabove. The MC) compounds may be provided by oral or parenteral N' administration or in any common manner known to be an 00 effective administration of a therapeutic agent to a Spatient in need thereof.

"Providing" as used herein with respect to providing a compound or substance covered by the invention, means 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 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 -21- 00 effective amount of a compound of formula I as described hereinabove.

Solid carriers suitable for use in the composition c of the invention include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aides, 00 binders, tablet-disintegrating agents or encapsulating Smaterials. In powders, the carrier may be a finely C divided solid which is in admixture with a finely divided 00 compound of formula I. In tablets, the formula I C, 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, osmoregulators, or the like. Examples of liquid carriers suitable for oral and parenteral administration include water (particularly containing additives as above, e.g., -22- 00 CI cellulose derivatives, preferably sodium carboxymethyl Scellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, glycols) or their CI derivatives, or oils fractionated coconut oil and arachis oil). For parenteral administration the carrier may also be an oily ester such as ethyl oleate or 0 0 isopropyl myristate.

c Compositions of the invention which are sterile CI solutions or suspensions are suitable for intramuscular, 00 10 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 terms HPLC and NMR designate high performance liquid chromatography and nuclear magnetic resonance, respectively. The terms THF and EtOAc designate tetrahydrofuran and ethyl acetate, respectively.

-23- 00 (C EXAMPLE 1

C

0b Preparation of t-Butyl 3-Hydroxy-l-pyrrolidinecarboxylate HO HO 00 'CNH

O(CO

2 t-Bu) 2

K

2

CO

3

\CN-CO

2 t-Bu c, 00 A stirred solution of 3-pyrrolidinol (5.0 g 57 mmol) and potassium carbonate (8.23 g, 60 mmol) in a mixture of CI 10 THF/0 is treated with a solution of di-t-butyl dicarbonate (12.5 g, 57 mmol) in THF over a 15 minute period at room temperature, stirred for 20 h at room temperature and diluted with EtOAc. The organic phase is separated, washed with HO, dried over NaSO, and concentrated in vacuo. The resultant residue is dissolved in EtOAc/hexane and filtered through a thin layer of silica gel. The silica gel layer is washed with EtOAc. The combined filtrates are concentrated in vacuo to give the title product as a white solid, 8.5 g, mp 52- 54°C, identified by NMR and mass spectral analyses.

EXAMPLE 2 Preparation of t-Butyl 3-(1H-Indol-4-yloxy)-1pyrrolidinecarboxvlate OH N-COz-t-Bu N-COt-Bu H HO N

H

A solution of 4-hydroxyindole (2.66 g, 20.0 mmol), t-butyl 3 -hydroxy-l-pyrrolidinecarboxylate (7.5 g, 40.0 -24- 00 mmol) and triphenylphosphine (PP) (10.5 g 40.0 mmol) in THF is treated with diethyl azodicarboxylate (DEAC)(6.3 O ml, 40.0 mmol) under nitrogen at room temperature, stirred for 2 h at room temperature and concentrated in vacuo. The resultant residue is stirred under ether, 00 cooled and filtered. The filtercake is washed with cold c ether. The filtrates are combined and concentrated in vacuo. The residue is purified by flash chromatography 00 (silica gel, EtOAc/hexane: 2/80) to give the title compound as a white solid, 3.98 g, mp 164-165 0

C,

identified by NMR and mass spectral analyses.

EXAMPLE 3 Preparation of 1-(Phenylsulfonyl)-4-(3-pyrrolidinyloxy)- 1H-indole Hydrochloride

'N-CO

2 t-Bu H CI F\ )Na1) NaH SO2) HCI H SOz A stirred solution of t-butyl 3-(1H-indol-4-yloxy)- 1-pyrrolidinecarboxylate (0.605 g 2.0 mmol) in THF is treated with sodium hydride (0.12 g, 60% in mineral oil, mmol) under nitrogen at room temperature. After minutes, benzenesulfonyl chloride (0.38 ml, 3.0 mmol) is added and the reaction mixture is stirred at room temperature for 48 h, quenched with ice-water and diluted with EtOAc. The organic phase is separated, washed sequentially with HO and brine, dried over MgSO, and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, EtOAc/hexane 2/8 to give the protected pyrrolidinyloxy intermediate as an 00 off-white foam, 0.50 g, mp 48-50 0 C, identified by NMR and ,mass spectral analyses.

A solution of thus-obtained t-butyl (phenylsulfonyl)-lH-indol-4-yl]oxy}-lpyrrolidinecarboxylate (0.41 g, 0.93 mmol) in methanol O and HC1 (5.0 ml, IM in ether) is heated at 60 0 C under 00 Snitrogen for 2 h and concentrated in vacuo. The residue is treated with ethyl acetate and filtered. The 00 filtercake is dried under vacuum to give the title 0 10 product as an off white solid, 0.301 g, mp 200-201C, C-i identified by NMR and mass spectral analyses.

EXAMPLES 4-9 Preparation of 1-(Arylsulfonyl)-4-(3-pvrrolidinyloxy)-1Hindole Hydrochloride 2b) RioS0 2

C

QI

N 3) HCI N

H

SOr-Rio Using essentially the same procedures described hereinabove for Examples 2 and 3 and employing the appropriate protected pyrrolidinol or piperidinol and arylsulfonyl chloride, the compounds shown in Table I are obtained and identified by NMR and mass spectral analyses.

-26- Table I

XII'X

(tN S02-RI 0 cl Ex.

MP

X O RiO M+H

RIO

4 3-pyrrolidinyl 3-pyrrolidiny.

6 3-pyrrolidinyl 7 3-pyrrolidinyl 8 4-piperidinyl 9 3-piperidinyl thiophene-2 -yl 4 -aminophenyl 1-naphthy.

5-chloro-1, 3dimethyl-lH-pyrazol 4-yl 4- axinophenyl 4 -arninophenyl 15 8-160 140 (dec) 179 (dec) 10 0 (dec) 342 359 393 395 372 372 117-119 160 (dec) EXAMPLE Preraono t-ty 3-(-ehl3ntohfO)prrol idin- 1-carboxylate

OH

3 ,Bac

N

+HOJ(

CNBoc

CH

3 No 2 -27- 00 A stirred solution of 3-nitro-2-methylphenol (7.6 g, S49.7 mmol), t-butyl 3-hydroxypyrrolidin-l-carboxylate h (9.3 g, 49.7 mmol) and triphenylphosphine (13.0 g, 49.7 mmol) in THF is treated with diethyl azodicarboxylate (8.7 g, 49.7 mmol), stirred at room temperature for 3 h OO and concentrated in vacuo. The resultant residue is 00

M

n mixed with ethyl acetate and filtered. The filtrate is 0 concentrated in vacuo to give a residue, which is OO purified by chromatography (SiO,, 25% EtOAc in hexanes) to afford the title compound as an off-white solid, 11.7 g CA identified by NMR and mass spectral analyses.

EXAMPLE 11 Preparation of t-Butyl 3-(3-Amino-2-methylphenoxy)pyrrolidin-1-carboxylate S N-Bo c o C H 2 cat. CH 3 NO2 NiNH A mixture of t-butyl 3-(2-methyl-3nitrophenoxy)pyrrolidin-l-carboxylate (11.0 g, 34.2 mmol) and 10% Pd/C (0.55 g) in ethanol is hydrogenated (45 psi) at room temperature overnight. After filtering off the catalyst, the filtrate is concentrated to afford the title compound as an off-white solid, 9.98 g, mp 137 0

C,

identified by NMR and mass spectral analyses.

-28- 00 EXAMPLE 12 Preparation of t-Butyl 3-(1H-Indazol-4-yloxy)pyrrolidin- 1-carboxylate 00 rN-Boc rN-Boc 00 3

H

3

N

I2

H

A solution of t-butyl 3-(3-amino-2methylphenoxy)pyrrolidin-l-carboxylate (4.6 g, 15.4 mmol), potassium acetate (1.81 g, 18.5 mmol) and acetic anhydride (5.02 g, 49.2 mmol) in benzene is treated dropwise with isoamylnitrite (4.13 ml, 30.8 mmol), heated at reflux temperature overnight, cooled to room temperature and filtered. The filtercake is washed with benzene. The combined filtrates are concentrated to give a yellow oil residue. The residue is purified by chromatography (SiO,, 25% EtOAc in hexanes). The resultant oil is dissolved in ethanol, treated with aqueous NaOH, heated at reflux temperature for 45 min, cooled with an ice-water bath, neutralized to pH 9 with concentrated HC1 and concentrated in vacuo. The resulting aqueous mixture is extracted with EtOAc. The combined extracts are washed with water and brine, dried over MgSO, and concentrated in vacuo to give the title compound as a tan solid, 2.6 g, mp 196-198 0 C, identified by NMR and mass spectral analyses.

-29- 00 EXAMPLE 13 Preparation of t-BUtyl 3-f [(1-Phenylsulfonyl) -lH-indazol- 4-vil oxivl -pvrrolidin-l-carboxylate 00 rN-B~ ~N~ 0 S02_ 0o +NaH H0 NI so 2

-I

A solution of t-butyl 3-(lH-indazol-4yloxy)pyrrolidin-l-carboxylate (0.303 g, 1.00 mmol) in dimethy. formamide is treated with sodium hydride (80 mg, mmol, 60% in mineral oil) at room temperature under nitrogen, stirred for 10 min, treated with benzenesulfonyl chloride (0.21 g, 1.20 mmol), stirred for 18 h, quenched with H 2 0 and diluted with ether. The organic phase is washed with HO0 and brine, dried over frgSO, and concentrated in vacuo. The residue is purified by chromatography (SiO 2 20% EtOAc in hexanes) to afford the title compound as a white solid, 0.42 g, mp 134-135 0

C,

identified by NNR and mass spectral analyses.

EXAMPLE 14 Preparation of 1- (Phenylsulfonvl) (pyrrolidin-3--yloxY) 1H-jna e trfuracetic acid salt N-BOc 0

N

("NH

2

CF

3 C0 2 0

N

IS02Q A mixture of t-butyl 3-([(l-phenylsulfoflyl)-lHindazol-4-yl]oxy}-pyrrolidif-l-carboxylate (354 mg, 0.80 mmol) and trifluoroacetic acid (3 mL) is prepared at 0 0

C,

stirred at room temperature for 90 min. and concentrated in vacuo. The residue is triturated with ether to afford the title compound as a white solid, 260 mg, mp 168-169 0

C,

identified by NNR and mass spectral analyses.

EXAMPLES 15-22 Preparation-of 1- (Arylsulfonyl) -4-(3-pyrrolidinyloxV) -lHindazole trifluoroacetic acid salt (rN- Boc 0

N~N

H-

CF

3 C0 2 I a) Nail 1b) R 10 S0 1

CI

2) TFA Using essentially the same procedures described hereinabove for Examples 8-12, and employing the appropriate arylsulfonyl chloride, the compounds shown in -31- Table II are obtained and identified by NNR and mass spectral analyses.

Table II (rNH 2

CF

3 CO2j 0 (b:N Ex.

No.

16 17 18 19 21 22 1 -naphthyl 2 -chiorophenyl 2- fluorophenyl 3. 4-dimethoxyphenyl 5 -chlorothiophene-2-yl 4-acetamido-3 -chlorophenyl 4-acetamidophenyl 8-quinolinyl

MP

OC

2 00-2 01 161-163 162-163 64-7 0 102-103 68-72 110-112 79 -32- 00 EXAMPLE 23 Ch Comparative Evaluation of 5-HT6 Binding Affinity of Test Compounds h The affinity of test compounds for the serotonin 00 SHT6 receptor is evaluated in the following manner.

r Cultured Hela cells expressing human cloned 5-HT6 C receptors are harvested and centrifuged at low speed 00 (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.HCl (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.HCl buffer and recentrifuged at the same speed. The final pellet is suspended in a small volume of Tris.HCl buffer and the tissue protein content is determined in aliquots of 10-25 pg 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 mg/ml of suspension. The prepared membrane suspension 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 1l. To each well is added the following mixture: 80.0 pl of incubation buffer made in 50 mM Tris.HC1 buffer (pH 7.4) containing 10.0 mM MgC1, and 0.5 mM EDTA and 20 iL of -33- 00

C

[H]-LSD 86.0 Ci/mmol, available from Amersham Life SScience), 3.0 nM. The dissociation constant, K, of the o [H]LSD at the human serotonin 5-HT6 receptor is 2.9 nM, CI as determined by saturation binding with increasing concentrations of ['H]LSD. The reaction is initiated by Ch the final addition of 100.0 41 of tissue suspension.

00 00 Nonspecific binding is measured in the presence of 10.0 S/iM methiothepin. The test compounds are added in 20.0 1l CK volume.

00 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 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 40.01i 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 10.0AM 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 IC, and the Kivalues of test compounds with 95% confidence limits. A linear regression line of data points is plotted, from which the IC 0 value is determined and the Ki value is determined based upon the following equation: Ki ICS, (1 L/K) -34where L is the concentration of the radioactive ligand used and K, 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 III, below.

Table III Test Compound (Ex. No.) 3 4 6 7 8 9 14 16 17 18 19 21 22 Comparative Examples Clozapine Loxapine Bromocriptine Methiothepin Mianserin Olanzepine 5-HT6 Binding Ki (nM) 25.0 13.0 11.0 19.0 19.0 25.0 75.0 12.0 124.0 22.0 5-HT6 Binding Ki (nM) 41.4 23.0 8.3 44.2 19.5 00 As can be seen from the results set forth above, the CI compounds of the present invention have a high degree'of affinity for the 5-HT6 receptor.

00 00 -36-

Claims (15)

1. A compound of formula I 00 \-I\V (RI)m "R 10 00 wherein is SO,, CO, coNH, CSNH or is 0, SO., or NR,,; Y is CR 12 or N; Z is CR,, or N with the proviso that when Y is N then Z must be CR 13 m and x are each independently 0 or an integer of 1, 2 or 3; Qis R9R 28 N-R 2 R 5 NJ R 5 NR 29 o R4 R32 R 3 R 2 R 3 R 29 R, is halogen, CN, COR,,, CONR,,R,, CNR,,NRR, S0 2 NR, 1 2 or a C-C~alkyl, C 2 C~alkeny1, C,- C 6 a ikynyl, C,-C~cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted; is H, CNR NR,,R, or a C,-C~alkyl, C,-C~alkenyl, C~alkynyl, C3-c~cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; -37- 00 RS, R, R R, and are each ,independently H or an optionally substituted C- Calkyl group; R0, is an optionally substituted C,-C 6 alkyl, aryl or heteroaryl group; OO n and p are each independently 0 or an integer of 1 Mor 2; R, is H or a C,-Calkyl, C 2 -Calkenyl, C,-Calkynyl, C,- OO Ccycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; C Ru and R, are each independently H, halogen or a C.- Calkyl, aryl, heteroaryl or C--C.alkoxy group each optionally substituted; is H, CORP or a C-Calkyl, C,-Calkenyl, C,- Calkynyl, aryl or heteroaryl group each optionally substituted; Rs, and are each independently H or a C.-C 6 alkyl, C,-C,alkenyl, C2-C6alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; R6 1 R 1 P0, R 24 R 2 s and R6 are each independently H or an optionally substituted C1-Calkyl group; R 2 and are each independently H or a C-Calkyl, aryl or heteroaryl group each optionally substituted; and R, is an optionally substituted C,-Calkyl, aryl, or heteroaryl group; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.

2. The compound according to claim 1 wherein W is SO 2 -38- 00

3. The compound according to claim 1 or claim 2 wherein X is 0.

4. The compound according to any one of claims 1 to 3 wherein Q is an optionally substituted 3- 00 pyrrolidinyl group. The compound according to any one of claims 1 00 to 3 wherein R. is an optionally substituted aryl or heteroaryl group.

6. The compound according to any one of claims 1 to 5 wherein Y is CR..

7. The compound according to any one of claims 1 to 6 wherein Z is N.

8. The compound according to claim 1 selected from the group consisting of: 1- (phenylsulfonyl) (3-pyrrolidinyloxy) -lH-indole; 4- (3-pyrrolidinyloxy)1- (thien-2-ylsulfonyl) -lH-indole; 4-f 4-(3 -pyrrolidinyloxy) -lH-indol-l-yl]I sulf onyll aniline; 1- (1-naphthylsulfonyl) (3-pyrrolidinyloxy) -1H-indole; 1- (5-chloro-l, 3-dimethyl-lH-pyrazol- 4 -yl) sulfonyll (3- pyrrolidinyloxy) -lH-indole; 1- (phenylsulf onyl) (3-pyrrolidinyloxy) -1H-indazole; I- (1-naphthylsulfonyl) (3-pyrrolidinyloxy) -1H-indazole; 1- II (2-chlorophenyl) sulfonyl] (3-pyrrolidinyloxy) -1H- indazole; 1- (2-f luorophenyl) sulfonyll (3-pyrrolidinyloxy) -lE- indazole; I- 3, 4 -dime thoxyphenyl) sulfonyl] (3-pyrrolidilyloxY) lE-indazole; 1- (5-chlorothien-2-yl) sulfonyl] (3-pyrrolidinyloxy) 1H-indazole; -39- 00 N-(2-chloro-4-( (3-pyrrolidinyloxy) -1H-indazo1-1- yl]I sulfonyllphenyl)acetamide; N- (3-pyrrolidinyloxy) -1H-indazol-ly}]Isulfonyl) phenyl)acetamide; (3-pyrrolidinyloxy) -1H-indazol-1-yl Isulfonyl} quinoline; 00 M 1- (1-raphthylsulf onyl) (piperidin-4-yloxy) -2H-indazole; 1- (l-naphthylsulfonyl) (piperidiri-3-yloxy) -1H-indazole; 00 (5-chlorothien-2-yl) sulfonyl] (piperidin-4-yloxy) 1H-indazole; c-i 1-j(5-chlorothien-2-yl)sulfonyll-4-(piperidin-3-yloxy)- 1H-indazole; 1- (phenylsulfonyl) (piperidin-3- yloxy) -lH-indole; 4- (piperidin-3 -yloxy) -1H-indol-1-ylJI sulf onyl) aniline; 1- (1-naphthylsulf onyl) (piperidin-3-yloxy) -lH-indole; 1- (phenylsulfonyl) (piperidin-4-yloxy) -iR-indole; 4-f 4- (piperidin-4-yloxy) -1H-indol-1-yl I sulf onyllaniline; 1- (1-naphthylsult onyl) (piperidin-4-yloxy) -1H-indole; 1- (phenylsulfonyl) (pyrrolidin-3-yloxy) -1H-indole; 1- (phenylsulfonyl) (pyrrolidin-3-yloxy) -1H-indole; 1- (phenylsulf onyl) (pyrrolidin-3-yloxy) -1H-indazole; 1- (phenylsulf onyl) (pyrrolidin-3-yloxy) -lH-indazole; the stereoisomers thereof; and the pharmaceutically acceptable salts thereof.

9. A method for the treatment of a disorder of the central nervous system related to or af fected by the 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 8; or a stereoisomer thereof or the pharmaceutically acceptable salts thereof I 00 The method according to claim 9 wherein said c- disorder is a motor disorder, anxiety disorder or cognitive disorder.

11. The method according to claim 9 wherein said 00 disorder is schizophrenia or depression.

12. The method according to claim 10 wherein said 00 disorder is Alzheimer's disease or Parkinson's disease. C

13. The method according to claim 10 wherein said disorder is attention deficit disorder.

14. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a compound of formula I as claimed in any one of Claims 1 to 8; or a stereoisomer thereof or the pharmaceutically acceptable salts thereof.

15. The composition according to claim 14 having a formula I compound wherein X is 0; Q is an optionally substituted 3-pyrrolidinyl group and R0 is an optionally substituted aryl or heteroaryl group.

16. A process for the preparation of a compound of formula I which comprises one of the following: a) reacting a compound of formula (B) -41- I 00 XI 0x c-I N 00 (Ri)m H OC wherein m, Q, X, Y, Z and R are as defined in claim 1, 00 with an appropriate sulphonylating, acylating, carbamoylating, thiocarbamoylating, arylating or C-I alkylating agent containing the group: S 0 -W- where R, 0 is as defined above and W is SO,, CO, CONH, CSNH or (CH said reactants protected on reactive sites and/or on reactive substituent groups as required, and removing any protecting groups, to give a corresponding compound of formula or b) removing a protecting group from a compound of formula X-QI (Rl)m WRio (C) wherein m, W, X, Y, Z, R, and R 1 are as defined in claim 1, and 7 Q R6 R7 RS R 6 R 7 R Q, is t )-R2 X N-P R R R o r R5 N, R 3 P 2 9 R RR R4R P R R3 R3 P R3 R29 -42- *fa~C 00 0 C where P is a protecting group to give a corresponding Scompound of formula wherein R, is H; or CO c) alkylating a compound of formula as defined in claim 1 wherein R, is hydrogen with an alkylating agent of Ch formula R,-L wherein L is a leaving group, such as 00 M halogen, and R, is as defined in claim 1 excepting r n hydrogen to give a corresponding compound of formula (N or 00 0 10 d) converting a compound of formula having a O reactive substituent group to a different compound of formula I; or e) converting a basic compound of formula to an acid addition salt or vice versa.

17. A method for the preparation of a compound of formula Ie ,Q X (Ri)m SOzRio (le) wherein X is O, SO, or NR,; Y is CR, or N; Z is CR, or N with the proviso that when Y is N then Z must be CR,; m is 0 or an integer of 1, 2 or 3; -43- 14 00 R 6 Rg pR 7 R 8 7 R 8 Qis R9R 28 5 R 5 IN R 29 or R 5 R 28 c-IR4R R 2 is halogen, CN, OR 1 4 COR,,, C0NRA 6 R 1 CNR 1 qNR, 00 m ~S0 2 NR3 1 R 2 2' SoR,, or a C 1 ,-C~alkyl, C,-C~alkenyl, C 2 C alkynyl, C -C 6cycloalkvl, cylhtrakl 00 phenyl or heteroaryl group each optionally substituted; c-i R, is H, CNR 24 NRR 26 or a C -Cak1 C 2 -C 6 ley, C 2 C~alkynyl, C 3 -C~cycloalkyl, cycloheteroalkyl., aryl or heteroaryl group each optionally substituted; R 1 R 6, and R2, are each independently H- or an optionally substituted C 1 C 6 alkyl group; is an optionally substituted C 1 C alkyl, aryl. or heteroaryl group; n and p are each independently 0 or an integer of 1 or 2; PR, is H or a C,-Calkyl, C 2 -C alkenyl, C,-Calknyl, C,- C cycloalkyl, cycloheteroalkyl, aryl. or heteroaryl group each optionally substituted; and are each independently H, halogen or a C~alkyl, aryl, heteroaryl or C 1 -C 6 alkoxy group each optionally substituted; is H, COP., or a C -C~alkyl, C,-C6 alkenyl, C 2 Co6al kynyl, aryl or heteroaryl group each optionally substituted; and are each independently H or a C 1 -C~alkyl, C 2 C 6 alkenyl, C,-C6a lkynyl, C 3 cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; -44- 00 R R17, RI,' R 19 0 P, Rs and R, are each independently H or an optionally substituted C,- Calkyl group; P Rand are each independently H or a C--Calkyl, aryl or heteroaryl group each optionally 00 substituted; and c is an optionally substituted C,-C,alkyl, aryl, or heteroaryl group 00 which process comprises reacting a compound of formula XIX /Q x (Rl)m wherein X, Y, Z, m and Q are as described hereinabove with a sulfonyl chloride, R 0 SOC1, wherein R, is as described hereinabove in the presence of a base to give the desired compound of formula Ie.