NZ552283A

NZ552283A - New compounds useful for the treatment of obesity, type II diabetes and CNS disorders

Info

Publication number: NZ552283A
Application number: NZ552283A
Authority: NZ
Inventors: Gary Johansson; Annika Jenmalm-Jensen; Katarina Beierlein
Original assignee: Biovitrum Ab Publ
Priority date: 2002-06-20
Filing date: 2003-06-19
Publication date: 2008-07-31
Also published as: MXPA04012914A; EP1513828A1; EA200600975A1; CN1662521A; EA200500054A1; NZ536600A; CA2486989A1; WO2004000828A1; SG156524A1; NO20050294L; IL165051A0; EA008835B1; AU2003243091A1; RS111204A; NZ552282A; BR0311952A; EA011581B1

Abstract

The disclosure relates to compounds of the formula (I), particularly to substituted phenyl-sulfonyl-piperazin-thieno-pyridine hydrochloride derivative compounds, wherein D, P, W, X, Y and R3 are as defined in the specification; 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 II diabetes, and/or CNS disorders, to achieve reduction of body weight and of body weight gain.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 552283 *10052999281 552283 NEW ZEALAND PATENTS ACT, 1953 No: Divided out of No. 533660 Date: Dated 19 June 2003 COMPLETE SPECIFICATION NEW COMPOUNDS USEFUL FOR THE TREATMENT OF OBESITY, TYPE II DIABETES AND CNS DISORDERS We, BIOVITRUM AB, of Lindhagensgatan 133, S-112 76 Stockholm, Sweden, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: (Followed by page la) 2 ' DEC 20® J jjecelvf n NEW COMPOUNDS USEFUL FOR THE TREATMENT OF OBESITY, TYPE II DIABETES AND CNS DISORDERS This is a divisional application of New Zealand patent application 536600. RELATED APPLICATIONS 10 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, and U.S. provisional application 60/464,701, filed on April 23,2003, the contents of which are incorporated herein by reference. 15 20 TECHNICAL FIELD 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. 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. la 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-HTg 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($ antagonist and 5-HTg antisense oligonucleotides to reduce food intake in rats has been reported (Bentley, J.C. et al. (1999) 10 Br J Pharmac. Suppl. 126, P66; Bentley, J.C. et al. (1997) J. Psychopharmacol. Suppl. A64,255; Wool Icy M.L. ct al. (2001) Neuropharmacology). Compounds with enhanced affinity and selectivity for the 5-HTg receptor have been identified, e.g. in WO 00/34242 and by Isaac, M. et al. (2000) 6-BicycIopiperazinyl-l-15 arylsulfonylindoles and 6-Bicyclopiperidinyl-l-arylsulfonylindoles derivatives as novel, potent and selective 5-HT6 receptor antagonists. Bioorganic & Medicinal Chemistry Letters 10: 1719-1721 (2000). ,' ■ INFORMATION DISCLOSURE ^ po : J. Med. Cheln. 1970, 13(4), 592-598 describes N-(4-{[2-(diethylamino)ethyl]amino}-l- .'-;W naphthyl)amides; N- {5,6,7,8-Tetrahydro-4-[(3-piperidinopropyl)amino]-l- naphthyl} amides and related amides and urea derivatives as schistosomicides. WO 99/42465 discloses sulphonamides derivatives that bind to the 5-HTg 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 Ibuse. WO 01/32646 Al discloses compounds that bind to the 5-HTg 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 99/37623 A2 discloses compounds that bind to the 5-HTg 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-HTg 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-HTg receptor and that are used for the treatment of CNS disorders. WO 99/02502 A2 discloses compounds that bind to the 5-HTg 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-HTg 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-HTjq 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-HTg 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 tfie 5-HTg receptor as antagonists at low nanomolar range. Compounds according to the invention and their pharmaceutically acceptable salts have 5-HTg 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 3 chorea arid/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 intake and energy expenditure, resulting in abnormal body (e.g., excessive) weight. Such body weight disorders include obesity. Definitions Unless otherwise stated or indicated, the term "Q.6 alkyl" (or "C2-6 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 andhexyl. Alkenyl groups have one or more double carbon-carbon bonds in the chain. .Unless otherwise stated or indicated, the term "Cj_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. Unless otherwise stated or indicated, the term "Cj.g 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. The expression "C2-6 alkenyl" as used herein refers to straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include virtyl, allyl, 2,3-dimethylallyl, 1-butenyl groups, 1-pentenyl, and 1-hexenyl groups. The expression "C2-6 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, CI, Br, I). The term "C3.7 cycloalkyl" denotes a cyclic alkyl group having a ring size from C3 to C7, which can be saturated or partially unsaturated. Examples of said cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, methylcyclohexyl, cyclohexenyl, cyclohexadienyl, and cycloheptyl. The term "C5-10 cycloalkenyl" denotes a cyclic alkenyl group having a ring size from C5 to Cio- Examples of said cycloalkenyl include 1-cyclopentyl, 2-cyclopentenyl, 1-cyclohexenyl, 1-cyclohepentyl, 1-cyclooctenyl, 1-cyclononenyl, and 1-cyclodecenyl groups. 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 O) as part of the ring. It includes saturated, unsaturated, aromatic, and nonaromatic heterocycles. Suitable heterocyclic groups include thienyl, furyl, pyridyl, pyrrolidinyl, imidazolyl, pyrazolyl, piperidyl, 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 andphenanthryl, 30 10 15 20 25 5 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 furyi, pyrrolyl, tbienyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, and indolyl groups. Compounds of Formula (I) One object of the present invention is a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein: ring D is a five-membered heterocyclic or 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 at least one group W is -N-; P is any one of formula (a), (b) or (c) P (I) ?or (a) (b) (c) wherein x = 0,1, or 2 and y = 0; - 2 JUL 2008 6 received and P and R3 can be attached to any carbon atom that allows the substitution, or when P is (c), then P can also be attached to any nitrogen in ring D that allows the substitution; (e) aryl carbonylmethyl, (g) C3.7 cycloalkyl-Ci-6 alkyl, wherein the cyclic ring is optionally partially unsaturated, or (h) a group Ar; wherein Ar is (a) phenyl, (b) 1-naphthyl, (c) 2-naphthyl, (d) aryl-Ci-6 alkyl, (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, 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 oxygen, nitrogen or sulfur; R2 is (a) H, (b) Ci_6 alkyl; or R1 and R2 are linked to form a group wherein v is 0-2, INTELLECTUAL PROPERTY OFFICE OF HZ. 1 -2 JUL 2008 ocficiwcn X and Y are independently (a) H, (b) halogen, (c)C,.6 alkyl, (d) CF3, (e) hydroxy, (f) Ci-6 alkoxy, (h) phenyl, (i) phenoxy, (j) benzyloxy, (m) -CN, (n) straight or branched Ci-6 hydroxyalkyl, (o) straight or branched Ci-6 alkylhalides, (r) -NR4R5; and R4 and R5 are independently (a) H, or (b) Ci-6 alkyl; and R3 is a group selected from any one of •j wherein R is optionally substituted on each carbon atom that allows the substitution with Rq groups, wherein Rq is independently H, or (Ci„6) alkyl, and wherein two Rq groups can be present on the same carbon atom simultaneously, wherein q = 1 or 2, and m = 1 or 2; and INTELLECTUAL PROPERTY OFFICE OF N.Z. 8 - 2 JUL 2008 received R6 is independently (a) H, (b) linear or branched Ci-6 alkyl. 10 INTELLECTUAL PROPERTY OFFICE OF N.Z. - 2 JUL 2008 11 INTFI i FCTLIAL PROPERTV OFFICE OF N.Z. - 2 JUL 2008 n r n r i \ / i- n INTEI I FCTLIAL PROPERTY OFFICE OF N.Z. - 2 JUL 2008 Dr^ciwrn A naphthalene ring has the following position numbers: wherein Pj-Pg denote the position on the naphthalene ring. A pyrrole ring, as ring D, has the following position numbers: 13 INTELLECTUAL PROPERTY OFFICE OF N.Z. - 2 JUL 2008 wherein P1-P3 denote the position on the pyrrole ring. 5 It is preferred that: R1 is (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 mono- or bi-cyclic heterocyclic ring, each containing 1 to 4 heteroatoms, selected from oxygen, nitrogen and sulfur, wherein when Ar is a bicyclic ring system comprising at least one heterocyclic ring according to (f) the group Ar is substituted in one or more positions with (a)H, 20 (b) halogen, (c) Ci-6 alkyl, (d) -CF3, , (f) Ci* alkoxy, (m) straight or branched Ci-6 hydroxyalkyl, 25 (n) phenyloxy, v (o) benzyloxy, pb5^v^sbnv -7 JUL®® I IrEC£]V_ED_ 14 R2 is (a) H, or (b) Cj.6 alkyl; X and Y are H; R4 and R5 are each independently H or C1-3 alkyl; and R3 is selected from any one of wherein R3 can be substituted on each caibon atom that allows the substitution with Rq groups, wherein Rq is independently H, or Ci-e alkyl, and wherein two Rq groups can be present on the same carbon atom simultaneously, wherein q = 1 or 2, m = 1 or 2, and INTELLECTUAL PROPERT OFFICE OF N.Z. I -2 JUL 2008 R6 is independently (a)H, (b) Ci-6 alkyl (preferably C1.3 alkyl), in particular methyl. It is especially preferred that R3 is selected from any one of wherein R3 can be substituted on each carbon atom that allows the substitution with 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 = 1 or 2; and R6 is independently (a)H, (b) Cm alkyl, H is further preferred that Rq is H, m is 1 or 2, R6 is independently H or methyl. 16 INTELLECTUAL PROPERTY OFFICE OF N.Z. . -2 JUL 2008 It is also preferred that R3 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. 17 | -2 JUL 2008 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'\ • 'A" (c) wherein R1, x, and y are as defined in claim 1. 10 It is also preferred that P is i R1 I k° o y~R R-NV 0 >' (a) or *' (b) wherein R1 and R2 are as defined in claim 1. It is preferred that R2 is H. 15 INTELLECTUAL PROPERTY OFFICE OF N.Z. - 2 JUL 2008 received Another object of the present invention is a compound of the general formula (IV) X- R° . (IV) wherein P is of the formula (c), R1, 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 ling, 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 R6 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: 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: 19 INTELLECTUAL PROPERTY OFFICE OF N.Z. - 2 JUL 2008 It is also preferred that D is furan and P is attached to the D ring, giving a skeleton as any of the following: r" ^ Co Another object of the present invention is a compound of the general formula (V) P (V) 10 wherein P is of the formula (c) as defined in claim 1, R1, 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 R6 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 (V) wherein P is of the formula (a) or (b) as defined in claim 1, preferably wherein R2 is H, X, 20 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 20 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) ,P X (VI) wherein P is of the formula (a) or (b) as defined in claim 1, preferably wherein R2 is H, X and Y are as defined in claim 1, and R3 is as defined in claim 2. 10 Another object of the present invention is a compound of the general formula (VET) ,P 15 (VII) wherein P is of the formula (a) or (b) as defined in claim 1, preferably wherein R2 is H, X and Y are as defined in claim 1, and R3 is as defined in claim 2. Another object of the present invention is a compound of the general formula (VIII) -N/P R" X (vnr> 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. 20 Another object of the present invention is a compound of the general formula (IX) N X R' wherein R7 in formula (IX) is: (a) H, (b) Ci-6 alkyl, 21 (IX) INTELLECTUAL PROPERTY OFFICE OF N.Z. - 2 JUL 2008 R E f! F I V F D (c) benzyl, (d) -CH2-CH2-OH, or (e) CH2-CH2-O-CH3, and wherein P is of the formula (a) or (b) as defined in claim 1, preferably wherein R2 is H, X, 5 Y, and R3 are as defined in claim 1. Another object of the present invention is a compound of the general formula (X) 10 (X) 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. 22 INTELLECTUAL PROPERTY OFFICE OF N.Z. - 2 JUL 2008 □ c o c 1 \/ c n 23 INTELLECTUAL PROPERTY OFFICE OF N.Z. - 2 JUL 2008 n r o r i \/ c n Preferred compounds of the formula (IV) are 4-(l ,4-Diazepan-1 -yl)-2-(phenylsulfonyl)thieno[3,2-c]pyridine hydrochloride; 10 4-(l,4-Diazepan-l-yl)-2-[(3,4-dichlorophenyl)sulfonyl]thieno[3,2-c]pyridine hydrochloride; 4-(l,4-Diazepan-l-yl)-2-[4-tert-butylphenylsulfonyl)thienot3,2-c]pyridine hydrochloride; 4-(l,4-Diazepan-l-yl)-2-[4-tert-butylphenylsulfonyl)thieno[3,2-c]pyridine hydrochloride; 4-(l ,4-Diazepan-1 -yl)-2-[3,4-dimethylphenylsulfonyl)thieno[3,2-c]pyridine hydrochloride; 15 2-[(4~Bromophenyl)sulfonyl]-4-(l,4-diazepan-l-yl)thieno[3,2-c]pyridine hydrochloride; 2-(Phenylsulfonyl)-4-piperazin-l-ylthieiio[3,2-c3pyridine hydrochloride; 2-(3-Methoxy-benzenesulfonyl)-4-piperazin-l-yl-thieno[3,2-c]pyridine hydrochloride; 2-(4-Methoxy-benzenesulfonyl)-4-piperazin-l-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-l-ylthieno[3,2-c]pyridine hydrochloride; 2-[(3,4-Dichlorophenyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride; 2-[(4-tert-Butylphenyl)sulfonyl]-4-piperazin-1 -ylthieno[3,2-c]pyridine hydrochloride; 25 2-(l-Naphthyl sulfonyl)-4-piperazin-l-ylthieno[3,2-c]pyridine hydrochloride; 2-[(3-Fluorophenyl)sulfonyl]-4-piperazin-l-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-l-ylthieno[3,2-c]pyridine hydrochloride; 2-[(2,4-Dimethylphenyl)sulfonyl]-4-piperazin-1 -ylthieno[3,2-c]pyridine hydrochloride; 2^(2,5^imeffiy1iiihieiiW 24 INTELLECTUAL PROPERTV OFFICE OF N.Z. . - 2 JUL 2008 % 2-[(2-Ethylphenyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine hydrochloride; 4-(Piperazinyl)-2-(3 -methoxybenzyl-sulfonyl)-thienopyridine hydrochloride; 2-(Benzylsulfonyl)-4-piperazin-l-ylthieno[3,2-c]pyridine hydrochloride; 4-Piperazin-l -yl-2- {[4-(trifluoromethyl)b enzyl] sulfonyl} thieno [3,2-c] pyridine 5 hydrochloride; 2-[(3-Bromobenzyl)suIfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine hydrochloride; 2-[(2,3-DifluorobenzyI)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine hydrochloride; 2-[(4-Bromobcnzyl)sulfonyl]-4-piperazm-l-ylthieno[3,2-c]pyridme hydrochloride; 2-{[2,5-bis(Trifluoromethyl)benzyl]sulfonyl}-4-piperazin-l-ylthieno[3,2-c]pyridine 10 hydrochloride; 2-[(4-McthyIbenzyl)sulfonyl]-4-piperazm-l-ylthieno[3,2-c]pyridine hydrochloride; 2-{[5-Chloro-2-(trifluoromethyl)benzyl]sulfonyl}-4-piperazin-l-ylthieno[3,2-c]pyridine hydrochloride; 2-{(3,5-Dimethoxybenzyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine hydrochloride; 15 2-[(2-Naphthylmethyl)sulfonyl]-4-piperazin-l-yltbieno[3,2-c]pyridine hydrochloride; 4-Piperazin-l-yl-2-{[4-(l,2,3-thiadiazol-4-yl)benzyl]sulfonyl}thieno[3,2-c]pyridine hydrochloride; l-(4-Pyrrolidin-l-ylphenyl)-2-[(4-piperazine-l-ylthieno[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- ltf-pyrrolo[3,2-cJpyridine hydrochloride; 25 1 -(3-Chloro-2-methylphenylsulphonyl)-4-piperazin-1 -yl- lH-pyrrolo[3,2-c]pyridine hydrochloride; l-(3,4-Dimethoxyphenylsulphonyl)-4-piperazin-l-yl-lif-pyrrolo[3,2-c]pyridine hydrochloride; 4-(4-Piperazin-l-yl-pyrrolo[3,2-c]pyridine-l-sulfonyl)-benzonitrile hydrochloride; 30 1 -(4,5-Dichloro-thiophene-2-sulfonyl)-4-piperazin-1 -yl- lH-pyrrolo[3,2-c]pyridine hydrochloride; 25 1 -(2-Chloro-4-fluorophenylsulphonyl)-4-piperazin-1 -yl- li/~pyrrolo[3,2-c]pyridine hydrochloride; 1 -Phenylmethanesulfonyl-4-piperazm-1 -yl-1 H-pyrrolo [3,2-c]pyridine hydrochloride; l-(5-Chloro-thiophene-2-sulfonyl)-4-piperazin-l-yl-lH-pyrrolo[3,2-c]pyridine 5 hydrochloride; l-(4-Butyl-benzenesulfonyl)-4-piperazin-l-yl-lH-pyrrolo(3,2-c)pyridine hydrochloride; 1 -(4-Phenoxy-benzenesulfonyl)-4-piperazin-1 -yl- lH-pyrrolo(3,2-c)pyridine hydrochloride; l-(Phenylsulfonyl)-4-piperazin-l -yl-lH-pyrrolo[3,2-c]pyridine hydrochloride; ^ 1 -[(4-Chlorophenyl)sulfonyl]-4-piperazin-1 -yl-1 H-pyrrolo[3,2-c]pyridine hydrochloride; 10 l-[(4-Methoxyphenyl)sulfonyl]-4-piperazin-l-yl-lH-pyrrolo[3,2-c]pyridine hydrochloride; 1-[(2-Methoxy-5-methylphenyl)sulfonyl]-4-piperazin-l-yl-lH-pyrrolo[3,2-c]pyridine hydrochloride; and 4-Pipera2an-l-yl-l-{[2-(triflxioromethyl)phenyl]sulfonyl}-lH-pyrrolo[3,2-c]pyridine hydrochloride. 15 Preferred compounds of the formula (VI) are N-(4-Methylphenyl)-4-(4-methylpiperazin-l-yl)thieno[3,2-c]pyridine-2-sulfonamide hydrochloride; 2-Bromo-4-(4-methyl-piperazin-l-yl)-thieno[3,2-c]pyridine-3-snlfonic acidp-tolylamide ^p£0 hydrochloride; 4-(4-Methylpiperazin-l-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-l-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-l-yl-thieno[3,2-c]pyridine-2-sulfonic acidp-tolylamide hydrochloride; 4-(4~Methylpiperazin-l-yl)-Ar- (2-cyclohex-l-en-l-ylethyl) thieno [3,2-c] pyridine-2-30 sulfonamide hydrochloride; 2-(4-(4-Methylpiperazin-l-yl) thieno [3,2-c] pyridin-2-ylsulfonyl)-l,2,3,4-tetrahydroisoquinoline hydrochloride; 26 4-(4-Methylpiperazin-1 -yl)-iV- (2-thien-2-ylethyl) thieno [3,2-c] pyridine-2-sulfonamide hydrochloride; 4-(4-Methylpiperazin-1 -yl)-7V- [l-(l-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-l-yl) thieno [3,2-c] pyridine-2-sulfonamide; 4-(4-Methylpiperazin-1 -yl)-iV- [l-(4-fluorophenyl) ethyl] thieno [3,2-c] pyridines-sulfonamide hydrochloride; 10 N- (2,3-Difluorobenzyl)-4-(4-methylpiperazin-l -yl) thieno [3,2-c] pyridine-2-sulfonamide hydrochloride; 4-(4-Methylpiperazin-l -yT)-N- (4-chloro-2,5-dimethoxyphenyl) thieno [3,2-c] pyridines-sulfonamide hydrochloride; 2-Bromo-4- (4-methylpiperazin-1 -yl)-N- (2-cyclohex-l-en-l-ylethyl) thieno [3,2-c] 15 pyridine-3-sulfonamide hydrochloride; 2-Bromo-4- (4-methylpiperazin-1 -yl)-N- [(15)-l-(2-naphthyl) ethyl] thieno [3,2-c] pyridine-3-sulfonamide hydrochloride; 2-Bromo-4- (4-methylpiperazin-1 -yl)-//- [l-(4-fluorophenyl) ethyl] thieno [3,2-c] pyridines-sulfonamide hydrochloride; £p0 2-Bromo-4- (4-methylpiperazin-1 -yl)-JV- (2,4,5-trimethoxyphenyl) thieno [3,2-c] pyridines-sulfonamide; N-(3,4-Dichlorophenyl)-4-piperazin-l-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride; N-(2,4-Difluorophenyl)-4-piperazin-l-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-l-ylthieno[3,2-c]pyridine-2-sulfonamide 30 hydrochloride; N-(4-Bromo-2-methylphenyl)-4-piperazin-l-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride; 27 2-(4-Piperazin-l-yl-thieno[3,2-c]pyridine-2-sulfonyl)-l,2,3,4-tetrahydro-isoquinoline hydrochloride; 4-Piperazin-l-yl-tliieno[3,2-c]pyridine-2-sulfonic acid (2-thiophen-2-yl-ethyl)-amide hydrochloride; 5 4-Piperazin-l-yl-thieno[3,2-c]pyridine-2-sulfonic acid (4-chloro-2,5-dimethoxy-phenyl)-amide hydrochloride; 4-Piperazin-l-yl-thicno[3,2-c]pyridine-2-sulfonic acid phenethyl-amide hydrochloride; 4-Piperazin-1 -yI-thicno[3,2-c]pyridine-2-sulfoiiic acid (2,6-diethyl-phenyl)-amide hydrochloride; 10 4-Pipcrazin-1 -yl-thicno[3,2-c]pyridine-2-sulfonic acid (3-phenyl-propyl)-amide hydrochloride; 4-Piperazin-l -yl-lhicno[3,2-c]pyridine-2-sulfonic acid (3,3-diphenyl-propyl)-amide hydrochloride; 4-Piperazin-l -yl-thieno[3,2-c]pyridine-2-sulfonic acid [2-(5-methoxy-lH-indol-3-yl)-15 ethyl]-amide hydrochloride; 4-Piperazin-l-yl-thieno[3,2-c]pyridine-2-sulfonic acid 4-trifluoromethyl-benzylamide hydrochloride; 4-Piperazin-l-yl-thieno[3,2-c]pyridine-2-sulfonic acid benzyl-ethyl-amide hydrochloride N-(3-Ethylphenyl)-4-piperazin-l-ylthieno[3,2-c]pyridme-3-sulfonamide hydrochloride; ^0 N-(4-Isopropylphenyl)-4-piperazin-l-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-Methylphenyl)-4-(piperidin-4-yloxy)thieno[3,2-c]pyridine-2-sulfonamide 25 hydrochloride; N-(2,3-Difluorobenzyl)-4-piperazin-l-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride; N-(3-Chlorobenzyl)-4-piperazin-l-ylthieno[3,2-c]pyridine-2-sulfonaraide hydrochloride; 4-Piperazin-l-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; 28 4-(4-Methyl-piperazin-l -yl)-thieno[3,2-c]pyridine-2-sulfonic acid phenylamide hydrochloride; 4-(4_Methyl-piperazin-l-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-l-ylthieno[2,3-c]pyridine-2-sulfonamide hydrochloride. 10 15 Preferred compounds of the formula (VII) are N-(4-methylphenyl)-4-piperazin-l -ylfuro[3,2-c]pyridine-2-sulfonamide hydrochloride; N-phenyl-4-piperazin-l-ylfuro[3,2-c]pyridine-2-sulfonamide hydrochloride; and N-phenyl-7-piperazin-l-ylfuro[2,3-c]pyridine-2-sulfonamide hydrochloride. A preferred compound of the formula (Vm) is 4-Piperazin-l-yl-tliiazolo[4,5-c]pyridine-2-sulfonic acid phenylamide hydrochloride. Preferred compounds of the formula (IX) are 20 N-(4-methylphenyl)-4-piperazin-l-yl-lH-pyrrolo[3,2-c]pyridine-2-sulfonamide hydrochloride; N-phenyl-4-piperazin-l-yl-lH-pyrrolo[3,2-c]pyridine-2-sulfonamide hydrochloride; and N-phenyl-7-piperazin-l-yl-lH-pyrrolo[2,3-c]pyridine-2-sulfonamide hydrochloride. 25 Preferred compounds of the formula (X) are 4-Chloro-N-[4-(pyrrolidin-3-yloxy)-l-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)-l-naphthyl3benzenesulfonamide hydrochloride; 30 4-Methoxy-N-[4-(piperidin-3-yloxy)-l -naphthyl]benzenesulfonamide hydrochloride; 5-Fluoro-2-methyl-N-[4-(piperidin-4-yloxy)-1 -naphthyl]benzenesulfonamide hydrochloride; 29 5-Chloro-N-[4-(piperidin-4-yloxy)-l-naphthyl]thiopliene-2-sulfoiiamide hydrochloride; 4-Chloro-N-{4-[(3S)-pyrrolidin-3-yloxy]-l-naphthyl}benzenesulfonamide hydrochloride; and 4-Chloro-N-{4-[(3R)-pyrrolidin-3-yloxy]-l-naphthyl}ben2:enesulfonamide hydrochloride. 5 • Described herein is a process for the preparation of a compound above, said method comprising the steps of: (a) Mitsonobu reaction of 4-nitro-l -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 die preparation of a compound above, wherein f <&v» //> Pis ° , 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 diazointeimediate; 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 diamine. Another object of the present invention is a process for the preparation of a compound 25 above, wherein R1 0= 1=02 N—Rz Pis ^ , said method comprising the steps of: preparation of the heteroaromatic 5-member ring fused pyridine; introduction of a carboxylic moiety; conversion 30 $#&.LECTUAL PROPERTY OFFICE OF N.Z. - 2 JUL 2008 carboxylic moiety to amine by Curtius rearrangement; reaction of the amine group with a sulphonylchloride. 10 15 Another object of the present invention is a process for the preparation of a compound above, wherein °=f=0 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 sulphonylchloride moiety with an aniline to obtained a sulfonamide; aromatic nucleophilic substitution of the chloro with a diamine. 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. 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, 31 alkylatnines, 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 maybe 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, for use in the 20 treatment or prophylaxis of a 5-HT(j 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. Another object of the present invention is a compound above for use in the treatment or 25 prophylaxis of disorders of the central nervous system. 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 R3 is of the formula INTELLECTUAL PROPERTY OFFICE OF N.Z. - 2 JUL 2008 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 R3 is of the formula 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, as an active ingredient, for use in the treatment of 10 33 - 2 JUL 2008 Pf C l\(rr prophylaxis of a 5-HTg 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 weightgain. 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 ring D is a pyrrole ring, P is of the formula (c) and R3 is of the formula 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 compound above, and for the case when ring D is a pyrrole ring, P is of the formula (c) and R3 is of the formula 34 - 2 JUL 2008 R E C EIV EDI 5 or 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. Described herein is a method for the treatment or prophylaxis of a 5- HT($ 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 R3 is substituted in position 1 on the naphthalene ring. 15 Described herein 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. CC UJ, QtN oo Described herein is a method for the treatment or prophylaxis of type crZ eg Q- ll 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 o k 25 salt forms or compositions that include the compounds or their salt forms, for the case m ° when rings A and B are both phenyl, P is any one of formula (a) or (c) substituted in — —position7 i3n fce-naphthakne iingj and R? is^ubstitutedinrposition lonthenaphthalene 35 ring, and for the case when ring D is a pyrrole ring, P is of the formula (c) and R3 is of the formula substituted in position 3 on the pyrrole ring. Described herein is a method for the treatment or prophylaxis of obesity, which comprises administering to a subject in need of such treatment an effective 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 substituted in position 3 on the pyrrole ring. Described herein is a method for modulating 5-HT6 receptor activity, comprising administering to a subject in need thereof 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. 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 5 their salt forms, for the manufacture of a medicament for use in the treatment or prophylaxis of a 5-HTg 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, and for the case when ring D is a pyrrole ring, P is of the formula (c) and R3 is of the formula 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. 20 25 37 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 R3 is of the formula R: M v R m or 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 method for improving 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^; - testormarker)orsubjective.(i.e.,siibjecLgivesanindicationof or feelsm Of 38 £5 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, 2nd Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John 39 Wiley and Sons (1994); and L. Paquette, ed, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof. This application has been divided out of application number 536600. A second divisional number 552282 was also filed out of that application number 536600. In the description in the current specification reference is still made to compounds and other subject matter which is not within the scope of the claims of the current application. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this application. The specific examples below are to be construed as merely illustrative, and not limitative 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. Methods 'H nuclear magnetic resonance (NMR) and 13C NMR were recorded on a Bruker Advance DPX 400 spcctromctcr 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 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 (19x50mm), eluents: MilliQ water, MeCN and MilliQ/MeCN/0.1%TFA and system B: XterraMS C18,5|im column (19x50mm), eluents: MilliQ water, MeCN andNELiHCOs (lOOmM). 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). Table 1 EXAMPLE R6 R4 1 6-Benzenesulfonyl-4-piperazm-l-yl-quinolme hydrochloride 9 0 2 6-[(2-Fluorophenyl)sulfonyl]-4-piperazin-l-ylquinoline hydrochloride <?, 0 3 6-( 1 -Naphthylsulfonyl)-4-piperazin-l -ylquinoline hydrochloride (jo 0 4 6-[(3,4-Dichlprophenyl)sulfonyl]-4-piperazin-l-ylquinoHne hydrochloride CI 0 . 5 6-[(3,5-Dhnethylphenyl)sulfonyi]-4-piperazin-l-ylquiiiolme hydrochloride 0 6 6-[(2-Chloro-6-methylphenyl)sulfonyl]-4-piperazin-l-ylquinoline hydrochloride -^•Cl 0 7 6-[(4-CMoropheayl)sulfonyl]-4-piperazin- 1-ylquinoline hydrochloride CI v vf>r 8 6-[(2-Methyl,4-tert-butyl-phenyl)suIfonyl]-4-piperazin-1 -ylquinoline hydrochloride 0 9 6-t(3,4-Dimethylphenyl)sulfonyl]-4-piperazin-l-ylquinoline hydrochloride 0 10 6-t(2,3-Dichlorophenyl)sulfonyl]-4-piperazin-l-ylquinoline hydrochloride ocl r^ci 0 11 6-[(4-tert-Butylphenyl)sulfonyl]-4-piperazin-1 -ylquinoline hydrochloride § 0 M 41 12 6-[(4-Isopropy]phenyl)sulfonyl]-4-piperazin-l-ylquinoline hydrochloride 9 0 N 13 (4-Piperazin-l-yl-6-{[4- (trifluoromethyl)phenyl]sulfonyl}quinoline hydrochloride 1F 0 14 6-[(4-tert-Butylphenyl)sulfonyl]-4-(l,4-diazepan-l-yl)quinoline hydrochloride 9 0 15 4-(l,4-Diazepan-l-yl)-6-[(4-isopropylphenyl)sulfonyl]quinoline hydrochloride $ 0 Scheme 1 rW/ / Legend to Scheme 1: i) Hydrogen gas, Pd/C, Methanol; ii) Sodium nitrite, Sulphuric acid, diverse thiols (R1-SH), 3h; iii) meta-chloroperoxybenzoic acid (m-CPBA), dichloromethane (CH2CI2), overnight; iv) phosphorus oxylchloride (POCI3), acetonitrile (CH3CN), 80 °C, 2h; v) aliphatic cyclic amines (R2), 80 °C, CH3CN; vi) HC1 in diethyl ether. Methods The assigned structures were confirmed by standard spectroscopical methods and elemental analysis and/or high resolution MS. 42 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 (8). 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-18 (Merck). 5 HPLC analysis were accomplished on a HP Seriesl 100, with a GROM-SIL 100 ODS-O AB column, 4.6x50mm. 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 H2O and CH3CN, both with 0.1 % TFA. The purity of the compounds was determined by HPLC. 10 Elemental analysis was performed at Structural Chemistry Department, Biovitnun AB, Stockholm. Melting points, when given, were obtained on a Biichi or a Gallenkamp melting point apparatus and are uncorrected. INTERMEDIATE 1 15 Synthesis of 6-Amlno-quiiioline 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+], NMR (270 MHz, CHCl3-d) 8 ppm 3.89 (s, 2 H) 6.87 (d, 7=2.64 Hz, 1H) 7.14 (dd, .7=8.97,2.64 Hz, 1 H) 7.25 (dd, /=8.44,4.22 Hz, 1 H) 7.88 (dd, /=7.92,1.58 Hz, 1H) 7.90 (d, /=8.97 Hz, 1 H) 8.63 (dd, >4.22,1.58 Hz, 1H). INTERMEDIATE 2 25 Synthesis of 6-phenylsulfanyl-quinoline A solution of sodium nitrite (1 g, 14 mmol) in water (6 inL) 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 43 purified by column chromatography (SiC>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, CD3CI) 8 ppm 734 (m, 4 H) 7.42 (m, 2 H) 7.57 (dd, ,7=8.97,2.11 Hz, 1 H) 7.67 (d, .7=2.11 Hz, 1 H) 7.99 (m, 2 H) 8.84 (dd, 5 .7=4.22, 1.58 Hz, 1 H). INTERMEDIATES Synthesis of 6-benzenesuIfonyI-quinoliiie 1-oxid A solution of mTchloroperbenzoic 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 NaHCCb (0.5 g) in DCM (10 mL). The reaction was left stirring over night, washed with water, NaHCCb 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-chIoro-quinoline A solution of 6-benzenesulfonyl-quinoline 1-oxid (135 mg, 0.47 mmol) in POCI3 (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 (NaSCU), the ^ volatiles were evaporated and the residue was purified by column chromatography (SiC>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-l-yl-qumolme 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 °C over night. The mixture was extracted with toluene and water. The organic phase was purified by chromatography on silica gel eluted with CHCI3 saturated with NH3 (gas). The pure product was dissolved in 30 ethyl acetate and HC1 (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+]. lH NMR (270 MHz, CH3OH-D4) 8 ppm 3.52 (m,4 H) 413 44 (m, 4 H) 7.36 (d, .7=7.18 Hz, 1 H) 7.57 (m, 3 H) 8.01 (m, .7=12.25,8.54 Hz, 3 H) 8.28 (d, /=8.91 Hz, 1 H) 8.63 (d, /=6.68 Hz, 1 H) 8.69 (s, 1H). Scheme 2 2a, n=0 ^ 2b, n=1 Legend for Scheme 2: i) Na/BuO, Pd(PPhj)4, n-BuOH, BOC-protected diamines; ii) tert-butyl piperazine-1-caiboxylate or fer/-butyl 1,4-diazepane-l-carboxylate, triethylamine or K2CO3, DMSO, thiols; iv) TFA, H2O2, NaOH; iv) HC1. 10 Method A Preparation of thiol derivatives tert-Butyl 4-(6-bromoquinolin-4-yl)-l,4-diazepaiie-l-carboxylate (0.5 g, 1.23 mmol) was mixed with the thiol (1 equiv.), NaOtBu (2 equiv.), Pd(PPh3)4 (0.05 equiv.) and n-BuOH (5 mL) in a reaction tube. N2 (g) was flushed through the mixture for 30 minutes. The reaction 5 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 H2O, dried (MgSC>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. H2O2 (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 1M. Extraction with DCM, drying with 45 MgSC>4 and evaporation gives the free bases of the products which are dissolved in MeOH, excess of HCl/ether (2M) was added and the solvent evaporated. The residues are purified on preparative HPLC/MS (Xterra MS CI 8, 5fim column) using a 10 to 40% MeCN-water gradient (containing 0.1 % HO Ac) over 10 minutes. The pure fractions are 5 pooled and lyophilised. The residues are dissolved in MeOH and treated with excess of HCl/ether (2M). After evaporation of solvent, a solid is obtained and triturated with diethyl ether giving the desired products as HCl-salts. Q INTERMEDIATES 10 tert-Butyl 4-(6-bromoqumoHn-4-yl)piperazme-l-carboxyiate 6-Bromo-4-chloroquinoline (5.0 g, 20.6 mmol), fe/?-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 100°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 CH2CI2 and evaporated. Yield 8.02 g. (97 %). Brown liquid. HPLC 98 %, Rr=3.01 (System Al, 10-97 % MeCN over 3 min). *H NMR (400 MHz, CDCI3) 8 ppm 1.52 (s, 9 H) 3.12-3.17 (m, 4 H) 3.69-3.75 (m, 4 H) 6.86 (d, .7=5.0 Hz, 1H) 7.72 (dd, .7=9.0,2.26 Hz, 1 H) 7.92 (d, .7=8.8 Hz, 1 H) 8.14 (d, .7=2.3 Hz, 1 H) 8.73 (d, >5.0 Hz, 1H). MS (ESI+) for CisHaaBrNsOa m/z 392.2 (M+H*) •> EXAMPLE 2 6-[(2-Fluorophenyl)sulfonyl]-4-piperazin-l-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). !H NMR (400 MHz, DMSO-d6) 8 ppm 3.30-3.42 (m, 4 H) 3.51-3.62 (m, 4 H) 7.28 (d, .7=5.27 Hz, 1 H) 7.42 (dd, .7=10.29, 8.78 Hz, 1H) 7.52 (t, >7.28 Hz, 1H) 7.77-7.84 (m, 1 30 H) 8.04-8.21 (m, 3 H) 8.62 (s, 1 H) 8.87 (d, >5.27 Hz, 1 H) 9.82 (br s, 2 H). MS (ESI+) for Ci9H18FN302S m/z 372.0 (M+H4). HRMS for C19H18FN3O2S: calcd, 371.1104; found, 371.1102. " 46 EXAMPLE 3 6-(l-NaphthylsuIfonyI)-4-piperazin-l-ylquinolme 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 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%, Ri=2.54 (System Al, 10-97% MeCN over 3 min). 'H NMR (400 MHz, DMSO-de) 8 ppm 3.33 (s, 4 H) 4.06 (s, 4 H) 7.38 (d, >6.78 Hz, 1H) 7.65 (d, >7.53 Hz, 1 10 H) 7.69-7.75 (m, 1 H) 7.82 (t, >7.78 Hz, 1H) 8.12 (d, >8.03 Hz, 1 H) 8.21-8.30 (m, 2 H) 8.38 (d, >8.03 Hz, 1 H) 8.56 (t, >8.53 Hz, 2 H) 8.74-8.79 (m, 2 H) 10.05 (s, 2 H). MS (ESI+) for C23H21N302S m/z 404.4 (M+H4) HRMS for C23H21N3O2S: calcd, 403.1354; found, 403.1365. 15 EXAMPLE 4 6-[(3,4-Dich!orophenyl)sulfonyl]-4-piperazin-l-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 temperature. Purification by column chromatography on silica gel 10-20 % MeOH in 10 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- d6) 8 ppm 3.35-3.41 (m, 4 H) 4.06-4.15 (m, 4 H) 7.40 (d, >6.78 Hz, 1H) 7.93 (d, >8.53 Hz, 1H) 8.04 (dd, >8.53, 2.01 Hz, 1H) 8.27 (d,>9.03 Hz, 1H) 8.32 (d, >2.01 Hz, 1H) 8.36-8.42 (m, 1 H) 8.73 (d, >1.51 Hz, 1H) 8.82 (d, >6.53 Hz, 1 H) 9.86 (s, 2 H). MS (ESI+) for Ci9 Hl7 Cl2 N3 25 02 S m/z 422.2 (M+H4). HRMS for Ci9Hi7Cl2N302S: calcd, 421.0419; found, 421.0422. HPLC 95%, Rt=2.69 (System Al, 10-97 % MeCN over 3 min) EXAMPLE 5 6-[(3,5-DimethylphenyI)suIfonyl]~4-piperazin-l-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. HPLC 47 90 % Rf=2.57 (System Al, 10-97 % MeCN over 3 min). MS (ESI+) for C21H23FN3O2S m/z 382.2. HRMS for C21H23FN302S: calcd, 381.1511; found, 381.1521. EXAMPLE 6 5 6-[(2-Chloro-6-methylphenyI)sulfonyl]-4-piperazin-l -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 HCl-salt. Yield 33 10 mg (7.5 %). White solid. !H NMR (400 MHz, DMSO-dtf) 8 ppm 2.13 (s, 3 H) 2.98 (s, 4 H) 3.72 (s, 4 H) 7.06 (d, >6.78 Hz, 1H) 7.14 (dd, >11.54, 8.03 Hz, 2 H) 7.23 (t, >7.78 Hz, 1H) 7.89 (d, J—8.78 Hz, 1H) 7.94-8.00 (m, 1H) 8.24 (s, 1H) 8.45 (d, >6.78 Hz, 1 H) 9.68 (s, 2 H). MS (ESI+) for C2oH2oC1N302S m/z 402.2 (M+H4). HRMS for C20H20CIN3O2S: calcd, 401.965; found, 401.967. HPLC 95 %, Rf=2.55 (System Al, 10-97 15 % MeCN over 3 min). EXAMPLE 7 6-[(4-Chlorophenyl)suIfonyl]-4-piperazin-l-ylquinoline hydrochloride A total amount of 2.25 mmol, of the appropriate thiophenol was used and the reaction was 0) 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 soUd. HPLC 95 % Rr=2.66 (System Al, 10-97 % MeCN over 3 min). MS (ESI+) for C19H18CIN3O2S m/z 388.2 (M+H4). HRMS for C19H18CIN3O2S: calcd, 387.0808; found, 25 387.0821. EXAMPLE 8 6-[(2-Methyl,4-tert-butyl-phenyl)sulfonyl]-4-piperazin-l-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 HCl-salt giving gray solid. Yield 17 mg (4 %). HPLC 95 %, Rf=2.81 48 (System Al, 10-97 % MeCN over 3 min). MS (ESI+) for C24H29N3O2S m/z 424.2 (M+H+). HRMS for C24H29N3O2S: calcd, 423.1980; found, 423.1969. EXAMPLE 9 6-[(3,4-Dimethylphenyl)suIfonyI]-4-piperazm-l-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 (he HCl-salt. Yield 33 mg (8 %). Yellow solid. NMR (400 MHz, DMSO- d(,) 5 ppm 2.27 (d. >6.27 Hz, 6 H) 3.34 (s, 4 H) 4.12 (s, 4 H) 7.39 (dd, >7.40, 2.13 Hz, 2 II) 7.75 (d. >7.78 Hz, 1H) 7.81 (s, 1H) 8.32 (s, 2H) 8.61 (s, 1 H) 8,78 (d, >6.78 Hz, 1 H) 10.18 (s, 2 H). MS (ESI+) for C21H23N3O2S m/z 382.2 (M+H1). HRMS for C21H23N3O2S: calcd, 381.1511; found, 381.1519. HPLC 95 %, Rf=2.54 (System Al, 10-97 % MeCN over 3 min), 15 EXAMPLE 10 6-1(2,3-Dichlorophenyl)sulfonyl]-4-piperazin-l-ylqumoline 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 620 gave the free amine which was converted to the HCl-salt. Yield 15 mg (3 %). Yellow solid. 'H NMR (400 MHz, DMSO-ds) 8 ppm 3.36 (m, 4 H) 4.10 (m, 4 H) 7.42 (d, >6.78 Hz, 1 H) 7.75 (t, >8.03 Hz, 1H) 8.07 (d, >8.03 Hz, 1 H) 8.24 (d, >9.04 Hz, 1H) 8.33 (dd, >13.93,8.41 Hz, 2 H) 8.70 (s, 1 H) 8.82 (d, >6.78 Hz, 1H) 10.00 (s, 2 H). MS (ESI+) for Ci9Hi7Cl2N302S m/z 422.2 (M+H4). HRMS for Ci9Hi7Cl2N302S: calcd, 421.0419; 25 found, 421.0408. HPLC 95 %, Rt-2.50 (System Al, 10-97 % MeCN over 3 min). EXAMPLE 11 6-l(4-tert-Butylphenyl)sulfonyll-4-piperazin-l-ylquiiioHne hydrochloride tert-Butyl4-{6-[(4-tert-butylphenyl)thio]quinolin-4-yl}piperazine-l-carboxylate 30 (0.60 g, 1.3 mmol) was dissolved in TFA (12 mL) and stirred for 30 minutes before H2O2 (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 5 10 49 diethyl ether (2x). The aqueous phase was adjusted to pH 10 with 1N NaOH and the mixture was extracted with CH2CI2 (2x), dried (MgSO,*) and evaporated. The residue was diluted with CH2CI2 and 1.3 mL 2N HC1 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 %, Rf=2.77 (System Al, 10-97 % MeCN over 3 rain). ]H NMR (400 MHz, DMSO-d6) 6 ppm 1.23 (s, 9 H) 3.38 (s, 4 H) 4.08 (s, 4 H) 7.39 (d, >7.03 Hz, 1 H) 7.65 (d, >8.53 Hz, 2 H) 7.96 (d, >8.53 Hz, 2 H) 8.25 (d, >8.78 Hz, 1 H) 8.30-8.36 (m, 1H) 8.66 (d, >1.76 Hz, 1 H) 8.81 (d, >7.03 Hz, 1 H) 9.85 (br. s, 2 H), MS % (ESI+) for C23H27N3O2S m/z 410.4 (M+H1). 10 EXAMPLE 12 6-[(4-Isopropylphenyl)suIfonyl]-4-piperazin-l-yIqulnoIine hydrochloride 4-Isopropylthiophenol (0.152 g, 1.0 mmol) was added dropwise to a suspension of teri-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 wilh 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 % H2O2 (1 mL) was added. The mixture was stirred for 2 hours and evaporated. The residue was dissolved in water and washed with CH2Cl2 00 (2x) and 2 N NaOH was added until pH reached 10 and the mixture was extracted with CH2Ci2 (3x), dried (MgS04) 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 CH2Cl2 and and excess of HC1 in diethyl ether was added and the mixture was evaporated. Yield 0.015 g (7 %). rH NMR (400 MHz, DMSO-de) 8 ppm 25 1.17 (d, >7.03 Hz, 6 H) 2.90-3.02 (m, 1 H) 3.34-3.42 (m, 4 H) 4.03-4.12 (m, 4 H) 7.39 (d, >6.78 Hz, 1H) 7.51 (d, >8.28 Hz, 2 H) 7.96 (d, >8.53 Hz, 2 H) 8.26 (d, >9,03 Hz, 1 H) 8.29-8.36 (m, 1 H) 8.66 (s, 1 H) 8.80 (d, >6.78 Hz, 1 H) 9.85-9.97 (m, 2 H). HPLC 95%, Rf=2.65 (System Al, 10-97% MeCN over 3 min). 30 EXAMPLE 13 4-Piperazin-l-yl-6-{[4-(trifluoromethyI)phenyI]suIfonyl}quinolinehydrochloride 50 4-TrifIuoromethylthiophenol (0.178 g, 1.0 mmol) was added dropwise to a suspension of tart-butyl 4-(6-bromo-quinolin-4-yl)-piperazine-l-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 % H2O2 (1 mL) was added. The mixture was stirred for 2 hours and evaporated. The residue was dissolved in water and washed with CH2CI2 _ (2x) and 2 N NaOH was added until pH reached 10 and the mixture was extracted with CH2CI2 (3x) dried (MgSO*) 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 CH2CI2 and excess of HC1 in diethyl ether was added and the mixture was evaporated. Yield 0.024 g (10%). lH NMR (400 MHz, DMSO-dg) 5 ppm 3.33-3.40 (m, 4 H) 4.13-4.21 (m, 4 H) 7.42 (d, .7=7.03 Hz, 1H) 8.02 (d, >8.53 Hz, 2 H) 8.25-8.35 (m, 3 H) 8.37-8.53 (m, 1H) 8.76 (d, J=1.76 Hz, 1H) 8.80 (d, >7.03 Hz, 1H) 9.95-10.05 (m, 2 15 H). Yellow oil. HPLC 95 %, Ri=2.66 (System Al, 10-97% MeCN over 3 min). INTERMEDIATE 6 tert-Butyl 4-(6-bromoquinolin-4-yl)-l,4-diazepane-l-carboxylate 6-Bromo-4-chloroquinoline (3.5 g, 14.5 mmol) was reacted with fcrf-butyl 1,4-diazepane-• 1-carboxylate (3.7 g, 18.8 mmol) and K2CO3 (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 (MgS04) 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, CDCI3) 8 ppm 1.47 (d, >5.5 Hz, 9 H) 2.08-2.16 25 (m, 2 H) 3.35-3.44 (m, 4 H) 3.60-3-73 (m, 4 H) 6.87 (d, >5.5 Hz, 1 H) 7.69 (dd, >9.0, 2.0 Hz, 1H) 7.88 (d, >8.5 Hz, 1 H) 8.16 (s, 1 H) 8.65 (d, >5.0 Hz, 1 H). MS (ESI+) for Ci9H24BrN302 m/z 406.4 (M+H)+. HRMS (EI) calcd for Ci9H24BrN3: 405.1052, found 405.1045. 30 INTERMEDIATE 7 51 tert-Butyl-4{3-[(4-tert-butyIphenyl)thio]quinolin-5-yl}-l,4-diazepane-l-carboxyIate (General Method A) The compound was prepared from tert-butyl 4-(6-bromoquinolin-4-yl)-l,4-diazepane-l-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 %, Rx: 3.76 min (5-99 % MeCN containing 0.1 % TFA over 3 min). INTERMEDIATE 8 tert-Butyl-4{3-|(4-isopropyIphenyI)thio]quinoIin-5-yl}-l,4-diazepane-l-carboxyIate 10 (General Method A} The compound was prepared from tert-butyl 4-(6-bromoquinolin-4-yl)-1,4-diazepane-1 -carboxylatc (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 %, Rr: 3.67 min (5-99 % MeCN containing 0.1 % TFA over 3 15 min); MS (ESI+) for C28H35N3O2S m/z 478.2 (M+H)+. EXAMPLE 14 6-[(4-tert-ButylpIienyl)sulfonyl]-4-(l,4-diazepan-l-yl)qumoIme hydrochloride (General Method B) 0 The compound was synthesized from tert-butyl-4 {3-[(4-tert-butylphenyl)thio]quinolin-5-yl}-l,4-diazepane-l -carboxylate (0.27 g, 0.55 mmol). Yield: 20 mg (8 %) of the title compound.; *H NMR (270 MHz, DMSO-dg) 8 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, 7=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, Jh8.7 Hz, 1 H) 25 8.26 (d, >8.7 1 H) 8.62 (d, >6.3 Hz, 1 H) 8.75 (s, 1H) 9.65 (br s, 2 H); MS (ESI+) for C24H29N3O2S m/z 424.2 (M+H)+. HPLC 93%, RT: 2.79 min (5-99 % MeCN over 3 min). EXAMPLE 15 4-(l,4~Diazepan-l-yl)-6-[(4-isopropylphenyl)sulfonyl]quino!ine hydrochloride 30 (General Method B) The compound was prepared from tert-Butyl-4{3-[(4-isopropylphenyl)thio]quinolin-5-yl}-i,4-diazepane-l -carboxylate (0.27 g, 0.57mmol). Yield: 15 mg (6 %) of the title 52 compound.; *H NMR (270 MHz, DMSO-4) 5 ppm 1.16 (d, J=6.9 Hz, 6 H) 2.31 (br s, 2 H) 2.96 (m, 1H) 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, /=8.2 Hz, 2 H) 7.94 (d, /=8.2 Hz, 2 H) 8.18 (d, /=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+) for C23H27N3O2S m/z 410.4 (M+H)+. HPLC 93 %, RT: 2.70 min (5-99 % MeCN over 3 min). Table 2 R' R 53 EXAMPLE R7 R1 16 7-(2-ChIoro-6-methyl-benzenesulfonyl)-l-piperazin-l-yl-isoquinoline hydrochloride 0 N 17 7-(2-?-Butyl-benzenesulfonyl)-l-piperazin-1 -yl-isoquinoline hydrochloride 9V 0 18 7-(3,4-Dichloro-benzenesulfonyl)-l -piperazin-1 -yl-isoquinoline hydrochloride C^' 0 19 7-(3,4-Dimethyl-benzenesulfonyl)-l-piperazdn-l -yl-isoquinoline hydrochloride 0 20 7-(2,5-Dimethyl-benzenesulfonyl)-l-piperazin-l-yl-isoquinoline hydrochloride v 0 N 21 7-(p-Chloro-benzen.esulfonyl)-l-piperazin-l-yl-isoquinoline hydrochloride & 0 22 7-Benzenesulfonyl-1 -[ 1,4]diazepan-1 -yl-isoquinolin .hydrochloride 9' o N—' 23 7-(4-tert-Butyl-benzenfiSulfonyl)-l-tl,4]diazepan-l-yl]-isoquinoline, hydrochloride o 0 N—' 24 7-(2-Chloro-6-methyI-benzenesulfonyl)-1-[ l,4]diazepan-l-yl]-isoquinoline hydrochloride 0 N—' 25 7-(3,5-Dimethyl-benzenesulfonyl)-l-[l,4]diazepan-l-yl]-isoquinoline hydrochloride V 0 N—/ 26 7-(3,4-Dichloro-benzenesulfonyl)-l-[l,4]diazepan-l-yl]-isoquinoline hydrochloride 0 N—/ 54 27 7-(4-Chloro-benzenesulfonyl)-l-[ l,4]diazepan-1 -yl]-isoquinoline hydrochloride 0 N—' 28 7-(3,4-Dimethyl-benzenesulfonyl)-l-[l,4]diazepan-l-yl]-isoquinoline hydrochloride 0 N— 29 7-(2-tert-Butyl-benzenesulfonyl)-l-[l,4]diazepan-l-yl]-isoquinoline hydrochloride 9? 0 N—' 30 7-Benzenesulfonyi-l-piperazin-yl-isoquinoline hydrochloride 9- 0 31 7-(4-tert-Butyl-benzenesulfonyl-l-piperazm-yl-isoquinoline hydrochloride V- 0 55 Scheme 3 iv, v Br n Legend to Scheme 3: i) POCI3; ii) K2C03, DMF, BOC-diamines; iii) Nat-BuO, thiophenols, Pd(PPh3)4; 11-5 BuOH; iv) TFA, H202; v) HC1 in diethyl ether. INTERMEDIATE 9 7-Br omo-1 -Chloroisoquinoline To phosphorus oxychloride (46.6 mL, 0.5 mol) at room temperature was added, 10 portionwise, 7-bromo-l-hydroxyisoquinoline (11.2 g, 0.05 mol). The mixture was heated to 100 °C for 90 min withrapidstirrmg. On cooling to room temperature, the mixture was 56 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. lE NMR (DMSO-d6) 5 8.4 (s, 1 H), 8.34-8.38 (d, J = 6 Hz, 1 H), 8.03-8.07 (m, 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-isoquinoIiiie-l-yI)-piperazine-l-carboxylic acid, tert-butyl ester To a suspension of 7-bromo-l-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 ware 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 (CDCI3) 8 8.20-8.22 (m, 1 H), 8.13-8.18 (d, /= 6 Hz, 1H), 7.65-7-71 (dd,/= 12,3 Hz, 1 H), 7.59-7.65 (d,/= 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-isoquinolme-l-yl)-[l,4]diazepane-l-carboxylic acid, tert-butyl ester 2.75 g (52 %) yellow oil isolated *H NMR (CDCI3) 8 8.19-8.24 (m, 1H), 8.06-8.12 (d, /= 9 Hz, 1 H), 7.54-7.68 (m, 2 H), 7.11 (m, 1 H), 3.47-3.74 (m, 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-l-chloroisoquinoline (1 mmol) in butan-l-ol (20 mL) at room temperature was added sodium tert-butoxide (481 mg, 5 mmol), thiol (1.5 mmol) and tetrakis 57 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-phenylsuIfanyl)-isoquinolin-l-yl]-piperazine-l-carboxylic acid tert-butyl ester A mixture of 4-(7-bromo-isoquinoline-l-yl)-piperazine-l-carboxylic acid, tert-butyl ester 10 (0.5 g, 1.3 mmol), 2-chloro-6-methyl-thiophenol (0.206 g, 1.3 mmol), NafBuO (0.44 g, 4.5 mmol), Pd(PPh3)4 (74 mg, 0.065 mmol) in hBuOH (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 (MgS04), filtered. The volatiles were evaporated and the residue was purified by 15 flash column chromatography (Si02, n-heptane: ethyl acetate 8:2) to give 530 mg of the title compound as colourless oil (yield 86.4 %). *H NMR (CDCb) 8 8.05 (d, 1H), 7.65 (d, 1H), 7.20-7.45 (m, 5H), 7.15 (d, 1H), 3.26-3.40 (m, 4H), 3.10-3.20 (m, 4H), 2.5 (s, 3H), 1.38 (s,9H). 0 INTERMEDIATE 13 4-[7-{2-*-butyl-phenylsulfanyl)-isoquinolin-l-yl]-piperaziiie-l-carboxylic acid tert-butyl ester A mixture of 4-(7-bromo-isoquinoline-l-yl)-piperazine-l-carboxylic acid, tert-butyl ester (0.5 g, 1.3 mmol), 2-^butyl-thiophenol (0.216 g, 1.3 mmol), Naf-BuO (0.44 g, 4.5 mmol), 25 Pd(PPh3)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 (MgS04), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (Si02, n-heptane: ethyl acetate 8:2) to give 440 mg of the 30 title compound as colorless oil (yield 71 %). 'H NMR (CDCI3) 8 8.00-8.10 (m, 2H), 7.15- 58 7.65 (m, 7H), 3.60-3.70 (m, 1H), 3.30-3.45 (m, 4H), 3.05-3.20 (m, 3H), 1.55 (s, 9H), 1.50 (s, 9H). INTERMEDIATE 14 5 4-[7-(3,4-Dichloro-phenyIsulfanyl)-isoquinoiiii-l-yl]-piperazine-l-carboxylic acid fert-butyl ester A mixture of 4-(7-bromo-isoquinoline-l-yl)-piperazine-l-carboxylic acid, tert-butyl ester (0.5 g, 1.3 mmol), 3,4-dichloro-thiophenol (165 uL, 1.3 mmol), NafBuO (0.44 g, 4.5 mmol), Pd(PPh3)4 (74 mg, 0.065 mmol) in »-BuOH (10 mL) was heated at 110 °C, 3h. The 10 reaction mixture was filtered. The jSltrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water (50 mL x 3), separated and dried (MgS04), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (SiC>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 (CDCfe) 8 8.10-8.20 (m, 2H), 15 7.90 (bs, 1H), 7.65-7.75 (m, 2H), 7.10-7.55 (m, 3H), 3.50-3.65 (m, 4H), 3.20-3.30 (m, 4H), 1.50 (s,9H). INTERMEDIATE 15 4-[7-(3,4-Dimethyl-phenyIsulfanyl)-isoquinolin-l-yl]-piperazine-l-carboxylic acid tert-20 butyl ester A mixture of 4-(7-bromo-isoquinoline-l-yl)-piperazine-l-carboxylic acid, tert-hv&yl ester (0.5 g, 1.3 mmol), 3,4-dimethyl-thiophenol (175 uL, 1.3 mmol), Na/BuO (0.44 g, 4.5 mmol), Pd(PPh3)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 25 in ethyl acetate. The organic phase was washed with water (50 mL x 3), separated and dried (MgS04), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (SiC>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 (CDCI3) 8 8.00-8.10 (m, 2H), 7.55-7.65 (m, 3H), 7.40-7.50 (m, 1H), 7.10-7.30 (m, 2H), 3.30-3.40 (m, 4H), 3.10-3.20 (m, 30 4H), 2.30 (s, 3H), 2.25 (s, 3H), 1.50 (s, 9H). 59 INTERMEDIATE 16 4-[7-(3,5-Dimethyl-phenylsulfanyl)-isoquinolin-l-yl]-piperazme-l-carboxylic acid tart-butyl ester A mixture of4-(7-bromo-isoquinoline-l-yl)-piperazine-l-carboxylic acid, tart-butyl ester (0.5 g, 1.3 mmol), 3,5-dimethyl-thiophenol (180 mg, 1.3 mmol), NaffiuO (0.44 g, 4.5 mmol), Pd(PPh3)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 (MgSC>4), filtered. The volatiles were evaporated and the residue was purified by 10 flash column chromatography (SiC>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 (CDCI3) 8 8.05-8.10 (m, 1H), 7.S0-7.S5 (m. 1H), 7.60-7.75 (m, 1H), 7.17-7.25 (m, 1H), 7.10 (bs, 2H), 7.00 (bs, 1H), 3.40-3.50 (m, 4H), 3.10-3.20 (m, 4H), 2.25 (bs, 6H), 1.50 (s, 9H). 15 INTERMEDIATE 17 4-[7-(/?-ChIoro-phenylsulfanyl)-isoquinoliu-l-yl]-piperazine-l-carboxj lic acid tart-butyl ester A mixture of 4-(7-bromo-isoquinoline-l-yl)-piperazine-l-carboxylic acid, tart-butyl ester (0.5 g, 1.3 mmol), j?-chloro-thiophenol (188 mg, 1.3 mmol), Na/BuO (0.44 g, 4.5 mmol), Jp Pd(PPh3)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 (MgSC>4), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (S1O2, n-pentane:ethyl acetate 9.5:0.5 -» 8:2) to give 300 mg of 25 the title compound as colourless oil (yield 50 %). ]H NMR (CDCI3) 8 8.05-8,15 (m, 2H), 7.60-7.70 (m, 2H), 7.40-7.50 (m, 2H), 7.15-7.30 (m, 3H), 3.45-3.55 (m, 4H), 3.10-3.15 (m, 4H), 1.50 (s, 9H). 60 INTERMEDIATE 18 4-(7-PhenyIsuIfanyI-isoquinoliiie-l-yI)-piperaziite-l-carboxyIic acid, tert-butyl ester LCMS: 422,423. 5 INTERMEDIATE 19 4-[7-(4-tert-ButyI-pbenyIsuIfanyI)-isoquinoIiiie-l-yl]-piperaziiie-l-carboxylic acid, tert-butyl ester LCMS: 478,479. 10 INTERMEDIATE 20 4-(7-Phcnylsulfanyl-isoquiDoliiie-l-yl)-[l,4]diazepane-l-carboxylic acid, tert-butyl ester MS: 368,369,370. 15 INTERMEDIATE 21 4-[7-(4-to^-Bu(yI-pIienylsuIfaiiyl)-isoquiiioliiie-l-yl]-[l,4]diazepane-l-carboxylic acid, tert-butyl ester MS: 424,425,426. >20 INTERMEDIATE 22 4-[7-(2-CWoro-6-methyl-pheiiylsulfanyl)-isoqumottiie-l-yl]-[l,4]diazepane-l-carboxylic acid, tert-butyl ester MS: 416,417,418. 25 INTERMEDIATE 23 4-[7-(3,4-Dimethyl-phenylsuIfanyl)-isoquiiioline-l-yl]-[l,4Jdiazepane-3-carboxylic acid, tert-butyl ester MS: 396,397,398. 30 INTERMEDIATE 24 4-[7-(3,4-Dichloro-phenylsulfanyl)-isoquinoline-l-yl]-[l,4]diazepane-l-carboxylic acid, tert-butyl ester 61 MS: 436,437438. INTERMEDIATE 25 4-[7~(4-ChIoro-phenylsuIfanyI)-isoquinoline-l-yI]-[l,4]diazepane-l-carboxyIic acid, 5 tert-butyl ester MS: 402,404. INTERMEDIATE 26 ^ 4-[7-(3,4-DimethyI-phenyIsulfanyl)-isoquinoline-l-yl]-[l,4]diazepane-l-carboxylic 10 acid, tert-butyl ester LCMS: 464,465,466. INTERMEDIATE 27 4-[7-(2-rert-ButyI-phenyIsulfanyI)-isoquinoline-l-yI]-[l,4]diazepane-l-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 ^0 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 (1M, 25 mL). Extraction of this mixture with ethyl acetate (3x50 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 HCl/Ether (1M, 1 mL) gave the final product as a white solid. EXAMPLE 16 30 7-(2-Chloro-6-methyl-benzenesulfonyI)-l-piperazin-l-yl-isoqu!noline hydrochloride A mixture of 4-[7-(2-chloro-6-methyl-phenylsulfanyl)-isoqudnolin-l-yl]-piperazine-l-" carboxylic acid tert-butyl ester (160 mg, 0.340 mmol), H2O2 (30% in water, 200 uL), 62 trifluoroacetic acid (2 mL) was heated at 50 °C, 2h. A water solution of NaOH (IN) was added (pH = 14), ethyl acetate was added and the organic phase was separated, dried (MgSC>4), filtered. The filtrated was concentrated and the residue was purified by flash column chromatography (SiC>2, dichlorome thane .-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 HC1 in diethyl ether. *H NMR (CHaOH-^) 8 8.88 (bs, 1H), 8.05-8.20 (m. 3H), 7.65 (d, 1H), 7.35-7.55 (m, 3H), 3.85-3.95 (m, 4H), 3.00-3.15 (m, 4H), 2.95 (s, 3H). 10 EXAMPLE 17 7-(2-*-Butyl-beuzenesuIfonyl)-l-piperazm-l-yl-isoguinoIine hydiochloride A mixture of 4-[7-(2-/butyl-phenylsulfanyl)-isoquinolin-l-yl}-piperazine-l-carboxylic acid tert-butyl ester (273 mg, 0.571 mmol), H2O2 (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 (IN) was added (pH 14), ethyl acetate was added and the organic phase was separated, dried (MgSC>4), filtered. The filtrated was concentrated and the residue was purified by flash column chromatography (Si02, 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 HC1 in diethyl ether. !H NMR (CHaOH-^) #20 8 8.55 (d, 1H), 8.25 (d, 1H), 7.95-8.10 (m, 3H), 7.55 (d, 1H), 7.55-7.65 (m, 2H), 7.4 (d, 1H), 3.60-3.75 (m, 4H), 3.40-3.50 (m, 4H), 1.55 (s, 9H). EXAMPLE 18 7-(3,4-Dichloro-benzenesulfonyl)-l-piperazin-l-yl-isoquinoline hydrochloride 25 A mixture of 4-[7-(3,4-dichloro-phenylsulfanyl)-isoquinolin-l-yl]-piperazine-l-carboxylic acid tert-butyl ester (230 mg, 0.47 mmol), H2O2 (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 (MgSC>4), filtered. The filtrated was concentrated and 30 the residue was purified by flash column chromatography (SiC>2, dichloromethane:methanol 9:1) The free base was converted into hydrochloride by 63 treatment with HC1 in diethyl ether to obtained 45 mg of the title compound. *H NMR (CHbOH-d#) 5 8.75-8.85 (m, 1H), 8.10-8.30 (m, 4H), 7.90-8.00 (m, 1H), 7.75-7.85 (m, 1H), 7.50-7.60 (m, 1H), 3.85-3.90 (m, 4H), 3.50-3.70 (m, 4H). 5 EXAMPLE 19 7-(3,4-DimethyI-benzenesuIfonyI)-l-piperazin-l-yl-isoquinoline hydrochloride A mixture of 4-[7-(3,4-dimethyl-phenylsulfanyl)-isoquinolin-1 -yl]-piperazine-1 -carboxylic acid ten-butyl ester (260 mg, 0.58 mmol), H2O2 (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 (MgS04), filtered. The filtrated was concentrated and the residue was purified by flash column chromatography (Si02, dichloromethane:methanol 9:1) The free base was converted into hydrochloride by treatment with HC1 in diethyl ether to obtained 20 mg of the title compound. *H NMR 15 (CH3OM) 5 8.75-8.80 (m, 1H), 8.10-8.25 (m, 3H), 7.70-7.85 (m, 2H), 7.60-7.70 (m, 1H), 7.35-7.40 (m, 1H), 3.90-4.00 (m, 4H), 3.55-3.65 (m, 4H), 2.35 (bs, 6H). EXAMPLE 20 7-(2,5-Dimethyl-benzenesuIfonyl)-l-piperazin-l-yl-isoquinoline hydrochloride #10 A mixture of 4-[7-(2,5-dimethyl-phenylsulfanyl)-isoquinolin-l-yl]-piperazine-l-carboxylic acid tert-butyl ester (380 mg, 0.846 mmol), H2O2 (30% in water, 0.5 mL), trifluoroacetic acid (3 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 (MgS04), filtered. The filtrated was concentrated and 25 the residue was purified by flash column chromatography (Si02, dichloromethane:methanol 9.8:0.2-»9.5:0.5) The free base was converted into hydrochloride by treatment with HC1 in diethyl ether to obtained 120 mg of the title compound. !H NMR (CH3OH-J,) 8 8.75-8.80 (m, 1H), 8.25-8.30 (m, 1H), 8.05-8.20 (m, 2H), 7.60-7.70 (m, 3H), 7.30-7.35 (m, 1H), 4.00-4.10 (m, 4H), 3.60-3.70 (m, 4H), 2.30-30 1.35 (bs, 6H). 64 EXAMPLE 21 7-Cp-Chloro-benzenesulfonyO-l-piperazin-l-yl-isoquinoline hydrochloride A mixture of 4-[7-(p-chioro-phenylsulfanyl)-isoquinolin-l-yl]-piperazine-l-carboxylic acid tert-butyl ester (297 mg, 0.65 mmol), H2O2 (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 (IN) was added (pH = 14), ethyl acetate was added and the organic phase was separated, dried (MgSO,}), filtered. The filtrated was concentrated and the residue was purified by flash column chromatography (Si02, dichloromethane:methanol 9.5:0.5-»9.0:1.0) The free base was converted into 10 hydrochloride by treatment with HC1 in diethyl ether to obtained 70 mg of the title compound. *H NMR (CHsOH-dV) 8 8.75-8.85 (m, 2H), 8.10-8.25 (m, 3H), 8.00-8.08 (m, 2H), 7.60-7.68 (m, 3H), 3.85-3.95 (m, 4H), 3.55-3.65 (m, 4H). EXAMPLE 22 15 7-BenzenesulfonyI-l-[l,4]diazepan-l-yl-isoquinoline hydrochloride 30 mg. *H NMR (DMSO-d6) 8 9.3 (s, 1 H), 8.58 (s, 1H), 8.26-8.30 (d, /= 9 Hz, 1H), 8.1-8.13 (m, 2 H), 8.01-8.06 (d, /= 6 Hz, 1 H), 7.6-7.76 (m, 3 H), 7.53-7.58 (d, /= 6 Hz, 1H), 3.70-3.90 (m, 4H) 3.58-3.66 (m, 2 H), 3.29-3.40 (m, 2H); LCMS: 368,369 HPLC: 98 %. '20 EXAMPLE 23 7-(4-ter/-Butyl-benzenesuIfonyI)-l-[l,4]diazepan-l-yl]-isoquinoline hydrochloride Isolated 69 mg. 'H NMR (DMSO-d6) 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, /= 15 Hz, 1 H), 7.89-7.96 (d, /= 9 Hz, 2 H), 7.60-7.67 (d, 7= 9 Hz, 2 H), 7.33-7.38 (d, /= 9 Hz, 1 H), 4.01-4.09 (m, 2 H), 3.83-3.91 (m, 2 H), 3.43-3.52 (m, 2 25 H), 3.23-3.33 (m, 2 H), 1.25 (s, 9 H); LCMS: 424,425, HPLC: 97 %. EXAMPLE 24 7-(2-Cbloro-6-methyl-benzenesulfonyl)-l-[l,4]diazepan-l-yI]-isoquinoIine hydrochloride 30 Isolated 27 mg *H NMR (DMSO-<4) 8 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 (m, 3 H), 7.36-7.42 (d, /= 6 Hz, 1 H), 3.75-3.86 (m, 2 65 H), 3.41-3.51 (m, 2 H), 3.18-3.32 (m, 2 H), 2.86 (s, 3 H), 2.14-2.19(m 2 H); LCMS: 416,418 HPLC: 98%. EXAMPLE 25 5 7-(3,5-Dimethyl-benzenesuIfonyl)-l-[l,4]diazepan-l-yl]-isoqumoIme hydrochloride Isolated 62 mg. !H NMR (DMSO-rf*) 8 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, /= 6 Hz, 1H), 7.30-7.35 (m, 1H), 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 0 H); LCMS: 436,438, HPLC: 95%. 10 EXAMPLE 26 7-(3,4-DicMoro-benzenesutfonyl)-l-[l,4]diazepan-l-yIHsoqutaoIlne, hydrochloride Isolated 11 mg. *H NMR (CD3OD) 6 8.88 (m, 1H), 8.23-8.29 (d, J= 12 Hz, 1H), 8.13-8.16 (d, J= 3 Hz, 1 H), 8.04-8.10 (d, /= 9 Hz, 1H), 7.88-7.94 (d, /= 9 Hz, 1 H), 7.79-15 7.84 (d, 6 Hz, 1 H), 7.67-7.73 (d, 9 Hz, 1 H), 7.42-7.46 (d, 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 7-(4-Chloro-benzenesulfonyl)-l-[l,4]diazepan-l-yI]-isoquinoIlne, hydrochloride Isolated 41 mg. lH NMR (DMSO-4) 5 9.27 (s, 1 H), 8.68 (m, 1H), 7.99-8.17 (m, 5 H), 7.66-7.75 (d, J=9Hz,2 H), 7.33-7,39 (d, J= 6 Hz, 1H), 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-(3j4-Dimethyl-benzenesulfonyl)-l-[l,4]diazepan-l-yl]-isoquinol!ne, hydrochloride Isolated 10 mg. JH NMR (DMSO-d6) 8 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, 9 Hz, 1 H), 7.32-7.42 (d, /= 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%. 66 EXAMPLE 29 7-(2-ferf-Butyl-benzenesulfonyI)-l-[l,4]diazepau-l-ylHsoqumolrae, hydrochloride Isolated 5 mg. !H NMR (DMSO-ck) 8 9.27 (s, 1 H), 8.52 (s, 1 H), 8.06-8.16 (m, 2 H), 5 7.97-7.97 (m, 2 H), 7.72-7.78 (m, 1H), 7.61-7.70 (m, 1H), 7.40-7.45 (d, J=9Hz,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 %. 9 EXAMPLE 30 10 7-BenzenesuIfonyI-l-piperazin-yI-isoquinoIine, hydrochloride Isolated 10 mg. *H NMR (DMSO-d6) 8 9.04 (s,. 1 H), 8.65 (s, 1H), 8.12-8.16 (d, /= 6 Hz, 1H), 7.98-8.05 (m, 5 H), 7.58-7.72 (m, 2 H), 7.32-7.36 (d, /= 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-fert-Butyl-benzenesulfonyI-l-piperazin-yl-isoquiiioIine, hydrochloride Isolated 10 mg. *H NMR (DMSO-^) 8 9.33 (s, 1 H), 8.57 (s, 1 H), 8.24-8.29 (d, /= 9 Hz, 1H), 8.11 (m, 2 H), 7.91-7.97 (d, J== 9 Hz, 2 H), 7.60-7.66 (d, /= 12 Hz, 2 H), 7.52-7.57 (d, /== 6 Hz, 1 H), 3.59-3.68 (m, 4 H), 3.29-3.40 (m, 4H), 1.24 (s, 9 H); LCMS: 410,411 #20 HPLC: 90%. Table 3 R 25 67 EXAMPLE NAME R* R3 32 4-Chloro-N-[4-(pyrrolidin-3-yloxy)-1 -naphthyl]benzenesulfonamide hydrochloride CI l l °H HN^ 33 4-Methoxy-N-[4-(pyrroIidin-3-yloxy)-1 -naphthyl]benzenesulfonamide hydrochloride (J) OMe 1 | % 34 5-Chloro-N-[4-(pyrrolidm-3-ylqxy)-l -naphthyl]thiophene-2-sulforanude hydrochloride 1 1 °H 35 4-Chloro-N-[4-(piperidin-3-yloxy)-l-naphthyl]benzenesulfonamide hydrochloride CI 0* 26 4-Methoxy-N-[4-(piperidin-3-yloxy)-l-naphthyl]benzenesulfonatnide hydrochloride OMe 37 5-Fluoro-2-methyl-N-[4-(piperidin-4-yloxy)-l-naphthyl]benzenesulfonattiide hydrochloride 0* 0 38 5-Chloro-N-[4-(piperidin-4-yloxy)-l-naphthyl]thiophene-2-sulfonarnide hydrochloride 0V $ 39 . 4-Chloro-H-{4-[(3S)-pyrrolidin-3-yloxy]-l-naphthyl}benzenesulfonamide hydrochloride °rx \ 0 1 4 68 40 4-CMoro-N-{4-[(3R)-pyirolidin-3-yloxy]-l-naphthyl}benzenesulfonamide hydrochloride CI XX o* -N H Scheme 4 Legend to Schieme 4;{i) tert-butyl 3-hydroxypyiroUdine-l-carbqxylate or tert-butyl 4-hydroxypiperidine-l-carboxylate, PPh3) DEAD, THF; (ii) H2(g), Pd/C, MeOH; (iii) Ri-S02-C1, pyridine, CH2C12; (iv) HC1 in diethyl ether General method C Mitsonobu reaction of 4-nitro-l-naphthol with boc-protected 3-hydroxypyrrolidine and 4-10 hydroxypiperidine 4-Nitro-l-naphthol (1 equiv.) was dissolved in THF (3 mL/mmol), tert-butyl 3-hydroxypyrrolidine-l-carboxylate (2 equiv.) was added followed by PPI13 (2 equiv.). The solution was kept under N2-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 69 formed precipitate was collected by filtration. The solution was concentrated in vacuo and purified by flash chromatography (SiCh, EtOAc:wo-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/rmnol), 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 CEfeCfe (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 HC1 (1M) (2 mL) and dried (MgS04). The volatiles were eliminated under vacuo and gave the crude product which were purified by flash chromatography (Si02, EtOAc: wo-hexane 1:4) to give desired sulfonamide. p) 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 HC1 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 (1 equiv.) was dissolved in MeOH (lmL/mmol) and cooled on ice-bath. (BOChO (1.1 equiv.) was added and the mixture was stirred for 2 h at ambient 30 temperature. Pyridine/water (10/1 OmL) was added and the mixture was stirred overnight. Evaporation of solvents and co-evaporation with toluene provided the desired boc-protected 3-hydroxypyrrolidine. 70 INTERMEDIATE 28 te/tf-Butyl 3-[(4-nitro-l-naphthyl)oxy]pyrrolidine-l-carboxylate (GeneralMethod C) The crude product was purified by column chromatography. The compound was prepared 5 from 4-nitro-l-naphthol (2.85 g, 15.1 mmol). The material thus obtained was dissolved in small amount of EtOAc and iso-hexme was added. The formed solid was collected by filtration and triturated with MeOH to give the pure title compound 4.6g (85%). HPLC 99%, Rf=2.70 (System Al, 10-97% MeCN over 3 min). *H NMR (400 MHz, CDC13) # 6 ppm 1.46 (d, 7.03 Hz, 9 H) 2.26-2.38 (m, 2 H) 3.60-3.81 (m, 4 H) 5.20 (br s, 1 H) 6.76 10 (d, /=8.53 Hz, 1 H) 7.58 (t, >=7.53 Hz, 1 H) 7.73 (t, J=7.53 Hz, 1H) 8.34 (dd, J=20.33, 8.78 Hz, 2 H) 8.75 (d, J=9.04 Hz, 1 H). MS (ESI+) for C19H22N2O5 m/z 376.2 (M+NH)+, 359.2 (M+H)+, 303.2 (M-/Bu)+. HPLC 99%, Rt=2.78 min (System Bl, 10-90% MeCN over 3 min). 15 INTERMEDIATE 29 ferf-Butyl 3-[(4-ammo-l-naphthyl)oxy]pyrrolidine-l-carboxylate (General Method D) The compound was prepared from intermediate 1 (2.6 g, 7.2 mmol), Yield: 2.1g (87 %) of tibe title compound as purple solid. HPLC 96 %, Rt=s1.768 min (System Al, 10-97 % MeCN over 3 min). HPLC 95 %, Ri=1.604 min (System Bl, 10-90% MeCN over 3 min). 0 *H NMR (400 MHz, DMSO-de) 5 ppm 1.37 (d, ,7=22.59 Hz, 9 H) 2.12 (s, 2 H) 3.43-3.46 (m, 4 H) 4.96 (s, 1 H) 5.50 (s, 2 H) 6.63 (d, J=8.03 Hz, 1 H) 6.81 (d, /-8.03 Hz, 1H) 7.41 (dd, >=6.02,3.01 Hz, 2 H) 7.94-8.01 (m, 2 H). MS (ESI+) for C19H24N2O3 m/z 329.2 (M+H)\ 273,2 (M-*Bu)+, 229.2 (M-Boc)\ 25 INTERMEDIATE 30 tot-Butyl 3-[(4-{[(4-chIoropheuyI)sulfouyI]amino}-l-naphthyl)ox>]pyrrolidiiie-l-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). *HNMR (400 MHz, CDCI3) Sppin 1.46 (d, /=4.02 Hz, 9 H) 2.18-2.30 (m, 2 H) 3.54-3.76 (m, 4 H) 5.05 (br s, 1 ~H) 6.62-6.65 (m, 1 H) 6.74-6.76 (m, 1H) 7.17-7.23 (m, 1 H) 7.32 (d, /=9.04 Hz, 2 H) 71 7.39-7.45 (m, 2 H) 7.62 (d, >8.53 Hz, 2H) 7.68-7.72 (m, 1 H) 8.16-8.19 (m, 1 H). MS (ESI+) for C25H27CIN2O5S m/z 520.2 (M+NHt)*, 447.0 (M-tBuf. HPLC 98%, Rr=2.738 min (System Bl, 10-90% MeCN over 3 min). INTERMEDIATE 31 tart-Butyl 3-[(4-{[(4-methoxyphenyI)sulfonyl]amino}-l-naphthyl)oxy]pyrroIidine-l-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%, Rf=2.617 min (System Al, 10-97% MeCN over 3 min). JH NMR (400 MHz, CDCI3) 8 ppm 1.45 (d, >=5.02 Hz, 9 H) 2.14-2.31 (m, 2 H)3.54-3.76 (m, 4H)3.79 (s, 3H) 5.04(br s, 1 H) 6.60-6.65 (m,2H) 6.81 (d, >8.53Hz, 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, 1H). MS (ESI+) for C26H30N2O6S m/z 516.4 (M+NH*)*, 443.0 (M-*Bu)+, 399.2 (M-Boc)+. INTERMEDIATE 32 tart-Butyl 3-[(4-{[(5-chloro-2-thienyl)sulfonyl]amino}-l-naphtliyl)oxy]pyrrolidine-l-carboxylate (General method E) The compound was prepared from intermediate 2 (0.2 g, 0.61 mmol), Yield: Q.21g (68%) of the title compound as a yellow solid. HPLC 99%, Rf=2.777 min (System Bl, 10-90% MeCN over 3 min). 'H NMR (400 MHz, CDCI3) 8 ppm 1.46 (d, >6.02 Hz, 9 H) 2.16-2.30 (m, 2 H) 3.55-3.74 (m, 4 H) 5.07 (br s, 1H) 6.67-6.70 (m, 1 H) 6.75 (d, >=4.02 Hz, 1H) 6.77 (br s, 1H) 7.13 (br s, 1H) 7.28-7.35 (m, 1 H) 7.46-7.48 (m, 2 H) 7.75-7.79 (m, 1H) 8.19-8,22 (m, 1H). MS (ESI+) for C23H25CIN2OSS2 m/z 526.2 (M+NH4)+> 453.0 (M-iBuf, 409.2 (M-Boc)+. HPLC 99%, Rr=2.767 min (System Al, 10-97% MeCN over 3 min). INTERMEDIATE 33 tart-Butyl 4-[(4-nitro-l-naphthyl)oxy]piperidine-l-carboxyIate (General method C) The compound was prepared from 4-nitro-l-naphthol (2 g, 10.6 mmol). The material obtained after flash chromatography was not pure according to NMR. Recrystallization from EtOAc/wo-hexane gave 2.3g (62%) of the title compound as a yellow solid. HPLC 98%, Rf=2.842 min (System Al, 10-97% MeCN over 3 min !H NMR (400 MHz, CDC13) 72 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, 7=9.04 Hz, 1 H) 7.59 (m, 1 H) 7.74 (m, 1 H) 8.38 (d, .7=8.53 Hz, 2 H) 8.77 (d, 7=8.53 Hz, 1 H). MS (ESI+) for C2oH24N205 m/z 373.0 (M+H)+, 390.2 (M+lSffiUf, 317.0 (M-®u)+. HPLC 98%, Rt=2.973 min (System B1,10-90% MeCN over 3 min). 5 INTERMEDIATE 34 tert-Butyl 4-[(4-amino-l-naphthyl)oxy]piperidine-l-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%, Rr=2.885 min (System Bl, 10-90% MeCN over 3 min). *H NMR 10 (400 MHz, CDCls) 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 C20H26N2O3 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-chIorophenyl)sulfonyl] amino}-l-naphthyI)oxy]piperidine-l-carboxylate (General method E) The compound was prepared from intermediate 7 (0.25 g, 0.73 mmol), Yield: 0.29g (77%). HPLC 98%, Rt=2.906 min (System Al, 10-97% MeCN over 3 min). *H NMR (400 MHz, #0 CDCI3) 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, 7=8.03 Hz, 1 H) 7.17 (d, 7=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 C26H29CIN205S m/z 534.0 <M+NH4)+, 461.2 (M-®u)+. HPLC 98%, Rt=2.843 min (System Bl, 10-90% MeCN over 3 min). 25 INTERMEDIATE 36 te/f-Butvl 4-[(4-{[(4-methoxypheiiyl)sulfoiiyI]aniino}-l-naphthyl)oxy]piperidine-l-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%, Rf=2.755 min (System Al, 10-97% 30 MeCN over 3 min). JH NMR (400 MHz, CDCI3) 8 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,1H) 6.69 73 (d, J=8.53 Hz, 1 H) 6.83-6.79 (m, 2 H) 7.17 (d, 7=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 C27H32N2O6S m/z 530.2 (M+NH4)* 457.2 (M-®u)+, 413.4 (M-Boc)+. HPLC 99%, Rf=2.668 min (System Bl, 10-90% MeCN over 3 min). 5 INTERMEDIATE 37 tert-Butyl 4-[(4-{[(5-fIuoro-2-inetIiylphenyI)suIfonyI]amiiio}-l-naphthyl)oxy]piperidine-l-carboxyIate (General method E) ^ The compound was prepared from tert-butyl 4-[(4-amino-l-naphthyl)oxy]piperidine-l-10 carboxylate (0.25 g, 0.73 mmol). Yield: 0.24 g (64 %) of the title compound as a pink solid. HPLC 99 %, Ri=2.809 min (System Bl, 10-90% MeCN over 3 min). *H NMR (400 MHz, CDCI3) 8 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, 2H) 4.64-4.68 (m, 1 H) 6.64-6.68 (m, 2 H) 7.03 (d, J=8.53 Hz, 1H) 7.10 (m, 1H) 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 C27H3iFN205S m/z 532.2 (M+NH4)+, 459.2 (M-tfiu)+, 415.2 (M-Boc)+. HPLC 100 %, Rr=2.877 min (System Al, 10-97% MeCN over 3 min). INTERMEDIATE 38 ^ tert-Butyl 4-[(4-{[(5-chIoro-2-thienyI)suIfonyl] ammo}-l-naphthyI)oxy]piperidine-l-carboxylate (General method E) The compound was prepared from tert-butyl 4-[(4-amino-l-naphthyl)oxy]pipeiidine-l-carboxylate (0.25g, 0.73mmol). Yield: 0.25 g (65 %) of the title compound as a pink solid. HPLC 98 %, Rt=2.827 min (System Bl, 10-90% MeCN over 3 min). lR NMR (400 MHz, 25 CDCI3) 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 (m, 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, 1H) 7.45-7.50 (m, 2 H) 7.76-7.79 (m, 1 H) 8.25-8.28 (m, 1 H) MS (ESI+) for C24H27CIN2O5S2 m/z 540.4 (M+NKtf, 467.2 (M-tBu)+. HPLC 99 %, Ri=2.910 min (System Al, 10-97 % MeCN over 3 min). 74 INTERMEDIATE 39 tert-Butyl (3R)-3-hydroxypyrroIidine-l-carboxylate (General method G) The compound was prepared from (3R)-3-hydroxypyrroIidine (5 g, 57.4 mmol). Yield: 9.6 g (90 %) of the title compound. NMR (400 MHz, CDCI3) 8 ppm 1.43 (s, 9 H) 1.90-1.98 5 (m, 2 H) 3.27-3.47 (m,4H) 4.40 (brs,lH). INTERMEDIATE 40 tert-Butyl (3S)-3-hydrovypyrrolidine-l-carboxyIate (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. 1HNMR(400MHz, CDCI3) 8ppm 1.40 (s, 9 H) 1.86-1.91 (m, 2 H) 3.24-3.42 (in. 4H) 4.36 (br s, 1H). INTERMEDIATE 41 tert-Butyl (3S)-3-[(4-nitro-l-naphthyI)oxy]pyrrolidine-l-carboxylate (General method 15 C) The compound was prepared from tert-butyl (3R)-3-hydroxypyrrolidine~l-carboxylate (3.56 g, 19 mmol) and 4-nitro-l-naphthol (3 g, 15.9 mmol). Yield: 5 g (88 %) of the title compound as yellow oil. *H NMR (400 MHz, CDCI3) 8 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, 1H) 6.74 (d, J=8.53 Hz, 1 H) 7.56 (t, #0 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 Q9H22N2O5 m/z 376.2 (M+ NH4)+, 303.2 (M-<Bu)+. HPLC 100 %, Rt=2.768 min (System Al, 10-97% MeCN over 3 min). INTERMEDIATE 42 25 tert-Butyl (3R)-3-[(4-nitro-l-naphthyl)oxy]pyrrolidme-l-carboxylate (General method C) The compound was prepared from tert -butyl (3S)-3-hydroxypyrrolidine-l-carboxylate (3.56 g, 19 mmol) and 4-nitro-l-naphthol (3 g, 15.9 mmol). Yield: 2.8 g (49 %) of the title compound as yellow oil. *H NMR (400 MHz, CDCI3) 8 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, 1H) 7.59 (t, 75 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 %, Rt=2.775 min (System Al, 10-97 % MeCN over 3 min). INTERMEDIATE 43 5 tert-Butyl (3S)-3-[(4-amino-l-naphthyI)oxy]pyrrolidine-l-carboxyIate (General method D) The compound was prepared from tert-butyl (3S)-3-[(4-nitro-l-naphthyl)oxy]pyrrolidine-1-carboxylate (5 g, 14 mmol). Yield: 3.5 g (76 %) of the title compound as dark pink solid. £ lE NMR (400 MHz, CDCI3) 5 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, 1H) 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 C19H24N2O3 m/z 329.2 (M+H)+, 273.2 (M-tBu)+, 229.2 (M-Boc)+. HPLC 95 %, Ri=l .854 min (System Al, 10-97 % MeCN over 3 min). 15 INTERMEDIATE 44 tert-Butyl (3R)-3-[(4-amino-l-naphthyl)oxy]pyrroIidine-l-carboxyIate (General method D) The compound was prepared from tert -butyl (3R)-3-[(4-nitro-l-naphthyl)oxy]pyirolidine-1-carboxylate (2.8 g, 7.8 mmol). Yield: 1.8 g (72 %) of the title compound as dark pink 0) solid. *H NMR (400 MHz, CDCI3) 5 ppm 1.46 (d, J=14.56 Hz, 9 H) 2.07-2.14 (m, 1H) 2.27-2.30 (m, 1H) 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 C19H24N203 m/z 329.2 (M+H)+, 273.2 (M-tBu)+, 229.2 (M-Boc)+. HPLC 94 %, Rt=1.751 min (System Al, 10-97% MeCN over 3 min). 25 INTERMEDIATE 45 tert-Butyl (3S)-3-[(4-{[(4-chIorophenyl)sulfonyl]amino}-l-naphthyl)oxy]pyrroIidine-l-carboxylate (General method E) The compound was prepared from tert-butyl (3S)-3-[(4-nitro-l-naphthyl)oxy]pyrrolidine-30 1-carboxylate (0.3 g, 0.9 mmol) and 4-chloro-phenylsulfonylchloride (0.23 g, 1.1 mmol). Yield: 0.23 g (50 %) of the title compound. *H NMR (400 MHz, CDCI3) 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, 1H) 6.62-6.71 (m, 2 H) 76 7.17-7.23 (m, 1 H) 7.33 (d, J=8.53 Hz, 1H) 7.39-7.43 (m, 2 H) 7.62-7.64 (m, 2 H) 7.65-7.70 (m, J=6.02 Hz, 1H) 8.18 (d, J=8.53 Hz, 1H) MS (ESI+) for C25H27C]N205S m/z 520.2 (M+NH4>+, 447.0 (M-tfiu)+. HPLC 100 %s Rf=2.772 min (System Al, 10-97 % MeCN over 3 min). 5 INTERMEDIATE 46 tert-Bntyl (3R)-3-[(4-{[(4-chIoropheiiyI)sulfonyI]ammo}~l-naphthyI)oxy]pyrrolidine-1-carboxylate (General method E) The compound was prepared from tert-butyl (3R)-3-[(4-nitro-l-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, 'h NMR (400 MHz, CDCI3) 5 ppm 1.46 (d, J=4,52Hz, 9 H) 2.15-2-34 (m, 2H) 3.54-3.74 (m, 4H) 5.05 (br s, 1H) 6.60-6.66 (m, 2H) 7.17-7.23 (m, 1 H) 7.33 (d, J=8.53 Hz, 1H) 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 C25H27C1N20sS m/z 15 520.2 (M+NH4)+, 447.0 (M-tBu)+. HPLC 100 %, Rf=2.769 min (System Al, 10-97 % MeCN over 3 min). EXAMPLE 32 4-Chloro-N-[4-(pyrrolidin-3-yloxy)-l-naphthyl]benzenesulfonamide 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 0.11 g (95%) of the title compound as white solid. HPLC 98%, Rr=1.810 min (System Al, 10-97% MeCN over 3 min). !H NMR (400 MHz, DMSO-d6) 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, 1H) 8.20-8.23 (m, 1 H). MS (ESI+) for C2oHi9ClN203S m/z 401.2 (M+H)+. HPLC 98%, Ri=1.651 min (System Bl, 10-90% MeCN over 3 min). 77 EXAMPLE 33 4-Methoxy-N-[4-(pyrroUdin-3-ytoxy)-l-naphthyl]benzenesuIfonamicle hydrochloride (General method F) The compound was prepared from intermediate 4 (0.18 g, 0.36 mmol), Yield: 0.12 g (76%) of the title compound as a white solid. HPLC 100%, Rr=1.490 min (System Bl, 10-90% MeCN over 3 min). 'H NMR (400 MHz, DMSO-d6) 8 ppm 2.20-2.25 (m, 2 H) 3.31-3.53 (m, 4 H) 3.78 (s, 3 H) 5.27 (br s, 1 H) 6.90-6.97 (m, 2 H) 7.00 (d, .7=8.53 Hz, 2 H) 7.43-7.48 (m, 2 H) 7.57 (d, .7=8.53 Hz, 2 H) 7.93-7.96 (m, 1 H) 8.19-8.22 (m, 1 H) 9.63 (br s, 2 H). MS (ESI+) for C21H22N2O4S m/z 409.2 (M+H)+. HPLC 100%, R^l.639 min "10 (System Al, 10-97% MeCN over 3 min). EXAMPLE 34 5-Chloro-N-[4-(pyrroIidin-3-yloxy)-l-naphthyl]tIiiophene-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 apale white solid. HPLC 99%, Rf=1.651 min (System Bl, 10-90% MeCN over 3 min). 'H NMR (400 MHz, DMSO-de) 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, 1H) 6.99 (d, J=8.53 Hz, 1 H) 7.13 (d, /=8.03 Hz, 1 H) 7.15 (d, <7=4.02 Hz, 1 H) 7.26 (d, /=4.02 Hz, 1 H) 7.48-7.52 (m, 2 H) 7.92 (dd, <7=6.53,3.01 Hz, 1 H) 8.25 (dd, .7=6.53,3.01 Hz, 1 H) 9.60 (s, 1 H). MS (ESI+) for C18H17CIN2O3S2 m/z 409.2 (M+H)+. HPLC 99%, Ri=l,818min (System Al, 10-97% MeCN over 3 min). EXAMPLE 35 25 4-Chloro-N-[4-(piperidin-3-yIoxy)-l-naphthyl]benzenesulfonamide hydrochloride (General method F) The compound was prepared from intermediate 8 (0.26 g, 0.50 mmol), Yield: 0.12 g (53%) ofthe title compound as a white solid. HPLC 100%, Ri=1.872 min (System Al, 10-97% MeCN over 3 min). *H NMR (400 MHz, DMSO-dg) 8 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, 1H) 6.92-6.99 (m, 2 H) 7.44-7.51 (m, 2 H) 7.57-7.65 (m, 4 H) 7.91 (d, 7=7.53 Hz, 1 H) 8.17 (d, .7=7.03 Hz, 1 H) 8.94 (br s, 1 78 H) 9.05 (br s, 1 H) 10.11 (s, 1H). MS (ESI+) for C2iH2iC1N203S m/z 415.2 (M+H)+. HPLC 99%, Ri=1.657 min (System Bl, 10-90% MeCN over 3 min). EXAMPLE 36 5 4-Methoxy-N-[4-(piperidin-3-yIoxy)-l-naphthyI]benzenesulfonamide hydrochloride (General method F) The compound was prepared from intermediate 9 (0.19 g, 037 mmol), Yield: 0.15 g (90%) of the title compound as a white solid. HPLC 97%, Rr=l .508 min (System Bl, 10-90% MeCN over 3 min). *H NMR (400 MHz, DMSO-de) 8 ppm 1.96 (m, 2 H) 2.16 (m, 2 H) 10 3.10 (m, 2 H) 3.26 (m, 7=6.02 Hz, 2 H) 3.78 (s, 3 H) 4.82 (m, 1H) 6.95 (q, >8.20 Hz, 1 H) 7.01 (d, 7=9.04 Hz, 2 H) 7.47 (m, 2 H) 7.57 (m, 2 H) 7.96 (m, 1H) 8.16 (m, 1 H) 8.96 (s, 1H) 9.07 (s, 1 H) 9.81 (s, 1 H). MS (ESI+) for C22H24N204S 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-methyI-N-[4-(piperidm-4-yIoxy)-l-naphthyl]benzenesuIfonainide 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). *H NMR (400 MHz, CH30H-d4) 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, >8.53 Hz, 1 H) 6.97 (d, 7=8.03 Hz, 1H) 7.10 (m, 1H) 7.24 (m, >8.53,5.52 Hz, 1 H) 7.35 (m, 3 H) 7.83 (m, 1H). MS (BSI+) for Q52H23FN2O3S m/z 415.2 (M+H)+. HPLC 96 %, R^l.628 min (System Bl, 10-90% MeCN over 3 min). 25 EXAMPLE 38 5-Chloro-N-[4-(piperidin-4-yloxy)-l-naphthyl]tbiophene-2-sulfonamide hydrochloride (General method F) The compound was prepared from tert-butyl 4-[(4-{[(5-fluoro-2 methylphenyl)-30 sulfonyl]amino}-l-naphthyl)oxy]piperidine-l-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-d6) 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, 79 1 H) 7.04-7.11 (m, 2 H) 7.16 (d, 7=4.02 Hz, 1 H) 7.26 (d, 7=4.02 Hz, 1H) 7.48-7.53 (m, 2 H) 7.92-7.94 (m, 1H) 8.19-8.21 (m, 1 H) 9.06 (br s, 1 H) 10.36 (br s, 1 H). MS (ESI+) for C19H19CIN2O3S2 m/z 423.0 (M+H)+. HPLC 99 %, Rt=1.861 min (System Al, 10-97 % MeCN over 3 min). 5 EXAMPLE 39 4-ChIoro-N-{4-[(3S)-pyrrolidin-3-yloxy]-l-naphthyl}benzenesulfonamide hydrochloride (General method F) ^ The compound was prepared from tert-butyl (3S)-3-[(4- {[(4-10 chlorophenyl)sulfonyl]amino}-l-naphthyl)oxy3pyrrolidine-l-carboxylate (0.22 g, 0.44 mmol). Yield: 0.15 g (78 %) of the title compound as a yellow solid. *H NMR (400 MHz, CH3OH-d4) 8 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, 7=8.03 Hz, 1 H) 7.14 (d, 7=8.03 Hz, 1 H) 7.38-7.47 (m, 4 H) 7.61 (d, 7=8.53 Hz, 2 H) 7.83 (d, 7=8.03 Hz, 1 H) 8.22 (d, 7=8.03 Hz, 1H). MS (ESI+) for C2oH19ClN203S 15 m/z 403.2 (M+H)+. HPLC 10Q %, Ri=l .826 min (System Al, 10-97 % MeCN over 3 min). EXAMPLE 40 4-Chloro-N-{4-[(3R)-pyrroIidin-3-yIoxyJ-l-napIithyI}benzenesuIfonamide hydrochloride (General method F) 20 Hie 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. *H NMR (400 MHz, CHjOH-dt) 8 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, 1H) 6.88 (d, J=8.53 Hz, 1H) 7.15 (d, J=8.03 Hz, 1H) 7.39-7.47 (m, 4 H) 7.60-7.62 25 (m, 2 H) 7.83 (d, J=7.53 Hz, 1H) 8.22 (d, J-8.03 Hz, 1 H). MS (ESI+) for C20H19CIN2O3S m/z 403.2 (M+H)+. HPLC 100 %, Rf=1.815 mill (System Al, 10-97 % MeCN over 3 min). Table 4 80 EXAMPLE R2 R3 R4 41 N-(4-Methylphenyl)-4-(4-methylpiperazin-1 -yl)thieno [3,2-c]pyridine-2-sulfonamide hydrochloride 1 h H CN) V ch3 42 2-Bromo-4-(4~methyl-piperazin-l-yl)-thieno[3,2-c]pyridine-3-sulfonic acid p-tolylamide hydrochloride Br °'sP XX i h 0 V ch3 43 4-(4-Methylpiperazin-l-yl)-N-phenylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride h 11 0 V ch3 44 4-Piperazin-1 -yl-thieno[3,2-c]pyridine-2-sulfonic acid (3-fluoro-5-trifluoromethyl-phenyl)-amide hydrochloride t 3 H H 0 N 45 4-Piperazm-l-yl-thieno[3,2-c]pyridine-2-sulfonic acid (4-chloro-phenyl)-amide hydrochloride s&o* 1 h H 0 N 46 4-Piperazin-l-yl-thieno[3,2-c]pyridine-2-sulfonic acid (4-isopropyl-phenyl)-amide hydrochloride H H 0 N 47 4-Piperazin-1 -yl-thieno[3,2-c]pyridine-2-sulfonic acid /7-tolylamide hydrochloride H H C) N 48 4-(4-Methylpiperazin-1 -yl)-N- (2-cyclohex-l-en-l-yletiiyl) thieno [3,2-c] pyridine-2-sulfonamide hydrochloride h H 9 49 2-(4-(4-Methylpiperazin-l-yl) thieno [3,2-c] pyridm-2-ylsulfonyl)-l,2,3,4-tetrahydroisoquinoline hydrochloride 0.--P K00 H $ 50 4-(4-Methylpiperazin-1 -yl)-N- (2-thien-2-ylethyl) thieno [3,2-c] pyridines-sulfonamide hydrochloride °^° i3 1 h H 9 81 51 4 -(4-Methylpiperazin-1 -yl) -AT- [ 1 -(1 -naphthyl) ethyl] thieno [3,2-c] pyridines-sulfonamide hydrochloride H Vi H $ 52 4-(4-Methylpiperazin-1 -yl)-vV- (4-hexylphenyl) thieno [3,2-c] pyridines-sulfonamide hydrochloride -r^^-n-heicyl H H 9 53 N- (3-Chlorobenzyl)-4-(4-methylpiperazin-1-yl) thieno [3,2-c] pyridine-2-sulfonamide 0. -P -■ray H "A Y 54 4-(4-Methylpiperazin-1 -yl)-N- [l-(4-fluorophenyl) ethyl] thieno [3,2-c] pyridine-2-sulfonamide hydrochloride °:1\x H "6 T 55 N- (2,3-Difluorobenzyl)-4-(4-methylpiperazin-l-yl) thieno [3,2-c] pyridine-2-sulfonamide hydrochloride *>;CO f H $ 56 4-(4-Methylpiperazin-l-yl)-iV- (4-chloro-2, 5-dimethoxyphenyl) thieno [3,2-c] pyridine-2-sulfonamide hydrochloride H 1 H $ 57 2-Bromo-4~ (4-methylpiperazin-1 -y\)-N-(2-cyclohex-l-en-l-ylethyl) thieno [3,2-c] pyiidine-3-sulforamide hydrochloride Br is '9 | 58 2-[2-Bromo-4-(4-methyl-piperazin-l- yl)-benzo[b]thiophene-3-sulfonyl]-l ,2,3,4-tetrahydro-isoquinoline Br 0,o-P x CO $ 59 2-Bromo-4- (4-methylpiperazin-1 -yl)-N-[l-(4-fluorophenyl) ethyl] thieno [3,2-c] pyridine-3-suifonaniide hydrochloride Br ?) Y 60 2-Bromo-4- (4-methylpiperazin-1 -yl)-N-(4-chloro)-(2, 5-dimethoxyphenyl) thieno [3,2-c] pyridine-3-sulfonatnide hydrochloride Br H ' "6 Y 82 61 N-(3,4-DicMorophenyl)-4-piperazin-l-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride vS'^Xlci H H 0 N 62 N-(2,4-Difluorophenyl)-4-piperazin-1 -ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride K-C'f h F H 0 N 63 4-Piperazin-l-yl-N-[-3-(trifluoromethyl)phenyl]thieno[3,2-c]pyridine-2-sulfonamide hydrochloride ,,°A '< n^CF, H 3 H 0 N 64 N-(3-Ethylphenyl)-4-piperazin-l- ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride H 1 H 0 IT 65 N-(3,4-Dimethoxyphenyl)-4-piperazm-l- ylthieno[3,2-c]pyridine-2-sulfonainide hydrochloride o.,» ft0" KS'N-^P H T H 0 N 66 N-(4-Bromo-2-methylphenyl)-4-piperazin- l-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride ^Br H 1 11 0 N 67 2-(4-Piperaziii-l-yl-lhieno[3,2-c]pyridme- 2-sulfonyl)-l,2,3,4-tetrahydro-isoqumoline hydrochloride 0. -P KC0 H (") N 68 4-Piperazin-1 -yl-thieno[3,2-c]pyridine-2-sulfonic acid (2-thiophen-2-yl-ethyl)-amide hydrochloride °,sp_ $y H H 0 69 4-Piperazin-l-yl-thienot3,2-c]pyridine-2-sulfonic acid (4-chloro-2,5-dimethoxy-phenyl)-amide hydrochloride %<xx, H ' H 0 N 83 70 4-Piperazin-1 -yl-thieno [3,2-c]pyridine-2-sulfonic acid phenethyl-amide hydrochloride H H C) N 71 4-Piperazin-l-yl-thieno[3,2-c]pyridine-2-sulfonic acid (2,6-diethyl-phenyl)-aniide hydrochloride H 0 N 72 > 4-Piperazin-l-yl-thieno[3,2-c]pyridine-2-sulfonic acid (3-phenyl-propyl)-anride hydrochloride H II 0 73 4-Piperazin-l-yl-thieno[3,2-c]pyridine-2-sulfonic acid (3,3-diphenyl-propyl)-amide hydrochloride v kjO KSnNJV^ Ho H C) N 74 4-Piperazin-1 -yl-thieno[3,2-c]pyridine-2-sulfonic acid [2-(5-methoxy-1 H-indol-3-yl)-ethyl]-amide hydrochloride vCA H N 75 4-Piperazin- l-yl-thieno[3>2-c]pyridine-2-sulfonic acid 4-trifluoromethyl-benzylamide hydrochloride %s;Xr°Fa H H 0 N 76 4-Piperazin- l-yl-thieno[3,2-c3pyridine~2-sulfonic acid ben2yl-ethyl-amide hydrochloride v° OX1 H 0 IT 77 N-(3-Ethylphenyl)-4-piperazin-l- yltMeno[3,2-c]pyridine-3-sulfonamide hydrochloride H v° Cr^ C) N 78 N-(4-Isopropylphenyl)-4-piperazin-l-ylthieno[3,2-c]pyridine-3-sulfonamide hydrochloride H v° 0 N 84 79 N-(4-Methylphenyl)-4-(pyrrolidin-3- yloxy)thieno[3,2-c]pyridine-2-sulfonamide hydrochloride I?] xx** h H ox^ 6 80 N-(4-Methylphenyl)-4-(piperidin-4- yloxy)thieno[3,2-c]pyridine-2-sulfonamide hydrochloride m "V- H 0^ 81 N-(2,3 -Difluorobenzyl)-4-piperazin-1 -ylthieno[3,2-c]pyridine-2-sulfonaniide hydrochloride m <x ^nh-so2- h 0 n 82 N-(3-Chlorobenzyl)-4-piperazin-l - yltfaieno[3,2-c]pyridine-2-sulfonamide hydrochloride [?] a" nh-so2- H 0 N Scheme 5 Legend to Scheme 5: i) Malonic acid, pyridine, piperidine, heat; ii) ethylchloroformate, acetone, NaN3 -10 5 °C-, iii) diphenyl ether, 220 °C; iv) POCI3, heat; v) gas SO2, n-BuLi, N-chlorosuccinunide, CH2C12; vi) R1-NH2, pyridine; vii) HR3, K2C03, DMSO, heat. INTERMEDIATE 47 (2iT)-3-(5-Bromothien-2-yl) acrylic acid 85 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 niglit. The volatiles were evaporated and the residue was dissolved in water and acidified with hydrochloric acid (pH 2). The crude product was crystallized in ethanol. Yield: 55.24 g (90.5 %). NMR (270 MHz, CHsOH-d,) 5 ppm 6.14 (d, 7=15.83 Hz, 1 H) 7.11-7.16 (m, 2 H) 7.68 (d, 7-16.36 Hz, 1 H); MS 233.1 (M - H)+; Purity (HPLC) 94 %. INTERMEDIATE 48 10 (2JE)-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 mmol) 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 MgS(>4, filtered and the solvent was removed to afford: 0.96 g (83.4 %). lR NMR (270 MHz CHaOH-dO 8 ppm 6,20 (d, 7=15.57 Hz, 1 H) 7.15-7.25 (m, 2 H) 7.80 (d, 7=15.57 Hz, 1 H); MS 258.1 (M - H)+; Purity (HPLC) 65%. INTERMEDIATE 49 2-Bromothieno [3,2-c] pyridin-4 (5J9f)-one A solution of (2£)-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 lh. 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 %). *H NMR (270 MHz, DMSO-d6) 8 ppm 6.82 (d, 7=7.13 Hz, 1 H) 7.27 (d, 7=6.86 Hz, 1 H) 7.54 (s, 1 H) 11.55 (s, 1 H); MS 230.1 (M - H)+; Purity (HPLC) 92 %. 30 86 INTERMEDIATE 50 2-Bromo-4-chloro-thieno [3,2-c] pyridine Phosphorus oxychloride (4.08 g, 26.6 mmol) was added dropwise to 2-bromothieno [3,2-c] pyridin-4 (5H)-one (2.04 g, 8.87 mmol) at 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, CHsOH-tU) 8 ppm 7.67 (d, 1 H) 7.88 (dddd, 7=6.33 Hz, 2 H) 8.19 (d, 7=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-suIfonyl chloride n-Butyl lithium (1.5 mL, 2.4 mmol) was added to 2-bromo-4-chlorothieno [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 SO2 (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-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 MgSC>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-Cliloro-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 p-Toludine (30 mg, 2.87 mmol) 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 87 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 4-(4-MethyI-piperazin-l-yl)-thieno[3,2-c]pyridine-2-sulfonic acid p-tolylamide hydrochloride and 2-bromo-4-(4-methyl-piperazin-l~yl)-thieno[3,2-c]pyridiiie-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 K2CO3 (28.5 mg, 0.21 mmol) was heated to 100°C over night. The reaction mixture was dissolved in water and extracted with ethyl acetate (3x10 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-l-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: *H NMR (270 MHz, Methanol^) 5 ppm 2.26 (s, 3H) 2.98 (s, 3 H) 3.40-3.55 (m, 8 H) 7.02-7.10 (m, 6 H) 7.55 (d, 7=5.81 Hz, 1 H) 7.69 (s, 1 H) 8.13 (d, 7=5.81 Hz, 1H); LC-MS 403 (M + H)+; Purity (LC-MS) 92 % and 3.8 mg 2-bromo-4-(4-methyl-piperazin-l-yl)-thieno[3,2-c]pyridine-3-sulfonic acid p-tolylamide. The free base was converted into the hydrochloride salt by ^0 treatment with HC1 in ether: *H NMR (270 MHz, Methanol-*^) 8 ppm 2.21 (s, 1H) 3.00 (d, 3H) 3.50-3.77 (m, 8 H) 7.00-7.10 (m, 6 H) 7.63 (d, 7=5.81 Hz, 1H) 8.19 (d, 7=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 Trisamine™ (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 1M aqueous HC1 (2 times). The combined organic phases were dried (MgS04), filtered, and the solvent was removed to give the sulfonamide product. In cases of low- 88 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) To the reaction mixtures from the Method H, dissolved in DMSO (2mL), amines (15 equiv.) and K2CO3 (1 equiv.) are added. The reactions are stirred at 100°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 ^>0%) 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 performed by first dissolving the substance in methanol and adding portions of 1M HCl/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 HC1 in diethyl ether. Stirring at ambient temperature overnight resulted in a precipitate which were collected by filtration to give the products as their corresponding hydrochloride salts. EXAMPLE 43 4-(4-Methylpiperaziii~l-yl)-N-phenylthieno[3,2-c]pyridme-2-sulfonamide hydrochloride 25 The synthesis was preformed essentially as described in Method H-L. Yield: 8.1 mg (33.8 %). lE NMR (270 MHz, CH3OH-d4) 8 ppm 8.13 (d, /=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-l-yI-thieno[3,2-c]pyridine-2-sulfopic acid (3-fluoro-5-trffluoromethyl-phenyl)-amide hydrochloride 89 4-[2-(3-Fluoro-5-trifluoromethyl-phenylsulfamoyl)-thieno[3,2-c]pyridin-4-yl]-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), Purity: 99 %. MS: 461 (M+l) *H NMR (270 MHz, CHsOH-dt) 8 ppm 3.47 (m, 4 H) 3.53 (s, 1 H) 3.87 (m, 4 H) 7.21 (m, 1 H) 7.29 (m, 1H) 7.33 (s, 1 H) 7.66 (d, J=6.33 Hz, 1 H). EXAMPLE 45 4-Piperazin-l -jI-lliicno|3,2-c]pyridine-2-sulfonic acid (4-chIoro-phenyl)-amide 10 hydrochloride 4-Chloro-thicno[3,2-c]pyTidine-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: tR= 0.905 (System: 30 % lo 60 % ACN in 1.5 min, Hypersil BDS), Purity: 97%. MS: 409 15 (M+l). 'H NMR (270 MHz, CHaOH-dj) 8 ppm 3.50 (m, 4 H) 3.91 (m, 4 H) 7.25 (m, 4 H) 7.71 (dd, /=6.33,0.53 Hz, 1 H) 7.96 (d, J=0.79 Hz, 1H) 8.04 (d, /=6.33 Hz, 1H). EXAMPLE 46 4-Piperazm-l-yl-thieno[3,2~c]pyridiiie-2-suIfonic acid (4-isopropyl-phenyI)-amide p hydrochloride 4-Chloro-thieno[3,2-c]pyridine-2-sulfonic acid (4-isopropyl-phenyl)-amide (0.201 mmol, 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: fa- 1.255 (System: 30% to 60 % ACN in 1.5 min, Hypersil BDS), Purity: 98 %. MS: 417 (M+l). *H NMR (270 25 MHz, CH3OH-d4) 8 ppm 1.18 (d, >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, .7=6.60 Hz, 1 H) 8.02 (m, 1H). EXAMPLE 47 4-Piperazin-l-yl-thieno[3,2-c]pyridine-2-sulfonic acid />-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 by j>tolylamine (0.307 g, 2.86 mmol). The reaction mixture was stirred at room temperature for 16 hours. The 90 mixture was concentrated and re-dissolved in DMSO (10 mL), piperazine-1 -carboxylic acid tert-butyl ester (1.34 g, 7.17 mmol) andK2C03 (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 organic phase was dried (NaaSO,*) and concentrated. The crude intermediate was purified by column chromatography on silica using EtOAc/w-pentane (1:1) as eluent. The intermediate was dissolved in EtOAc/MeOH and diethyl ether saturated with HC1 (g) was added. The mixture was stirred at room temperature for 16 hours. The precipitate was collected by filtration and washed with diethyl ether/rc-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-dg, 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 (m, 4H), 3.68-3.59 (m, 4H), 3.33-3.22 (m, 4H), 2.20 (s, 3H); m/z (posESI) 399 (M+H). 15 EXAMPLE 48 4-(4-Methylpiperazin-l-yI)-iV- (2-cyclohex-l-en-l-ylethyl) thieno [3,2-c] pyridines-sulfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. Yield: 25.6 mg *H NMR (270 MHz, DMSO-d6) 8 ppm 10.49-10.48 (m, 1H) 8.23-7.95 (m, 3H) 7.72-7.71 (m, 1H) 5.34-5.33 (m, 1H) 4.14-4.11 (m, 2H) 3.53-3.51 (m, 2H) 3.29-3.25 (m, 2H) 2.98-2.97 (m, 2H) 2.85 (s, 3H) 2.04-1.81 (m, 4H) 1.57-1.15 (m, 8H); LC-MS 420.17 (M - H)+; Purity (LC-MS) 97%. EXAMPLE 49 25 2-(4~(4-Methylpiperazin-l-yi) thieno [3,2-c] pyridin-2-ylsulfonyl)-l,2,3,4-tetrahydroisoquinoline hydrochloride The synthesis was preformed essentially as described in Method H-L. Yield: 15.5 mg *H NMR (270 MHz, DMSO-d6) 8 ppm 10.49-10.48 (m, 1H) 8.17-8.15 (m, 1H) 7.86-7.85 (m, 1H) 7.70-7.65 (m, 2H) 7.28-7.12 (m, 3H) 3.97-3.94 (m, 2H) 3.87-3.85 (m, 2H) 3.25-3.18 30 (m, 2H) 2.84 (s, 3H) 1.67-1.65 (m, 2H) 3.51-3.34 (6H obscured by solvent signal); LC-MS 428.13 (M - H)+; Purity (LC-MS) 99 %. 91 10 EXAMPLE 50 4-(4-Methylpiperazin-l-yl)-iV- (2-thien-2-ylethyl) thieno [3,2-c] pyridine-2-sulfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. Yield: 29.5 mg ]H NMR (270 MHz, DMSO-dg) 5 ppm 10.28-10.27 (m, IH) 8.34-8.33 (m, IH) 8.19-8.17 (m, IH) 8.01-8,00 (m, IH) 7.71-7,69 (m, IH) 7.31-7.30 (m, IH) 6.91-6.87 (m, IH) 4.13-4.10 (m, 2H) 3.53-3.51 (m, 2H) 3.29-3.25 (m, 2H) 3.17-3.16 (m, 2H) 2.99-2.95 (m 4H) 2.86 (s, 3H); LC-MS 422.09 (M - H)+; Purity (LC-MS) 99%. EXAMPLE 51 4-(4-Metliylpiperazin-l-yl)-iV- [l-(l-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-de) 8 ppm 10.28-10.27 (m, IH) 8.85-8.84 (m, IH) 8.02-8.01 (m, IH) 7.67-7.60 (m, 4H) 7.53-7.50 (m, 2H) 7.39-7.36 (m, 2H) 4.72-4.70 (m, IH) 3.87-3.84 (m, IH) 3.72-3.70 (m, IH) 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 %. 120 EXAMPLE 52 4-(4-Methylpiperazin-l-yl)-iV- (4-hexylphenyl) thieno [3,2-c] pyridine-2-sulfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. 8,0 mg *H NMR (270 MHz, DMSO-de) 8 ppm 10.39-10.38 (m, IH) 8.16-8.15 (m, IH) 7.90-7.89 (m, IH) 25 7.66-7.65 (m, IH) 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, 2H) 1.24-1.22 (m, 8H) 0.82-0.81 (m, 3H); LC-MS 472.20 (M - H)4; Purity (LC-MS) 98 %. 92 EXAMPLE 53 N- (3-ChlorobenzyI)-4-(4-methyIpiperazin-l-yl) thieno [3,2-c] pyridme-2-sulfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. 30.7 mg *H NMR 5 (270 MHz, DMSO-d6) 8 ppm 10.25-10.24 (m, IH) 8.78-8.77 (m, IH) 8.18-8.17 (m, IH) 7.91-7.90 (m, IH) 7.68-7.67 (m, IH) 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-l-yl)-iV- [l-(4-fluorophenyI) ethyl] thieno [3,2-c] pyridines-sulfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. 32.9 mg !H NMR (270 MHz, r>MSO-d6) 8 ppm 10.16-10.15 (m, IH) 8.75-8.73 (m, IH) 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 00 Ar- (2,3-Difluorobenzyl)-4-(4-methylpiperazin-l-yl) thieno [3,2-c] pyridine-2-sulfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. 26.7 mg *H NMR (270 MHz, DMSO-de) 8 ppm 10.36-10.35 (m, IH) 8.82-8.81 (m, IH) 7.96-7.95 (m, IH) 7.69-7.68 (m, IH) 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 (m, 2H) 2.68 (s, 3H) 2.86-2.60 (2H obscured by solvent signal); LC-MS 438.10 (M - H)+; Purity (LC-MS) 93 %. 93 EXAMPLE 56 4-(4-Methylpiperazin-l-yl)-iV- (4-chIoro-2,5-dimethoxyphenyl) thieno [3,2-c] pyridine-2-suIfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. 14.6 mg 'H NMR 5 (270 MHz, DMSO-de) 8 ppm 10.27-10.26 (m, IH) 10.14-10.13 (m, IH) 8.18-8.17 (m, IH) 7.83-7.82 (m, IH) 7.69-7.68 (m, IH) 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 (LCMS) 95 %. 10 EXAMPLE 57 2-Bromo-4- (4-methylpiperazin-l-yl)-A- (2-cyclohex-l-en-l-ylethyI) thieno [3,2-c] pyridine-3-sulfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. 4.6 mg *H NMR (270 MHz, DMSO-de) 8 ppm 10.30-10.29 (m, IH) 8.31-8.27 (m, 2H) 7.89-7.88 (m, IH) 15 5.27-5.26 (m, IH) 3.68-3.52 (m, 4H) 3.05-3.04 (m, 2H) 2.88-2.87 (m, 3H) 2.04-2.03 (m, 2H) 2.77-1.81 (m, 2H) 1.54-1.15 (m, 10H); LC-MS 498.08 (M - H)+; Purity (LC-MS) 93 %. EXAMPLE 58 ^O 2-[2-Bromo-4-(4-methyI-piperazin-l-yl)-benzo[b]thiophene-3-sulfonyl]-l ,2,3,4-tetrahydro-isoquinoIine hydrochloride The synthesis was preformed essentially as described in Method H-L. Yield: 3 .7 mg JH NMR (270 MHz, DMSO-d6) 8 ppm 10.30-10.29 (m, IH) 9.24-9.22 (m, IH) 8.09-8.08 (m, IH) 7.67-7.35 (m, 7H) 4.69-4.66 (m, IH) 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-l-yl)-7V- [l-(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 JH NMR (270 MHz, DMSO-d6) 8 ppm 10.35-10.34 (m, IH) 9.16-9.14 (m, IH) 8.23-8.22 (m, 94 IH) 7.80-7.79 (m, IH) 7.26-7.25 (m, IH) 4.55-4.52 (m, IH) 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%. EXAMPLE 60 2-Bromo-4- (4-methylpiperazin-l-yI)-Ar- (4-chloro)-(2,5-dimethoxyphenyl) thieno [3,2-c;] pyrldine-3-suIfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. Yield: 0.7 mg, LCMS 561.91(M - H)+; Purity (LC-MS) 95%. EXAMPLE 61 N-(3,4-dichIorophenyI)-4-piperazin-l-yIthieno[3,2-c]pyridine-2-sulfonamide hydrochloride 3,4-Dichloroaniline (0.49 mmol), was dissolved in acetonitrile (1 mL) and pyridine (0.440 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 K2CO3 (1 equiv.) was added. The 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, CH3OH-CI4) 8 ppm 8.07-8.05 (m, 2 H) 7.73 (d, .7=6.60 Hz, 1 H) 7.46-7.41 (m, 2 H) 7.16 (dd, .7=8.71,2.38 Hz, 1H) 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%. EXAMPLE 62 N-(2,4-Difluorophenyl)-4-piperazin-l-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 %). *H NMR (270 MHz, CHsOH-dt) 8 ppm 8.22 (s, 1 H) 8.07-8.01 (m, 2H) 7.79-7.72 (m, IH) 7.55-7.47 (m, IH) 7.04-6.94 (m, 2H) 4.00-3.96 8m, 4H) 3.53-3.43 (m, 4H) 2.66 (s, IH); LC-MS 411 (M - H)+; Purity (HPLC) 98 %. 95 EXAMPLE 63 4-Piperazin-l-yl-N-I-3-(trifluoromethyl)phenyl]thieno[3,2-c]pyridine-2-sulfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. Yield: 2.6 mg (1.2 %). lH NMR (270 MHz, CH3OH-d4) 6 ppm 8.05 (d, >6.60 Hz, 2 H) 7.81-7.60 (m, 3H) 7.50-7.47 (m, 2H) 3.94-3.90 (m, 4H) 3.56-3.49 (m, 4H); LC-MS 443 (M - H)+; Purity (HPLC) 99 %. EXAMPLE 64 N-(3-Ethylpbenyl)-4-piperazin-l-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 %). lH NMR (270 MHz, CH3OH-d4) 8 ppm 8.35 (s, IH) 7.58-6.92 (m, 7H) 3.54-3.44 (m, 2H) 3.01-2.95 (m, 4H) 2.66 (s, IH) 2.18-2.01 (m, 3H)); LC-MS 403 (M - H)+; Purity (HPLC) 100 %. EXAMPLE 65 N-(3,4-Dimetlioxyphenyl)-4-piperazin-l-yltluenol3,2-c]pyridine-2-sulfonamide hydrochloride The synthesis was preformed essentially as described in Method H-L. Yield: 7.7 mg (3.6 °/o). JH NMR (270 MHz, CHaOH-d^ 8 ppm 8.04 (d, >6.60 Hz, 1H) 7.77-7.75 /m, 2H) 6.85-6.83 (m, 2H) 6.68-6.83 (m, IH) 3.87-3.85 (m, 4H) 3.77-3.75 (m, 6H) 3.49-3.45 (m, 4H) 2.65 (s, IH); LC-MS 435 (M - H)+; Purity (HPLC) 98 %. EXAMPLE 66 N-(4-Bromo-2-methylphenyl)-4-piperazin-l-ylthieuo[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, CHaOH-di) 8 ppm 8.07 (d, 7=6.33 Hz, 1 H) 7.86-7.79 (m, 2H) 7.40 (d, >1.58 Hz, 1H) 7.30-7.29 (m, IH) 7.08 (d, >8.71 Hz, 1 H) 3.96-3.92 (m, 4H) 3.53-3.51 (4H) 2.66 (s, IH) 2.11 (s, 3H); LC-MS 467 (M - H)+; Purity (HPLC) 90 %. 96 EXAMPLE 67 2-(4-Piperazin-l-yl-thieno[3,2-c]pyridine-2-suIfonyl)-l,2,3,4-tetrahydro-isoqumoliiie hydrochloride 5 The synthesis was preformed essentially as described in Method H-L from 4-[2-(3,4-dihydro-lH-isoquinoline-2-sulfonyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-l-carboxylic acid /err-butyl ester (0.235 mmol, 1 equiv.). Yield: 4.0 mg. LC/MS: tR= 0.801 (System: 30 % to GO % ACN in 1.5 min, Hypersil BDS), Purity: 92%. MS: 415 (M+l) IH NMR (270 9 MHz, DMSO-d(>) 5 ppm 2.87 (t, 7=5.81 Hz, 2 H) 3.30 (s, 4 H) 4.43 (s, 2 H) 7.15 (m, 4 H) 10 7.70 (d, 7=5.54 Hz, 1 H) 8.12 (s, 1 H) 8.18 (d, 7=5.54 Hz, 1 H) 6 aliphatic protons were obscurcd by the w ater-peak in the spectra and so could not be analyzed. EXAMPLE 68 4-Piperazio-l-yI-thienol3,2-c]pyridine-2-suIfonic acid (2-thiophen-2~yl-ethyI)-aiiiide 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-l-carboxylic acid tert-butylester (0.235 mmol, 1 equiv.). Yield: 8.7 mg. LC/MS: tR= 0.430 (System: 30 % to 60 °/o ACN in 1.5 min, Hypersil BDS), Purity: 93 %. MS: 409 (M+l) 'H NMR (270 MHz, 0tO DMSO-d6)Sppm 2.25 (s, 1 H) 2.75 (s, 1H) 2.96 (t, 7=6.99 Hz, 1 H) 3.16 (q,7=6.51 Hz, 1 H) 3.31 (s, 4 H) 3.70 (s, 4 H) 6.90 (m, 1 H) 7.32 (t, 7=5.54 Hz, 1H) 7.70 (d, 7=5.81 Hz, 1 H) 8.04 (d, 7=1.85 Hz, 1 H) 8.18 (d, 7*5.54 Hz, 1H) 8.36 (m, 1 H) 9.05 (s, 1 H). EXAMPLE 69 25 4-Piperazin-l-yl-tliieno[3,2-c]pyridme-2-sulfonic acid (4-ehloro-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-yl]-piperazine-l-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+l) lH NMR (270 MHz, DMSO- d6) 8 ppm 3.17 (s, 1H) 3.27 (s, 4 H) 3.38 (s, 97 3 H) 3.58 (d, .7=4.22 Hz, 4 H) 3.77 (s, 3 H) 7.08 (s, 1H) 7.69 (d, 7=5.81 Hz, 1 H) 7.81 (s, 1 H) 8.16 (d, 7=5.81 Hz, 1 H) 9.07 (s, 1 H) 10.17 (s, 1 H). EXAMPLE 70 4-Piperazin-l-yI-thieno[3,2-c]pyridine-2-suIfonic 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-l-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+l) *H NMR (270 MHz, CHaOH-d,) 8 ppm *10 1.44 (d, 7=7.13 Hz, 2 H) 3.51 (d, .7=4.75 Hz, 4 H) 3.54 (s, 2 H) 3.94 (m, 4 H) 7.05 (m, 4 H) 7.16 (m, IH) 7.62 (s, 1 H) 7.72 (d, .7=6.60 Hz, 1 H) 8.00 (d, 7=6.60 Hz, 1H). EXAMPLE 71 4-Piperazin-l-yl-thieno[3,2-c]pyridine-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. LC/MS: tR= 0.830 (System: 30 % to 60 % ACN in 1.5 min, YMC), Purity: 92 %. MS: 431 (M+l) *H NMR (270 MHz, DMSO-D6) 8 £0 ppm 0.96 (t, 7=7.52 Hz, 6 H) 2.25 (m, 1H) 2.43 (s, 2 H) 2.75 (t, 7=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, 1H) 7.73 (d, 7=5.81 Hz, 1 H) 7.77 (s, 1 H) 8.19 (d, 7=5.81 Hz, 1H) 9.04 (s, 1H) 9.95 (s, 1 H). EXAMPLE 72 25 4-Piperazin-l-yl-thieno[3,2-c]pyridine-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-l-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+l) lH NMR (270 MHz, CHaOH-d,) 8 ppm 1.82 (m, 2 H) 2.63 (m, 2 H) 3.04 (t, 7=6.86 Hz, 2 H) 3.55 (s, 4 H) 4.09 (s, 4 H) 7.16 (m, 4 H) 7.82 (d, 7=6.60 Hz, 1 H) 8.05 (d, 7=6.33 Hz, 1 H) 8.14 (s, 1 H). 98 EXAMPLE 73 4-Piperazm-l-yl-thieno[3,2-c]pyridine-2-suIfonic 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-l-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+l) *H NMR (270 MHz, DMSO-d6) 9 8 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, /=5.81 Hz, 1 H) 7.95 (s, IH) 8.18 (d, 7=5.81 Hz, 1 H) 8.27 (m, 2 H) 9.13 (s, 2 H). EXAMPLE 74 4-Piperazin-l-yl-thieno[3,2-c]pyridine-2-sulfonic acid [2-(5-methoxy-lII-indoI-3-yl)-15 ethyl]-amide hydrochloride The synthesis was preformed essentially as described in Method H-L from 4-{2-[2-(5-methoxy-lH-indol-3-yl)-ethylsulfamoyl]-tiiieno[3,2-c]pyridin-4-yl}-piperazine-l-carboxylic acid tert-butyl ester (0.112 mmol, 1 equiv.). Yield: 6.1 mg. LC/MS: tR= 0.364 (System: 30 % to 60 % ACN in 1.5 min, YMC), Purity: 91 %. MS: 472 (M+l) *H NMR 0) (270 MHz, CHsOH-d,) 8 ppm 2.85 (t, /=6.20 Hz, 2 H) 3.48 (t, .7=6.20 Hz, 2 H) 3.55 (m, 4 H) 3.80 (s, 3 H) 4.02 (m, 4 H) 6.44 (dd, .7=8.71,2.37 Hz, 1 H) 6.80 (m, 2 H) 6.97 (s, 1 H) 7.64 (s, 1H) 7.67 (s, 1H) 7.97 (d, J=6.60 Hz, 1H). EXAMPLE 75 25 4-Piperazin-l-yl-thieno[3,2-c]pyridine-2-suIfonicacid4-trifluoromethyI-benzylaniide 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+l) NMR (270 MHz, CHsOH-dj) 8 ppm 3.54 (m, 4 H) 3.98 (m, 4 H) 4.36 (s, 2 H) 7.49 (m, 4 H) 7.74 (d, /=6.86 Hz, 1 H) 8.02 (s, 1 H) 8.07 (d, .7=6.60 Hz, 1 H). 99 EXAMPLE 76 4-Piperazin-l-yl-thieno[3,2-c]pyridine-2-sulfonic acid benzyl-ethyl-amide hydrochloride The synthesis was preformed essentially as described in Method H-L from 4-[2-(benzyl-ethyl-sulfamoyl)-thieno[3,2-c]pyiidin-4-yl]-piperazine-l-carboxylic acid /ert-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+l) lH NMR (270 MHz, CHaOH-df) 8 ppm 1.03 (t, .7=7.13 Hz. 3 H) 3.37 (m, 2H) 3.57 (s, 2 H) 3.75 (m, 2 H) 4.11 (s, 2 H) 4.50 (s, 2 '10 H) 5.80 (s, I H) 7.32 (m, 5 H) 7.84 (d, .7=6.60 Hz, 1 H) 8.07 (d, .7=6.60 Hz, 1 H) 8.14 (s, 1 H). INTERMEDIATE 55 ter/-Butyl-4-(3-{l(3-etliylphenyI)amiao]sulfonyl}tliieno[3,2-c]pyridm-4-yl)piperazine-15 1-carboxylate Prepared from /e;-/-butyl 4-[3-(chlorosulfonyl)thieno[3,2-c]pyridin-4-yl]piperazine-l-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, CDCla) 8 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 0 (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, 1H), 9.80 (s, 1H). 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-EthyIphenyl)-4-piperazin-l-ylthieno[3,2-c]pyridme-3-sulfonamide hydrochloride Prepared from tert-butyl 4-(3-{[(3-ethylphenyl)amino]sulfonyl}thieno[3,2-c]pyridin-4-yl)piperazine-l-carboxylate (81.1 mg, 0.161 mmol) which afforded 19 mg (98 %) ofthe product as a white solid (38.0 mg, 54 %). 'H NMR (400 MHz, CH3OH-d4) 8 1.09 (t, /= 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), 836 (d, 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). 100 INTERMEDIATE 56 te/tf-Butyl 4-(3-bromothieno[3,2-c]pyridin-4-yl)piperazine-l-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 K2CO3 (811 mg, 5.87 mmol) in DMSO (45 mL) was stirred for 5 days at 100 °C. After addition of H2O 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-t). 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, CH3OH-d4) 5 1.48 (s, 9 H), 3.21 (br.s, 4 H), 3.71 (sbr., 4H), 7.61 (d, J= 6.1 Hz, 1 H), 7.72 (s, 1H), 8.08 (d,/= 5.6 Hz, 1 H). MS (ESI+) m/z 398.2 (M+H)+. INTERMEDIATE 57 15 {4-[4-(tert-Butoxycarbouyl)piperazin-l-yl]thieno[3,2-c]pyridin-3-yl}sulfonyI)lithium To a suspension of tert-Butyl 4-(3-bromothieno[3,2-c]pyridin-4-yl)piperazine-1 -carboxylate (4.055 g, 10.18 mmol) in diethyl ether (30 mL) at —78 °C under N2 atmosphere was added dropwise an 1.6 M solution of w-BuLi in hexanes (9.5 mL, 15.2 mmol). After 1 h of stirring, a saturated solution of SO2 in THF (25 mL) at -78 °C was transferred via a 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. *H 25 NMR (400 MHz, CHsOH-d,) 8 1.48 (s, 9 B), 3,22 (br.s, 4 H), 3.72 (s br„ 4 H), 7.60 (d, J= 5.5 Hz, 1H), 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). 101 INTERMEDIATE 58 tert-Butyl-4-[3-(chlorosulfonyl)thieno[3,2-c]pyridm-4-yI]piperazine-l-carboxylate To a suspension of ( {4-[4-(tert-butoxycarbonyl)piperazin-l -yl]thieno[3,2-c]pyridin-3-yl}sulfonyl)Iithium (2.751 g, 7.06 mmol (3.126 g of the crude product mixture)) in DCM 5 (40 mL) at 0 °C was added iV-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 MgSC>4. 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 %). *H NMR (400 MHz, CHsOH-d,) 5 1.47 (s, 9 H), 3.11 (br.s, 4 H), 3.2-4.3 (s br., 4 H), 7.68 (d, /= 5.5 Hz, 1 H), 8.45 (d, 5.5 Hz, 1H), 8.60 (s, 1 H). MS (ESI+) m/z418.2 (M+H)+. HPLC 92%, RT: 3.76 min (5-99% MeCN over 3 min). 15 INTERMEDIATE 59 fert-Butyl-4-(3-{[(4-isopropyIphenyI)amino]sulfonyl}thieno[3,2~c]pyridin-4-yl)piperazine-l-carboxylate Prepared from tert-butyl 4-[3-(chlorosulfonyl)thieno[3,2-c]pyridin-4-yl]piperazine-l-carboxylate (90.0 mg, 0.215 mmol) and 4-isopropylaniline (37.9 mg, 0.28 mmol) to give the title compound as an off-white solid (58.3 mg, 52 %). NMR (400 MHz, CDCI3) 8 1.12 (d, /= 7.0 Hz, 6 H), 1.47 (s, 9 H), 2.76 (sept., 6.9 Hz, 2 H), 3.01-3.53 (m, 6 H), 4.04-4.41 (m, 2 H), 6; 79 (d,/= 8.5 Hz, 2 H), 6.66 (d, /= 8.5 Hz, 2 H), 7.69 (d, J= 5.5 Hz, 1H), 8.23 (s, 1 H), 8.40 (d, J= 5.5 Hz, 1 H), 9.90 (s, 1 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-IsopropylphenyI)-4-piperazin-l-ylthieno[3,2-c]pyridme-3-sulfonamide hydrochloride Prepared from tert-butyl 4-(3- {[(4-isopropylphenyl)amino]sulfonyl}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, 102 CHaOH-cLt) 5 1.16 (d, 7= 7.0 Hz, 6 H), 2.81 (sept., 7= 6.8 Hz, 1 H), 3.59 (s, br., 8 H), 7.00 (d, 7= 8.0 Hz, 2 H), 7.10 (d, 7= 8.0 Hz, 2 H), 8.07 (s, br., 1 H), 8.37 (s, br., 1 H), 8.50 (s, 1 H), MS (ESI+) mh 417.2 (M+H)+. HPLC 94%, RT: 3.14 min (5-99% MeCN over 3 min). EXAMPLE 79 N-(4-MethyIphenyl)-4-(pyrrolidm-3-yIoxy)thleno[3,2-c]pyridme-2-sulfonamide hydrochloride 4-Chloro-Ar-(4-methylphenyl)thieno [3,2-c]pyridine-2-sulfonamide (60.0 mg, 0.17 mmol) in diy 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 %). !H NMR (270 MHz, CH3OH-&1) 8 ppm 8.09 (s, IH) 7.71 (d, 7=6.93 Hz, 1H) 7.46 (d, 7=6.93 Hz, 1 H) 7.47.7,44 (m, 4H) 4.67 (d, 7=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-}0 methylphenyl)-4-(pyrrolidin-3-yloxy)thieno[3,2-c]pyridine-2-sulfonamide hydrochloride. Yield: 16.2 mg (22.7 %). lH. NMR (270 MHz, CHaOH-d,) 8 ppm 7.81-7.78 (m, 2H) 7.62 (d, Hz, IE) 7.13-7.04 (m, 4H) 4.05-3.94 (m, IH) 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-Difluorobenzjl)-4-piperazin-l-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride Yield: 74.4 mg (39.2 %). 'H NMR (270 MHz, CHaOH-dt) 8 ppm 8.10-8.03 (m, 2H) 7.81 30 (d, 7=6.68 Hz, 1H) 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 %. 103 EXAMPLE 82 N-(3-Chlorobenzyl)-4-piperazin-l-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride Yield: 74.4 mg (44.7 %). !H NMR (270 MHz, CH3OH-&,) 5 ppm 8.04-8.01 7.85 (d, 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); LCMS 423 (M - H)+; Purity (HPLC) 90%. Table 5 R4 example Rz R" 83 4-(l,4-Diazepan-l-yl)-2-(phenylsidfonyl)thieno[3,2-c]pyridine hydrochloride a O n—' 84 4-( 1,4-Diazepan-1 -yl)-2-[(3,4-dichlorophenyl)sulfonyl]thieno[3,2-c]pyridine hydrochloride 0 0 O n—' 85 4~( 1,4-Diazepan-1 -yI)-2-[ 1 -naphthylsu!fonyl)thieno[3,2-c]pyridine hydrochloride O n—' 86 4-(l,4-Diazepan-l-yl)-2-[4-tert-butylphenylsulfonyl)thieno[3}2-c]pyridine hydrochloride O n—' 87 4-(l,4-Diazepan-l-yl)-2-[3J4-dimethylphenylsulfonyl)thieno[3,2-c]pyridine hydrochloride O n—' 104 88 2-[(4-Bromophenyl)sulfonyl]-4-( 1,4-diazepan-1 -yl)thieno[3,2-c]pyridine hydrochloride Br*^ 0 89 2-(Phenylsulfoayl)-4-piperazm-l-ylthieno[3,2-c]pyridine hydrochloride 0" (") N 90 2-(3-Methoxy-benzenesulfonyl)-4-piperazin-l-yl-thieno[3,2-c]pyridine hydrochloride 0 N , 91 2-(4-Methoxy-benzenesulfonyl)-4-piperazin-l-yl-thieno[3,2-cjpyridine hydrochloride 0 N 92 4-Piperazin-1 -yl-2- {[4-trifluoromethyl)phenyl]sulfonyl} thieno[3,2-cjpyridine hydrochloride LLLL 0 N 93 2-[[2-tert-Butylphenyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-cjpyridine hydrochloride 0 N 94 2-[(3,4-Dichlorophenyl)stxlfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride CI ft N 95 2-[(4-tert-Butylphenyl)sulfonyl]-4-piperazin-l-yltibieno[3,2-c]pyridine hydrochloride 0 N 96 2-(l-Naphthyl sulfonyl)-4-piperazin-l -ylthieno[3,2-c]pyridine hydrochloride $ CN) N 97 2-[(3-Fluorophenyl)sulfonyl]-4-piperazin-1 -ylthieno[3,2-c]pyridine-2-sulfonamide hydrochloride Q"' F 0 N 105 98 2-(Mesitylsulfonyl)-4-piperazin-1 -ylthieno[3,2-c]pyridine hydrochloride j6c- 0 N 99 2-[(2-Methoxyphenyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine hydrochloride cf? 0 N 100 2-[(2,4-Dimethoxyphenyl)sulfonyl]-4-piperazin-l-ylthieno[3s2-c]pyriditie hydrochloride o N 101 2-[(2,4-Dimethylphenyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine hydrochloride jx 0 N 102 2-[(2,5-Dimethylphenyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine hydrochloride o N 103 2-t(2-Ethylphenyl)sulfonyl]-4-piperazin-l-yllhieno[3^2-c]pyridixie hydrochloride 0 N 104 4-(Piperazinyl)-2-(3-methoxybenzyl-sulfonyl)-thienopyridine hydrochloride 0 N 105 2-(Benzylsulfonyl)-4-piperazin-l-ylthieno[3,2-c]pyridine hydrochloride o N 106 4-Piperazin-1 -yl-2- {[4-(trifluoromethyl)benzyl]sulfonyl} thieno[3,2-c]pyridine hydrochloride F 0 N 107 2-[(3-Bromobenzyl)sulfonyl]-4-piperazin-1 -ylthieno[3,2-c]pyridine hydrochloride o N 108 2-[(2,3-Difluorobenzyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-cjpyridine hydrochloride F c") N 106 109 2-[(4-Bromobenzyl)sulfonyl]-4-piperazin-1 -ylthieno[3,2-c]pyridine hydrochloride 0 N 110 2-{[2,5-bis(Trifluororaetliyl)benzyl]sulfonyl}-4-piperazin-l-ylthieno[3,2-c]pyridine hydrochloride °*T0£ 0 N 111 2-f(4-Methylbenzyl)sulfonyl]-4-piperazin-l-yltiiieno[3,2-c]pyridme hydrochloride 1 (*) N 112 2-{[5-Chloro-2-(trifluoroinethyl)benzyl]sulfonyl}-4-piperazin-l-ylthieno[3,2-c]pyridine hydrochloride ax£. a N 113 2-[(3,5-Dimethoxybenzyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridrtie hydrochloride '°nr^ ,0 0 N 114 2-[(2-Naphthylmethyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine hydrochloride 0 N 115 4-Piperazm4-yl-2-{[4-(ls2,3-tbiadiazol-5-yl)benzyl]sulfonyl}thieno[3,2-c]pyridine hydrochloride 'N'S 0 N 116 1 -(4-Pyrrolidin-l -ylphenyl)-2-t(4-piperazine-l -ylthieno[3,2-c]pyridin-2-yl) sulfonyl] propanone hydrochloride 0 N 117 l-[4-(Diethylamino)phenyl3-2-[(4-piperazine-l-yHhienot3,2-c]pyridin-2-yl) sulfonyl] propanone hydrochloride 0 N 118 1 -(4-Bromophenyl)-2-[(4-piperazin-l -ylthieno[3,2-c]pyridin-2-yl) sulfonyl] propanone 0 N 107 119 1 -(3-Methoxyphenyl)-2-[(4-piperazin-1 -ylthieno[3,2-c]pyridin-2-yl) sulfonyl] propanone 0 N 120 1 -Phenyl-2-[(4-piperazin-1 -ylthieno[3,2-c]pyridii>-2-yl)sulfonyl]propanone O N Scheme 6 5 Legend to Scheme 6: i) BOC protected amines (R4), K2C03, DMSO; ii) thiophenols (Rl-SH), Cu2(I)0, DMF; iii) NaOAc, oxone, water; iv) a.TFA, b.HCl, methanol INTERMEDIATE 60 *ert~Butyl 4-(2-bromothienol3,2-c]pyridin-4-yl)piperazine-l-earboxylate 10 2-Bromo-4-chlorothieno[3,2-c3pyridine (5.0 g, 20.24 mmol) and K.2CO3 (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 mmol). 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 (MgSO/t) 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. JH NMR (270 MHz, CDCI3) 6 1.48 (s, 9H), 1.52-1.63 (m, IH), 3.42-3.47 (m, 4H), 3.61-3.64 (m, 4H), 7.22 (dd, J= 5.4,1 Hz, IH), 7.35 (d, J= 1 Hz, IH), 8.04 (d, J= 5.4 Hz, IH). m/z -20 398.91 (M+H), bromide pattern. 108 10 25 INTERMEDIATE 61 tert-butyl 4-(2-bromothieno[3,2-c]pyridin-4-yl)-l,4-diazepane-l-carboxylate The same procedure above intermediate was used starting from 2-bromo-4-chlorothieno[3,2-c]pyridine (7.5 g, 30.45 mmol), K2CO3 (6.7 g, 33.5 mmol) and tert-butyl 1,4-diazepane-l-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%; !H NMR (270 MHz, CDC13) 5 1.38 (s, 4.5 H), 1.43 (s, 4.5 H), 1.96-2.11 (m, 2H), 3.36-3.41 (m, IH), 3.46-3.51 (m, IH), 3.65-3.87 (m, 6H), 7.02-7.04 (m, IH), 7.40-7.42 (m, IH), 7.94 (d, J= 5.4 Hz, 1I I). m/z = 411.97 (M+H). Coupling with thiophenols (Method M) INTERMEDIATE 62 tert-butyl 4-(2-phenylthio)thieno[3,2-c]pyridin-4-yI)-l,4-diazepane-l-carboxylate 15 tert-Butyl 4-(2-bromothienb[3,2-c]pyridin-4-yl)-l,4-diazepane-l-carboxylate . (0.31 g, 0.752 mmol), pulverized KOH (0.084 g, 1.5 mmol) and Cu2(I)0 (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) inDMF (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. iO 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. lK NMR (270 MHz, CDCh) 6 1.37 (s, 4.5H), 1.43 (s, 4.5 H), 1.97-2.10 (m, 2H), 3.36-3.43 (m, lH), 3.46-3.53 (m, 1H), 3.64-3.73 (m, 2H), 3.78-3.96 (m, 4H), 7.05 (d, J= 5.4 Hz, IH), 7.22-7.32 (m, 5H), 7.59-7.63 (m, IH), 7.97 (d, J= 5.4 Hz, IH). m/z = 442.15 (M+H). Oxidation of thio-derivatives (Method N) INTERMEDIATE 63 tert-Butyl 4-(2-phenylsulfonyl)thieno[3,2-c]pyridin-4-yI)-l,4-diazepane-l-carboxyIate 30 A solution of tert-Butyl 4-(2-phenylthio)thieno[3,2-c]pyridin-4-yl)-l,4-diazepane-l- carboxylate (0.21 g, 0.48 mmol) 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 109 mixture was stirred at RT for 16k Additional Oxone (0.32 g) in water (lmL) 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 (MgS04), the solvent was 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, CDC13) 5 1.28 (s, 4.5 H), 1.38 (s, 4.5 H), 1.99-2.03 (m, 2H), 3.31-3.40 (m, 1H), 3.42-3.47 (m, IH), 3.63-3.69 (m, 2H), 3.85-3.98 (m, 4H), 7.02 (d, J- 5.4 Hz, IH), 7.48-7.61 (m, 3H), 7.76-8.01 (m, 3H), 8.06-8.08 (m, IH). m/z = 474.01 (M+H). Removal of the tf-butyl-carboxylate protecting group (Method O) EXAMPLE 83 4-(l,4-Diazepan-l-yI)-2-(phenylsulfonyl)thieno[3,2-c]pyridine hydrochloride tert-Butyl 4-(2-phenylsulfonyl)thieno [3,2-c]pyridin~4-yl)-1,4-diazepane-1 -carboxylate (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 HCl in ether Was added (x 3) to give 0.118 g of the desired HCl salt, yield 85%, 98% pure. *H NMR (270 MHz, CHOH-dj) 5 2.45-2.52 (m, 2H), 3.45-3.52 (m, 2H), 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, IH), 8.11 (dd, J=5.4,1 Hz, IH), 8.41 (d, J= 1 Hz, IH). m/z - 374.09 (M+H-HC1). INTERMEDIATE 64 tert-Butyl 4-[2-(4-te/tf-butyIphenyl)thio]thieno[3,2-c]pyridin-4-yl)-l,4-diazepane-l-carboxylate 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. lH NMR (270 MHz, CDC13) 8 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, IH), 3.46-3.52 (m, 1H), 3.62-3.72 (m, 2H), 3.77-3.93 (4H), 7.04 (d, J= 5.4 Hz, IH), 7.27-7.34 (m, 4H), 7.54-7.56 (m, IH), 7.95 (d, J= 5.4 Hz, IH). m/z = 498.0 (M+H). 110 10 INTERMEDIATE 65 tert-Butyl 4-[2-(4-tert-butylphenyI)sulfonyl]thieno[3,2-c]pyridm-4-yl)-l,4-diazepane-l-carboxylate Procedure B from tert-butyl 4-[2-(4-tert-butylphenyl)thio]thieno[3,2-c]pyridin-4-yl)-l,4-diazepane-1-carboxylate (0.035 g, 0,070 mmol), Oxone (0.17 g, 0.28 nrniol), NaOAc (0.5 g) in EtOH (2 mLfollowed by reversed phase chromatography (40~»70), gave 6 mg of the product. Yield 17%, 98% pure.'H NMR (270 MHz, CDCh) 8 1.32 (s, 9H), 1.35 (s, 9H), 2.05-2.15 (m, 2H), 3.45-3.62 (m, 2H), 3.75-4.13 (m, 6H), 7.20-7.27 (m, 5H), 7.58 (d, J= 10.8 Hz, IH), 7.93 (d, J= 10.8 Hz, IH). m/z = 530.0 (M+H). INTERMEDIATE 66 tert-Butyl 4-[2-(3,4-dimethylpIienyl)thio]thieno[3,2-c]pyridin-4-yl)-l,4-diazepane-l~ carboxylate The title compound was obtained according to Method M. Purification by flash 15 chromatography using ethyl acetate/hexanes (2/8) as eluent gave 0.022 g, 95% pure. !H NMR (270 MHz, CDCh) 5 1.38 (s, 4.5 H), 1.43 (s, 4.5 H), 1.96-2.04 (m, 2H), 2.21 (s, 3H), 2.22 (s, 3H), 3.37-3.45 (m, 2H), 3.47-3.50 (m, 2H), 3.77-3.95 (m, 4H), 7.01-7.12 (m, 3H), 7.16 (s, IH), 7.53 (dd, J= 5.4,1 Hz, IH), 7.94 (d, J= 5.4 Hz, IH). m/z = 470.3 (M+H). >0 INTERMEDIATE 67 tert-Butyl 4-[2-(3,4-dimetliylpkenyI)sulfonyl]thieno[3,2-c]pyridm-4-yl)-l,4-diazepane-l-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 mg of the product. Yield 38%, 92% pure.1HNMR(270 MHz, CDCI3) 8 1.35 (s, 9H), 2.08-2.20 (m, 2H), 2.33 (s, 6H), 3.52-3.59 (m, 2H), 3.83-3.88 (m, 2H), 4.08-4.18 (m, 4H), 7.21-7.28 (m, 2H), 7.31-7.35 (m, IH), 7.73-7.75 (m, 2H), 8.02 (d, J= 5.4 Hz, IH). m/z = 502.21 (M+H). 30 111 INTERMEDIATE 68 tert-Butyl 4-[2-(l-naphthyI)thio]thieno[3,2-c]pyridm-4-yI)-l,4-diazepane-l-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 %; 'H NMR (270 MHz, CDC13) 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, IH), 7.39 (dd, J= 8.1, 1 Hz, IH), 7.50-7.61 (m, 5H), 7.79-7.88(m,2H), 7.92(d, J= 5.4Hz, 1H), 8.40-8.44 m (m, 1H). m/z = 498.26 (M+H). INTERMEDIATE 69 ten- Butyl 4-12-(l-naphthyl)sulfonyl]thieiio[3,2-c]pyridm-4-yl)-l,4-diazepane-l-carboxylate Procedure B from tert-Butyl 4-[2-( 1 -naphthyl)thio]thieno[3,2-c]pyridin-4-yl)-1,4-15 diazepane-l-carboxylate (0.055 g, 0.112 mmol); Oxone (0.27 g, 0.448 imnol); NaOAc (0.5 g) in EtOH (2 mL) followed reversed phase chromatography (40-»70) gave 15 mg of the product. Yield 26%, 93% pure, JH NMR (270 MHz, CDCI3) 8 1.34 (s, 9H), 2.06-2.10 (m, 2H), 3.48-3.62 (m, 2H), 3.78-3.86 (m, 2H), 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, IH), 8.50-8.53 (m, IH), 8.77-8.80 ^0 (m, IH). m/z = 524.22 (M+H); EXAMPLE 84 4-(l,4-Diazepan-l-y!)-2-[(3,4-dichlorophenyl)sulfonyIJthieno[3,2-c]pyridine hydrochloride 25 fert-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. lH NMR (CDCI3) 8 8.27-8.14 (m, IH), 8.11-8.04 (m, 2H), 7.87-7.80 (m, IH), 7.67-7.62 (m, IH), 7.26-7.20 (m, IH), 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 9H); MS m/z 542 (M+l).The title compound (50 mg, 95%) was obtained as a beige solid, by the application of the general procedure C described above. !H NMR (270 MHz, 112 CHsOH-d*) 8 8.48 (s, 1H), 8.30 (d, J= 1.85 Hz, 1H), 8.05 (dd, J= 8.58,1.98 Hz, IH), 7.92 (d, /= 6.86 Hz, 1H), 7.83 (d, /= 8.44 Hz, IH), 7.69 (d, /= 6.86 Hz, IH), 4.4.41-4.34 (m, 2H), 4.24-4.16 (m, 2H), 3.76-3.69 (m, 2H), 3.51-3.43 (m, 2H), 2.52-2.42 (m, 2H); MS w/z442(M+l). 5 EXAMPLE 85 4-(l,4-Diazepan-l-yI)-2-[l-naphthylsuifonyl)thieno[3,2-cJpyridme hydrochloride The title compound was obtained from tert-butyl 4-[2-(l-naphthyl)sulfonyl]thieno-[3,2-c]pyridin-4-yl)-l,4-diazepane-l-carboxylate (15 mg, 0.029 mmol) following Method O to 10 give 12 mg of the desired product yield 90 %, 95 % pure. lH NMR (270 MHz, QHbOH-dt) 8 2.40-2.50 (m, 2H), 3.45-3.55 (m, 2H), 3.65-3.75 (m, 2H), 4.06-4.26 (m, 2H), 4.27-4.46 (m, 2H), 7.58-7.80 (m, 4H), 7.83-7.86 (m, IH), 8.06 (d, J= 8.1 Hz, IH), 8.20 (d, J= 8.1 Hz, IH), 8.48 (s, IH), 8.53-8.56 (m, IH), 8.83-8.86 (m, 1). m/z = 424.06 (M+H-HC1). 15 EXAMPLE 86 4-(l,4-Diazepan-l-yl)-2~[4-te//-butylphenylsulfonyl)thieiio[3,2-c]pyridine hydrochloride The title compound was obtained from tert-butyl 4-[2-(4-tert-butylphenyl)-sulfouyl]thieno[3,2-c]pyridin-4-yl)-1,4-diazepane- 1-carboxylate (6 mg, 11.3 mmol) following Method O to give 4 mg of the desired product, yield 76 %, 88 % pure. !H NMR (270 MHz, CH30H-d4) 8 1.33 (s, 9H), 2.41-2.47 (m, 2H), 3.41-3.49 (m, 2H), 3.65-3.78 (m, 2H), 4.15-4.25 (m, 2H), 4.29-4.40 (m, 2H), 7.65-7.70 (m, 3H), 7.90 (d, J= 5.4 Hz, IH), 8.00-8.04 (m, 2H), 8.37 (s, IH). m/z = 430.06 (M+H- 25 EXAMPLE 87 4-(l ,4-Diazepan-l -yl)-2-[3,4-dimethylpheny!sulfonyl)thieiio[3,2-cJpyridiiie hydrochloride The title compound was obtained from tert-butyl 4-[2-(3,4 dimethylphenyl)-sulfonyl]thieno[3,2-c]pyridin-4-yl)-l,4-diazepane-l-carboxylate (6 mg, 0.012 mmol) 30 following Method O to give 6 mg of the desired product, yield 88 %, 89 % pure. lH NMR (270 MHz, CH3OH-d4) 8 2.34 (s, 6H), 2.45-2.55 (m, 2H), 3.42-3.51 (m, 2H), 3.67-3.76 (m, 113 2H), 4.10-4.20 (m, 2H), 3.58-3.70 (xn, 2H), 7.39-7.41 (m, 1H), 7.64-7.67 (m, IH), 7.79-7.84 (m, 2H), 7.89-7.91 (m, IH), 8.36 (s, IH). m/z = 402.07 (M+H-HC1). EXAMPLE 88 5 2-[(4-BromophenyI)sulfonyl]-4-(l,4-diazepan-l-yl)thieno[3,2-cJpyridine hydrochloride Trifluoroacetic acid (1 mL) was added slowly to a solution of tert-butyl 4- {2-[(4-bromophenyl)thioJthieno[3,2-c]pyridin-4-yl}-l,4-diazepane-l-carboxylate (26 mg, 0.047 ^ mmol) in CH2CI2 at 0 °C. The reaction mixture was allowed to reach room temperature, TO 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 1M HCl 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. *H NMR (270 MHz, CH3OH-d4) 8 8.41 (s, IH), 8.06-7.99 (m, 2H), 7.92 (d, J- 6.86 Hz, 1H), 7.87-15 7.80 (m, 2H), 7.66 (d, /== 6.86 Hz, IH), 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+l). EXAMPLE 89 2-(PhenylsulfonyI)-4-piperazin-i-yIthieno[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, die chromatogram showed two major peaks, the product and the N-oxide. After purification by preparative HPLC, the resulting Boc-material was treated with HCl in ether. The solution 25 was centrifiigated and the supernatant was removed. Ether was added, then centrifugated and decanted (repeated three times) to remove the excess HCl. 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, CHsOH-c^) 5 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, 1H) 8.04 (d, 7=6.33 Hz, 1 H) 8.12 (m, 2 H) 8.39 (d, 30 J=0.79 Hz, 1 H). 114 EXAMPLE 90 2-(3-Methoxy-benzenesulfonyl)-4-piperazin-l-yl-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 JBrom 3-methoxy£hiophenol (130 pi, 1 mmol) and tert-Butyl 4-(2-bromothieno[3,2-c]pyridin-4-yl)piperazine-l-carboxylate (215 mg, 0.52 mmol). 120 mg, 50%) were obtained by the application of the general Method M described above. *H NMR (270 MHz, CDC13) S 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, /=5.81 Hz, 1H); MS m/z 458 (M+l). 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 Ihe general procedures B and C described above. *H NMR (270 MHz, CD3OD) 8 8.31 (s, IH), 8.09 (4 J = 6.33 Hz, 1H), 7.71-7.62 (m, 2H), 7.59-7.50 (m, 2H), 7.30-7.23 (m, IH), 3.98-3.92 (m, 4H), 3.87 (s, 3H), 3.54-3.48 (m, 4H); 15 MS m/z 390 (M+l). EXAMPLE 91 2-(4-Methoxy-benzenesulfonyI)-4-piperazin-l-yI-thieno[3,2-c]pyridine hydrochloride 4-[2-(4-Methoxy-phenylsulfanyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-|f.O 1-carboxylic acid tert-butyl ester was obtained ftom 4-methoxythiophenol (130 ul, 1 mmol) and tert-butyl 4-(2-bromothieno[3,2-c]pyridin-4-yl)piperazine-l-carboxylate (215 mg, 0.52 mmol). 100 mg, 42% were isolated by the application of the general Method M described above. *H NMR (270 MHz, CDCI3) S 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, 1H), 7.35 (s, 1H), 25 7.38-7.43 (m, 2 H), 7.99 (d, J=5.81 Hz, 1H); MS m/z 458 (M+l). 4-[2-(4-methoxy-phenylsulfanyl)-thieno[352-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. lH NMR (270 MHz, CDCI3) 8 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, IH), 7.93 (d, J = 8.97 Hz, 2H), 30 8.01-8.19 (m, 2H); MS m/z 490 (M+l). The title compound was thereby obtained following Procedure C): JH NMR (CD3OD) 8 8.25 (s, IH), 8.09-7.89 (m, 3H), 7.69 (d, J - 115 6.33 Hz, IH), 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+l). EXAMPLE 92 5 4-Piperazin-l-yl-2-{[4-trifluoromethyl)phenyl]suIfonyI}thieno[3,2-c]pyridine hydrochloride 2- {[4-(Trifluoromethyl)phenyl]1hio} -4-piperazin-1 -ylthieno[3,2-c]pyridine (0.42 mmol) was dissolved in TFA (1.5 mL) at 0°C, stirred for 15 min and H2O2 (100 jaL) 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 NaS04, 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*) 8 ppm 9.79 (s, IH) 8.56 (s, 1 H) 8.35 (d, 7=8.44 Hz, 2 H) 8.12-8.05 (m, 3H) 7.79 (d, 7=6.33 Hz, 1H) 3.98-3.96 (m, 4H) 3.32-3.31 (m, 4H); LC-MS 428 (M - H)+; Purity (HPLC) 95% 15 EXAMPLE 93 2-[[2-tert-Butylphenyl)sulfonyI]-4-piperazin-l-ylthieno[3,2-c]pyridine hydrochloride The title compound was prepared following Method M-O. Yield: 10.6 mg (6.3 %) of 2-[[2-te^butylphenyl)sulfonyl]-4-piperazin-1 -ylthieno[3,2-c]pyridine hydrochloride. *H NMR y (270 MHz, DMSO-dfi) 8 ppm 9.57 (s, 1H) 8.42 (s, 1 H) 8.26-8.22 (m, IH) 8.06-8.04 (m, IH) 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-DicIiloroplieuyl)suIfonyl]-4-piperazin-l-ylthietto[3,2-c]pyridine-2-sulfonamide hydrochloride The title compound was prepared following Method M-O. Yield: 47.9 mg (22.9 %). JH NMR (270 MHz, DMSO-d6) 8 ppm 9.36 (s, 1H) 8.51 (s, 1H) 8.38 (d, 7=2.11 Hz, 1 H 8.06-7.94 (m, 3H) 7.70-7.68 (m, IH) 3.81-3.77 (m, 4H) 3.31-3.29 (m, 4H); LC-MS 427 (M 30 - H)+; Purity (HPLC) 95 %. 116 EXAMPLE 95 2-[(4-fe//,-ButylphenyI)suIfonyl]-4-piperaziii-l-ylthieno|3>2-c]pyridme 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-l-ylthieno[3,2-c]pyridine (0.42 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, CHaOH-dt) 8 ppm 8.38 (s, 1 H) 8.05-8.01 (m, 3H) 7.80 (d, >6.59 Hz, 1 10 H) 7.71-7.69 (m, 2H) 4.15-4.13 (m, 4H) 3.59-3.57 (4H) 1.37-1.33 (m, 9H); LC-MS 416 (M -H)+; Purity (HPLC) 95%. EXAMPLE 96 2-(l-NaphthyIsulfonyI)-4-piperazm-l-ylthieno[3,2-c]pyridine hydrochloride 15 The title compound was prepared following Method M-O. Yield: 3.4 mg (0.2 %). *H NMR (270 MHz, DMSO-d6) 8 ppm 9.34 (s, 1 H) 8.82 (s, 1H) 8.44 (s, 1 H) 8.26-8.06 (m, 5H) 7.79-7.65 (m, 3H) 3.79-3.78 (m, 4H) 3.32-3.30 (m, 4H); LC-MS 410 (M - H)+; Purity (HPLC) 95%. EXAMPLE 97 2-[(3-Fluorophenyl)sulfottyl]-4-piperazm-l-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 CU2O (71 mg, 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, H2O2 (100 jxL) 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 %) 'H NMR (270 MHz, DMSO-d*) 8 ppm 9,34 (s, 1 H) 8.45 (s, 1 H) 8.16 (d, >5.69 Hz, 1 H) 7.97-7.93 (m, 2H) 7.76-7.62 (m, 117 3H) 3.30 (s, 4 H) (4H obscured by solvent signal); LC-MS 378 (M - H)+; Purity (HPLC) 99%. EXAMPLE 98 5 2-(MesitylsuIfonyI)-4-piperaziii-l-yIthieno[3>2-c]pyridme hydrochloride The title compound was prepared following Method M-O. Yield: 32.0 mg (16.1 %). NMR (270 MHz, DMSO-d6) 8 ppm 9.32 (s, 1 H) 8.20-8.14 (m, 2H) 7.66 (d, >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%. EXAMPLE 99 2-[(2-Methoxyphenyl)sulfonyI]-4-piperazin-l-ylthieno[3,2-c]pyridine hydrochloride The title compound was prepared following Method M-O.Yield: 14.7 mg (7.6 %). *H NMR (270 MHz, DMSO-d6) 5 ppm 9.33 (s, 1 H) 8.24 (s, 1 H) 8.15 (d, >5.94 Hz, 1 H) 15 8.00 (dd, >7.92,1.48 Hz, 1H) 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 - Hy^urity (HPLC) 99%. EXAMPLE 100 2-1(2,4-Dimethoxyphenyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine hydrochloride The title compound was prepared following Method M-O. Yield: 42.7 mg (20.5 %). *H NMR (270 MHz, DMSO-de) 8 ppm 9.39 (s, 1 H) 8.37 (s, 1 H) 8.13 (d, >5.69 Hz, 1H) 7.68-7.66 (m, 2H) 7,54 (d, >2.23 Hz, 1 H) 7.19 (d, >8.66 Hz, 1H) 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-l-yltliieno[3,2-c]pyridine hydrochloride The title compound was prepared following Method M-O. Yield: 17.8 mg (9.3 %). !H NMR(270MHz, DMSO-d6) 8ppm 9.32 (a, IH) 8.27 (s, 1 H) 8.15 (d, >5.94Hz, 1H) 30 8.00 (d, >8.17 Hz, 1 H) 7.67 (d, >5.94 Hz, 1H) 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%. 118 EXAMPLE 102 2-[(2,5-Dimethylphenyl)sulfonyl]-4-piperazm-l-yIthieiio[3,2-c]pyridine hydrochloride The title compound was prepared following Method M-O. Yield: 16.9 mg (8.8 %). NMR (270 MHz, DMSO-d6) 8 ppm 9.17 (s, 1 H) 8.29 (s, 1H) 8.18-18.15 (m, IH) 7.94 (s, 1H) 7.66 (d, > 5.69 Hz, IH) 7.47 (d, >7.67 Hz, 1H) 7.32 (d, >8.16 Hz, 1H) 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-EthyIphenyI)sulfonyl]-4-piperazin-l-yltliieiio[3,2-c]pyridine hydrochloride The title compound was prepared following Method M-O. Yield: 22.6 mg (11.2 %). *H NMR (270 MHz, DMSO-d6) 8 ppm 9.19 (s, 1H) 8.32 (s, 1 H) 8.17 (d, >5.69 Hz, 1 H) 8.08 (d, >7.92 Hz, 1 H) 7.73-7.66 (m, 2H) 7.52 (t, >7.67 Hz, 2 H) 3.29 (s, 4 H) 3.00 (q, 15 >7.34 Hz, 2 H) 1.10(m, 3 H) (4H obscured by solvent signal); LC-MS 388 (M - H)+; Purity (IJPLC) 100%. Scheme 7 20 i;» C ) 01 .p + N^=Sr\ -P ? ■ iv;v \AS Legend to Scheme 7: i) uBuLi, diethyl ether; ii) S02gas; iii) t»enzylbroraine(s), DMF, heat; iv) diamine(s), K2C03, DMF, heat; v) HCl, diethyl ether. INTERMEDIATE 70 25 Lithium 4-chlorothieno[3,2-e]pyridiiie-2-sulfmate 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. SO2 (g) was then bubbled threw the reaction mixture for lh. After the gas bubbling had stopped the 119 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. JH NMR (270 MHz, DMSO-d6) 6 ppm 7.26 (s, 1 H) 7.99 (d, >5.54 Hz, 1 H) 5 8.14 (d, >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 ^ 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, 1.0M) 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-(benzyIsulfouyI)thieno[3,2-c]pyridm-4-yl]piperazine-l-carboxylate 30 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 tert-butyl-piperazine-1 -carboxylate as described in Method Q. Yield 0.009 g (7 % over two 120 steps). *H NMR (300 MHz, CDCI3) 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 S2 m/z 474 (M+H)+. HPLC 77%, RT 3.93 min (ACE3 C8 50x4mm, 5-50% acetonitrile in 3 min). INTERMEDIATE 72 tert-Butyl-4-(2-{[4-(trifluoromethyI)benzyl]sulfonyl}tMeno[3,2-c]pyridm-4-yl)piperazine-l-carboxyIate Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 4-10 (trifluoromethyl)benzyIbromide (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, CDCI3) 8 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 (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 S2 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-bromobenzyI)suIfonyl]thieno[3,2-c]pyridin-4-yl}piperazme-l-carboxylate Lithium 4-chlorothieno[3s2-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 fert-butyl-piperazine-l-carboxylate as described in Method Q. Yield 0.023 g (10 % over two steps). Beige solid. 'H NMR (300 MHz, CDCI3) 8 8.16 (d, J=6 Hz, IH), 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 S2 m/z 554 (M+H)+. HPLC 77 %, Rx 4.07min (ACE3 C8 50x4.6mm, 5-50% acetonitrile in 3 min). INTERMEDIATE 74 ter/-Butyl-4-(2-{[3-(trifluoromethyl)benzyl]suLfonyl}tliienoI3,2-c]pyridiii-4-30 yl)piperazine-l-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 121 reacted further with tert-butyl-piperazine-1 -carboxylate as described in Method Q. Yield 0.023 g (10 % over two steps). Beige solid. NMR (300 MHz, CDCI3) 8 8.14 (d, J= 6 Hz, 1 H), 7.85-7.91 (m, 1 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 S2 m/z 542 (M+H)+. HPLC 85 %, Rx 2.13min (YMC ODS AQ, 33x3mm, 10-90% acetonitrile in 3 min). INTERMEDIATE 75 tert-ButyI-4-(2-{[2,5-bis(trifluoromethyI)benzyI]sulfonyl}thieno[3,2-c]pyridm-4-10 yl)piperazine-l-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. *H NMR (300 MHz, CDCI3) 8 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 S2 m/z 610 (M+H)+. HPLC 73 %, Rt 2.36min (YMC ODS AQ, 33x3mm, 10-90 % acetomtrile in 3 min). INTERMEDIATE 76 ^0 tert-Butyl 4-{2-[(4-methylbeuzyl)suIfonyl]thieno[3,2-c]pyridin-4-yl}piperazine-l-carboxylate Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 4-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 25 (3 % over two steps). Beige solid. lE NMR (300 MHz, CDC13) 8 8.15 (d, M 6 Hz 1H), 7.40 (s, 1H), 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 %, Rt 2.06min (YMC ODS AQ, 33x3mm, 10-90 % acetonitrile in 3 min). 30 122 INTERMEDIATE 77 tert-Butyl 4-(2-{[5-chloro-2-(trifluorometJhyl)benzyI]sulfonyl}thieno|3,2-c]pyridm-4-yI)piperazine-l-carboxy!ate Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 5-chloro-5 2-(trifIuoromethyl)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, CDCI3) 8 8.12-8.14 (m, 1 H), 7.80-7.88 (m, 2 H), 7.47-7.66 (m, 2H), 4.71 (s, 2 H), 3.74-3.83 (m, 4 H), 3.63-3.72 (m, 0 4 H), 1.49 (s, 9 H); MS (ESI+) for C24 H25 CI F3 N3 04 S2 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)sulfonyl]thieno[3,2-c]pyridin-4-yI}piperazine-l-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, CDCI3) 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, E H), 1.49 (s, 9 H); MS 00 (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-dlinethoxybenzyl)sulfonyl]thieno[3,2-c]pyridm-4-yl}piperazine-l-25 carboxylate Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfmate (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. JH NMR (300 MHz, CDCI3) 8 8.14-8.18 (m, 1 H), 7.55 30 (s, 1 H), 6.40-6.45 (m, 1H), 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 S2 m/z 534 (M+H)+. HPLC 69 %, RT 1.99min (YMC ODS AQ, 33x3mm, 10-90 % acetonitrile in 3 min). 123 EXAMPLE 104 4-(PiperazmyI)-2-(3-methoxybenzyl-sulfonyl)-thienopyridine A 1:1 mixture of lithium 4-chloro-thienopyridine-2-sulfmate (0.176 g, 0.734 mmol) and 2-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-sulfony!)-thienopytidine. The boc-protected product was dissolved in 2 10 mL of MeOH and 4 ni L of HCl/ether was added to obtain 21.9 mg of 4-(piperazinyl)-2-(3-methox^en/yl-sulfonyD-thienopyridine. lHNMR (CD3OD/D201:1) 8 6.42-6.38 (m, IH), 7.51-7.4S (m, 1H), 7.39-7.35 (m, IH), 6.92-6.85 (m, IH), 6.64-6.59 (m, IH), 6.48-6.39 (m, 2H), 3.64-3.58 (m, 4H), 3.19-3.13 (m, 4H), 2.96 (s, 3H), 2.92 (s, 2H); MS (ESI) 404 (M + H)+; Purity (HPLC, column YMC) 94%. 15 INTERMEDIATE 80 tert-Butyl-4-[2-(beiizyIsulfonyl)thieno[3,2-c]pyridin-4-yl]piperazine-l-carboxylate 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 0 tert-butyl-piperazine-1 -carboxylate as described in Method Q. Yield 0.00 g (7 % over two steps). Beige solid. *H NMR (300 MHz, CDCI3) 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 S2 m/z 474 (M+H)+. HPLC 77 %, RT 3.93min (ACE3 C8 50x4mm, 5-50 % acetonitrile in 3 min). 25 EXAMPLE 105 2-(Benzylsttlfonyl)-4-piperazin-l-ylthieno[3,2-c]pyridine 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. *H NMR (300 MHz, DMSO-d6) 8 8.98 (s, 1H), 8.13-8.20 (d, J~8 Hzl H), 8.00 (s, 1H), 7.64-7.71 (m, 1 H), 7.18-7.35 (m, 5 H), 4.93 (s, 2 124 H), 3.60-3.70 (m, 4 H), 3.22.3.34 (m, 4 H); MS (ESI-)-) for C18 H19 N3 02 S2. CI H m/z 374 (M-l-H)+. HPLC 90%, Rt 2.91min (ACE3 C8 50x4.6mm, 5-50% acetonitrile in 3 min). INTERMEDIATE 81 tert-Butyi-4-(2-{[4-(trifluoromethyl)benzyl]suIfonyl}thieno[3,2-c]pyridiii-4-yl)piperazine-l-carboxyIate 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. lH NMR (300 MHz, CDCI3) 8 8.16 (d, J^6 Hzl H), 7.53-7.61 (d, /= 9 Hz 2 H), 7.49 (s, 1H), 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 S2 m/z 542 (M+H)+. HPLC 71 %, Rt 4.07min (ACE3 C8 50x4mm, 5-50 % acetonitrile in 3 min). 15 EXAMPLE 106 4-Piperazin-l-yI-2-{[4-(trifluoromethyI)benzyl]sulfonyI}thieno[3,2-c]pyridine hydrochloride tert-Butyl 4-(2-{[4-(trifluoromethyl)benzyl]sulfonyl}tMeno[3,2-c]pyridin-4-yI)piperazine-^0 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. !H 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 . CI H m/z 442 (M+H)+. HPLC 90 %, Rt 3.53min (ACE3 C8 50x4.6mm, 5-50 % acetomtrile in 3 min). 25 INTERMEDIATE 82 tert-Butyl-4-{2-[(3-bromobenzyl)suIfonyI]thieno[3,2-c]pyridin-4-yI}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. !H NMR (300 MHz, CDCI3) 8 8.16 (d, J=6 Hz, IH), 125 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 S2 m/z 554 (M+H)+. HPLC 77 %, Rx 4.07min (ACE3 C8 50x4.6mm, 5-50 % acetonitrile in 3 min). 5 EXAMPLE 107 2-[(3-BromobenzyI)suIfouyI]-4-piperazin-l-yltliieno[3,2-c]pyridine hydrochloride tert-Butyl 4-{2-[(3-bromobenzyl)sulfbnyl]thieno[3,2-c]pyridin-4-yl}piperazine-l-carboxylate (0.023 g, 0.04 mmol) was treated as described in Method R to give the desired product as a white solid. Yield 0.013 g (67 %) White solid. 'H NMR (300 MHz, DMSO-• d6) 5 9.19 (s, 1 H), 8.18 (d, 7= 6 Hz, 1 H), 8.05 (s, 1 H), 7.70 (d, J= 6 Hz, 1H), 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 CI8 HI8 Br N3 02 S2. CI H m/z 452 (M+H)+. HPLC 90 %, RT 3.30min (ACE3 C8 50x4.6mm, 5-50 % acetonitrile in 3 min). 15 INTERMEDIATE 83 tert-Butyl 4-{2-[(3,4-difluorobenzyI)sulfonyl]thieno[3,2-c]pyridm-4~yl}piperazine-l-carboxylate Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 3,4-bis(trifliioromethyl)benzylbromide (0.59 mmol) as described in Method P above and then 20 reacted further with tert-butyl-piperazine-l-carboxylate as described in Method Q. Yield ^ 0.014 g (6 % over two steps). Beige solid. 5H NMR (300 MHz, CDCU) 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 (ESI+) for C23 H25 F2 N3 04 S2 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-Dilluorobenzyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine hydrochloride The BOC group was removed ftom tert-butyl 4- (2-[(3,4- difluorobenzyl)sulfonyl3thieno[3,2-c]pyridin-4-yl}piperazine-l-carboxylateusingMethod 30 R. Yield 0.068 g (100 %). White solid. 'H NMR (300 MHz, DMSO-ds) 8 9.34 (s, 1 H), 8.22 (s, 1H), 8.18 (d, /=5.5 Hz, 1 H), 7.70 (d, J-5.5 Hz, 1H), 7.26-7.35 (m, 1H), 7.15-7.22 (m, 1H), 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); 126 MS (ESI+) for C18 H17 F2 N3 02 S2. CI H m/z 410 (M+H)+. HPLC 90 %, RT 1.07min (YMC ODS AQ, 33x3mm, 20-50 % acetonitrile in 1.5 min). EXAMPLE 109 2-[(4-Bromobenzyl)sulfoiiyl]-4-piperazm-l-yIthieno[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, 1H), 8.02 (s, 1 H), 7.69 (d, J= 5.5 Hz, 1H), 7.53 (d, 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. CI H m/z 454 (M+H)+. HPLC 90 %, RT 1.24min (YMC ODS AQ, 33x3mm, 20-50 % acetonitrile in 1.5 min). 15 INTERMEDIATE 84 tert-Butyl-4-(2-{[2,5-bis(trifluoromethyl)benzyl]sulfonyl}thieno[3,2-c]pyridin-4-yl)piperazine-l-carboxy!ate Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 2,5-|K) 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. ^ NMR (300 MHz, CDCI3) 8 8.16 (d, J= 5.8 Hzl H), 8.00 (s, 1H), 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)benzyl]sulfonyl}-4-piperazin-l-ylthieno[3,2-c]pyridme 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-l-carboxylate using Method R. Yield 0.024 g (100 %). White solid. JH NMR (300 MHz, DMSO-4) 8 9.30 (s, 1 H), 8.25 (s, 1 127 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, Jh5.5 Hz, 1 H), 5.22 (s, 2 H), 3.24-3.33 (m, 4 H); MS (ESI+) for C20 H17 F6 N3 02 S2 . CI H m/z 510 (M+H)+. HPLC 90 %, Rt 1.08mm (YMC ODS AQ, 33x3mm, 30-60 % acetonitrile in 1.5 min). INTERMEDIATE 85 tert-Butyl 4-{2-[(4-methylbenzyl)sulfonyI]thieno[3,2-c]pyridin-4-yl}piperazine-l-carboxylate Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 4-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. *H NMR (300 MHz, CDCI3) 6 8.15 (d, J= 6 Hz 1H), 7.40 (s, 1H), 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 %, Rx 2.06min (YMC ODS AQ, 33x3mm, 10-90 % acetonitrile in 3 min). EXAMPLE Ul 2-[(4-Methylbenzyl)sulfoiiyl]-4-piperaziii-l-ylthieno[3,2-c]pyridine hydrochloride The BOC group was removed from tert-butyl 4-{2-[(4-methylbenzyl)sulfonyl]thieno[3,2-c]pyridin-4-yl}piperazine-l-carboxylate using Method R. Yield 0.05 g (75 %). White soUd. lK NMR (300 MHz, DMSO-d6) 8 9.18 (s, 1 H), 8.17 (d, J=5.5 Hz, 1H), 8.01 (s, 1 H), 7.67 (d,J=5.5 Hz, 1H), 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 H21N3 02 S2 . CI H m/z 388 (M+H)+.HPLC 90 %, RT 1.65 min (ACE3 C8 50x3.0mm, 10-97 % acetonitrile in 3 min). INTERMEDIATE 86 tert-Butyl 4-(2-{[5-cliloro-2-(trifluoromethyl)benzyl]sulfoiiyl}thieno[3,2-c]pyridm-4-yI)piperazine-l-carboxylate Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 5-chloro-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, CDC13) 5 8.12-8.14 (m, 1 128 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 CI F3 N3 04 S2 m/z 576 (M+H)+, HPLC 74 %, Rt 2.30min (YMC ODS AQ, 33x3mm, 10-90 % acetonitrile in 3 min). EXAMPLE 112 2-{[5-Chloro-2-(trifluoromethyI)benzyl]suIfonyI}-4-piperazin-l-ylthieno[3,2-ejpyridine 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-l-carboxylate using 10 Method r. Yield 0.012 g (92 %). White solid. !H NMR (300 MHz, DMSO-de) 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 CI 9 HI 7 CI F3 N3 02 S2. CI Hm/z 476 (M+H)+. HPLC 90 %, RT 1.65 min (ACE3 C8 50x3.0mm, 10-97 % acetomtrile in 3 min). 15 INTERMEDIATE 87 tert-Butyl 4-{2-[(3,5-dimethoxybenzji)siilfonyl]thieno[3,2-c]pyridin-4-yl}piperazine-l-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, CDCI3) 8 8.14-8.18 (m, 1H), 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 H31N3 06 S2 m/z 534 <M+H)+. HPLC 69 %, RT1.99min (YMC 25 ODS AQ, 33x3mm, 10-90 % acetonitrile in 3 min). EXAMPLE 113 2-[(3,5-Dimethoxybenzyl)sulfonyI]-4-piperazin-l-ylthieno[3,2-c]pyridiae hydrochloride 30 The BOC group was removed from tert-butyl 4-{2-[(3,5- dimethoxybenzyl)sulfonyl]thieno[3,2-c]pyridin-4-yl}piperazine-l-carboxylate using Method R. Yield O.Olg (62%). White solid. ]H NMR (300 MHz, DMSO-d6) 8 9.09 (s, 1 129 n H), 8.18 (d, /= 6.7 Hz, 1 H), 8.02 (s, 1 H), 7.69 (d, 6.7 Hz, IH), 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 C20H22N3O4S2 m/z 434 (M+H)+. HPLC 90 %, RT1.60 min (ACE3 €8 50x3.0nmi, 10-97 % acetonitrile in 3 min). EXAMPLE 114 2-[(2-NaphthylmethyI)sulfonyl]-4-piperaziii-l-ylthieno[3,2-c;]pyridine hydrochloride 2-(Bromomethyl)naphtbalene was used according to Method P-R to give 12.4 mg of the desired product. lH NMR (270 MHz, CH3OH-AO 5 ppm (obscured by CH3OH, 4H) 3.70-0 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+l) 424. EXAMPLE 115 4-Piperazin-l-yl-2-{[4-(l,2,3-thiadiazol-4-yl)benzyI]sulfonyl}thieno[3,2-c]pyridine 15 hydrochloride 4-[4-(Bromomethyl)phenyl]-l,2,3-thiadiazole was used according to Method P-R to give 4.8 mg of the desired product, *H NMR (270 MHz, CH3OH-CI4) 8 ppm 3.41-3.50 (m, 4 H) 3.54 (s, 2 H) 3.89-3.98 (m, 4 H) 7.45 (d, 7=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+l) 458. 4° EXAMPLE 116 1-(4-Pyrrolidin-l-ylphenyl)-2-[(4-piperazine-l-yIthieno[3,2-c]pyridin-2-yI) sulfonyl] ethanone hydrochloride 2-Bromo-l-(4-pyrrolidin-l-ylphenyl)ethanone was used according to Method P-R to give 25 19.6 mg of the desired product. *H NMR (270 MHz, CH3OH-d4) 8 ppm 2.02-2.12 (m, 4 H) 2.69 (s, 1H) 3.37 (t, /=6.73 Hz, 4 H) 3.54 (s, 1H) 3.56.3.64 (m, 4 H) 4.12-4.22 (m, 4 H) 6.55 (d, 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+l) 471. 30 130 EXAMPLE 117 1-[4-(Diethyiammo)phenyl]-2-[(4-piperazine-l-yIthieno[3,2-c]pyridin-2-yl) sulfonyl] ethanone hydrochloride 2-Bromo-l-[4-(diethylamino)phenyl]ethanone ethanone was used according to Method P-5 R to give 9.0 mg of the desired product. 'H NMR (500 MHz, CH3OH-CI4) 5 ppm 1-16 (t, .7=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, >6.59 Hz, 1 H) 7.98 (d, >8.48 Hz, 2 H) 8.03 (d, J=6.59 Hz, 1 H) 8.47 (s, 1 H). MS (M+l) 473. 0 EXAMPLE 118 10 l-(4-Bromophenyl)-2-[(4-piperazin-l-ylthieno[3,2-c]pyridin-2-yl) sulfonyl] ethanone 2-Bromo-l-(4-bromophenyl)ethanone was used according to method A to give 3.4 mg of the desired product. *H NMR (270 MHz, CH3OH-CI4) 5 ppm 3.55 (s, 2 H) 3.56-3,67 (m, 4 H) 4.08-4.26 (m, 4 H) 7.68 (d, /=8.44 Hz, 2 H) 7.79-7.98 (m, 3 H) 8.06 (d, >6.60 Hz, 1 H) 8.45 (s, 1 H). MS (M+l) 481. 15 EXAMPLE 119 1-(3-Methoxyphenyl)-2-[(4-piperazin-l-ylthieno[3,2~c]pyridin-2-yI) sulfonyl] ethanone 2-bromo-l -(3-methoxyphenyl)ethanone was used according to method A to give 1.0 mg of the desired product. !H NMR (270 MHz, CHsOH-d^ 8 ppm 3.54 (s, 2 H) 3.55-6.62 (m, ^0 >10.03 Hz, 4 H) 3.82 (s, 3 H) 4.06-4.18 (m, 4 H) 7.20 (dd, >=8.05,2.24 Hz, 1H) 7.34-7.49 (m, 2 H) 7.57 (d, >7.39 Hz, 1 H) 7.84 (d, >6.60 Hz, 1 H) 8.06 (d, >6.60 Hz, 1H) 8.41 (s, 1 H). MS (M+l) 432. EXAMPLE 120 25 l-Phenyl-2-[(4-piperazin-l-ylthieno[3,2-c]pyridin-2-yl)sulfonyl]ethanone 2-Bromo-l-phenylethanone was used according to method A to give 1.2 mg of the desired product. *H NMR (270 MHz, CHsOH-dt) 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, >7.39 Hz, 1 H) 7.86 (d, >6.60 Hz, 1 H) 8.02 (dd, >14.12,6.99 Hz, 3 H) 8.46 (s, 1 H). MS (M+l) 402. Table 6 O* .R1 or i R EXAMPLE R* R4 121 4-Piperazin-l-yl-l-(toluene-4-sulfo nyl)-lH-pyrrolo[3,2-c]pyridine hydrochloride > 0 N 122 l-(3-Chloro-2-meth.yl-benzenesulfony l)-4-piperazin-l-yl-lH-pyrrolo[3,2-c]pyridine hydrochloride 6c cn) N 123 l-(3,4-Dimethoxy-benzenesulfonyl)-4 -piperazin-1 -yl-1 H-pyrrolo[3,2-c]py ridine hydrochloride o \ 0 N 124 4-(4-Piperazin-l-yl-pyrrolo[3,2-c}p yridine-l-sulfonyl)-benzonitrile hydrochloride § CN 0 N 125 l-(4,5-Dichloio-thiophene-2-8ulfonyl)-4-piperazin-l-yl-lH-pyrrolo[3,2-c]pyridine hydrochloride CI C) N 126 l-(2-Chloro-4-fluoro-benzenesulfoiiy l)-4-piperazin-l-yl-lH-pyrroto[3,2-cjpyridine hydrochloride (^r° F (") N 132 127 1 -Phenylmethanesulfonyl-4-piperazin-1 -yl-1 H-pyrrolo [3,2-cjpyridine hydrochloride s 6 0 N 128 1 -(5-Chloro-thiophene-2-sulfonyl)-4 -piperazin-l-yl-lH-pyrrolo[3,2-c]py ridine hydrochloride 0 N 129 l-(4-Butyl-beuzenesulfonyl)-4-piperazin-l-yl-lH-pyrrolo(3,2-c)pyridine hydrochloride 0 N 130 l-(4-Phenoxy-benzenesulfonyl)-4-piperazm-l-yl-lH-pyrrolo(3,2-c)pyridine hydrochloride b ph'° 0 N 131 l-(Phenylsulfonyl)-4-piperazin-l-yl-lH-pyrrolo[3,2-c]pyridme hydrochloride 6 0 N 132 l-[(4-Chloropheayl)s\xlfonyl]-4-piperazin-l-yl-lH-pyrrolo[3,2-c]pyridine hydrochloride CN) N 133 l-[(4-Methoxyphenyl)sulfonyl]-4-piperazin-l-yl-lH-pyrrolo[3,2-c]pyridine hydrochloride $ 'yO 0 N 134 l-[(2-Methoxy-5-methylphenyl)sulfoayl]-4-piperazin-l-yl-lH-pyirolo[3,2-c]pyridine hydrochloride / O 0 N 133 135 4-Piperazin-1 -yl-1 - {[2-(trifluoromethyl)phenyl]sulfonyl} -1H- (") N pyrrolo[3,2-c]pyridine hydrochloride c Scheme 8 Legend to Scheme 8: i) Ethylchloroformate, TEA, acetone, NaN3; ii) Bu3N, DCM and diphenylether; iii) POGl3, NaOH; iv) BOC protected amines (R4), K2C03, DMSO; v) NH3 gas Na, NH4CI, THF vi) Sulphonyl chlorides (R1), NaH, THF; vii) HCl/diethyl ether, methanol. 10 INTERMEDIATE 88 (2E)-3-(l-Benzyl-lH-pyrrol-2-yl)acryloyl azide To a mixture of l-benzyl-lH-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 NaN3 (13 g, 0.200 mol) in H2O 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 89 134 l-BenzyH,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); 'HNMR 10 (DMSO-J6, 25 °C, 270.16) 5 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 l-Benzyl-4-chIoro-111-indole 15 POCI3 (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 (MgSO^, 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 #0 the next step. INTERMEDIATE 91 tert-Butyl 4-(l-benzyl-lH-pyrrolo[3,2-c]pyridin-4-yl)piperazine-l-carboxylate A mixture of l-benzyl-4-chloro-lH-indole (1.17 g, 4.82 mmol), K2CO3 (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 (CD3OD) 8 7.87-7.85 (m, IH), 7.25-30 7.24 (m, 3H), 7.04-6.98 (m, 3H), 6.73-6.71 (m, 1H), 6.53-6.52 (m, IH), 5.19 (s, 2H), 3.63-3.59 (m, 8H), 1.47 (s, 9H); MS (ESI) 393 (M + H)+; Purity (HPLC, column ACE) 95% 135 INTERMEDIATE 92 tert-Butyl 4-( lH-pyrrolo[3,2-c]pyridin-4-yI)piperazine-l-carboxylate tert-Butyl 4-(l-benzyl-lH-pyrrolo[3,2-c]pyridin-4-yl)piperazine-l-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 NH4CI (sat) was added and the reaction was let to room temperature The THF was removed and the residue was extracted with DCM. Recrystallization (DCMZHeptane) gave ^ 112 mg of a white solid. 'HNMR (CD3OD) 8 8.66 (s, IH), 7.89 (d, IH, J = 5.80 Hz), 7.13-10 7.11 (m, IH), 6.89-6.86 (m, IH), 6.57-6.56 (m, IH), 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-(li/-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-( ltf-pyrrolo[3,2-c]pyridin-4-yl)piperazine-l-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 jxL) and PS-Trisamine (3 equiv.) ^0 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. 136 INTERMEDIATE 93 tert-ButyI-4-[l-(phenylsulfonyI)-lH-pyrrolo[3,2-c]pyridin-4-yl]piperazine-l-carboxvlate Purification by recrystallization gave 16 mg (56 %) after Boc-deprotection. 5 1HNMR (CDC13) 8 8.03-8.01 (m, 1H), 7.89-7.86 (m, 2H), 7.57-7.39 (in, 5H), 6.67-6.64 (m, IH), 3.55-3.52 (m, 8H), 1.47 (s, 9H); MS (ESI) 443 (M + H)+; Purity (HPLC, column ACE) 95%. INTERMEDIATE 94 10 tert-ButyI-4-{l-[(4-chIorophenyl)sulfonyl]~lH-pyrrolo[3,2-c]pyridin-4-yl}piperazine-1-carboxylate Purification by preparative HPLC gave 4 mg (11 %) after Boc-deprotection. ,HNMR (CDCI3) 8 8.03-7.51 (m, 7H), 6.89-6.87 (m, 1H), 3.91-3.66 (m, 8H), 1.47 (s, 9H); MS (ESI) 377 (M + H)+; Purity (HPLC, column ACE) 95%. 15 INTERMEDIATE 95 fert-Butyl-4-{l-[(4-methoxyphenyl)sulfonyl]-lH-pyrrolo[3,2-c]pyridin-4-yl}piperazine-l-carboxyIate Purification by recrystallization (MeOH/Ethear) gave 21 mg (67 %) after boc-deprotection. 0 'HNMR (CDCI3) 8 8.02-8.00 (m, IH), 7.84-7.80 (m, 2H), 7.48-7.46 (m, IH), 7.41-7.38 (m, IH), 6.92-6.86 (m, 2H), 6.64-6.62 (m, IH), 3.79 (s, 3H), 3.57-3.52 (m, 8H), 1.48 (s, 9H); MS (ESI) 473 (M + H)+; Purity (HPLC, column ACE) 95%. INTERMEDIATE 96 25 tert-Butyl 4-(l-{[2-(trifluoromethyl)phenyl]su!fonyl}-lH-pyrroloI3,2-c]pyridiu-4-yl)piperazine-l-carboxylate Purification by preparative HPLC gave 8.6 mg (25 %) after boc-deprotection. 1HNMR (CDCI3) 6 8.14-8.11 (m, IH), 8.01-7.94 (m, 2H), 7.89-7.72 (m, 3H), 7.37-7.34 (m, IH), 6.89-6.88 (m, IH), 3.93-3.89 (m, 4H), 3.71-3.67 (m, 4H), 1.47 (s, 9H); MS (ESI) 511 (M + 30 H)+; Purity (HPLC, column ACE) 95%. 137 INTERMEDIATE 97 tert-Butyl 4-{l-[(2-methoxy-5-methylphenyl)suIfonyl]-lH-pyrroIo[3,2-c]pyridin-4-yl}piperazme-l-carboxylate Purification by preparative HPLC gave 10.3 mg (32 %) after boc-deprotection. 1HNMR 5 (CDC13) 5 7.95-7.92 (m, 2H), 7.74-7.72 (m, IH), 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 3 4-Piperazin-1-> I-1-((oIuene-4-suIfottyl)-lH-pyrrolo[3,2-c]pyridine hydrochloride p-Toulenesulfonyl chloridc (24.6 mg) was added to tert-butyl 4-(liJ-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+l) 1HNMR (CD3OD) 5 ppm 2.39 (s, 3 H) 3.48 (m, 4 H) 4.06 (m, 4 H) 7.22 (d, >3.71 Hz, 1 H) 7.43 (d, >8.16 Hz, 5 2 H) 7.95 (m, 5 H). EXAMPLE 122 l-(3-Chloro-2-methyl-benzenesulfonyl)-4-piperazin-l-yl-lH-pyrrolo[3,2-c]pyridine hydrochloride 0 3-Chloro-2-methylbenzenesulfonyl chloride (29.0 mg) was added to tert-butyl 4-(lH-pyrrolo[3,2-c]pyridin-4-yl)piperazine-l-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+l). 25 EXAMPLE 123 l-(3,4-Dimethoxy-benzenesulfonyl)-4-piperazin-l-yi-lH-pyrroIoi3,2-c]pyridiiie hydrochloride 3,4-Dimethoxybenzenulfonyl chloride (30.5 mg) was added to tert-butyl 4-(l#-pyrrolo[3,2-c]pyridin-4-yl)piperazine-l-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+l) 1HNMR (CD3OD) 6 ppm 3.50 (m, >4.21 Hz, 2 H) 3.85 (d, >3.22 Hz, 4 H) 4.10 138 (m, >3,96 Hz, 2 H) 7.11 (d, >8.66 Hz, 1 H) 7.23 (d, >3.46 Hz, 1 H) 7.48 (d, >1.73 Hz, 1 H) 7.74 (dd, >8.54,1.86 Hz, 1 H) 7.92 (s, 2 H) 8.07 (d, >3.46 Hz, IH). EXAMPLE 124 4-(4-Piperazin-l-yI-pyrrolo[3,2-c]pyridme-l-sulfonyI)-benzonitriIe hydrochloride 4-Cyanobenzenesulfonyl chloride (26.0mg) was added to tert-butyl 4-(li7-pyrrolo[3,2- * c]pyridin-4-yl)piperazine-l-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+l) lHNMR (CD3OD) 8 ppm 3.50 (m, 4 H) 4.08 (m, 4 H) 7.29 (d, >3.71 Hz, 2 H) 7.98 (in, 4 H) 8.29 '10 (d, >8.66 Hz, 2 H). EXAMPLE 125 l-(4,5-Dichloro-thiophene-2-sull'onyl)-4-piperazin-l-yI-lH-pyrrolo[3,2-c]pyridine hydrochloride 15 4,5-Dichloro-thiophene-2-sulfonyl chloride (32.4 mg) was added to tert-butyl 4-(l;H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-l-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+l). JO EXAMPLE 126 1-(2-Chloro-4-fluoro-benzenesuIfonyl)-4-piperazm-l-yl-lH-pyrroIo[3,2-c]pyridine hydrochloride 2-Chloro-4-flourobenzenesulfonyl chloride (29.5 mg) was added to tert-butyl 4-(lH-pyrrolo[3,2-c]pyridin-4-yl)piperazine-l-carboxylate the title compound (2.4 mg). LC/MS 25 Rt: 1.361 (System 10 till 40% MeCN over 1.5 min, ACE C8), Purity. 90%. MS: 396 (M+l) *HNMR (CD3OD) 8 ppm 3.51 (m, 4 H) 4.08 (m, 4 H) 7.23 (dd, >3.96, 0.49 Hz, 1 H) 7.47 (m, 1H) 7.55 (dd, >8.41,2.47 Hz, 2 H) 7.62 (d, >6.93 Hz, 1H) 7.91 (d, >7.18 Hz, 1 H) 8.06 (d, >3.96 Hz, 1H). 30 139 EXAMPLE 127 l-Pheiiylmethanesulfonvl-4-piperazin-l-yl-lH-pyrrolo [3,2-c]pvridiiie hydrochloride Phenyl-methanesulfonyl chloride (24.6 mg) was added to tert-butyl 4-(l#-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+l). EXAMPLE 128 l-(5-Chloro-thiophene-2-sulfonyl)-4-piperazm-l-yl-lH-pyrrolo[3,2-c]pyridine hydrochloride ' 10 5-Chlorothiophene-2-sulfonyl chloride (28.0 mg) was added to tert-butyl 4-(lH- pyrrolo[3,2-c]pyridin-4-yl)piperazine-l-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+l). 15 EXAMPLE 129 l-(4-ButyI-beiizenesulfonyI)-4-piperazin-l-yI-lH-pyrrolo(3,2-c)pyridijie hydrochloride 4-N-Butylbenzenesulfonylchloride (30.0 mg) was added to tert-butyl 4-(lif-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+l) 1HNMR 20 (CD3OD) 8 ppm 0.90 (t, .7=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, .7=3.96 Hz, 4 H) 7.25 (d, >3.71 Hz, 2 H) 7.44 (d, >8.16 Hz, 2 H) 7.91 (m,2H)8.02(m,2H). EXAMPLE 130 25 l-(4-Phenoxy-benzenesuIfonyl)-4-piperaziii-l-yMH-pyrrolo(3,2-c)pyridine hydrochloride (4-Phenoxy)beDzene)sulfonyl chloride (34.7 mg) was added to tert-butyl 4-(l#~ pyrrolo[3,2-c]pyridin-4-yl)piperazine-l-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+l) 1HNMR (CD3OD) 8 ppm 3.50 (m, >3.96 Hz, 4 H) 4.09 (m, >4.45 Hz, 4 H) 7.05 (dd, >8.16,6.43 Hz, 2 H) 7.26 (m, 2 H) 7.44 (t, >7.79 Hz, 2 H) 7.90 (m, 3 H) 8.01 (d, >3.71 Hz, 2 H) 8.07 (d, >8.91 Hz, 2 H). 140 EXAMPLE 131 l-(PhenyIsulfonyI)-4~piperazin-l-yl-lH-pyrroIo[3,2-c]pyridine 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 l-[(4-ChIorophenyl)sulfonyI]-4-piperaziii-l-yI-lH-pyrroIo[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 l-[(4-Methoxyphenyl)suIfonyl]-4-piperazin-l-yI-lH-pyrrolo[3,2-cJpyridine 15 . hydrochloride Purification by recrystallization (MeOH/Ether) gave 21 mg (67 %) after Boc-deprotection. MS (ESI) 373 (M + H)+; Purity (HPLC, column ACE) 92% EXAMPLE 134 l-[(2~Methoxy-5-methylphenyl)sulfonyl]-4-piperazin-l-yl-lH-pyrroIo[3,2-c]pyridine hydrochloride Purification by preparative HPLC gave 10.3 mg (32 %) after Boc-deprotection. MS (ESI) 3E7 (M + H)+; Purity (HPLC, column ACE) 95%. 25 EXAMPLE 135 4-Piperazin-l-yl-l-{[2-(trifluoromethyl)phenyl]sulfony!}-lH-pyrrolo[3,2-c]pyridjbae hydrochloride Purification by preparative HPLC gave 8.6 mg (25 %) after Boc-deprotection. MS (ESI) 411 (M + H)+; Purity (HPLC, column ACE) 94%. 30 141 BIOLOGICAL TESTS The ability of a compound according to the invention to bind a 5-HTg receptor, and to be pharmaceutically useful, can be determined using in vivo and in vitro assays known in the 5 art. (a) 5-HT6 binding Assay ^ Binding affinity experiment for the 5-HTg receptor are performed in HEK293 cells 10 transfected with 5-HT6 receptor using (3H)-LSD as labeled ligand according to the general method as described by Boess F.Get al. Neuropharmacology vol. 36(4/5) 713-720, 1997. Materiais 15 Cell culture The HEK-293 cell line transfected with the 5-HTg receptor was cultured in Dulbeccos Modified Eagles Medium containing 5 % dialyzed foetal bovine serum, (Gibco BRL 10106-169), 0.5 raM sodium pyruvate and 400 jig/ml Geneticin (G-418) (Gibco BRL10131^019). The cells were passaged 1:10, twice a week. Chemicals The radioligand [3H] 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) 142 in the presence of Microscint™ 20 scintillation fluid (Packard Bioscience, Meriden, CT, USA). Buffer 5 The binding buffer consisted of 20 mMHEPES, 150mMNaCl, 10 mM MgC^, and 1 mM, EDTA, pH 7.4. Methods Membrane preparation 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, lOOOx g for 5 min. Finally, the membranes were collected by high-speed centrifugation (20 OOOx 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 HEK293 cells expressing the human 5-HT6 receptor instead of from HeLa cells (Dinh DM, Zaworski PG, Gill GS, Schlachter SIC, Lawson CF, Smith MW. Validation of human 5-HT6 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 143 [3H]LSD was saturable, while the non-specific binding increased linearly with ihe concentration of added radioligand. [3H] LSD bound with high affinity to 5-HTg 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 [3H] 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 [3Hj LSD binding with an over all average Ki value of236 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-HTg receptor are presented in Table 7. All unlabelled ligands displaced the specific binding of [3H] 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 0 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 TopCount™ 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 [3HJ 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 144 in the presence of 5 |iM lisuride. Bmax and the dissociation constant, K&, 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. £ max- Lu Lu + Kd (equation 1) 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 IC50 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 K,- value was calculated using the method of [Cheng Y.C. Biochetn. Pharmacol. 22,3099-3108,1973S] equation 2. ICso , . s Ki = y (equation 2) L = concentration of radioligand 15 K4 - Affinity of radioligand (b) 5-HT6 Intrinsic Activity Assay Antagonists to the 5-HTg receptor were characterized by measuring inhibition of 5-HT 20 induced increase in cAMP in HEK 293 cells expressing the human 5-HT5 receptor (see Boess et al. (1997) Neuropharmacology 36:713-720). Briefly, HEK293/5-HT6 cells were seeded in polylysine coated 96-well plates at a density of25,000 / 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% CO2 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 jal dissolved in assay medium, the cells were incubated for 10 min at 37°C in a 5% CO2 incubator. The medium was again aspirated and the cAMP content was determined using a radioactive cAMP kit (Amersham Pharmacia 145 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. EC50) evoked increase in cAMP, using the formula IC5o)Coir=IC5o/(l+[5HT]/EC5o). 5 The compounds in accordance with the invention have a selective affinity to 5-HTg receptors with Kj and ICso.corr values between 0.5 nM and 5 |iM or display a % inhibition of [3H] LSD > 20 % at 50 nM and are antagonists, agonist or partial agonist at 5-HTg . The ^ compounds show good selectivity over 5-HTia, 5-HT2a, 5-HT2a, 5-HT2b, 5-HT20. 10 (c) In vivo assay of reduction offood intake For a review on serotonin and food intake, see Blundell, JJB. 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 (b hours of infusion of compounds is recorded. Male mice (obese C57BL/6JBom-Lepob and lean wild-type C57Bl/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 146 acid, saline. Fresh solutions are made for each study. Doses of 30, SO and 100 mg kg"1 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. Alzet osmotic minipumps (Model 2001D; infusion rate 8 fxl/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 arc implanted subcutaneously in the neck/back region under short acting anesthesia (mcto fane/en flurane). 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. Hie 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. 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- 147 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 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. Table 7. Biological data In vitro binding at the human 5-HTg receptor EXAMPLE Kj(nM) human 5-HT6 1 10 11 6.5 20 10.5 40 7.5 43 4.5 68 13 85 32 131 5 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 The term "comprising" as used in this specification means "consisting at least in part of'. When interpreting each statement in this specification that includes the term "comprising", features other than that or those prefaced by the term may also be present. Related terms such as "comprise" and "comprises" are to be interpreted in the same maimer. WHAT WE CLAIM IS: 1. A compound of the formula (I): or a pharmaceutically acceptable salt thereof, wherein: ring D is a five-membered heterocyclic or heteroaryl ring, said ring comprising one or two 10 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 at least one group W is -N-; 15 Pis any one of formula (a), (b) or (c) R1 r1 r1 a & °4"R2 Ns(0)^]y R NV o y V , or ; (a) (b) (c) wherein x = 0,1, or 2 and y = 0; and P and R3 can be attached to any carbon atom that allows the substitution, or when P is 20 (c), then P can also be attached to any nitrogen in ring D that allows the substitution; R1 is (e) aryl carbonylmethyl, (g) C3.7 cycloalkyl-Ci-6 alkyl, wherein the cyclic ring is optionally partially unsaturated, or 25 (h) a group Ar; -149- , £9*a' .1 evi 10 15 wherein Ar is (a) phenyl, (b) 1-naphthyl, (c) 2-naphthyl, (d) aryl-Ci.6 alkyl, (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, 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 oxygen, nitrogen or sulfur; R2 is (a) H, 20 (b) Ci_6 alkyl; 1 J or R and R are linked to form a group ^N' 25 30 (CH2, wherein v is 0-2, X and Y are independently (a)H, (b) halogen, (c) Ci.6 alkyl, (d) CF3, (e) hydroxy, (f) Ci-6 alkoxy, -150- pflo; -1^- cr (h) phenyl, (i) phenoxy, (j) benzyloxy, (m) -CN, 5 (n) straight or branched Ci-6 hydroxyalkyl, (o) straight or branched Ci-6 alkylhalides, (r) -NR4R5; and R4 and R5 are independently 10 (a) H, or (b) Ci-6 alkyl; and R3 is a group selected from any one of 15 20 I RqH j J 1 N | I R6 R6 R, and R6 wherein R3 is optionally substituted on each carbon atom that allows the substitution with Rq groups, wherein Rq is independently H, or (Cj-6) alkyl, and wherein two Rq groups can be present on the same carbon atom simultaneously, wherein q = 1 or 2, and m = 1 or 2; and 25 R6 is independently (a) H, (b) linear or branched Ci-6 alkyl. 30 2. The compound according to claim 1, wherein R1 is (e) a group Ar; -151- \ .10- IqECEIM- k\ ~L. T0 10 25 Ar is (a) phenyl, (b) 1-naphthyl, (c) 2-naphthyl, or (f) a 5 to 7-membered, optionally aromatic, partially saturated or completely saturated, 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) H, (b) halogen, (c) Ci„6 alkyl, (d) -CF3, (f) Ci.6 alkoxy, (n) phenyloxy; (a)H, or (b) Cj.6 alkyl; X and Y are H; R4 and R5 are each independently H or C1.3 alkyl; and R3 is selected from any one of wherein m = 1 or 2, and R6 is independently (a) H, or (b) methyl. -152- 3. The compound according to any one of claims 1 to 2, wherein D is pyrrolyl, thienyl or furanyl. 4. The compound according to any one of claims 1 to 3, wherein P is R Xs(0)'^], (C). 5. The compound according to any one of claims 1 to 3, wherein P is .1 I .O 2 ?*0 R-Nv- o^-R o^Sy (a) or ' (b). 6. The compound according to claim 5, wherein R2 is H. 7. The compound according to claim 4 of the general formula (IV) N' X- (IV) 8. The compound according to any one of claims 5 and 6 of the general formula (VI) N R- (VI). 9. The compound according to any one of claims 5 and 6 of the general formula (VII) ,P N R* Y (VII). 10. The compound according to claim 7, which is the compound 4-( 1,4-Diazepan-1 -yl)-2-(phenylsulfonyl)thieno[3,2-c]pyridine; 4-( 1,4-Diazepan-l -yl)-2-[(3,4-dichlorophenyl)sulfonyl]thieno[3,2-c]pyridine; -153- _ I JUL » 4-( 1,4-Diazepan-1 -yl)-2- [4-tert-butylphenylsulfonyl)thieno[3,2-c]pyridine; 4-(l,4-Diazepan-l-yl)-2-[4-tert-butylphenylsulfonyl)thieno[3,2-c]pyridine; 4-( 1,4-Diazepan-1 -yl)-2- [3,4-dimethylphenylsulfonyl)thieno [3,2-c]pyridine; 2-[(4-Bromophenyl)sulfonyl]-4-(l,4-diazepan-l-yl)thieno[3,2-c]pyridine; 5 2-(Phenylsulfonyl)-4-piperazin-1 -ylthieno [3,2-c]pyridine; 2-(3-Methoxy-benzenesulfonyl)-4-piperazin-l-yl-thieno[3,2-c]pyridine; 2-(4-Methoxy-benzenesulfonyl)-4-piperazin-l-yl-thieno[3,2-c]pyridine; 4-Piperazin-1 -yl-2- {[4-trifluoromethyl)phenyl] sulfonyl} thieno [3,2-c]pyridine; 2-[[2-tert-Butylphenyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine; 10 2-[(3,4-Dichlorophenyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine-2-sulfonamide; 2-[(4-tert-Butylphenyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine; 2-(l-Naphthyl sulfonyl)-4-piperazin-l-ylthieno[3,2-c]pyridine; 2- [(3 -Fluorophenyl)sulfonyl] -4-piperazin-1 -ylthieno[3,2-c]pyridine-2-sulfonamide; 2-(Mesitylsulfonyl)-4-piperazin-1 -ylthieno [3,2-c]pyridine; 15 2-[(2-Methoxyphenyl)sulfonyl] -4-piperazin-1 -ylthieno [3,2-c]pyridine; 2-[(2,4-Dimethoxyphenyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine; 2-[(2,4-Dimethylphenyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine; 2-[(2,5-Dimethylphenyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine; 2- [(2-Ethylphenyl)sulfonyl] -4-piperazin-1 -ylthieno [3,2-c]pyridine; 20 4-(Piperazinyl)-2-(3-methoxybenzyl-sulfonyl)-thienopyridine; 2-(Benzylsulfonyl)-4-piperazin-1 -ylthieno[3,2-c]pyridine; 4-Piperazin-l-yl-2-{[4-(trifluoromethyl)benzyl]sulfonyl}thieno[3,2-c]pyridine; 2-[(3-Bromobenzyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine; 2-[(2,3-Difluorobenzyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine; 25 2-[(4-Bromobenzyl)sulfonyl]-4-piperazin-1 -ylthieno [3,2-c]pyridine; 2- {[2,5-bis(Trifluoromethyl)benzyl] sulfonyl} -4-piperazin-1 -ylthieno [3,2-c]pyridine; 2-[(4-Methylbenzyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine; 2- {[5 -Chloro-2-(trifluoromethyl)benzyl] sulfonyl} -4-piperazin-1 -ylthieno [3,2-c]pyridine; 2-[(3,5-Dimethoxybenzyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine; 30 2-[(2-Naphthylmethyl)sulfonyl]-4-piperazin-l-ylthieno[3,2-c]pyridine; 4-Piperazin-1 -yl-2- {[4-( 1,2,3 -thiadiazol-4-yl)benzyl] sulfonyl} thieno [3,2-c]pyridine; 1 -(4-Pyrrolidin-1 -ylphenyl)-2- [(4-piperazine-1 -ylthieno [3,2-c]pyridin-2-yl) sulfonyl] ethanone; or -154- r^^6BTV -^ci\/£D' 1 -[4-(Diethylamino)phenyl]-2-[(4-piperazine-l-ylthieno [3,2-c]pyridin-2-yl) sulfonyl] ethanone, or a pharmaceutically acceptable salt thereof. 11. The compound according to claim 7, which is the compound: 1 -(4-Methylphenylsulphonyl)-4-piperazin-1 -yl-1 //-pyrrolo[3,2-c]pyridine; l-(3-Chloro-2-methylphenylsulphonyl)-4-piperazin-l-yl-l//-pyrrolo[3,2-c]pyridine; 1 -(3,4-Dimethoxyphenylsulphonyl)-4-piperazin-1 -yl-1 //-pyrrolo[3,2-c]pyridine; 4-(4-Piperazin-1 -yl-pyrrolo [3,2-c]pyridine-1 -sulfonyl)-benzonitrile; 1 -(4,5-Dichloro-thiophene-2-sulfonyl)-4-piperazin-1 -yl-1 H-pyrrolo[3,2-c]pyridine; l-(2-Chloro-4-fluorophenylsulphonyl)-4-piperazin-l-yl-l//-pyrrolo[3,2-c]pyridine; 1 -Phenylmethanesulfonyl-4-piperazin-1 -yl-1 H-pyrrolo [3,2-c]pyridine; l-(5-Chloro-thiophene-2-sulfonyl)-4-piperazin-l-yl-lH-pyrrolo[3,2-c]pyridine; 1 -(4-Butyl-benzenesulfonyl)-4-piperazin-1 -yl-1 H-pyrrolo(3,2-c)pyridine; 1 -(4-Phenoxy-benzenesulfonyl)-4-piperazin-1 -yl-1 H-pyrrolo(3,2-c)pyridine; 1 -(Phenylsulfonyl)-4-piperazin-1 -yl-1 H-pyrrolo [3,2-c]pyridine; l-[(4-Chlorophenyl)sulfonyl]-4-piperazin-l-yl-lH-pyrrolo[3,2-c]pyridine; 1 -[(4-Methoxyphenyl)sulfonyl]-4-piperazin-1 -yl-1 H-pyrrolo[3,2-c]pyridine;

1-[(2-Methoxy-5-methylphenyl)sulfonyl]-4-piperazin-l-yl-lH-pyrrolo[3,2-c]pyridine; or 4-Piperazin-l-yl-l-{[2-(trifluoromethyl)phenyl] sulfonyl }-l H-pyrrolo [3,2-c]pyridine, or a pharmaceutically acceptable salt thereof. 12. The compound according to claim 8, which is the compound N-(4-Methylphenyl)-4-(4-methylpiperazin-l-yl)thieno[3,2-c]pyridine-2-sulfonamide; 2-Bromo-4-(4-methyl-piperazin-l-yl)-thieno[3,2-c]pyridine-3-sulfonic acid p-tolylamide; 4-(4-Methylpiperazin-l-yl)-n-phenylthieno[3,2-c]pyridine-2-sulfonamide; 4-Piperazin-1 -yl-thieno [3,2-c]pyridine-2-sulfonic acid (3 -fluoro-5 -trifluoromethyl-phenyl)-amide; 4-Piperazin-1 -yl-thieno[3,2-c]pyridine-2-sulfonic acid (4-chloro-phenyl)-amide; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (4-isopropyl-phenyl)-amide; 4-Piperazin-1 -yl-thieno [3,2-c]pyridine-2-sulfonic acid p-tolylamide; 4-(4-Methylpiperazin-l-yl)-iV- (2-cyclohex-l-en-l-ylethyl) thieno [3,2-c] pyridines-sulfonamide; -155- 2-(4-(4-Methylpiperazin-l-yl) thieno [3,2-c] pyridin-2-ylsulfonyl)-l,2,3,4-tetrahydroisoquinoline; 4-(4-Methylpiperazin-1 -yl)-N- (2-thien-2-ylethyl) thieno [3,2-c] pyridine-2-sulfonamide; 4-(4-Methylpiperazin-1 -yl)-/V- [l-(l-naphthyl) ethyl] thieno [3,2-c] pyridines-sulfonamide; 4-(4-Methylpiperazin-l-yl)-iV- (4-hexylphenyl) thieno [3,2-c] pyridine-2-sulfonamide; N- (3-Chlorobenzyl)-4-(4-methylpiperazin-l-yl) thieno [3,2-c] pyridine-2-sulfonamide; 4-(4-Methylpiperazin-l-yl)-iV- [l-(4-fluorophenyl) ethyl] thieno [3,2-c] pyridine-2-sulfonamide; N- (2,3-Difluorobenzyl)-4-(4-methylpiperazin-l-yl) thieno [3,2-c] pyridine-2-sulfonamide; 4-(4-Methylpiperazin-l-yl)-A/- (4-chloro-2, 5-dimethoxyphenyl) thieno [3,2-c] pyridine-2 -sulfonamide; 2-Bromo-4- (4-methylpiperazin-1 -yl)-N- (2-cyclohex-1-en-1-ylethyl) thieno [3,2-c] pyridine-3 -sulfonamide; 2-Bromo-4- (4-methylpiperazin-l-yl)-iV- [(1S)-1 -(2-naphthyl) ethyl] thieno [3,2-c] pyridine-3 -sulfonamide; 2-Bromo-4- (4-methylpiperazin-1 -yl)-jV- [l-(4-fluorophenyl) ethyl] thieno [3,2-c] pyridine- 3-sulfonamide; 2-Bromo-4- (4-methylpiperazin-1 -y\)-N- (2,4,5-trimethoxyphenyl) thieno [3,2-c] pyridine- 3-sulfonamide; N-(3,4-Dichlorophenyl)-4-piperazin-l-ylthieno[3,2-c]pyridine-2-sulfonamide; N-(2,4-Difluorophenyl)-4-piperazin-1 -ylthieno[3,2-c]pyridine-2-sulfonamide; 4-Piperazin-l-yl-N-[-3-(trifluoromethyl)phenyl]thieno[3,2-c]pyridine-2-sulfonamide; N-(3-Ethylphenyl)-4-piperazin-l-ylthieno[3,2-c]pyridine-2-sulfonamide; N-(3,4-Dimethoxyphenyl)-4-piperazin-l-ylthieno[3,2-c]pyridine-2-sulfonamide; N-(4-Bromo-2-methylphenyl)-4-piperazin-l-ylthieno[3,2-c]pyridine-2-sulfonamide; 2-(4-Piperazin-1 -yl-thieno [3,2-c]pyridine-2-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline; 4-Piperazin-l-yl-thieno[3,2-c]pyridine-2-sulfonic acid (2-thiophen-2-yl-ethyl)-amide; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (4-chloro-2,5-dimethoxy-phenyl)-amide; 4-Piperazin-l-yl-thieno[3,2-c]pyridine-2-sulfonic acid phenethyl-amide; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (2,6-diethyl-phenyl)-amide; 4-Piperazin-l-yl-thieno[3,2-c]pyridine-2-sulfonic acid (3-phenyl-propyl)-amide; 4-Piperazin-l-yl-thieno[3,2-c]pyridine-2-sulfonic acid (3,3-diphenyl-propyl)-amide; -156- 4-Piperazin-1 -yl-thieno [3,2-c]pyridine-2-sulfonic acid [2-(5-methoxy-1 H-indol-3 -yl)-ethyl]-amide; 4-Piperazin-1 -yl-thieno[3,2-c]pyridine-2-sulfonic acid 4-trifluoromethyl-benzylamide; 4-Piperazin-l-yl-thieno[3,2-c]pyridine-2-sulfonic acid benzyl-ethyl-amide; 5 N-(3-Ethylphenyl)-4-piperazin-1 -ylthieno[3,2-c]pyridine-3-sulfonamide; N-(4-Isopropylphenyl)-4-piperazin-l-ylthieno[3,2-c]pyridine-3-sulfonamide; N-(4-Methylphenyl)-4-(pyrrolidin-3-yloxy)thieno[3,2-c]pyridine-2-sulfonamide; N-(4-Methylphenyl)-4-(piperidin-4-yloxy)thieno [3,2-c]pyridine-2-sulfonamide; N-(2,3-Difluorobenzyl)-4-piperazin-l-ylthieno[3,2-c]pyridine-2-sulfonamide; 10 N-(3-Chlorobenzyl)-4-piperazin-l -ylthieno[3,2-c]pyridine-2-sulfonamide; 4-Piperazin-l-yl-thieno[3,2-c]pyridine-2-sulfonic acid phenylamide; 4-Piperazin-1-yl-thieno[3,2-c]pyridine-2-sulfonic acid (4-tert-butyl-phenyl)-amide; 4-(4-Methyl-piperazin-l-yl)-thieno[3,2-c]pyridine-2-sulfonic acid phenylamide; 4-(4-Methyl-piperazin-l-yl)-thieno[3,2-c]pyridine-2-sulfonic acid (3-chloro-phenyl)-15 amide;

2-Bromo-4-(4-methyl-piperazin-1 -yl)-thieno[3,2-c]pyridine-

3-sulfonic acid phenylamide;

4-(4-Methyl-piperazin-1 -yl)-thieno [3,2-c]pyridine-3 -sulfonic acid (4-methylphenyl)-amide; or N-Phenyl-7-piperazin-l-ylthieno[2,3-c]pyridine-2-sulfonamide, 20 or a pharmaceutically acceptable salt thereof. 13. A process for the preparation of a compound according to claim 4, wherein P is R1 //> 0 , said method comprising the steps of: preparation of the heteroaromatic

5-member ring fused halogen-substituted pyridine, 25 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 halogen with a diamine. -157- jssgsftf®"" .1 JUL 14. A process for the preparation of a compound according to claim 5, wherein P is R1 I 0=s=0 I 2 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 carboxylic moiety to amine by Curtius rearrangement; reaction of the amine group with a 5 sulphonylchloride. 15. A process for the preparation of a compound according to claim 5, wherein P is 2 /r1 R—N 0=S—o , said method comprising the steps of: preparation of the heteroaromatic 5-member ring fused pyridine; introduction of sulfonylchloride moiety by nucleophilic 10 addition; reaction of sulphonylchloride moiety with an aniline to obtained a sulfonamide; aromatic nucleophilic substitution of the chloro with a diamine. 16. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 12 as an active ingredient, in combination with a pharmaceutically acceptable diluent 15 or carrier. 17. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 12, for use in the treatment or prophylaxis of type II diabetes. 20 18. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 12, for use in the treatment or prophylaxis of obesity, to achieve reduction of body weight and of body weight gain. 19. Use of a compound according to any one of claims 1 to 12, for the manufacture of a 25 medicament for use in the treatment or prophylaxis of type II diabetes. -158- \ _ i JUL \ I v# c ni 20. Use of a compound according to any one of claims 1 to 12, 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. -159- .1 JUL oegeiyss </div>