AU2003243091A1

AU2003243091A1 - New compounds useful for the treatment of obesity, type ii diabetes and cns disorders

Info

Publication number: AU2003243091A1
Application number: AU2003243091A
Authority: AU
Inventors: Katarina Beierlein; Annika Jenmalm-Jensen; Gary Johansson
Original assignee: Biovitrum AB
Current assignee: Swedish Orphan Biovitrum AB
Priority date: 2002-06-20
Filing date: 2003-06-19
Publication date: 2004-01-06
Also published as: EA200600975A1; MXPA04012914A; NZ536600A; CA2486989A1; SG156524A1; EA008835B1; CN1662521A; EA011581B1; NZ552282A; EP1513828A1; IL165051A0; NO20050294L; NZ552283A; EA200500054A1; WO2004000828A1; BR0311952A; RS111204A

Description

WO 2004/000828 PCT/SE2003/001061 NEW COMPOUNDS USEFUL FOR THE TREATMENT OF OBESITY, TYPE || DIABETES AND CNS DISORDERS RELATED APPLICATIONS 5 This application claims priority to Swedish application number 0201925-5, filed on June 20, 2002, Swedish application number 0202908-0, filed on October 1, 2002, Swedish application number 0202181-4, filed on July 11, 2002, Swedish application number 0300357-1, filed on February 10, 2003, U.S. provisional application 60/406,120, filed on August 26, 2002, U.S. provisional application 60/434,010, filed on December 17, 2002, 10 and U.S. provisional application 60/464,701, filed on April 23, 2003, the contents of which are incorporated herein by reference. TECHNICAL FIELD 15 The present invention relates to substituted sulphone and sulphonamide compounds, to pharmaceutical compositions comprising these compounds, and to the use of the compounds for the prophylaxis and treatment of medical conditions relating to obesity, type 2 diabetes, and/or disorders of the central nervous system (CNS), to achieve reduction of body weight and of body weight gain, as well as for cosmetic use. 20 BACKGROUND ART Obesity is a condition characterized by an increase in body fat content resulting in excess body weight above accepted norms. Obesity is the most important nutritional disorder in 25 the western world and represents a major health problem in all industrialized countries. This disorder leads to increased mortality due to increased incidences of diseases such as cardiovascular disease, digestive disease, respiratory disease, cancer and type 2 diabetes. Searching for compounds, which reduce body weight has been going on for many decades. One line of research has been activation of serotoninergic systems, either by direct 30 activation of serotonin receptor subtypes or by inhibiting serotonin reuptake. The exact receptor subtype profile required is however not known.

WO 2004/000828 PCT/SE2003/001061 Serotonin (5-hydroxytryptamine or 5-HT), a key transmitter of the peripheral and central nervous system, modulates a wide range of physiological and pathological functions, including anxiety, sleep regulation, aggression, feeding and depression. Multiple serotonin receptor subtypes have been identified and cloned. One of these, the 5-HT 6 receptor, was 5 cloned by several groups in 1993 (Ruat, M. et al. (1993) Biochem. Biophys. Res. Commun.193: 268-276; Sebben, M. et al. (1994) NeuroReport 5: 2553-2557). This receptor is positively coupled to adenylyl cyclase and displays affinity for antidepressants such as clozapine. Recently, the effect of 5-HT 6 antagonist and 5-HT 6 antisense oligonucleotides to reduce food intake in rats has been reported (Bentley, J.C. et al. (1999) 10 Br J Pharmac. Supply. 126, P66; Bentley, J.C. et al. (1997) J. Psychopharmacol. Suppl. A64, 255; Woolley M.L. et al. (2001) Neuropharmacology). Compounds with enhanced affinity and selectivity for the 5-HT 6 receptor have been identified, e.g. in WO 00/34242 and by Isaac, M. et al. (2000) 6-Bicyclopiperazinyl-1 15 arylsulfonylindoles and 6-Bicyclopiperidinyl-1-arylsulfonylindoles derivatives as novel, potent and selective 5-HT 6 receptor antagonists. Bioorganic & Medicinal Chemistry Letters 10: 1719-1721 (2000). INFORMATION DISCLOSURE 20 J. Med. Chem. 1970, 13(4), 592-598 describes N-(4-{[2-(diethylamino)ethyl]amino}-l naphthyl)amides; N-{ 5,6,7,8-Tetrahydro-4-[(3-piperidinopropyl)amino]- 1 naphthyl} amides and related amides and urea derivatives as schistosomicides. WO 99/42465 discloses sulphonamides derivatives that bind to the 5-HT 6 receptor and that 25 can be used for the treatment of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, cognitive disorders, ADHD, anorexia and bulimia schizophrenia, drug abuse. WO 01/32646 Al discloses compounds that bind to the 5-HT 6 receptor and that are used for the treatment of CNS disorders and which inter alia may be used for the treatment of 30 eating disorders.

WO 2004/000828 PCT/SE2003/001061 WO 99/37623 A2 discloses compounds that bind to the 5-HT 6 receptor and that are used for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders. WO 99/42465 A3 discloses compounds that bind to the 5-HT 6 receptor and that are used 5 for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders. EP 0 815 861 Al discloses compounds that bind to the 5-HT 6 receptor and that are used for the treatment of CNS disorders. WO 99/02502 A2 discloses compounds that bind to the 5-HT 6 receptor and that are used 10 for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders. WO 98/27081 Al discloses compounds that bind to the 5-HT 6 receptor and that are used for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders. 15 EP 0701819 discloses compounds that bind to the 5-HT1D receptor and that are used for the treatment of CNS disorders and obesity. US 6,191,141 and WO 01/12629 disclose compounds that bind to the 5-HT 6 receptor and that are used for the treatment of CNS disorders. 20 DISCLOSURE OF THE INVENTION It has surprisingly been found that the compounds of formula (I) show affinity for the 5

HT

6 receptor as antagonists at low nanomolar range. Compounds according to the invention and their pharmaceutically acceptable salts have 5-HT 6 receptor antagonist, 25 agonist and partial agonist activity and are believed to be of potential use in the treatment or prophylaxis of obesity and type 2 diabetes, to achieve reduction of body weight and of body weight gain, as well as in the treatment or prophylaxis of disorders of the central nervous system such as anxiety, depression, panic attacks, memory disorders, cognitive disorders, sleep disorders, migraine, anorexia, bulimia, binge disorders, obsessive 30 compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease, Huntington's WO 2004/000828 PCT/SE2003/001061 chorea and/or schizophrenia, Attention Deficit Hyperactive Disorders (ADHD), drug abuse. The reduction of body weight and of body weight gain (e.g. treating body-weight disorders) is achieved inter alia by reduction of food intake. As used herein, the term "body weight disorders" refers to the disorders caused by an imbalance between energy 5 intake and energy expenditure, resulting in abnormal body (e.g., excessive) weight. Such body weight disorders include obesity. Definitions 10 Unless otherwise stated or indicated, the term "C 1

.

6 alkyl" (or "C 2

.

6 alkenyl") denotes a straight or branched hydrocarbon chain group having from 1 to 6 carbon atoms (or 2 to 6 carbon atoms). Examples of said lower alkyl include methyl, ethyl, n-propyl, iso-propyl, n butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl. Alkenyl groups have one or more double carbon-carbon bonds in the chain. 15 Unless otherwise stated or indicated, the term "C 1

-

6 alkoxy" denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms. Examples of said lower alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and branched-chain pentoxy and hexoxy. 20 Unless otherwise stated or indicated, the term "C 1-6 alkoxyalkyl" denotes a straight or branched alkoxyalkyl group having from 1 to 6 carbon atoms. Examples of said lower alkoxyalkyl include methoxymethyl, ethoxymethyl, iso-propoxymethyl, n-butoxymethyl, t butoxyethyl and straight- and branched-chain pentoxymethyl. 25 The expression "C 2

-

6 alkenyl" as used herein refers to straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl, allyl, 2,3-dimethylallyl, 1-butenyl groups, 1-pentenyl, and 1-hexenyl groups.

WO 2004/000828 PCT/SE2003/001061 The expression "C 2

-

6 alkynyl" as used herein refers to straight-chained and branched alkynyl groups containing from 2 to 6 carbon atoms. Typical examples include ethynyl, 1 propynyl, 1-butynyl, 1-pentynyl, and 1-hexynyl groups. 5 Unless otherwise stated or indicated, the term "halogen" shall mean fluorine, chlorine, bromine or iodine. The term "alkylhalide" refers to an alkyl group substituted with one or more halogen groups (e.g., F, Cl, Br, I). 10 The term "C 3

-

7 cycloallcyl" denotes a cyclic alkyl group having a ring size from C 3 to C 7 , which can be saturated or partially unsaturated. Examples of said cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, methylcyclohexyl, cyclohexenyl, cyclohexadienyl, and cycloheptyl. 15 The term "C 5

-

10 cycloalkenyl" denotes a cyclic alkenyl group having a ring size from C 5 to C 1 0. Examples of said cycloalkenyl include 1-cyclopentyl, 2-cyclopentenyl, 1 cyclohexenyl, 1-cyclohepentyl, 1-cyclooctenyl, 1-cyclononenyl, and 1-cyclodecenyl groups. 20 The term "heterocyclic" refers to a hydrocarbon ring system containing 4 to 8 ring members that have at least one heteroatom (e.g., S, N, or 0) as part of the ring. It includes saturated, unsaturated, aromatic, and nonaromatic heterocycles. Suitable heterocyclic groups include thienyl, furyl, pyridyl, pyrrolidinyl, imidazolyl, pyrazolyl, piperidyl, 25 azepinyl, morpholinyl, pyranyl, dioxanyl, pyridazinyl, pyrimidinyl, and piperazinyl groups Unless otherwise stated or indicated, the term "aryl" refers to a hydrocarbon ring system having at least one aromatic ring. Examples of aryl groups include phenyl, cinnamyl, pentalenyl, indenyl, 1-naphthyl, 2-naphthyl, anthryl and phenanthryl. 30 WO 2004/000828 PCT/SE2003/001061 The term "heteroaryl" refers to a hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as 0, N, or S. Examples of heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, and indolyl groups. 5 Compounds of Formula (I) One object of the present invention is a compound having the general formula (I): P X Y I 10 3(I) or a pharmaceutically acceptable salt thereof, wherein: Wx WW D Y ring B is W or ; in which D is a five-membered heterocyclic or 15 heteroaryl ring, said heteroaryl ring comprising one or two atoms selected from the group consisting of nitrogen, sulfur and oxygen, with the proviso that when D contains an oxygen atom, D is heteroaryl; each W is independently -N-, -(CH)-, or -C- provided that not more than three groups W 20 are -N- in both rings A and B together; P is any one of formula (a), (b) or (c) WO 2004/000828 PCT/SE2003/001061 1R R 2:: o N-R S(O) ] ,or (a) (b) (c) wherein x =0, 1, or 2 and y = 0, 1, or 2; and P and R 3 can be attached to any carbon atom that allows the substitution in one of either the A- or B-ring, or when ring A contains at least one nitrogen atom and P is (c), 5 then P can also be attached to any nitrogen in ring B that allows the substitution; the dashed bonds denote that P and R 3 , respectively, may be attached to either the A or B ring; but each P or R 3 may not be simultaneously bound to both rings A and B; 10 R is (a) C 1

-

6 alkyl, (b) C 1

-

6 alkoxyalkyl, (c) straight-chained or branched C 1

-

6 hydroxyalkyl, (d) straight-chained or branched C1- 6 alkylhalides, 15 (e) aryl carbonylmethyl, (f) C 3

.

7 cycloalkyl, which is optionally partially unsaturated, (g) C3.

7 cycloalkyl-C1.6 alkyl, wherein the cyclic ring is optionally partially unsaturated, or (h) a group Ar; 20 wherein Ar is (a) phenyl, (b) 1-naphthyl, (c) 2-naphthyl, (d) aryl-C 1

.

6 alkyl, 25 (e) cinnamyl, WO 2004/000828 PCT/SE2003/001061 (f) a 5 to 7-membered, optionally aromatic, partially saturated or completely saturated, mono- or bi-cyclic heterocyclic ring, each containing 1 to 4 heteroatoms, selected from oxygen, sulfur, and nitrogen, (g) a bicyclic ring system comprising at least one heterocyclic ring according to (f) and a 5 group Ar, wherein the group Ar is substituted in one or more positions with (a) H, X or Y, or (b) a 5 to 7-membered, optionally aromatic, partially saturated or completely saturated, heterocyclic ring each containing 1 to 4 heteroatoms selected from 10 oxygen, nitrogen or sulfur; R2 is (a) H, (b) C 1

-

6 alkyl, 15 (c) C 2

-

6 alkoxyalkyl, (d) straight or branched C 1

.

6 hydroxyalkyl, or (c) straight or branched C 1 .6 alkylhalides; (f) a group Ar, 20 or R1 and R 2 are linked to form a group -CH 2

CH

2 0CH 2

CH

2 - or N

(CH

2 )v wherein v is 0-2, X and Y are independently (a) H, 25 (b) halogen, (c) C 1

.

6 alkyl, (d) CF 3 , (e) hydroxy, (f) C 1

-

6 alkoxy, WO 2004/000828 PCT/SE2003/001061 (g) C 2

-

6 alkenyl, (h) phenyl, (i) phenoxy, (j) benzyloxy, 5 (k) benzoyl, (1) -OCF 3 , (m) -CN, (n) straight or branched C 1

.

6 hydroxyalkyl, (o) straight or branched C 1

.

6 alkylhalides, 10 (p) -NH 2 , (q) -NHIR 4 , (r) -NR 4

R

5 , (s) -NO 2 , (t) -CONR 4

R

5 , 15 (u) -NHSO 2

R

4 , (v) -NR 4 COR, (x) -SO 2

NR

4

R

5 , (z) -C(=O)R 4 , (aa) -C0 2

R

4 , or 20 (ab) -S(O)nR 4 , wherein n is 0, 1, 2 or 3, (ac) -S-(C 1

.

6 ) alkyl, or (ad) -SCF 3 ; and

R

4 and R are independently 25 (a) H, (b) C 1

-

6 alkyl, (c) C 3

-

7 cycloalkyl, or (d) Ar, as defined above for R1; alternatively, R 4 and R 5 are linked to form a group -CH 2 0CH 2 -, -CH 2 CH20CH 2

CH

2 - or 30 (CH 2 )3-s; WO 2004/000828 PCT/SE2003/001061

R

3 is a group selected from any one of N N N O N-R Rq N NII N R( Rq Rq 16N '6 N R m RR N-R Rq R Rq Rq N N N N-R 6 N 16' 6 R 16 R R R R 0 ~0 0 Rq ]m N N Rq [ M 1 6 6/6W/NR R R R [0 N n N' N ind Rq Im Rq wherein R 3 is optionally substituted on each carbon atom that allows the 5 substitution with Rq groups, wherein Rq is independently H, or (C 1

.

6 ) alkyl, and wherein two Rq groups can be present on the same carbon atom simultaneously, wherein q= 1, 2, 3, 4, 5 or 6, m= 1 or 2, and 10 n= 0, 1 or 2;

R

6 is independently (a) H, (b) linear or branched C 1

.

6 alkyl, WO 2004/000828 PCT/SE2003/001061 (c) benzyl, (d) -CH 2

-CH

2 -OH, or (e) -CH 2

-CH

2 -0-C 1

.

6 alkyl; 5 P and R 3 can be attached to the same ring or to different rings of rings A and B; provided that R RI LO 2 1 O- R N.. R2_ when P is (a) or (b), and P and R 3 both are attached to ring A in the meta- or para-position relative to one another then R 3 is selected from any one of 0 1> -1-11 n' 0' R m m R R N N16 16 16 R1 R R R N-R N-R Rq Rq Rq

NN-R

6 NN 1 06 R R4 Rq ] NC I Y Rq wL ,w-iTY R -N, when ring B is w , and P is (a), then P and R 3 are simultaneously attached to the same ring A or B; WO 2004/000828 PCT/SE2003/001061 R S(O). when ring B is w , and Pis ' ,wherein y= 0, then P and R3 are attached to the different rings of rings A and B; when the ring system A + B is benzofurane or benzothiophene, and P is R S(O)., y 5 ' (c) and attached to position 3 in the A+B ring system, and R 3 is a group selected from any one of N N N [N> q CN ]m C]2 Im 6 R and attached to position 7 in the A+B ring system, then y 1 or 2; 10 when the ring system A + B is indole, and P is R (c) and P is attached to position 3 in the A+B ring system, and R is a group selected from any one of N ~ N N Rq Rq Rq and N NN 66 '6 N m N 15 R R R and R3 is attached to any one of positions 5, 6 or 7 in the A+B ring system, then y = 1 or 2; or WO 2004/000828 PCT/SE2003/001061 when ring B is W and R 1 = Ar is partially saturated bi-cyclic heterocyclic ring containing a N atom, the N atom in Ar cannot be attached to the S atom in P; with the proviso that: when rings A and B are both phenyl, P is any one of formula (a) or (c) substituted in 5 position 7 on the naphthalene ring, then R3 is not substituted in position 1 on the naphthalene ring; and with the proviso that: when ring D is a pyrrole ring, P is of the formula (c), then R 3 is not of the formula N N R q ]M Rq or Rq N N N N 16 16 6 R m R R6 10 substituted in position 3 on the pyrrole ring. A naphthalene ring has the following position numbers:

P

5 P 4

P

6 P3 P 7 P 2 15 Sa wherein P 1

-P

8 denote the position on the naphthalene ring. A pyrrole ring, as connected to an A ring, has the following position numbers: 20 WO 2004/000828 PCT/SE2003/001061

P

3 W" W N

P

1 wherein PI-P 3 denote the position on the pyrrole ring. 5 It is preferred that: R, is (a) C 1

-

6 alkyl, or (e) a group Ar; 10 Ar is (a) phenyl, (b) 1-naphthyl, (c) 2-naphthyl, or (f) a 5 to 7-membered, optionally aromatic, partially saturated or completely saturated, 15 heterocyclic ring containing 1 to 4 heteroatoms, selected from oxygen, nitrogen and sulfur, wherein the group Ar is substituted in one or more positions with (a) I, (b) halogen, (c) C 1

.

6 alkyl, 20 (d) -CF 3 , (f) C 1

.

6 alkoxy, (g) C 2

-

6 alkenyl (preferably C 2

-

4 alkenyl), (1) -OCF 3 , (m) straight or branched C 1

.

6 hydroxyalkyl, 25 (n) phenyloxy, (o) benzyloxy, (v) -NR 4 COR, (x) -SO 2

NR

4 5

,

WO 2004/000828 PCT/SE2003/001061 (z) -C(=O)R 4 , (ab) -S(O),R 4 , wherein n is 0, 1, 2 or 3; (ac) -S-(C 1

.

6 ) alkyl, or (ad) -SCF 3 ; 5

R

2 is (a) H, or (b) C 1

-

6 alkyl; 10 or RI and R2 are linked to form a group -CH 2

CH

2 0CH 2

CH

2 -; X and Y are H;

R

4 and R are each independently H or C1- 3 alkyl; and 15

R

3 is selected from any one of R N]m Rq Rq NI N N R R R 0 r0 0 4 R n Rn N-R Rq Im ]Rqt. RN 1 R Rq N-R N IM N N 16N 1 1 6 6 R and N R R R R wherein R 3 can be substituted on each carbon atom that allows the substitution with 20 Rq groups, wherein Rq is independently H, or C1- 6 alkyl, and wherein two Rq groups can be present on the same carbon atom simultaneously, wherein q= 1 or 2, m= 1 or 2, n = 0, and WO 2004/000828 PCT/SE2003/001061 R is independently (a) H, (b) C1.6 alkyl (preferably Cp3 alkyl), in particular methyl, (d) -CH 2

-CH

2 -OH, or 5 (e) -CH 2

-CH

2

-OCH

3 . It is especially preferred that R 3 is selected from any one of Ox N 0 R R N R N R R Rq Imq N N N N 6 I I and NR wherein R can be substituted on each carbon atom that allows the substitution with 10 Rq groups, wherein Rq is independently H, or CI 2 alkyl, and wherein two Rq groups can be present on the same carbon atom simultaneously, wherein q = 1 or 2, m= I or 2; and R6 is independently 15 (a) H, (b) CI-3 alkyl, (d) -CH 2

-CH

2 -OH, or (e) -CH 2

-CH

2

-OCH

3 . 20 It is also preferred that R 3 is selected from any one of 1o --- - Sn R 0 N-R Rq NM qm Nf m' R9< -61~ R an d N6 6m N 16 ad N R R R R R wherein R3 can be substituted on each carbon atom that allows the substitution with Rq groups, wherein Rq is independently H, or C 1

-

6 alkyl, and wherein two Rq groups can be present on the same carbon atom simultaneously, wherein WO 2004/000828 PCT/SE2003/001061 q= 1 or 2, m= 1 or 2, n= 0, and R' is independently 5 (a) H, (b) C 1

.

3 alkyl, (d) -CH 2

-CH

2 -OH, or (e) -CH 2

-CH

2

-OCH

3 . 10 It is also preferred that R 3 is selected from any one of N N N N Nr NIjI N N NN '6 16 6 16 6 R R R R R N

-

N N N N NNN 16 R 6 6 R6R R/ R R

R

6 is independently (a) H, 15 (b) C 1

.

3 alkyl, (d) -CH 2

-CH

2 -OH, or (e) -CH 2

-CH

2

-OCH

3 . It is preferred that R 6 is H or methyl. 20 It is also preferred that R 3 is piperazine; homopiperazine; 2,6-dimethylpiperazine; 3,5 dimethylpiperazine; 2,5-dimethylpiperazine; 2-methylpiperazine; 3-methylpiperazine; 2,2-dimethylpiperazine; 3,3-dimethylpiperazine; piperidine; 1,2,3,6-tetrahydro-pyrazine; or 4-pyrrolidin-3-yloxy.

WO 2004/000828 PCT/SE2003/001061 It is preferred that the groups Y and X are attached to any unsubstituted carbon atom. It is preferred that D is pyrrolyl, thienyl or furanyl. 5 It is preferred that P is R S(O), ''- (c) wherein R', x, and y are as defined in claim 1. 10 It is also preferred that P is R R 1 -2 LO N-R S:O OZ R N' O0 (a) or ' (b) wherein R 1 and R 2 are as defined in claim 1. It is preferred that R 2 is H. 15 Another object of the present invention is a compound of the general formula (II) R Y x N R wherein R 1 , x, y, X, and Y are as defined in claim 1, and R 3 is as defined in claim 2. 20 It is preferred that y = 0 and x = 2. Another object of the present invention is a compound of the general formula (III) WO 2004/000828 PCT/SE2003/001061 R\ Y N Y R 3 wherein R', x, y, X, and Y are as defined in claim 1, and R 3 is as defined in claim 2. It is preferred that y = 0 and x= 2 5 Another object of the present invention is a compound of the general formula (IV) X DY

R

3 (y) wherein P is of the formula (c), R 1 , x, y, X, and Y are as defined in claim 1, and R3 is as defined in claim 2, and 10 wherein D is a five-membered heteroaryl ring, said ring comprising one or two atoms selected from the group consisting of nitrogen, sulfur and oxygen; and when the heteroaryl ring comprises one or two nitrogen atoms, a group R 6 is attached at any nitrogen atom which allows the substitution. 15 It is preferred that D is a thiophene and P is attached to the D ring, giving a skeleton as any of the following: N IN NS S 20 It is also preferred that D is pyrrole and P is attached to the nitrogen atom in the D ring, giving a skeleton as any of the following: WO 2004/000828 PCT/SE2003/001061 H NNNH N / H It is also preferred that D is furan and P is attached to the D ring, giving a skeleton as any of the following: 5 N N O N > NN 0 0 Another object of the present invention is a compound of the general formula (V) P X DY 10 wherein P is of the formula (c) as defined in claim 1, R', x, y, X, Y, and R3 are as defined in claim 1, and wherein D is a five-membered heteroaryl ring, said heteroaryl ring comprising one or two atoms selected from the group consisting of nitrogen, sulfur and oxygen; and when the heteroaryl ring comprises one or two nitrogen atoms, a group R 6 is attached at any nitrogen 15 atom which allows the substitution. Another object of the present invention is a compound of the general formula (V) P X Y R (V) wherein P is of the formula (a) or (b) as defined in claim 1, preferably wherein R2 is H, X, 20 Y, and R are as defined in claim 1, and wherein D is a five-membered heteroaryl ring, said heteroaryl ring comprising one or two atoms selected from the group consisting of nitrogen, sulfur and oxygen; and when the WO 2004/000828 PCT/SE2003/001061 heteroaryl ring comprises one or two nitrogen atoms, a group R6 is attached at any nitrogen atom which allows the substitution. Another object of the present invention is a compound of the general formula (VI) 5 x (VI) wherein P is of the formula (a) or (b) as defined in claim 1, preferably wherein R 2 is H, X and Y are as defined in claim 1, and R 3 is as defined in claim 2. 10 Another object of the present invention is a compound of the general formula (VII) R 3 i 0 Yy X (VII) wherein P is of the formula (a) or (b) as defined in claim 1, preferably wherein R 2 is H, X and Y are as defined in claim 1, and R 3 is as defined in claim 4. 15 Another object of the present invention is a compound of the general formula (VIII)

R

3 N X (VIII) wherein P is of the formula (a) or (b) as defined in claim 1, preferably wherein R 2 is H, X, Y, and R 3 are as defined in claim 1. 20 Another object of the present invention is a compound of the general formula (IX) NAN X R (IX) wherein R 7 in formula (IX) is: (a) H, (b) C 1

.

6 alkyl, WO 2004/000828 PCT/SE2003/001061 (c) benzyl, (d) -CH 2

-CH

2 -OH, or (e) CH 2

-CH

2 -0-CH 3 , and wherein P is of the formula (a) or (b) as defined in claim 1, preferably wherein R 2 is H, X, 5 Y, and R 3 are as defined in claim 1. Another object of the present invention is a compound of the general formula (X) 3 N R y x (X) 10 wherein P is of the formula (a) or (b) as defined in claim 1, preferably wherein R is H, X, Y, and R3 are as defined in claim 1. Another object of the present invention is a compound of the general formula (XI) P Y 15 R (XI). wherein P is of the formula (a) or (b) as defined in claim 1, preferably wherein R 2 is H, X and Y are as defined in claim 1, and R 3 is as defined in claim 4. 20 Another object of the present invention is a compound of the general formula (XII): P Y--A (W, XI

R

3

(XII)

WO 2004/000828 PCT/SE2003/001061 or a pharmaceutically acceptable salt thereof, wherein P and R 3 are attached to the same ring or to different rings of rings A and B, wherein A, B, Y, P, and R 3 are as defined in claim 1. 5 Preferred compounds of the formula (II) are 6-Benzenesulfonyl-4-piperazin-1-yl-quinoline hydrochloride; 6-[(2-Fluorophenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride; 6-(1-Naphthylsulfonyl)-4-piperazin-1-ylquinoline hydrochloride; 6-[(3,4-Dichlorophenyl)sulfonyl] -4-piperazin-1 -ylquinoline hydrochloride; 10 6-[(3,5-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride; 6-[(2-Chloro-6-methylphenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride; 6-[(4-Chlorophenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride; 6-[(2-Methyl,4-tert-butyl-phenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride; 6-[(3,4-Dimethylphenyl)sulfonyl]-4-piperazin- 1 -ylquinoline hydrochloride; 15 6-[(2,3-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride; 6-[(4-tert-Butylphenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride; 6-[(4-Isopropylphenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride; (4-Piperazin-1-yl-6- {[4-(trifluoromethyl)phenyl]sulfonyl}quinoline hydrochloride; 6-[(4-tert-Butylphenyl)sulfonyl]-4-(1,4-diazepan-1-yl)quinoline hydrochloride; and 20 4-(1,4-Diazepan-1-yl)-6-[(4-isopropylphenyl)sulfonyl]quinoline hydrochloride. Preferred compounds of the formula (III) are 7-(2-Chloro-6-methyl-benzenesulfonyl)- 1 -piperazin- 1 -yl-isoquinoline hydrochloride; 7-(2-t-Butyl-benzenesulfonyl)- 1 -piperazin- 1 -yl-isoquinoline hydrochloride; 25 7-(3,4-Dichloro-benzenesulfonyl)-l-piperazin-1-yl-isoquinoline hydrochloride; 7-(2,4-Dimethyl-benzenesulfonyl)- 1 -piperazin- 1 -yl-isoquinoline hydrochloride; 7-(2,5-Dimethyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinoline hydrochloride; 7-(p-Chloro-benzenesulfonyl)- 1 -piperazin- 1 -yl-isoquinoline hydrochloride; 7-Benzenesulfonyl-1 -[1,4]diazepan-I -yl-isoquinolinehydrochloride; 30 7-(4-tert-Butyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline, hydrochloride; 7-(2-Chloro-6-methyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline hydrochloride; 7-(3,5-Dimethyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline hydrochloride; WO 2004/000828 PCT/SE2003/001061 7-(3,4-Dichloro-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline hydrochloride; 7-(4-Chloro-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline hydrochloride; 7-(3,4-Dimethyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline hydrochloride; 7-(2-tert-Butyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline hydrochloride; 5 7-Benzenesulfonyl-1-piperazin-yl-isoquinoline hydrochloride; and 7-(4-tert-Butyl-benzenesulfonyl- 1 -piperazin-yl-isoquinoline hydrochloride Preferred compounds of the formula (IV) are 4-(1,4-Diazepan-1-yl)-2-(phenylsulfonyl)thieno[3,2-c]pyridine hydrochloride; 10 4-(1,4-Diazepan-1-yl)-2-[(3,4-dichlorophenyl)sulfonyl]thieno[3,2-c]pyridine hydrochloride; 4-(1,4-Diazepan-1-yl)-2-[4-tert-butylphenylsulfonyl)thieno[3,2-c]pyridine hydrochloride; 4-(1,4-Diazepan-1-yl)-2-[4-tert-butylphenylsulfonyl)thieno[3,2-c]pyridine hydrochloride; 4-(1,4-Diazepan-1-yl)-2-[3,4-dimethylphenylsulfonyl)thieno[3,2-c]pyridine hydrochloride; 15 2-[(4-Bromophenyl)sulfonyl]-4-(1,4-diazepan-1-yl)thieno[3,2-c]pyridine hydrochloride; 2-(Phenylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-(3-Methoxy-benzenesulfonyl)-4-piperazin-1-yl-thieno[3,2-c]pyridine hydrochloride; 2-(4-Methoxy-benzenesulfonyl)-4-piperazin-1-yl-thieno[3,2-c]pyridine hydrochloride; 4-Piperazin-1-yl-2-{[4-trifluoromethyl)phenyl]sulfonyl}thieno[3,2-c]pyridine 20 hydrochloride; 2-[[2-tert-Butylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-[(3,4-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride; 2-[(4-tert-Butylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 25 2-(1-Naphthyl sulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-[(3-Fluorophenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride; 2-(Mesitylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-[(2-Methoxyphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 30 2-[(2,4-Dimethoxyphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-[(2,4-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-[(2,5-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; WO 2004/000828 PCT/SE2003/001061 2-[(2-Ethylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 4-(Piperazinyl)-2-(3 -methoxybenzyl-sulfonyl)-thienopyridine hydrochloride; 2-(Benzylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 4-Piperazin-1-yl-2- {[4-(trifluoromethyl)benzyl]sulfonyl}thieno[3,2-c]pyridine 5 hydrochloride; 2-[(3-Bromobenzyl)sulfony]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-[(2,3-Difluorobenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-[(4-Bromobenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-{[2,5-bis(Trifluoromethyl)benzy]sulfonyl}-4-piperazin-1-ylthieno[3,2-c]pyridine 10 hydrochloride; 2-[(4-Methylbenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-{15-Chloro-2-(trifluoromethyl)benzyl]sulfony}-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-[(3,5-Dimethoxybenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 15 2-[(2-Naphthylmethyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 4-Piperazin-1-yl-2-{[4-(1,2,3-thiadiazol-4-yl)benzyl]sulfonyl}thieno[3,2-c]pyridine hydrochloride; 1-(4-Pyrrolidin-1-ylphenyl)-2-[(4-piperazine-1-yltbieno[3,2-c]pyridin-2-yl) sulfonyl] ethanone hydrochloride; and 20 1-[4-(Diethylamino)phenyl]-2-[(4-piperazine-1-ylthieno[3,2-c]pyridin-2-yl) sulfonyl] ethanone hydrochloride. Also preferred compounds of the formula (IV) are 1-(4-Methylphenylsulphonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine hydrochloride; 25 1-(3-Chloro-2-methylphenylsulphonyl)-4-piperazin-1-yl-lH-pyrrolo[3,2-c]pyridine hydrochloride; 1-(3,4-Dimcthoxyphenylsulphonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine hydrochloride; 4-(4-Piperazin-1-yl-pyrrolo[3,2-c]pyridine-1-sulfonyl)-benzonitrile hydrochloride; 30 1-(4,5-Dichloro-thiophene-2-sulfonyl)-4-piperazin-1-yl-IH-pyrrolo[3,2-c]pyridine hydrochloride; WO 2004/000828 PCT/SE2003/001061 1-(2-Chloro-4-fluorophenylsulphonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine hydrochloride; 1-Phenylmethanesulfonyl-4-piperazin-1-yl-1H-pyrrolo [3,2-c]pyridine hydrochloride; 1-(5-Chloro-thiophene-2-sulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine 5 hydrochloride; 1-(4-Butyl-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo(3,2-c)pyridine hydrochloride; 1-(4-Phenoxy-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo(3,2-c)pyridine hydrochloride; 1-(Phenylsulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine hydrochloride; 1-[(4-Chlorophenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine hydrochloride; 10 1-[(4-Methoxyphenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine hydrochloride; 1-[(2-Methoxy-5-methylphenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine hydrochloride; and 4-Piperazin-1-yl-1-{[2-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrolo[3,2-c]pyridine hydrochloride. 15 Preferred compounds of the formula (VI) are N-(4-Methylphenyl)-4-(4-methylpiperazin-1-yl)thieno[3,2-c]pyridine-2-sulfonamide hydrochloride; 2-Bromo-4-(4-methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-3-sulfonic acid p-tolylamide 20 hydrochloride; 4-(4-Methylpiperazin-1-yl)-n-phenylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (3-fluoro-5-trifluoromethyl-phenyl) amide hydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (4-chloro-phenyl)-amide 25 hydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (4-isopropyl-phenyl)-amide hydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acidp-tolylamide hydrochloride; 4-(4-Methylpiperazin-1-yl)-N- (2-cyclohex-1-en-1-ylethyl) thieno [3,2-c] pyridine-2 30 sulfonamide hydrochloride; 2-(4-(4-Methylpiperazin-1-yl) thieno [3,2-c] pyridin-2-ylsulfony)-1,2,3,4 tetrahydroisoquinoline hydrochloride; WO 2004/000828 PCT/SE2003/001061 4-(4-Methylpiperazin-1-yl)-N- (2-thien-2-ylethyl) thieno [3,2-c] pyridine-2-sulfonamide hydrochloride; 4-(4-Methylpiperazin-1-yl)-N- [1-(1-naphthyl) ethyl] thieno [3,2-c] pyridine-2-sulfonamide hydrochloride; 5 4-(4-Methylpiperazin-1-yl)-N- (4-hexylphenyl) thieno [3,2-c] pyridine-2-sulfonamide hydrochloride; N- (3-Chlorobenzyl)-4-(4-methylpiperazin-1-yl) thieno [3,2-c] pyridine-2-sulfonamide; 4-(4-Methylpiperazin-1-yl)-N- [1-(4-fluorophenyl) ethyl] thieno [3,2-c] pyridine-2 sulfonamide hydrochloride; 10 N- (2,3-Difluorobenzyl)-4-(4-methylpiperazin-1-yl) thieno [3,2-c] pyridine-2-sulfonamide hydrochloride; 4-(4-Methylpiperazin- 1 -yl)-N- (4-chloro-2, 5-dimethoxyphenyl) thieno [3,2-c] pyridine-2 sulfonamide hydrochloride; 2-Bromo-4- (4-methylpiperazin-1-yl)-N- (2-cyclohex-1-en-1-ylethyl) thieno [3,2-c] 15 pyridine-3-sulfonamide hydrochloride; 2-Bromo-4- (4-methylpiperazin-1-yl)-N- [(1S)-1-(2-naphthyl) ethyl] thieno [3,2-c] pyridine-3-sulfonamide hydrochloride; 2-Bromo-4- (4-methylpiperazin-1-yl)-N- [1-(4-fluorophenyl) ethyl] thieno [3,2-c] pyridine 3-sulfonamide hydrochloride; 20 2-Bromo-4- (4-methylpiperazin-1-yl)-N- (2,4,5-trimethoxyphenyl) thieno [3,2-c] pyridine 3-sulfonamide; N-(3,4-Dichlorophenyl)-4-piperazin-1 -ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride; N-(2,4-Difluorophenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide 25 hydrochloride; 4-Piperazin-1-yl-N-[-3-(trifluoromethyl)phenyl]thieno[3,2-c]pyridine-2-sulfonamide hydrochloride; N-(3-Ethylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride; N-(3,4-Dimethoxyphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide 30 hydrochloride; N-(4-Bromo-2-methylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride; WO 2004/000828 PCT/SE2003/001061 2-(4-Piperazin- 1 -yl-thieno[3,2-c]pyridine-2-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (2-thiophen-2-yl-ethyl)-amide hydrochloride; 5 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (4-chloro-2,5-dimethoxy-phenyl) amide hydrochloride; 4-Piperazin-1 -yl-thieno[3,2-c]pyridine-2-sulfonic acid phenethyl-amide hydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (2,6-diethyl-phenyl)-amide hydrochloride; 10 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (3-phenyl-propyl)-arnide hydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (3,3-diphenyl-propyl)-amide hydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid [2-(5-methoxy-1H-indol-3-yl) 15 ethyl]-anide hydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid 4-trifluoromethyl-benzylamide hydrochloride; 4-Piperazin-1 -yl-thieno[3,2-c]pyridine-2-sulfonic acid benzyl-ethyl-amide hydrochloride; N-(3-Ethylphenyl)-4-piperazin- 1 -ylthieno[3,2-c]pyridine-3-sulfonamide hydrochloride; 20 N-(4-Isopropylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-3-sulfonamide hydrochloride; N-(4-Methylphenyl)-4-(pyrrolidin-3-yloxy)thieno[3,2-c]pyridine-2-sulfonamide hydrochloride; N-(4-Methylpheny1)-4-(piperidin-4-yloxy)thieno[3,2-c]pyridine-2-sulfonamide 25 hydrochloride; N-(2,3-Difluorobenzyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride; N-(3-Chlorobenzyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride; 4-Piperazin- 1 -yl-thieno[3,2-c]pyridine-2-sulfonic acid phenylamide hydrochloride; 30 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (4-tert-butyl-phenyl)-amide hydrochloride; WO 2004/000828 PCT/SE2003/001061 4-(4-Methyl-piperazin- 1 -yl)-thieno[3,2-c]pyridine-2-sulfonic acid phenylamide hydrochloride; 4-(4-Methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-2-sulfonic acid (3-chloro-phenyl)-amide hydrochloride; 5 2-Bromo-4-(4-methyl-piperazin- 1 -yl)-thieno[3,2-c]pyridine-3-sulfonic acid phenylamide hydrochloride; 4-(4-Methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-3-sulfonic acid (4-methylphenyl)-amide hydrochloride; and N-Phenyl-7-piperazin- 1 -ylthieno[2,3-c]pyridine-2-sulfonamide hydrochloride. 10 Preferred compounds of the formula (VII) are N-(4-methylphenyl)-4-piperazin-1 -ylfuro[3,2-c]pyridine-2-sulfonamide hydrochloride; N-phenyl-4-piperazin- 1 -ylfuro[3,2-c]pyridine-2-sulfonamide hydrochloride; and N-phenyl-7-piperazin-1-ylfuro[2,3-c]pyridine-2-sulfonamide hydrochloride. 15 A preferred compound of the formula (VIII) is 4-Piperazin-1-yl-thiazolo[4,5-c]pyridine-2-sulfonic acid phenylamide hydrochloride. Preferred compounds of the formula (IX) are 20 N-(4-methylphenyl)-4-piperazin-1-yl-1H-pyrrolo[ 3 ,2-c]pyridine-2-sulfonamide hydrochloride; N-phenyl-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine-2-sulfonamide hydrochloride; and N-phenyl-7-piperazin-1-yl-1H-pyrrolo[2,3-c]pyridine-2-sulfonamide hydrochloride. 25 Preferred compounds of the formula (X) are 4-Chloro-N-[4-(pyrrolidin-3-yloxy)-1-naphthyl]benzenesulfonamide hydrochloride; 4-Methoxy-N-[4-(pyrrolidin-3-yloxy)-1-naphthyl]benzenesulfonamide hydrochloride; 5-Chloro-N-[4-(pyrrolidin-3-yloxy)-l-naphthyl]thiophene-2-sulfonamide hydrochloride; 4-Chloro-N-[4-(piperidin-3-yloxy)-1-naphthyl]benzenesulfonamide hydrochloride; 30 4-Methoxy-N-[4-(piperidin-3-yloxy)-1-naphthyl]benzenesulfonamide hydrochloride; 5-Fluoro-2-methyl-N-[4-(piperidin-4-yloxy)-1-naphthyl]benzenesulfonamide hydrochloride; WO 2004/000828 PCT/SE2003/001061 5-Chloro-N-[4-(piperidin-4-yloxy)-1-naphthyl]thiophene-2-sulfonamide hydrochloride; 4-Chloro-N-{4-[(3S)-pyrrolidin-3-yloxy]-1-naphthyl}benzenesulfonamide hydrochloride; and 4-Chloro-N-{4-[(3R)-pyrrolidin-3-yloxy]-1-naphthyl}benzenesulfonamide hydrochloride. 5 Another object of the present invention is a process for the preparation of a compound above, said method comprising the steps of: (a) Mitsonobu reaction of 4-nitro-1 -naphthol with boc-protected 3-hydroxypyrrolidine or 4-hydroxypiperidine; 10 (b) reduction of the nitro group in the nitronaphthalene obtained in step (a) to form an aminonaphthalene derivative; and (c) synthesis of a sulfonamide by reacting the aminonaphthalene obtained in step (b) with a suitable sulfonyl chloride. 15 Another object of the present invention is a process for the preparation of a compound above, wherein R 0 P is , said method comprising the steps of: preparation of the heteroaromatic 5-member ring fused halogen-substituted pyridine, reduction of an aromatic nitro group; aromatic nucleophilic substitution with a thiol via a 20 diazointermediate; oxidation of the thiol derivative to a sulphone; introduction of a halogen atom by electrophilic aromatic substitution; aromatic nucleophilic substitution of the halogen with a dianine. Another object of the present invention is a process for the preparation of a compound 25 above, wherein R 1 2 N-R P is + , said method comprising the steps of: preparation of the heteroaromatic 5 member ring fused pyridine; introduction of a carboxylic moiety; conversion of the WO 2004/000828 PCT/SE2003/001061 carboxylic moiety to amine by Curtius rearrangement; reaction of the amine group with a sulphonylchloride. Another object of the present invention is a process for the preparation of a compound 5 above, wherein

RI

P is , said method comprising the steps of: preparation of the heteroaromatic 5 member ring fused pyridine; introduction of sulfonylchloride moiety by nucleophilic addition; reaction of sulphonylehloride moiety with an aniline to obtained a sulfonamide; aromatic nucleophilic substitution of the chloro with a diamine. 10 All diastereomeric forms possible (pure enantiomers, tautomers, racemic mixtures and unequal mixtures of two enantiomers) are within the scope of the invention. Such compounds can also occur as cis- or trans-, E- or Z- double bond isomer forms. All isomeric forms are contemplated. 15 The compounds of the formulae (I) to (XII) may be used as such or, where appropriate, as pharmacologically acceptable salts (acid or base addition salts) thereof. The pharmacologically acceptable addition salts as mentioned above are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that the compounds 20 are able to form. Compounds that have basic properties can be converted to their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid. Exemplary acids include inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulphuric acid, phosphoric acid; and organic acids such as acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic 25 acid, maleic acid, malonic acid, oxalic acid, benzenesulphonic acid, toluenesulphonic acid, methanesulphonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid and the like. Exemplary base addition salt forms are the sodium, potassium, calcium salts, and salts with pharmaceutically acceptable amines such as, for example, ammonia, WO 2004/000828 PCT/SE2003/001061 alkylamines, benzathine, and amino acids, such as, e.g. arginine and lysine. The term addition salt as used herein also comprises solvates which the compounds and salts thereof are able to form, such as, for example, hydrates, alcoholates and the like. 5 For clinical use, the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. Pharmaceutical formulations are usually prepared by mixing the active substance, or a pharmaceutically acceptable salt thereof, with conventional pharmaceutical excipients. The formulations can be further prepared by known 10 methods such as granulation, compression, microencapsulation, spray coating, etc. The formulations may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections. Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules may be 15 coated in a conventional manner. Another object of the present invention is a compound above for use in therapy. Another object of the present invention is a compound above, and for the case when rings 20 A and B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R3 is substituted in position 1 on the naphthalene ring, for use in the treatment or prophylaxis of a 5-HT 6 receptor related disorder, such as obesity, type II diabetes, and/or disorders of the central nervous system, to achieve reduction of body weight and of body weight gain. 25 Another object of the present invention is a compound above for use in the treatment or prophylaxis of disorders of the central nervous system. Another object of the present invention is a compound above, for the case when rings A 30 and B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R 3 is substituted in position 1 on the naphthalene ring, and for the case when ring D is a pyrrole ring, P is of the formula (c) and R 3 is of the formula WO 2004/000828 PCT/SE2003/001061 N N Rq N1m Rq or Rq N N N N 16 6 6 R m R 6 substituted in position 3 on the pyrrole ring, for use in the treatment or prophylaxis of type 5 II diabetes. Another object of the present invention is a compound above, and for the case when ring D is a pyrrole ring, P is of the formula (c) and R 3 is of the formula N N Rq Rq or Rq N N N N 16 16 6 R m R 16 10 substituted in position 3 on the pyrrole ring, for use in the treatment or prophylaxis of obesity, to achieve reduction of body weight and of body weight gain. 15 Another object of the present invention is a pharmaceutical formulation comprising a compound above as an active ingredient, in combination with a pharmaceutically acceptable diluent or carrier. Another object of the present invention is a pharmaceutical formulation comprising a 20 compound above, and for the case when rings A and B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R 3 is substituted in position 1 on the naphthalene ring, as an active ingredient, for use in the treatment or WO 2004/000828 PCT/SE2003/001061 prophylaxis of a 5-HT 6 receptor related disorder, such as obesity, type II diabetes, and/or disorders of the central nervous system, to achieve reduction of body weight and of body weight gain. 5 Another object of the present invention is a compound above as an active ingredient, for use in the treatment or prophylaxis of disorders of the central nervous system. Another object of the present invention is a pharmaceutical formulation comprising a compound above, for the case when rings A and B are both phenyl, P is any one of formula 10 (a) or (c) substituted in position 7 on the naphthalene ring, and R 3 is substituted in position 1 on the naphthalene ring, and for the case when ring D is a pyrrole ring, P is of the formula (c) and R3 is of the formula N N R- Rq or Rq N N N N 66 6 15 substituted in position 3 on the pyrrole ring, as an active ingredient, for use in the treatment or prophylaxis of type II diabetes. Another object of the present invention is a pharmaceutical formulation comprising a 20 compound above, and for the case when ring D is a pyrrole ring, P is of the formula (c) and

R

3 is of the formula WO 2004/000828 PCT/SE2003/001061 N N Rq Rq or Rq N N N N 16 6 16 R mR1 R substituted in position 3 on the pyrrole ring, as an active ingredient, for use in the treatment or prophylaxis of obesity, to achieve reduction of body weight and of body weight gain. 5 Another object of the present invention is a method for the treatment or prophylaxis of a 5

HT

6 receptor related disorder, such as obesity, type II diabetes, and/or disorders of the central nervous system, to achieve reduction of body weight and of body weight gain, which comprises administering to a subject (e.g., a mammal, a human, a horse, a dog, or a 10 cat) in need of such treatment an effective amount of one or more compounds of any of the formulae described above, their salt forms or compositions that include the compounds or their salt forms, and for the case when rings A and B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R is substituted in position 1 on the naphthalene ring. 15 Another object of the present invention is a method for the treatment or prophylaxis of disorders of the central nervous system, which comprises administering to a subject in need of such treatment an effective amount of one or more compounds of any of the formulae described above, their salt forms or compositions that include the compounds or their salt 20 forms. Another object of the present invention is a method for the treatment or prophylaxis of type II diabetes, which comprises administering to a subject in need of such treatment an effective amount of one or more compounds of any of the formulae described above, their 25 salt forms or compositions that include the compounds or their salt forms, for the case when rings A and B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R 3 is substituted in position 1 on the naphthalene WO 2004/000828 PCT/SE2003/001061 ring, and for the case when ring D is a pyrrole ring, P is of the formula (c) and R3 is of the formula N N Rq m Rq or Rq N N N N 16 R 16 R m R R 5 substituted in position 3 on the pyrrole ring. Another object of the present invention is a method for the treatment or prophylaxis of obesity, which comprises administering to a subject in need of such treatment an effective 10 amound of one or more compounds of any of the formulae described above, their salt forms or compositions that include the compounds or their salt forms, and for the case when ring D is a pyrrole ring, P is of the formula (c) and R3 is of the formula N N R Rq or Rq N N N N 6 16 6 R m R R6 15 substituted in position 3 on the pyrrole ring. Another object of the present invention is a method for modulating 5-HT 6 receptor activity, comprising administering to a subject in need thereof an effective amount of one 20 or more compounds of any of the formulae described above, their salt forms or compositions that include the compounds or their salt forms.

WO 2004/000828 PCT/SE2003/001061 Another object of the present invention is the use of one or more compounds of any of the formulae described above, their salt forms or compositions that include the compounds or their salt forms, and for the case when rings A and B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R3 is substituted in 5 position 1 on the naphthalene ring, for the manufacture of a medicament for use in the treatment or prophylaxis of a 5-HT 6 receptor related disorder, such as obesity, type II diabetes, and/or disorders of the central nervous system, to achieve reduction of body weight and of body weight gain. 10 Another object of the present invention is the use of one or more compounds of any of the formulae described above, their salt forms or compositions that include the compounds or their salt forms for the manufacture of a medicament for use in the treatment or prophylaxis of disorders of the central nervous system. 15 Another object of the present invention is the use of one or more compounds of any of the formulae described above, their salt forms or compositions that include the compounds or their salt forms, for the case when rings A and B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R3 is substituted in position 1 on the naphthalene ring, and for the case when ring D is a pyrrole ring, P is of the 20 formula (c) and R3 is of the formula qN m N R RR or Rq N N N N 6 6 6 R m R R substituted in position 3 on the pyrrole ring, for the manufacture of a medicament for use 25 in the treatment or prophylaxis of type II diabetes.

WO 2004/000828 PCT/SE2003/001061 Another object of the present invention is the use of one or more compounds of any of the formulae described above, their salt forms or compositions that include the compounds or their salt forms, and for the case when ring D is a pyrrole ring, P is of the formula (c) and

R

3 is of the formula 5 N N R im Rg or Rq N N N N 16 16 6 R m R R6 substituted in position 3 on the pyrrole ring, for the manufacture of a medicament for use in the treatment or prophylaxis of obesity, to achieve reduction of body weight and of body 10 weight gain. The methods delineated herein can also include the step of identifying that the subject is in need of treatment of obesity, type II diabetes, or disorders of the central nervous system, or in need of reducing body weight and of body weight gain. 15 The invention further relates to cosmetic use of one or more compounds of any of the formulae described herein, for causing loss of weight, as well as cosmetic compositions containing said compounds. 20 Still further, the invention relates to a non-therapeutic metod for impriving the bodily appearance of a mammal, including a human, in which the method comprises orally administering to said mammal one or more compounds of any of the formulae described herein. 25 "An effective amount" refers to an amount of a compound that confers a therapeutic effect on the treated subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).

WO 2004/000828 PCT/SE2003/001061 For clinical use, the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. Usually the amount of active compounds is between 0.1-95% by weight of the preparation, preferably 5 between 0.2-20% by weight in preparations for parenteral use and preferably between 1 and 50% by weight in preparations for oral administration. The typical daily dose of the active substance varies within a wide range and will depend on various factors such as, for example, the individual requirement of each patient and the 10 route of administration. In general, oral and parenteral dosages will be in the range of 5 to 1000 mg per day of active substance, preferably 50 to 150 mg per day. Processes for preparation In a further aspect the invention relates to methods of making compounds of any of the 15 formulae herein comprising reacting any one or more of the compounds of the formulae delineated herein, including any processes delineated herein. The compounds of the formulae above may be prepared by, or in analogy with, conventional methods, and especially according to or in analogy with the following methods. 20 The chemicals used in the above-described synthetic route may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents. The methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compounds of any of the formulae described above, their 25 salt forms, or compositions that include the compounds or their salt forms. In addition, various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing applicable compounds are known in the art and include, for example, those described in R. Larock, 30 Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2 "d Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagentsfor Organic Synthesis, John WO 2004/000828 PCT/SE2003/001061 Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia ofReagentsfor Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof. The specific examples below are to be construed as merely illustrative, and not limitative 5 of the remainder of the disclosure in any way whatsoever. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. All publications cited herein are hereby incorporated by reference in their entirety. 10 Methods 1H nuclear magnetic resonance (NMR) and 1 3 C NMR were recorded on a Bruker Advance DPX 400 spectrometer at 400.1 and 100.6 MHz, respectively. All spectra were recorded using residual solvent or tetramethylsilane (TMS) as internal standard. IR spectra were recorded on a Perkin-Elmer Spectrum 1000 FT-IR spectrophotometer. Ionspray mass 15 spectrometry (MS) spectra were obtained on a Perkin-Elmer API 150EX mass spectrometer. Accurate mass measurements were performed on a Micromass LCT dual probe. Preparative HPLC/MS was performed on a Waters/Micromass Platform ZQ system equipped with System A: ACE 5 C8 column (19x5Omm), eluents: MilliQ water, McCN and MilliQ/MeCN/0.1%TFA and system B: Xterra MS C18, 5grm column (19x5Omm), 20 eluents: MilliQ water, MeCN and NH 4

HCO

3 (100mM). Analytical HPLC were performed on Agilent 1100, column: ACE 3 C8 (system A) or column: YMC-Pack (system B), eluents: MilliQ/0. 1 %TFA and MeCN. Elemental analyses were performed on a Vario El instrument. Preparative flash chromatography was performed on Merck silica gel 60 (230 400 mesh). 25 Table 1 R6 R4 30 30 N WO 2004/000828 PCT/SE2003/001061 EXAMPLE R 1 6-Benzenesulfonyl-4-piperazin-1 -yl-quinoline hydrochloride 9N 2 6-[(2-Fluorophenyl)sulfonyl]-4-piperazin-1-ylquinoline CN) hydrochloride qK)F N 3 6-(l -Naphthylsulfonyl)-4-piperazin-1-ylquinoline hydrochloride 0 N 4 6-[(3,4-Dichloropheny)sulfony1]-4-piperazin-1 -ylquinoline C1 hydrochloride NNI 0 5 6-[(3,5-Dimethylphenyl)sulfonyl]-4-piperazin-1 -ylquinoline(N hydrochloride N 6 6-[(2-Chloro-6-methylphenyl)sulfonyl]-4-piperazin- 1- (N ylquinoline hydrochloride OfCI N 7 6-[(4-Chlorophenyl)sulfonyl]-4-piperazin-1.ylquinoline C1 N) hydrochlorideN 8 6-[(2-Methyl,4-tert-butyl-phenyl)sulfonyl]-4-piperazin-1- CN ylquinolmne hydrochloride N) 9 6- [(3 ,4-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylquinoline CN hydrochloride N K 10 6-[(2,3-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride 0N I1I 6

-[(

4 -tert-Butylphenyl)sulfonyl]-4-piperazin-1-ylquinoline N hydrochloride 0 WO 2004/000828 PCT/SE2003/001061 12 6-[(4-Isopropylphenyl)sulfonyl]-4-piperazin-1-ylquinoline (N hydrochloride N 13 (4-Piperazin-1-yl-6-{[4- F F N (trifluoromethyl)phenyl]sulfonyl}quinoline hydrochloride N 14 6-[(4-tert-Butylphenyl)sulfonyl]-4-(1,4-diazepan-1-yl)quinoline N hydrochloride 15 4-(1,4-Diazepan- 1 -yl)-6-[(4-isopropylphenyl)sulfonyl]quinoline N hydrochloride Scheme 1 O~ HN S 0 N (i N ii)N (iii) 0 2 RR 0 CI RK R Ii ' N N oR I ~O ( R .HCI N (iv) N (V); (Vi)N 0 5 Legend to Scheme 1: i) Hydrogen gas, Pd/C, Methanol; ii) Sodium nitrite, Sulphuric acid, diverse thiols (R 1 SH), 3h; iii) meta-chloroperoxybenzoic acid (n-CPBA), dichloromethane (CH 2 C1 2 ), overnight; iv) phosphorus oxylchloride (POCl 3 ), acetonitrile (CH 3 CN), 80 *C, 2h; v) aliphatic cyclic amines (R2), 80 *C,

CH

3 CN; vi) HC in diethyl ether. 10 Methods The assigned structures were confirmed by standard spectroscopical methods and elemental analysis and/or high resolution MS.

WO 2004/000828 PCT/SE2003/001061 NMR spectra were obtained on Bruker 500 MHz or JEOL 270 MHz spectrometers at 25*C, and the chemical shift values are reported as parts per million (S). MS spectra were acquired on a 2690 Separation Module (Waters) with a Platform LCZ (Micromass). Flash chromatography was performed on Silica gel 60 (Merck) or LiChroprep RP-1 8 (Merck). 5 HPLC analysis were accomplished on a HP Series1 100, with a GROM-SIL 100 ODS-0 AB column, 4.6x5Omm. The HPLC purifications were performed on preparative HPLC/ Mass system using YMC Combi prep ODS-AQ column, 56x20 mm, Gilson pumps, Dynamax UV-1 detector and Finnigan Mass detector. The used eluents were H 2 0 and

CH

3 CN, both with 0.1% TFA. The purity of the compounds was determined by HPLC. 10 Elemental analysis was performed at Structural Chemistry Department, Biovitrum AB, Stockholm. Melting points, when given, were obtained on a Bichi or a Gallenkamp melting point apparatus and are uncorrected. INTERMEDIATE 1 15 Synthesis of 6-Amino-quinoline A suspension of 6-nitro-quinoline (8.7 g, 5 mmol), palladium on charcoal (10 %) (0.1 g) in methanol (0.2 L) was hydrogenated at room temperature for 24 with stirring. The catalyst was filtered and the solvent evaporated to yield a yellow solid. Crystallisation from ethyl acetate yielded the pure title compound as a pale yellow solid (3.3 g , 46 %). MS m/z: 145 20 [M+H+]. 1H NMR (270 MHz, CHCl 3 -d) S ppm 3.89 (s, 2 H) 6.87 (d, J=2.64 Hz, 1 H) 7.14 (dd, J=8.97, 2.64 Hz, 1 H) 7.25 (dd, J=8.44, 4.22 Hz, 1 H) 7.88 (dd, J=7.92, 1.58 Hz, 1 H) 7.90 (d, J=8.97 Hz, 1 H) 8.63 (dd, J=4.22, 1.58 Hz, 1 H). INTERMEDIATE 2 25 Synthesis of 6-phenylsulfanyl-quinoline A solution of sodium nitrite (1 g, 14 mmol) in water (6 mL) was slowly added to a stirred solution of 6-amino-quinoline (1.44 g, 10 mmol) in sulfuric acid (50 %) (8 mL). The temperature was kept below 5 *C during the addition. The reaction mixture was poured into a solution of potassium hydroxide (9 g, 16 mmol) and thiophenol (1 mL, 9 mmol) in 30 water (30 mL). The reaction mixture was refluxed for 3 h, cooled and extracted with diethyl ether. The insoluble material was eliminated by filtration. During filtration most of the material was trapped in the solid phase. The filtrate was evaporated and the residue was WO 2004/000828 PCT/SE2003/001061 purified by column chromatography (SiO 2 , ethyl acetate:hexane, 1:2) to yield a colorless oil (100 mg, 4% PS: the low yield is due to the loss of the material during the filtration procedure). MS m/z: 238 [M+H+]. 'H NMR (270 MHz, CD 3 C1) 6 ppm 7.34 (m, 4 H) 7.42 (m, 2 H) 7.57 (dd, J=8.97, 2.11 Hz, 1 H) 7.67 (d, J=2.11 Hz, 1 H) 7.99 (i, 2 H) 8.84 (dd, 5 J=4.22, 1.58 Hz, 1 H). INTERMEDIATE 3 Synthesis of 6-benzenesulfonyl-quinoline 1-oxid A solution of m-chloroperbenzoic acid (1 g, 5.8 mmol) in DCM (10 mL) was added to a 10 stirred solution of 6-phenylsulfanyl-quinoline (0.25 g, 1 mmol) and NaHCO 3 (0.5 g) in DCM (10 mL). The reaction was left stirring over night, washed with water, NaHCO 3 solution and evaporated. Trituration of the residue in diethyl ether gave the pure title product as a slightly yellow solid (0.14 g, 30 %). MS m/z: 287 [M+H+]. 15 INTERMEDIATE 4 Synthesis of 6-benzenesulfonyl-4-chloro-quinoline A solution of 6-benzenesulfonyl-quinoline 1-oxid (135 mg, 0.47 mmol) in POC1 3 (4 mL) was heated at 90 c for 2 h after which the solution was poured on ice, ammonium hydroxide was added and extraction with DCM. The organic phase was dried (NaS04), the 20 volatiles were evaporated and the residue was purified by column chromatography (SiO 2 , ethyl acetate:petroleum ether, 1:1) to yield a white solid (39 mg, 27 %). MS m/z: 305 [M+H+]. EXAMPLE 1 25 Synthesis of 6-benzenesulfonyl-4-piperazin-1-yl-quinoline hydrochloride A solution of 6-benzenesulfonyl-4-chloro-quinoline (35 mg, 0.11 mmol) and piperazine (0.5 g, 2.5 mmol) in acetonitrile (2 mL) was heated at 80 oc over night. The mixture was extracted with toluene and water. The organic phase was purified by chromatography on silica gel eluted with CHC1 3 saturated with NH 3 (gas). The pure product was dissolved in 30 ethyl acetate and HCl (gas) in diethyl ether was added. The resulting oily residue was dissolved in methanol and ethyl acetate and evaporated to yield a white solid (24 mg, 77%). MS m/z: 354 [M+H+]. 'H NMR (270 MHz, CH 3

OH-D

4 ) 8 ppm 3.52 (m, 4 H) 4.13 WO 2004/000828 PCT/SE2003/001061 (m, 4 H) 7.36 (d, J=7.18 Hz, 1 H) 7.57 (m, 3 H) 8.01 (m, J=12.25, 8.54 Hz, 3 H) 8.28 (d, J=8.91 Hz, 1 H) 8.63 (d, J=6.68 Hz, 1 H) 8.69 (s, I H). Scheme 2 OY 0YO H CIH N 0 N N CI N(CH2 n N'(CH 2 )n N (CH 2 )n Br Br H ii; iv NN NN N 2a, n=0 5 2b, n=1 Legend for Scheme 2: i) NatBuO, Pd(PPh 3

)

4 , n-BuOH, BOC-protected diamines; ii) tert-butyl piperazine-1 carboxylate or tert-butyl 1,4-diazepane-1-carboxylate, triethylamine or K 2 C0 3 , DMSO, thiols; iv) TFA,

H

2 0 2 , NaOH; iv) HC1. 10 Method A Preparation of thiol derivatives tert-Butyl 4

-(

6 -bromoquinolin-4-yl)-1,4-diazepane-1-carboxylate (0.5 g, 1.23 mmol) was mixed with the thiol (1 equiv.), NaOtBu (2 equiv.), Pd(PPh 3

)

4 (0.05 equiv.) and n-BuOH (5 mL) in a reaction tube. N 2 (g) was flushed through the mixture for 30 minutes. The reaction 15 mixture was heated to 120*C overnight. The precipitate was filtrated and the reaction mixture concentrated in vacuo. The residue was dissolved in EtOAc and washed with H 2 0, dried (MgSO 4 ) and evaporated. Purification by flash chromatography using DCM: MeOH 98:2 as eluent afforded the title product that was used in the next step without further purification. 20 Method B Oxidation of thiol derivatives to sulphone derivatives The appropriate thiophenols derivatives are dissolved in TFA (5 mL) and stirred for 15 minutes at room temperature. H 2 0 2 (2 mL) was added and the reaction was left stirring 25 overnight. The reaction mixtures are evaporated and the residues are portioned between diethyl ether and water. The layers are separated and the water layer is extracted with diethyl ether and made basic by adding NaOH IM. Extraction with DCM, drying with WO 2004/000828 PCT/SE2003/001061 MgSO 4 and evaporation gives the free bases of the products which are dissolved in MeOH, excess of HC1/ether (2M) was added and the solvent evaporated. The residues are purified on preparative HPLC/MS (Xterra MS C18, 5 im column) using a 10 to 40% MeCN-water gradient (containing 0.1% HOAc) over 10 minutes. The pure fractions are 5 pooled and lyophilised. The residues are dissolved in MeOH and treated with excess of HC1/ether (2M). After evaporation of solvent, a solid is obtained and triturated with diethyl ether giving the desired products as HCl-salts. INTERMEDIATE 5 10 tert-Butyl 4-(6-bromoquinolin-4-yl)piperazine-1-carboxylate 6-Bromo-4-chloroquinoline (5.0 g, 20.6 mmol), tert-butyl-1-piperazine (4.1 g, 22 mmol), triethylamine (3 mL, 22 mmol) and DMSO (20 mL) were mixed and heated overnight in an oil bath at 1 00*C. The reaction was cooled and diluted with diethyl ether and washed with water (5x), dried (MgS04) and evaporated. The residue was filtered through a short 15 column of silica (2.5-5 %) MeOH in CH 2

C

2 and evaporated. Yield 8.02 g. (97 %). Brown liquid. HPLC 98 %, RT=3.01 (System Al, 10-97 % MeCN over 3 min). 'H NMR (400 MHz, CDC1 3 ) 8 ppm 1.52 (s, 9 H) 3.12-3.17 (m, 4 H) 3.69-3.75 (m, 4 H) 6.86 (d, J=5.0 Hz, 1 H) 7.72 (dd, J=9.0, 2.26 Hz, 1 H) 7.92 (d, J=8.8 Hz, 1 H) 8.14 (d, J=2.3 Hz, 1 H) 8.73 (d, J=5.0 Hz, 1 H). MS (ESI+) for Ci 8

H

22 BrN 3 0 2 m/z 392.2 (M+H+) 20 EXAMPLE 2 6-[(2-Fluorophenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride A total amount of 2.25 mmol, of the appropriate thiophenol was used and the reaction was prolonged with 8 hours. The oxidation step was completed after 24 hours at ambient 25 temperature. Purification by column chromatography on silica gel 10-20 % MeOH in DCM gave the free amine that was additionally purified by preparative HPLC. Yield 15 mg (4 %) Yellow solid. HPLC 95 %, RT=2.33 (System Al, 10-97 % MeCN over 3 min). 1H NMR (400 MHz, DMSO-d 6 ) 5 ppm 3.30-3.42 (m, 4 H) 3.51-3.62 (m, 4 H) 7.28 (d, J=5.27 Hz, 1 H) 7.42 (dd, J=10.29, 8.78 Hz, 1 H) 7.52 (t, J=7.28 Hz, 1 H) 7.77-7.84 (m, 1 30 H) 8.04-8.21 (m, 3 H) 8.62 (s, 1 H) 8.87 (d, J=5.27 Hz, 1 H) 9.82 (br s, 2 H). MS (ESI+) for C1 9 Hi 8

FN

3 0 2 S m/z 372.0 (M+H). HRMS for C1 9

H

18

FN

3 0 2 S: calcd, 371.1104; found, 371.1102.

WO 2004/000828 PCT/SE2003/001061 EXAMPLE 3 6-(1-Naphthylsulfonyl)-4-piperazin-1-ylquinoline hydrochloride A total amount of 2.25 mmol, of the appropriate thiophenol was used and the reaction was 5 prolonged with 8 hours. The oxidation step was completed after 24 hours at ambient temperature. Purification by column chromatography on silica gel 10-20 % MeOH in DCM gave the free amine that was converted to the HCl-salt. Yield 14 mg (4 %). Grey solid. HPLC 95%, RT=2.54 (System Al, 10-97% MeCN over 3 min). 1H NMR (400 MHz, DMSO-d 6 ) 8 ppm 3.33 (s, 4 H) 4.06 (s, 4 H) 7.38 (d, J=6.78 Hz, 1 H) 7.65 (d, J=7.53 Hz, 1 10 H) 7.69-7.75 (m, 1 H) 7.82 (t, J=7.78 Hz, 1 H) 8.12 (d, J=8.03 Hz, 1 H) 8.21-8.30 (m, 2 H) 8.38 (d, J=8.03 Hz, 1 H) 8.56 (t, J=8.53 Hz, 2 H) 8.74-8.79 (m, 2 H) 10.05 (s, 2 H). MS (ESI+) for C 23 11 2 1

N

3 0 2 S m/z 404.4 (M+H*) HRMS for C 23

H

21

N

3 0 2 S: called, 403.1354; found, 403.1365. 15 EXAMPLE 4 6-[(3,4-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride A total amount of 2.25 rnmol, of the appropriate thiophenol was used and the reaction was prolonged with 8 hours. The oxidation step was completed after 24 hours at ambient temperature. Purification by column chromatography on silica gel 10-20 % MeOH in 20 DCM gave the free amine which was converted to the HCl-salt giving yellow solid. Yield 15 mg (3 %). Yellow solid.. 'H NMR (400 MHz, DMSO- d 6 ) 8 ppm 3.35-3.41 (in, 4 H) 4.06-4.15 (m, 4 H) 7.40 (d, J=6.78 Hz, 1 H) 7.93 (d, J=8.53 Hz, 1 H) 8.04 (dd, J=8.53, 2.01 Hz, 1 H) 8.27 (d, J=9.03 Hz, 1 H) 8.32 (d, J=2.01 Hz, 1 H) 8.36-8.42 (m, 1 H) 8.73 (d, J=1.51 Hz, 1 H) 8.82 (d, J=6.53 Hz, 1 H) 9.86 (s, 2 H). MS (ESI+) for C 19

H

17 C1 2

N

3 25 02 S m/z 422.2 (M+H+). HIRMS for C1 9 H1 7 Cl 2

N

3 0 2 S: caled, 421.0419; found, 421.0422. HPLC 95%, RT=2.69 (System Al, 10-97 % MeCN over 3 min) EXAMPLE 5 6-[(3,5-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride 30 The oxidation step was completed after 2 hours at ambient temperature. Purification by column chromatography on silica gel 10-20 % MeOH in DCM gave the free amine which was converted to the HCl-salt giving grey solid. Yield 0.007 g (2 %). Yellow solid. HIPLC WO 2004/000828 PCT/SE2003/001061 90 %, Rr=2.57 (System Al, 10-97 % MeCN over 3 min). MS (ESI+) for C 2 1

H

23

FN

3 0 2 S m/z 382.2. HRMS for C 21

H

23

FN

3 0 2 S: called, 381.1511; found, 381.1521. EXAMPLE 6 5 6-[(2-Chloro-6-methylphenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride A total amount of 2.25 mmol, of the appropriatethiophenol was used and the reaction was prolonged with 8 hours. Additional H202 (1 mL) was added and the reaction mixture was stirred at 50 'C for another 48 hours. Purification by column chromatography on silica gel 10-20 % MeOH in DCM gave the free amine that was converted to the HCI-salt. Yield 33 10 mg (7.5 %). White solid. 'H NMR (400 MHz, DMSO-d 6 ) 5 ppm 2.13 (s, 3 H) 2.98 (s, 4 H) 3.72 (s, 4 H) 7.06 (d, J=6.78 Hz, 1 H) 7.14 (dd, J=11.54, 8.03 Hz, 2 H) 7.23 (t, J=7.78 Hz, 1 H) 7.89 (d, J=8.78 Hz, 1 H) 7.94-8.00 (m, 1 H) 8.24 (s, 1 H) 8.45 (d, J=6.78 Hz, 1 H) 9.68 (s, 2 H). MS (ESI+) for C 20

H

20 C1N 3 0 2 S m/z 402.2 (M+H). HRMS for

C

2 oH 20 C1N 3 0 2 S: calcd, 401.965; found, 401.967. HPLC 95 %, Rr=2.55 (System Al, 10-97 15 % MeCN over 3 min). EXAMPLE 7 6-[(4-Chlorophenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride A total amount of 2.25 mmol, of the appropriate thiophenol was used and the reaction was 20 prolonged for another 8 hours. The oxidation step was completed after 24 h at ambient temperature. Purification by column chromatography on silica gel 10-20 % MeOH in DCM gave the free amine that was converted to the HCl-salt. Yield 14 mg (3 %). Yellow solid. HPLC 95 %, Rr=2.66 (System Al, 10-97 % MeCN over 3 min). MS (ESI+) for C1 9 Hi 8 C1N 3 0 2 S m/z 388.2 (M+H*). HRMS for C 1 9 HisC1N 3 0 2 S: calcd, 387.0808; found, 25 387.0821. EXAMPLE 8 6-[(2-Methyl,4-tert-butyl-phenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride The oxidation step was completed after 2 hours at ambient temperature. Purification by 30 column chromatography on silica gel 10-20 % MeOH in DCM gave the free amine which was converted to the HCI-salt giving gray solid. Yield 17 mg (4 %). HPLC 95 %, Rr=2.81 WO 2004/000828 PCT/SE2003/001061 (System Al, 10-97 % MeCN over 3 min). MS (ESI+) for C 24

H

29

N

3 0 2 S m/z 424.2 (M+H*). HRMS for C 24

H

29

N

3 0 2 S: called, 423.1980; found, 423.1969. EXAMPLE 9 5 6-[(3,4-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride The oxidation step was completed after 2 hours at ambient temperature. Purification by column chromatography on silica gel 10-20 % MeOH in DCM gave the free amine which was converted to the HCl-salt. Yield 33 mg (8 %). Yellow solid. 'H NMR (400 MHz, DMSO- d 6 ) 6 ppm 2.27 (d, J=6.27 Hz, 6 H) 3.34 (s, 4 H) 4.12 (s, 4 H) 7.39 (dd, J=7.40, 10 2.13 Hz, 2 H) 7.75 (d, J=7.78 Hz, I H) 7.81 (s, 1 H) 8.32 (s, 2 H) 8.61 (s, 1 H) 8.78 (d, J=6.78 Hz, 1 H) 10.18 (s, 2 H). MS (ESI+) for C 2 1

H

23

N

3 0 2 S m/z 382.2 (M+H*). HRMS for

C

2 1

H

23

N

3 0 2 S: called, 381.1511; found, 381.1519. HPLC 95 %, RT=2.54 (System Al, 10-97 % MeCN over 3 min). 15 EXAMPLE 10 6-[(2,3-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride A total amount of 2.25 mmol, of the appropriate thiophenol was used and the reaction was prolonged for another 8 hours. The oxidation step was completed after 24 hours at ambient temperature. Purification by column chromatography on silica gel 10-20% MeOH in DCM 20 gave the free amine which was converted to the HCI-salt. Yield 15 mg (3 %). Yellow solid. 'H NMR (400 MHz, DMSO-d) 8 ppm 3.36 (in, 4 H) 4.10 (m, 4 H) 7.42 (d, J=6.78 Hz, 1 H) 7.75 (t, J=8.03 Hz, 1 H) 8.07 (d, J=8.03 Hz, 1 H) 8.24 (d, J=9.04 Hz, 1 H) 8.33 (dd, J=13.93, 8.41 Hz, 2 H) 8.70 (s, 1 H) 8.82 (d, J=6.78 Hz, 1 H) 10.00 (s, 2 H). MS (ESI+) for C 1 9 H1 7 C1 2

N

3 0 2 S m/z 422.2 (M+H+). HRMS for C 19 H1 7 C1 2

N

3 0 2 S: calcd, 421.0419; 25 found, 421.0408. HPLC 95 %, R-r=2.50 (System Al, 10-97 % MeCN over 3 min). EXAMPLE 11 6-[(4-tert-Butylphenyl)sulfonyll-4-piperazin-1-ylquinoline hydrochloride tert-Butyl 4-{6-[(4-tert-butylphenyl)thio]quinolin-4-yl}piperazine-1-carboxylate 30 (0.60 g, 1.3 mmol) was dissolved in TFA (12 mL) and stirred for 30 minutes before H 2 0 2 (0.65 mL, 6.3 mmol) was added. The mixture was stirred for 2 hours and water (5 mL) was added. The mixture was evaporated and the residue was taken up in water and washed with WO 2004/000828 PCT/SE2003/001061 diethyl ether (2x). The aqueous phase was adjusted to pH 10 with 1 N NaOH and the mixture was extracted with CH 2 C1 2 (2x), dried (MgSO 4 ) and evaporated. The residue was diluted with CH 2

C

2 and 1.3 mL 2N HCI in diethyl ether was added under vigorous stirring and the mixture was evaporated and washed with diethyl ether (2 x) and dried.Yield: 0.40 5 g (69 %). Grey solid. HPLC 95 %, R,1=2.77 (System Al, 10-97 % MeCN over 3 min). 'H NMR (400 MHz, DMSO-d 6 ) S ppm 1.23 (s, 9 H) 3.38 (s, 4 H) 4.08 (s, 4 H) 7.39 (d, J=7.03 Hz, 1 H) 7.65 (d, J=8.53 Hz, 2 H) 7.96 (d, J=8.53 Hz, 2 H) 8.25 (d, J=8.78 Hz, I H) 8.30 8.36 (m, 1 H) 8.66 (d, J=1.76 Hz, 1 H) 8.81 (d, J=7.03 Hz, 1 H) 9.85 (br. s, 2 H), MS (ESI+) for C 23

H

27

N

3 0 2 S m/z 410.4 (M+H+). 10 EXAMPLE 12 6-[(4-Isopropylphenyl)sulfonyll-4-piperazin-1-ylquinoline hydrochloride 4-Isopropylthiophenol (0.152 g, 1.0 mmol) was added dropwise to a suspension of tert butyl 4-(6-bromo-quinolin-4-yl)-piperazine-1-carboxylate (0.2 g, 0.51 mmol), Na-t 15 butoxide (0.192 g, 2.0 mmol) and Pd[P(Ph) 3

]

4 (0.030 g, 0.025 mmol) in ethanol (3 mL) at 90*C and the mixture was stirred for 18 h. The mixture was diluted with THF and filtered through a plug of silica and evaporated. The crude product was dissolved in TFA (5 mL) and stirred for 15 minutes before 30 % H 2 0 2 (1 mL) was added. The mixture was stirred for 2 hours and evaporated. The residue was dissolved in water and washed with CH 2

C

2 20 (2x) and 2 N NaOH was added until pH reached 10 and the mixture was extracted with

CH

2 Cl 2 (3x), dried (MgSO4) and evaporated. The crude product was purified by preparative HPLC 5-95 water/acetonitrile collecting on m/z 395.2. After evaporation the free amine was dissolved in CH 2 Cl 2 and and excess of HCI in diethyl ether was added and the mixture was evaporated. Yield 0.0 15 g (7 %). 'H NMR (400 MHz, DMSO-d 6 ) 5 ppm 25 1.17 (d, J=7.03 Hz, 6 H) 2.90-3.02 (in, 1 H) 3.34-3.42 (in, 4 H) 4.03-4.12 (in, 4 H) 7.39 (d, J=6.78 Hz, 1 H) 7.51 (d, J=8.28 Hz, 2 H) 7.96 (d, J=8.53 Hz, 2 H) 8.26 (d, J=9.03 Hz, 1 H) 8.29-8.36 (in, I H) 8.66 (s, 1 H) 8.80 (d, J=6.78 Hz, 1 H) 9.85-9.97 (in, 2 H). HPLC 95%, RT=2.65 (System Al, 10-97% MeCN over 3 min). 30 EXAMPLE 13 4-Piperazin-1-yl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}quinoline hydrochloride WO 2004/000828 PCT/SE2003/001061 4-Trifluoromethylthiophenol (0.178 g, 1.0 mmol) was added dropwise to a suspension of tert-butyl 4-(6-bromo-quinolin-4-y)-piperazine-1-carboxylate (0.2 g, 0.51 mmol), Sodium t-butoxide (0.192 g, 2.0 mmol) and Pd[P(Ph) 3

]

4 (0.030 g, 0.025 mmol) in ethanol (3 mL) at 90'C and the mixture was stirred for 18h. The mixture was diluted with THF and filtered 5 through a plug of silica and evaporated. The crude product was dissolved in TFA (5 mL) and stirred for 15 minutes before 30 % H202 (1 mL) was added. The mixture was stirred for 2 hours and evaporated. The residue was dissolved in water and washed with CH 2 C1 2 (2x) and 2 N NaOH was added until pH reached 10 and the mixture was extracted with

CH

2 Cl 2 (3x) dried (MgSO 4 ) and evaporated. The crude was purified by preparative HPLC 10 5-95 water/acetonitrile collecting on m/z 421.1. After evaporation the free amine was dissolved in CH 2 C1 2 and excess of HCl in diethyl ether was added and the mixture was evaporated. Yield 0.024 g (10%). 'H NMR (400 MHz, DMSO-d 6 ) 5 ppm 3.33-3.40 (m, 4 H) 4.13-4.21 (in, 4 H) 7.42 (d, J=7.03 Hz, I H) 8.02 (d, J=8.53 Hz, 2 H) 8.25-8.35 (in, 3 H) 8.37-8.53 (in, 1 H) 8.76 (d, J=1.76 Hz, 1 H) 8.80 (d, J=7.03 Hz, 1 H) 9.95-10.05 (in, 2 15 H). Yellow oil. HPLC 95 %, R1=2.66 (System Al, 10-97% MeCN over 3 min). INTERMEDIATE 6 tert-Butyl 4-(6-bromoquinolin-4-yl)-1,4-diazepane-1-carboxylate 6-Bromo-4-chloroquinoline (3.5 g, 14.5 mmol) was reacted with tert-butyl 1,4-diazepane 20 1-carboxylate (3.7 g, 18.8 nimol) and K 2 C0 3 (4 g, 29 mmol) in DMSO at 100 *C overnight. After cooling the mixture was poured into water and extracted with DCM. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was purified by flash chromatography using a gradient of EtOAc:hexane 1:1 to 2:1 giving 2.1 g (36 %) of yellow oil. 'H NMR (400 MHz, CDCl 3 ) 5 ppm 1.47 (d, J=5.5 Hz, 9 H) 2.08-2.16 25 (in, 2 H) 3.35-3.44 (in, 4 H) 3.60-3-73 (i, 4 H) 6.87 (d, J=5.5 Hz, 1 H) 7.69 (dd, J=9.0, 2.0 Hz, 1 H) 7.88 (d, J=8.5 Hz, 1 H) 8.16 (s, 1 H) 8.65 (d, J=5.0 Hz, 1 H). MS (BSI+) for

C

19

H

24 BrN 3 0 2 m/z 406.4 (M+H)+. HRMS (EI) calcd for C 1 9H 24 BrN 3 : 405.1052, found 405.1045. 30 INTERMEDIATE 7 WO 2004/000828 PCT/SE2003/001061 tert-Butyl-4{3-[(4-tert-butylphenyl)thio]quinolin-5-yl}-1,4-diazepane-1-carboxylate (General Method A) The compound was prepared from tert-butyl 4-(6-bromoquinolin-4-yl)-1,4-diazepane-1 carboxylate (0.5 g, 1.23 mmol) and p-tert-butylbenzenethiol (0.2 g, 1.23 mmol).Yield: 0.27 5 g (44 %) of the title compound. HPLC 89 %, RT: 3.76 min (5-99 % MeCN containing 0.1 % TFA over 3 min). INTERMEDIATE 8 tert-Butyl-4{3-[(4-isopropylphenyl)thiolquinolin-5-yl}-1,4-diazepane-1-carboxylate 10 (General Method A) The compound was prepared from tert-butyl 4-(6-bromoquinolin-4-yl)-1,4-diazepane-1 carboxylate (0.5 g, 1.23 mmol) and 4-isopropylbenzenethiol (0.19 g, 1.23 mmol). Yield: 0.27 g (46 %) of the title compound that was used in the next step without further purification. HPLC 89 %, RT: 3.67 min (5-99 % MeCN containing 0.1 % TFA over 3 15 min); MS (ESI+) for C 2 8

H

35

N

3 0 2 S m/z 478.2 (M+H)*. EXAMPLE 14 6-[(4-tert-Butylphenyl)sulfonyl]-4-(1,4-diazepan-1-yl)quinoline hydrochloride (General Method B) 20 The compound was synthesized from tert-butyl-4 {3-[(4-tert-butylphenyl)thio]quinolin-5 yl}-1,4-diazepane-1-carboxylate (0.27 g, 0.55 mmol). Yield: 20 mg (8 %) of the title compound.; 1 H NMR (270 MHz, DMSO-d 6 ) 5 ppm 1.25 (s, 9 H) 2.31 (br s, 2 H) 3.25 (br s, 2 H) 3.49 (br s, 2 H) 4.11 br s, 2 H) 4.26 (br s, 2 H) 7.16 (d, J=7.1 Hz, 1 H) 7.65 (d, J=8.2 Hz, 2 H) 7.94 (d, J=8.2 Hz, 2 H) 8.19 (d, J=8.7 Hz, 1 H) 25 8.26 (d, J=8.7 1 H) 8.62 (d, J=6.3 Hz, 1 H) 8.75 (s, 1 H) 9.65 (br s, 2 H); MS (ESI+) for

C

24

H

29

N

3 0 2 S m/z 424.2 (M+H)*. HPLC 93%, RT: 2.79 min (5-99 % MeCN over 3 min). EXAMPLE 15 4-(1,4-Diazepan-1-yl)-6-[(4-isopropylphenyl)sulfonyllquinoline hydrochloride 30 (General Method B) The compound was prepared from tert-Butyl-4{3-[(4-isopropylphenyl)thio]quinolin-5-yl} 1,4-diazepane-1-carboxylate (0.27 g, 0.57mmol). Yield: 15 mg (6 %) of the title WO 2004/000828 PCT/SE2003/001061 compound.; IH NMR (270 MHz, DMSO-d 6 ) S ppm 1.16 (d, J=6.9 Hz, 6 H) 2.31 (br s, 2 H) 2.96 (m, 1 H) 3.25 (br s, 2 H) 3.49 (br s, 2 H) 4.11 (br s, 2 H) 4.26 (br s, 2 H) 7.16 (d, J=6.9 Hz, 1 H) 7.51 (d, J=8.2 Hz, 2 H) 7.94 (d, J=8.2 Hz, 2 H) 8.18 (d, J=8.7 Hz, 1 H) 8.30 (d, J=8.4 Hz, 1 H) 8.62 (d, J=6.1 Hz, 1 H) 8.75 (s, 1 H) 9.62 (br s, 2 H); MS (ESI+) 5 for C 23

H

27

N

3 0 2 S m/z 410.4 (M+H)+. HPLC 93 %, RT: 2.70 min (5-99 % MeCN over 3 min). Table 2 R 7 R 100 WO 2004/000828 PCT/SE2003/001061 EXAMPLE R 16 7

-(

2 -Chloro-6-methyl-benzeriesulfonyl)-1-piperazin-1-yl- (N isoquinoline hydrochloride c1 N) 17 7-(2-t-Butyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinoline (N hydrochlorideN 18 7-(3,4-Dichloro-benzenesulfonyl)-1 -piperazin-1-yl-isoquinoline C1C (N) hydrochloride N) 19 7-(3,4-Dimethyl-benzenesulfonyl)-l-piperaz in-I -yI-isoquinoline (N hydrochloride iK 20 7

-(

2 ,5-Dimethyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinoline (N hydrochloride 21 7-(pChloro-benzenesulfonyl)-1-piperazin-1-yl-isoquinoline C (N) hydrochloride N) 22 7-Benzenesulfonyl- I -[ 1,4]diazepani-1I-yl-isoquinolin ,hydrochloride 9(N) 23 7-(4-tert-Butyl-benzenesulfonyl)-1 -[1 ,4]diazepan-1-yl] isoquinoline, hydrochloride 24 7-(2-Chloro-6-methyl-benzenesulfonyl)-1-[1 ,4]diazepan-1-y3- (N isoquinoline hydrochloride N 25 7-(3,5-Dimethyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]- (N isoquinoline hydrochloride N) 26 7-(3,4-Dichloro-benzenesulfonyl)-1.{l,4]diazepan- yl]- 'N (N) isoquinoline hydrochloride

N

WO 2004/000828 PCT/SE2003/001061 27 7-(4-Chloro-benzenesulfonyl)-1-[l,4]diazepan-1-yl]-isoquinoline N hydrochloride 28 7-(3,4-Dimethyl-benzenesulfonyl)- 1-[1 ,4]diazepan-1-yl]- (N isoqumnoline hydrochloride NjD 29 7-(2.-tert-13utyl-benzenesulfony1)-1-[1,4]diazepan-1-y]- ( isoquinoline hydrochloride 30 7-Benzenesulfonyl-l-piperazin-yl-isoquinohne hydrochloride 31 7-(4-tert-Butyl-benzenesulfonyl--piperazin-yl-isoquinoline(N hydrochlorideN WO 2004/000828 PCT/SE2003/001061 Scheme 3 0 N Br Lancaster N Cl N N H N Br jj N N N Br N Br NN S R NN R N C Cl 0 N0 N-ON NO N R N R ~N Legend to Scheme 3: i) POCl 3 ; ii) K 2 C0 3 , DMF, BOC-diamines; iii) Nat-BuO, thiophenols, Pd(PPh 3

)

4 ; n 5 BuOH; iv) TFA, H 2 0 2 ; v) HC1 in diethyl ether. INTERMEDIATE 9 7-Bromo-1-Chloroisoquinoline To phosphorus oxychloride (46.6 mL, 0.5 mol) at room temperature was added, 10 portionwise, 7-bromo-1-hydroxyisoquinoline (11.2 g, 0.05 mol). The mixture was heated to 100 'C for 90 min with rapid stirring. On cooling to room temperature, the mixture was WO 2004/000828 PCT/SE2003/001061 poured, cautiously onto ice/water (200 mL). Dropwise addition of aqueous ammonia raised the pH=8 and the resulting precipitate was collected by filtration, washing with cold water. The solid was dried under reduced vacuum at 45 'C for 12 h. 13.86 g (115 %) Beige solid isolated. 1H NMR (DMSO-d 6 ) 8 8.4 (s, 1 H), 8.34-8.38 (d, J= 6 Hz, 1 H), 8.03-8.07 (in, 2 5 H), 7.91-7.96 (d, J = 6 Hz, 1 H); HPLC: 96%; LCMS: 242,244,246. Nucleophilic displacement of Chlorine INTERMEDIATE 10 10 4-(7-Bromo-isoquinoline-1-yl)-piperazine-l-carboxylic acid, tert-butyl ester To a suspension of 7-bromo-1-chloroisoquinoline (3.14 g, 1 3 mmol) in DMSO (20 mL) at room temperature was added either carboxylic acid tert-butyl (BOC)piperazine (7.23 g, 38.8 mmol) or BOC-homopiperazine (7.77 g, 38.8 mmol) and then potassium carbonate (5.36 g, 39 mmol). The mixture was heated to 110 'C for 24 h. On cooling, the mixture 15 was poured onto ice/water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with water 50 mL) and brine (50 mL). Before drying over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave crude product. Purification was performed by applying the crude material to a plug of silica in a filter funnel and eluting with heptane/ethyl acetate (2:1) and gave 2.73 g (54 %) 20 yellow oil. 'H NMR (CDCl 3 ) 8 8.20-8.22 (m, 1 H), 8.13-8.18 (d, J= 6 Hz, 1 H), 7.65-7-71 (dd, J= 12, 3 Hz, 1 H), 7.59-7.65 (d, J= 12 Hz, 1 H), 7.21-7.25 (m, 1 H), 3.64-3.73 (m, 4 H), 7.27-7.36 (m, 4 H), 1.49 (s, 9 H); LCMS: 392,394,395. INTERMEDIATE 11 25 4-(7-Bromo-isoquinoline-1-yl)-[1,4]diazepane-1-carboxylic acid, tert-butyl ester 2.75 g (52 %) yellow oil isolated 'H NMR (CDCl 3 ) 6 8.19-8.24 (m, 1 H), 8.06-8.12 (d, J= 9 Hz, 1 H), 7.54-7.68 (in, 2 H), 7.11 (m, 1 H), 3.47-3.74 (in, 8 H), 1.98-2.16 (m, 2 H), 1.48 (s, 9 H); LCMS: 406,407,408. 30 Palladium-catalysed aryl thiol coupling To 7-bromo-1-chloroisoquinoline (1 mmol) in butan-1-ol (20 mL) at room temperature was added sodium tert-butoxide (481 mg, 5 mmol), thiol (1.5 mmol) and tetrakis WO 2004/000828 PCT/SE2003/001061 triphenylphosphine palladium (60 mg, catalytic). The mixture was heated to 120 'C for 16 h. On cooling to room temperature, the mixture was filtered through silica eluting with THF. Removal of solvent under reduced pressure gave the crude product which was used without further purification in the subsequent step. 5 INTERMEDIATE 12 4-[7-(2-Chloro-6-methyl-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylic acid tert-butyl ester A mixture of 4-(7-bromo-isoquinoline- 1 -yl)-piperazine- 1 -carboxylic acid, tert-butyl ester 10 (0.5 g, 1.3 mmol), 2-chloro-6-methyl-thiophenol (0.206 g, 1.3 imol), NatBuO (0.44 g, 4.5 mmol), Pd(PPh 3

)

4 (74 mg, 0.065 mmol) in nBuOH (10 mL) was heated at 110 C, 3h. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water (50 mL x 3), separated and dried (MgSO 4 ), filtered. The volatiles were evaporated and the residue was purified by 15 flash column chromatography (SiO 2 , n-heptane: ethyl acetate 8:2) to give 530 mg of the title compound as colourless oil (yield 86.4 %). 111 NMR (CDCl 3 ) 8 8.05 (d, 1H), 7.65 (d, 1H), 7.20-7.45 (in, 5H), 7.15 (d, 1H), 3.26-3.40 (in, 4H), 3.10-3.20 (in, 4H), 2.5 (s, 3H), 1.38 (s, 9H). 20 INTERMEDIATE 13 4-[7-(2-t-butyl-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylic acid tert butyl ester A mixture of 4-(7-bromo-isoquinoline-1-yl)-piperazine-l-carboxylic acid, tert-butyl ester (0.5 g, 1.3 mmol), 2-t-butyl-thiophenol (0.216 g, 1.3 mmol), Nat-BuO (0.44 g, 4.5 mmol), 25 Pd(PPh 3

)

4 (74 mg, 0.065 mmol) in n-BuOH (10 mL) was heated at 110 *C, 3h. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water (50 mL x 3), separated and dried (MgSO 4 ), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (SiO 2 , n-heptane: ethyl acetate 8:2) to give 440 mg of the 30 title compound as colorless oil (yield 71 %). 'H NMR (CDCl 3 ) 8 8.00-8.10 (in, 2H), 7.15- WO 2004/000828 PCT/SE2003/001061 7.65 (in, 711), 3.60-3.70 (in, 1H), 3.30-3.45 (in, 4H), 3.05-3.20 (in, 3H), 1.55 (s, 9H), 1.50 (s, 9H). INTERMEDIATE 14 5 4-17-(3,4-Dichloro-phenylsulfanyl)-isquinolin-1-yl]-piperazine-1-carboxylic acid tert butyl ester A mixture of 4-(7-bromo-isoquinoline-1-yl)-piperazine-l-carboxylic acid, tert-butyl ester (0.5 g, 1.3 mmol), 3,4-dichloro-thiophenol (165 uL, 1.3 mmol), NatBuO (0.44 g, 4.5 mmol), Pd(PPh 3

)

4 (74 mg, 0.065 mmol) in n-BuOH (10 mL) was heated at 110 'C, 3h. The 10 reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water (50 mL x 3), separated and dried (MgSO 4 ), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (SiO 2 , n-pentane:ethyl acetate 9.5:0.5->8:2) to give 230 mg of the title compound as colorless oil (yield 36 %). 'H NMR (CDC1 3 ) 8 8.10-8.20 (in, 2H), 15 7.90 (bs, 1H), 7.65-7.75 (in, 2H), 7.10-7.55 (m, 3H), 3.50-3.65 (in, 4H), 3.20-3.30 (in, 4H), 1.50 (s, 911). INTERMEDIATE 15 4-[7-(3,4-Dimethyl-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylic acid tert 20 butyl ester A mixture of 4-(7-bromo-isoquinoline-1-yl)-piperazine-l-carboxylic acid, tert-butyl ester (0.5 g, 1.3 mmol), 3,4-dimethyl-thiophenol (175 uL, 1.3 mmol), NatBuO (0.44 g, 4.5 minmol), Pd(PPh 3

)

4 (74 mg, 0.065 minol) in n-BuOH (10 mL) was heated at 110 *C, 3h. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved 25 in ethyl acetate. The organic phase was washed with water (50 mL x 3), separated and dried (MgSO 4 ), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (SiO 2 , n-pentane:ethyl acetate 9.5:0.5->8:2) to give 260 mg of the title compound as colorless oil (yield 44 %). 'H NMR (CDC1 3 ) 6 8.00-8.10 (m, 211), 7.55-7.65 (in, 311), 7.40-7.50 (in, 1H), 7.10-7.30 (in, 2H), 3.30-3.40 (in, 4H), 3.10-3.20 (in, 30 4H), 2.30 (s, 3H), 2.25 (s, 3H), 1.50 (s, 9H).

WO 2004/000828 PCT/SE2003/001061 INTERMEDIATE 16 4

-[

7

-(

3 ,5-Dimethyl-phenylsulfanyl)-isoquinolin-1-yi]-piperazine-1-carboxylic acid tert butyl ester A mixture of 4-(7-bromo-isoquinoline- 1 -yl)-piperazine- I -carboxylic acid, tert-butyl ester 5 (0.5 g, 1.3 mmol), 3,5-dimethyl-thiophenol (180 mg, 1.3 nimol), NatBuO (0.44 g, 4.5 mmol), Pd(PPh 3

)

4 (74 mg, 0.065 mmol) in nBuOH (10 mL) was heated at 110 *C, 3h. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water (50 mL x 3), separated and dried (MgSO 4 ), filtered. The volatiles were evaporated and the residue was purified by 10 flash column chromatography (SiO 2 , n-pentane:ethyl acetate 9.8:0.2-+8:2) to give 380 mg of the title compound as colourless oil (yield 65 %). 'H NMR (CDC 3 ) 8 8.05-8.10 (m, 1H), 7.80-7.85 (m. 111), 7.60-7.75 (m, 1H), 7.17-7.25 (m, 1H), 7.10 (bs, 2H), 7.00 (bs, 111), 3.40-3.50 (m, 4H), 3.10-3.20 (in, 4H), 2.25 (bs, 6H), 1.50 (s, 9H). 15 INTERMEDIATE 17 4-[7-(p-Chloro-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylic acid tert butyl ester A mixture of 4 -(7-bromo-isoquinoline- 1 -yl)-piperazine-1 -carboxylic acid, tert-butyl ester (0.5 g, 1.3 mmol), p-chloro-thiophenol (188 mg, 1.3 mmol), NatBuO (0.44 g, 4.5 mmol), 20 Pd(PPh 3

)

4 (74 mg, 0.065 mmol) in nBuOH (10 mL) was heated at 110 *C, 3h. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water (50 mL x 3), separated and dried (MgSO 4 ), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (SiO 2 , n-pentane:ethyl acetate 9.5:0.5 -+ 8:2) to give 300 ing of 25 the title compound as colourless oil (yield 50 %). 1H NMR (CDC 3 ) 8 8.05-8.15 (m, 2H), 7.60-7.70 (m, 211), 7.40-7.50 (m, 211), 7.15-7.30 (m, 3H), 3.45-3.55 (in, 4H), 3.10-3.15 (m, 411), 1.50 (s, 911).

WO 2004/000828 PCT/SE2003/001061 INTERMEDIATE 18 4 -(7-Phenylsulfanyl-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butyl ester LCMS: 422,423. 5 INTERMEDIATE 19 4-[7-(4-tert-Butyl-phenyasulfanyl)-isoquinoline-1-yl]-piperazine-1-carboxylic acid, tert-butyl ester LCMS: 478,479. 10 INTERMEDIATE 20 4

-(

7 -Phenylsulfanyl-isoquinoline-1-yl)-[1,4]diazepane-1-carboxylic acid, tert-butyl ester MS: 368,369,370. 15 INTERMEDIATE 21 4-[7-(4-tert-Butyl-phenylsulfanyl)-isoquinoline-1-yl]-[1,4]diazepane-1-carboxylic acid, tert-butyl ester MS: 424,425,426. 20 INTERMEDIATE 22 4-[7-(2-Chloro-6-methyl-phenylsulfanyl)-isoquinoline-1-yl]-[1,4]diazepane-l carboxylic acid, tert-butyl ester MS: 416,417,418. 25 INTERMEDIATE 23 4-[7-(3,4-Dimethyl-phenylsulfanyl)-isoquinoline-1-yl]-[1,4]diazepane-1-carboxylic acid, tert-butyl ester MS: 396,397,398. 30 INTERMEDIATE 24 4

-[

7

-(

3

,

4 -Dichloro-phenylsulfanyl)-isoquinoUne-1-yl]-[1,4]diazepane-1-carboxylic acid, tert-butyl ester WO 2004/000828 PCT/SE2003/001061 MS: 436,437438. INTERMEDIATE 25 4 -[7-( 4 -Chloro-phenylsulfanyl)-isoquinoline-1-yil]-[1,4]diazepane-1-carboxylic acid, 5 tert-butyl ester MS: 402,404. INTERMEDIATE 26 4 -[7-(3,4-Dimethyl-phenylsulfanyl)-isoquinoline-1-yl]-[1,4]diazepane-1-carboxylic 10 acid, tert-butyl ester LCMS: 464,465,466. INTERMEDIATE 27 4 -[7-(2-tert-Butyl-phenylsulfanyl)-isoquinoline-1-yli-[1,4]diazepane-1-carboxylic acid, 15 tert-butyl ester LCMS: 492,493,494. BOC deprotection and oxidation of thiols to sulphone derivatives Each thiol (0.2-1.14 mmol) was dissolved in trifluoroacetic acid (1.5 mL) at 0 *C and 20 stirred for 15 mins at this temperature. To this was added 33% aqueous hydrogen peroxide solution (5-100 mL). The resulting mixture was stirred at room temperature for 90 min and then treated with sodium hydroxide solution (LM, 25 mL). Extraction of this mixture with ethyl acetate (3 x 50 mL) was followed by the washing of the combined organic layers with brine (50mL). The organic extracts were dried over anhydrous sodium sulfate and 25 then the solvent was removed under reduced pressure. The crude product was purified by preparative LCMS. Treatment of the purified material with HCI/Ether (iM, 1 mL) gave the final product as a white solid. EXAMPLE 16 30 7

-(

2 -Chloro- 6 -methyl-benzenesuIfonyl)-1-piperazin-1-yi-isoquinoline hydrochloride A mixture of 4

-[

7

-(

2 -chloro-6-methyl-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1 carboxylic acid tert-butyl ester (160 mg, 0.340 mmol), H202 (30% in water, 200 uL), WO 2004/000828 PCT/SE2003/001061 trifluoroacetic acid (2 mL) was heated at 50 0 C, 2h. A water solution of NaOH (IN) was added (pH = 14), ethyl acetate was added and the organic phase was separated, dried (MgSO 4 ), filtered. The filtrated was concentrated and the residue was purified by flash column chromatography (SiO 2 , dichloromethane:methanol 8:2) to lead to 77 mg of the 5 product compound as free base (yield 56 %). The free base was converted into hydrochloride by treatment with HCl in diethyl ether. 1H NMR (CH 3 0H-d 4 ) 8 8.88 (bs, 11), 8.05-8.20 (in. 3H), 7.65 (d, 1H), 7.35-7.55 (in, 3H), 3.85-3.95 (in, 4H), 3.00-3.15 (in, 4H), 2.95 (s, 3H). 10 EXAMPLE 17 7-(2-t-Butyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinoline hydrochloride A mixture of 4-[7-(2-tbutyl-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylic acid tert-butyl ester (273 mg, 0.571 mmol), H 2 0 2 (30% in water, 1 mL), trifluoroacetic acid (3 mL) was heated at 50 *C, 2h. The reaction was continued overnight at 35 'C. A water 15 solution of NaOH (1N) was added (pH =14), ethyl acetate was added and the organic phase was separated, dried (MgSO 4 ), filtered. The filtrated was concentrated and the residue was purified by flash column chromatography (SiO 2 , dichloromethane:methanol 8:2) to lead to 50 mg of the title compound as free base (yield 56 %). The free base was converted into hydrochloride by treatment with HCI in diethyl ether. 'H NMR (CH 3 0H-d 4 ) 20 8 8.55 (d, 1H), 8.25 (d, 11), 7.95-8.10 (in, 311), 7.55 (d, 1H), 7.55-7.65 (in, 2H), 7.4 (d, 111), 3.60-3.75 (in, 4H), 3.40-3.50 (in, 4H), 1.55 (s, 91H). EXAMPLE 18 7-(3,4-Dichloro-benzenesulfonyl)-1-piperazin-1-y-isoquinoline hydrochloride 25 A mixture of 4-[7-(3,4-dichloro-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylic acid tert-butyl ester (230 mg, 0.47 mmol), H202 (30% in water, 0.5 mL), trifluoroacetic acid (1.5 mL) was heated at 50 *C, 2h. The reaction was continued overnight at 35 *C. A water solution of NaOH (IN) was added (pH = 14), ethyl acetate was added and the organic phase was separated, dried (MgSO 4 ), filtered. The filtrated was concentrated and 30 the residue was purified by flash column chromatography (SiO 2 , dichloromethane:methanol 9:1) The free base was converted into hydrochloride by WO 2004/000828 PCT/SE2003/001061 treatment with HC1 in diethyl ether to obtained 45 mg of the title compound. 'H NMR

(CH

3 0H-d 4 ) 8 8.75-8.85 (in, 1H), 8.10-8.30 (in, 4H), 7.90-8.00 (in, 1H), 7.75-7.85 (in, 1H), 7.50-7.60 (in, 1H), 3.85-3.90 (in, 4H), 3.50-3.70 (m, 411). 5 EXAMPLE 19 7-(3,4-Dimethyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinoline hydrochloride A mixture of 4-[7-(3,4-dimethyl-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylic acid tert-butyl ester (260 mg, 0.58 mmol), H202 (30% in water, 0.5 mL), trifluoroacetic acid (1.5 mL) was heated at 50 *C, 2h. The reaction was continued overnight at 35 *C. A 10 water solution of NaOH (1N) was added (pH = 14), ethyl acetate was added and the organic phase was separated, dried (MgSO 4 ), filtered. The filtrated was concentrated and the residue was purified by flash column chromatography (SiO 2 , dichloromethane:methanol 9:1) The free base was converted into hydrochloride by treatment with HCl in diethyl ether to obtained 20 mg of the title compound. 11 NMR 15 (CH 3 0H-d 4 ) 8 8.75-8.80 (in, 1H), 8.10-8.25 (m, 3H), 7.70-7.85 (m, 2H), 7.60-7.70 (in, 1H), 7.35-7.40 (in, 1H), 3.90-4.00 (in, 4H), 3.55-3.65 (in, 4H), 2.35 (bs, 6H). EXAMPLE 20 7-(2,5-Dimethyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinoline hydrochloride 20 A mixture of 4-[7-(2,5-dimethyl-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylic acid tert-butyl ester (380 ing, 0.846 mmol), H202 (30% in water, 0.5 mL), trifluoroacetic acid (3 nL) was heated at 50 'C, 2h. The reaction was continued overnight at 35 'C. A water solution of NaOH (1N) was added (pH = 14), ethyl acetate was added and the organic phase was separated, dried (MgSO4), filtered. The filtrated was concentrated and 25 the residue was purified by flash column chromatography (SiO 2 , dichloromethane:methanol 9.8:0.2->9.5:0.5) The free base was converted into hydrochloride by treatment with HCl in diethyl ether to obtained 120 mg of the title compound. 1H NMR (CH 3 0H-d 4 ) 8 8.75-8.80 (in, 1H), 8.25-8.30 (in, 1H), 8.05-8.20 (in, 2H), 7.60-7.70 (m, 3H), 7.30-7.35 (in, 1H), 4.00-4.10 (in, 4H), 3.60-3.70 (in, 411), 2.30 30 1.35 (bs, 6H).

WO 2004/000828 PCT/SE2003/001061 EXAMPLE 21 7-(p-Chloro-benzenesulfonyl)-1-piperazin-1-yl-isoquinoline hydrochloride A mixture of 4-[7-(p-chloro-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylic acid tert-butyl ester (297 mg, 0.65 mmol), H 2 0 2 (30% in water, 0.5 mL), trifluoroacetic 5 acid (3 mL) was heated at 50 "C, 2h. The reaction was continued overnight at 35 *C. A water solution of NaOH (1N) was added (pH = 14), ethyl acetate was added and the organic phase was separated, dried (MgSO 4 ), filtered. The filtrated was concentrated and the residue was purified by flash column chromatography (SiO 2 , dichloromethane:methanol 9.5:0.5->9.0:1.0) The free base was converted into 10 hydrochloride by treatment with HCI in diethyl ether to obtained 70 mg of the title compound, H NMR (CH 3 0H-d 4 ) 8 8.75-8.85 (m, 2H), 8.10-8.25 (in, 3H), 8.00-8.08 (in, 2H), 7.60-7.68 (in, 3H), 3.85-3.95 (m, 4H), 3.55-3.65 (in, 4H). EXAMPLE 22 15 7-Benzenesulfonyl-1-[1,4]diazepan-1-yl-isoquinoline hydrochloride 30 mg. 'H NMR (DMSO-d 6 ) 6 9.3 (s, 1 H), 8.58 (s, 1 H), 8.26-8.30 (d, J= 9 Hz, 1 H), 8.1 8.13 (in, 2 H), 8.01-8.06 (d, J= 6 Hz, 1 H), 7.6-7.76 (in, 3 H), 7.53-7.58 (d, J= 6 Hz, 1 H), 3.70-3.90 (in, 4H) 3.58-3.66 (in, 2 H), 3.29-3.40 (in, 2H); LCMS: 368,369 HPLC: 98 %. 20 EXAMPLE 23 7-(4-tert-Butyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline hydrochloride Isolated 69 mg. 1H NMR (DMSO-d 6 ) 8 9.2 (s, 1 H), 8.65 (s, 1 H), 8.09-8.15 (d, J= 6 Hz, 1 H), 8.03-8.08 (d, J= 15 Hz, 1 H), 7.89-7.96 (d, J= 9 Hz, 2 H), 7.60-7.67 (d, J= 9 Hz, 2 H), 7.33-7.38 (d, J= 9 Hz, 1 H), 4.01-4.09 (m, 2 H), 3.83-3.91 (in, 2 H), 3.43-3.52 (in, 2 25 H), 3.23-3.33 (m, 2 H), 1.25 (s, 9 H); LCMS: 424,425, HPLC: 97 %. EXAMPLE 24 7-(2-Chloro-6-methyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline hydrochloride 30 Isolated 27 mg 'H NMR (DMSO-d 6 ) 5 8.81 (s, 1 H), 8.28 (m, 1 H), 8.10-8.18 (d, J= 6 Hz, 1 H), 7.94-8.08 (m, 2 H), 7.45-7.62 (in, 3 H), 7.36-7.42 (d, J= 6 Hz, 1 H), 3.75-3.86 (m, 2 WO 2004/000828 PCT/SE2003/001061 H), 3.41-3.51 (m, 2 H), 3.18-3.32 (m, 2 H), 2.86 (s, 3 H), 2.1 4 -2.19(m 2 H); LCMS: 416,418 HPLC: 98 %. EXAMPLE 25 5 7-(3,5-Dimethyl-benzenesulfonyl)-1-[1,4]diazepan-1-yll-isoquinoline hydrochloride Isolated 62 mg. 'H NMR (DMSO-d 6 ) 6 9.35 (s, 1 H), 8.67 (m, 1 H), 8.00-8.18 (m, 3 H), 7.58-7.69 (m, 2 H), 7.45-7.41 (d, J= 6 Hz, 1 H), 7.30-7.35 (m, 1 H), 4.06-4.14 (m, 2 H), 3.86-3.97 (m, 2 H), 3.42-3.52 (m, 2 H), 3.23-3.31 (m, 2 H), 2.33 (s, 6 H) 2.23-2.25 (m 2 H); LCMS: 436,438, HPLC: 95 %. 10 EXAMPLE 26 7-(3,4-Dichloro-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline, hydrochloride Isolated 11 mg. 1 H NMR (CD 3 0D) 6 8.88 (m, 1 H), 8.23-8.29 (d, J= 12 Hz, 1 H), 8.13 8.16 (d, J= 3 Hz, 1 H), 8.04-8.10 (d, J= 9 Hz, 1 H), 7.88-7.94 (d, J= 9 Hz, 1 H), 7.79 15 7.84 (d, J= 6 Hz, 1 H), 7.67-7.73 (d, J= 9 Hz, 1 H), 7.42-7.46 (d, J= 6 Hz, 1 H), 4.28 4.35 (m, 2 H), 4.09-4.16 (m, 2 H), 3.69-3.75 (m, 2 H), 2.33-2.46 (m, 2 H); LCMS: 368,369; HPLC: 97 %. EXAMPLE 27 20 7-(4-Chloro-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline, hydrochloride Isolated 41 mg. 1 H NMR (DMSO-d 6 ) 5 9.27 (s, 1 H), 8.68 (m, 1 H), 7.99-8.17 (m, 5 H), 7.66-7.75 (d, J= 9 Hz, 2 H), 7.33-7.39 (d, J= 6 Hz, 1 H), 4.03-4.11 (m, 2 H), 3,83-3.93 (m, 2 H), 3.43-3.53 (m, 2 H), 3.23-3.32 (m, 2 H), 2.19-2.30 (m, 2 H); LCMS: 402,404; HPLC: 98 %. 25 EXAMPLE 28 7

-(

3

,

4 -Dimethyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline, hydrochloride Isolated 10 mg. 'H NMR (DMSO-d 6 ) 5 9.41 (s, 1 H), 8.67 (s, 1 H), 8.00-8.16 (m, 3 H), 7.76-7.82 (m, 1 H), 7.68-7.77 (d, J= 9 Hz, 1 H), 7.32-7.42 (d, J= 9 Hz, 2 H), 3.99-4.40 30 (m, 4 H), 3.49 (m, 2 H), 3.33 (m, 2 H), 2.29 (s, 3 H), 2.25 (s, 3 H); LCMS: 396,397; HPLC: 92 %.

WO 2004/000828 PCT/SE2003/001061 EXAMPLE 29 7-(2-tert-Butyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline, hydrochloride Isolated 5 mg. 'H NMR (DMSO-do) 8 9.27 (s, 1 H), 8.52 (s, 1 H), 8.06-8.16 (m, 2 H), 5 7.97-7.97 (n, 2 H), 7.72-7.78 (m, 1 H), 7.61-7.70 (m, 1 H), 7.40-7.45 (d, J= 9 Hz, 2 H), 3.69-3.99 (m, 4 H), 3.43 (s, 2 H), 3.25 (s, 2 H), 2.05-2.26(m, 2 H);1.52 (s, 9 H); LCMS: 424,425; HPLC: 90 %. EXAMPLE 30 10 7-Benzenesulfonyl-1-piperazin-yl-isoquinoline, hydrochloride Isolated 10 mg. IH NMR (DMSO-d 6 ) 5 9.04 (s, 1 H), 8.65 (s, 1 H), 8.12-8.16 (d, J= 6 Hz, 1 H), 7.98-8.05 (m, 5 H), 7.58-7.72 (m, 2 H), 7.32-7.36 (d, J= 6 Hz, 1 H), 3.98-4.04 (m, 4 H), 3.80-3.86 (m, 4 H); LCMS: 354,355; HPLC: 98 %. 15 EXAMPLE 31 7-(4-tert-Butyl-benzenesulfonyl-1-piperazin-yl-isoquinoline, hydrochloride Isolated 10 mg. 1H NMR (DMSO-d 6 ) 6 9.33 (s, 1 H), 8.57 (s, 1 H), 8.24-8.29 (d, J= 9 Hz, 1 H), 8.11 (m, 2 H), 7.91-7.97 (d, J= 9 Hz, 2 H), 7.60-7.66 (d, J= 12 Hz, 2 H), 7.52-7.57 (d, J=6 Hz, 1 H), 3.59-3.68 (m, 4 H), 3.29-3.40 (m, 4 H), 1.24 (s, 9 H); LCMS: 410,411 20 HPLC: 90%. Table 3 RI HN O R3 25 WO 2004/000828 PCT/SE2003/001061 EXAMPLE NAME R R 32 4-Chloro-N-[4-(pyffolidin-3-yloxy)-1--- 0 naphthyl]benzenesulfonamide hydrochlorideHN C1 33 4-Methoxy-N-[4-(pyrrolidin-3-yloxy)-l- - 0 naphthyl]benzenesulfonamide hydrochloride H OMe 34 5-Chloro-N-[4-{pyrrolidin-3-yloxy)-1- 0 naphthiyl]thiophene-2-sulfonamide hydrochloride / \H S C1 35 4-Chloro-N-[4-(piperidin-3-yloxy)-1- naphthyl]benzenesulfonarniide hydrochloride Cl H 26 4-Methoxy-N-[4-(piperidin-3-yloxy)-l - uaphthyl]benzenesulfbnamide hydrochloride OMe H 37 5-Fluoro-2-niiethyl-N-[4-(piperidin-4-yloxy)-l- Fq naphthylbenzenesulfonamide hydrochloride 6 H 38 5-Chloro-N-44-(pipexidin-4-yloxy)-l- I naphthyl]thiophene-2-sulfonamide hydrochloride/ N H 39 4-Chloro-N-{44[(3S)-pyrrolidin-3-yloxy]-l- C~ naphthylbenzenesulfonamnide hydrochloride 6 N

H

WO 2004/000828 PCT/SE2003/001061 40 4-Chloro-N-{4-[(3R)-pyrrolidin-3-yloxy]-1- a naphthyl}benzenesulfonamide hydrochloride )C N H Scheme 4 ON+O O'N+-O

NH

2 OH 0 O boc boc RI R1 Og 0s HN 0 HN' 0 iv 0- 0 1 O O0I boc Legend to Scheme 4: (i) tert-butyl 3-hydroxypyrrolidine-1-carboxylate or tert-butyl 4-hydroxypiperidine-1 5 carboxylate, PPh 3 , DEAD, THF; (ii) H 2 (g), Pd/C, MeOH; (iii) RI-SO 2 -Cl, pyridine, CH 2 Cl 2 ; (iv) HCl in diethyl ether General method C Mitsonobu reaction of 4-nitro-1-naphthol with boc-protected 3-hydroxypyrrolidine and 4 10 hydroxypiperidine 4-Nitro-1-naphthol (1 equiv.) was dissolved in THF (3 mL/Ummol), tert butyl 3-hydroxypyrrolidine-1-carboxylate (2 equiv.) was added followed by PPh 3 (2 equiv.). The solution was kept under N 2 -atmosphere and cooled with ice-bath. Diethylazodicarboxylate (DEAD; 2 equiv.) was added dropwise. The ice-bath was removed after 10 min and the reaction mixture was stirred at ambient temperature 15 overnight. The solvent was evaporated and the residue was re-dissolved in EtOAc. The WO 2004/000828 PCT/SE2003/001061 formed precipitate was collected by filtration. The solution was concentrated in vacuo and purified by flash chromatography (SiO 2 , EtOAc:iso-hexane 2:8->EtOAc) General method D 5 Reduction of nitronaphthalene derivatives To a solution of corresponding nitronaphthalenes (1 equiv.) (prepared by General method A) in MeOH (2 mL/mmol), was added Pd/C (10%) and the reaction mixture was stirred overnight under hydrogen (1 atm). The reaction mixture was filtered and the filtrate was concentrated in vacuo to give corresponding aminonaphthalene derivatives. 10 General method E Reaction of aminonaphthalene derivatives with sulfonyl chlorides To a solution of the aminonaphthalene derivatives (1 equiv.) in CH 2 Cl 2 (8 mL/mmol) was added pyridine (3 equiv.) followed by the corresponding sulfonyl chloride (1.2 equiv.). The 15 mixtures were stirred at ambient temperature overnight, washed with HCl (1M) (2 mL) and dried (MgSO 4 ). The volatiles were eliminated under vacuo and gave the crude product which were purified by flash chromatography (SiO 2 , EtOAc:iso-hexane 1:4) to give desired sulfonamide. 20 General method F Deprotection of boc-group The sulfonamide derivatives (prepared by General Method C) were dissolved in a small amount of MeOH and treated with an excess of HCl in diethyl ether (1M). Stirring at ambient temperature overnight resulted in a precipitate which were collected by filtration 25 giving the title compounds as its hydrochloride salts. General method G 3-Hydroxypyrrolidine (lequiv.) was dissolved in MeOH (lmL/mmol) and cooled on ice bath. (BOC) 2 0 (1. lequiv.) was added and the mixture was stirred for 2 h at ambient 30 temperature. Pyridine/water (10/1 0mL) was added and the mixture was stirred overnight. Evaporation of solvents and co-evaporation with toluene provided the desired boc protected 3-hydroxypyrrolidine.

WO 2004/000828 PCT/SE2003/001061 INTERMEDIATE 28 tert-Butyl 3-[(4-nitro-1 -naphthyl)oxylpyrrolidine-1-carboxylate (General Method C) The crude product was purified by column chromatography. The compound was prepared 5 from 4-nitro-1 -naphthol (2.85 g, 15.1 mmol). The material thus obtained was dissolved in small amount of EtOAc and iso-hexane was added. The formed solid was collected by filtration and triturated with MeOH to give the pure title compound 4.6g (85%). HPLC 99%, R1=2.70 (System Al, 10-97% MeCN over 3 min). 'H NMR (400 MHz, CDC1 3 ) 8 ppm 1.46 (d, J=7.03 Hz, 9 H) 2.26-2.38 (m, 2 H) 3.60-3.81 (n, 4 H) 5.20 (br s, 1 H) 6.76 10 (d, J=8.53 Hz, 1 H) 7.58 (t, J=7.53 Hz, 1 H) 7.73 (t, J=7.53 Hz, 1 H) 8.34 (dd, J=20.33, 8.78 Hz, 2 H) 8.75 (d, J=9.04 Hz, 1 H). MS (ESI+) for C 19

H

22

N

2 0 5 m/z 376.2 (M+NH)*, 359.2 (M+H)+, 303.2 (M-tBu)*. HPLC 99%, Rr=2.78 min (System B1, 10-90% MeCN over 3 min). 15 INTERMEDIATE 29 tert-Butyl 3-[( 4 -amino-1-naphthyl)oxy]pyrrolidine-1-carboxylate (General Method D) The compound was prepared from intermediate 1 (2.6 g, 7.2 mmol), Yield: 2. 1g (87 %) of the title compound as purple solid. HPLC 96 %, R1=1.768 min (System Al, 10-97 % MeCN over 3 min). HPLC 95 %, R-r=1.604 min (System B1, 10-90% MeCN over 3 min). 20 'H NMR (400 MHz, DMSO-d 6 ) S ppm 1.37 (d, J=22.59 Hz, 9 H) 2.12 (s, 2 H) 3.43-3.46 (in, 4 H) 4.96 (s, 1 H) 5.50 (s, 2 H) 6.63 (d, J=8.03 Hz, 1 H) 6.81 (d, J=8.03 Hz, 1 H) 7.41 (dd, J=6.02, 3.01 Hz, 2 H) 7.94-8.01 (in, 2 H). MS (ESI+) for C 19

H

24

N

2 0 3 m/z 329.2 (M+H)*, 273.2 (M-tBu)*, 229.2 (M-Boc)'. 25 INTERMEDIATE 30 tert-Butyl 3-[(4-{[(4-chlorophenyl)sulfonylamino}-1-naphthyl)oxy]pyrrolidine-1 carboxylate (General method E) The compound was prepared from intermediate 2 (0.2 g, 0.61 mmol). The crude material was triturated with CH3CN to give 0.14 g (46 %) of the title compound as a pale pink solid. 30 HPLC 97 %, RT=2.703 min (System Al, 10-97 % MeCN over 3 min). 1 H NMR (400 MHz, CDC1 3 ) S ppm 1.46 (d, J=4.02 Hz, 9 H) 2.18-2.30 (in, 2 H) 3.54-3.76 (m, 4 H) 5.05 (br s, 1 H) 6.62-6.65 (m, I H) 6.74-6.76 (in, 1 H) 7.17-7.23 (m, 1 H) 7.32 (d, J=9.04 Hz, 2 H) WO 2004/000828 PCT/SE2003/001061 7.39-7.45 (m, 2 H) 7.62 (d, J=8.53 Hz, 2 H) 7.68-7.72 (m, 1 H) 8.16-8.19 (m, 1 H). MS (ESI+) for C 2 5

H

27 C1N 2 0 5 S mI/z 520.2 (M+NH 4 )*, 447.0 (M-tBu)*. HPLC 98%, Rr=2.738 min (System B1, 10-90% MeCN over 3 min). 5 INTERMEDIATE 31 tert-Butyl 3-[(4-{ [( 4 -methoxyphenyl)suffonylamino}-1-naphthyl)oxylpyrrolidine-1 carboxylate (General method E) The compound was prepared from intermediate 2 (0.2 g, 0.61 mmol), Yield: 0.2g (66%) of the title compound as a pink oil. HPLC 98%, RT=2.617 min (System Al, 10-97% MeCN 10 over 3 min). 1H NMR (400 MHz, CDC1) 8 ppm 1.45 (d, J=5.02 Hz, 9 H) 2.14-2.31 (m, 2 H) 3.54-3.76 (m, 4 H) 3.79 (s, 3 H) 5.04 (br s, 1 H) 6.60-6.65 (m, 2 H) 6.81 (d, J=8.53 Hz, 2 H) 7.15-7.24 (m, 1H) 7.38-7.44 (m, 2 H) 7.60-7.64 (m, 2 H) 7.71-7.76 (m, 1 H) 8.14 8.18 (m, 1 H). MS (ESI+) for C 26

H

3 0

N

2 0 6 S m/z 516.4 (M+NH 4 )*, 443.0 (M-tBu)*, 399.2 (M-Boc)*. 15 INTERMEDIATE 32 tert-Butyl 3-[(4-{[(5-chloro-2-thienyl)sulfonyl]amino}-1-naphthyl)oxylpyrrolidine-1 carboxylate (General method E) The compound was prepared from intermediate 2 (0.2 g, 0.61 mmol), Yield: 0.21g (68%) 20 of the title compound as a yellow solid. HPLC 99%, R-r=2.777 min (System B1, 10-90% MeCN over 3 min). 'H NMR (400 MHz, CDC 3 ) 8 ppm 1.46 (d, J=6.02 Hz, 9 H) 2.16-2.30 (m, 2 H) 3.55-3.74 (m, 4 H) 5.07 (br s, 1 H) 6.67-6.70 (m, 1 H) 6.75 (d, J=4.02 Hz, 1 H) 6.77 (br s, 1 H) 7.13 (br s, 1 H) 7.28-7.35 (m, 1 H) 7.46-7.48 (m, 2 H) 7.75-7.79 (m, 1 H) 8.19-8.22 (m, 1 H). MS (ESI+) for C 23

H

25 C1N 2 0 5

S

2 m/z 526.2 (M+NH 4 )+, 453.0 (M-tBu)+, 25 409.2 (M-Boc)*. HPLC 99%, RT=2.767 min (System Al, 10-97% MeCN over 3 min). INTERMEDIATE 33 tert-Butyl 4-[(4-nitro-1 -naphthyl)oxylpiperidine-1-carboxylate (General method C) The compound was prepared from 4-nitro-l-naphthol (2 g, 10.6 mmol). The material 30 obtained after flash chromatography was not pure according to NMR. Recrystallization from EtOAc/iso-hexane gave 2.3g (62%) of the title compound as a yellow solid. HPLC 98%, RT=2.842 min (System Al, 10-97% MeCN over 3 min 'H NMR (400 MHz, CDCl 3

)

WO 2004/000828 PCT/SE2003/001061 8 ppm 1.48 (s, 9 H) 1.99 (m, 4 H) 3.54 (m, 2 H) 3.70 (m, 2 H) 4.87 (m, 1 H) 6.82 (d, J=9.04 Hz, 1 H) 7.59 (m, 1 H) 7.74 (m, 1 H) 8.38 (d, J=8.53 Hz, 2 H) 8.77 (d, J=8.53 Hz, 1 H). MS (ESI+) for C 20

H

24

N

2 0 5 m/z 373.0 (M+H)*, 390.2 (M+NH4)+, 317.0 (M-tBu)+. HPLC 98%, RT=2.973 min (System B1, 10-90% MeCN over 3 min). 5 INTERMEDIATE 34 tert-Butyl 4

-[(

4 -amino-1-naphthyl)oxylpiperidine-1-carboxylate (General Method C) The compound was prepared from intermediate 6 (2.3 g, 7.0 mmol), Yield: 2g (95%) as pink oil. HPLC 94%, RT=2.885 min (System B1, 10-90% MeCN over 3 min). 1H NMR 10 (400 MHz, CDC 3 ) 8 ppm 1.46 (s, 9 H) 1.80-1.98 (m, 4 H) 3.35-3.41 (m, 2 H) 3.46 (s, 3 H) 3.69-3.75 (m, 2 H) 3.88 (br s, 1 H) 4.50-4.54 (m, 1 H) 7.45-7.50 (m, 2 H) 7.79-7.81 (m, 1 H) 8.22-8.24 (m, 1 H). MS (ESI+) for C 20

H

26

N

2 0 3 m/z 343.2 (M+H)*. HPLC 94%, R1=2.735 min (System Al, 10-97% MeCN over 3 min). 15 INTERMEDIATE 35 tert-Butyl 4-[(4-{[(4-chlorophenyl)sulfonyl]amino}-1-naphthyl)oxylpiperidine-1 carboxylate (General method E) The compound was prepared from intermediate 7 (0.25 g, 0.73 mmol), Yield: 0.29g (77%). HPLC 98%, Rr=2.906 min (System Al, 10-97% MeCN over 3 min). 'H NMR (400 MHz, 20 CDC1 3 ) 8 ppm 1.47 (s, 9 H) 1.88 (m, 2 H) 1.98 (m, 2 H) 3.47 (m, 2 H) 3.68 (m, 2 H) 4.69 (m, 1 H) 6.61 (s, 1 H) 6.70 (d, J=8.03 Hz, 1 H) 7.17 (d, J=8.03 Hz, 1 H) 7.32 (m, 2 H) 7.43 (m, 2 H) 7.62 (m, 2 H) 7.70 (m, 1 H). MS (ESI+) for C 26

H

29 C1N 2 0 5 S m/z 534.0 (M+NH 4 )+, 461.2 (M-tBu)*. HPLC 98%, R1=2.843 min (System B1, 10-90% MeCN over 3 min). 25 INTERMEDIATE 36 tert-Butyl 4-[(4-{[(4-methoxyphenyl)sulfonyl]amino}-1-naphthyl)oxylpiperidine-1 carboxylate (General method E) The compound was prepared from intermediate 7 (0.25 g, 0.73 mmol). Yield: 0.21g (56%) of the title compound as pink solid. HPLC 100%, Rp=2.755 min (System Al, 10-97% 30 MeCN over 3 min). 1 HNMR (400 MHz, CDCl 3 ) 3 ppm 1.47 (s, 9 H) 1.86-2.01 (m, 4 H) 3.43-3.49 (m, 2 H) 3.65-3.71 (m, 2 H) 3.79 (s, 3 H) 4.65-4.70 (m, 1 H) 6.58 (s, 1 H) 6.69 WO 2004/000828 PCT/SE2003/001061 (d, J=8.53 Hz, 1 H) 6.83-6.79 (m, 2 H) 7.17 (d, J=8.03 Hz, 1 H) 7.39-7.44 (m, 2 H) 7.61 7.64 (m, 2 H) 7.75-7.77 (m, 1 H) 8.21-8.24 (m, 1 H). MS (ESI+) for C 27

H

3 2

N

2 0 6 S m/z 530.2 (M+NH 4 )*, 457.2 (M-tBu)*, 413.4 (M-Boc)*. HPLC 99%, R-1=2.668 min (System B1, 10-90% MeCN over 3 min). 5 INTERMEDIATE 37 tert-Butyl 4-[(4-{[(5-fluoro-2-methylphenyl)sulfonyl]amino}-1 naphthyl)oxylpiperidine-1-carboxylate (General method E) The compound was prepared from tert-butyl 4-[(4-ainino-1-naphthyl)oxy]piperidine-1 10 carboxylate (0.25 g, 0.73 mmol). Yield: 0.24 g (64 %) of the title compound as a pink solid. HPLC 99 %, R-r=2.809 min (System B1, 10-90% MeCN over 3 min). 1 H NMR (400 MHz, CDCl 3 ) 6 ppm 1.46 (s, 9 H) 1.83-1.98 (m, 4 H) 2.54 (s, 3 H) 3.42-3.48 (m, 2 H) 3.63-3.69 (m, 2 H) 4.64-4.68 (m, 1 H) 6.64-6.68 (m, 2 H) 7.03 (d, J=8.53 Hz, 1 H) 7.10 (m, 1 H) 7.22 (dd, J=8.53, 5.02 Hz, 1 H) 7.44-7.48 (m, 2 H) 7.55 (dd, J=8.53, 2.51 Hz, 1 15 H) 7.83-7.86 (m, 1 H) 8.24 (m, 1 H). MS (ESI+) for C 2 7

H

3 1

FN

2 0 5 S m/z 532.2 (M+NH 4 )*, 459.2 (M-tBu)+, 415.2 (M-Boc)*. HPLC 100 %, RT=2.877 min (System Al, 10-97% MeCN over 3 min). INTERMEDIATE 38 20 tert-Butyl 4-[(4-{[(5-chloro-2-thienyl)sulfonyl]amino}-1-naphthyl)oxy]piperidine-1 carboxylate (General method E) The compound was prepared from tert-butyl 4-[(4-amino-1-naphthyl)oxy]piperidine-1 carboxylate (0.25g, 0.73mmol). Yield: 0.25 g (65 %) of the title compound as a pink solid. HPLC 98 %, RT=2.8 2 7 min (System Bl, 10-90% MeCN over 3 min). 1H NMR (400 MHz, 25 CDCl 3 ) 8 ppm 1.47 (s, 9 H) 1.86-2.03 (m, 4 H) 3.45-3.51 (m, 2 H) 3.66-3.72 (m, 2 H) 4.69-4.74 (in, 1 H) 6.66 (s, 1 H) 6.74-6.76 (m, 2 H) 7.14 (d, J=4.02 Hz, 1 H) 7.30 (d, J=8.03 Hz, 1 H) 7.45-7.50 (m, 2 H) 7.76-7.79 (m, 1 H) 8.25-8.28 (m, 1 H) MS (ESI+) for

C

24

H

27 ClN 2 0sS 2 m/z 540.4 (M+NH4), 467.2 (M-tBu)*. HPLC 99 %, RI=2.910 min (System Al, 10-97 % MeCN over 3 min). 30 WO 2004/000828 PCT/SE2003/001061 INTERMEDIATE 39 tert-Butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (General method G) The compound was prepared from (3R)-3-hydroxypyrrolidine (5 g, 57.4 mmol). Yield: 9.6 g (90 %) of the title compound. 1H NMR (400 MHz, CDC1 3 ) 8 ppm 1.43 (s, 9 H) 1.90-1.98 5 (m, 2 H) 3.27-3.47 (m, 4H) 4.40 (br s, 1H). INTERMEDIATE 40 tert-Butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (General method G) The compound was prepared from (3S)-3-hydroxypyrrolidine (5 g, 57.4 mmol). Yield: 8 g 10 (86 %) of the title compound. 1H NMR (400 MHz, CDCl 3 ) 8 ppm 1.40 (s, 9 H) 1.86-1.91 (m, 2 H) 3.24-3.42 (m, 4H) 4.36 (br s, 1H). INTERMEDIATE 41 tert-Butyl (3S)-3-[(4-nitro-1-naphthyl)oxylpyrrolidine-1-carboxylate (General method 15 C) The compound was prepared from tert-butyl (3R)-3-hydroxypyrrolidine-1 -carboxylate (3.56 g, 19 mmol) and 4-nitro-1-naphthol (3 g, 15.9 mmol). Yield: 5 g (88 %) of the title compound as yellow oil. 'H NMR (400 MHz, CDCl 3 ) S ppm 1.45 (d, J=7.03 Hz, 9 H) 2.22-2.38 (m, 2 H) 3.54-3.83 (m, 4 H) 5.18 (br s, 1 H) 6.74 (d, J=8.53 Hz, 1 H) 7.56 (t, 20 J=7.78 Hz, 1 H) 7.71 (t, J=7.78 Hz, 1 H) 8.29 (d, J=8.53 Hz, 1 H) 8.33 (d, J=8.53 Hz, 1 H) 8.72 (d, J=8.53 Hz, 1 H). MS (ESI+) for C1 9

H

22

N

2 0s m/z 376.2 (M+ NH4), 303.2 (M tBu) . HPLC 100 %, Rr=2.768 min (System Al, 10-97% MeCN over 3 min). INTERMEDIATE 42 25 tert-Butyl (3R)-3-[(4-nitro-1-naphthyl)oxy]pyrrolidine-1-carboxylate (General method C) The compound was prepared from tert -butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (3.56 g, 19 mmol) and 4-nitro-1-naphthol (3 g, 15.9 mmol). Yield: 2.8 g (49 %) of the title compound as yellow oil. 'H NMR (400 MHz, CDCl 3 ) S ppm 1.46 (d, J=7.03 Hz, 9 H) 30 2.26-2.38 (m, 2 H) 3.55-3.81 (m, 4 H) 5.20 (br s, 1 H) 6.77 (d, J=8.53 Hz, 1 H) 7.59 (t, WO 2004/000828 PCT/SE2003/001061 J=7.53 Hz, 1 H) 7.72-7.76 (m, 1 H) 8.32 (d, J=8.03 Hz, 1 H) 8.37 (d, J=8.53 Hz, 1 H) 8.76 (d, J=8.53 Hz, 1 H). HPLC 95 %, R1=2.775 min (System Al, 10-97 % MeCN over 3 min). INTERMEDIATE 43 5 tert-Butyl (3S)-3-[(4-amino-l-naphthyl)oxy]pyrrolidine-1-carboxylate (General method D) The compound was prepared from tert -butyl (3S)-3-[(4-nitro-1-naphthyl)oxy]pyrrolidine 1-carboxylate (5 g, 14 mmol). Yield: 3.5 g (76 %) of the title compound as dark pink solid. 'H NMR (400 MHz, CDC1 3 ) 8 ppm 1.46 (d, J=14.56 Hz, 9 H) 2.08-2.13 (m, 1 H) 2.27-2.30 10 (m, J=13.05 Hz, 1 H) 3.54-3.77 (m, 4 H) 3.88 (br s, 2 H) 4.96 (br s, 1 H) 6.65-6.70 (m, 2 H) 7.45-7.51 (m, 2 H) 7.79-7.81 (m, 1 H) 8.15-8.19 (m, 1H). MS (ESI+) for C 19

H

24

N

2 0 3 m/z 329.2 (M+H), 273.2 (M-tBu)+, 229.2 (M-Boc)+. HPLC 95 %, RT=1.85 4 min (System Al, 10-97 % MeCN over 3 min). 15 INTERMEDIATE 44 tert-Butyl (3R)-3-[(4-amino-1-naphthyl)oxy]pyrrolidine-1-carboxylate (General method D) The compound was prepared from tert -butyl (3R)-3-[(4-nitro-1-naphthyl)oxy]pyrrolidine 1-carboxylate (2.8 g, 7.8 mmol). Yield: 1.8 g (72 %) of the title compound as dark pink 20 solid. IH NMR (400 MHz, CDCl 3 ) 8 ppm 1.46 (d, J=14.56 Hz, 9 H) 2.07-2.14 (m, 1 H) 2.27-2.30 (m, 1 H) 3.54-3.77 (m, 4 H) 3.93 (br s, 2 H) 4.96 (br s, 1 H) 6.65-6.70 (m, 2 H) 7.45-7.51 (m, 2 H) 7.79-7.81 (m, 1 H) 8.16-8.18 (m, 1H). MS (ESI+) for C 1 9

H

24

N

2 0 3 m/z 329.2 (M+H)+, 273.2 (M-tBu)*, 229.2 (M-Boc)*. HPLC 94 %, R1=1.751 min (System Al, 10-97% MeCN over 3 min). 25 INTERMEDIATE 45 tert-Butyl (3S)-3-[(4-{[(4-chlorophenyl)sulfonyllamino}-1-naphthyl)oxylpyrrolidine-1 carboxylate (General method E) The compound was prepared from tert-butyl (3S)-3-[(4-nitro-1-naphthyl)oxy]pyrrolidine 30 1 -carboxylate (0.3 g, 0.9 mmnol) and 4-chloro-phenylsulfonylchloride (0.23 g, 1.1 mmol). Yield: 0.23 g (50 %) of the title compound. 1 H NMR (400 MHz, CDC1 3 ) 6 ppm 1.46 (d, J=4.52 Hz, 9 H) 2.15-2-34 (m, 2 H) 3.54-3.74 (m, 4 H) 5.05 (br s, 1 H) 6.62-6.71 (m, 2 H) WO 2004/000828 PCT/SE2003/001061 7.17-7.23 (m, 1 H) 7.33 (d, J=8.53 Hz, 1 H) 7.39-7.43 (m, 2 H) 7.62-7.64 (m, 2 H) 7.65 7.70 (m, J=6.02 Hz, 1 H) 8.18 (d, J=8.53 Hz, 1 H) MS (ESI+) for C 2 5

H

2 7 C1N 2 0 5 S m/z 520.2 (M+NH 4 )*, 447.0 (M-tBu)+. HPLC 100 %, Rr=2.772 min (System Al, 10-97 % MeCN over 3 min). 5 INTERMEDIATE 46 tert-Butyl (3R)-3-[(4-{[(4-chlorophenyl)sulfonylamino}-1-naphthyl)oxylpyrrolidine 1-carboxylate (General method E) The compound was prepared from tert-butyl (3R)-3-[(4-nitro-1-naphthyl)oxy]pyrrolidine 10 1-carboxylate (0.3 g, 0.9 mmol) and 4-chloro-phenylsulfonylchloride (0.23 g, 1.1 mmol). Yield: 0.4 g (87 %) of the title compound. 1 H NMR (400 MHz, CDC1 3 ) 8 ppm 1.46 (d, J=4.52 Hz, 9 H) 2.15-2-34 (m, 2 H) 3.54-3.74 (m, 4 H) 5.05 (br s, 1 H) 6.60-6.66 (m, 2 H) 7.17-7.23 (m, 1 H) 7.33 (d, J=8.53 Hz, 1 H) 7.39-7.43 (m, 2 H) 7.62-7.64 (m, 2 H) 7.65 7.70 (m, J=6.02 Hz, 1 H) 8.18 (d, J=8.53 Hz, 1 H) MS (ESI+) for C 25

H

27 C1N 2 0 5 S m/z 15 520.2 (M+NH 4 )+, 447.0 (M-tBu)*. HPLC 100 %, Rr=2.769 min (System A1, 10-97 % MeCN over 3 min). EXAMPLE 32 4-Chloro-N-[4-(pyrrolidin-3-yloxy)-1-naphthyllbenzenesulfonamide hydrochloride 20 (General method F) The compound was prepared from intermediate 3 (0.13 g, 0.26 mmol). The solid was further purified by trituration with diethyl ether giving 0.1 1g (95%) of the title compound as white solid. HPLC 98%, Rf=1.810 min (System Al, 10-97% MeCN over 3 min). 'H NMR (400 MHz, DMSO-d 6 ) 8 ppm 2.21-2.26 (m, 2 H) 3.32-3.37 (m, 2 H) 3.48-3.50 (m, 2 25 H) 5.28 (br s, 1 H) 6.91-6.98 (m, 2 H) 7.44-7.50 (m, 2 H) 7.56-7.64 (m, 4 H) 7.88-7.90 (m, 1 H) 8.20-8.23 (m, 1 H). MS (ESI+) for C 2 0 Hj 9 C1N 2 0 3 S m/z 401.2 (M+H)+. HPLC 98%, R1=1.651 min (System B1, 10-90% MeCN over 3 min).

WO 2004/000828 PCT/SE2003/001061 EXAMPLE 33 4-Methoxy-N-[4-(pyrrolidin-3-yloxy)-1-naphthyllbenzenesulfonamide hydrochloride (General method F) The compound was prepared from intermediate 4 (0.18 g, 0.36 mmol), Yield: 0.12 g 5 (76%) of the title compound as a white solid. HPLC 100%, RT=1.490 min (System B1, 10 90% MeCN over 3 min). I H NMR (400 MHz, DMSO-d 6 ) 5 ppm 2.20-2.25 (m, 2 H) 3.3 1 3.53 (m, 4 H) 3.78 (s, 3 H) 5.27 (br s, 1 H) 6.90-6.97 (m, 2 H) 7.00 (d, J=8.53 Hz, 2 H) 7.43-7.48 (m, 2 H) 7.57 (d, J=8.53 Hz, 2 H) 7.93-7.96 (m, 1 H) 8.19-8.22 (i, 1 H) 9.63 (br s, 2 H). MS (ESI+) for C 2 1

H

22

N

2 0 4 S m/z 409.2 (M+H)*. HPLC 100%, RT=1.639 min 10 (System Al, 10-97% MeCN over 3 min). EXAMPLE 34 5-Chloro-N-[4-(pyrrolidin-3-yloxy).--naphthyljthiophene-2-sulfonamide hydrochloride (General method F) 15 The compound was prepared from intermediate 5 (0.20 g, 0.39 mmol), Yield: 0.14 g (80%) of the title compound as a pale white solid. HPLC 99%, R1=1.651 min (System Bi, 10 90% MeCN over 3 min). 'H NMR (400 MHz, DMSO-d 6 ) 8 ppm 2.23-2.26 (m, 2 H) 3.28 3.39 (m, 2 H) 3.40-3.56 (m, 2 H) 5.32 (br s, 1 H) 6.99 (d, J=8.53 Hz, 1 H) 7.13 (d, J=8.03 Hz, 1 H) 7.15 (d, J=4.02 Hz, 1 H) 7.26 (d, J=4.02 Hz, 1 H) 7.48-7.52 (m, 2 H) 7.92 (dd, 20 J=6.53, 3.01 Hz, 1 H) 8.25 (dd, J=6.53, 3.01 Hz, 1 H) 9.60 (s, 1 H). MS (ESI+) for Ci 8

H

17 ClN 2 03S 2 m/z 409.2 (M+H)*. HPLC 99%, R,1=1.818 min (System Al, 10-97% MeCN over 3 min). EXAMPLE 35 25 4-Chloro-N-[4-(piperidin-3-yloxy)-1-naphthyllbenzenesulfonamide hydrochloride (General method F) The compound was prepared from intermediate 8 (0.26 g, 0.50 mmol), Yield: 0.12 g (53%) of the title compound as a white solid. HPLC 100%, R1=1.872 min (System Al, 10 97% MeCN over 3 min). 1H NMR (400 MHz, DMSO-d 6 ) S ppm 1.95-1.99 (m, 2 H) 2.14 30 2.19 (m, 2 H) 3.11 (br s, 2 H) 3.26 (br s, 2 H) 4.84 (br s, 1 H) 6.92-6.99 (m, 2 H) 7.44-7.51 (m, 2 H) 7.57-7.65 (m, 4 H) 7.91 (d, J=7.53 Hz, 1 H) 8.17 (d, J=7.03 Hz, 1 H) 8.94 (br s, 1 WO 2004/000828 PCT/SE2003/001061 H) 9.05 (br s, 1 H) 10.11 (s, 1 H). MS (ESI+) for C 21

H

21 C1N 2 0 3 S m/z 415.2 (M+H)*. HPLC 99%, RT=1.657 min (System B1, 10-90% MeCN over 3 min). EXAMPLE 36 5 4-Methoxy-N-[4-(piperidin-3-yloxy)-1-naphthyl]benzenesulfonamide hydrochloride (General method F) The compound was prepared from intermediate 9 (0.19 g, 0.37 mmol), Yield: 0.15 g (90%) of the title compound as a white solid. HPLC 97%, Rr=1.508 min (System BI, 10-90% MeCN over 3 min). 1H NMR (400 MHz, DMSO-d 6 ) 8 ppm 1.96 (m, 2 H) 2.16 (m, 2 H) 10 3.10 (m, 2 H) 3.26 (m, J=6.02 Hz, 2 H) 3.78 (s, 3 H) 4.82 (m, 1 H) 6.95 (q, J=8.20 Hz, 1 H) 7.01 (d, J=9.04 Hz, 2 H) 7.47 (m, 2 H) 7.57 (m, 2 H) 7.96 (m, 1 H) 8.16 (m, I H) 8.96 (s, 1 H) 9.07 (s, 1 H) 9.81 (s, 1 H). MS (ESI+) for C 22

H

24

N

2 0 4 S m/z 413.4 (M+H). HPLC 97%, RT=1.713 min (System Al, 10-97% MeCN over 3 min). 15 EXAMPLE 37 5-Fluoro-2-methyl-N-[4-(piperidin-4-yloxy)-1-naphthylbenzenesulfonamide hydrochloride (General method F) The compound was prepared from intermediate 10 (0.24 g, 0.47 mmol). Yield: 0.21 g (9 9 %) of the title compound as an off-white solid. HPLC 100 %, RT=1.823 20 min (System Al, 10-97 % MeCN over 3 min). 1H NMR (400 MHz, CH 3 0H-d 4 ) 8 ppm 2.13 (m, 4 H) 2.42 (s, 3 H) 3.18 (m, 2 H) 3.37 (m, 2 H) 4.83 (m, 1 H) 6.81 (d, J=8.53 Hz, 1 H) 6.97 (d, J=8.03 Hz, 1 H) 7.10 (m, 1 H) 7.24 (m, J=8.53, 5.52 Hz, 1 H) 7.35 (m, 3 H) 7.83 (m, 1 H). MS (ESI+) for C 22

H

2 3

FN

2 03S m/z 415.2 (M+H)*. HPLC 96 %, R'=1.628 min (System B1, 10-90% MeCN over 3 min). 25 EXAMPLE 38 5-Chloro-N-[4-(piperidin-4-yloxy)-l-naphthyl]thiophene-2-sulfonamide hydrochloride (General method F) The compound was prepared from tert-butyl 4-[(4-{[(5-fluoro-2 methylphenyl) 30 sulfonyl]amino}-1-naphthyl)oxy]piperidine-1-carboxylate (0.24 g, 0.46 mmol). Yield: 0.16 g (76 %) of the title compound as a white solid. 'H NMR (400 MHz, DMSO-d 6 ) 8 ppm 1.96-2.03 (m, 2 H) 2.16-2.22 (m, 2 H) 3.09-3.14 (m, 2 H) 3.25-3.31 (m, 2 H) 4.86-4.89 (m, WO 2004/000828 PCT/SE2003/001061 1 H) 7.04-7.11 (m, 2 H) 7.16 (d, J=4.02 Hz, 1 H) 7.26 (d, J=4.02 Hz, 1 H) 7.48-7.53 (m, 2 H) 7.92-7.94 (m, I H) 8.19-8.21 (m, I H) 9.06 (br s, 1 H) 10.36 (br s, I H). MS (ESI+) for C1 9 H1 9 ClN 2 03S 2 m/z 423.0 (M+H)*. HPLC 99 %, Rf=1.861 min (System Al, 10-97 % MeCN over 3 min). 5 EXAMPLE 39 4 -Chloro-N-{ 4

-[(

3 S)-pyrrolidin-3-yloxy]--1naphthyl}benzenesulfonamide hydrochloride (General method F) The compound was prepared from tert-butyl (3S)-3-[(4-{[(4 10 chlorophenyl)sulfonyl] amino} -1-naphthyl)oxy]pyrrolidine- 1 -carboxylate (0.22 g, 0.44 mmol). Yield: 0.15 g (78 %) of the title compound as a yellow solid. 'H NMR (400 MHz,

CH

3 0H-d 4 ) 5 ppm 2.37-2.49 (m, 2 H) 3.52-3.56 (m, 2 H) 3.61-3.71 (m, 2 H) 5.37 (br s, 1 H) 6.87 (d, J=8.03 Hz, 1 H) 7.14 (d, J=8.03 Hz, 1 H) 7.38-7.47 (m, 4 H) 7.61 (d, J=8.53 Hz, 2 H) 7.83 (d, J=8.03 Hz, 1 H) 8.22 (d, J=8.03 Hz, 1 H). MS (ESI+) for C 2 oH1 9 ClN 2 0 3 S 15 m/z 403.2 (M+H)*. HPLC 100 %, Rr=1.826 min (System Al, 10-97 % MeCN over 3 min). EXAMPLE 40 4-Chloro-N-{4-[(3R)-pyrrolidin-3-yloxy]-1-naphthyl}benzenesulfonamide hydrochloride (General method F) 20 The compound was prepared from tert-butyl (3R)-3-[(4-{[(4 chlorophenyl)sulfonyl]amino} -1 -naphthyl)oxy]pyrrolidine-1 -carboxylate (0.37 g, 0.74 mmol). Yield: 0.27 g (82 %) of the title compound as a off-white solid. 1H NMR (400 MHz, CH 3 0H-d 4 ) S ppm 2.37-2.49 (m, 2 H) 3.52-3.56 (m, 2 H) 3.61-3.71 (m, 2 H) 5.37 (br s, 1 H) 6.88 (d, J=8.53 Hz, 1 H) 7.15 (d, J=8.03 Hz, 1 H) 7.39-7.47 (m, 4 H) 7.60-7.62 25 (m, 2 H) 7.83 (d, J=7.53 Hz, 1 H) 8.22 (d, J=8.03 Hz, 1 H). MS (ESI+) for C 2 oH1 9 C1N 2 0 3 S m/z 403.2 (M+H)+. HPLC 100 %, R1=1.815 min (System Al, 10-97 % MeCN over 3 min). Table 4

R

4

R

3 N 2 WO 2004/000828 PCT/SE2003/001061 EXAMPLE R 2

R

3 41 N-(4-Methylphenyl)-4-(4-methylpiperazin- H N 1-yl)thieno[3,2-c]pyridine-2-sulfonamide Sj s ' hydrochloride H CH 42 2-Bromo-4-(4-methyl-piperazin-1-yl)- Br N thieno[3,2-c]pyridine-3-sulfonic acid p- jSN tolylamide hydrochloride H CH 3 43 4-(4-Methylpiperazin-1-yl)-N- H N phenylthieno[3,2-c]pyridine-2 sulfonamide hydrochloride H CH, 44 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- F H N sulfonic acid (3-fluoro-5-trifluoromethyl- 0 p O N phenyl)-amide hydrochloride N N CFa H 45 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- C1 H N sulfonic acid (4-chloro-phenyl)-amide (jS N hydrochloride H 46 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- H N sulfonic acid (4-isopropyl-phenyl)-amide o" .. O N hydrochloride N H 47 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- H N sulfonic acid p-tolylamide hydrochloride N N H 48 4-(4-Methylpiperazin-1-yl)-N- (2- H cyclohex-1-en-1-ylethyl) thieno [3,2-c] - N pyridine-2-sulfonamide hydrochloride H N 49 2-(4-(4-Methylpiperazin-1-yl) thieno [3,2- o. 0 H c] pyridin-2-ylsulfonyl)-1,2,3,4- N N tetrahydroisoquinoline hydrochloride 50 4-(4-Methylpiperazin-1-y)-N- (2-thien-2- H _A ylethyl) thieno [3,2-c] pyridine-2- S S sulfonamide hydrochloride H WO 2004/000828 PCT/SE2003/001061 51 4-(4-Methylpiperazin-1-yl)-N- [1-(1- o o H naphthyl) ethyl] thieno [3,2-c] pyridine-2- ( N sulfonamide hydrochloride 52 4-(4-Methylpiperazin-1-y)-N- (4- n-hexy' H hexylphenyl) thieno [3,2-c] pyridine-2- i K) sulfonamide hydrochloride 53 N- (3-Chlorobenzyl)-4-(4-methylpiperazin- o so C, H 1-yl) thieno [3,2-c] pyridine-2-sulfonanide H .N) 54 4-(4-Methylpiperazin-1-yl)-N- [1-(4- 0 o H fluorophenyl) ethyl] thieno [3,2-c] F) pyridine-2-sulfonamide hydrochloride 55 N- (2,3-Difluorobenzyl)-4-(4- o - H methylpiperazin- l-yl) thieno [3,2-c] (N pyridine-2-sulfonamide hydrochloride F N 56 4-(4-Methylpiperazin-1-yl)-N- (4-chloro-2, _H 5-dimethoxyphenyl) thieno [3,2-c] 0gs (N pyridine-2-sulfonamide hydrochloride H 57 2-Bromo-4- (4-methylpiperazin-1-yl)-N- Br o o N (2-cyclohex-1-en-1-ylethyl) thieno [3,2-c]N pyridine-3-sulfonamide hydrochloride H N 58 2-[2-Bromo-4-(4-methyl-piperazin-1- Br o0 .o yl)-benzo[b]thiophene-3-sulfonyl]- N N ,2,3,4-tetrahydro-isoquinoline 59 2-Bromo-4- (4-methylpiperazin-I-yl)-N- Br 0. ' N .N [1-(4-fluorophenyl) ethyl] thieno [3,2-c] F pyridine-3-sulfonamide hydrochloride 60 2-Bromo-4- (4-methylpiperazin-1-yl)-N- Br NN (4-chloro)-(2, 5-dimethoxyphenyl) thieno oK) [3,2-c] pyridine-3-sulfonamide H hydrochloride WO 2004/000828 PCT/SE2003/001061 61 N-(3,4-Dichlorophenyl)-4-piperazn-1- O.~ C1 H ( yltbieno[3,2-c]pyridine-2-sulfonamide -SN CI N hydrochloride 62 N-(2,4-Difluorophenyl)-4-piperazin-1- 0,s.IO F (N ylthieno[3,2-c]pyridine-2-sulfonamideXNN hydrochloride 63 4-Piperazin-1-yl-N-[-3- 0 r, H(N (trifluoromethyl)phenyl]thieno[3,2- K c]pyridine-2-sulfonamide hydrochloride 64 N-(3-Ethylphenyl)-4-piperazin-1- H HN ylthieno[3,2-c]pyridine-2-sulfonamide - KNI H hydrochloride 65 N-(3,4-Dimethoxyphenyl)-4-piperazin-l - 0H(N ylthieno[3,2-c]pyridine-2-sulfonamide 'N'- N hydrochloride 66 N-(4-Bromo-2-methylphenyl)-4-piperazin- Br H(N 1-ylthieno[3,2-c]pyridine-2-sulfonamide < O- N hydrochloride 67 2-(4-Piperazin-l-yl-thieno[3,2-c]pyridmne- o.0 H ( 2-sulfonyl)-1 ,2,3,4-tetrahydro-isoquinolineN hydrochloride 68 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- ~..~H sulfonic acid (2-thiophen-2-yl-ethyl)- S, N s amiide hydrochlorideH sulfonic acid (4-chloro-2,5-dimnethoxy- (N phenyl)-amide hydrochloride

H

WO 2004/000828 PCT/SE2003/001061 70 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- NH 0N sulfonic acid phenethyl-amide SNN hydrochlorideH 71 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- H (N) sulfonic acid (2,6-diethyl-phenyl)-amiide o" N* hydrochloride 1,K 72 4-Piperazin-1-yl-tbieno[3,2-c]pyridine-2- H HN sulfonic acid (3-phenyl-propyl)-amide N <Sp"' hydrochlorideH 73 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- 0,S H N sulfonic acid (3,3-diphenyl-propyl)-amide 'S.N N hydrochloride A 74 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- 0, P H N sulfonic acid [2-(5-methoxy-1H-indol-3- rS IN yl)-ethyl]-amide hydrochloride 0r 75 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- 0,. F H (N) sulfonic acid 4-trifluoromethyl-N benzylamide hydrochloride 76 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2- 00H(N sulfonic acid benzyl-ethyl-amideN hydrochloride 77 N-(3-Ethylphenyl)-4-piperazin-1- H (N), ylthieno[3,2-c]pyridine-3-sulfonaniide N hydrochloride 78 N-(4-Isopropylphenyl)-4-piperazin-1- H "o\ N ylthieno[3,2-cjpyridine-3-sulfonamide hydrochloride

C

WO 2004/000828 PCT/SE2003/001061 79 N-(4-Methylphenyl)-4-(pyrrolidin-3- [?] H yloxy)thieno[3,2-c]pyridine-2-sulfonamide hydrochloride 1&5NSO2 N H H 80 N-(4-Methylphenyl)-4-(piperidin-4- [?] Ix yloxy)thieno[3,2-c]pyridine-2-sulfonamide 0 hydrochloride NSSO N 2N H N H 81 N-(2,3-Difluorobenzyl)-4-piperazin-1- [?] H N ylthieno[3,2-c]pyridine-2-sulfonaniide F N hydrochlorideN F

NH-SO

82 N-(3-Chlorobenzyl)-4-piperazin-1- [?] H N ylthieno[3,2-c]pyridine-2-sulfonamide C0 hydrochloride N

NH-SO

2 Scheme 5 Br : Br - OH Br N H 0 0 0 cl 01-s 0 cl R1 S.O ci Ri- S' R3 Br / N iv: Br / N Br / N vi Br N v : Br N S S S S/S s ci ci R3 clO N viRNHO vN i RNHO oI .' t-ts0s' Legend to Scheme 5: i) Malonic acid, pyridine, piperidine, heat; ii) ethylchloroformate, acetone, NaN 3 -10 5 *C; iii) diphenyl ether, 220 *C; iv) POC1 3 , heat; v) gas SO 2 , n-BuLi, N-chlorosuccinimide, CH 2 Cl 2 ; vi) Rl

NH

2 , pyridine; vii) HR, K 2

CO

3 , DMSO, heat. INTERMEDIATE 47 (2E)-3-(5-Bromothien-2-yl) acrylic acid WO 2004/000828 PCT/SE2003/001061 Malonic acid (44.40 g, 426.7 mmol) was added to a mixture of 5-bromothiophene-2 carbaldehyde (50 g, 261.7 mmol), piperidine (2.84 mL) and pyridine (150 mL). The mixture was refluxed for 1 h at 80*C and than at 100 *C over night. The volatiles were evaporated and the residue was dissolved in water and acidified with hydrochloric acid (pH 5 2). The crude product was crystallized in ethanol. Yield: 55.24 g (90.5 %). 'H NMR (270 MHz, CH30H-d 4 ) 8 ppm 6.14 (d, J=15.83 Hz, 1 H) 7.11-7.16 (in, 2 H) 7.68 (d, J=16.36 Hz, 1 H); MS 233.1 (M - H)*; Purity (HPLC) 94 %. INTERMEDIATE 48 10 (2E)-3-(5-Bromothien-2-yl) acryloyl azide Thionyl chloride (1.04 mL) was added to a solution of (2E)-3-(5-bromothien-2-yl) acrylic acid (1.04 g, 4.46 inmol) in chloroform (20 mL) and the mixture was refluxed for 2h at 75*C and than used in the next step. The above solution was added drop wise to a stirred suspension of sodium azide (0.58 g, 8.93 mmol), dioxane (3 mL) and water (3 mL) in an 15 ice bath. After 10 min a precipitate appeared which was filtered off and washed with water. The residue was dissolved in dichloromethane, dried with MgS04, filtered and the solvent was removed to afford: 0.96 g (83.4 %). 'H NMR (270 MHz CH 3 0H-d 4 ) 8 ppm 6.20 (d, J=15.57 Hz, 1 H) 7.15-7.25 (in, 2 H) 7.80 (d, J=15.57 Hz, 1 H); MS 258.1 (M - H)+ Purity (HPLC) 65 %. 20 INTERMEDIATE 49 2-Bromothieno [3,2-c] pyridin-4 (5H)-one A solution of (2E)-3-(5-bromothien-2-yl) acryloyl azide (18.00 g, 69.7 mmol) solved in dichloromethane (100 mL) was added dropwise to diphenyl ether (90 mL) at 150 *C. The 25 temperature was increased to 220"C for 1h. The mixture was cooled to room temperature followed by the addition of ether. The solid precipitated and was separated by filtration. Yield: 13.58 g (84.6 %). 1 H NMR (270 MHz, DMSO-d 6 ) 6 ppm 6.82 (d, J=7.13 Hz, 1 H) 7.27 (d, J=6.86 Hz, 1 H) 7.54 (s, 1 H) 11.55 (s, 1 H); MS 230.1 (M - H)*; Purity (HPLC) 92%. 30 WO 2004/000828 PCT/SE2003/001061 INTERMEDIATE 50 2-Bromo-4-chloro-thieno 13,2-el pyridine Phosphorus oxychloride (4.08 g, 26.6 mmol) was added dropwise to 2-bromotbieno [3,2-c] pyridin-4 (5H)-one (2.04 g, 8.87 mmol) at 0 0 C. The mixture was heated at 135 *C for 5 2.5h, then carefully poured over ice water. The precipitated was collected by filtration and dried to yield 1.78 g (80.7 %) of title product. 'H NMR (270 MHz, CH 3 0H-d 4 ) 8 ppm 7.67 (d, I H) 7.88 (dddd, J=6.33 Hz, 2 H) 8.19 (d, J=5.54 Hz, 1 H); MS 248.0 (M - H)+; Purity (HPLC) 100 %. 10 INTERMEDIATE 51 and INTERMEDIATE 52 4-Chlorothieno [3,2-c] pyridine-2-sulfonyl chloride and 2-bromo-4-chlorothieno [3,2 c] pyridine-3-sulfonyl chloride n-Butyl lithium (1.5 mL, 2.4 nimol) was added to 2-bromo-4-cblorothieno [3,2-c] pyridine (0.5 g, 2 mmol) dissolved in dry THF (15 ml) at -78"C under nitrogen. The mixture was 15 stirred for 40 min. The above solution was added to a dry ether saturated with SO 2 (gas) at -78'C. The mixture was warmed to room temperature, followed by the addition of ether. The precipitate was separated by filtration. The two title products were obtained and taken to the next step without further purification as follows: N-chlorosuccinimide (2.07 g, 10.3 mmol) was added to [(4-chlorothieno [3,2-c] pyridin-2-yl) sulfonyl] lithium and [(2-bromo 20 4-chlorothieno [3,2-c] pyridin-3-yl) sulfonyl] lithium in dichloromethane (150 mL) at 0 *C. The mixture was heated at 60 *C for 2h, extracted with water (3 x 50 mL). The organic phase was separated, dried with MgSO 4 , filtrated and the volatiles were eliminated by vacuum distillation. The crude products were used in the next step without further purification. 25 INTERMEDIATE 53 and INTERMEDIATE 54 4-Chloro-2-thieno [3,2-c] pyridine-2- sulfonic acid p-tolylamide and 2-bromo-4 chloro-thieno[3,2-cpyridine-3-sulfonic acid p-tolylamide p-Toludine (30 mg, 2.87 mnol) was added to a solution of 4-chlorothieno [3,2-c] pyridine 30 2-sulfonyl chloride and 2-bromo-4-chlorothieno [3,2-c] pyridine-3-sulfonyl chloride (0.07 g, 0.26 mmol) in dichloromethane and pyridine (0.19 mL). The reaction was stirred at WO 2004/000828 PCT/SE2003/001061 room temperature for 2h. The solvent was removed and the crude mixture was taken to the next step without further purification. EXAMPLE 41 and EXAMPLE 42 5 4-(4-Methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-2-sulfonic acid p-tolylamide hydrochloride and 2-bromo-4-(4-methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-3 sulfonic acid p-tolylamide hydrochloride A mixture of 4-chloro-2-thieno [3,2-c] pyridine-2- sulfonic acid p-tolylamide and 2 bromo-4-chloro-thieno[3,2-c]pyridine-3-sulfonic acid p-tolylamide (70 mg, 0.21 mmol) in 10 DMSO (2 mL), 1-methyl piperazine (0.344 mL, 3.1 mmol) and K 2 C0 3 (28.5 mg, 0.21 mmol) was heated to 1 00*C over night. The reaction mixture was dissolved in water and extracted with ethyl acetate (3 x 10 mL). The organic layers were collected and the solvent was removed. The products were purified by HPLC to afford 1.9 mg of 4-(4-Methyl piperazin-1-yl)-thieno[3,2-c]pyridine-2-sulfonic acid p-tolylamide. The free base was 15 converted into the hydrochloride salt by treatment with HC1 in ether: 1H NMR (270 MHz, Methanol-d 4 ) 8 ppm 2.26 (s, 3H) 2.98 (s, 3 H) 3.40-3.55 (in, 8 H) 7.02-7.10 (m, 6 H) 7.55 (d, J=5.81 Hz, 1 H) 7.69 (s, 1 H) 8.13 (d, J=5.81 Hz, 1 H); LC-MS 403 (M + H)+; Purity (LC-MS) 92 % and 3.8 ing 2-bromo-4-(4-methyl-piperazin-1-y)-thieno[3,2-c]pyridine- 3 sulfonic acid p-tolylamide. The free base was converted into the hydrochloride salt by 20 treatment with HCI in ether: 1 H NMR (270 MHz, Methanol-d 4 ) S ppm 2.21 (s, 1H) 3.00 (d, 3H) 3.50-3.77 (in, 8 H) 7.00-7.10 (m, 6 H) 7.63 (d, J=5.81 Hz, 1 H) 8.19 (d, J=5.81 Hz, 1 H); LC-MS 481 (M + H) ; Purity (LC-MS) 98 %. Reaction of sulfonyl chloride with amines (Method H) 25 To a solution of the amine (1.3 equiv.) and pyridine (8 equiv.) in DCM was added the sulfonyl chloride (1 equiv.) and the reaction mixture was stirred over night. After addition of TrisamineTM (ca 2 equiv.), the mixture was gently shaken for additional 3 h. The suspension was then filtered through a short silica plug by the aid of DCM and ethyl acetate. The solvent was evaporated, and the residue was dissolved in DCM and washed 30 with 1 M aqueous HC1 (2 times). The combined organic phases were dried (MgSO 4 ), filtered, and the solvent was removed to give the sulfonamide product. In cases of low- WO 2004/000828 PCT/SE2003/001061 purity material, the products were purified by silica gel flash chromatography. The products are used in the next step (Procedure B). Coupling with aromatic amines (Method I) 5 To the reaction mixtures from the Method H, dissolved in DMSO (2mL), amines (15 equiv.) and K 2 C0 3 (1 equiv.) are added. The reactions are stirred at 1 00*C for 24 and than concentrated. The products are purified by LC-MS. The solvents are removed under vacuum by SpeedVac and purified by preparative LC/MS. The products that were not pure enough (Purity :90%) were purified by preparative chromatography using acetonitrile 10 water gradients containing 0.1% triflouroacetic acid. After HPLC analysis fractions that were > 90% pure were collected and concentrated. Deprotection of the amine in the piperazine was perfonned by first dissolving the substance in methanol and adding portions of 1M HCI/ether. The reactions are analyzed by TLC. The solvents were concentrated under vacuum by a SpeedVac. 15 Deprotection of BOC-group (Method L) The sulfone or sulfonamide derivative (prepared by Methods H and I) were dissolved in a small amount of MeOH/DCM 1:1 and treated with an excess of 1 M HC in diethyl ether. Stirring at ambient temperature overnight resulted in a precipitate which were collected by 20 filtration to give the products as their corresponding hydrochloride salts. EXAMPLE 43 4-(4-Methylpiperazin-1-yl)-N-phenylthieno[3,2-cJpyridine-2-sulfonamide hydrochloride 25 The synthesis was preformed essentially as described in Method H-L. Yield: 8.1 mg (33.8 %). 'H NMR (270 MHz, CH 3 0H-d 4 ) 5 ppm 8.13 (d, J=5.81 Hz, 1 H) 7.67 (s, 1 H) 7.54 (d, J=5.81 Hz, 1 H) 7.55-7.53 (m, 5H) 2.97 (s, 3 H) (4H obscured by solvent signal); LC-MS 389 (M - H)*; Purity (HPLC) 100 %. 30 EXAMPLE 44 4-Piperazin-1-yl-thieno[3,2-clpyridine-2-sulfonic acid (3-fluoro-5-trifluoromethyl phenyl)-amide hydrochloride WO 2004/000828 PCT/SE2003/001061 4-[2-(3-Fluoro-5-trifluoromethyl-phenylsulfamoyl)-thieno[3,2-c]pyridin-4-y]-piperazine 1-carboxylic acid tert-butyl ester (0.235 mmol, 1 equiv.) was used as the thienopyridine in Method H-L. Yield: 25.7 mg HPLC: tR= 3.395 (System: 5% to 50 % ACN in 3 min, C8), Purity: 100 %, LC/MS: tR= 1.375 (System: 30% to 60% ACN in 1.5 min, Hypersil BDS), 5 Purity: 99 %. MS: 461 (M+1) 1H NMR (270 MHz, CH 3 0H-d 4 ) 6 ppm 3.47 (m, 4 H) 3.53 (s, 1 H) 3.87 (m, 4 H) 7.21 (m, 1 H) 7.29 (m, 1 H) 7.33 (s, 1 H) 7.66 (d, J=6.33 Hz, 1 H). EXAMPLE 45 4-Piperazin-1-yl-thieno[3,2-cjpyridine-2-sulfonic acid (4-chloro-phenyl)-amide 10 hydrochloride 4-Chloro-thieno[3,2-c]pyridine-2-sulfonic acid (3-fluoro-5-trifluoromethyl-phenyl)-amide (0.208 mmol, 1 equiv.) was used as the thienopyridine in Method H-L. Yield: 7.2 mg HPLC: tR= 3.039 (System: 5 % to 50 % ACN in 3 min, C8), Purity: 100%, LC/MS: tR7 0.905 (System: 30 % to 60 % ACN in 1.5 min, Hypersil BDS), Purity: 97%. MS: 409 15 (M+1). 1H NMR (270 MHz, CH 3 0H-d 4 ) 6 ppm 3.50 (m, 4 H) 3.91 (m, 4 H) 7.25 (m, 4 H) 7.71 (dd, J=6.33, 0.53 Hz, 1 H) 7.96 (d, J=0.79 Hz, 1 H) 8.04 (d, J=6.33 Hz, 1 H). EXAMPLE 46 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (4-isopropyl-phenyl)-amide 20 hydrochloride 4-Chloro-thieno[3,2-c]pyridine-2-sulfonic acid (4-isopropyl-phenyl)-amide (0.201 nunol, 1 equiv.) was used as the thienopyridine in Method H-L. Yield: 6.9 mg HPLC: tR= 3.255 (System: 5 % to 50 % ACN in 3 min, C8), Purity: 95%, LC/MS: tR= 1.255 (System: 30% to 60 % ACN in 1.5 min, Hypersil BDS), Purity: 98 %. MS: 417 (M+1). 'H NMR (270 25 MHz, CH 3 0H-d4) 8 ppm 1.18 (d, J=6.86 Hz, 6 H) 2.83 (m, 2 H) 3.52 (m, 4 H) 4.00 (m, 4 H) 7.14 (m, 3 H) 7.75 (d, J=6.60 Hz, 1 H) 8.02 (m, 1 H). EXAMPLE 47 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfouic acid p-tolylamide hydrochloride 30 To a solution of 4-chloro-thieno[3,2-c]pyridine-2-sulfonyl chloride (0.640 g, 2.39 mmol) in DCM (20 mL) was added pyridine (1.9 mL, 23.9 mmol) followed byp-tolylamine ( 0.307 g, 2.86 mmol). The reaction mixture was stirred at room temperature for 16 hours. The WO 2004/000828 PCT/SE2003/001061 mixture was concentrated and re-dissolved in DMSO (10 mL), piperazine-1-carboxylic acid tert-butyl ester (1.34 g, 7.17 mmol) andK 2

CO

3 (0.989 g, 7.17 mmol) were added. The mixture was stirred at 100 *C for 16 hours and then concentrated. The crude reaction mixture was dissolved in EtOAc (100 mL) and washed with brine (2 x 50 mL). The 5 organic phase was dried (Na 2

SO

4 ) and concentrated. The crude intermediate was purified by column chromatography on silica using EtOAc/n-pentane (1:1) as eluent. The intermediate was dissolved in EtOAc/MeOH and diethyl ether saturated with HCI (g) was added. The mixture was stirred at room temperature for 16 hours. The precipitate was collected by filtration and washed with diethyl ether/n-pentane to give 0.475 g of the crude 10 product. Purification by preparative reversed phase HPLC gave 0.133 g of the pure product: 'H NMR (DMSO-d 6 , 25 *C, 270.17 MHz) 8 10.61 (br s, 1H), 9.23 (br s, 2H), 8.13 (d, J = 5.80 Hz, 1H), 7.91 (s, 1H); 7.67 (d, J = 5.80 Hz, 1H), 7.09-7.07 (in, 4H), 3.68-3.59 (in, 4H), 3.33-3.22 (m, 4H), 2.20 (s, 3H) ; m/z (posESI) 399 (M+H). 15 EXAMPLE 48 4-(4-Methylpiperazin-1-yl)-N- (2-cyclohex-1-en-1-ylethyl) thieno [3,2-c] pyridine-2 sulfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. Yield: 25.6 mg IH NMR (270 MHz, DMSO-d 6 ) S ppm 10.49-10.48 (in, 1H) 8.23-7.95 (in, 3H) 7.72-7.71 (m, 20 1H) 5.34-5.33 (m, 1H) 4.14-4.11 (in, 2H) 3.53-3.51 (in, 2H) 3.29-3.25 (in, 2H) 2.98-2.97 (in, 2H) 2.85 (s, 3H) 2.04-1.81 (in, 4H) 1.57-1.15 (in, 8H); LC-MS 420.17 (M - H)*; Purity (LC-MS) 97 %. EXAMPLE 49 25 2-(4-(4-Methylpiperazin-1-yl) thieno 13,2-c] pyridin-2-ylsulfony)-1,2,3,4 tetrahydroisoquinoline hydrochloride The synthesis was preformed essentially as described in Method H-L. Yield: 15.5 ing IH NMR (270 MHz, DMSO-d 6 ) S ppm 10.49-10.48 (in, 1H) 8.17-8.15 (in, 1H) 7.86-7.85 (in, 1H) 7.70-7.65 (in, 2H) 7.28-7.12 (in, 3H) 3.97-3.94 (in, 2H) 3.87-3.85 (in, 2H) 3.25-3.18 30 (in, 2H) 2.84 (s, 3H) 1.67-1.65 (in, 2H) 3.51-3.34 (6H obscured by solvent signal); LC-MS 428.13 (M - H)*; Purity (LC-MS) 99 %.

WO 2004/000828 PCT/SE2003/001061 EXAMPLE 50 4-(4-Methylpiperazin-1-yl)-N- (2-thien-2-ylethyl) thieno [3,2-cl pyridine-2 sulfonamide hydrochloride 5 The synthesis was preformed essentially as described in Method H-L. Yield: 29.5 mg 1H NMR (270 MHz, DMSO-d 6 ) 8 ppM 10.28-10.27 (m, 1H) 8.34-8.33 (m, 1H) 8.19-8.17 (m, 1H) 8.01-8.00 (m, 11) 7.71-7.69 (m, 1H) 7.31-7.30 (m, 1H) 6.91-6.87 (m, 1H) 4.13-4.10 (m, 2H) 3.53-3.51 (m, 2H) 3.29-3.25 (m, 211) 3.17-3.16 (m, 2H) 2.99-2.95 (m 4H) 2.86 (s, 311); LC-MS 422.09 (M - H)+; Purity (LC-MS) 99%. 10 EXAMPLE 51 4-(4-Methylpiperazin-1-yl)-N- [1-(1-naphthyl) ethyl] thieno [3,2-c] pyridine-2 sulfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. 20.1 mg 'H NMR 15 (270 MHz, DMSO-d 6 ) 8 ppm 10.28-10.27 (m, 1H) 8.85-8.84 (m, 1H) 8.02-8.01 (m, 1H) 7.67-7.60 (m, 4H) 7.53-7.50 (m, 2H) 7.39-7.36 (m, 2H) 4.72-4.70 (m, 1H) 3.87-3.84 (m, 1H) 3.72-3.70 (m, 1H) 3.23-3.13 (m, 4H) 2.84 (s, 3H) 1.42-1.40 (m 3H); LC-MS 466.15 (M - H)+; Purity (LC-MS) 99 %. 20 EXAMPLE 52 4-(4-Methylpiperazin-1-yl)-N- (4-hexylphenyl) thieno [3,2-c] pyridine-2-sulfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. 8.0 mg 1H NMR (270 MHz, DMSO-d 6 ) 8 ppm 10.39-10.38 (m, 1H) 8.16-8.15 (m, 1H) 7.90-7.89 (m, 1H) 25 7.66-7.65 (m, 1H) 7.09-7.08 (m, 4H) 4.00-3.98 (m, 2H) 3.51-3.48 (m, 2H) 3.26-3.22 (m, 2H) 2.85 (s, 3H) 2.49-2.45 (m, 2H) 1.48-1.46 (m, 211) 1.24-1.22 (m, 8H) 0.82-0.81 (m, 3H); LC-MS 472.20 (M - H)*; Purity (LC-MS) 98 %.

WO 2004/000828 PCT/SE2003/001061 EXAMPLE 53 N- (3-Chlorobenzyl)-4-(4-methylpiperazin-1-yl) thieno [ 3 ,2-c] pyridine-2-sulfonamide hydrochloride The synthesis was prefonned essentially as described in Method H-L. 30.7 mg 1 H NMR 5 (270 MHz, DMSO-d 6 ) S ppm 10.25-10.24 (i, 1H) 8.78-8.77 (m, 1H) 8.18-8.17 (m, 1H) 7.91-7.90 (m, 1H) 7.68-7.67 (m, 1H) 7.26-7.19 (m, 3H) 4.21-4.20 (m, 2H) 4.08-4.05 (m, 2H) 3.54-3.51 (m, 2H) 3.28-3-23 (m, 2H) 2.87 (s, 3H) 2.84-2.60 (2H obscured by solvent signal); LC-MS 436.08 (M - H)+; Purity (LC-MS) 94 %. 10 EXAMPLE 54 4-(4-Methylpiperazin-1-y)-N- [1-(4-fluorophenyl) ethyl] thieno [3,2-cl pyridine-2 sulfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. 32.9 mg 1H NMR (270 MHz, DMSO-d 6 ) 8 ppM 10.16-10.15 (m, 1H) 8.75-8.73 (m, 1H) 7.63-7.62 (m, 2H) 15 7.25-7.24 (m, 2H) 6.91-6.88 (m, 2H) 4.58-4.55 (m, IH) 4.02-3.95 (m, 2H) 3.55-3.53 (m, 2H) 3.25-3-21 (m, 2H) 2.68 (s, 3H) 1.31-1.30 (m, 3H) 2.70-2.64 (2H obscured by solvent signal); LC-MS 434.12 (M - H)+; Purity (LC-MS) 92 %. EXAMPLE 55 . 20 N- (2,3-Difluorobenzyl)-4-(4-methylpiperazin-1-yl) thieno [3,2-cl pyridine-2 sulfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. 26.7 mg 1H NMR (270 MHz, DMSO-d 6 ) S ppm 10.36-10.35 (m, 1H) 8.82-8.81 (m, 1H) 7.96-7.95 (m, 1H) 7.69-7.68 (m, 1H) 7.27-7.10 (m, 2H) 4.26-4.25 (m, 2H) 4.11-4.08 (m, 2H) 3.54-3.52 (m, 25 2H) 3.28-3-24 (i, 2H) 2.68 (s, 3H) 2.86-2.60 (2H obscured by solvent signal); LC-MS 438.10 (M - H)+; Purity (LC-MS) 93 %.

WO 2004/000828 PCT/SE2003/001061 EXAMPLE 56 4-(4-Methylpiperazin-1-yl)-N- (4-chloro-2, 5-dimethoxyphenyl) thieno [3,2-cl pyridine-2-sulfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. 14.6 mg 'H NMR 5 (270 MHz, DMSO-d 6 ) S ppm 10.27-10.26 (m, 1H) 10.14-10.13 (m, 1H) 8.18-8.17 (m, 1H) 7.83-7.82 (m, 111) 7.69-7.68 (m, 1H) 7.09-7.07 (m, 2H) 4.00 (s 2H) 3.76-3.75 (m, 2H) 3.51-3.48 (m, 2H) 3.24-3.22 (m, 2H) 2.85 (s, 3H); LC-MS 482.08 (M - H)*; Purity (LC MS) 95 %. 10 EXAMPLE 57 2-Bromo-4- (4-methylpiperazin-1-yl)-N- (2-cyclohex-1-en-1-ylethyl) thieno [3,2-c] pyridine-3-sulfonamide hydrochloride The synthesis was prefonned essentially as described in Method H-L. 4.6 mg 1H NMR (270 MHz, DMSO-d 6 ) S ppm 10.30-10.29 (m, 1H) 8.31-8.27 (m, 2H) 7.89-7.88 (m, 1H) 15 5.27-5.26 (m, 1H) 3.68-3.52 (m, 4H) 3.05-3.04 (m, 2H) 2.88-2.87 (m, 3H) 2.04-2.03 (m, 211) 2.77-1.81 (m, 2H) 1.54-1.15 (m, 10H); LC-MS 498.08 (M - H)-; Purity (LC-MS) 93 EXAMPLE 58 20 2-[2-Bromo-4-(4-methyl-piperazin-1-yl)-benzo[b]thiophene-3-sulfonyl]-1 ,2,3,4-tetrahydro-isoquinoline hydrochloride The synthesis was preformed essentially as described in Method H-L. Yield: 3.7 mg 1IH NMR (270 MHz, DMSO-d 6 ) S ppM 10.30-10.29 (m, 1H) 9.24-9.22 (m, 1H) 8.09-8.08 (m, 1H) 7.67-7.35 (m, 7H) 4.69-4.66 (m, 1H) 2.86-2.85 (m, 3H) 1.50-1.48 (m, 3H) 3.23-2.51 25 (8H obscured by solvent signal); LC-MS 544.06 (M - H)+; Purity (LC-MS) 92 %. EXAMPLE 59 2-Bromo-4- (4-methylpiperazin-1-yl)-N- [1-(4-fluorophenyl) eth-2-yl] thieno [3,2-c] pyridine-3-sulfonamide hydrochloride 30 The synthesis was preformed essentially as described in Method H-L. Yield: 4.3 mg '1H NMR (270 MHz, DMSO-d 6 ) S ppm 10.35-10.34 (m, 1H) 9.16-9.14 (m, 1H) 8.23-8.22 (m, WO 2004/000828 PCT/SE2003/001061 1H) 7.80-7.79 (m, 1H) 7.26-7.25 (m, 1H) 4.55-4.52 (m, 1H) 3.54-3.52 (m, 2H) 2.88-2.87 (m, 3H) 1.38-1.36 (m, 3H) 3.17-2.83 (6H obscured by solvent signal); LC-MS 512.04 (M H)+; Purity (LC-MS) 93 %. 5 EXAMPLE 60 2-Bromo-4- (4-methylpiperazin-1-yl)-N- (4-chloro)-(2, 5-dimethoxyphenyl) thieno [3,2-cl pyridine-3-sulfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. Yield: 0.7 mg, LC MS 561.91(M - H)*; Purity (LC-MS) 95%. 10 EXAMPLE 61 N-(3,4-dichlorophenyl)-4-piperazin-1-ylthieno[3,2-]pyridine-2-sulfonamide hydrochloride 3,4-Dichloroaniline (0.49 mmol), was dissolved in acetonitrile (1 mL) and pyridine (0.440 15 mL, 4.03 mmol) was added to a solution of 4-chlorothieno [3,2-c] pyridine-2-sulfonyl chloride (0.445 mmol) dissolved in acetonitrile (1 mL). The reaction was shaken for lh, controlled with HPLC and the solvent was removed. The crude product was used in the next step without further purification. To the reaction mixture from the previous step, dissolved in DMSO (lmL), piperazine (15 equiv.) and K 2 C0 3 (1 equiv.) was added. The 20 reaction was stirred at 100 "C for 24 and than concentrated. The product was purified by LC-MS and gave 5.8 mg (2.6 %) of the title product. 'H NMR (270 MHz, CH 3 0H-d 4 ) 8 ppm 8.07-8.05 (m, 2 H) 7.73 (d, J=6.60 Hz, 1 H) 7.46-7.41 (m, 2 H) 7.16 (dd, J=8.71, 2.38 Hz, 1 H) 3.94-3.90 (m, 4 H) 3.92 (m, 4 H) 3.53-3.50 (m, 4 H); LC-MS 443 (M - H)+ Purity (HPLC) 95%. 25 EXAMPLE 62 N-(2,4-Difluorophenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. Yield: 4.3 mg (2.1 30 %). 'H NMR (270 MHz, CH 3 0H-d 4 ) 8 ppm 8.22 (s, 1 H) 8.07-8.01 (m, 2H) 7.79-7.72 (m, 1H) 7.55-7.47 (m, 1H) 7.04-6.94 (m, 2H) 4.00-3.96 8m, 4H) 3.53-3.43 (m, 4H) 2.66 (s, 1H); LC-MS 411 (M - H)*; Purity (HPLC) 98 %.

WO 2004/000828 PCT/SE2003/001061 EXAMPLE 63 4-Piperazin-1-yl-N-[-3-(trifluoromethyl)phenyllthieno[3,2-clpyridine-2-sulfonamide hydrochloride 5 The synthesis was preformed essentially as described in Method H-L. Yield: 2.6 mg (1.2 %). 'IH NMR (270 MiHz, CH 3 OH-d 4 ) 8 ppm 8.05 (d, J=6.60 Hz, 2 H) 7.81-7.60 (m, 3H) 7.50-7.47 (in, 2H) 3.94-3.90 (m, 4H) 3.56-3.49 (m, 4H); LC-MS 443 (M - H)*; Purity (HPLC) 99 %. 10 EXAMPLE 64 N-(3-Ethylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. Yield: 1.4 mg (0.7 %). 1H NMR (270 MHz, CH 3 0H-d 4 ) 6 ppm 8.35 (s, 1H) 7.58-6.92 (m, 7H) 3.54-3.44 (m, 2H) 3.01-2.95 (m, 4H) 2.66 (s, 1H) 2.18-2.01 (m, 3H)); LC-MS 403 (M - H)*; Purity 15 (HPLC) 100 %. EXAMPLE 65 N-(3,4-Dimethoxyphenyl)-4-piperazin-1-ylthieno[3,2-clpyridine-2-sulfonamide hydrochloride 20 The synthesis was preformed essentially as described in Method H-L. Yield: 7.7 mg (3.6 %). 'H NMR (270 MHz, CH 3 0H-d 4 ) 5 ppm 8.04 (d, J=6.60 Hz, 1 H) 7.77-7.75 /m, 2H) 6.85-6.83 (m, 2H) 6.68-6.83 (m, 111) 3.87-3.85 (m, 4H) 3.77-3.75 (m, 6H) 3.49-3.45 (m, 4H) 2.65 (s, 1H); LC-MS 435 (M - H)+; Purity (HPLC) 98 %. 25 EXAMPLE 66 N-(4-Bromo-2-methylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. Yield: 12.2 mg (5.3 %). 'H NMR (270 MHz, CH 3 0H-d4) 5 ppm 8.07 (d, J=6.33 Hz, 1 H) 7.86-7.79 (m, 2H) 30 7.40 (d, J=1.58 Hz, 1 H) 7.30-7.29 (m, 111) 7.08 (d, J=8.71 Hz, 1 H) 3.96-3.92 (m, 4H) 3.53-3.51 (4H) 2.66 (s, 1H) 2.11 (s, 3H); LC-MS 467 (M - H)+; Purity (HPLC) 90 %.

WO 2004/000828 PCT/SE2003/001061 EXAMPLE 67 2

-(

4 -Piperazin-1-yl-thieno[3,2-clpyridine-2-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride 5 The synthesis was preformed essentially as described in Method H-L from 4-{2-(3,4 dihydro-1H-isoquinoline-2-sulfony)-thieno[ 3

,

2 -c]pyridin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.235 mmol, 1 equiv.). Yield: 4.0 mg. LC/MS: tR7 0.801 (System: 30 % to 60 % ACN in 1.5 min, Hypersil BDS), Purity: 92%. MS: 415 (M+1) 1H NMR (270 MHz, DMSO-d 6 ) 8 ppm 2.87 (t, J=5.81 Hz, 2 H) 3.30 (s, 4 H) 4.43 (s, 2 H) 7.15 (m, 4 H) 10 7.70 (d, J=5.54 Hz, 1 H) 8.12 (s, 1 H) 8.18 (d, J=5.54 Hz, 1 H) 6 aliphatic protons were obscured by the water-peak in the spectra and so could not be analyzed. EXAMPLE 68 4 -Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (2-thiophen-2-yl-ethyl)-amide 15 hydrochloride The synthesis was preformed essentially as described in Method H-L from 4-[2-(2 thiophen-2-yl-ethylsulfamoyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-1-carboxylic acid tert butylester (0.235 mmol, 1 equiv.). Yield: 8.7 mg. LC/MS: tR= 0.430 (System: 30 % to 60 % ACN in 1.5 min, Hypersil BDS), Purity: 93 %. MS: 409 (M+1) 1 H NMR (270 MHz, 20 DMSO-d 6 ) 8 ppm 2.25 (s, 1 H) 2.75 (s, 1 H) 2.96 (t, J=6.99 Hz, 1 H) 3.16 (q, J=6.51 Hz, 1 H) 3.31 (s, 4 H) 3.70 (s, 4 H) 6.90 (m, 1 H) 7.32 (t, J=5.54 Hz, 1 H) 7.70 (d, J=5.81 Hz, 1 H) 8.04 (d, J=1.85 Hz, 1 H) 8.18 (d, J=5.54 Hz, 1 H) 8.36 (m, 1 H) 9.05 (s, 1 H). EXAMPLE 69 25 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (4-chloro-2,5-dimethoxy phenyl)-amide hydrochloride The synthesis was preformed essentially as described in Method H-L from 4-[2-(4-chloro 2 ,5-dimethoxy-phenylsulfamoyl)-thieno[3,2-c]pyridin-4-y1]-piperazine-1-carboxylic acid tert-butyl ester (0.112 mmol, 1 equiv.) was used as the thienopyridine in Method C. Yield: 30 14.7 mg. LC/MS: tR = 0.610 (System: 30 % to 60 % ACN in 1.5 min, YMC), Purity: 92 %. MS: 469 (M+1) 1H NMR (270 MHz, DMSO- d) 8 ppm 3.17 (s, 1 H) 3.27 (s, 4 H) 3.38 (s, WO 2004/000828 PCT/SE2003/001061 3 H) 3.58 (d, J=4.22 Hz, 4 H) 3.77 (s, 3 H) 7.08 (s, 1 H) 7.69 (d, J=5.81 Hz, 1 H) 7.81 (s, 1 H) 8.16 (d, J=5.81 Hz, 1 H) 9.07 (s, 1 H) 10.17 (s, 1 H). EXAMPLE 70 5 4-Piperazin-1-yl-thieno[3,2-lpyridine-2-sulfonic acid phenethyl-amide hydrochloride The synthesis was preformed essentially as described in Method H-L from 4-(2 phenethylsulfamoyl-thieno[3,2-c]pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.112 mmol, 1 equiv.). Yield: 3.8 mg. LC/MS: tR= 0.410 (System: 30% to 60% ACN in 1.5 min, YMC), Purity: 91 %. MS: 403 (M+1) 1 H NMR (270 MHz, CH 3 0H-d 4 ) 8 ppm 10 1.44 (d, J=7.13 Hz, 2 H) 3.51 (d, J=4.75 Hz, 4 H) 3.54 (s, 2 H) 3.94 (m, 4 H) 7.05 (m, 4 H) 7.16 (m, 1 H) 7.62 (s, 1 H) 7.72 (d, J=6.60 Hz, 1 H) 8.00 (d, J=6.60 Hz, 1 H). EXAMPLE 71 4-Piperazin-1-yl-thieno[3,2-cjpyridine-2-sulfonic acid (2,6-diethyl-phenyl)-amide 15 hydrochloride The synthesis was preformed essentially as described in Method H-L from 4-[2-(2,6 dethyl-phenylsulfamoyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.112 mmol, 1 equiv.). Yield: 9.0 mg. LCIMS: tR= 0.830 (System: 30 % to 60 % ACN in 1.5 min, YMC), Purity: 92 %. MS: 431 (M+1) 1 H NMR (270 MHz, DMSO-D6) 8 20 ppm 0.96 (t, J=7.52 Hz, 6 H) 2.25 (m, 1 H) 2.43 (s, 2 H) 2.75 (t, J=1.72 Hz, 1 H) 3.26 (s, 4 H) 3.62 (s, 4 H) 7.09 (s, 1 H) 7.12 (s, 1 H) 7.23 (m, 1 H) 7.73 (d, J=5.81 Hz, 1 H) 7.77 (s, I H) 8.19 (d, J=5.81 Hz, 1 H) 9.04 (s, 1 H) 9.95 (s, 1 H). EXAMPLE 72 25 4-Piperazin-1-yl-thieno[3,2-lpyridine-2-sulfonic acid (3-phenyl-propyl)-amide hydrochloride The synthesis was preformed essentially as described in Method H-L from 4-[2-(3-phenyl propylsulfamoyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.112 mmol, 1 equiv.). Yield: 13.0 mg. LC/MS: tR= 0.726 (System: 30 % to 60 % ACN in 30 1.5 min, YMC), Purity: 91 %. MS: 417 (M+1) 1 H NMR (270 MHz, CH 3 0H-d 4 ) 6 ppm 1.82 (m, 2 H) 2.63 (m, 2 H) 3.04 (t, J=6.86 Hz, 2 H) 3.55 (s, 4 H) 4.09 (s, 4 H) 7.16 (m, 4 H) 7.82 (d, J=6.60 Hz, 1 H) 8.05 (d, J=6.33 Hz, 1 H) 8.14 (s, 1 H).

WO 2004/000828 PCT/SE2003/001061 EXAMPLE 73 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (3,3-diphenyl-propyl)-amide hydrochloric acid 5 The synthesis was preformed essentially as described in Method H-L from 4-[2-(3,3 diphenyl-propylsulfamoyl)-thieno[3,2-c]pyridin- 4 -yl]-piperazine-1-carboxylic acid tert butyl ester (0.112 mmol, 1 equiv.). Yield: 14.4 mg. LC/MS: tR= 1.109 (System: 30 % to 60 % ACN in 1.5 min, YMC), Purity: 93 %. MS: 493 (M+1) 1H NMR (270 MHz, DMSO-d,) 5 ppm 2.20 (m, 2 H) 2.80 (m, 2 H) 3.29 (s, 4 H) 3.67 (d, J=5.01 Hz, 4 H) 4.01 (m, 1 H) 10 7.14 (m, 8 H) 7.71 (d, J=5.81 Hz, 1 H) 7.95 (s, 1 H) 8.18 (d, J=5.81 Hz, 1 H) 8.27 (m, 2 H) 9.13 (s, 2 H). EXAMPLE 74 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid [2-(5-methoxy-1H-indol-3-yl) 15 ethyl]-amide hydrochloride The synthesis was preformed essentially as described in Method H-L from 4-{2-[2-(5 methoxy-1H-indol-3-yl)-ethylsulfamoyl]-thieno[3,2-c]pyridin-4-yl} -piperazine-1 carboxylic acid tert-butyl ester (0.112 mmol, 1 equiv.). Yield: 6.1 Mg. LC/MS: tR7 0.364 (System: 30 % to 60 % ACN in 1.5 min, YMC), Purity: 91 %. MS: 472 (M+1) 1 H NMR 20 (270 MHz, CH 3 0H-d 4 ) 8 ppm 2.85 (t, J=6.20 Hz, 2 H) 3.48 (t, J=6.20 Hz, 2 H) 3.55 (m, 4 H) 3.80 (s, 3 H) 4.02 (m, 4 H) 6.44 (dd, J=8.71, 2.37 Hz, 1 H) 6.80 (m, 2 H) 6.97 (s, 1 H) 7.64 (s, 1 H) 7.67 (s, 1 H) 7.97 (d, J=6.60 Hz, 1 H). EXAMPLE 75 25 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid 4-trifluoromethyl-benzylamide hydrochloride The synthesis was preformed essentially as described in Method H-L from 4-[2-(4 trifluoromethyl-benzylsulfamoyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-l-carboxylic acid tert-butyl ester (0.112 mmol, 1 equiv.) was used as the thienopyridine in Method C. Yield: 30 1.9 mg. LC/MS: tR= 0.771 (System: 30% to 60% ACN in 1.5 min, YMC), Purity: 91%. MS: 457 (M+1) 'H NMR (270 MHz, CH 3 0H-d 4 ) S ppm 3.54 (m, 4 H) 3.98 (m, 4 H) 4.36 (s, 2 H) 7.49 (m, 4 H) 7.74 (d, J=6.86 Hz, 1 H) 8.02 (s, 1 H) 8.07 (d, J=6.60 Hz, 1 H).

WO 2004/000828 PCT/SE2003/001061 EXAMPLE 76 4-Piperazin-1-yl-thieno[3,2-clpyridine-2-sulfonic acid benzyl-ethyl-amide hydrochloride 5 The synthesis was preformed essentially as described in Method H-L from 4-[2-(benzyl ethyl-sulfamoyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.112 mmol, 1 equiv.). Yield: 6.4 mg. LC/MS: tR= 0.930 (System: 30 % to 60 % ACN in 1.5 min, YMC), Purity: 95 %. MS: 417 (M+1) 1 H NMR (270 MHz, CH 3 0H-d 4 ) 8 ppm 1.03 (t, J=7.13 Hz, 3 H) 3.37 (m, 2 H) 3.57 (s, 2 H) 3.75 (m, 2 H) 4.11 (s, 2 H) 4.50 (s, 2 10 H) 5.80 (s, 1 H) 7.32 (m, 5 H) 7.84 (d, J=6.60 Hz, 1 H) 8.07 (d, J=6.60 Hz, 1 H) 8.14 (s, 1 H). INTERMEDIATE 55 tert-Butyl-4-(3-{ [(3-ethylphenyl)aminojsulfonyl}thieno[3,2-c]pyridin-4-yl)piperazine 15 1-carboxylate Prepared from tert-butyl 4

-[

3 -(chlorosulfonyl)thieno[3,2-c]pyridin-4-y1]piperazine-1 carboxylate (90.0 mg, 0.215 mmol) and 3-ethylaniline (33.9 mg, 0.28 mmol) to give the title compound as an off-white solid (82.7 mg, 76 %). 'H NMR (400 MHz, CDCl 3 ) 5 1.03 (t, J = 7.5 Hz, 3 H), 1.48 (s, 9 H), 2.47 (q, J = 7.7 Hz, 2 H), 3.00-3.53 (m, 6 H), 4.02-4.44 20 (m, 2 H), 6.66 (d, J= 8.0 Hz, 1 H), 6.75 (s, 1 H), 6.66 (d, J = 8.0 Hz, 1 H), 7.02 (t, J = 7.8 Hz, 1 H), 7.67 (d, J = 5.5 Hz, 1 H), 8.24 (s, 1 H), 8.39 (d, J = 5.5 Hz, 1 H), 9.80 (s, 1 H). MS (ESI+) m/z 503.2 (M+H)*. HPLC 97 %, RT: 3.93 min (5-99 % MeCN over 3 min). EXAMPLE 77 25 N-(3-Ethylphenyl)-4-piperazin-1-ylthieno[3,2-cpyridine-3-sulfonamide hydrochloride Prepared from tert-butyl 4-(3-{[(3-ethylphenyl)amino]sulfonyl}thieno[3,2-c]pyridin-4 yl)piperazine-1-carboxylate (81.1 mg, 0.161 mmol) which afforded 19 mg (98 %) of the product as a white solid (38.0 mg, 54 %). 'H NMR (400 MHz, CH 3 0H-d 4 ) 8 1.09 (t, J= 7.5 Hz, 3 H), 2.51 (q, J= 7.5 Hz, 2 H), 3.59 (br.s, 8 H), 6.89-6.92 (m, 3 H), 7.12-7.14 (m, 30 1 H), 8.06 (d, J= 6.0 Hz, 1 H), 8.36 (d, J= 6.0 Hz, 1 H), 8.49 (s, 1 H). MS (ESI+) m/z 403.2 (M+H)+. HPLC 95%, RT: 3.02 min (5-99% MeCN over 3 min).

WO 2004/000828 PCT/SE2003/001061 INTERMEDIATE 56 tert-Butyl 4-(3-bromothieno[3,2-cepyridin-4-yl)piperazine-1-carboxylate A mixture of 3-bromo-4-chlorothieno[3,2-c]pyridine (729 mg, 2.93 mmol), tert-butyl piperazine-1-carboxylate (1.64 g, 8.80 mmol) and K 2 C0 3 (811 mg, 5.87 mmol) in DMSO 5 (45 mL) was stirred for 5 days at 100 'C. After addition of H 2 0 and ethyl acetate, the layers were separated. The water phase was extracted twice with ethyl acetate, and the combined organic phases were washed with water and brine and dried (MgSO 4 ). After filtration and removal of the solvent, the residue was purified by silica gel flash chromatography (pentane/ethyl acetate, 8:2) to give the product as a white powder (398 10 mg, 34 %). HPLC 99%, RT: 3.27 min (5-99% MeCN over 3 min).'H NMR (400 MHz,

CH

3 0H-d 4 ) 8 1.48 (s, 9 H), 3.21 (br.s, 4 H), 3.71 (s br., 4 H), 7.61 (d, J= 6.1 Hz, 1 H), 7.72 (s, 1 H), 8.08 (d, J= 5.6 Hz, 1 H). MS (ESI+) m/z 398.2 (M+H)*. INTERMEDIATE 57 15 {4-[4-(tert-Butoxycarbonyl)piperazin-1-yllthieno[3,2-clpyridin-3-yllsulfonyl)lithium To a suspension of tert-Butyl 4-(3-bromothieno[3,2-c]pyridin-4-yl)piperazine-l carboxylate (4.055 g, 10.18 mmol) in diethyl ether (30 mL) at -78 'C under N 2 atmosphere was added dropwise an 1.6 M solution of n-BuLi in hexanes (9.5 mL, 15.2 mmol). After 1 h of stirring, a saturated solution of SO 2 in THF (25 mL) at -78 *C was transferred via a 20 cannula to the mixture. The reaction was allowed to gradually increase to ambient temperature over night. The solvent was evaporated, and the residue was washed with several portions of diethyl ether and then dried under vacuum to give 4.094 g of an off white solid consisting of 66 % of the title compound and 34 % of (n-butylsulfonyl)lithium as by-product. This mixture was used without any further purification in the next step. 1 H 25 NMR (400 MHz, CH 3 0H-d 4 ) 6 1.48 (s, 9 H), 3.22 (br.s, 4 H), 3.72 (s br., 4 H), 7.60 (d, J= 5.5 Hz, 1 H), 8.06 (d, J= 5.5 Hz, 1 H), 8.14 (s, 1 H). MS (ESI+) m/z 384.0 (M+H)*. HPLC RT: 2.62 min (5-99% MeCN over 3 min).

WO 2004/000828 PCT/SE2003/001061 INTERMEDIATE 58 tert-Butyl-4-[3-(chlorosulfonyl)thieno[3,2-cjpyridin-4-yllpiperazine-1-carboxylate To a suspension of ({4-[4-(tert-butoxycarbonyl)piperazin-1-yl]thieno[3,2-c]pyridin-3 yl}sulfonyl)lithium (2.751 g, 7.06 mmol (3.126 g of the crude product mixture)) in DCM 5 (40 mL) at 0 *C was added N-chlorosuccinimide (1.338 g, 10.0 mmol). After 20 minutes, the temperature was raised to ambient, and the reaction mixture was stirred for an additional 2.5 h. The resulting product solution was washed with water, and the water phase was extracted with DCM. The combined organic extracts were washed with brine and dried over MgS04. After filtration and evaporation of the solvent, the residue was 10 washed with several portions of pentane to yield the product as an off-white solid (2.024 g, 69 %). 1H NMR (400 MHz, CH 3 0H-d 4 ) 5 1.47 (s, 9 H), 3.11 (br.s, 4 H), 3.2-4.3 (s br., 4 H), 7.68 (d, J= 5.5 Hz, 1 H), 8.45 (d, J= 5.5 Hz, 1 H), 8.60 (s, 1 H). MS (ESI+) m/z 418.2 (M+H)+. HPLC 92%, RT: 3.76 min (5-99% MeCN over 3 min). 15 INTERMEDIATE 59 tert-Butyl-4-(3-{[(4-isopropylphenyl)amino]sulfonyl}thieno[3,2-c]pyridin-4 yl)piperazine-1-carboxylate Prepared from tert-butyl 4-[3-(chlorosulfonyl)thieno[3,2-c]pyridin-4-yl]piperazine-1 carboxylate (90.0 mg, 0.215 mmol) and 4-isopropylaniline (37.9 mg, 0.28 mmol) to give 20 the title compound as an off-white solid (58.3 mg, 52 %). 1H NMR (400 MHz, CDC1 3 ) 6 1.12 (d, J= 7.0 Hz, 6 H), 1.47 (s, 9 H), 2.76 (sept., J= 6.9 Hz, 2 H), 3.01-3.53 (in, 6 H), 4.04-4.41 (in, 2 H), 6.79 (d, J= 8.5 Hz, 2 H), 6.66 (d, J= 8.5 Hz, 2 H), 7.69 (d, J= 5.5 Hz, 1 H), 8.23 (s, 1 H), 8.40 (d, J= 5.5 Hz, 1 H), 9.90 (s, I H). MS (ESI+) m/z 517.2 (M+H)*. HPLC 97%, RT: 4.01 min (5-99% MeCN over 3 min). 25 EXAMPLE 78 N-(4-Isopropylphenyl)-4-piperazin-1-ylthieno[3,2-clpyridine-3-sulfonamide hydrochloride Prepared from tert-butyl 4-(3-{[(4-isopropylphenyl)amino]sulfony}thieno[3,2-c]pyridin 30 4-yl)piperazine-l-carboxylate (60.0 mg, 0.116 mmol) which afforded 19 mg (98 %) of the product as a white solid (25.8 mg, 49 %) according to Method H-L. 'H NMR (400 MHz, WO 2004/000828 PCT/SE2003/001061

CH

3 0H-d 4 ) 8 1.16 (d, J= 7.0 Hz, 6 H), 2.81 (sept., J=6.8 Hz, I H), 3.59 (s, br., 8 H), 7.00 (d, J= 8.0 Hz, 2 H), 7.10 (d, J= 8.0 Hz, 2 H), 8.07 (s, br., 1 H), 8.37 (s, br., 1 H), 8.50 (s, 1 H). MS (ESI+) m/z 417.2 (M+H)*. HPLC 94%, RT: 3.14 min (5-99% MeCN over 3 min). 5 EXAMPLE 79 N-(4-Methylphenyl)-4-(pyrrolidin-3-yloxy)thieno[3,2-cjpyridine-2-sulfonamide hydrochloride 4-Chloro-N-(4-methylphenyl)thieno[3,2-c]pyridine-2-sulfonamide (60.0 mg, 0.17 mmol) in dry DMF (1 mL) and NaH (5,1 mg, 0.21 mmol) was added to pyrrolidin-3-ol (18.5 mg, 10 0.21 mmol) under nitrogen. The mixture was heated in the microwave at 200'C in 5 min. The product was purified by preparative HPLC. Yield: 29.9 mg (43.4 %). 1H NMR (270 MHz, CH 3 0H-d 4 ) 8 ppm 8.09 (s, 1H) 7.71 (d, J=6.93 Hz, 1 H) 7.46 (d, J=6.93 Hz, 1 H) 7.47-7.44 (m, 4H) 4.67 (d, J=3.22 Hz, 1 H) 3.97 (s, 2 H) 2.26 (s, 3H). LC-MS 390 (M H)*; Purity (HPLC) 99 %. 15 EXAMPLE 80 N-(4-Methylphenyl)-4-(piperidin-4-yloxy)thieno[3,2-c]pyridine-2-sulfonamide hydrochloride The synthesis was preformed essentially as described for compound of N-(4 20 methylphenyl)-4-(pyrrolidin-3-yloxy)thieno[3,2-c]pyridine-2-sulfonamide hydrochloride. Yield: 16.2 mg (22.7 %). 'H NMR (270 MHz, CH 3 0H-d 4 ) 8 ppm 7.81-7.78 (m, 2H) 7.62 (d, J=6.93 Hz, 1 H) 7.13-7.04 (m, 4H) 4.05-3.94 (m, 1H) 3.90-3.88 (m, 2H) 3.63-3.58 (m, 2H), 2.27 (s, 3H) 2.06-2.03 (m, 2H) 2.01-1.71 (m, 2H); LC-MS 404 (M - H)*; Purity (HPLC) 99 %. 25 EXAMPLE 81 N-(2,3-Difluorobenzyl)-4-piperazin-1-ylthieno[3,2-cpyridine-2-sulfonamide hydrochloride Yield: 74.4 mg (39.2 %). 'H NMR (270 MHz, CH 3 OH-d 4 ) 8 ppm 8.10-8.03 (m, 211) 7.81 30 (d, J=6.68 Hz, I H) 7.16-7.05 (m, 3H) 4.37 (s, 2 H) 4.11-4.07 (m, 4H) 3.59-3.53 (m, 4H); LC-MS 425 (M - H)*; Purity (HPLC) 90 %.

WO 2004/000828 PCT/SE2003/001061 EXAMPLE 82 N-(3-Chlorobenzyl)-4-piperazin-1-ylthieno[3,2-clpyridine-2-sulfonamide hydrochloride Yield: 74.4 mg (44.7 %). 'H NMR (270 MHz, CH 3 0H-d4) 8 ppm 8.04-8.01 7.85 (d, 5 J=6.93 Hz, 1 H) 7.22-7.15 (m, 4H) 4.30 (s, 2 H) 4.14-4.10 (m, 4H) 3.60-3.54 (m, 4H); LC MS 423 (M - H)*; Purity (HPLC) 90%. Table 5 10 R EXAMPLE RR 83 4-(1,4-Diazepan-1-yl)-2-(phenylsulfony1)thieno[3,2-c]pyridine (N hydrochloride 04 0 84 4-(1,4-Diazepan-1-yl)-2-[(3,4-dichlorophenyl)sulfony]thieno[3,2 c]pyridine hydrochloride )N 85 4-(1,4-Diazepan-1-yl)-2-[1-naphthylsulfonyl)thieno[3,2-clpyridine N hydrochloride N 86 4-(1,4-Diazepan-1-y1)-2-[4-tert-butylphenylsulfonyl)thieno[3,2 c]pyridine hydrochloride

N

87 4-(1,4-Diazepan-1-yl)-2-[3,4-dimethylphenylsulfonyl)thieno[3,2 c]pyridine hydrochloride N- WO 2004/000828 PCT/SE2003/001061 88 2-[(4-Bromophenyl)sutfonyll-4-(l,4-diazepan-1-yl)thieno[3,2- ( c]pyridine hydrochloride ND 89 2-(Phenylsulfonyl)-4-piperazin-l -ylthieno[3,2-c]pyridine(N hydrochloride f 90 2-(3-Methoxy-benzenesulfonyl)-4-piperazin-l-yl-thieno[3,2- I (N) c]pyridine hydrochloride ~Q NI 91 2-(4-Methoxy-benzenesulfonyl)-4-piperazin-l -yl-thieno[3,2-(N c]pyridmne hydrochloride Y~ N 92 4-Piperazixi-l-y1-2-{ [4-trifluoromethyl)phenyl]sulfonyllthieno[3,2-N c]pyridine hydrochloride Fr 7' FE N 93 2-[[2-tert-Butylphenyl)sulfonyl]-4-piperazin-l-yltieno[3,2-C N c]pyridine hydrochloride IK 94 2- [(3 ,4-Dichlorophenyl)sulfonyl]-4-piperazin-l-yltbieno [3 ,2- (N) c~pyridine-2-sulfonaniide hydrochloride K CI N C1 95 2-[(4-tert-Butylphenyl)sulfonyl]-4-piperazin- l-ylthienoll3,2- (N) c]pyridine hydrochloride i' II N 96 2-(l-Naphthyl sulfonyl)-4-piperazin-l-ylthienol3,2-c]pyridine(N hydrochloride KN 97 2-[(3-Fluorophenyl)sulfonyl]-4-piperazn-l-yltiieno[3,2-c]pyridie-(N 2-sulfonamide hydrochloride KN

F

WO 2004/000828 PCT/SE2003/001061 98 2-(Mesitylsulfonyl)-4-piperazin--ylthieno[3,2-c]pyridileN hydrochloride (NL ) 99 2[(2Methoxyphenyl)sulfony1]-4-piperazin-l-ythieno[3,2-c]pyidile (N hydrochloride t1.I 100 2-[(2,4-Dimethoxyphenyl)sulfonyl] -4-piperazin-l-ylthieno[13,2- (N) cipyridine hydrochloride 0-:f 101 2-[(2,4-Dimethylphenyl)sulfonyll-4-piperazin- l-yltienoi3,2-(N cilpyridine hydrochloride cji( KN 12 2-[(2,5-Dimethylphenyl)sulfonyl]-4-piperazin--ylthielo[3,2-(N 12 c]pyridine hydrochloride -C ~ C,11 103 2-(-typey~ufnl--ieai--lheo32cprdn hydrochloride 14 hydrochloride u 105 2-(Benzylsulfonyl)-4-piperazin- l-ylthienoll3,2-cpyridine (N hydrochloride 106 4Piprazin--yl-2-[4-(trifluoromethy)benzy]sulfoflyl}thielo[ 3

,

2

-

('zN) c]pyridine hydrochloride FK 107 2-( -r m b ny~ uf nl -- i eai -- lh e o32 cp rd n Br ( N hydrochloride -K N 108 2-[(2,3-Difluorobcnzyl)sulfonyl]-4-piperazin-l-ylthieno[3,2- I(N)> c]pyridine hydrochlorideF KN

F

WO 2004/000828 PCT/SE2003/001061 109 2-(4-Bromobenzyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine IN) hydrochloride 1r K1!0I 110 2-{[2,5-bis(Trifluoromethyl)benzyl]sulfonyl}-4-piperazin-l- CF 3 .. y- 6 N ylthieno[3,2-c]pyridine hydrochloride CF 3 I K ) 11 2-[(4-Methylbenzyl)sulfonyl]-4-piperazm- 1 -yltbieno[3,2-c]pyridine (N) hydrochloride 'lijl 12 2-{[5-Chloro-2-(trifluoromethyl)benzyllsulfonyl}-4-piperazin-1- C 12 yltbieno[3 ,2-clpyridine hydrochloride NQN N NF 113 2-(3,5-Dimethoxybenzyl)sulfonyl]-4-piperazin-1-ylthienol3,2- (N c]pyridine hydrochlorideK ) -0o 114 2-[(2-Naplithylmethyl)sulfonyl]-4-piperazin-1-ylthlieno[3,2- ( N c~pyridine hydrochloride 115 4-Piperazin- l-yl-2- f{[4-(1 ,2,3-tliiadiazol-5- (N) yl)benzyl]sulfonyllthieno[3,2-c]pyridine hydrochloride ~II NN 116 1-(4-Pyrrolidin-1-ylphenyl)-2-[(4-piperazine-l-ylthieno[3,2- 0 (N c]pyridin-2-yl) sulfonyl] propanone hydrochloride I iIv~ ~ 117 1 [4 (Diethyamino)phcnyl]-2-(4-piperazine-1 -yltbienolI3,2- 0 N c]pyridin-2-yl) sulfonyl] propanone hydrochloride 1 N 18 1-(4-Bromophenyl)-2-[(4-piperazin-l-ylthieno[3,2-c]pyridin- 2 -yl)(N sulfonyl] propanone BrK ) WO 2004/000828 PCT/SE2003/001061 119 N 1-(3-Methoxyphenyl)-2-[(4-piperazin-1-ylthieno[3,2-c]pyridin-2-yl) (N sulfonyl] propanone 0O 120 1-Phenyl-2-[(4-piperazin-1-ylthieno[3,2-c]pyridin-2- a N yl)sulfonyl]propanone Scheme 6 CI 4 R4 Br / BN i / 0 s 5 Legend to Scheme 6: i) BOC protected amines (R 4 ), K 2 C0 3 , DMSO; ii) thiophenols (R'-SH), Cu 2 (I)O, DMF; iii) NaOAc, oxone, water; iv) a.TFA, b.HCI, methanol INTERMEDIATE 60 tert-Butyl 4-(2-bromothieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate 10 2-Bromo-4-chlorothieno[3,2-c]pyridine (5.0 g, 20.24 mmol) and K 2 C0 3 (13.97 g, 101.2 mmol) was stirred in DMSO (20 mL) followed by addintion of tert-butyl piperazine-1 carboxylate (4.14 g, 22.26 nmnol). The reaction mixture was stirred at 100 'C for 6 days. The reaction mixture was filtered to eliminate the carbonate and addition of water (50 mL) and ethyl was followed. The phases were separated and the aqueous phase was extracted 15 with ethyl acetate. The combined organic phases were dried (MgS04) and the solvent was evaporated. The crude product was purified by flash chromatography using ethyl acetate/hexanes (2/8) as eluent to give 2 g of the desired product, yield 25%, 99% pure. 1H NMR (270 MHz, CDC1 3 ) 5 1.48 (s, 9H), 1.52-1.63 (in, 1H), 3.42-3.47 (in, 4H), 3.61-3.64 (m, 4H), 7.22 (dd, J= 5.4, 1 Hz, 1H), 7.35 (d, J= 1 Hz, 1H), 8.04 (d, J= 5.4 Hz, 111). m/z 20 398.91 (M+H), bromide pattern.

WO 2004/000828 PCT/SE2003/001061 INTERMEDIATE 61 tert-butyl 4-(2-bromothieno[3,2-clpyridin-4-yl)-1,4-diazepane-1-carboxylate The same procedure above intermediate was used starting from 2-bromo-4 chlorothieno[3,2-c]pyridine (7.5 g, 30.45 mmol), K 2 C0 3 (6.7 g, 33.5 mmol) and tert-butyl 5 1,4-diazepane-1 -carboxylate (21.0 g, 152.2 mmol) in DMSO (30 mL). Purification by flash chromatography 3.04 g of the title compound (Yield 25%).HPLC purity 92%; 1H NMR (270 MHz, CDC1 3 ) 8 1.38 (s, 4.5 H), 1.43 (s, 4.5 H), 1.96-2.11 (in, 2H), 3.36-3.41 (m, 1H), 3.46-3.51 (in, 1H), 3.65-3.87 (in, 6H), 7.02-7.04 (in, 1H), 7.40-7.42 (m, 1H), 7.94 (d, J= 5.4 Hz, 1H). m/z = 411.97 (M+H). 10 Coupling with thiophenols (Method M) INTERMEDIATE 62 tert-butyl 4-(2-phenylthio)thieno[3,2-cjpyridin-4-yl)-1,4-diazepane-1-carboxylate 15 tert-Butyl 4-(2-bromothieno[3,2-c]pyridin-4-y)-1,4-diazepane-1-carboxylate (0.31 g, 0.752 mmol), pulverized KOH (0.084 g, 1.5 mmol) and Cu 2 (I)O (0.1 g, 0.75 mmol) was mixed with DMF (1 mL) before the addition of a solution of benzenethiol (.016 g, 1.5 mmol) in DMF (1 mL). The reaction mixture was heated to 120 'C for 15 h. The reaction mixture was poured in a silica plug and eluted with chloroform, to give the crude product. 20 The crude product was purified by flash chromatography using ethyl acetate/hexanes (2/8) as eluent to give 0.21 g of the desired product, yield 64%, 90% pure. 'H NMR (270 MHz, CDCl 3 ) 8 1.37 (s, 4.5H), 1.43 (s, 4.5 H), 1.97-2.10 (m, 2H), 3.36-3.43 (in, 1H), 3.46-3.53 (in, 1H), 3.64-3.73 (in, 2H), 3.78-3.96 (in, 4H), 7.05 (d, J= 5.4 Hz, 1H), 7.22-7.32 (in, 5H), 7.59-7.63 (m, 111), 7.97 (d, J= 5.4 Hz, 1H). m/z= 442.15 (M+H). 25 Oxidation of thio-derivatives (Method N) INTERMEDIATE 63 tert-Butyl 4-(2-phenylsulfonyl)thieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1-carboxylate 30 A solution of tert-Butyl 4-(2-phenylthio)thieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1 carboxylate (0.21 g, 0.48 nrnol) and NaOAc (0.5 g) in ethanol (10 mL), (pH ~5) followed by the addition of Oxone (0.64 g, 1.04 mmol) dissolved in water (1 mL). The reaction WO 2004/000828 PCT/SE2003/001061 mixture was stirred at RT for 16 h. Additional Oxone (0.32 g) in water (1mL) was added. Full conversion of the SM was obtained after 8 h. Water (50 mL) and chloroform (30 mL) were added. The phases were separated and the aqueous phase was extracted with chloroform. The combined organic phases were dried over (MgSO4), the solvent was 5 evaporated to give the crude product which was purified by reverse-phase chromatography (10->90), to give 0.191 g of the desired product as yellow oil (Yield 86%) 98% pure. 'H NMR (270 MHz, CDC1 3 ) 6 1.28 (s, 4.5 H), 1.38 (s, 4.5 H), 1.99-2.03 (m, 211), 3.31-3.40 (m, 111), 3.42-3.47 (m, 1H), 3.63-3.69 (m, 2H), 3.85-3.98 (m, 4H), 7.02 (d, J= 5.4 Hz, 1H), 7.48-7.61 (m, 3H), 7.76-8.01 (m, 3H), 8.06-8.08 (m, 1H). m/z = 474.01 (M+H). 10 Removal of the t-butyl-carboxylate protecting group (Method 0) EXAMPLE 83 4-(1,4-Diazepan-1-yl)-2-(phenylsulfonyl)thieno[3,2-cJpyridine hydrochloride tert-Butyl 4-(2-phenylsulfonyl)thieno[3,2-c]pyridin-4-y)-1,4-diazepane-1-carboxylate 15 (0.165 g, 0.348 mmol) was dissolved in DCM (2 mL) and TFA (1 mL) was added. The reaction mixture was stirred for 2 h. The solvent was evaporated. Methanol and HCI in ether was added (x 3) to give 0.118 g of the desired HC1 salt, yield 85%, 98% pure. 'H NMR (270 MHz, CHOH-d 4 ) 6 2.45-2.52 (m, 2H), 3.45-3.52 (m, 211), 3.70-3.79 (m, 2H), 4.18-4.22 (m, 2H), 4.30-4.40 (m, 2H), 7.62-7.76 (m, 5H), 7.91 (d, J = 5.4 Hz, 111), 8.11 20 (dd, J= 5.4, 1 Hz, 111), 8.41 (d, J= 1 Hz, 11). m/z= 374.09 (M+H-HC1). INTERMEDIATE 64 tert-Butyl 4-[2-(4-tert-butylphenyl)thio]thieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1 carboxylate 25 The product was prepared according to Method M. Purification by flash chromatography using ethyl acetate/hexanes (2/8) as eluent gave 0.035 g, 99% pure. 'H 1NMR (270 MHz, CDC1 3 ) 5 1.28 (s, 9H), 1.38 (s, 4.5 H), 1.43 (s, 4.5 H), 1.98-2.03 (m, 2H), 3.35-3.41 (m, 1H), 3.46-3.52 (m, 1H), 3.62-3.72 (m, 2H), 3.77-3.93 (4H), 7.04 (d, J= 5.4 Hz, 1H), 7.27 7.34 (m, 4H), 7.54-7.56 (m, 1H), 7.95 (d, J= 5.4 Hz, 1H). m/z = 498.0 (M+H). 30 WO 2004/000828 PCT/SE2003/001061 INTERMEDIATE 65 tert-Butyl 4-[2-(4-tert-butylphenyl)sulfonyllthieno[3,2-clpyridin-4-yl)-1,4-diazepane-1 carboxylate Procedure B from tert-butyl 4-[2-(4-tert-butylphenyl)thio]thieno[3,2-c]pyridin-4-yl)-1,4 5 diazepane-l-carboxylate (0.035 g, 0.070 nimol), Oxone (0.17 g, 0.28 mmol), NaOAc (0.5 g) in EtOH (2 mLfollowed by reversed phase chromatography (40->70), gave 6 mg of the product. Yield 17%, 98% pure.

1 H NMR (270 MHz, CDCl 3 ) 8 1.32 (s, 9H), 1.35 (s, 9H), 2.05-2.15 (m, 2H), 3.45-3.62 (in, 2H), 3.75-4.13 (in, 6H), 7.20-7.27 (in, 511), 7.58 (d, J= 10.8 Hz, 1H), 7.93 (d, J= 10.8 Hz, 1H). m/z = 530.0 (M+H). 10 INTERMEDIATE 66 tert-Butyl 4-[2-(3,4-dimethylphenyl)thiolthieno[3,2-clpyridin-4-yl)-1,4-diazepane-1 carboxylate The title compound was obtained according to Method M. Purification by flash 15 chromatography using ethyl acetate/hexanes (2/8) as fluent gave 0.022 g, 95% pure. 1H NMR (270 MHz, CDCl 3 ) 8 1.38 (s, 4.5 H), 1.43 (s, 4.5 H), 1.96-2.04 (in, 2H), 2.21 (s, 3H), 2.22 (s, 3H), 3.37-3.45 (in, 2H), 3.47-3.50 (in, 2H), 3.77-3.95 (in, 4H), 7.01-7.12 (in, 3H), 7.16 (s, 1H), 7.53 (dd, J= 5.4, 1 Hz, 1H), 7.94 (d, J= 5.4 Hz, 1H). m/z = 470.3 (M+H). 20 INTERMEDIATE 67 tert-Butyl 4-[2-(3,4-dimethylphenyl)sulfonylthieno[3,2-c]pyridin-4-yl)-1,4-diazepane 1-carboxylate Procedure B from tert-Butyl 4-[2-(3,4-dimethylphenyl)thio]thieno[3,2-c]pyridin-4-yl)-1,4 diazepane-1-carboxylate (0.022 g, 0.047 mmol); OXONE (0.11 g, 0.19 mmol); NaOAc 25 (0.5 g) inEtOH (2 mL) followed by reversed phase chromatography (40->70), 9 ing of the product. Yield 38%, 92% pure.IH NMR (270 MHz, CDCl 3 ) 8 1.35 (s, 9H), 2.08-2.20 (in, 2H), 2.33 (s, 6H), 3.52-3.59 (in, 2H), 3.83-3.88 (in, 2H), 4.08-4.18 (in, 411), 7.21-7.28 (in, 2H), 7.31-7.35 (in, 1H), 7.73-7.75 (in, 2H), 8.02 (d, J= 5.4 Hz, 1H). m/z = 502.21 (M+H). 30 WO 2004/000828 PCT/SE2003/001061 INTERMEDIATE 68 tert-Butyl 4-[2-(1-naphthyl)thio]thieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1 carboxylate The title compound was obtained according to Method M. Purification by flash 5 chromatography using ethyl acetate/hexanes (2/8) as eluent gave 0.055 g. HPLC purity 99 %; 1 H NMR (270 MHz, CDC1 3 ) 8 1.37 (s, 4.5 H), 1.43 (s, 4.5 H), 1.89-2.20 (m, 2H), 3.30 3.40 (m, 1H), 3.43-3.50 (m, 1H), 3.60.3.90 (m, 6H), 6.99 (d, J= 5.4 Hz, 111), 7.39 (dd, J= 8.1, 1 Hz, 111), 7.50-7.61 (m, 511), 7.79-7.88 (m, 2H), 7.92 (d, J= 5.4 Hz, 1H), 8.40-8.44 (m, 1H). m/z = 498.26 (M+H). 10 INTERMEDIATE 69 tert-Butyl 4-[2-(1-naphthyl)sulfonyl]thieno[3,2-clpyridin-4-yl)-1,4-diazepane-1 carboxylate Procedure B from tert-Butyl 4-[2-(1-naphthyl)thio]thieno[3,2-c]pyridin-4-yl)-1,4 15 diazepane-1-carboxylate (0.055 g, 0.112 mmol); Oxone (0.27 g, 0.448 mmol); NaOAc (0.5 g) in EtOH (2 mL) followed reversed phase chromatography (40->70) gave 15 mg of the product. Yield 26%, 93% pure. 'H NMR (270 MHz, CDCl 3 ) 8 1.34 (s, 9H), 2.06-2.10 (m, 211), 3.48-3.62 (m, 2H), 3.78-3.86 (m, 211), 3.95-4.16 (m, 4H), 7.19-7.31 (m, 2H), 7.60 7.75 (m, 3H), 7.92-7.99 (m, 2H), 8.18 (m, J= 8.1 Hz, 1H), 8.50-8.53 (m, 111), 8.77-8.80 20 (m, 1H). m/z = 524.22 (M+H); EXAMPLE 84 4-(1,4-Diazepan-1-yl)-2-[(3,4-dichlorophenyl)sulfonyljthieno[3,2-c]pyridine hydrochloride 25 tert-Butyl 4-{2-[(3,4-dichlorophenyl)sulfonyl]thieno[3,2-c]pyridin-4-yl}-1,4-diazepane-1 carboxylate was prepared from 3,4-dichlorothiophenol (60 mg, 15%), as a beige solid, by the application of the general procedures A and B described above. 'H NMR (CDCl 3 ) 5 8.27-8.14 (m, 1H), 8.11-8.04 (m, 2H), 7.87-7.80 (m, 1H), 7.67-7.62 (m, 111), 7.26-7.20 (m, 1H), 4.18-3.98 (m, 4H), 3.87-3.74 (m, 2H), 3.61-3.44 (m, 2H), 2.20-2.00 (m, 2H), 1.33 (s, 30 911); MS m/z 542 (M+1).The title compound (50 mg, 95%) was obtained as a beige solid, by the application of the general procedure C described above. 1H NMR (270 MHz, WO 2004/000828 PCT/SE2003/001061

CH

3 0H-d4) 45 8.48 (s, 1H), 8.30 (d, J= 1.85 Hz, 1H), 8.05 (dd, J= 8.58,1.98 Hz, 1H), 7.92 (d, J= 6.86 Hz, 1H), 7.83 (d, J= 8.44 Hz, 1H), 7.69 (d, J= 6.86 Hz, 1H), 4.4.41-4.34 (m, 2H), 4.24-4.16 (m, 2H), 3.76-3.69 (m, 211), 3.51-3.43 (m, 2H), 2.52-2.42 (m, 2H); MS m/z 442 (M+1). 5 EXAMPLE 85 4-(1,4-Diazepan-1-yl)-2-[1-naphthylsulfonyl)thieno[3,2-cjpyridine hydrochloride The title compound was obtained from tert-butyl 4-[2-(1-naphthyl)sulfonyl]thieno-[3,2 c]pyridin-4-yl)-1,4-diazepane-1 -carboxylate (15 mg, 0.029 mmol) following Method 0 to 10 give 12 mg of the desired product yield 90 %, 95 % pure. 'H NMR (270 MHz, CH 3 0H-d 4 ) 8 2.40-2.50 (m, 2H), 3.45-3.55 (m, 2H), 3.65-3.75 (m, 211), 4.06-4.26 (m, 2H), 4.27-4.46 (m, 2H), 7.58-7.80 (m, 4H), 7.83-7.86 (m, 1H), 8.06 (d, J= 8.1 Hz, 1H), 8.20 (d, J= 8.1 Hz, 1H), 8.48 (s, 1H), 8.53-8.56 (m, 1H), 8.83-8.86 (m, 1). m/z = 424.06 (M+H-HCl). 15 EXAMPLE 86 4-(1,4-Diazepan-1-yl)-2-[4-tert-butylphenylsulfonyl)thieno[3,2-cjpyridine hydrochloride The title compound was obtained from tert-butyl 4-[2-(4-tert-butylphenyl) sulfonyl]thieno[3,2-c]pyridin-4-yl)--1,4-diazepane-1-carboxylate (6 mg, 11.3 mmol) 20 following Method 0 to give 4 mg of the desired product, yield 76 %, 88 % pure. 'H NMR (270 MHz, CH 3 0H-d 4 ) 8 1.33 (s, 9H), 2.41-2.47 (m, 2H), 3.41-3.49 (m, 211), 3.65-3.78 (m, 2H), 4.15-4.25 (m, 211), 4.29-4.40 (m, 2H), 7.65-7.70 (m, 3H), 7.90 (d, J= 5.4 Hz, 1H), 8.00-8.04 (m, 2H), 8.37 (s, 1H). n/z = 430.06 (M+H 25 EXAMPLE 87 4-(1,4-Diazepan-1-yl)-2-[3,4-dimethylphenylsulfonyl)thieno[3,2-cjpyridine hydrochloride The title compound was obtained from tert-butyl 4-[2-(3,4 dimethylphenyl) sulfonyl]thieno[3,2-c]pyridin-4-yl)-1,4-diazepane-1-carboxylate (6 mg, 0.012 mmol) 30 following Method 0 to give 6 mg of the desired product, yield 88 %, 89 % pure. IH NMR (270 MHz, CH 3 0H-d 4 ) 8 2.34 (s, 6H), 2.45-2.55 (m, 2H), 3.42-3.51 (m, 2H), 3.67-3.76 (m, WO 2004/000828 PCT/SE2003/001061 2H), 4.10-4.20 (m, 2H), 3.58-3.70 (m, 2H), 7.39-7.41 (m, 1H), 7.64-7.67 (m, 1H), 7.79 7.84 (m, 2H), 7.89-7.91 (m, 1H), 8.36 (s, 1H). m/z = 402.07 (M+H-HCl). EXAMPLE 88 5 2-[(4-Bromophenyl)sulfonyl]-4-(1,4-diazepan-1-yl)thieno[3,2-clpyridine hydrochloride Trifluoroacetic acid (1 nL) was added slowly to a solution of tert-butyl 4- {2-[(4 bromophenyl)thio]thieno[3,2-c]pyridin-4-yl}-1,4-diazepane-1-carboxylate (26 mg, 0.047 mmol) in CH 2 C1 2 at 0 *C. The reaction mixture was allowed to reach room temperature, 10 stirred for 40 min and then concentrated in vacuo. The residue was twice re-dissolved in MeOH and concentrated in vacuo. The residue was again dissolved in MeOH and an excess of 1 M HC1 in diethyl ether (4 mL) was slowly added to the solution. Removal of the solvents in vacuo afforded the title compound (21 mg, 91 %) as a yellowish solid. 1H NMR (270 MHz, CH30H-d4) 8 8.41 (s, 1H), 8.06-7.99 (m, 2H), 7.92 (d, J= 6.86 Hz, 1H), 7.87 15 7.80 (m, 2H), 7.66 (d, J= 6.86 Hz, 1H), 4.38-4.31 (m, 2H), 4.22-4.14 (m, 2H), 3.74-3.67 (m, 2H), 3.50-3.42 (m, 2H), 2.51-2.39 (m, 2H); MS m/z 452 (M+1). EXAMPLE 89 2-(Phenylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride 20 To a stirred solution of tert-butyl 4 -[2-(phenylthio)thieno[3,2-c]pyridin-4-yl]piperazine-1 carboxylate (350 mg, 0.819 mmol) in ethanol was added oxone in water solution. The reaction was monitored by LCMS. When all starting material was consumed, the chromatogram showed two majQr peaks, the product and the N-oxide. After purification by preparative HPLC, the resulting Boc-material was treated with HCI in ether. The solution 25 was centrifugated and the supernatant was removed. Ether was added, then centrifugated and decanted (repeated three times) to remove the excess HC1. The remaining ether was finally evaporated in a SpeedVac concentrator. Yield 18 %, HPLC purity = 98%, m/z= 360.0 (M+H). 'H NMR (270 MHz, CH 3 0H-d 4 ) 6 ppm 3.56 (m, 4 H) 4.08 (m, 4 H) 7.68 (m, 4 H) 7.77 (dd, J=6.60, 0.79 Hz, 1 H) 8.04 (d, J=6.33 Hz, I H) 8.12 (m, 2 H) 8.39 (d, 30 J=0.79 Hz, 1 H).

WO 2004/000828 PCT/SE2003/001061 EXAMPLE 90 2

-(

3 -Methoxy-benzenesulfonyl)-4-piperazin-1-yi-thieno[3,2-c]pyridine hydrochloride 4

-[

2 -(3-Methoxy-phenylsulfanyl)-thieno[3,2-c]pyridin-4-yl]-piperazine 1-carboxylic acid tert-butyl ester was obtained from 3-methoxythiophenol (130 pl, 1 5 mmol) and tert-Butyl 4

-(

2 -bromothieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate (215 mg, 0.52 mmol). 120 mg, 50%) were obtained by the application of the general Method M described above. 1H NMR (270 MHz, CDC1 3 ) 5 1.48 (s, 9 H), 3.42-3.51 (m, 4 H), 3.58 3.67 (m, 4 H), 3.74 (s, 3 H), 6.76 (dd, J=8.18, 2.38 Hz, 1 H), 6.84-6.92 (m, 2 H), 7.16-7.23 (m, 2 H), 7.51 (s, 1 H), 8.04 (d, J=5.81 Hz, 1 H); MS m/z 458 (M+1). The title compound 10 was therefore obtained from 4

-[

2 -(3-methoxy-phenylsulfanyl)-thieno[3,2-c]pyridin-4-yl] piperazine-1-carboxylic acid tert-butyl (7 mg, 7%), after triturating with diethyl ether, as a beige solid, by the application of the general procedures B and C described above. 1H NMR (270 MHz, CD 3 0D) 8 8.31 (s, 1H), 8.09 (d, J= 6.33 Hz, 1H), 7.71-7.62 (m, 2H), 7.59-7.50 (m, 2H), 7.30-7.23 (m, 1H), 3.98-3.92 (m, 4H), 3.87 (s, 3H), 3.54-3.48 (m, 4H); 15 MS m/z 390 (M+1). EXAMPLE 91 2-(4-Methoxy-benzenesulfonyl)-4-piperazin-1-yl-thieno[3,2-clpyridine hydrochloride 4

-[

2

-(

4 -Methoxy-phenylsulfanyl)-thieno[3,2-c]pyridin-4-yl]-piperazine 20 1-carboxylic acid tert-butyl ester was obtained from 4-methoxythiophenol (130 ul, 1 mmol) and tert-butyl 4 -(2-bromothieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate (215 mg, 0.52 mmol). 100 mg, 42% were isolated by the application of the general Method M described above. 1H NMR (270 MHz, CDC1 3 ) d 1.48 (s, 9 H), 3.40-3.47 (m, 4 H), 3.58 3.65 (m, 4 H), 3.79 (s, 3 H), 6.83-6.89 (m, 2 H), 7.15 (d, J=5.54 Hz, 1 H), 7.35 (s, 1 H), 25 7.38-7.43 (m, 2 H), 7.99 (d, J=5.81 Hz, 1 H); MS m/z 458 (M+1). 4-[2-(4-methoxy-phenylsulfanyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester was obtained (25 mg, 23%) as a clear liquid by the application of the general procedure B described above. 'H NMR (270 MHz, CDCl 3 ) 5 1.48 (s, 9 H), 3.67 3.91 (m, 11 H), 7.01 (d, J = 8.97 Hz, 2H), 7.27-7.37 (m, 1H), 7.93 (d, J= 8.97 Hz, 211), 30 8.01-8.19 (m, 2H); MS m/z 490 (M+1). The title compound was thereby obtained following Procedure C): 'H NMR (CD 3 OD) 6 8.25 (s, 1H), 8.09-7.89 (m, 3H), 7.69 (d, J WO 2004/000828 PCT/SE2003/001061 6.33 Hz, 1H), 7.17-7.10 (m, 2H), 4.00-3.93 (m, 4H), 3.87 (s, 3H), 3.55-3.48 (m, 4H); MS m/z 390 (M+1). EXAMPLE 92 5 4-Piperazin-1-y-2-{[4-trifluoromethyl)phenylsulfonyl}thieno[3,2-cpyridine hydrochloride 2-{[4-(Trifluoromethyl)phenyl]thio}-4-piperazin-1-ylthieno[3,2-c]pyridine (0.42 mmol) was dissolved in TFA (1.5 mL) at 0 0 C, stirred for 15 min and H 2 0 2 (100 pL) was added. The mixture was stirred at room temperature over night. NaOH (2 M) was added, 10 extraction with ethyl acetate (3X), washed with brine, dried over NaSO 4 , The solvent was removed and the product was purified by preparative HPLC to afford 154.7 mg (86.2 %). 'H NMR (270 MHz, DMSO-d 6 ) 3 ppm 9.79 (s, 1H) 8.56 (s, 1 H) 8.35 (d, J-=8.44 Hz, 2 H) 8.12-8.05 (m, 3H) 7.79 (d, J=6.33 Hz, 1 H) 3.98-3.96 (m, 4H) 3.32-3.31 (m, 411); LC-MS 428 (M - H); Purity (HPLC) 95% 15 EXAMPLE 93 2-[[2-tert-Butylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-cjpyridine hydrochloride The title compound was prepared following Method M-O. Yield: 10.6 mg (6.3 %) of 2-[[2 tert-butylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride. 'H NMR 20 (270 MHz, DMSO-d 6 ) 8 ppm 9.57 (s, 1 H) 8.42 (s, 1 H) 8.26-8.22 (m, 1H) 8.06-8.04 (m, 1H) 7.68-7.55 (m, 4H) 3.87-3.86 (m, 4H) 3.34-3.33 (m, 4H) 1.51-1.43 (m, 9H); LC-MS 400 (M - H)+; Purity (HPLC) 90%. EXAMPLE 94 25 2-[(3,4-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-cjpyridine-2-sulfonamide hydrochloride The title compound was prepared following Method M-0. Yield: 47.9 mg (22.9 %). 11 NMR (270 MHz, DMSO-d 6 ) 8 ppm 9.36 (s, 1 H) 8.51 (s, 1 H) 8.38 (d, J=2.11 Hz, 1 H 8.06-7.94 (m, 3H) 7.70-7.68 (m, 1H) 3.81-3.77 (m, 4H) 3.31-3.29 (m, 4H); LC-MS 427 (M 30 - H)*; Purity (HPLC) 95 %.

WO 2004/000828 PCT/SE2003/001061 EXAMPLE 95 2-[(4-tert-Butylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride Oxone (0.52 g, 0.84 mmol) in water (4 mL), buffered to pH - 6 with sodium oxide acetate, was added to 2-[(4-tert-butylphenyl)thio]-4-piperazin-1-ylthieno[3,2-c]pyridine (0.42 5 mmol) in ethanol (30 mL). The mixture was stirred in room temperature for 2 h and more oxone (0.52 g, 0.84 mmol) was added. The reaction was stirred over night. Water was added to the mixture, extraction with dichloromethane (2X 20 mL) and the solvent was removed. The products were purified by preparative HPLC. Yield: 41.9 mg (22.0%). 'H NMR (500 MHz, CH 3 0H-d 4 ) 8 ppm 8.38 (s, 1 H) 8.05-8.01 (in, 3H) 7.80 (d, J=6.59 Hz, 1 10 H) 7.71-7.69 (m, 2H) 4.15-4.13 (in, 4H) 3.59-3.57 (4H) 1.37-1.33 (in, 9H); LC-MS 416 (M - H)*; Purity (HPLC) 95%. EXAMPLE 96 2-(1-Naphthylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride 15 The title compound was prepared following Method M-0. Yield: 3.4 mg (0.2 %). IH NMR (270 MHz, DMSO-d 6 ) 8 ppm 9.34 (s, 1 H) 8.82 (s, 1 H) 8.44 (s, 1 H) 8.26-8.06 (in, 5H) 7.79-7.65 (in, 311) 3.79-3.78 (m, 4H) 3.32-3.30 (in, 4H); LC-MS 410 (M - H)*; Purity (HPLC) 95%. 20 EXAMPLE 97 2-[(3-Fluorophenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride 2-Bromo-4-chlorothieno[3,2-c]pyridine (190 mg, 0.50 mmol) in DMF (1 mL) was added to 3-fluorobenzenethiol (95.5 mg, 1.0 mmol), KOH (56 mg, 0.2 mmol) and Cu 2 O (71 ing, 25 0.5 mmol) in DMF (1 mL). The reaction was heated to 120*C over night. The mixture was filtrated through a silica plug and the solvent was removed. The product was dissolved in TFA (1.5 mL) at 0*C and the solution were stirred for 15 min, H202(100 pL) was added and the mixture was stirred at room temperature over night. 2M NaOH was added, extraction with etylacetate, washed with brine and solvent was removed. The product was 30 purified by preparative HPLC. Yield: 30.1 mg (16.1%) 1H NMR (270 MHz, DMSO-d 6 ) 8 ppm 9.34 (s, 1 H) 8.45 (s, 1 H) 8.16 (d, J=5.69 Hz, 1 H) 7.97-7.93 (in, 2H) 7.76-7.62 (in, WO 2004/000828 PCT/SE2003/001061 3H) 3.30 (s, 4 H) (4H obscured by solvent signal); LC-MS 378 (M - H)*; Purity (HPLC) 99%. EXAMPLE 98 5 2-(Mesitylsulfonyl)-4-piperazin-1-ylthieno[3,2-cjpyridine hydrochloride The title compound was prepared following Method M-0. Yield: 32.0 mg (16.1 %). 'H NMR (270 MHz, DMSO-d 6 ) S ppm 9.32 (s, 1 H) 8.20-8.14 (m, 2H) 7.66 (d, J=5.69 Hz, 1 H) 7.14 (s, 2 H) 3.29 (s, 4 H) 2.65 (s, 6H) 2.28 (s, 3H) (4H obscured by solvent signal); LC-MS 402 (M - H)*; Purity (HPLC) 95%. 10 EXAMPLE 99 2-2-Meth oxyphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-clpyridine hydrochloride The title compound was prepared following Method M-O.Yield: 14.7 mg (7.6 %). 'H NMR (270 MHz, DMSO-d 6 ) 8 ppm 9.33 (s, I H) 8.24 (s, 1 H) 8.15 (d, J=5.94 Hz, 1 H) 15 8.00 (dd, J=7.92, 1.48 Hz, 1 H) 7.77-7.68 (m, 2H) 7.28-7.18 (m, 2H) 3.30 (s, 4H) (7H obscured by solvent signal); LC-MS 390 (M - H)*Purity (HPLC) 99%. EXAMPLE 100 2-[(2,4-Dimethoxyphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-clpyridine 20 hydrochloride The title compound was prepared following Method M-0. Yield: 42.7 mg (20.5 %). IH NMR (270 MHz, DMSO-d 6 ) 6 ppm 9.39 (s, I H) 8.37 (s, 1 H) 8.13 (d, J=5.69 Hz, 1 H) 7.68-7.66 (m, 2H) 7.54 (d, J=2.23 Hz, 1 H) 7.19 (d, J=8.66 Hz, 1 H) 3.29 (s, 4 H) (10H obscured by solvent signal); LC-MS 420 (M - H)+; Purity (HPLC) 98%. 25 EXAMPLE 101 2-[(2,4-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-cpyridine hydrochloride The title compound was prepared following Method M-0. Yield: 17.8 mg (9.3 %). 'H NMR (270 MHz, DMSO-d 6 ) S ppm 9.32 (s, 1H) 8.27 (s, 1 H) 8.15 (d, J=5.94 Hz, 1 H) 30 8.00 (d, J=8.17 Hz, 1 H) 7.67 (d, J=5.94 Hz, 1 H) 7.35-7.26 (m, 2H) 3.29 (s, 4H) 2.34 (s, 3H) (7H obscured by solvent signal); LC-MS 388 (M - H)*Purity (HPLC) 98%.

WO 2004/000828 PCT/SE2003/001061 EXAMPLE 102 2-[(2,5-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-cipyridine hydrochloride The title compound was prepared following Method M-0. Yield: 16.9 mg (8.8 %). 1H 5 NMR (270 MHz, DMSO-d 6 ) 8 ppm 9.17 (s, 1 H) 8.29 (s, 1 H) 8.18-18.15 (m, 1H) 7.94 (s, 1 H) 7.66 (d, J=5.69 Hz, 1 H) 7.47 (d, J=7.67 Hz, 1 H) 7.32 (d, J=8.16 Hz, 1 H) 3.29 (s, 2 H) 2.42 (s, 3 H) (7H obscured by solvent signal); LC-MS 388 (M - H)+; Purity (HPLC) 99%. 10 EXAMPLE 103 2-[(2-Ethylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride The title compound was prepared following Method M-O. Yield: 22.6 mg (11.2 %). 1H NMR (270 MHz, DMSO-d 6 ) 8 ppm 9.19 (s, 1 H) 8.32 (s, 1 H) 8.17 (d, J=5.69 Hz, 1 H) 8.08 (d, J=7.92 Hz, 1 H) 7.73-7.66 (m, 2H) 7.52 (t, J=7.67 Hz, 2 H) 3.29 (s, 4 H) 3.00 (q, 15 J=7.34 Hz, 2 H) 1.10 (m, 3 H) (4H obscured by solvent signal); LC-MS 388 (M - H); Purity (HPLC) 100%. Scheme 7 C1 C C( CC 2 0 Br N R s LiN 'S s o 0 ~i~ 20ivv N / Legend to Scheme 7: i) nBuLi, diethyl ether; ii) S02 gas; iii) benzylbromine(s), DMIF, heat; iv) diamine(s),

K

2 CO3, DMF, heat; v) HC1, diethyl ether. INTERMEDIATE 70 25 Lithium 4-chlorothieno[3,2-cjpyridine-2-sulfinate 2-Bromo-4-chlorothieno[3,2-c]pyridine (5.00 g, 20.1 mmol) was suspended in dry ether (100 ml) and the mixture was cooled to -78 *C under N2-atmosphere. n-BuLi (1.6M in hexane, 15 mL) was added and the reaction mixture was stirred at -78 C for 2h. SO 2 (g) was then bubbled threw the reaction mixture for lh. After the gas bubbling had stopped the WO 2004/000828 PCT/SE2003/001061 reaction mixture was stirred fore one more hour at -78 *C and was then allowed to warm to room temperature. The precipitate that had formed was filtered and washed with ether to give the sulfonate lithium salt (3.59 g, 74 %) that was used in the next step without further purification. 'H NMR (270 MHz, DMSO-d 6 ) 5 ppm 7.26 (s, 1 H) 7.99 (d, J=5.54 Hz, 1 H) 5 8.14 (d, J=5.54 Hz, 1 H). MS (M-Li+1) 234. Benzylation of sulfinate salts (Method P) To a suspension of lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (100 mg, 0.42 mmol) in dry DMF (2 mL) was added a benzylbromide (0.83 mmol, 2 equiv.) and the mixture 10 heated with stirring for 16 h at 110 'C. Analysis by LCMS showed desired product and no starting material remaining. The mixture was treated with polystyrene-thiophenol (200 mg) and was rolled for 16 h. The suspension was filtered washing with further DMF (2mL). This material was reacted further without purification. 15 Nucleophilic substitution of chlorine (Method Q) To a crude solutions of benzylsulfone in DMF (4 mL) are added potassium carbonate (172 mg, 1.25 mmol) and tert-butyl-piperazine-1-carboxylate (155 mg, 0.84 mmol). The resulting mixtures are heated for 16 h at 110 'C. LCMS shows desired compound and no starting material. The reaction mixtures are filtered and then the solvent removed under 20 reduced pressure. The desired compounds are isolated pure following preparative HPLC. BOC-deprotection (Method R) The BOC N-protected piperazine derivatives are dissolved in HCl/ diethyl ether (1 mL, 1.OM) at room temperature and stirred for 16 h. Removal of the solvent under reduced 25 pressure gave the crude hydrochloride salts. Trituration with acetonitrile gives the desired compound as a white solid. INTERMEDIATE 71 tert-Butyl-4-[2-(benzylsulfonyl)thieno[3,2-cjpyridin-4-yljpiperazine-1-carboxylate 30 Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with benzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.009 g (7 % over two WO 2004/000828 PCT/SE2003/001061 steps). 1 H NMR (300 MHz, CDC1 3 ) 8 8.14 (d, J=5.5 Hz 1 H), 7.27-7.40 (m, 5 H), 7.15 7.21 (m, 2 H), 4.45 (s, 2 H), 3.50-3.56 (m, 4 H), 3.40-3.45 (m, 4 H), 1.49 (s, 9 H); MS (ESI+) for C23 H27 N3 04 S 2 m/z 474 (M+H)*. HPLC 77%, RT 3.93 min (ACE3 C8 50x4mm, 5-50% acetonitrile in 3 min). 5 INTERMEDIATE 72 tert-Butyl-4-(2-{[4-(trifluoromethyl)benzyl]sulfonyl}thieno[3,2-clpyridin-4 yl)piperazine-1-carboxylate Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 4 10 (trifluoromethyl)benzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine-1-carboxylate as described in Method QF. Yield 0.02 g(16 % over two steps). Beige solid. 'H NMR (300 MHz, CDC1 3 ) 5 8.16 (d, J=6 Hzl H), 7.53-7.61 (d, J= 9 Hz 2 H), 7.49 (s, I H), 7.26-7.36 (m, 4 H), 4.51 (s, 2 H), 3.49-3.60 (m, 4 H), 3.36-3.49 (m, 4 H), 1.49 (s, 9 H); MS (ESI+) for C24 H26 F3 N3 04 S 2 m/Z 542 15 (M+H)*. HPLC 71 %, RT 4.07min (ACE3 C8 50x4mm, 5-50% acetonitrile in 3 min). INTERMEDIATE 73 tert-Butyl-4-{2-[(3-bromobenzyl)sulfonyljthieno[3,2-c]pyridin-4-yl}piperazine-1 carboxylate 20 Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 3 bromobenzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine-1-carboxylate as described in Method Q, Yield 0.023 g (10 % over two steps). Beige solid. 1 H NMR (300 MHz, CDC1 3 ) 8 8.16 (d, J=6 Hz, 1H), 7.50-7.55 (m, 2 H), 7.32-7.40 (m, 2 H), 7.10-7.24 (m, 3 H), 4.44 (s, 2 H), 3.61-3.73 (m, 8 25 H), 1.50 (s, 9 H); MS (ESI+) for C23 H26 Br N3 04 S 2 m/z 554 (M+H)*. HPLC 77 %, Rr 4.07min (ACE3 C8 50x4.6mm, 5-50% acetonitrile in 3 min). INTERMEDIATE 74 tert-Butyl-4-(2-{[3-(trifluoromethyl)benzyllsulfonyl}thieno[3,2-cjpyridin-4 30 yl)piperazine-1-carboxylate Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 3 (trifluoromethyl)benzylbromide (0.59 mmol) as described in Method P above and then WO 2004/000828 PCT/SE2003/001061 reacted further with tert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.023 g (10 % over two steps). Beige solid. 1H NMR (300 MHz, CDCl 3 ) 8 8.14 (d, J= 6 Hz, I H), 7.85-7.91 (m, I H), 7.61-7.72 (m, 2 H), 7.50-7.60 (m, 1 H), 7.12-7.31 (m, 2 H), 4.74 (s, 2 H), 3.52-3.71 (m, 8 H), 1.50 (s, 9 H); MS (ESI+) for C24 H26 F3 N3 04 S 2 m/z 5 542 (M+H)*. HPLC 85 %, RT 2.13min (YMC ODS AQ, 33x3mm, 10-90% acetonitrile in 3 min). INTERMEDIATE 75 tert-Butyl-4-(2-{[2,5-bis(trifluoromethyl)benzylJsulfonyl}thieno[3,2-cjpyridin-4 10 yl)piperazine-1-carboxylate Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 2,5 bis(trifluoromethyl)benzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine-1 -carboxylate as described in Method Q. Yield 0.01 g (4 % over two steps). Beige solid. 1 H NMR (300 MHz, CDCl 3 ) 5 8.16 (d, J= 5.8 15 Hzl H), 8.00 (s, 1 H), 7.74-7.85 (m, 3 H), 4.76 (s, 2 H), 3.56-3.64 (m, 4 H), 3.47-3.56 (m, 4 H), 1.49 (s, 9 H); MS (ESI+) for C25 H25 F6 N3 04 S 2 m/z 610 (M+H)*. HPLC 73 %, RT 2.36min (YMC ODS AQ, 33x3mm, 10-90 % acetonitrile in 3 min). INTERMEDIATE 76 20 tert-Butyl 4-{2-[(4-methylbenzyl)sulfonyljthieno[3,2-cpyridin-4-yI}piperazine-1 carboxylate Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 4 methylbenzylbronide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.005 g 25 (3 % over two steps). Beige solid. 1 H NMR (300 MHz, CDCl 3 ) 8 8.15 (d, J= 6 Hz 1 H), 7.40 (s, 1 H), 7.00-7.16 (m, 4 H), 4.42 (s, 2 H), 3.46-3.60 (m, 4 H), 3.37-3.46 (m, 4 H), 2.34 (s, 3 H), 1.49 (s, 9 H); MS (ESI+) for C24 H29 N3 04 S 2 m/z 488 (M+H)*. HPLC 69 %, R-r 2.06min (YMC ODS AQ, 33x3mm, 10-90 % acetonitrile in 3 min). 30 WO 2004/000828 PCT/SE2003/001061 INTERMEDIATE 77 tert-Butyl 4-(2-{[ 5 -chloro-2-(trifluoromethyl)benzyl1sulfonyl}thieno[3,2-c]pyridin-4 yl)piperazine-1-carboxylate Lithium 4 -chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 5-chloro 5 2-(trifluoromethyl)benzylbromide (0.59 rmol) as described in Method P above and then reacted further with tert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.019 g (7.5 % over two steps). Beige solid. 'H NMR (300 MHz, CDC1 3 ) 8 8.12-8.14 (m, 1 H), 7.80-7.88 (m, 2 H), 7.47-7.66 (m, 2 H), 4.71 (s, 2 H), 3.74-3.83 (m, 4 H), 3.63-3.72 (m, 4 H), 1.49 (s, 9 H); MS (ESI+) for C24 H25 Cl F3 N3 04 S 2 m/z 576 (M+H)*. HPLC 74 10 %, RT 2.30min (YMC ODS AQ, 33x3mm, 10-90 % acetonitrile in 3 min). INTERMEDIATE 78 tert-Butyl 4

-{

2

-[(

3

,

4 -difluorobenzyl)sulfonylthieno[3,2-clpyridin-4-ylpiperazine-1 carboxylate 15 Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 3,4 bis(trifluoromethyl)benzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine-1 -carboxylate as described in Method Q. Yield 0.014 g (6 % over two steps). Beige solid. 'H NMR (300 MHz, CDC1 3 ) 8 8.17-8.21 (m, 1 H), 7.71 (s, 1 H), 7.07-7.39 (m, 4 H), 4.59 (s, 2 H), 3.55-3.68 (m, 8 H), 1.49 (s, 9 H); MS 20 (ESI+) for C23 H25 F2 N3 04 S2 m/z 510 (M+H)+. HPLC 64 %, RT 2.02min (YMC ODS AQ, 33x3mm, 10-90 % acetonitrile in 3 min). INTERMEDIATE 79 tert-Butyl 4

-{

2 -[(3,5-dimethoxybenzyl)sulfonylthieno[ 3 ,2-clpyridin-4-yl}piperazine-1 25 carboxylate Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 3,5 dimethoxybenzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.02 g (10 % over two steps). Beige solid. 'H NMR (300 MHz, CDCl 3 ) 8 8.14-8.18 (m, 1 H), 7.55 30 (s, I H), 6.40-6.45 (m, 1 H), 6.26-6.34 (m, 2 H), 4.39 (s, 2 H), 3.54-3.72 (m, 14 H), 1.50 (s, 9 H); MS (ESI+) for C25 H31 N3 06 S 2 m/z 534 (M+H) t . HPLC 69 %, RT 1.99min (YMC ODS AQ, 33x3mm, 10-90 % acetonitrile in 3 min).

WO 2004/000828 PCT/SE2003/001061 EXAMPLE 104 4 -(Piperazinyl)-2-(3-methoxybenzyl-sulfonyl)-thienopyridine A 1:1 mixture of lithium 4 -chloro-thienopyridine-2-sulfinate (0.176 g, 0.734 mmol) and 2 5 methoxybenzylbromide (0.295 g, 1.47 mmol) in DMF (5 mL) was heated at 100 *C for 2h. To the mixture was added Boc-piperazine (546 mg, 2.94 mmol) and the reaction was heated at 110 *C for 1.5h. The solvent was removed and the crude product was purified by preparative HPLC to obtain 17.4 mg of 4 -(4-t-butyl-oxy-carbonyl-piperazinyl)-2-(3 methoxybenzyl-sulfonyl)-thienopyridine. The boc-protected product was dissolved in 2 10 mL of MeOH and 4 mL of HCl/ether was added to obtain 21.9 mg of 4-(piperazinyl)-2-(3 methoxybenzyl-sulfonyl)-thienopyridine. 1 HNMR (CD 3 0D/D 2 0 1:1) 5 6.42-6.38 (m, 1H), 7.51-7.48 (m, 1H), 7.39-7.35 (m, 11), 6.92-6.85 (m, 1H), 6.64-6.59 (m, 1H), 6.48-6.39 (m, 2H), 3.64-3.58 (m, 411), 3.19-3.13 (m, 4H), 2.96 (s, 3H), 2.92 (s, 211); MS (ESI) 404 (M + H)*; Purity (HPLC, column YMC) 94%. 15 INTERMEDIATE 80 tert-Butyl-4-[2-(benzylsulfonylthieno[3,2-clpyridin-4-yl]piperazine-1-carboxylate Lithium 4-chlorothieno[3,2-cjpyridine-2-sulfinate (0.44 mmol) was treated with benzylbromide (0.59 mmol) as described in Method P above and then reacted further with 20 tert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.00 g (7 % over two steps). Beige solid. 'H NMR (300 MHz, CDC 3 ) 8 8.14 (d, J=5.5 Hz 1 H), 7.27-7.40 (m, 5 H), 7.15-7.21 (m, 2 H), 4.45 (s, 2 H), 3.50-3.56 (m, 4 H), 3.40-3.45 (m, 4 H), 1.49 (s, 9 H); MS (ESI+) for C23 H27 N3 04 S 2 m/z 474 (M+H)*. HPLC 77 %, RT 3.93min (ACE3 C8 5Ox4mm, 5-50 % acetonitrile in 3 min). 25 EXAMPLE 105 2

-(

3 enzylsulfonyl)-4-piperazin-1-ylthieno[3,2-epyridine hydrochloride tert-Butyl 4

-[

2 -(benzylsulfonyl)thieno[3,2-c]pyridin-4-yl]piperazine-l-carboxylate (0.01 g, 0.02 mmol) was treated as described in Method R to give the desired product as a white 30 solid. Yield 0.009 g, (100 %). White solid. 1H NMR (300 MHz, DMSO-d6) 5 8.98 (s, 1 H), 8.13-8.20 (d, J=8 Hz1 H), 8.00 (s, 1 H), 7.64-7.71 (m, 1 H), 7.18-7.35 (m, 5 H), 4.93 (s, 2 WO 2004/000828 PCT/SE2003/001061 H), 3.60-3.70 (m, 4 H), 3.22.3.34 (m, 4 H); MS (ESI+) for C18 H119 N3 02 S2. Cl H m/z 374 (M+H)*. HPLC 90%, RT 2.91min (ACE3 C8 50x4.6mm, 5-50% acetonitrile in 3 min). 5 INTERMEDIATE 81 tert-Butyl-4-(2-{[4-(trifluoromethyl)benzylIsulfonyl}thieno[3,2-cpyridin- 4 yl)piperazine-1-carboxylate Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 4 (trifluoromethyl)benzylbromide (0.59 mmol) as described in Method P above and then 10 reacted further with tert-butyl-piperazine-1 -carboxylate as described in Method Q. Yield 0.02 g (16 % over two steps). Beige solid. 'H NMR (300 MHz, CDC1 3 ) 6 8.16 (d, J=6 Hzl H), 7.53-7.61 (d, J= 9 Hz 2 H), 7.49 (s, 1 H), 7.26-7.36 (i, 4 H), 4.51 (s, 2 H), 3.49-3.60 (m, 4 H), 3.36-3.49 (m, 4 H), 1.49 (s, 9 H); MS (ESI+) for C24 H26 F3 N3 04 S2 m/z 542 (M+H)'. IIPLC 71 %, RT 4.07min (ACE3 C8 50x4mm, 5-50 % acetonitrile in 3 min). 15 EXAMPLE 106 4-Piperazin-1-yl-2-{[4-(trifluoromethyl)benzylsulfonyl}thieno[3,2-clpyridine hydrochloride tert-Butyl 4-(2-{[4-(trifluoromethyl)benzyl1]sulfonyl}thieno[3,2-c]pyridin-4-yl)piperazine 20 1-carboxylate (0.02 g, 0.03 mmol) was treated as described in Method R to give the desired product as a white solid. Yield 0.014 g (100 %) White solid. 1H NMR (300 MHz, DMSO d6) 8 9.25 (s, 1 H), 8.12-8.22 (m, 2 H), 7.66-7.77 (m, 4 H), 7.41-7.52 (m, 2 H), 5.12 (s, 2 H), 3.22-3.35 (m, 4 H); MS (ESI+) for C19 H18 F3 N3 02 S2. Cl H m/z 442 (M+H)*. HPLC 90 %, RT 3.53min (ACE3 C8 50x4.6mm, 5-50 % acetonitrile in 3 min). 25 INTERMEDIATE 82 tert-Butyl-4-{2-[(3-bromobenzyl)sulfonyl thieno[3,2-cjpyridin-4-yl}piperazine-l carboxylate Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 3 30 bromobenzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.023 g (10 % over two steps). Beige solid. 1H NMR (300 MHz, CDC1 3 ) 8 8.16 (d, J=6 Hz, 1H), WO 2004/000828 PCT/SE2003/001061 7.50-7.55 (m, 2 H), 7.32-7.40 (m, 2 H), 7.10-7.24 (m, 3 H), 4.44 (s, 2 H), 3.61-3.73 (m, 8 H), 1.50 (s, 9 H); MS (ESI+) for C23 H26 Br N3 04 S 2 m/z 554 (M+H) . HPLC 77 %, RT 4.07min (ACE3 C8 50x4.6mm, 5-50 % acetonitrile in 3 min). 5 EXAMPLE 107 2-[(3-Bromobenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride tert-Butyl 4- {2-[(3-bromobenzyl)sulfonyl]thieno[3,2-c]pyridin-4-yl}piperazine-1 carboxylate (0.023 g, 0.04 mmol) was treated as described in Method R to give the desired product as a white solid. Yield 0.0 13 g (67 %) White solid. 'H NMR (300 MHz, DMSO 10 d6) 8 9.19 (s, 1 H), 8.18 (d, J= 6 Hz, 1 H), 8.05 (s, 1 H), 7.70 (d, J= 6 Hz, 1 H), 7.53-7.58 (m, 1 H), 7.43-7.45 (m, 1 H), 7.19-7.32 (m, 2 H), 4.98 (s, 2 H), 3.24-3.35 (m, 4 H); MS (ESI+) for C18 H18 Br N3 02 S2. C1 H m/z 452 (M+H)+. HPLC 90 %, RT 3.30min (ACE3 CS 50x4.6mm, 5-50 % acetonitrile in 3 min). 15 INTERMEDIATE 83 tert-Butyl 4-{2-[(3,4-difluorobenzyl)sulfonyl]thieno[3,2-c]pyridin-4-yl}piperazine-1 carboxylate Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 3,4 bis(trifluoromethyl)benzylbromide (0.59 mmol) as described in Method P above and then 20 reacted further with tert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.014 g (6 % over two steps). Beige solid. 1H NMR (300 MHz, CDC1 3 ) 6 8.17-8.21 (m, 1 H), 7.71 (s, 1 H), 7.07-7.39 (m, 4 H), 4.59 (s, 2 H), 3.55-3.68 (m, 8 H), 1.49 (s, 9 H); MS (ESI+) for C23 H25 F2 N3 04 S 2 m/z 510 (M+H)*. HPLC 64 %, RT 2.02 min (YMC ODS AQ, 33x3mm, 10-90 % acetonitrile in 3 min). 25 EXAMPLE 108 2-[(2,3-Difluorobenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride The BOC group was removed from tert-butyl 4-{2-[(3,4 difluorobenzyl)sulfonyl]thieno[3,2-c]pyridin-4-y}piperazine-1-carboxylate using Method 30 R. Yield 0.068 g (100 %). White solid. 'H NMR (300 MHz, DMSO-d 6 ) 6 9.34 (s, 1 H), 8.22 (s, 1 H), 8.18 (d, J=5.5 Hz, 1 H), 7.70 (d, J=5.5 Hz, 1 H), 7.26-7.35 (m, I H), 7.15 7.22 (m, 1 H), 7.05-7.14 (m, 1 H), 5.08 (s, 2 H), 3.34-3.42 (m, 4 H), 3.25-3.34 (m, 4 H); WO 2004/000828 PCT/SE2003/001061 MS (ESI+) for C18 H17 F2 N3 02 S2. Cl H m/z 410 (M+H)+. HPLC 90 %, RT 1.07min (YMC ODS AQ, 33x3mm, 20-50 % acetonitrile in 1.5 min). EXAMPLE 109 5 2-[(4-Bromobenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.42 mmol) was treated with 4 bromobenzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine- 1-carboxylate as described in Method Q. The BOC protecting group was removed using Method R. Yield 0.024 g (12 % over three steps). 10 White solid. 'H NMR (300 MHz, DMSO-d6) 8 8.99 (s, 1 H), 8.18 (d, J= 5.5 Hz, 1 H), 8.02 (s, 1 H), 7.69 (d, J= 5.5 Hz, 1 H), 7.53 (d, J= 8.5 Hz, 2 H), 7.17 (d, J= 8.5 Hz, 2H), 4.95 (s, 2 H), 3.62-3.68 (m, 4 H), 3.27-3.32 (m, 4 H); MS (ESI+) for C18 H18 Br N3 02 S2 . Cl H m/z 454 (M+H)+. HPLC 90 %, R-r 1.24min (YMC ODS AQ, 33x3mm, 20-50 % acetonitrile in 1.5 min). 15 INTERMEDIATE 84 tert-Butyl-4-(2-{[2,5-bis(trifluoromethyl)benzyllsulfonyl}thieno[3,2-c]pyridin-4 yl)piperazine-1-carboxylate Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 2,5 20 bis(trifluoromethyl)bcnzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.01 g (4 % over two steps). Beige solid. 1H NMR (300 MHz, CDCl 3 ) 6 8.16 (d, J= 5.8 Hz1 H), 8.00 (s, 1 H), 7.74-7.85 (m, 3 H), 4.76 (s, 2 H), 3.56-3.64 (m, 4 H), 3.47-3.56 (m, 4 H), 1.49 (s, 9 H); MS (ESI+) for C25 H25 F6 N3 04 S2 m/z 610 (M+H)*. HPLC 73 %, 25 RT 2.36min (YMC ODS AQ, 33x3mm, 10-90 % acetonitrile in 3 min). EXAMPLE 110 2-{[2,5-Bis(trifluoromethyl)benzyllsulfonyl}-4-piperazin-1-ylthieno[3,2-cepyridine hydrochloride 30 The BOC group was removed from tert-butyl 4-(2-{[2,5-(trifluoromethyl) benzyl]sulfonyl}thieno[3,2-c]pyridin-4-yl)piperazine-1-carboxylate using Method R. Yield 0.024 g (100 %). White solid. 1 H NMR (300 MHz, DMSO-d 6 ) 8 9.30 (s, 1 H), 8.25 (s, 1 WO 2004/000828 PCT/SE2003/001061 H), 8.19 (d, J=5.5 Hz, 1 H), 8.00-8.07 (m, 2 H), 7.85 (s, 1 H), 7.69 (d, J=5.5 Hz, 1 H), 5.22 (s, 2 H), 3.24-3.33 (m, 4 H); MS (ESI+) for C20 H17 F6 N3 02 S2 . Cl H m/z 510 (M+H) . HPLC 90 %, RT 1.08min (YMC ODS AQ, 33x3mm, 30-60 % acetonitrile in 1.5 minl). 5 INTERMEDIATE 85 tert-Butyl 4-{2-[(4-methylbenzyl)sulfonyl]thieno[3,2-cjpyridin-4-yllpiperazine-1 carboxylate Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 4 10 methylbenzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine- 1 -carboxylate as described in Method Q. Yield 0.005 g (3 % over two steps). Beige solid. 11H NMR (300 MHz, CDC 3 ) 8 8.15 (d, J= 6 Hz 1 H), 7.40 (s, 1 H), 7.00-7.16 (m, 4 H), 4.42 (s, 2 H), 3.46-3.60 (m, 4 H), 3.37-3.46 (m, 4 H), 2.34 (s, 3 H), 1.49 (s, 9 H); MS (ESI+) for C24 H29 N3 04 S2 m/z 488 (M+H)+. HPLC 69 15 %, RT 2.06min (YMC ODS AQ, 33x3nm, 10-90 % acetonitrile in 3 min). EXAMPLE 111 2-[(4-Methylbenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-clpyridine hydrochloride The BOC group was removed from tert-butyl 4-{2-[(4-methylbenzyl)sulfonyl]thieno[3,2 20 c]pyridin-4-yl}piperazine-1-carboxylate using Method R. Yield 0.05 g (75 %). White solid. 'H NMR (300 MHz, DMSO-d6) 8 9.18 (s, 1 H), 8.17 (d, J=5.5 Hz, 1 H), 8.01 (s, 1 H), 7.67 (d, J=5.5 Hz, 1 H), 7.38 (s, 1 H), 7.19 (s, 1 H), 7.11 (s, 1 H), 7.00 (s, 1 H), 4.86 (s, 2 H); MS (ESI+) for C19 H21 N3 02 S2 . Cl H m/z 388 (M+H)*.HPLC 90 %, RT 1.65 min (ACE3 C8 50x3.0mm, 10-97 % acetonitrile in 3 min). 25 INTERMEDIATE 86 tert-Butyl 4-(2-{[5-chloro-2-(trifluoromethyl)benzyl]sulfonyl}thieno[3,2-c]pyridin-4 yl)piperazine-1-carboxylate Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 5-chloro 30 2-(trifluoromethyl)benzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.019 g (7.5 % over two steps). Beige solid. 'H NMR (300 MHz, CDC1 3 ) 8 8.12-8.14 (m, 1 WO 2004/000828 PCT/SE2003/001061 H), 7.80-7.88 (m, 2 H), 7.47-7.66 (m, 2 H), 4.71 (s, 2 H), 3.74-3.83 (m, 4 H), 3.63-3.72 (m, 4 H), 1.49 (s, 9 H); MS (ESI+) for C24 H25 C1 F3 N3 04 S 2 m/z 576 (M+ HPLC 74 %, RT 2.30min (YMC ODS AQ, 33x3mm, 10-90 % acetonitrile in 3 min). 5 EXAMPLE 112 2-{[5-Chloro-2-(trifluoromethyl)benzyl]sulfonyl}-4-piperazin-1-ylthieno[3,2 cipyridine hydrochloride The BOC group was removed from tert-butyl 4-(2-{[5-chloro-2 (trifluoromethyl)benzyl] sulfonyl}thieno[3,2-c]pyridin-4-yl)piperazine- 1 -carboxylate using 10 Method r. Yield 0.012 g (92 %). White solid. 'H NMR (300 MHz, DMSO-d 6 ) 8 9.05 (s, 1 H), 8.18-8.23 (m, 2 H), 7.78-7.83 (m, 1 H), 7.72-7.76 (m, 1 H), 7.69 (d, J=5.5 Hz, 1 H), 7.62-7.65 (m, 1 H), 5.07 (s, 2 H), 3.65-3.72 (m, 4 H), 7.25-7.34 (m, 4 H); MS (ESI+) for C19 H17 Cl F3 N3 02 S2 . Cl H m/z 476 (M+H)*. HPLC 90 %, RT 1.65 min (ACE3 C8 50x3.0mm, 10-97 % acetonitrile in 3 min). 15 INTERMEDIATE 87 tert-Butyl 4-{2-[(3,5-dimethoxybenzyl)sulfonyl]thieno[3,2-cjpyridin-4-yl}piperazine-1 carboxylate Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 3,5 20 dimethoxybenzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine- 1 -carboxylate as described in Method Q. Yield 0.02 g (10 % over two steps). Beige solid. 1H NMR (300 MHz, CDC1 3 ) 6 8.14-8.18 (m, 1 H), 7.55 (s, 1 H), 6.40-6.45 (m, 1 H), 6.26-6.34 (m, 2 H), 4.39 (s, 2 H), 3.54-3.72 (m, 14 H), 1.50 (s, 9 H); MS (ESI+) for C25 H31 N3 06 S 2 m/z 534 (M+H)+. HPLC 69 %, RT 1.99min (YMC 25 ODS AQ, 33x3mm, 10-90 % acetonitrile in 3 min). EXAMPLE 113 2-[(3,5-Dimethoxybenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-cipyridine hydrochloride 30 The BOC group was removed from tert-butyl 4-{2-[(3,5 dimethoxybenzyl)sulfonyl]thieno[3,2-c]pyridin-4-yl}piperazine-1-carboxylate using Method R. Yield 0.01g (62%). White solid. 1H NMR (300 MHz, DMSO-d 6 ) 8 9.09 (s, 1 WO 2004/000828 PCT/SE2003/001061 H), 8.18 (d, J= 6.7 Hz, 1 H), 8.02 (s, 1 H), 7.69 (d, J= 6.7 Hz, 1H), 6.45-6.48 (m, 1 H), 6.35-6.38 (m, 2 H), 4.84 (s, 2H), 3.61-3.67 (m, 4H), 3.58 (s, 6H), 3.24-3.33 (m, 4H).MS (ESI+) for C 20

H

22

N

3 0 4

S

2 m/z 434 (M+H)*. IHPLC 90 %, RT 1.60 min (ACE3 C8 50x3.Omm, 10-97 % acetonitrile in 3 min). 5 EXAMPLE 114 2-[(2-Naphthylmethyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride 2-(Bromomethyl)naphthalene was used according to Method P-R to give 12.4 mg of the desired product. 1H NMR (270 MHz, CH 3 0H-d 4 ) 6 ppm (obscured by CH 3 0H, 4H) 3.70 10 3.79 (m, 4 H) 4.95 (s, 2 H) 7.36-7.58 (m, 3 H) 7.70-7.91 (m, 6 H) 8.02 (d, J=6.60 Hz, 1 H). MS (M+1) 424. EXAMPLE 115 4-Piperazin-1-yl-2-{[4-(1,2,3-thiadiazol-4-yl)benzyllsulfonyl}thieno[3,2-cipyridine 15 hydrochloride 4-[4-(Bromomethyl)phenyl]-1,2,3-thiadiazole was used according to Method P-R to give 4.8 mg of the desired product. 1H NMR (270 MHz, CH 3 0H-d 4 ) 8 ppm 3.41-3.50 (m, 4 H) 3.54 (s, 2 H) 3.89-3.98 (m, 4 H) 7.45 (d, J=8.44 Hz, 2 H) 7.75 (d, J=6.33 Hz, 1 H) 7.96 8.13 (m, 4 H) 9.31 (s, 1 H). MS (M+1) 458. 20 EXAMPLE 116 1-(4-Pyrrolidin-1-ylphenyl)-2-[(4-piperazine-1-ylthieno[3,2-clpyridin-2-yI) sulfonyll ethanone hydrochloride 2-Bromo- 1 -(4-pyrrolidin- 1 -ylphenyl)ethanone was used according to Method P-R to give 25 19.6 mg of the desired product. 'H NMR (270 MHz, CH 3 0H-d 4 ) 6 ppm 2.02-2.12 (m, 4 H) 2.69 (s, 1 H) 3.37 (t, J=6.73 Hz, 4 H) 3.54 (s, 1 H) 3.56.3.64 (m, 4 H) 4.12-4.22 (m, 4 H) 6.55 (d, J=8.97 Hz, 2 H) 7.78-7.90 (m, 3 H) 8.03 (d, J=6.86 Hz, 1 H) 8.41 (s, 1 H). MS (M+1) 471. 30 WO 2004/000828 PCT/SE2003/001061 EXAMPLE 117 1-[4-(Diethylamino)phenyl]-2-[(4-piperazine-1-ylthieno[3,2-clpyridin-2-yl) sulfonyl] ethanone hydrochloride 2-Bromo-1-[4-(diethylamino)phenyl]ethanone ethanone was used according to Method P 5 R to give 9.0 mg of the desired product. 11H NMR (500 MHz, CH 3 0H-d 4 ) 8 ppm 1.16 (t, J=7.06 Hz, 6 H) 3.49-3.66 (m, 10 H) 4.14-4.27 (m, 4 H) 7.13 (br.s, 2 H) 7.85 (d, J=6.59 Hz, 1 H) 7.98 (d, J=8.48 Hz, 2 H) 8.03 (d, J=6.59 Hz, 1 H) 8.47 (s, 1 H). MS (M+1) 473. EXAMPLE 118 10 1-(4-Bromophenyl)-2-[(4-piperazin-1-ylthieno[3,2-c]pyridin-2-yl) sulfonyl] ethanone 2-Bromo-1-(4-bromophenyl)ethanone was used according to method A to give 3.4 mg of the desired product. IH NMR (270 MHz, CH 3 0H-d 4 ) 3 ppm 3.55 (s, 2 H) 3.56-3.67 (m, 4 H) 4.08-4.26 (in, 4 H) 7.68 (d, J=8.44 Hz, 2 H) 7.79-7.98 (m, 3 H) 8.06 (d, J=6.60 Hz, 1 H) 8.45 (s, 1 H). MS (M+1) 481. 15 EXAMPLE 119 1-(3-Methoxyphenyl)-2-[(4-piperazin-1-ylthieno[3,2-c]pyridin-2-yl) sulfonyll ethanone 2-bromo-1-(3-methoxyphenyl)ethanone was used according to method A to give 1.0 mg of the desired product. 1H NMR (270 MHz, CH 3 0H-d 4 ) 3 ppm 3.54 (s, 2 H) 3.55-6.62 (m, 20 J=10.03 Hz, 4 H) 3.82 (s, 3 H) 4.06-4.18 (m, 4 H) 7.20 (dd, J=8.05, 2.24 Hz, 1 H) 7.34 7.49 (m, 2 H) 7.57 (d, J=7.39 Hz, 1 H) 7.84 (d, J=6.60 Hz, 1 H) 8.06 (d, J=6.60 Hz, 1 H) 8.41 (s, 1 H). MS (M+1) 432. EXAMPLE 120 25 1-Phenyl-2-[(4-piperazin-1-ylthieno[3,2-clpyridin-2-yl)sulfonyl]ethanone 2-Bromo- 1 -phenylethanone was used according to method A to give 1.2 mg of the desired product. 'H NMR (270 MHz, CH 3 0H-d 4 ) 8 ppm 3.55 (s, 2 H) 3.57-3.66 (m, 4 H) 4.10-4.24 (m, 4 H) 7.46-4.57 (m, 2 H) 7.66 (t, J=7.39 Hz, 1 H) 7.86 (d, J=6.60 Hz, 1 H) 8.02 (dd, J=14.12, 6.99 Hz, 3 H) 8.46 (s, 1 H). MS (M+1) 402. 30 WO 2004/000828 PCT/SE2003/001061 Table 6 0 SR 1 '0 EXAMPLE R 121 4-Piperazin-1-yl-1-(toluene-4-sulfo (N) nyl)-1H-pyrrolo[3,2-clpyridine hydrochloride C 122 1-(3-Chloro-2-methyl-benzenesulfony (N) 1)-4-piperazin-1-yl-lH-pyrrolo[3,2 c~pyridine hydrochloride C 123 1-(3,4-Dimethoxy-benzenesulfonyl)-4 N -piperazin-1-yl-1H-pyrrolo[3,2-c]py0 ridine hydrochloride

N

124 4-(4-Piperazin-1-yl-pyrrolo[3,2-c]p (N) yridine-l-sulfonyl)-benzonitrile hydrochloride ON 125 1-(4,5-Dichloro-thiophene-2-sulfonyl)-4-piperazin-1 -yl-1H- CI S (N) pyrrolo[3,2-c]pyridine hydrochloride N C1 126 1-(2-Chloro-4-fluoro-benzenesulfony

(N)

l)-4-piperazin-1 -yl-1H-pyrrolo[3,2- C1 cipyridine hydrochlorideIN WO 2004/000828 PCT/SE2003/001061 127 1-Phenylrnethanesulfonyl-4-piperazin-1-yl-lH-pyrrolo [3,2 cipyridine hydrochloride 0N 128 l-(5-Chloro-thiophene-2-sulfonyl)-4 ci S -piperazin-1-yl-lH-pyrrolol3,2-clpy (N' ) ridine hydrochloride N 129 1-(4-Butyl-benzenesulfonyl)-4-piperazin-1-yl-lH-pyrrolo(3,2- ---- (N c)pyridine hydrochloride 130 1-(4-Phenoxy-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo(3,2- N c)pyridine hydrochloride Wh 0 131 1-(Phenylsulfonyl)-4-piperazin-1 -yl-1H-pyrrolo[3,2-c]pyridine

(N)

hydrochloride 132 1 {(4-Choropheny1)sufony1]-4-piperazin-1-y1-1H-pyrroo[13 ,2- - - -- (N) c]pyridmne hydrochloride C1 133 1 -[(4-Methoxyphenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2- ( .N) c]pyridinc hydrochloride N" 134 l-[(2-Methoxy-5-methylphenyl)sulfonyl]-4-piperazin-1-yl-1H- N pyrrolo[3,2-c]pyridine hydrochloride .~0 ) WO 2004/000828 PCT/SE2003/001061 135 4-Piperazin-1-yl-1-{[2-(trifluoromethyl)phenyl]sulfonyl}-1H- _ _ F N pyrrolo[3,2-c]pyridine hydrochloride F N Scheme 8 .. N N H NN N o C1 H R1 iv v N N - N R 4vii R44 5 R4 Legend to Scheme 8: i) Ethylchloroformate, TEA, acetone, NaN 3 ; ii) Bu 3 N, DCM and diphenylether; iii) POCl 3 , NaOH; iv) BOC protected amines (R 4 ), K 2 C0 3 , DMSO; v) NH 3 gas Na, NH 4 Cl, THF vi) Sulphonyl chlorides (R'), NaH, THF; vii) HCl/diethyl ether, methanol. 10 INTERMEDIATE 88 (2E)-3-(1-Benzyl-1H-pyrrol-2-yl)acryloyl azide To a mixture of 1-benzyl-1H-pyrrole-2-carbaldehyde (28.4g, 0.125mol) and TEA (13.5 mL, 0.187 mol) in acetone (300 mL) was added ethylchloroformate (17.9 mL, 0.87 mol) dropwise. The reaction was stirred for 1.5 h after which NaN 3 (13 g, 0.200 mol) in H20 15 (100 mL) was added. After 2h, the reaction was diluted with water and left overnight. The acetone was removed and the product was filtered off to afford 21.4 g of a light brown solid. This compound was taken to the next step. INTERMEDIATE 89 WO 2004/000828 PCT/SE2003/001061 1-Benzyl-1,5-dihydro-pyrrolo[3,2-c]pyridin-4-one was prepared by the literature procedure according to C. Ducrocq; E. Bisangi; J-M, Lhoste; J. Mispelter; Tetrahedron, Vol 32, pp 773-780, (1976). To a stirred solution of n-tributylamine (30 mL) in diphenyl ether (150 mL) heated to 195 5 *C was slowly added during 30 minutes a solution of the acyl azide dissolved in DCM (150 mL). The reaction mixture was stirred at 195 *C for 1 hour and then cooled to room temperature. Pentane (1.0 L) and ether (1.0 L) was added to the reaction mixture and the precipitate was collected by filtration. The crude solid was triturated with ether to give 6.89 g (81%) of the pure product. Purity HPLC >95%; MS (ESI) m/z 225 (m+H); 'H NMR 10 (DMSO-d6, 25 *C, 270.16) 8 10.84 (br s, 1 H), 7.43-7.14 (m, 6 H), 7.00 (d, J = 7.12 Hz, 1 H), 6.57-6.49 (m, 2 H), 5.83 (s, 2 H). INTERMEDIATE 90 1-Benzyl-4-chloro-1lH-indole 15 POCl 3 (3.11 mL, 33.4 mmol) was added to 1-benzyl-1,5-dihydro-4H-pyrrolo[3,2 c]pyridin-4-one (3.75 g, 16.7 mmol) and the reaction was stirred at 120*C for 2h. NaOH (1M) was added and the mixture was extracted with DCM three times. The organic layers were dried (MgSO4), filtered and the solvent was removed. Flash chromatography (DCM/Heptane/MeOH 4:15:1) gave 1.17 g (29 %) of product. The product was taken to 20 the next step. INTERMEDIATE 91 tert-Butyl 4-(1-benzyl-1H-pyrrolo[3,2-clpyridin-4-yl)piperazine-1-carboxylate A mixture of 1-benzyl-4-chloro-1H-indole (1.17 g, 4.82 mmol), K 2 C0 3 (2.0 g, mmol) and 25 Boc-piperazine (1.79 g, 9.64 mmol) in DMSO (75 mL) was stirred at 120 *C for 48 h. Additional of Boc-piperazine (4 equiv.) was added and the reaction was run for another 48 h. The reaction was diluted with ethyl acetate (200 mL) and the mixture was washed with several portions of water. Flash chromatography (DCM/MeOH/Heptane 4:1:15) gave 0.51 g of starting material and 0.38 g of product. 'HNMR (CD 3 OD) 6 7.87-7.85 (in, 1H), 7.25 30 7.24 (m, 3H), 7.04-6.98 (in, 3H), 6.73-6.71 (m, 1H), 6.53-6.52 (in, 1H), 5.19 (s, 2H), 3.63 3.59 (m, 8H), 1.47 (s, 9H); MS (ESI) 393 (M + H)*; Purity (HPLC, column ACE) 95% WO 2004/000828 PCT/SE2003/001061 INTERMEDIATE 92 tert-Butyl 4-( 1H-pyrrolo[3,2-cjpyridin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(1-benzyl-IH-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate (383 mg, 5 0.488 mmol) was dissolved in THF (6 mL) and liquid ammonia (10 mL) in a 30 mL vial. Na (67 mg, 2.93 mmol) was added in portions and the reaction turned violet. After 30 min

NH

4 Cl (sat) was added and the reaction was let to room temperature The THF was removed and the residue was extracted with DCM. Recrystallization (DCM/Heptane) gave 112 mg of a white solid. 1 HNMR (CD 3 0D) 8 8.66 (s, 1H), 7.89 (d, 1H, J = 5.80 Hz), 7.13 10 7.11 (m, 1H), 6.89-6.86 (m, 1H), 6.57-6.56 (m, 1H), 3.67-3.60 (m, 8H), 1.48 (s, 9H); MS (ESI) 303 (M + H)-; Purity (HPLC, column ACE) 95%. Method S for sulphonylation: tert-butyl 4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1 carboxylate (total 1.391 mmol, 1 equiv.) dissolved in THF (14 mL) and dispense to 10 mL 15 vials with screwcap. A suspension of NaH (0.1488 mmol, 1.5 equiv.) in THF (15 mL) was dispense evenly to the vials containing the solution of tert-butyl 4-(1H-pyrrolo[3,2 c]pyridin-4-yl)piperazine-1-carboxylate and stired for approximately for 15 min. Different sulfonylchlorides were dissolved in THF (2 mL) each and added drop-wise to the reaction mixtures. The reactions were quenched with MeOH (100 pL) and PS-Trisamine (3 equiv.) 20 was added to each vial and shake for 2 hours. The mixtures were filtered and the filtrates were concentrate under vacuum. The products that were not pure enough ( Purity < 90%) were purified by preparative chromatography using acetonitrile-water gradients containing 0.1% triflouroacetic acid. After HPLC analysis fractions that were > 90% pure were collected and. concentrated. 25 Method T BOC deprotection; The Boc-protected compound was dissolved in MeOH (2 mL) and HCL/ether (2 mL) was added. After 45 min the solvent was removed.

WO 2004/000828 PCT/SE2003/001061 INTERMEDIATE 93 tert-Butyl-4-[1-(phenylsulfonyl)-1H-pyrrolo[3,2-c]pyridin-4-yl]piperazine-1 carboxylate Purification by recrystallization gave 16 mg (56 %) after Boc-deprotection. 5 'HNMR (CDC1 3 ) 5 8.03-8.01 (in, 1H), 7.89-7.86 (in, 2H), 7.57-7.39 (in, 5H), 6.67-6.64 (m, 1H), 3.55-3.52 (m, 8H), 1.47 (s, 9H); MS (ESI) 443 (M + H)+; Purity (HPLC, column ACE) 95%. INTERMEDIATE 94 10 tert-Butyl-4-{1-[(4-chlorophenyl)sulfonyl]-1H-pyrrolo[3,2-cjpyridin-4-yl}piperazine 1-carboxylate Purification by preparative HPLC gave 4 mg (11 %) after Boc-deprotection. HNMR (CDC1 3 ) 6 8.03-7.51 (in, 711), 6.89-6.87 (in, 1H), 3.91-3.66 (in, 8H), 1.47 (s, 9H); MS (ESI) 377 (M + H)*; Purity (HPLC, column ACE) 95%. 15 INTERMEDIATE 95 tert-Butyl-4-{1-[(4-methoxyphenyl)sulfonyl]-1H-pyrrolo[3,2-clpyridin-4 yl}piperazine-1-carboxylate Purification by recrystallization (MeOH/Ether) gave 21 mg (67 %) after boc-deprotection. 20 'HNMR (CDC1 3 ) 5 8.02-8.00 (m, 1H), 7.84-7.80 (in, 2H), 7.48-7.46 (in, 1H), 7.41-7.38 (in, 1H), 6.92-6.86 (m, 2H), 6.64-6.62 (in, 1H), 3.79 (s, 3H), 3.57-3.52 (in, 8H), 1.48 (s, 9H); MS (ESI) 473 (M + H)+; Purity (HPLC, column ACE) 95%. INTERMEDIATE 96 25 tert-Butyl 4-(1-{[2-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrolo[3,2-clpyridin-4 yl)piperazine-1-carboxylate Purification by preparative HPLC gave 8.6 mg (25 %) after boc-deprotection. HNMR (CDC1 3 ) 8 8.14-8.11 (m, 1H), 8.01-7.94 (m, 2H), 7.89-7.72 (m, 3H), 7.37-7.34 (in, 1H), 6.89-6.88 (m, 1H), 3.93-3.89 (m, 4H), 3.71-3.67 (in, 4H), 1.47 (s, 911); MS (ESI) 511 (M + 30 H)"; Purity (HPLC, column ACE) 95%.

WO 2004/000828 PCT/SE2003/001061 INTERMEDIATE 97 tert-Butyl 4-{1-[(2-methoxy-5-methylphenyl)sulfonyl]-1H-pyrrolo[3,2-clpyridin-4 yl}piperazine-1-carboxylate Purification by preparative HPLC gave 10.3 mg (32 %) after boc-deprotection. IHNMR 5 (CDC13) 8 7.95-7.92 (m, 2H), 7.74-7.72 (m, 1H), 7.44-7.40 (m, 2H), 6.85-6.77 (m, 2H), 3.92-3.88 (m, 4H), 3.70 (s, 3H), 3.69-3.66 (m, 4H), 2.39 (s, 3H), 1.47 (s, 9H); MS (ESI) 487 (M + H)+; Purity (HPLC, column ACE) 95%. EXAMPLE 121 10 4-Piperazin-1-yl-1-(toluene-4-sulfonyl)-1H-pyrrolo[3,2-cipyridine hydrochloride p-Toulenesulfonyl chloride (24.6 mg) was added to tert-butyl 4-(1H-pyrrolo[3,2-c]pyridin 4-yl)piperazine-1-carboxylate the title compound (4.3 mg). LC/MS RT: 1.374 (System 10 till 40% MeCN over 1.5 min, ACE C8), Purity. 91%. MS: 357 (M+1) 1HNMR (CD 3 0D) S ppm 2.39 (s, 3 H) 3.48 (m, 4 H) 4.06 (m, 4 H) 7.22 (d, J=3.71 Hz, 1 H) 7.43 (d, J=8.16 Hz, 15 2 H) 7.95 (m, 5 H). EXAMPLE 122 1-(3-Chloro-2-methyl-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-cpyridine hydrochloride 20 3-Chloro-2-methylbenzenesulfonyl chloride (29.0 mg) was added to tert-butyl 4-(1H pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate the title compound (6.3 mg). LC/MS RT: 1.563 (System 10 till 40% MeCN over 1.5 min, ACE C8), Purity. 96%. MS: 392 (M+1). 25 EXAMPLE 123 1-(3,4-Dimethoxy-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-cpyridine hydrochloride 3,4-Dimethoxybenzenulfonyl chloride (30.5 mg) was added to tert-butyl 4-(1H pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate the title compound (8.5 mg). LC/MS 30 RT: 1.284 (System 10 till 40% MeCN over 1.5 min, ACE C8), Purity. 92%. MS: 404 (M+1) IHNMR (CD 3 OD) S ppm 3.50 (m, J=4.21 Hz, 2 H) 3.85 (d, J=3.22 Hz, 4 H) 4.10 WO 2004/000828 PCT/SE2003/001061 (m, J=3.96 Hz, 2 H) 7.11 (d, J=8.66 Hz, 1 H) 7.23 (d, J=3.46 Hz, 1 H) 7.48 (d, J=1.73 Hz, 1 H) 7.74 (dd, J=8.54, 1.86 Hz, 1 H) 7.92 (s, 2 H) 8.07 (d, J=3.46 Hz, 1 H). EXAMPLE 124 5 4

-(

4 -Piperazin-1-yl-pyrrolo[3,2-c]pyridine-1-sulfonyl)-benzonitrile hydrochloride 4-Cyanobenzenesulfonyl chloride (26.0mg) was added to tert-butyl 4-(1H-pyrrolo[3,2 c]pyridin-4-yl)piperazine-1-carboxylate the title compound (9.1 mg). LC/MS RT: 1.150 (System 10 till 40% MeCN over 1.5 min, ACE C8), Purity. 93%. MS: 369 (M+1) 1 HNMR

(CD

3 0D) 5 ppm 3.50 (m, 4 H) 4.08 (m, 4 H) 7.29 (d, J=3.71 Hz, 2 H) 7.98 (m, 4 H) 8.29 10 (d, J=8.66 Hz, 2 H). EXAMPLE 125 1-( 4

,

5 -Dichloro-thiophene-2-sulfonyl)-4-piperazin-1-yl-1IH-pyrrolo[3,2-clpyridine hydrochloride 15 4,5-Dichloro-thiophene-2-sulfony chloride (32.4 mg) was added to tert-butyl 4-(1H pyrrolo[3, 2 -c]pyridin-4-yl)piperazine-1-carboxylate the title compound (0.3 mg). LC/MS RT: 1.119 (System 10 till 40% MeCN over 1.5 min, ACE C8), Purity. 92%. MS: 418 (M+1). 20 EXAMPLE 126 1-( 2 -Chloro-4-fluoro-benzenesulfonyl)-4-piperazin-1-yl-1IH-pyrrolo[3,2-cipyridine hydrochloride 2-Chloro-4-flourobenzenesulfonyl chloride (29.5 mg) was added to tert-butyl 4-(1H pyrrolo[3,2-c]pyridin-4-yl)piperazine- 1 -carboxylate the title compound (2.4 mg). LC/M\IS 25 RT: 1.361 (System 10 till 40% MeCN over 1.5 min, ACE C8), Purity. 90%. MS: 396 (M+1) 1 HNMR (CD 3 0D) 8 ppm 3.51 (m, 4 H) 4.08 (m, 4 H) 7.23 (dd, J=3.96, 0.49 Hz, 1 H) 7.47 (m, 1 H) 7.55 (dd, J=8.41, 2.47 Hz, 2 H) 7.62 (d, J=6.93 Hz, 1 H) 7.91 (d, J=7.18 Hz, 1 H) 8.06 (d, J=3.96 Hz, 1 H). 30 WO 2004/000828 PCT/SE2003/001061 EXAMPLE 127 1-Phenylmethanesulfonyl-4-piperazin-1-yl-1H-pyrrolo [3,2-c]pyridine hydrochloride Phenyl-methanesulfonyl chloride (24.6 mg) was added to tert-butyl 4-(1H-pyrrolo[3,2 c]pyridin-4-yl)piperazine-1-carboxylate the title compound (0.2 mg). LC/MS RT: 1.007 5 (System 10 till 40% MeCN over 1.5 min, ACE C8), Purity. 90%. MS: 357 (M+1). EXAMPLE 128 1-(5-Chloro-thiophene-2-sulfonyl)-4-piperazin-1-yl-lH-pyrrolo[3,2-cjpyridine hydrochloride 10 5-Chlorothiophene-2-sulfonyl chloride (28.0 mg) was added to tert-butyl 4-(1H pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate the title compound (7.2 mg). LC/MS RT: 1.381 (System 10 till 40% MeCN over 1.5 min, ACE C8), Purity. 97%. MS: 483 (M+1). 15 EXAMPLE 129 1-(4-Butyl-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo(3,2-c)pyridine hydrochloride 4-N-Butylbenzenesulfonylchloride (30.0 mg) was added to tert-butyl 4-(1H-pyrrolo[3,2 c]pyridin-4-yl)piperazine-1-carboxylate the title compound (11.9 mg). LC/MS RT: 1.904 (System 10 till 40% MeCN over 1.5 min, ACE C8), Purity. 95%. MS: 400 (M+1) 1 HNMR 20 (CD 3 0D) 8 ppm 0.90 (t, J=7.18 Hz, 3 H) 1.31 (m, 2 H) 1.55 (m, 2 H) 2.67 (m, 2 H) 3.50 (m, 4 H) 4.09 (m, J=3.96 Hz, 4 H) 7.25 (d, J=3.71 Hz, 2 H) 7.44 (d, J=8.16 Hz, 2 H) 7.91 (m, 2 H) 8.02 (m, 2 H). EXAMPLE 130 25 1-(4-Phenoxy-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo(3,2-c)pyridine hydrochloride (4-Phenoxy)benzene)sulfonyl chloride (34.7 mg) was added to tert-butyl 4-(1H pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate the title compound (12.8 mg). LC/MS RT: 1.839 (System 10 till 40% MeCN over 1.5 min, ACE C8), Purity. 95%. MS: 436 30 (M+1) 'HNMR (CD 3 0D) 8 ppm 3.50 (m, J=3.96 Hz, 4 H) 4.09 (m, J=4.45 Hz, 4 H) 7.05 (dd, J=8.16, 6.43 Hz, 2 H) 7.26 (m, 2 H) 7.44 (t, J=7.79 Hz, 2 H) 7.90 (m, 3 H) 8.01 (d, J=3.71 Hz, 2 H) 8.07 (d, J=8.91 Hz, 2 H).

WO 2004/000828 PCT/SE2003/001061 EXAMPLE 131 1-(Phenylsulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-clpyridine hydrochloride Purification by recrystallization gave 16 mg (56 %) after Boc-deprotection. MS (ESI) 5 343.1 (M + H)*; Purity (HPLC, column ACE) 94%. EXAMPLE 132 1-[(4-Chlorophenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine hydrochloride 10 Purification by preparative HPLC gave 4 mg (11 %) after Boc-deprotection. MS (ESI) 377 (M + H)*; Purity (HPLC, column ACE) 96%. EXAMPLE 133 1-[(4-Methoxyphenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-cjpyridine 15 hydrochloride Purification by recrystallization (MeOH/Ether) gave 21 ng (67 %) after Boc-deprotection. MS (ESI) 373 (M + H)+; Purity (HPLC, column ACE) 92% EXAMPLE 134 20 1-[(2-Methoxy-5-methylphenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-clpyridine hydrochloride Purification by preparative HPLC gave 10.3 mg (32 %) after Boc-deprotection. MS (ESI) 387 (M + H)+; Purity (HPLC, column ACE) 95%. 25 EXAMPLE 135 4-Piperazin-1-yl-1-{[2-(trifluoromethyl)phenylsulfonyl}-1H-pyrrolo[3,2-c]pyridine hydrochloride Purification by preparative HPLC gave 8.6 mg (25 %) after Boc-deprotection. MS (ESI) 411 (M + H)*; Purity (HPLC, column ACE) 94%. 30 WO 2004/000828 PCT/SE2003/001061 BIOLOGICAL TESTS The ability of a compound according to the invention to bind a 5-HT 6 receptor, and to be pharmaceutically useful, can be determined using in vivo and in vitro assays known in the 5 art. (a) 5-HT 6 binding Assay Binding affinity experiment for the 5-HT 6 receptor are performed in HEK293 cells 10 transfected with 5-HT 6 receptor using (3H)-LSD as labeled ligand according to the general method as described by Boess F.G et al. Neuropharmacology vol. 36(4/5) 713-720, 1997. Materials 15 Cell culture The HEK-293 cell line transfected with the 5-HT 6 receptor was cultured in Dulbeccos Modified Eagles Medium containing 5 % dialyzed foetal bovine serum, (Gibco BRL 10 106-169), 0.5 mM sodium pyruvate and 400 pg/ml Geneticin (G-418) (Gibco BRL10131-019). The cells were passaged 1:10, twice a week. 20 Chemicals The radioligand [ 3 H] LSD 60-240 Ci/mmol, obtained from Amersham Pharmacia Biotech, (Buckinghamshire, England) was in ethanol and stored at -20'C. The unlabelled ligands, representing different selectivity profiles, are presented in Table 1. The compounds were 25 dissolved in 100% DMSO and diluted with binding buffer. Disposable Compounds were diluted in Costar 96 well V-bottom polypropylene plates (Corning Inc. Costar, NY, USA). Samples were incubated in Packard Optiplate (Packard Instruments 30 B.V., Groningen, The Netherlands). The total amount of added radioligand was measured in Packard 24-well Barex plates (Packard Instruments B.V., Groningen, The Netherlands) WO 2004/000828 PCT/SE2003/001061 in the presence of Microscint m 20 scintillation fluid (Packard Bioscience, Meriden, CT, USA). Buffer 5 The binding buffer consisted of 20 mM HEPES, 150 mM NaCl, 10 mM MgC1 2 , and 1 mM, EDTA, pH 7.4. Methods Membrane preparation 10 Cells were grown to approximately 90% confluence on 24.5 x 24.5 NUNC culture dishes. The medium was aspirated, and after rinsing with ice-cold PBS, the cells were scraped off using 25 ml Tris buffer (50 mM Tris-HCl, 1 mM EDTA, 1 mM EGTA, pH 7.4) and a window scraper. The cells were then broken with a Polytron homogeniser, and remaining particulate matter was removed by low-speed centrifugation, 1 000x g for 5 min. Finally, 15 the membranes were collected by high-speed centrifugation (20 000x g), suspended in binding buffer, and frozen in aliquots at -70'C. Radioligand binding Frozen cell membranes were thawed, immediately rehomogenized with a Polytron 20 homogenizer, and coupled to SPA wheat germ agglutinin beads (Amersham Life Sciences, Cardiff, England) for 30 min under continuous shaking of the tubes. After coupling, the beads were centrifuged for 10 minutes at 1000 g, and subsequently suspended in 20 ml of binding buffer per 96-well plate The binding reaction was then initiated by adding radioligand and test compounds to the bead-membrane suspension. Following incubation 25 at room temperature, the assay plates were subjected to scintillation counting. The original SPA method was followed except for that membranes were prepared from 1HEK293 cells expressing the human 5-HT 6 receptor instead of from HeLa cells (Dinh DM, Zaworski PG, Gill GS, Schlachter SK, Lawson CF, Smith MW. Validation of human 5-HT 6 receptors expressed in HeLa cell membranes: saturation binding studies, 30 pharmacological profiles of standard CNS agents and SPA development. The Upjohn Company Technical Report 7295-95-064 1995;27 December). The specific binding of WO 2004/000828 PCT/SE2003/001061

[

3 H]LSD was saturable, while the non-specific binding increased linearly with the concentration of added radioligand. [3H] LSD bound with high affinity to 5-HT 6 receptors. The Kd value was estimated to 2.6+ 0.2 nM based on four separate experiments. 5 The total binding at 3 nM of [ 3 H] LSD, the radioligand concentration used in the competition experiments, was typically 6000 dpm, and the specific binding more than 70%. 5-HT caused a concentration dependent inhibition of [3 H] LSD binding with an over all average Ki value of 236 nM when tested against two different membrane preparations. The inter assay variability over three experiments showed a CV of 10% with an average Kj 10 values of 173 nM (SD 30) and a Hill coefficient of 0.94 (SD 0.09). The intra assay variation was 3% (n=4). Ki values for a limited set of reference compounds with reported binding affinities at 5-HT 6 receptor are presented in Table 7. All unlabelled ligands displaced the specific binding of [ 3 H] LSD in a concentration-dependent manner, albeit at different potencies. The rank order of potency for the compounds was methiothepin (2 nM) 15 >mianserin (190 nM) ~5-HT (236 nM) >methysergide (482 nM) >mesulergide (1970 nM). Protein determination Protein concentrations were determined with BioRad Protein Assay (Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing 20 the principle of protein-dye binding. Anal Biochem 1976;72:248-54). Bovine serum albumin was used as standard. Scintillation counting The radioactivity was determined in a Packard TopCountTM scintillation counter (Packard 25 Instruments, Meriden, CT, USA) at a counting efficiency of approximately 20 %. The counting efficiency was determined in separate sets of experiments. Saturation experiments At least 6 concentrations in duplicates of radioligand (0.1-20 nM of [ 3 H] LSD) were used 30 in saturation experiments. The specific binding was calculated as the difference between total binding and non-specific binding, which was determined as the binding of radioligand WO 2004/000828 PCT/SE2003/001061 in the presence of 5 gM lisuride. Bmax and the dissociation constant, Kd, were determined from the non-linear regression analysis using equation 1. Lu is the unbound concentration of radioligand, and is y is the amount bound. Bmax. Lu = Lu + Kd (equation 1) 5 Competition experiments Total- and non-specific binding of radioligand was defined in eight replicates of each. Samples containing test compound were run in duplicate at 11 concentrations. Incubations were carried out at room temperature for 3 hours. The IC 50 value, i.e. the concentration of 10 test compound that inhibited 50% of the specific binding of radioligand, was determined with non linear regression analysis and the Ki value was calculated using the method of [Cheng Y.C. Biochem. Pharmacol. 22, 3099-3108, 1973S] equation 2. ICso Ki = L (equation 2) 1+- Kd L = concentration of radioligand 15 Kd= Affinity of radioligand (b) 5-HT 6 Intrinsic Activity Assay Antagonists to the 5-HT 6 receptor were characterized by measuring inhibition of 5-HT 20 induced increase in cAMP in HEK 293 cells expressing the human 5-HT 6 receptor (see Boess et al. (1997) Neuropharmacology 36: 713-720). Briefly, HEK293/5-HT 6 cells were seeded in polylysine coated 96-well plates at a density of 25,000 / well and grown in DMEM (Dulbecco's Modified Eagle Medium) (without phenol-red) containing 5% dialyzed Foetal Bovine Serum for 48 h at 37'C in a 5% CO 2 incubator. The medium was 25 then aspirated and replaced by 0.1 ml assay medium (Hanks Balance Salt Solution containing 20 mM HEPES, 1.5 mM isobutylmethylxanthine and 1 mg/ml bovine serum albumin). After addition of test substances, 50 pl dissolved in assay medium, the cells were incubated for 10 min at 37*C in a 5% CO 2 incubator. The medium was again aspirated and the cAMP content was determined using a radioactive cAMP kit (Amersham Pharmacia WO 2004/000828 PCT/SE2003/001061 Biotech, BIOTRAK RPA559). The potency of antagonists was quantified by determining the concentration that caused 50% inhibition of 5-HT (at [5-HT]= 8 times EC 5 o) evoked increase in cAMP, using the formula IC 5 o,cof=IC 5 o/(1+[5HT]/ECo). 5 The compounds in accordance with the invention have a selective affinity to 5-HT 6 receptors with Ki and ICo,cmr values between 0.5 nM and 5 piM or display a % inhibition of [ 3 H] LSD > 20 % at 50 nM and are antagonists, agonist or partial agonist at 5-HT 6 . The compounds show good selectivity over 5-HTia, 5-HT2a, 5-HT2a, 5-HT2b, 5-HT 2 c. 10 (c) In vivo assay of reduction offood intake For a review on serotonin and food intake, see Blundell, J.E. and Halford, J.C.G. (1998) Serotonin and Appetite Regulation. Implications for the Pharmacological Treatment of Obesity. CNS Drugs 9:473-495. 15 Obese (ob/ob) mouse is selected as the primary animal model for screening as this mutant mouse consumes high amounts of food resulting in a high signal to noise ratio. To further substantiate and compare efficacy data, the effect of the compounds on food consumption is also studied in wild type (C57BL/6J) mice. The amount of food consumed during 15 20 hours of infusion of compounds is recorded. Male mice (obese C57BL/6JBom-Lepob and lean wild-type C57B1/6JBom; Bomholtsgaard, Denmark) 8-9 weeks with an average body weight of 50 g (obese) and 25 g (lean) are used in all the studies. The animals are housed singly in cages at 23±1*C, 40 25 60 % humidity and have free access to water and standard laboratory chow. The 12/12-h light/dark cycle is set to lights off at 5 p.m. The animals are conditioned for at least one week before start of study. The test compounds are dissolved in solvents suitable for each specific compound such as 30 cyclodextrin, cyclodextrin/methane sulfonic acid, polyethylene glycol/methane sulfonic WO 2004/000828 PCT/SE2003/001061 acid, saline. Fresh solutions are made for each study. Doses of 30, 50 and 100 mg kg-day 1 are used. The purity of the test compounds is of analytical grade. The animals are weighed at the start of the study and randomized based on body weight. 5 Alzet osmotic minipumps (Model 2001D; infusion rate 8 Ll/h) are used and loaded essentially as recommended by the Alzet technical information manual (Alza Scientific Products, 1997; Theeuwes, F. and Yam, S.I. Ann. Biomed. Eng. 4(4). 343-353, 1976). Continuous subcutaneous infusion with 24 hours duration is used. The minipumps are either filled with different concentrations of test compounds dissolved in vehicle or with 10 only vehicle solution and maintained in vehicle pre-warmed to 37*C (approx. lh). The minipumps are implanted subcutaneously in the neck/back region under short acting anesthesia (metofane/enflurane). This surgical procedure lasts approximately 5 min. It takes about 3 h to reach steady state delivery of the compound. 15 The weight of the food pellets are measured at 5 p.m. and at 8 p. m. for two days before (baseline) and one day after the implantation of the osmotic minipumps. The weigh-in is performed with a computer assisted Mettler Toledo PR 5002 balance. Occasional spillage is corrected for. At the end of the study the animals are killed by neck dislocation and trunk blood sampled for later analysis of plasma drug concentrations. 20 The plasma sample proteins are precipitated with methanol, centrifuged and the supernatant is transferred to HPLC vials and injected into the liquid chromatography /mass spectrometric system. The mass spectrometer is set for electrospray positive ion mode and Multiple Reaction Monitoring. A linear regression analysis of the standards forced through 25 the origin is used to calculate the concentrations of the unknown samples. Food consumption for 15 hours is measured for the three consecutive days and the percentage of basal level values is derived for each animal from the day before and after treatment. The values are expressed as mean ± SD and ± SEM from eight animals per dose 30 group. Statistical evaluation is performed by Kruskal-Wallis one-way ANOVA using the percent basal values. If statistical significance is reached at the level of p<0.05, Mann- WO 2004/000828 PCT/SE2003/001061 Whitney U-test for statistical comparison between control and treatment groups is performed. The compounds according to the invention show an effect in the range of 5-200 mg/kg. 5 Table 7. Biological data In vitro binding at the human 5-HT 6 receptor EXAMPLE K, (nM) human 5-HT 6 1 10 11 6.5 20 10.5 40 7.5 43 4.5 68 13 85 32 131 5 10 In vivo efficacy data EXAMPLE % FI reduction* Css, u (uM) 1 12 0.44 11 47.1 0.02 40 44 0.2 *Effect on Food Intake reduction In Ob/ob mice Single administration 50 mg/kg/d measured at steady state

Claims

1. A compound of the formula (I): P I i XI Y 5 (I) or a pharmaceutically acceptable salt thereof, wherein: W D w ring B is W or ; in which D is a five-membered heterocyclic or 10 heteroaryl ring, said ring comprising one or two atoms selected from the group consisting of nitrogen, sulfur and oxygen, with the proviso that when D contains an oxygen atom,-D is heteroaryl; each W is independently -N-, -(CH)-, or -C- provided that not more than three groups W 15 are -N- in both rings A and B together; P is any one of formula (a), (b) or (c) R i iR SZO O -R2 S(O). 210 0~ V() R-N<' O~ ,or (a) (b) (c) wherein x = 0, 1, or 2 and y = 0, 1, or 2; WO 2004/000828 PCT/SE2003/001061 and P and R 3 can be attached to any carbon atom that allows the substitution in one of either the A- or B-ring, or when ring A contains at least one nitrogen atom and P is (c), then P can also be attached to any nitrogen in ring B that allows the substitution; 5 the dashed bonds denote that P and R 3 , respectively, may be attached to either the A or B ring; but each P or R 3 may not be simultaneously bound to both rings A and B; R, is 10 (a) C 1 - 6 alkyl, (b) C 1 - 6 alkoxyalkyl, (c) straight-chained or branched C1- 6 hydroxyalkyl, (d) straight-chained or branched C 1 - 6 alkylhalides, (e) aryl carbonylmethyl, 15 (f) C 3 - 7 cycloalkyl, which is optionally partially unsaturated, (g) C 3 .7 cycloalkyl-C 1 - 6 alkyl, wherein the cyclic ring is optionally partially unsaturated, or (h) a group Ar; wherein Ar is 20 (a) phenyl, (b) 1-naphthyl, (c) 2-naphthyl, (d) aryl-C 1 - 6 alkyl, (e) cinnamyl, 25 (f) a 5 to 7-membered, optionally aromatic, partially saturated or completely saturated, mono- or bi-cyclic heterocyclic ring, each containing 1 to 4 heteroatoms, selected from oxygen, sulfur, and nitrogen, (g) a bicyclic ring system comprising at least one heterocyclic ring according to (f) and a group Ar, 30 wherein the group Ar is substituted in one or more positions with (a) H, X or Y, or WO 2004/000828 PCT/SE2003/001061 (b) a 5 to 7-membered, optionally aromatic, partially saturated or completely saturated, heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; 5 R2 is (a) H, (b) C 1 - 6 alkyl, (c) C 2 - 6 alkoxyalkyl, (d) straight or branched C 1 - 6 hydroxyalkyl, or 10 (e) straight or branched C1.6 alkylhalides; (f) a group Ar, or R' and R 2 are linked to form a group -CH 2 CH 2 0CH 2 CH 2 - or N (CH2)v 15 wherein v is 0-2, X and Y are independently (a) H, (b) halogen, 20 (c) C 1 . 6 alkyl, (d) CF 3 , (e) hydroxy, (f) C 1 . 6 alkoxy, (g) C 2 .6 alkenyl, 25 (h) phenyl, (i) phenoxy, (j) benzyloxy, (k) benzoyl, (1) -OCF 3 , WO 2004/000828 PCT/SE2003/001061 (m) -CN, (n) straight or branched C 1 . 6 hydroxyalkyl, (o) straight or branched C 1 . 6 alkylhalides, (p) -NH 2 , 5 (q)--NHR 4 , (r) -NR 4 R 5 , (s) -NO 2 , (t) -CONReR, (u) -NHSO 2 R 4 , 10 (v) -NR 4 COR 5 , (x) -SO 2 NR 4 R 5 , (z) -C(=O)R 4 , (aa) -C0 2 R 4 , or (ab) -S(O)nR 4 , wherein n is 0, 1, 2 or 3, 15 (ac) -S-(C1.6) alkyl, or (ad) -SCF 3 ; and R 4 and R are independently (a) H, 20 (b) C 1 . 6 alkyl, (c) C 3 -7 cycloalkyl, or (d) Ar, as defined above for R1; alternatively, R 4 and Rs are linked to form a group -CH 2 0CH 2 -, -CH 2 CH 2 0CH 2 CH 2 - or (CH 2 ) 3-; 25 R 3 is a group selected from any one of WO 2004/000828 PCT/SE2003/001061 NR NN N O N-R Rq- RR N N N N R R N R4m R nR Rq R R RR R SNn N N-R 6 R161 '61 RqR R R R o wi RI n t oq r i n Im Rq om N N 6 R6 R6/ 6 5 wherei R 1, 2,6, ,R oR6 N N N and N Rq 4 m N Rq-SP Rq ~ 1~M n6 = 0,1or2 wherein R 3 is optionally substituted on each carbon atom that allows the substitution with Rq groups, wherein Rq is independently H, or (C 1 6 ) alkyl, and wherein two Rq groups can be present on the same carbon atom simultaneously, 5 wherein q =1, 2, 3, 4, 5 or 6, m = 1or 2,and n=O, 1 or2; 10 R 6 is independently (a) H, (b) linear or branched C1. 6 alkyl, (c) benzyl, (d) -CH 2 -CH 2 -OH, or WO 2004/000828 PCT/SE2003/001061 (e) -CH 2 -CH 2 -0-C 1 - 6 alkyl; P and R3 can be attached to the same ring or to different rings of rings A and B; 5 provided that R 1 R2-Ng/ .-_N R - ~ NISzo when P is (a) or (b), and P and RW both are attached to ring A in the meta- or para-position relative to one another then R3 is selected from any one of 1 00 Rq ]mM IM R N N RN Im 16 N 16 RR 16 R R N-R N-R RqRqm Rm Rq Rq R6 R R RY R Rq~~ ~ NNmR Ir N N Rq~~I 6'q m R R6 R~ 10 when ring B is w , and P is (a), then P and R3 are simultaneously attached to the same ring A or B; WO 2004/000828 PCT/SE2003/001061 R KW> Y S(0)" when ring B is w , and Pis ,wherein y = 0, then P and R 3 are attached to the different rings of rings A and B; when the ring system A + B is benzofurane or benzothiophene, and P is R S(O), Y 5 ' (c) and attached to position 3 in the A+B ring system, and R3 is a group selected from any one of N N N '6 R and attached to position 7 in the A+B ring system, then y 1 or 2; 10 when the ring system A + B is indole, and P is R S(O)" (c) and P is attached to position 3 in the A+B ring system, and R 3 is a group selected from any one of N N N Rq Rq Rq and N N N N 16 ~ 6 16 15 R R R and R 3 is attached to any one of positions 5, 6 or 7 in the A+B ring system, then y 1 or 2; or WO 2004/000828 PCT/SE2003/001061 when ring B is W and R1 = Ar is partially saturated bi-cyclic heterocyclic ring containing a N atom, the N atom in Ar cannot be attached to the S atom in P; with the proviso that: when rings A and B are both phenyl, P is any one of formula (a) or (c) substituted in 5 position 7 on the naphthalene ring, then R 3 is not substituted in position 1 on the naphthalene ring; and with the proviso that: when ring D is a pyrrole ring, P is of the formula (c), then R 3 is not of the formula N N Rq ) Rq or Rq N N N N 6 16 16 R m R R 10 substituted in position 3 on the pyrrole ring.

2. The compound according to claim 1, wherein R 1 is 15 (a) C 1 - 6 alkyl, or (e) a group Ar; Ar is (a) phenyl, 20 (b) 1-naphthyl, (c) 2-naphthyl, or (f) a 5 to 7-membered, optionally aromatic, partially saturated or completely saturated, heterocyclic ring containing I to 4 heteroatoms, selected from oxygen, nitrogen and sulfur, wherein the group Ar is substituted in one or more positions with 25 (a) H, WO 2004/000828 PCT/SE2003/001061 (b) halogen, (c) C 1 - 6 alkyl, (d) -CF 3 , (f) C1.6 alkoxy, 5 (g) C 2 - 6 alkenyl, (1) -OCF 3 , (rn) straight or branched C 1 . 6 hydroxyalkyl, (n) phenyloxy, (o) benzyloxy, 10 (v) -NR 4 CORs, (x) -SO 2 NR 4 R 5 , (z) -C(=O)R 4 , (ab) -S(O)nR 4 , wherein n is 0, 1, 2 or 3; (ac) -S-(C 1 . 6 ) alkyl, or 15 (ad) -SCF 3 ; R 2 is (a) H, or (b) C1- 6 alkyl; 20 or R' and R 2 are linked to form a group -CH 2 CH 2 0CH 2 CH 2 -; X and Y are H; 25 R 4 and R are each independently H or C 1 . 3 alkyl; and R 3 is selected from any one of N Rq Rq Rq NRIm N N R R I R WO 2004/000828 PCT/SE2003/001061 0 O ~ -0-04 Rq 1n R n R m N-R im N N 6N 6 6 r R and '6 R6 R R R wherein R 3 can be substituted on each carbon atom that allows the substitution with Rq groups, wherein Rq is independently H, or C 1 . 6 alkyl, and wherein two Rq groups can be present on the same carbon atom simultaneously, wherein 5 q= 1 or2, m= 1 or 2, n = 0, and R 6 is independently (a) H, 10 (b) C1- 6 alkyl, in particular methyl, (d) -CH 2 -CH 2 -OH, or (e) -CH 2 -CH 2 -OCH 3 .

3. The compound according to claims 1 or 2 wherein R 3 is selected from any one of N0 Rq Rq Rq N~m N N N6N I Ie I and N, 15R R R R wherein R 3 can be substituted on each carbon atom that allows the substitution with Rq groups, wherein Rq is independently H, or C 1 .. 2 alkyl, and wherein two Rq groups can be present on the same carbon atom simultaneously, wherein q= 1 or 2, 20 m = I or 2; and R 6 is independently (a) H, (b) C-3 alkyl, (d -CH2-CH2-OH, or WO 2004/000828 PCT/SE2003/001061 (e) -CH 2 -CH 2 -OCH 3 .

4. The compound according to claim 1 or 2 wherein R 3 is selected from any one of R R m N-R Im N Rq" RI-N "i n Rq R 1 6 Nf 1 1 1 R and 6 R6 R R R 5 wherein R 3 can be substituted on each carbon atom that allows the substitution with Rq groups, wherein Rq is independently H, or C 1 .6 alkyl, and wherein two Rq groups can be present on the same carbon atom simultaneously, wherein q= 1 or 2, m = 1 or 2, 10 n = 0, and R 6 is independently (a) H, (b) C 1 .. 3 alkyl, (d) -CH 2 -CH 2 -OH, or 15 (e) -CH 2 -CH 2 -OCH 3 .

5. The compound according to claim 1 or 2 wherein R 3 is selected from any one of N N N N N~r NN)" (N N) (N I I 16 R R R R R 16 N NN N N ND N N 6 16 6/ 61 R 6 R R R 20 R6 is independently WO 2004/000828 PCT/SE2003/001061 (a) H, (b) C 1 3 alkyl, (d) -CH 2 -CH 2 -OH, or (e) -CH 2 -CH 2 -OCH 3 . 5

6. A compound according to any one of claims 1 to 5 wherein R6 is H or methyl.

7. A compound according to claim 1 or 2 wherein R 3 is piperazine; homopiperazine; 2,6-dimethylpiperazine; 3,5-dimethylpiperazine; 2,5-dimethylpiperazine; 10 2-methylpiperazine; 3-methylpiperazine; 2,2-dimethylpiperazine; 3,3-dimethylpiperazine; piperidine; 1,2,3,6-tetrahydro-pyrazine; or 4-pyrrolidin-3-yloxy.

8. The compound according to any one of claims 1 to 7 wherein the groups Y and X are attached to any unsubstituted carbon atom. 15

9. The compound according to any one of claims 1 to 8, wherein D is pyrrolyl, thienyl or furanyl.

10. The compound according to any one of claims 1 to 9, wherein P is RI S(O), 1 20 ' (c) wherein R , x, and y are as defined in claim 1.

11. The compound according to any one of claims 1 to 9, wherein P is R ~R 1 1 -2 LO N-R 0 01 R-N 1, y (a) or (b) 25 wherein R' and R 2 are as defined in claim 1. WO 2004/000828 PCT/SE2003/001061

12. The compound according to claim 11, wherein R 2 is H.

13. The compound according to claim 10 of the general formula (II) RI Y x N (1) 5 wherein R 1 , x, y, X, and Y are as defined in claim 1, and R 3 is as defined in claim 2.

14. The compound according to claim 13 wherein y =0 and x = 2

15. The compound according to claim 10 of the general formula (III) R\ S(O)X [ N N Y X 10 R 3 (11) wherein R 1 , x, y, X, and Y are as defined in claim 1, and R3 is as defined in claim 2.

16. The compound according to claim 15 wherein y = 0 and x = 2 15

17. The compound according to claim 10 of the general formula (IV) x N~D y R P(IV) wherein P is of the formula (c), R , x, y, X, and Y are as defined in claim 1, and R3 is as defined in claim 2, and wherein D is a five-membered heteroaryl ring, said ring comprising one or two atoms 20 selected from the group consisting of nitrogen, sulfur and oxygen; and when the heteroaryl ring comprises one or two nitrogen atoms, a group R6 is attached at any nitrogen atom which allows the substitution WO 2004/000828 PCT/SE2003/001061

18. The compound according to claim 17 wherein D is a thiophene and P is attached to the D ring. 5

19. The compound according to claim 17 wherein D is pyrrole and P is attached to the nitrogen atom in the D ring.

20. The compound according to claim 17 wherein D is furan and P is attached to the D ring. 10

21. The compound according to claim 10 of the general formula (V) P X DY R (V) wherein P is of the formula (c) as defined in claim 1, R', x, y, X, Y, and R 3 are as defined in claim 1, and 15 wherein D is a five-membered heteroaryl ring, said heteroaryl ring comprising one or two atoms selected from the group consisting of nitrogen, sulfur and oxygen; and when the heteroaryl ring comprises one or two nitrogen atoms, a group R 6 is attached at any nitrogen atom which allows the substitution. 20

22. The compound according to claim 11 or 12 of the general formula (V) P X DY R (V) wherein P is of the formula (a) or (b) as defined in claim 1, preferably wherein R2 is H, X, Y, and R3 are as defined in claim 1, and wherein D is a five-membered heteroaryl ring, said heteroaryl ring comprising one or two 25 atoms selected from the group consisting of nitrogen, sulfur and oxygen; and when the heteroaryl ring comprises one or two nitrogen atoms, a group R 6 is attached at any nitrogen atom which allows the substitution. WO 2004/000828 PCT/SE2003/001061

23. The compound according to any one of claims 11 and 12 of the general formula (VI) RaY X (Vi) wherein P is of the formula (a) or (b) as defined in claim 1, preferably wherein R 2 is H, X 5 and Y are as defined in claim 1, and R 3 is as defined in claim 2.

24. The compound according to any one of claims 11 and 12 of the general formula (VII) R 3 C Y x (VII) wherein P is of the formula (a) or (b) as defined in claim 1, preferably wherein R 2 is H, X 10 and Y are as defined in claim 1, and R 3 is as defined in claim 4.

25. The compound according to any one of claims 11 and 12 of the general formula (VIII) N 3 N 4 P R 10:Sy X (VIII) wherein P is of the formula (a) or (b) as defined in claim 1, preferably wherein R 2 is H, X, 15 Y, and R 3 are as defined in claim 1.

26. The compound according to any one of claims 11 and 12 of the general formula (IX) R3 X W(IX) wherein R 7 in formula (IX) is: 20 (a) H, (b) C 1 . 6 alkyl, (c) benzyl, (d) -CH 2 -CH 2 -OH, or (e) CH 2 -CH 2 -O-CH 3 , and WO 2004/000828 PCT/SE2003/001061 wherein P is of the formula (a) or (b) as defined in claim 1, preferably wherein R 2 is H, X, Y, and R 3 are as defined in claim 1.

27. The compound according to claim 10 of the general formula (X) 5 3 N R x P (X) wherein P is of the formula (a) or (b) as defined in claim 1, preferably wherein R 2 is H, X, Y, and R 3 are as defined in claim 1. 10

28. The compound according to claim 12 of the general formula (XI) P Y x (XI) wherein P is of the formula (a) or (b) as defined in claim 1, preferably wherein R2 is H, X 15 and Y are as defined in claim 1, and R3 is as defined in claim 4.

29. A compound according to any one of claims 1 to 12 of the general formula (XII): P W Y-H WM R 3 (XII) or a pharmaceutically acceptable salt thereof, wherein P and R3 are attached to the same 20 ring or to different rings of rings A and B, wherein A, B, Y, P, and R 3 are as defined in claim 1. WO 2004/000828 PCT/SE2003/001061

30. The compound according to claim 13, which is the compound 6 -Benzenesulfonyl-4-piperazin-1-yl-quinoline hydrochloride; 6 -[( 2 -Fluorophenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride; 5 6-(1-Naphthylsulfonyl)-4-piperazin-1-ylquinoline hydrochloride; 6-[(3,4-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride; 6-[(3,5-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride; 6 -[(2-Chloro-6-methylphenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride; 6-[(4-Chlorophenyl)sulfony]-4-piperazin-1-ylquinoline hydrochloride; 10 6-[(2-Methyl,4-tert-butyl-phenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride; 6-[(3, 4 -Dimethylphenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride; 6 -[(2,3-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride; 6 -[( 4 -tert-Butylphenyl)sulfonyl]-4-piperazin-1-ylquinoline hydrochloride; 6 -[( 4 -Isopropylphenyl)sulfony]-4-piperazin-1-ylquinoline hydrochloride; 15 (4-Piperazin- 1 -yl-6-{[4-(trifluoromethyl)phenyl] sulfonyl} quinoline hydrochloride; 6-[(4-tert-Butylphenyl)sulfonyl]-4-(1,4-diazepan- 1 -yl)quinoline hydrochloride; or 4-(1,4-Diazepan- 1 -yl)- 6 -[(4-isopropylphenyl)sulfonyl]quinoline hydrochloride.

31. The compound according to claim 15, which is the compound 20 7 -( 2 -Chloro-6-methyl-benzenesulfonyl)- 1-piperazin- 1 -yl-isoquinoline hydrochloride; 7-(2-t-Butyl-benzenesulfonyl)-1-piperazin-1-yl-isoquinoline hydrochloride; 7-(3,4-Dichloro-benzenesulfonyl)-1-piperazin-1-yl-isoquinoline hydrochloride; 7-(2,4-Dimethyl-benzenesulfony)- 1 -piperazin- 1 -yl-isoquinoline hydrochloride; 7-(2,5-Dimethyl-benzenesulfonyl)- 1 -piperazin- 1 -yl-isoquinoline hydrochloride; 25 7-(p-Chloro-benzenesulfonyl)-1-piperazin-1-yl-isoquinoline hydrochloride; 7-Benzenesulfonyl-1-[1,4]diazepan-1-yl-isoquinoline,hydrochloride; 7-(4-tert-Butyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline, hydrochloride; 7-(2-Chloro-6-methyl-benzenesulfony)-1-[1,4]diazepan-1-yl]-isoquinoline hydrochloride; 7-(3,5-Dimethyl-benzenesulfonyl)-I-[1,4]diazepan-1-yl]-isoquinoline hydrochloride; 30 7-(3,4-Dichloro-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline hydrochloride; 7-(4-Chloro-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline hydrochloride; 7-(3,4-Dimethyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline hydrochloride; WO 2004/000828 PCT/SE2003/001061 7-(2-tert-Butyl-benzenesulfonyl)-1-[1,4]diazepan-1-yl]-isoquinoline hydrochloride; 7-Benzenesulfonyl-1 -piperazin-yl-isoquinoline hydrochloride; or 7-(4-tert-Butyl-benzenesulfonyl-1-piperazin-yl-isoquinoline hydrochloride 5

32. The compound according to claim 17, which is the compound 4-(1,4-Diazepan- 1 -yl)-2-(phenylsulfonyl)thieno[3,2-c]pyridine hydrochloride; 4-(1,4-Diazepan-1 -yl)-2-[(3,4-dichlorophenyl)sulfonyllthieno[3,2-c]pyridine hydrochloride; 4-(1,4-Diazepan-1-yl)-2-[4-tert-butylphenylsulfonyl)thieno[3,2-clpyridine hydrochloride; 10 4-(1,4-Diazepan- 1 -y)-2-[4-tert-butylphenylsulfonyl)thieno[3,2-cpyridine hydrochloride; 4-(1,4-Diazepan-1-yl)-2-[3,4-dimethylphenylsulfonyl)tbieno[3,2-c]pyridine hydrochloride; 2-[(4-Bromophenyl)sulfonyl]-4-(1,4-diazcpan-1-yl)thieno[3,2-c]pyridine hydrochloride; 2-(Phenylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-(3-Methoxy-benzenesulfonyl)-4-piperazin-1 -yl-thieno,[3,2-c]pyridine hydrochloride; 15 2-(4-Methoxy-benzenesulfonyl)-4-piperazin-1-yl-thieno[3,2-c]pyridine hydrochloride; 4-Piperazin-1-yl- 2 -{[4-trifluoromethyl)phenyl]sulfonyl}thieno[3,2-c]pyridine hydrochloride; 2-[[2-tert-Butylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-{(3,4-Dichlorophenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide 20 hydrochloride; 2-[(4-tert-Butylpheny1)sulfony1]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-(1-Naphthyl sulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-[(3-Fluorophenyl)sulfonyl]-4-piperazin-1-yltbieno[3,2-c]pyridine-2-sulfonamide hydrochloride; 25 2-(Mesitylsulfonyl)-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-[(2-Methoxyphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-[(2,4-Dimethoxyphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-[(2,4-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-[(2,5-Dimethylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 30 2-[(2-Ethylphenyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-cjpyridine hydrochloride; 4-(Piperaziny1)-2-(3-methoxybenzyl-sulfonyl)-thienopyridine hydrochloride; 2-(Benzylsulfonyl)-4-piperazin-1-ylthieno[3,2-clpyridine hydrochloride; WO 2004/000828 PCT/SE2003/001061 4-Piperazin-1-yl-2-{[4-(trifluoromethyl)benzyl]sulfonyl}thieno[3,2-c]pyridine hydrochloride; 2-[(3-Bromobenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-[(2,3-Difluorobenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 5 2-[(4-Bronobenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-{[2,5-bis(Trifluoromethyl)benzyl]sulfony}-4-piperazin-1-yltbieno[3,2-c]pyridine hydrochloride; 2-[(4-Methylbenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 2-{[5-Chloro-2-(trifluoromethyl)benzyl]sulfonyl}-4-piperazin-1-ylthieno[3,2-c]pyridine 10 hydrochloride; 2-[(3,5-Dimethoxybenzyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-cpyridine hydrochloride; 2-[(2-Naphthylmethyl)sulfonyl]-4-piperazin-1-ylthieno[3,2-c]pyridine hydrochloride; 4-Piperazin-1-yl-2-{[4-(1,2,3-thiadiazol-4-yl)benzyl]sulfonyl}thieno[3,2-c]pyridine hydrochloride; 15 1-(4-Pyrrolidin-1-ylphenyl)-2-[(4-piperazine-1-ylthieno[3,2-c]pyridin-2-yl) sulfonyl] ethanone hydrochloride; or 1-[4-(Diethylamino)phenyl]-2-[(4-piperazinc-1-ylthieno[3,2-c]pyridin-2-yl) sulfonyl] ethanone hydrochloride. 20

33. The compound according to claim 17, which is the compound: 1-(4-Methylphenylsulphonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine hydrochloride; 1-(3-Chloro-2-methylphenylsulphony)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine hydrochloride; 1-(3,4-Dimethoxyphenylsulphonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine 25 hydrochloride; 4-(4-Piperazin- 1 -yl-pyrrolo[3,2-c]pyridine- 1 -sulfonyl)-benzonitrile hydrochloride; 1-(4,5-Dichloro-thiophene-2-sulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine hydrochloride; 1-(2-Chloro-4-fluorophenylsulphony)-4-piperazin-1-yl-IH-pyrrolo[3,2-c]pyridine 30 hydrochloride; 1-Phenylmethanesulfonyl-4-piperazin-1-yl-1H-pyrrolo [3,2-c]pyridine hydrochloride; WO 2004/000828 PCT/SE2003/001061 1-(5-Chloro-thiophene-2-sulfony)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine hydrochloride; 1-(4-Butyl-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo(3,2-c)pyridine hydrochloride; 1-(4-Phenoxy-benzenesulfonyl)-4-piperazin-1-yl-1H-pyrrolo(3,2-c)pyridine hydrochloride; 5 1-(Phenylsulfonyl)-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine hydrochloride; 1-[(4-Chlorophenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine hydrochloride; 1-[(4-Methoxyphenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine hydrochloride; 1-[(2-Methoxy-5-methylphenyl)sulfonyl]-4-piperazin-1-yl-1H-pyrrolo[3,2-c]pyridine hydrochloride; or 10 4-Piperazin-1-yl-l-{[2-(trifluoromethyl)phenyl]sulfony}-1H-pyrrolo[3,2-c]pyridine hydrochloride.

34. The compound according to claim 23, which is the compound N-(4-Methylphenyl)-4-(4-methylpiperazin-1-yl)thieno[3,2-c]pyridine-2-sulfonamide 15 hydrochloride; 2-Bromo-4-(4-methyl-piperazin- 1 -yl)-thieno[3,2-c]pyridine-3-sulfonic acid p-tolylamide hydrochloride; 1 4-(4-Methylpiperazin-1-yl)-n-phenylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (3-fluoro-5-trifluoromethyl-phenyl) 20 amide hydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (4-chloro-phenyl)-amide hydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (4-isopropyl-phenyl)-amide hydrochloride; 25 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid p-tolylamide hydrochloride; 4-(4-Methylpiperazin-1-yl)-N- (2-cyclohex-1-en-1-ylcthyl) thieno [3,2-c] pyridine-2 sulfonamide hydrochloride; 2-(4-(4-Methylpiperazin-1-yl) thieno [3,2-c] pyridin-2-ylsulfonyl)-1,2,3,4 tetrahydroisoquinoline hydrochloride; 30 4-(4-Methylpiperazin-1-yl)-N- (2-thien-2-ylethyl) thieno [3,2-c] pyridine-2-sulfonamide hydrochloride; WO 2004/000828 PCT/SE2003/001061 4-(4-Methylpiperazin-1-yl)-N- [1-(1-naphthyl) ethyl] thieno [3,2-c] pyridine-2-sulfonamide hydrochloride; 4-(4-Methylpiperazin-1-yl)-N- (4-hexylphenyl) thieno [3,2-c] pyridine-2-sulfonamide hydrochloride; 5 N- (3-Chlorobenzyl)-4-(4-methylpiperazin-1-yl) thieno [3,2-c] pyridine-2-sulfonamide; 4-(4-Methylpiperazin-1-yl)-N- [1-(4-fluorophenyl) ethyl] thieno [3,2-c] pyridine-2 sulfonamide hydrochloride; N- (2,3-Difluorobenzyl)-4-(4-methylpiperazin-1-yl) thieno [3,2-c] pyridine-2-sulfonamide hydrochloride; 10 4-(4-Methylpiperazin- 1 -yl)-N- (4-chloro-2, 5-dimethoxyphenyl) thieno [3,2-c] pyridine-2 sulfonamide hydrochloride; 2-Bromo-4- (4-methylpiperazin-1-yl)-N- (2-cyclohex-l-en-1-ylethyl) thieno [3,2-c] pyridine-3-sulfonamide hydrochloride; 2-Bromo-4- (4-methylpiperazin-1-yl)-N- [(1S)-1-(2-naphthyl) ethyl] thieno [3,2-c] 15 pyridine-3-sulfonamide hydrochloride; 2-Bromo-4- (4-methylpiperazin-1-yl)-N- [1-(4-fluorophenyl) ethyl] thieno [3,2-c] pyridine 3-sulfonamide hydrochloride; 2-Bromo-4- (4-methylpiperazin-1-yl)-N- (2,4,5-trimethoxyphenyl) thieno [3,2-c] pyridine 3-sulfonamide; 20 N-(3,4-Dichlorophenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride; N-(2,4-Difluorophenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride; 4-Piperazin-1-yl-N-[-3-(trifluoromethy)phenyl]thieno[3,2-c]pyridine-2-sulfonamide 25 hydrochloride; N-(3-Ethylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride; N-(3,4-Dimethoxyphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride; N-(4-Bromo-2-methylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide 30 hydrochloride; 2-(4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride; WO 2004/000828 PCT/SE2003/001061 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (2-thiophen-2-yl-ethyl)-amide hydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (4-chloro-2,5-dimethoxy-phenyl) amide hydrochloride; 5 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid phenethyl-amide hydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (2,6-diethyl-phenyl)-amide hydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (3-phenyl-propyl)-anide hydrochloride; 10 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (3,3-diphenyl-propyl)-amide hydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid [2-(5-methoxy-1H-indol-3-yl) ethyl]-amide hydrochloride; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid 4-trifluoromethyl-benzylamide 15 hydrochloride; 4-Piperazin- I -yl-thieno [3,2-c]pyridine-2-sulfonic acid benzyl-ethyl-amide hydrochloride; N-(3-Ethylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-3-sulfonamide hydrochloride; N-(4-Isopropylphenyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-3-sulfonamide hydrochloride; 20 N-(4-Methylphenyl)-4-(pyrrolidin-3-yloxy)thieno[3,2-c]pyridine-2-sulfonamide hydrochloride; N-(4-Methylphenyl)-4-(piperidin-4-yloxy)thieno[3,2-c]pyridine-2-sulfonamide hydrochloride; N-(2,3-Difluorobenzyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide 25 hydrochloride; N-(3-Chlorobenzyl)-4-piperazin-1-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride; 4-Piperazin- 1 -yl-thieno[3,2-c]pyridine-2-sulfonic acid phenylamide hydrochloride; 4-Piperazin-1-yl-thieno[3,2-cjpyridine-2-sulfonic acid (4-tert-butyl-phenyl)-amide hydrochloride; 30 4-(4-Methyl-piperazin- 1-yl)-thieno[3,2-c]pyridine-2-sulfonic acid phenylamide hydrochloride; WO 2004/000828 PCT/SE2003/001061 4-(4-Methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-2-sulfonic acid (3-chloro-phenyl)-amide hydrochloride; 2-Bromo-4-(4-methyl-piperazin-1 -yl)-thieno[3,2-c]pyridine-3 -sulfonic acid phenylamide hydrochloride; 5 4-(4-Methyl-piperazin-1-yl)-thieno[3,2-c]pyridine-3-sulfonic acid (4-methylphenyl)-amide hydrochloride; or N-Phenyl-7-piperazin-1-ylthieno[2,3-c]pyridine-2-sulfonamide hydrochloride.

35. A compound according to claim 24, which is the compound 10 N-(4-methylphenyl)-4-piperazin-1-ylfuro[3,2-c]pyridine-2-sulfonamide hydrochloride; N-phenyl-4-piperazin-1-ylfuro[3,2-c]pyridine-2-sulfonamide hydrochloride; or N-phenyl-7-piperazin-1-ylfuro[2,3-c]pyridine-2-sulfonamide hydrochloride.

36. A compound according to claim 25, which is the compound 15 4-Piperazin- 1 -yl-thiazolo[4,5-c]pyridine-2-sulfonic acid phenylamide hydrochloride.

37. A compound according to claim 26, which is the compound N-(4-methylphenyl)-4-piperazin-1-yl-H-pyrrolo[3,2-c]pyridine-2-sulfonamide hydrochloride; 20 N-phenyl-4-piperazin-1-yl- 1H-pyrrolo[3,2-c]pyridine-2-sulfonamide hydrochloride; or N-phenyl-7-piperazin-1-yl-1H-pyrrolo[2,3-c]pyridine-2-sulfonamide hydrochloride.

38. A compound according to claim 27, which is the compound 4-Chloro-N-[4-(pyrrolidin-3-yloxy)-1-naphthyl]benzenesulfonanide hydrochloride; 25 4-Methoxy-N-[4-(pyrrolidin-3-yloxy)-l-naphthyl]benzenesulfonamide hydrochloride; 5-Chloro-N-[4-(pyrrolidin-3-yloxy)-1-naphthyl]thiophene-2-sulfonamide hydrochloride; 4-Chloro-N-[4-(piperidin-3-yloxy)- 1 -naphthyl]benzenesulfonamide hydrochloride; 4-Methoxy-N-[4-(piperidin-3-yloxy)-l-naphthyl]benzenesulfonamide hydrochloride; 5-Fluoro-2-methyl-N-[4-(piperidin-4-yloxy)-1-naphthyl]benzenesulfonamide 30 hydrochloride; 5-Chloro-N-[4-(piperidin-4-yloxy)-1-naphthyl]thiophene-2-sulfonamide hydrochloride; WO 2004/000828 PCT/SE2003/001061 4-Chloro-N-{4-[(3S)-pyrrolidin-3-yloxy]-1-naphthyl}benzenesulfonaniide hydrochloride; or 4-Chloro-N-{4-[(3R)-pyrrolidin-3-yloxy]-1-naphthyl}benzenesulfonamide hydrochloride. 5

39. A process for the preparation of a compound according to any one of claims 1 to 38, said method comprising the steps of: (a) Mitsonobu reaction of 4-nitro-1 -naphthol with boc-protected 3-hydroxypyrrolidine or 4-hydroxypiperidine; (b) reduction of the nitro group in the nitronaphthalene obtained in step (a) to form an 10 aminonaphthalene derivative; and (c) synthesis of a sulfonamide by reacting the aminonaphthalene obtained in step (b) with a suitable sulfonyl chloride.

40. A process for the preparation of a compound according to claim 10, wherein P is R4 09 15 , said method comprising the steps of: preparation of the heteroaromatic 5-member ring fused halogen-substituted pyridine, reduction of an aromatic nitro group; aromatic nucleophilic substitution with a thiol via a diazointermediate; oxidation of the thiol derivative to a sulphone; introduction of a halogen atom by electrophilic aromatic substitution; aromatic nucleophilic substitution of the 20 halogen with a diamine.

41. A process for the preparation of a compound according to claim 11, wherein P is RI N-R , said method comprising the steps of: preparation of the heteroaromatic 5 member ring fused pyridine; introduction of a carboxylic moiety; conversion of the 25 carboxylic moiety to amine by Curtius rearrangement; reaction of the amine group with a sulphonylchloride. WO 2004/000828 PCT/SE2003/001061

42. A process for the preparation of a compound according to claim 11, wherein P is R:N-RN , said method comprising the steps of: preparation of the heteroaromatic 5 member ring fused pyridine; introduction of sulfonylchloride moiety by nucleophilic addition; reaction of sulphonyichloride moiety with an aniline to obtained a sulfonamide; 5 aromatic nucleophilic substitution of the chloro with a diamine.

43. A compound according to any one of claims 1 to 38 for use in therapy.

44. A compound according to any one of claims 1 to 38, and for the case when rings A and 10 B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R3 is substituted in position 1 on the naphthalene ring, for use in the treatment or prophylaxis of a 5-HT 6 receptor related disorder, such as obesity, type II diabetes, and/or disorders of the central nervous system, to achieve reduction of body weight and of body weight gain. 15

45. A compound according to any one of claims 1 to 38 for use in the treatment or prophylaxis of disorders of the central nervous system.

46. A compound according to any one of claims 1 to 38, for the case when rings A and B 20 are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and RW is substituted in position 1 on the naphthalene ring, and for the case when ring D is a pyrrole ring, P is of the formula (c) and R2 is of the formula N N Rq 1m Rq or Rq N N N N 6 6 6 RmM R R6 WO 2004/000828 PCT/SE2003/001061 substituted in position 3 on the pyrrole ring, for use in the treatment or prophylaxis of type II diabetes. 5

47. A compound according to any one of claims I to 38, and for the case when ring D is a pyrrole ring, P is of the formula (c) and R3 is of the formula N N Rq Rq or Rq N N N N 6 6 16 Re m R6 R 10 substituted in position 3 on the pyrrole ring, for use in the treatment or prophylaxis of obesity, to achieve reduction of body weight and of body weight gain.

48. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 38 as an active ingredient, in combination with a pharmaceutically acceptable diluent 15 or carrier.

49. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 38, and for the case when rings A and B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R 3 is substituted in position 1 on 20 the naphthalene ring, as an active ingredient, for use in the treatment or prophylaxis of a 5 HT 6 receptor related disorder, such as obesity, type II diabetes, and/or disorders of the central nervous system, to achieve reduction of body weight and of body weight gain.

50. A pharmaceutical formulation comprising a compound according to any one of claims 25 1 to 38 as an active ingredient, for use in the treatment or prophylaxis of disorders of the central nervous system. WO 2004/000828 PCT/SE2003/001061

51. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 38, for the case when rings A and B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R 3 is substituted in position I on the naphthalene ring, and for the case when ring D is a pyrrole ring, P is of the formula (c) and 5 R 3 is of the formula N N Rq Rq or Rq N N N N 6 6 16 R m 1R R substituted in position 3 on the pyrrole ring, as an active ingredient, for use in the treatment 10 or prophylaxis of type II diabetes.

52. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 38, and for the case when ring D is a pyrrole ring, P is of the formula (c) and R 3 is of the formula 15 N N Rq Rq or Rq N N N N 16 16 1R R m R 6 substituted in position 3 on the pyrrole ring, as an active ingredient, for use in the treatment or prophylaxis of obesity, to achieve reduction of body weight and of body weight gain. 20

53. A method for the treatment or prophylaxis of a 5-HT 6 receptor related disorder, such as obesity, type II diabetes, and/or disorders of the central nervous system, to achieve WO 2004/000828 PCT/SE2003/001061 reduction of body weight and of body weight gain, which comprises administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 38, and for the case when rings A and B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R 3 is substituted in 5 position I on the naphthalene ring.

54. A method for the treatment or prophylaxis of disorders of the central nervous system, which comprises administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 38. 10

55. A method for the treatment or prophylaxis of type II diabetes, which comprises administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 38, for the case when rings A and B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R 3 is 15 substituted in position 1 on the naphthalene ring, and for the case when ring D is a pyrrole ring, P is of the formula (c) and R 3 is of the formula N N R Rq or Rq N N N N 16 6 6 R m 6 R 20 substituted in position 3 on the pyrrole ring.

56. A method for the treatment or prophylaxis of obesity and to achieve reduction of body weight and of body weight gain, which comprises administering to a subject in need of such treatment an effective amound of a compound according to any one of claims 1 to 38, 25 and for the case when ring D is a pyrrole ring, P is of the formula (c) and R 3 is of the formula WO 2004/000828 PCT/SE2003/001061 N N R] Rq or Rq N N N N 1 6 16 RS m substituted in position 3 on the pyrrole ring. 5

57. A method for modulating 5-HT 6 receptor activity, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-38.

58. Use of a compound according to any one of claims 1 to 38, and for the case when rings 10 A and B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R 3 is substituted in position 1 on the naphthalene ring, for the manufacture of a medicament for use in the treatment or prophylaxis of a 5-HT 6 receptor related disorder, such as obesity, type II diabetes, and/or disorders of the central nervous system, to achieve reduction of body weight and of body weight gain. 15

59. Use of a compound according to any one of claims 1 to 38 for the manufacture of a medicament for use in the treatment or prophylaxis of disorders of the central nervous system. 20

60. Use of a compound according to any one of claims I to 38, for the case when rings A and B are both phenyl, P is any one of formula (a) or (c) substituted in position 7 on the naphthalene ring, and R 3 is substituted in position 1 on the naphthalene ring, and for the case when ring D is a pyrrole ring, P is of the formula (c) and R 3 is of the formula WO 2004/000828 PCT/SE2003/001061 N N Rqm Rq or Rq N N N N 6 16 16 substituted in position 3 on the pyrrole ring, for the manufacture of a medicament for use in the treatment or prophylaxis of type II diabetes. 5

61. Use of a compound according to any one of claims I to 38, and for the case when ring D is a pyrrole ring, P is of the formula (c) and R 3 is of the formula N N Rq ]m ) Rq or Rq N N N N 6 16 16 10 substituted in position 3 on the pyrrole ring, for the manufacture of a medicament for use in the treatment or prophylaxis of obesity, to achieve reduction of body weight and of body weight gain. WO 2004/000828 PCT/SE2003/001061 INTERNATIONAL SEARCH REPORT International application No. PCT/SE 03/01061 A. CLASSIFICATION OF SUBJECT MATTER C07D 401/04, 495/04, 405/04, 471/04. 493/04, 513/04, 207/12, 211/40, I PC7: A6 1K 31/496, A6 1P 3/04, 3/10, 25/0 According to Initernationia1~Pia-tendassification (IPC) or to both national classification and IPC B. IELDS SEARCHIED Minimum documentation searched (classification system followed by classification symbols) IPC7: C070, A61K Documentation searched other than minirnum documentation to the extent that such documents are included in the fields searched SE,DK,FI,NO classes As above Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) EPO-INTERNAL, WPI DATA, CHEM. ABS DATA, PAJ C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relceant to claim No. X WO 02100822 Al (BIOVITRUM AB), 19 December 2002 1-61 (19.12.02), compound no. 95, page 26, page 79, line 24 - page 80, line 24, claim 8, page 118, line 7, the claims, the examples X WO 02098857 Al (F. HOFFMAN-LA ROCHE AG), 1-61 12 December 2002 (12.12.02), the examples, the claims X WO 02092585 Al (BIOVITRUM AB), 21 November 2002 1-61 (21.11.02) Further documents are listed in the continuation of Box C. [ See patent fsrnily annex. *. Special categories of cited documents: "T' later documentpublished after the international fling date or priority "A" document defining the general state of the art which is not considered date ad not in conflict ith the aplicationbul cited to understand Wd be of particular relevance the principle or theory underlyingthe invention "E" earlier application or patent but published an or after the international 'X" document of particular relevance: the elaimediavention cannot be fling date considered novel or cannot b6'considered to involve sr inventive "L" document which may throw doubts on priority claime(s) or which is step wiep the douent is taken ston cited to establish the publication date of another citation or thrir special reason (as specified) Y conere o pevelan rne. te che the canot "" documerit referring to an oral discloere, use, exhibition or other cosiued t one or s e tep h document in nicass being obvious to a person ettiWie in the art "P" document published prior to the international filing date but later than ot t"eT"priority date elaimeddocument pblishe ate tenternili Date of the actual completion of the international search Date of mailing of the international search report '2 -09- 2003 9 Sept 2003 Name and mseailing address of the ISAc Authorizetd oaiicer Swedish Patent Office box 5055, o ce102 42 STOCKHOf Gerd Strandel l/E n Facsiodile No. 46 8 666 il2 86 ihTelephoe No. + 46 8 782 25 d0 h boren PCbo/ISA)s10 secondd sheet) (July t99h) WO 2004/000828 PCT/SE2003/001061 INTERNATIONAL SEARCH REPORT International application No. PCT/SE 03/01061 C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X WO 0232863 Al (BIOVITRUM AB), 25 April 2002 1-61 (25.04.02) X WO 9827081 Al (SMITHKLINE BEECHAM PLC), 1-61 25 June 1998 (25.06.98), page 9, line 33 - page 10, line 8, the examples, the claims X EP 0701819 A2 (PFIZER INC.), 20 March 1996 1-61 (20.03.96), page 31, line 39 - line 54, the claims X WO 9421619 Al (PFIZER INC.), 29 Sept 1994 1-61 (29.09.94), page 43, line 3 - line 20, the claims X WO 0132646 A2 (SMITHKLINE BEECHAM P.L.C.), 10 May 1-61 2001 (10.05.01) X WO 0132660 Al (NPS ALLELIX CORP.), 10 May 2001 1-61 (10.05.01) X Bioorganic & Medicinal Chemistry Letters, Vol. 10, 1-61 No. 15, 2000, Methvin Isaac et al: "6-Bicyclopiperazinyl-1-arylsulfonylindoles and 6-Bicyclopiperidinyl-l-arylsulfonylindoles Derivatives as Novel, Potent, and Selective 5-HT6 Receptor Antagonists", page 1719 - page 1721, compound 3 X WO 0012073 Al (SMITHKLINE BEECHAM P.L.C.), 1-61 9 March 2000 (09.03.00) X US 4808595 A (JACOB M. HOFFMAN, JR.), 1-52 28 February 1989 (28.02.89) Form PCT/I A/210 (continuation of second sheet) (July 1998) WO 2004/000828 PCT/SE2003/001061 INTERNATIONAL SEARCH REPORT International application No. PCT/SE 03/01061 C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X WO 0196336 A2 (WARNER-LAMBERT COMPANY), 1-52 20 December 2001 (20.12.01) X WO 0185722 Al (CORTHERAPEUTICS, INC.), 1-52 15 November 2001 (15.11.01) X .WO 0055159 A2 (GLAXO GROUP LIMITED), 21 Sept 2000 1-52 (21.09.00) A GB 947606 A (IMPERIAL CHEMICAL INDUSTRIES LIMITED), 1-61 22 January 1964 (22.01.64), the claims Form PCT/ISA/210 (continuation of second sheet) (July 1998)