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US20070066598A1 - Compounds - Google Patents

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Publication number
US20070066598A1
US20070066598A1 US11/509,914 US50991406A US2007066598A1 US 20070066598 A1 US20070066598 A1 US 20070066598A1 US 50991406 A US50991406 A US 50991406A US 2007066598 A1 US2007066598 A1 US 2007066598A1
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US
United States
Prior art keywords
hydrochloride
piperazin
nmr
methyl
benzenesulfonamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/509,914
Inventor
Gary Johansson
Andrew Mott
Markus Thor
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Swedish Orphan Biovitrum AB
Original Assignee
Biovitrum AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from SE0102048A external-priority patent/SE0102048D0/en
Priority claimed from SE0102386A external-priority patent/SE0102386D0/en
Priority claimed from SE0103437A external-priority patent/SE0103437D0/en
Application filed by Biovitrum AB filed Critical Biovitrum AB
Priority to US11/509,914 priority Critical patent/US20070066598A1/en
Assigned to BIOVITRUM AB reassignment BIOVITRUM AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: THOR, MARKUS, JOHANSSON, GARY, MOTT, ANDREW
Publication of US20070066598A1 publication Critical patent/US20070066598A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
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    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/40—Nitrogen atoms attached in position 8
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to substituted sulfonamide 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 II diabetes, and CNS disorders.
  • 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 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 II 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 activation of serotonin receptor subtypes or by inhibiting serotonin reuptake. The exact receptor subtype profile required is however not known.
  • Serotonin (5-hydroxytryptamine or 5-HT), a key transmitter of the peripheral and central nervous system, modulates a wide range of physiological and pathological functions, including anxiety, sleep regulation, aggression, feeding and depression.
  • Multiple serotonin receptor subtypes have been identified and cloned.
  • One of these, the 5-HT 6 receptor was 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.
  • WO 99/42465 discloses sulphonamides derivatives that bind to the 5-HT 6 receptor and that can be used for the treatment of CNS disorders such as anxiety, depression, epilexy, obsessive compulsive disorders, cognitive disorders, ADHD, anorexia and bulimia schizophrenia, drug abuse.
  • WO 01/32646 A1 discloses compounds that binds to the 5-HT 6 receptor and that are used for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders.
  • WO 99/37623 A2 discloses compounds that binds to the 5-HT 6 receptor and that are used for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders.
  • WO 99/42465 A3 discloses compounds that binds to the 5-HT 6 receptor and that are used for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders.
  • EP 0 815 861 A1 discloses compounds that binds to the 5-HT 6 receptor and that are used for the treatment of CNS disorders.
  • WO 99/02502 A2 discloses compounds that binds to the 5-HT 6 receptor and that are used for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders.
  • WO 98/27081 A1 discloses compounds that binds to the 5-HT 6 receptor and that are used for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders.
  • the compounds of formula (I) show affinity for the 5-HT 6 receptor as antagonists at low nanomolar range.
  • Compounds according to the invention and their pharmaceutically acceptable salts have 5-HT 6 receptor antagonist activity and are believed to be of potential use in the treatment or prophylaxis of obesity and type II diabetes, as well as in the treatment or prophylaxis of disorders of the central nervous system such as anxiety, depression, panic attacks, memory disorders, sleep disorders, migraine, anorexia, bulimia, binge disorders, obsessive compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease, Huntington's chorea and/or schizophrenia, Attention Deficit Hyperactive Disorders (ADHD), drug abuse.
  • ADHD Attention Deficit Hyperactive Disorders
  • C 1-6 alkyl denotes a straight or branched alkyl group having from 1 to 6 carbon atoms.
  • examples of said lower alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
  • C 1-6 alkoxy denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms.
  • examples of said lower alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and branched-chain pentoxy and hexoxy.
  • halogen shall mean fluorine, chlorine, bromine or iodine.
  • C 3-7 cycloalkyl denotes a cyclic alkyl group having a ring size from C 3 to C 7 .
  • Examples of said cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl and cycloheptyl.
  • 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 is 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
  • heteroaryl refers to a hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as O, N, or S.
  • heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, and indolyl groups.
  • the present invention provides a compound having the general formula I: or a pharmaceutically acceptable salt thereof, wherein: W is N or —(CH)—, provided that not more than three groups W are N; P is with the proviso that P and R 3 can only be in meta or para position to each other;
  • R 1 is (a) C 1-6 alkyl, (b) C 1-6 alkoxyalkyl, (c) straight or branched C 1-6 hydroxyalkyl, (d) straight or branched C 1-6 alkylhalides; or (e) a group Ar;
  • Ar is (a) phenyl, (b) 1-naphthyl, (c) 2-naphthyl, (d) benzyl, (e) cinnamoyl, (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, or (g) a bicyclic ring
  • this invention features a compound of the formula (I): or a pharmaceutically acceptable salt thereof, wherein: ring B is in which 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; W is N or —(CH)—, provided that not more than three groups W are N in both rings A and B together; P is P and R 3 are bound to the same ring and are disposed in the meta- or para-positions relative to each other; R 1 is (a) C 1-6 alkyl, (b) C 1-6 alkoxyalkyl, (c) straight or branched C 1-6 hydroxyalkyl, (d) straight or branched C 1-6 alkylhalides; or (e) a group Ar; Ar is (a) phenyl, (b) 1-naphthyl, (c) 2-na
  • the invention provides naphthalene compounds of the formula (II), isoquinoline compounds of the formula (III), quinoline compounds of the formula (IV), 1,7-naphthyridine compounds of the formula (V), and benzofuran, benzothiophene, or indole compounds of the formula (VI): wherein R 3 , P, X and Y are as defined for formula (I); and wherein D in formula (VI) 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.
  • R 1 is (a) C 1-6 alkyl, or (e) a group Ar
  • Ar is (a) phenyl, (b) 1-naphthyl, (c) 2-naphthyl, or (f) a 5 to 7-membered, partially or completely saturated, mono- or bi-cyclic heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; wherein the group Ar is substituted in one or more positions with X or Y; wherein X or Y is (a) H, (b) halogen, (c) C 1-6 alkyl, (d) —CF 3 , (f) C 1-6 alkoxy
  • Preferred compounds of the formula II are para-substituted naphthalene compounds wherein P is wherein R 1 and R 2 are as defined for formula (I); and X and Y are H, halogens, methyl, methoxy, (cf. Table I).
  • R 1 is phenyl, methylphenyl, methoxyphenyl, dimethoxyphenyl, 1-naphthyl, 2-naphthyl, fluoromethylphenyl, chlorophenyl, dichlorophenyl, fluorochlorophenyl, dichlorothienyl, chlorothienyl, trifluoromethylphenyl, or methoxymethylphenyl
  • R 2 is H or methyl
  • R 3 is piperazinyl or homopiperazinyl, 3,5-dimethylpiperazine, 4-piperidine, 4-(4,3)-dihydropyridine, 4-(1,2,3,6)-tetrahydropyridine
  • R 6 is H, methyl, ethyl, isopropyl.
  • Further preferred compounds of the formula II are compounds with a group P and a group R 3 in para-position.
  • Further preferred compounds of the formula II are compounds with a group P and a group R 3 in para-position, wherein P is wherein R 1 and R 2 are as defined for formula (I) (cf. Table III); and X or Y are H, methyl, ethyl, isopropyl, methoxy, thiomethyl, 1-naphthyl, phenyloxy, trifluoromethoxy, trifluorothienyl (cf. Table II).
  • R 1 is phenyl, 1-naphthyl, phenyloxyphenyl, dimethoxyphenyl, dimethylphenyl, methylchlorophenyl, isopropylphenyl, fluorophenyl, 1(2H)-3,4-dihydroquinolin, R 2 is H or methyl, R 3 is piperazinyl, and R 6 is H.
  • Preferred compounds of the formula III are isoquinoline compounds wherein P is and occupies position 3 of the ring, wherein R 1 and R 2 are as defined for formula (I); and X or Y are H, methyl, bromo, methoxy, acethylamino (cf. Table IV). Particularly preferred of such compounds are those wherein R 1 is phenyl, bromophenyl, methylchlorophenyl, methylphenyl, methoxyphenyl, trimethylphenyl, dimethoxyphenyl, bromomethoxyphenyl; R 2 is H or methyl; and R 3 is methylpiperazinyl.
  • Preferred compounds of the formula IV are quinoline compounds wherein P is and occupies position 5 of the ring, wherein R 1 and R 2 are as defined for formula (I); and X, Y is H (cf. Table V). Particularly preferred of such compounds are those wherein R 1 is phenyl; R 2 is H or methyl; and R 3 is piperidinyl.
  • Preferred compounds of the formula V are 1,7-naphthyridine compounds wherein P is and occupies position 8 of the ring, wherein R 1 and R 2 are as defined for formula (I); and X and Y are halogen, methoxy (cf. Table V). Particularly preferred of such compounds are those wherein R 1 is phenyl, dimethoxyphenyl, 1-naphthyl; R 2 is H or methyl; and R 3 is piperidinyl;
  • Preferred compounds of the formula VI are benzofuran compounds wherein P is and occupies position 5 of the ring, wherein R 1 and R 2 are as defined for formula (I) and wherein D in formula (VI) 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.
  • the group Y can be attached to any unsubstituted carbon atom in D.
  • the heteroaryl ring comprises one or two nitrogen atoms
  • a group R 6 could be attached at the secondary nitrogen; and
  • X and Y are halogen, methoxy (cf. Table V).
  • R 1 is phenyl, dichlorophenyl, bromophenyl, dichloromethylphenyl, 1-naphthyl, phenyl, methylphenyl, fluorophenyl, thiophenyl, chlorothiophenyl;
  • R 2 is H or methyl;
  • R 3 is piperidinyl or N-methylpiperidinyl.
  • R 2 and X, Y are H: TABLE VI
  • Compound name R1 R3 137 4-Methyl-N-(8-piperazin-1- yl-1,7-naphthyridin-6- yl)benzenesulfonamide, trifluoroacetic acid 138 4-Bromo-N-(8-piperazin-1- yl-1,7-naphthyridin-6- yl)benzenesulfonamide, trifluoroacetic acid 139 N-(8-Piperazin-1-yl-1,7- naphthyridin-6- yl)naphthalene-1- sulfonamide, trifluoroacetic acid 140 N-(8-Piperazin-1-yl-1,7- naphthyridin-6-yl)butane-1- sulfonamide, trifluoroacetic acid 141 3-Trifluoromethyl-N-(8- piperazin-1-y
  • R 2 and X, Y are H: TABLE VII
  • Compound name R1 R3 146 3-Cyanophenyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride 147 4-Phenoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride 148 1-Naphthyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride 149 N-(7-Piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride 150 5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonic acid (7-piperazin-1-yl-benzofuran-5-yl)-amide, hydrochloride 151 N
  • the compounds according to the invention can be prepared starting from halo-nitro substituted bicyclic aromatic rings by base (potassium carbonate) catalyzed aromatic nucleophilic substitution of a halogen in the desired position of the central bicyclic ring with the diamine of choice (R 3 ). Reduction of a nitro group properly positioned on the central bicyclic ring by Raney-Ni catalyzed reaction leads to the aniline that is substituted further by sulfonylation with the alkyl- or aryl-sulfonylchloride of choice (R 1 —SO 2 —Cl).
  • the compounds according to the invention can be prepared starting from fluoro substituted bicyclic aromatic rings in which the sulfonylchloride functionality is introduced by acid catalyzed sulfonylation.
  • the sulfonyl group is reacted further with anilines of choice (R 1 —NH 2 ).
  • the diamine group (R 3 ) is introduced by base catalyzed aromatic nucleophilic substitution.
  • the compounds according to the invention can be prepared starting from iodo substituted bicyclic aromatic rings.
  • the diamine group (R 3 ) is introduced by Palladium catalysed nucleophilic substitution. Reduction of a nitro group properly positioned on the central bicyclic ring by Raney-Ni catalyzed reaction leads to the aniline that is substituted further by sulfonylation with the alkyl- or aryl-sulfonylchloride of choice (R 1 —SO 2 —Cl).
  • 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 formula (I).
  • 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, Comprehensive Organic Transformations , VCH Publishers (1989); T. W. Greene and P. G. M.
  • the end products of the formula (I) are obtained either in neutral or salt form. Both the free base and the salts of these end products are within the scope of the invention.
  • Acid addition salts of the new compounds may in a manner known per se be transformed into the free base using basic agents such as alkali or by ion exchange.
  • the free base obtained may also form salts with organic or inorganic acids.
  • acids which form suitably therapeutically acceptable salts.
  • examples of such acids are hydrohalogen acids, sulfuric acid, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxyl or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybensoic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, halogenbensenesulfonic acid, toluenesulfonic acid, mandelic acid or naphthalenesulfonic acid.
  • compositions 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 methods such as granulation, compression, microencapsulation, spray coating, etc.
  • This invention relates to a method of treatment or prophylaxis of obesity, type II diabetes, and/or disorders of the central nervous system.
  • the method includes administering to a subject (e.g., a mammal, a human, a horse, a dog, or a cat) in need thereof an effective amount of one or more compounds of the formula (I) described above.
  • a subject e.g., a mammal, a human, a horse, a dog, or a cat
  • This invention also features a method for reducing body-weight (e.g., treating body-weight disorders) or reducing food intake.
  • the method includes administering to a subject in need thereof an effective amount of a compound of the formula (I).
  • body weight disorders refers to the disorders caused by an imbalance between energy intake and energy expenditure, resulting in abnormal body (e.g., excessive) weights. Such body weight disorders include obesity.
  • the method includes administering to a subject in need thereof an effective amount of a compound of the formula (I).
  • 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 or reducing food intake.
  • an effective amount refers to an amount of a compound which confers a therapeutic effect on the treated subject.
  • the therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration.
  • the amount of active compounds is between 0.1-95% by weight of the preparation, preferably between 0.2-20% by weight in preparations for parenteral use and preferably between 1 and 50% by weight in preparations for oral administration.
  • 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.
  • Diamines (1.2 eq) are added to a suspension of chloronaphthalenes derivatives (1 eq) and K 2 CO 3 (3.5) in DMF. The suspensions are stirred at 65° C. for 16 hours followed by filtration. Elimination of volatiles to give a crude residue. The residues are purified by flash chromatography (SiO 2 , CHCl 3 ⁇ CHCl 3 /10% MeOH/0.4% aq. NH 3 ) to give the corresponding products as free bases.
  • 1-Methyl-4-(4-nitro-1-naphthyl)-1,4-diazepane To a suspension of 1-chloro-4-nitronaphthalene (1.0 g, 4.82 mmol) and K 2 CO 3 (2.0 g, 14.46 mmol) in DMF (10 mL) was added 1-methyl-1,4-diazepane (0.66 g, 5.78 mmol). The suspension was stirred at 65° C. for 16 hours followed by filtration. Elimination of volatiles to give a crude residue. The residue was purified by flash chromatography (SiO 2 , CHCl 3 ⁇ CHCl 3 /10% MeOH/0.4% aq.
  • tert-Butyl 4-(4-nitro-1-naphthyl)-1-piperazinecarboxylate—1-Chloro-4-nitronaphthalene (2.7 g, 13 mmol), tert-butyl-1-piperazinecarboxylate (2.4 g, 13 mmol) and potassium carbonate (2 g) were heated together in DMSO (100 mL) at 90° C. overnight. The solution was allowed to cool to room temperature and poured into water (500 mL).
  • 5-Nitro-8-quinolinyl trifluoromethanesulfonate To a solution of 5-nitro-8-quinolinol (1.89 g, 9.40 mmol) and Et 3 N (6.60 mL, 4.70 mmol) in CH 2 Cl 2 (125 mL) was added N-phenyl-trifluoromethanesulfonimide (5.06 g, 14.1 mmol). The mixture was stirred at room temperature for 16 hours and then more of added N-phenyl-trifluoromethanesulfonimide (1.0 equiv.) was added and the mixture was stirred from another 16 hours.
  • the crude intermediate was purified via column chromatography on silica using CHCl 3 /CHCl 3 +10% MeOH+0.4% NH 3 to give 0.230 g of the boc-protected intermediate. Removal of the boc-group was accomplished by dissolving the intermediate in MeOH and then adding ether saturated with HCl-gas.
  • Naphthalene-1-sulfonic acid (4-piperazin-1-yl-naphthalen-1-yl)-amide, hydrochloride
  • the compound was prepared 1-tert-butyl-4-(4- ⁇ bis[(2-naphthalene)sulfonyl]amino ⁇ -1-naphthyl)-1-piperazinecarboxylate and potassium carbonate (120 mg, 0.87 mmol) in acetone (2 ml) was added iodomethane (44 ⁇ l, 0.7 mmol) and the mixture was stirred at room temperature over night. The mixture was diluted with acetonitrile, filtered and concentrated in vacuo. The residue was redissolved in DCM (3 ml) and treated with concentrated TFA (1 ml) at 0° C. for 30 min and then allowed to reach room temperature.
  • the obtained crude product was purified by flash-chromatography using MeOH (10%) in pentane, to give the desired product as a tar. To increase the purity, the product was purified by recrystallising (EtOAc/hexanes). This gave the product with a purity of 95%.
  • the final product was obtained as following: 5-Fluoro-2-methyl-N-[4-(4-(tert-butoxycarbonyl)-1-hydroxypiperidin-1-yl)-1-naphthyl]benzenesulfonamide (0.022 g, 0.043 mmol) was dissolved in formic acid (5 mL) and stirred at RT for 24 h. HPLC showed complex reaction mixture. The reaction mixture was stirred at 100° C. for 4 h. One compound was seen on HPLC. The solvent was evaporated. The crude was transformed to the HCl salt (0.020 g) for the desired product, purity 98%.
  • reaction mixtures were stirred at 100° C. for 3 h, diluted with ethyl acetate (50 mL), washed with sat. Na 2 CO 3 (3 ⁇ 50 mL), dried (Na 2 SO 4 ) and evaporated with an excess of HCl in ether, giving the hydrochlorides. No purification was necessary for compounds 20-23, while compounds 24-27 were purified with HPLC (YMC combiprep ODS-AQ, 50 ⁇ 20 mm I.D.).
  • the final product was prepared according to Method F: A stirred solution of 1-[(4-fluoro-1-naphthyl)sulfonyl]-1,2,3,4-tetrahydroquinoline (50 mg, 0.15 mmol) and piperazine (80 mg, 0.9 mmol) in DMSO (1 ml) was heated at 95° C. over night. The reaction mixture was allowed to reach room temperature and was subsequently added dropwise into water. The formed solid was isolated, re-dissolved in MeOH and treated with an excess of 1M HCl in diethyl ether. Removal of the solvents in vacuo afforded the title compound (60 mg, 83%) as a white solid.
  • the title compound was prepared from 1-(4-methyl-1-piperazinyl)-3-isoquinolinylamine (commercially available; 0.209 g, 0.862 mmol) using the method described in the example that follows: yield 0.152 g (65%); 1 H NMR (DMSO-d6) ⁇ ; 11.35 (s, 1H), 11.09 (br s, 1H), 8.15-8.04 (m, 1H), 7.97-7.90 (m, 1H), 7.83-7.35 (m, 5H), 6.95 (s, 1H), 3.70-3.10 (m, 8H), 2.85-2.75 (m, 3H); MS (posESI) m/z 419 (M+H).
  • the amine was dissolved in CH 2 Cl 2 (6.0 mL) and pyridine (0.785 mL, 9.73 mmol) and benzenesulfonyl chloride (0.178 mL, 1.39 mmol) was added.
  • the reaction mixture was stirred at room temperature for 16 hours and then washed with saturated aqueous NaHCO 3 .
  • the organic phase was dried with Na 2 SO 4 , filtered and concentrated.
  • 6-Amino-8-bromo-1,7-naphthyridine—3-(Cyanomethyl)pyridine-2-carbonitrile (4.0 g, 28 mmol) was added carefully to HBr in acetic acid (33%) (25 ml) at rt. The red suspension was stirred for 1.5 h and filtered. The red solid was washed with EtOAc (3 ⁇ ) and suspended in water. 1N NaOH was added dropwise until pH-8, and the suspension was stirred for 45 minutes and filtered. The red solid was washed with water (2 ⁇ ) and dried. The crude product was suspended in 5% MeOH in CH 2 Cl 2 and filtered through a short plug of silica, washing with 5% MeOH in CH 2 Cl 2 .
  • the ability of a compound according to the invention to bind a 5-HT 6 receptor, and to be pharmaceutically useful, can be determined using in vivo and in vitro assays known in the art.
  • Antagonists to the 5-HT 6 receptor were characterized by measuring inhibition of 5-HT induced increase in cAMP in HEK 293 cells expressing the human 5-HT 6 receptor (see Boess et al. (1997) Neuropharmacology 36: 713-720). Briefly, HEK293/5-HT 6 cells were seeded in polylysine coated 96-well plates at a density of 25,000/well and grown in DMEM (Dulbecco's Modified Eagle Medium) (without phenol-red) containing 5% dialyzed Foetal Bovine Serum for 48 h at 37° C. in a 5% CO 2 incubator.
  • DMEM Dynamic Eagle Medium
  • the medium was 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 ⁇ l dissolved in assay medium, the cells were incubated for 10 min at 37° C. in a 5% CO 2 incubator. The medium was again aspirated and the cAMP content was determined using a radioactive cAMP kit (Amersham Pharmacia Biotech, BIOTRAK RPA559).
  • the compounds in accordance with the invention have a selective affinity to 5-HT 6 receptors with K i values between 0.5 nM and 5 ⁇ M.
  • the compounds show good selectivity for 5-HT 1a , 5-HT 2a , 5-HT 2a , 5-HT 2b , 5-HT 2c .
  • 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.
  • the effect of the compounds on food consumption is also studied in wild type (C57BL/6J) mice. The amount of food consumed during 15 hours of infusion of compounds is recorded.
  • mice Male mice (obese C57BL/6JBom-Lep ob and lean wild-type C57B1/6JBom; Bomholtsgaard, Denmark) 8-9 weeks with an average body weight of 50 g (obese) and 25 g (lean) are used in all the studies.
  • the animals are housed singly in cages at 23 ⁇ 1° C., 40-60% 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.
  • test compounds are dissolved in solvents suitable for each specific compound such as cyclodextrin, cyclodextrin/methane sulfonic acid, polyethylene glycol/methane sulfonic acid, saline. Fresh solutions are made for each study. Doses of 30, 50 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 ⁇ L/h) are used and loaded essentially as recommended by the Alzet technical information manual (Alza Scientific Products, 1997; Teeuwes and Yam, 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 only vehicle solution and maintained in vehicle pre-warmed to 37° C. (approx. 1 h).
  • the minipumps are implanted subcutaneously in the neck/back region under short acting anesthesia (metofane/enflurane). This surgical procedure lasts approximately 5 min. It takes about 3 h to reach steady state delivery of the compound.
  • the weight of the food pellets are measured at 5 p.m. and at 8 p. m. for two days before (baseline) and one day after the implantation of the osmotic minipumps.
  • the weigh-in is performed with a computer assisted Mettler Toledo PR 5002 balance. Occasional spillage is corrected for.
  • 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 (MRM with the transition m/z 316 221). A linear regression analysis of the standards forced through 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 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-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 50-200 mg/kg.
  • TABLE VI In vivo efficacy data on the effect of the compounds on Food Intake reduction In vivo efficacy - Food intake (15 h) in ob/ob mouse % Inhibition of Food Intake Free plasma concentration in ob/ob mice at of the compounds at steady EXAMPLES 50 mg/Kg/day, 15 h state (Css, u) 48 23.8 0.008 13 24.1 0.035 53 25.7 a ND 34 51.4 0.078 24 46.2 0.0076 19 69.6 0.150 27 68.9 0.008 30 60.1 0.275 29 71 0.33 14 41 b 0.23 a
  • the effect on Food Intake reported in the table was obtained at the dose of 14.8 mg/kg/d b
  • the effect on Food Intake reported in the table was obtained at the dose of 100 mg/kg/d

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Abstract

The present invention relates to substituted sulfonamide compounds of the general formula (I), wherein P is sulfonamide or amide-substituted sulfonic acid, which compounds are potentially useful for the prophylaxis and treatment of medical conditions relating to obesity, type II diabetes and/or disorders of the central nervous system.
Figure US20070066598A1-20070322-C00001

Description

    RELATED APPLICATIONS
  • This application claims priority to Swedish application number 0102048-6, filed on Jun. 11, 2001, Swedish application number 0102386-0, filed on Jul. 3, 2001, and Swedish application number 0103437-0, filed on Oct. 16, 2001, the contents of which are incorporated herein by reference.
    • TECHNICAL FIELD
  • The present invention relates to substituted sulfonamide 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 II diabetes, and CNS disorders.
    • 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 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 II 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 activation of serotonin receptor subtypes or by inhibiting serotonin reuptake. The exact receptor subtype profile required is however not known.
  • 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-HT6 receptor, was 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-HT6 antagonist and 5-HT6 antisense oligonucleotides to reduce food intake in rats has been reported (Bentley, J. C. et al. (1999) Br J Pharmac. Suppl. 126, P66; Bentley, J. C. et al. (1997) J. Psychopharmacol. Suppl. A64, 255).
  • Compounds with enhanced affinity and selectivity for the 5-HT6 receptor have been identified, e.g. in WO 00/34242 and by Isaac, M. et al. (2000) 6-Bicyclopiperazinyl-1-arylsulfonylindoles and 6-Bicyclopiperidinyl-1-arylsulfonylindoles derivatives as novel, potent and selective 5-HT 6 receptor antagonists. Bioorganic & Medicinal Chemistry Letters 10: 1719-1721 (2000).
    • INFORMATION DISCLOSURE
  • J. Med. Chem. 1970, 13(4), 592-598 describes N-(4-{[2-(diethylamino)ethyl]amino}-1-naphthyl)amides; N-{5,6,7,8-Tetrahydro-4-[(3-piperidinopropyl)amino]-1-naphthyl}amides and related amides and urea derivatives as schistosomicides.
  • WO 99/42465 discloses sulphonamides derivatives that bind to the 5-HT6 receptor and that can be used for the treatment of CNS disorders such as anxiety, depression, epilexy, obsessive compulsive disorders, cognitive disorders, ADHD, anorexia and bulimia schizophrenia, drug abuse.
  • WO 01/32646 A1 discloses compounds that binds to the 5-HT6 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 99/37623 A2 discloses compounds that binds to the 5-HT6 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 binds to the 5-HT6 receptor and that are used for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders.
  • EP 0 815 861 A1 discloses compounds that binds to the 5-HT6 receptor and that are used for the treatment of CNS disorders.
  • WO 99/02502 A2 discloses compounds that binds to the 5-HT6 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 98/27081 A1 discloses compounds that binds to the 5-HT6 receptor and that are used for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders.
    • DISCLOSURE OF THE INVENTION
  • It has surprisingly been found that the compounds of formula (I) show affinity for the 5-HT6 receptor as antagonists at low nanomolar range. Compounds according to the invention and their pharmaceutically acceptable salts have 5-HT6 receptor antagonist activity and are believed to be of potential use in the treatment or prophylaxis of obesity and type II diabetes, as well as in the treatment or prophylaxis of disorders of the central nervous system such as anxiety, depression, panic attacks, memory disorders, sleep disorders, migraine, anorexia, bulimia, binge disorders, obsessive compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease, Huntington's chorea and/or schizophrenia, Attention Deficit Hyperactive Disorders (ADHD), drug abuse.
  • Definitions
  • Unless otherwise stated or indicated, the term “C1-6 alkyl” denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said lower alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
  • Unless otherwise stated or indicated, the term “C1-6 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 “halogen” shall mean fluorine, chlorine, bromine or iodine.
  • The term “C3-7 cycloalkyl” denotes a cyclic alkyl group having a ring size from C3 to C7. Examples of said cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl and cycloheptyl.
  • 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 is 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
  • The term “heteroaryl” refers to a hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as O, N, or S. Examples of heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, and indolyl groups.
  • Compounds of Formula I
  • In a first aspect, the present invention provides a compound having the general formula I:
    Figure US20070066598A1-20070322-C00002
    or a pharmaceutically acceptable salt thereof, wherein:
    W is N or —(CH)—, provided that not more than three groups W are N;
    P is
    Figure US20070066598A1-20070322-C00003
    with the proviso that P and R3 can only be in meta or para position to each other;
    R1 is
    (a) C1-6 alkyl,
    (b) C1-6 alkoxyalkyl,
    (c) straight or branched C1-6 hydroxyalkyl,
    (d) straight or branched C1-6 alkylhalides; or
    (e) a group Ar;
    Ar is
    (a) phenyl,
    (b) 1-naphthyl,
    (c) 2-naphthyl,
    (d) benzyl,
    (e) cinnamoyl,
    (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, or
    (g) a bicyclic ring system comprising at least one heterocyclic ring according to (f).
  • 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, mono- or bi-cyclic heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;
        R2 is
        (a) H,
        (b) C1-6 alkyl,
        (c) C1-6 alkoxyalkyl,
        (d) straight or branched C1-6 hydroxyalkyl, or
        (e) straight or branched C1-6 alkylhalides;
        R3 is a group
        Figure US20070066598A1-20070322-C00004
        X and Y are independently
        (a) H,
        (b) halogen,
        (c) C1-6 alkyl,
        (d) CF3,
        (e) hydroxy,
        (f) C1-6 alkoxy,
        (g) C1-4 alkenyl;
        (h) phenyl;
        (i) phenoxy,
        (j) benzyloxy,
        (k) benzoyl,
        (l) —OCF3,
        (m) —CN,
        (n) straight or branched C1-6 hydroxyalkyl,
        (o) straight or branched C1-6 alkylhalides,
        (p) —NH2,
        (q) —NHR4,
        (r) —NR4R5,
        (s) —NO2,
        (t) —CON R4R5,
        (u) —NHSO2 R4,
        (v) —NR6COR5,
        (x) —SO2NR4R5,
        (z) —C(═O)R4,
        (aa) —CO2 R4, or
        (ab) —S(O)n R4; wherein n is 0, 1, 2 or 3,
        (ac) —S—(C1-6)alkyl
        (ad) —SCF3
        R4 and R5 are independently
        (a) H,
        (b) C1-6 alkyl,
        (c) C3-7 cycloalkyl, or
        (d) Ar, as defined above for R1; alternatively, R4 and R5 are linked to form a group (CH2)2O, (CH2)4O or (CH2)3-5; and
        R6 is
        (a) H, or
        (b) C1-6 alkyl.
  • In one aspect, this invention features a compound of the formula (I):
    Figure US20070066598A1-20070322-C00005
    or a pharmaceutically acceptable salt thereof, wherein:
    ring B is
    Figure US20070066598A1-20070322-C00006
    in which 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;
    W is N or —(CH)—, provided that not more than three groups W are N in both rings A and B together;
    P is
    Figure US20070066598A1-20070322-C00007
    P and R3 are bound to the same ring and are disposed in the meta- or para-positions relative to each other;
    R1 is
    (a) C1-6 alkyl,
    (b) C1-6 alkoxyalkyl,
    (c) straight or branched C1-6 hydroxyalkyl,
    (d) straight or branched C1-6 alkylhalides; or
    (e) a group Ar;
    Ar is
    (a) phenyl,
    (b) 1-naphthyl,
    (c) 2-naphthyl,
    (d) benzyl,
    (e) cinnamoyl,
    (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, or
    (g) a bicyclic ring system comprising at least one heterocyclic ring according to (f).
  • 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) C1-6 alkyl,
        (c) C1-6 alkoxy,
        (d) straight or branched C1-6 hydroxyalkyl, or
        (e) straight or branched C1-6 alkylhalides;
        or R1 and R2 are linked to form a group (CH2)4O, which represents (CH2)—(CH2)—O—(CH2)—(CH2);
        One of R3 is a group
        Figure US20070066598A1-20070322-C00008
        X and Y are independently
        (a) H,
        (b) halogen,
        (c) C1-6 alkyl,
        (d) —CF3,
        (e) hydroxy,
        (f) C1-6 alkoxy,
        (g) C1-4 alkenyl;
        (h) phenyl;
        (i) phenoxy,
        (j) benzyloxy,
        (k) benzoyl,
        (l) —OCF3,
        (m) —CN,
        (n) straight or branched C1-6 hydroxyalkyl,
        (o) straight or branched C1-6 alkylhalides,
        (p) —NH2,
        (q) —NHR4,
        (r) —NR4R5,
        (s) —NO2,
        (t) —CONR4R5,
        (u) —NHSO2R4,
        (v) —NR4COR5,
        (x) —SO2NR4R5,
        (z) —C(═O)R4,
        (aa) —CO2R4, or
        (ab) —S(O)nR4; wherein n is 0, 1, 2 or 3;
        (ac) —S—(C1-6)alkyl
        (ad) —SCF3
        R4 and R5 are independently
        (a) H,
        (b) C1-6 alkyl,
        (c) C3-7 cycloalkyl, or
        (d) Ar, as defined above for R1;
        alternatively, R4 and R5 are linked to form a group (CH2)2O, (CH2)4O or (CH2)3-5; in which (CH2)2O represents (CH2)—O—(CH2) and (CH2)4O represents (CH2)—(CH2)—O—(CH2)—(CH2); and
        R6 is
        (a) H, or
        (b) straight of branched C1-6 alkyl.
  • In preferred forms, the invention provides naphthalene compounds of the formula (II), isoquinoline compounds of the formula (III), quinoline compounds of the formula (IV), 1,7-naphthyridine compounds of the formula (V), and benzofuran, benzothiophene, or indole compounds of the formula (VI):
    Figure US20070066598A1-20070322-C00009
    wherein R3, P, X and Y are as defined for formula (I); and wherein D in formula (VI) 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. The group Y can be attached to any unsubstituted carbon atom in D. When the heteroaryl ring comprises one or two nitrogen atoms, a group R6 could be attached at the secondary nitrogen.
    Preferred compounds of the general formulas (I), (II), (III), and (IV), (V), (VI) are those wherein:
    R1 is
    (a) C1-6 alkyl, or
    (e) a group Ar;
    Ar is
    (a) phenyl,
    (b) 1-naphthyl,
    (c) 2-naphthyl, or
    (f) a 5 to 7-membered, partially or completely saturated, mono- or bi-cyclic heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;
    wherein the group Ar is substituted in one or more positions with X or Y; wherein X or Y is
    (a) H,
    (b) halogen,
    (c) C1-6alkyl,
    (d) —CF3,
    (f) C1-6 alkoxy,
    (g) C1-4 alkenyl;
    (l) —OCF3, or
    (m) straight or branched C1-6 hydroxyalkyl
    (n) phenyloxy
    (o) benzyloxy
    (ab) —S(O)nR4; wherein n is 0, 1, 2 or 3,
    (ac) —S—(C1-6)alkyl
    (ad) —SCF3
    (v) —NR4COR5,
    (x) —SO2NR4R5,
    (z) —C(═O)R4.
    R2 is
    (a) H, or
    (b) C1-3 alkyl, in particular methyl;
    or R1 and R2 are linked to form a group (CH2)4O;
    Figure US20070066598A1-20070322-C00010
  • wherein R6 is
      • (a) H, or
      • (b) C1-6 alkyl, in particular methyl;
        X and Y are H; and/or
        D is furanyl.
  • Preferred compounds of the formula II are para-substituted naphthalene compounds wherein P is
    Figure US20070066598A1-20070322-C00011
    wherein R1 and R2 are as defined for formula (I); and X and Y are H, halogens, methyl, methoxy, (cf. Table I). Particularly preferred of such compounds are those wherein R1 is phenyl, methylphenyl, methoxyphenyl, dimethoxyphenyl, 1-naphthyl, 2-naphthyl, fluoromethylphenyl, chlorophenyl, dichlorophenyl, fluorochlorophenyl, dichlorothienyl, chlorothienyl, trifluoromethylphenyl, or methoxymethylphenyl; R2 is H or methyl; and R3 is piperazinyl or homopiperazinyl, 3,5-dimethylpiperazine, 4-piperidine, 4-(4,3)-dihydropyridine, 4-(1,2,3,6)-tetrahydropyridine; R6 is H, methyl, ethyl, isopropyl. Further preferred compounds of the formula II are compounds with a group P and a group R3 in para-position.
  • Further preferred compounds of the formula II are compounds with a group P and a group R3 in para-position, wherein P is
    Figure US20070066598A1-20070322-C00012
    wherein R1 and R2 are as defined for formula (I) (cf. Table III); and X or Y are H, methyl, ethyl, isopropyl, methoxy, thiomethyl, 1-naphthyl, phenyloxy, trifluoromethoxy, trifluorothienyl (cf. Table II). Particularly preferred of such compounds are those wherein R1 is phenyl, 1-naphthyl, phenyloxyphenyl, dimethoxyphenyl, dimethylphenyl, methylchlorophenyl, isopropylphenyl, fluorophenyl, 1(2H)-3,4-dihydroquinolin, R2 is H or methyl, R3 is piperazinyl, and R6 is H.
  • Preferred compounds of the formula III are isoquinoline compounds wherein P is
    Figure US20070066598A1-20070322-C00013
    and occupies position 3 of the ring, wherein R1 and R2 are as defined for formula (I); and X or Y are H, methyl, bromo, methoxy, acethylamino (cf. Table IV). Particularly preferred of such compounds are those wherein R1 is phenyl, bromophenyl, methylchlorophenyl, methylphenyl, methoxyphenyl, trimethylphenyl, dimethoxyphenyl, bromomethoxyphenyl; R2 is H or methyl; and R3 is methylpiperazinyl.
  • Preferred compounds of the formula IV are quinoline compounds wherein P is
    Figure US20070066598A1-20070322-C00014
    and occupies position 5 of the ring, wherein R1 and R2 are as defined for formula (I); and X, Y is H (cf. Table V). Particularly preferred of such compounds are those wherein R1 is phenyl; R2 is H or methyl; and R3 is piperidinyl.
  • Preferred compounds of the formula V are 1,7-naphthyridine compounds wherein P is
    Figure US20070066598A1-20070322-C00015
    and occupies position 8 of the ring, wherein R1 and R2 are as defined for formula (I); and X and Y are halogen, methoxy (cf. Table V). Particularly preferred of such compounds are those wherein R1 is phenyl, dimethoxyphenyl, 1-naphthyl; R2 is H or methyl; and R3 is piperidinyl;
  • Preferred compounds of the formula VI are benzofuran compounds wherein P is
    Figure US20070066598A1-20070322-C00016
    and occupies position 5 of the ring, wherein R1 and R2 are as defined for formula (I) and wherein D in formula (VI) 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. The group Y can be attached to any unsubstituted carbon atom in D. When the heteroaryl ring comprises one or two nitrogen atoms, a group R6 could be attached at the secondary nitrogen; and X and Y are halogen, methoxy (cf. Table V). Particularly preferred of such compounds are those wherein R1 is phenyl, dichlorophenyl, bromophenyl, dichloromethylphenyl, 1-naphthyl, phenyl, methylphenyl, fluorophenyl, thiophenyl, chlorothiophenyl; R2 is H or methyl; and R3 is piperidinyl or N-methylpiperidinyl.
    Table I
    Para-substituted naphthalene compounds of the formula II wherein P is
    Figure US20070066598A1-20070322-C00017
  • and X, Y are H:
    Figure US20070066598A1-20070322-C00018
    Compound name R1 R3 R2
    1 N-(4-Methylphenyl)-4-(1-piperazinyl)-1-naphthalenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00019
    Figure US20070066598A1-20070322-C00020
         		H
    2 N-(2,4-Dimethoxyphenyl)-4-(1-piperazinyl)-1-naphthalenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00021
    Figure US20070066598A1-20070322-C00022
         		H
    3 N-(3,4-di-Fluorophenyl)-4-(4-methyl-1,4-diazepan-1-yl)-1- naphthalenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00023
    Figure US20070066598A1-20070322-C00024
         		H
    4 N-(3-Fluorophenyl)-4-(4-methyl-1,4-diazepan-1-yl)-1- naphthalenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00025
    Figure US20070066598A1-20070322-C00026
         		H
    5 4-(4-Ethyl-1-piperazinyl)-N-phenyl-1-naphthalenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00027
    Figure US20070066598A1-20070322-C00028
         		H
    6 4-Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl-N-(4-methylphenyl)-1- naphthalenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00029
    Figure US20070066598A1-20070322-C00030
         		H
    7 N-(3,4-Dimethoxyphenyl)-4-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl-1- naphthalenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00031
    Figure US20070066598A1-20070322-C00032
         		H
    8 4-(4-Ethyl-1-piperazinyl)-N-(4-methylphenyl)-1-naphthalenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00033
    Figure US20070066598A1-20070322-C00034
         		H
    9 N-(3,4-Dimethoxyphenyl)-4-(3-methyl-1-piperazinyl)-1- naphthalenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00035
    Figure US20070066598A1-20070322-C00036
         		H
    10 N-(4-Methylphenyl)-4-(4-methyl-1-piperazinyl)-1-naphthalenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00037
    Figure US20070066598A1-20070322-C00038
         		H
    11 N-[4-(2,5-Diazabicyclo[2.2.1]hept-2-yl)-1-naphthyl]-4- methylbenzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00039
    Figure US20070066598A1-20070322-C00040
         		H
    12 N-(4-Methylphenyl)-4-(3-methyl-1-piperazinyl)-1-naphthalenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00041
    Figure US20070066598A1-20070322-C00042
         		H
    13 N-(2-Naphthyl)-4-(1-piperazinyl)-1-naphthalenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00043
    Figure US20070066598A1-20070322-C00044
         		H
    14 N-Methyl-N-(4-methylphenyl)-4-(1-piperazinyl)-1-naphthalenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00045
    Figure US20070066598A1-20070322-C00046
         		—CH3
    15 4-(1,4-Diazepan-1-yl)-N-(4-methylphenyl)-1-naphthalenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00047
    Figure US20070066598A1-20070322-C00048
         		H
    16 4-(1,4-Diazepan-1-yl)-N-(2-methoxy-4-methylphenyl)-1- naphthalenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00049
    Figure US20070066598A1-20070322-C00050
         		H
    17 N-(2-Methoxy-4-methylphenyl)-4-(3,5-trimethyl-1-piperazinyl)-1- naphthalenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00051
    Figure US20070066598A1-20070322-C00052
         		H
    18 4-(4-Isopropyl-1-piperazinyl)-N-(4-methylphenyl)-1- naphthalenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00053
    Figure US20070066598A1-20070322-C00054
         		H
    19 4-Bromo-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00055
    Figure US20070066598A1-20070322-C00056
         		H
    20 2,5-di-Chloro-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00057
    Figure US20070066598A1-20070322-C00058
         		H
    21 2-Chloro-4-fluoro-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00059
    Figure US20070066598A1-20070322-C00060
         		H
    22 2,3-di-Chloro-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00061
    Figure US20070066598A1-20070322-C00062
         		H
    23 2,4-di-Chloro-5-methyl-N-[4-(1-piperazinyl)-1- naphthyl]benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00063
    Figure US20070066598A1-20070322-C00064
         		H
    24 3-tri-Fluoromethyl-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00065
    Figure US20070066598A1-20070322-C00066
         		H
    25 2-tri-Fluoromethyl-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00067
    Figure US20070066598A1-20070322-C00068
         		H
    26 4-Bromo-N-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)- benzenesulfonamide, hydrochloride.
    Figure US20070066598A1-20070322-C00069
    Figure US20070066598A1-20070322-C00070
         		CH3
    27 Naphthalene-1-sulfonic acid (4-piperazin-1-yl-naphthalen-1-yl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00071
    Figure US20070066598A1-20070322-C00072
         		H
    28 2,5-Dichloro-thiophene-3-sulfonic acid (4-piperazin-1-yl-naphthalen-1-yl)- amide, hydrochloride
    Figure US20070066598A1-20070322-C00073
    Figure US20070066598A1-20070322-C00074
         		H
    29 4-Methoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00075
    Figure US20070066598A1-20070322-C00076
         		H
    30 4-Chloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00077
    Figure US20070066598A1-20070322-C00078
         		H
    31 2-Chloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00079
    Figure US20070066598A1-20070322-C00080
         		H
    32 N-(4-Piperazin-1-yl-naphthalen-1-yl)-4-trifluoromethyl-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00081
    Figure US20070066598A1-20070322-C00082
         		H
    33 4-Fluoro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00083
    Figure US20070066598A1-20070322-C00084
         		H
    34 5-Fluoro-2-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)- benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00085
    Figure US20070066598A1-20070322-C00086
         		H
    35 4-Phenoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00087
    Figure US20070066598A1-20070322-C00088
         		H
    36 2-Bromo-4-iodo-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00089
    Figure US20070066598A1-20070322-C00090
         		H
    37 Thiophene-2-sulfonic acid (4-piperazin-1-yl-naphthalen-1-yl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00091
    Figure US20070066598A1-20070322-C00092
         		H
    38 5-Chloro-thiophene-2-sulfonic acid (4-piperazin-1-yl-naphthalen-1-yl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00093
    Figure US20070066598A1-20070322-C00094
         		H
    39 3-Methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00095
    Figure US20070066598A1-20070322-C00096
         		H
    40 4-Butyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide hydrochloride
    Figure US20070066598A1-20070322-C00097
    Figure US20070066598A1-20070322-C00098
         		H
    41 2,4,6-Trimethyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide hydrochloride
    Figure US20070066598A1-20070322-C00099
    Figure US20070066598A1-20070322-C00100
         		H
    42 2,4,5-Trichloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00101
    Figure US20070066598A1-20070322-C00102
         		H
    43 4-Iodo-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00103
    Figure US20070066598A1-20070322-C00104
         		H
    44 2-Methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00105
    Figure US20070066598A1-20070322-C00106
         		H
    45 3,4-Dichloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00107
    Figure US20070066598A1-20070322-C00108
         		H
    46 5-Bromo-2-methoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)- benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00109
    Figure US20070066598A1-20070322-C00110
         		H
    47 2-Bromo-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00111
    Figure US20070066598A1-20070322-C00112
         		H
    48 3-Chloro-2-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)- benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00113
    Figure US20070066598A1-20070322-C00114
         		H
    49 2,6-Dichloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00115
    Figure US20070066598A1-20070322-C00116
         		H
    50 3-Methoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00117
    Figure US20070066598A1-20070322-C00118
         		H
    51 3-Chloro-4-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)- benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00119
    Figure US20070066598A1-20070322-C00120
         		H
    52 4-Bromo-2-fluoro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00121
    Figure US20070066598A1-20070322-C00122
         		H
    53 2,4-Dichloro-6-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)- benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00123
    Figure US20070066598A1-20070322-C00124
         		H
    Figure US20070066598A1-20070322-C00125
    54 4-Bromo-2-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)- benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00126
    Figure US20070066598A1-20070322-C00127
         		H
    55 4,5-Dichloro-thiophene-2-sulfonic acid (4-piperazin-1-yl-naphthalen-1-yl)- amide, hydrochloride
    Figure US20070066598A1-20070322-C00128
    Figure US20070066598A1-20070322-C00129
         		H
    56 N-Methyl-N-(4-bromo-2-methylphenyl)-4-(1-pyperazinyl)-1- napthalenesulphonamide, hydrochloride
    Figure US20070066598A1-20070322-C00130
    Figure US20070066598A1-20070322-C00131
         		CH3
    57 N-Methyl-N-(5-fluoro-2-methylphenyl)-4-(1-pyperazinyl)-1- napthalenesulphonamide, hydrochloride
    Figure US20070066598A1-20070322-C00132
    Figure US20070066598A1-20070322-C00133
         		CH3
    58 N-Methyl-N-(2-methylphenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide, hydrochloride
    Figure US20070066598A1-20070322-C00134
    Figure US20070066598A1-20070322-C00135
         		CH3
    59 N-Methyl-N-(3-chloro-2-methylphenyl)-4-(1-pyperazinyl)-1- napthalenesulphonamide, hydrochloride
    Figure US20070066598A1-20070322-C00136
    Figure US20070066598A1-20070322-C00137
         		CH3
    60 2,5-di-Chlorothiophen-3-yl-N-Methyl-N-(2,5-dichlorothiophen-3-yl)-4-(1- pyperazinyl)-1-napthalenesulphonamide, hydrochloride
    Figure US20070066598A1-20070322-C00138
         		2
    Figure US20070066598A1-20070322-C00139
         		CH3
    61 N-Methyl-N-(1-naphthyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide, hydrochloride
    Figure US20070066598A1-20070322-C00140
    Figure US20070066598A1-20070322-C00141
         		CH3
    62 N-Methyl-N-(1-naphthyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide, hydrochloride
    Figure US20070066598A1-20070322-C00142
    Figure US20070066598A1-20070322-C00143
         		CH3
    63 N-Methyl-N-(4-chlorophenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide, hydrochloride
    Figure US20070066598A1-20070322-C00144
    Figure US20070066598A1-20070322-C00145
         		CH3
    64 N-Methyl-N-(4-methoxyphenyl)-4-(1-pyperazinyl)-1- napthalenesulphonamide, hydrochloride
    Figure US20070066598A1-20070322-C00146
    Figure US20070066598A1-20070322-C00147
         		CH3
    65 5-Fluoro-2-methyl-N-{4-[(2R,5S)-2,5-dimethyl-1-]piperazin-1-yl-1- naphthyl}benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00148
    Figure US20070066598A1-20070322-C00149
         		H
    66 5-Fluoro-2-methyl-N-[4-(1,2,3,6-tetrahydropyridin-4-yl)-1- naphthyl]benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00150
    Figure US20070066598A1-20070322-C00151
         		H

    3-Substituted naphthalene compounds of the formula II wherein P is
    Figure US20070066598A1-20070322-C00152
  • and X, Y are H:
    TABLE II
    Figure US20070066598A1-20070322-C00153
    Compound name R1 R3 R2
    67 N-[4-(Methyl-1-piperazinyl)-2-naphthyl]benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00154
    Figure US20070066598A1-20070322-C00155
         		H

    5-Substituted naphthalene compounds of the formula II wherein P is
    Figure US20070066598A1-20070322-C00156
  • and X, Y and R4 are H:
    TABLE III
    Figure US20070066598A1-20070322-C00157
    Compound name R1 R3 R2
    68 4-Piperazin-1-yl-naphthalene-1-sulfonic acid phenylamide, hydrochloride
    Figure US20070066598A1-20070322-C00158
    Figure US20070066598A1-20070322-C00159
         		H
    69 4-Piperazin-1-yl-naphthalene-1-sulfonic acid (2-methoxy-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00160
    Figure US20070066598A1-20070322-C00161
         		H
    70 4-(cis-3,5-Dimethyl-piperazin-1-yl)-naphthalene-1-sulfonic acid (2-methoxy- phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00162
    Figure US20070066598A1-20070322-C00163
         		H
    71 4-(cis-3,5-Dimethyl-piperazin-1-yl)-naphthalene-1-sulfonic acid (3-chloro-phenyl)- amide, hydrochloride
    Figure US20070066598A1-20070322-C00164
    Figure US20070066598A1-20070322-C00165
         		H
    72 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (3-chloro-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00166
    Figure US20070066598A1-20070322-C00167
         		H
    73 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid phenylamide hydrochloride
    Figure US20070066598A1-20070322-C00168
    Figure US20070066598A1-20070322-C00169
         		H
    74 4-Piperazin-1-yl-naphthalene-1-sulfonic acid (3-chloro-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00170
    Figure US20070066598A1-20070322-C00171
         		H
    75 4-Piperazin-1-yl-naphthalene-1-sulfonic acid (2-methylsulfanyl-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00172
    Figure US20070066598A1-20070322-C00173
         		H
    76 4-Piperazin-1-yl-naphthalene-1-sulfonic acid methyl-naphthalen-1-yl-amide, hydrochloride
    Figure US20070066598A1-20070322-C00174
    Figure US20070066598A1-20070322-C00175
         		H
    77 4-Piperazin-1-yl-naphthalene-1-sulfonic acid (2,3-dihydro-benzo[1,4]dioxin-6-yl)- methyl-amide, hydrochloride
    Figure US20070066598A1-20070322-C00176
    Figure US20070066598A1-20070322-C00177
         		CH3
    78 4-Piperazin-1-yl-naphthalene-1-sulfonic acid (2,3-dihydro-benzo[1,4]dioxin-6-yl)- amide, hydrochloride
    Figure US20070066598A1-20070322-C00178
    Figure US20070066598A1-20070322-C00179
         		H
    79 4-Piperazin-1-yl-naphthalene-1-sulfonic acid methyl-(2-methylsulfanyl-phenyl)- amide, hydrochloride
    Figure US20070066598A1-20070322-C00180
    Figure US20070066598A1-20070322-C00181
         		CH3
    80 4-Piperazin-1-yl-naphthalene-1-sulfonic acid, methyl-(3-trifluoromethyl-phenyl)- amide, hydrochloride
    Figure US20070066598A1-20070322-C00182
    Figure US20070066598A1-20070322-C00183
         		CH3
    81 4-Piperazin-1-yl-naphthalene-1-sulfonic acid (3-chloro-4-methyl-phenyl)-methyl- amide, hydrochloride
    Figure US20070066598A1-20070322-C00184
    Figure US20070066598A1-20070322-C00185
         		CH3
    82 4-Piperazin-1-yl-naphthalene-1-sulfonic acid (3-ethyl-phenyl)-methyl-amide, hydrochloride
    Figure US20070066598A1-20070322-C00186
    Figure US20070066598A1-20070322-C00187
         		CH3
    83 4-(3,5-Dimethyl-piperazin-1-yl)-naphthalene-1-sulfonic acid (2-isopropyl-phenyl)- amide, hydrochloride
    Figure US20070066598A1-20070322-C00188
    Figure US20070066598A1-20070322-C00189
         		H
    84 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (2-isopropyl-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00190
    Figure US20070066598A1-20070322-C00191
         		H
    85 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (3-ethyl-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00192
    Figure US20070066598A1-20070322-C00193
         		H
    86 N-(2-Fluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00194
    Figure US20070066598A1-20070322-C00195
         		H
    87 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (3-trifluoromethyl-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00196
    Figure US20070066598A1-20070322-C00197
         		H
    88 N-(2,4-di-Fluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00198
    Figure US20070066598A1-20070322-C00199
         		H
    89 4-Piperazin-1-yl-naphthalene-1-sulfonic acid (2-trifluoromethoxy-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00200
    Figure US20070066598A1-20070322-C00201
         		H
    90 4-Piperazin-1-yl-naphthalene-1-sulfonic acid (3-trifluoromethoxy-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00202
    Figure US20070066598A1-20070322-C00203
         		H
    91 4-Piperazin-1-yl-naphthalene-1-sulfonic acid (3-trifluoromethoxy-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00204
    Figure US20070066598A1-20070322-C00205
         		H
    92 4-Piperazin-1-yl-naphthalene-1-sulfonic acid (2-chloro-5-methyl-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00206
    Figure US20070066598A1-20070322-C00207
         		H
    93 4-Piperazin-1-yl-naphthalene-1-sulfonic acid (4-isopropyl-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00208
    Figure US20070066598A1-20070322-C00209
         		H
    94 N-(3,5-di-Fluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00210
    Figure US20070066598A1-20070322-C00211
         		H
    95 1-[4-(3,4-Dihydroquinolin-1(2H)-ylsulfonyl)-1-naphthyl]piperazine, hydrochloride
    Figure US20070066598A1-20070322-C00212
    Figure US20070066598A1-20070322-C00213
         		H
    96 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (3-nitro-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00214
    Figure US20070066598A1-20070322-C00215
         		H
    97 4-Piperazin-1-yl-naphthalene-1-sulfonic acid (3-nitro-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00216
    Figure US20070066598A1-20070322-C00217
         		H
    98 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (3-nitro-phenyl)-methyl-amide, hydrochloride
    Figure US20070066598A1-20070322-C00218
    Figure US20070066598A1-20070322-C00219
         		CH3
    99 N-(4-methylphenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00220
    Figure US20070066598A1-20070322-C00221
         		H
    100 N-(3-chloro-4-methylphenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00222
    Figure US20070066598A1-20070322-C00223
         		H
    101 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (2,3-dimethyl-phenyl)-methyl- amide, hydrochloride
    Figure US20070066598A1-20070322-C00224
    Figure US20070066598A1-20070322-C00225
         		CH3
    102 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (4-isopropyl-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00226
    Figure US20070066598A1-20070322-C00227
         		H
    103 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (4-isopropyl-phenyl)-methyl- amide, hydrochloride
    Figure US20070066598A1-20070322-C00228
    Figure US20070066598A1-20070322-C00229
         		CH3
    104 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (2,4-dimethyl-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00230
    Figure US20070066598A1-20070322-C00231
         		H
    105 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (2-chloro-5-methyl-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00232
    Figure US20070066598A1-20070322-C00233
         		H
    106 4-Piperazin-1-yl-naphthalene-1-sulfonic acid (2,5-dimethoxy-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00234
    Figure US20070066598A1-20070322-C00235
         		H
    107 4-Piperazin-1-yl-naphthalene-1-sulfonic acid (3-acetyl-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00236
    Figure US20070066598A1-20070322-C00237
         		H
    108 4-Piperazin-1-yl-naphthalene-1-sulfonic acid (2,4-dimethyl-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00238
    Figure US20070066598A1-20070322-C00239
         		H
    109 4-Piperazin-1-yl-naphthalene-1-sulfonic acid (3-trifluoromethyl-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00240
    Figure US20070066598A1-20070322-C00241
         		H
    110 4-Piperazin-1-yl-naphthalene-1-sulfonic acid biphenyl-2-ylamide, hydrochloride
    Figure US20070066598A1-20070322-C00242
    Figure US20070066598A1-20070322-C00243
         		H
    111 4-Piperazin-1-yl-naphthalene-1-sulfonic acid (3-benzyloxy-phenyl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00244
    Figure US20070066598A1-20070322-C00245
         		H
    112 N-(4-fluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00246
    Figure US20070066598A1-20070322-C00247
         		H
    113 N-(3-Ethylphenyl)-4-piperazin.1.ylnaphthalene-1-sulphonamine, hydrochloride
    Figure US20070066598A1-20070322-C00248
    Figure US20070066598A1-20070322-C00249
         		H
    114 4-Piperazinyl-N-[3-(trifluoromethyl)phenyl]naphthalene-1-sulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00250
    Figure US20070066598A1-20070322-C00251
         		H
    115 4-Piperazinyl-N-[3-benzoylphenyl]naphthalene-1-sulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00252
    Figure US20070066598A1-20070322-C00253
         		H
    116 4-Piperazinyl-N-[3-(4-bromo-1-methyl-1H-pyrazol-3-yl)phenyl]naphthalene-1- sulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00254
    Figure US20070066598A1-20070322-C00255
         		H
    117 4-Piperazinyl-N-[3-biphenylphenyl]naphthalene-1-sulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00256
    Figure US20070066598A1-20070322-C00257
         		H
  • Meta-substituted isoquinoline compounds of the formula III wherein P is
    Figure US20070066598A1-20070322-C00258
  • and X, Y are H:
    TABLE IV
    Figure US20070066598A1-20070322-C00259
    Compound name R1 R3 R2
    118 N-[1-(4-methyl-1-piperazinyl)-3- isoquinolinyl]benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00260
    Figure US20070066598A1-20070322-C00261
         		H
    119 2,4-di-Fluoro-N-[1-(4-methyl-1- piperazinyl)-3- isoquinolinyl]benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00262
    Figure US20070066598A1-20070322-C00263
         		H
    120 4-Bromo-N-[1-(4-methyl- piperazin-1-yl)-isoquinolin-3-yl)- benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00264
    Figure US20070066598A1-20070322-C00265
         		H
    121 5-Chloro-3-methyl- benzo[b]thiophene-2-sulfonic acid [1-(4-methyl-piperazin-1-yl)- isoquinolin-3-yl]-amide, hydrochloride
    Figure US20070066598A1-20070322-C00266
    Figure US20070066598A1-20070322-C00267
         		H
    122 3-Chloro-2-methyl-N-[1-(4-methyl- piperazin-1-yl)-isoquinolin-3-yl]- benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00268
    Figure US20070066598A1-20070322-C00269
         		H
    123 3,4-Dichloro-N-[1 -(4-methyl- piperazin-1-yl)-isoquinolin-3-yl]- benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00270
    Figure US20070066598A1-20070322-C00271
         		H
    124 4-Methyl-N-[1-(4-methyl- piperazin-1-yl)-isoquinolin-3-yl]- benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00272
    Figure US20070066598A1-20070322-C00273
         		H
    125 3-Methoxy-N-[1-(4-methyl- piperazin-1-yl)-isoquinolin-3-yl]- benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00274
    Figure US20070066598A1-20070322-C00275
         		H
    126 5-Chloro-thiophene-2-sulfonic acid [1-(4-methyl-piperazin-1-yl)- isoquinolin-3-yl]-amide, hydrochloride
    Figure US20070066598A1-20070322-C00276
    Figure US20070066598A1-20070322-C00277
         		H
    127 N-{2-Chloro-4-[1-(4-methyl- piperazin-1-yl)-isoquinolin-3- ylsulfamoyl]-phenyl}-acetamide hydrochloride
    Figure US20070066598A1-20070322-C00278
    Figure US20070066598A1-20070322-C00279
         		H
    128 2,5-Dichloro-thiophene-3-sulfonic acid [1-(4-methyl-piperazin-1-yl)- isoquinolin-3-yl]-amide, hydrochloride
    Figure US20070066598A1-20070322-C00280
    Figure US20070066598A1-20070322-C00281
         		H
    129 N-[1-(4-Methyl-piperazin-1-yl)- isoquinolin-3-yl]-3-trifluoromethyl- benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00282
    Figure US20070066598A1-20070322-C00283
         		H
    130 N-[1-(4-Methyl-piperazin-1-yl)- isoquinolin-3-yl]-4-phenoxy- benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00284
    Figure US20070066598A1-20070322-C00285
         		H
    131 5-Bromo-2-methoxy-N-[1-(4- methyl-piperazin-1-yl)-isoquinolin- 3-yl]-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00286
    Figure US20070066598A1-20070322-C00287
         		H
    132 2-Methanesulphonayl-N-[1-(4- methyl-piperazin-1-yl)-isoquinolin- 3-yl]-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00288
    Figure US20070066598A1-20070322-C00289
         		H
    133 3,5-Dimethyl-isoxazole-4-sulfonic acid [1-(4-methyl-piperazin-1-yl)- isoquinolin-3-yl]-amide, hydrochloride
    Figure US20070066598A1-20070322-C00290
    Figure US20070066598A1-20070322-C00291
         		H
    134 2,4,6-Trimethyl-N-[1-(4-methyl- piperazin-1-yl)-isoquinolin-3-yl]- benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00292
    Figure US20070066598A1-20070322-C00293
         		H
    135 3,4-Dimethoxy-N-[1-(4-methyl- piperazin-1-yl)-isoquinolin-3-yl]- benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00294
    Figure US20070066598A1-20070322-C00295
         		H

    5-Substituted quinoline compounds of the formula IV wherein P is
    Figure US20070066598A1-20070322-C00296
  • and X, Y are H:
    TABLE V
    Figure US20070066598A1-20070322-C00297
    Compound name R1 R3 R2
    136 N-(8-{[2-(di- Methylamino)ethyl]amino}-5- quinolinyl)benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00298
    Figure US20070066598A1-20070322-C00299
         		H

    1.7-Naphthyridine compounds of the formula V wherein P is
    Figure US20070066598A1-20070322-C00300
  • R2 and X, Y are H:
    TABLE VI
    Figure US20070066598A1-20070322-C00301
    Compound name R1 R3
    137 4-Methyl-N-(8-piperazin-1- yl-1,7-naphthyridin-6- yl)benzenesulfonamide, trifluoroacetic acid
    Figure US20070066598A1-20070322-C00302
    Figure US20070066598A1-20070322-C00303
    138 4-Bromo-N-(8-piperazin-1- yl-1,7-naphthyridin-6- yl)benzenesulfonamide, trifluoroacetic acid
    Figure US20070066598A1-20070322-C00304
    Figure US20070066598A1-20070322-C00305
    139 N-(8-Piperazin-1-yl-1,7- naphthyridin-6- yl)naphthalene-1- sulfonamide, trifluoroacetic acid
    Figure US20070066598A1-20070322-C00306
    Figure US20070066598A1-20070322-C00307
    140 N-(8-Piperazin-1-yl-1,7- naphthyridin-6-yl)butane-1- sulfonamide, trifluoroacetic acid
    Figure US20070066598A1-20070322-C00308
    Figure US20070066598A1-20070322-C00309
    141 3-Trifluoromethyl-N-(8- piperazin-1-yl-1,7- naphthyridin-6- yl)benzenesulfonamide, trifluoroacetic acid
    Figure US20070066598A1-20070322-C00310
    Figure US20070066598A1-20070322-C00311
    142 3,4-Dimethoxy-N-(8- piperazin-1-yl-1,7- naphthyridin-6- yl)benzenesulfonamide, trifluoroacetic acid
    Figure US20070066598A1-20070322-C00312
    Figure US20070066598A1-20070322-C00313
    143 2,4-Dichloro-N-(8- piperazin-1-yl-1,7- naphthyridin-6- yl)benzenesulfonamide, trifluoroacetic acid
    Figure US20070066598A1-20070322-C00314
    Figure US20070066598A1-20070322-C00315
    Figure US20070066598A1-20070322-C00316
    144 N-(8-Piperazin-1-yl-1,7- naphthyridin-6- yl)thiophene-2- sulfonamide, trifluoroacetic acid
    Figure US20070066598A1-20070322-C00317
    Figure US20070066598A1-20070322-C00318
    145 1-Phenyl-N-(8-piperazin-1- yl-1,7-naphthyridin-6- yl)methanesulfonamide, trifluoroacetic acid
    Figure US20070066598A1-20070322-C00319
    Figure US20070066598A1-20070322-C00320

    5-Substituted benzofuran compounds of the formula VI wherein P is
    Figure US20070066598A1-20070322-C00321
  • R2 and X, Y are H:
    TABLE VII
    Figure US20070066598A1-20070322-C00322
    Compound name R1 R3
    146 3-Cyanophenyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00323
    Figure US20070066598A1-20070322-C00324
    147 4-Phenoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00325
    Figure US20070066598A1-20070322-C00326
    148 1-Naphthyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00327
    Figure US20070066598A1-20070322-C00328
    149 N-(7-Piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00329
    Figure US20070066598A1-20070322-C00330
    150 5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonic acid (7-piperazin-1-yl-benzofuran-5-yl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00331
    Figure US20070066598A1-20070322-C00332
    151 N-[7-(4-Methylpiperazin-1-yl)-1-benzofuran-5-yl]-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00333
    Figure US20070066598A1-20070322-C00334
    152 4-Methyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00335
    Figure US20070066598A1-20070322-C00336
    153 3,4-Dimethoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00337
    Figure US20070066598A1-20070322-C00338
    154 4-Bromo-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00339
    Figure US20070066598A1-20070322-C00340
    155 2,3-Dichloro-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00341
    Figure US20070066598A1-20070322-C00342
    156 2,4-Dichloro-5-methyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00343
    Figure US20070066598A1-20070322-C00344
    157 4-Methoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00345
    Figure US20070066598A1-20070322-C00346
    158 4-Chloro-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00347
    Figure US20070066598A1-20070322-C00348
    159 N-(7-Piperazin-1-yl-benzofuran-5-yl)-4-trifluoromethyl-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00349
    Figure US20070066598A1-20070322-C00350
    160 5-Fluoro-2-methyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
    Figure US20070066598A1-20070322-C00351
    Figure US20070066598A1-20070322-C00352
    161 5-Chloro-thiophene-2-sulfonic acid (7-piperazin-1-yl-benzofuran-5-yl)-amide, hydrochloride
    Figure US20070066598A1-20070322-C00353
    Figure US20070066598A1-20070322-C00354

    Methods for Preparation
  • The compounds according to the invention (Tables I, II, IV, V, VI) can be prepared starting from halo-nitro substituted bicyclic aromatic rings by base (potassium carbonate) catalyzed aromatic nucleophilic substitution of a halogen in the desired position of the central bicyclic ring with the diamine of choice (R3). Reduction of a nitro group properly positioned on the central bicyclic ring by Raney-Ni catalyzed reaction leads to the aniline that is substituted further by sulfonylation with the alkyl- or aryl-sulfonylchloride of choice (R1—SO2—Cl). Scheme 1 and Scheme 3
  • The compounds according to the invention (Tables III) can be prepared starting from fluoro substituted bicyclic aromatic rings in which the sulfonylchloride functionality is introduced by acid catalyzed sulfonylation. The sulfonyl group is reacted further with anilines of choice (R1—NH2). The diamine group (R3) is introduced by base catalyzed aromatic nucleophilic substitution. Scheme 2
  • The compounds according to the invention (Tables VII) can be prepared starting from iodo substituted bicyclic aromatic rings. The diamine group (R3) is introduced by Palladium catalysed nucleophilic substitution. Reduction of a nitro group properly positioned on the central bicyclic ring by Raney-Ni catalyzed reaction leads to the aniline that is substituted further by sulfonylation with the alkyl- or aryl-sulfonylchloride of choice (R1—SO2—Cl). Scheme 4
  • 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 formula (I). 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, 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 Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.
  • Depending on the process conditions, the end products of the formula (I) are obtained either in neutral or salt form. Both the free base and the salts of these end products are within the scope of the invention.
  • Acid addition salts of the new compounds may in a manner known per se be transformed into the free base using basic agents such as alkali or by ion exchange. The free base obtained may also form salts with organic or inorganic acids.
  • In the preparation of acid addition salts, preferably such acids are used which form suitably therapeutically acceptable salts. Examples of such acids are hydrohalogen acids, sulfuric acid, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxyl or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybensoic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, halogenbensenesulfonic acid, toluenesulfonic acid, mandelic acid or naphthalenesulfonic acid.
  • Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof where such isomers exist. 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.
  • 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 methods such as granulation, compression, microencapsulation, spray coating, etc.
  • This invention relates to a method of treatment or prophylaxis of obesity, type II diabetes, and/or disorders of the central nervous system. The method includes administering to a subject (e.g., a mammal, a human, a horse, a dog, or a cat) in need thereof an effective amount of one or more compounds of the formula (I) described above.
  • This invention also features a method for reducing body-weight (e.g., treating body-weight disorders) or reducing food intake. The method includes administering to a subject in need thereof an effective amount of a compound of the formula (I). 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) weights. Such body weight disorders include obesity.
  • Also within the scope of this invention is a method for modulating (e.g., inhibiting) 5-HT6 receptor activity. The method includes administering to a subject in need thereof an effective amount of a compound of the formula (I).
  • 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 or reducing food intake.
  • “An effective amount” refers to an amount of a compound which confers a therapeutic effect on the treated subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). 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 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 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.
  • 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.
    • EXAMPLES Synthesis of Examples and Intermediates in Table I
  • Figure US20070066598A1-20070322-C00355
    In scheme 1, the following symbols are used: (i) K2CO3, DMF, diamine of choice; (ii) H2, Raney-Ni or Pd/C, THF:Ethanol; (iii) (BOC)2O, NaOH; (iv) R1—SO2—Cl, Py, CH2Cl2; (v) HCl in diethyl ether; (vi) alkylhalides. TfO=trifluoromethanesulfonate.
    General Method A
    Reduction of Nitronapthalenes Derivatives to Naphthylamine Derivatives
  • To a solution of nitronapthalenes derivatives (1 eq) in EtOH:THF (4:1) was added is Raney-Ni (˜1.0 mL suspension in EtOH) followed by hydrazine monohydrate (6 eq). The mixtures are stirred vigorously for 3 hours and then filtered through celite pretreated with water. The filtrate was concentrated, followed by the addition of toluene. Purifications are performed by flash column chromatography (SiO2, CHCl3/MeOH/NH3 9:1:0.4% and 2 parts of light petroleum) to obtain the free base of napthylamine derivatives.
  • General Method B
  • Reaction of 4-nitro-chloronaphthalenes with diamines
  • Diamines (1.2 eq) are added to a suspension of chloronaphthalenes derivatives (1 eq) and K2CO3 (3.5) in DMF. The suspensions are stirred at 65° C. for 16 hours followed by filtration. Elimination of volatiles to give a crude residue. The residues are purified by flash chromatography (SiO2, CHCl3→CHCl3/10% MeOH/0.4% aq. NH3) to give the corresponding products as free bases.
  • (a) Intermediates for Preparation of Compounds in Tables I, II, IV and V According to Scheme 1
  • Intermediate 1
  • 1-Methyl-4-(4-nitro-1-naphthyl)-1,4-diazepane—To a suspension of 1-chloro-4-nitronaphthalene (1.0 g, 4.82 mmol) and K2CO3 (2.0 g, 14.46 mmol) in DMF (10 mL) was added 1-methyl-1,4-diazepane (0.66 g, 5.78 mmol). The suspension was stirred at 65° C. for 16 hours followed by filtration. Elimination of volatiles to give a crude residue. The residue was purified by flash chromatography (SiO2, CHCl3→CHCl3/10% MeOH/0.4% aq. NH3) to give 0.79 g (57%) of the free base: 1H NMR (CDCl3) δ 8.85-8.75 (m, 1H), 8.35-8.25 (m, 1H), 8.20-8.12 (m, 1H), 7.70-7.60 (m, 1H), 7.55-7.45 (m, 1H), 6.97-6.90 (m, 1H), 3.70-3.55 (m, 4H), 2.83-2.71 (m, 4H), 2.44 (s, 3H), 2.09-1.97 (m, 2H); 13C NMR (CDCl3) δ 157.47, 139.13, 129.26, 127.82, 127.66, 126.53, 125.69, 125.40, 123.94, 111.22, 58.37, 57.37, 55.44, 54.71, 46.97, 27.88; MS (posES-FIA) m/z=found 285.1463, calc 285.1477.
  • Intermediate 2
  • 4-(4-Methyl-1,4-diazepan-1-yl)-1-naphthylamine—To a solution of 1-methyl-4-(4-nitro-1-naphthyl)-1,4-diazepane (0.793 g, 2.78 mmol) in 40 mL of EtOH:THF (4:1) was added Raney-Ni (˜1.0 mL suspension in EtOH) followed by hydrazine monohydrate (0.696 g, 13.9 mmol). The mixture was stirred vigorously for 3 hours and then filtered through celite pretreated with water. The filtrate was concentrated, followed by the addition of toluene. Purification by flash column chromatography (SiO2, CHCl3/MeOH/NH3 9:1:0.4% and 2 parts of light petroleum) gave 0.441 g (62%) of the free base: 1H NMR (CDCl3) δ 8.37-8.29 (m, 1H), 7.85-7.76 (m, 1H), 7.55-7.40 (m, 2H), 7.07-7.01 (m, 1H), 6.75-6.68 (m, 1H), 3.96 (br s, 2H), 3.36-3.20 (m, 4H), 2.95-2.76 (m, 4H), 2.48 (s, 3H), 2.10-1.95 (m, 2H); MS (posESI) m/z=256 (M+H).
  • Intermediate 3
  • 1-Ethyl-4-(4-nitro-1-naphthyl)piperazine—To a mixture of 1-chloro-4-nitronaphthalene (0.794 g, 3.82 mmol), and K2CO3 (0.791 g, 5.73 mmol) in DMF (3 mL) was added N-ethyl piperazine (0.486 mL, 3.82 mmol). The mixture was heated in a microwave oven at 100 W for 1 minute. The reaction mixture was allowed to cool down and the procedure was repeated 5 times. The mixture was filtered and concentrated. The crude product was purified by column chromatography (SiO2, CHCl3→CHCl3/MeOH/NH3 9:1:0.4%) to give 0.950 g (87%) of a reddish brown solid: 1H NMR (CDCl3) δ 8.75-8.70 (m, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.24-8.20 (m, 1H), 7.72-7.66 (m, 1H), 7.60-7.54 (m, 1H), 7.02 (d, J=8.4 Hz, 1H), 3.32-3.24 (m, 4H), 2.85-2.70 (m, 4H), 2.54 (q, J=7.3 Hz, 2H), 1.17 (tr, J=7.3 Hz, 3); MS (posEI) m/z 385 (M+).
  • Intermediate 4
  • (cis)-3,5-Dimethyl-1-(4-nitro-1-naphthyl)piperazine—This compound was prepared from 1-chloro-4-nitronaphthalene (0.481 g, 2.32 mmol) and cis-2,6-dimethylpiperazine (0.481 g, 2.32 mmol) by the method described above, yield 0.554 g (84%) of the pure product as a reddish brown solid; 1H NMR (CDCl3) δ 8.76-8.71 (m, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.23-8.14 (m, 1H), 7.72-7.66 (m, 1H), 7.61-7.55 (m, 1H), 7.0 (d, J=8.4 Hz, 1H), 3.45-3.37 (m, 2H), 3.35-3.25 (m, 2H), 2.55-2.47 (m, 2H), 1.17-1.4 (m, 6H); MS (posEI) m/z 385 (M+).
  • Intermediate 5
  • 3-Methyl-1-(4-nitro-1-naphthyl)piperazine—This compound was prepared from 1-chloro-4-nitronaphthalene (0.395 g, 1.90 mmol) and 2-methylpiperazine (0.395 g, 1.90 mmol) by the method described above: yield 0.470 g (84%) of the pure product as a solid; 1H NMR (CDCl3) δ 8.75-8.70 (m, 1H), 8.29 (d, J=8.55 Hz, 1H), 8.24-8.20 (m, 1H), 7.72-7.65 (m, 1H), 7.61-7.55 (m, 1H), 7.00 (d, J=8.55 Hz, 1H), 3.46-3.37 (m, 2H), 3.31-3.15 (m, 3H), 2.95-2.89 (m, 1H), 2.61-2.53 (m, 1H), 1.15 (d, J=6.4 Hz, 3H)); MS (EI) m/z 271 (M+).
  • Intermediate 6
  • 2-(4-Nitro-1-naphthyl)octahydropyrrolo[1,2-a]pyrazine—This compound was prepared from 1-chloro-4-nitronaphthalene (0.306 g, 1.47 mmol) and octahydropyrrolo[1,2-a]pyrazine (0.185 g, 1.47 mmol) by the method described above, yield 0.332 g (76%) of the pure product as a yellow oil; 1H NMR (CDCl3) δ 8.75-8.71 (m, 1H), 8.29 (d, J=8.5 Hz, 1H), 8.23-8.20 (m, 1H), 7.72-7.67 (m, 1H), 7.60-7.55 (m, 1H), 7.05 (d, J=8.5 Hz, 1H), 3.64-3.59 (m, 1H), 3.54-3.48 (m, 1H), 3.27-3.10 (m, 3H), 2.90-2.80 (m, 1H), 2.70-2.65 (m, 1H), 2.60-2.30 (m, 2H), 2.00-1.80 (m, 3H), 1.65-1.50 (m, 1H); MS (posESI) m/z 298 (M+H).
  • Intermediate 7
  • 1-(4-Nitro-1-naphthyl)-1,4-diazepane—To a solution of 1-chloro-4-nitronaphthalene (0.971 g, 4.68 mmol) and K2CO3 (0.973 g, 7.10 mmol) in CH3CN (5.0 mL) was added homopiperazine (0.711 g, 7.10 mmol). The reaction mixture was heated in a closed sealed vessel at 120° C. in a microwave oven for 10 min. The suspension was filtered and concentrated. Purification by column chromatography (SiO2, CHCl3→CHCl3/MeOH 9:1) gave 0.952 g of the pure product; 1H NMR (CDCl3) δ 8.80-8.74 (m, 1H), 8.29 (d, J=8.5 Hz, 1H), 8.25-8.19 (m, 1H), 7.71-7.63 (m, 1H), 7.57-7.49 (m, 1H), 7.03 (d, J=8.5 Hz, 1H), 3.57-3.48 (m, 4H), 3.18-3.10 (m, 4H), 2.10-1.95 (m, 2H); MS (posEI) m/z 272 (M+).
  • Intermediate 8
  • tert-Butyl 4-(4-nitro-1-naphthyl)-1-piperazinecarboxylate—1-Chloro-4-nitronaphthalene (2.7 g, 13 mmol), tert-butyl-1-piperazinecarboxylate (2.4 g, 13 mmol) and potassium carbonate (2 g) were heated together in DMSO (100 mL) at 90° C. overnight. The solution was allowed to cool to room temperature and poured into water (500 mL). The product was collected by filtration and recrystallised from methanol/water to yield 2.8 g (60%) of the title compound; mp 158.2° C.; 1H NMR (CDCl3) δ 1.52 (s, 9H), 3.2 (br, 4H), 3.75 (br, 4H), 7.04 (d, J=8.53 Hz, 1H), 7.62 (t, J=7.02 Hz, 1H), 7.73 (t, J=7.02 Hz, 1H), 8.25 (d, J=8.53 Hz, 1H), 8.3 (d, J=8.54 Hz, 1H), 8.73 (d, J=8.53 Hz, 1H).
  • Intermediate 9
  • 1-tert-Butyl 4-(4-{bis[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylate—tert-Butyl 4-(4-nitro-1-naphthyl)-1-piperazinecarboxylate (1 g, 2.8 mmol) in ethanol (200 mL) was hydrogenated at atmospheric pressure over Pd/C (10%, 0.2 g) for 3 hours after which time the uptake of hydrogen ceased. The solution was filtered and evaporated. The residue was dissolved in toluene (100 mL) and evaporated to give an off white solid. The solid was dissolved in acetonitrile (50 mL) containing 4-dimethylaminopyridine (0.73 g). Toluene sulfonyl chloride (1.14 g, 6 mmol) was added and the mixture stirred at 35° C. overnight. Brine was added and the product extracted into ethyl acetate (2×100 mL). The organic extracts were dried over MgSO4 and evaporated to give a pale brown solid which was re-crystallized from ethanol. Yield 1.04 g (58%) of a white solid. Mp 176-178; 1H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 2.36 (s, 6H), 3.0 (br, 4H), 3.6 (br, 4H), 6.81 (AB, J=8.03 Hz, 1H), 6.89 (AB, J=8.03 Hz, 1H), 7.17 (m, 1H), 7.19 (d, J=7.53 Hz, 4H), 7.32 (m, 1H), 7.45 (d, J=8.53 Hz, 1H), 7.70 (d, J=8.54 Hz, 4H), 8.03 (d, J=8.03 Hz, 1H).
  • Intermediate 10
  • 1-tert-Butyl 4-(4-{[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylate—1-tert-Butyl 4-(4-{bis[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylate (1 g, 1.6 mmol) was dissolved in ethanol (50 mL). Potassium hydroxide (85%, 0.54 g) was added and the solution refluxed for 12 hours. The solution was poured into water (100 mL) and acidified with acetic acid (0.6 mL). The product precipitated and was collected by filtration, washed with water and dried. Yield 0.81 g; 1H NMR (400 MHz, CDCl3) δ 1.36 (s, 9H), 2.22 (s, 3H), 2.8 (br, 4H), 3.5 (br, 4H), 6.47 (s, 1H), 6.79 (d, J=8.03 Hz, 1H), 7.03 (d, J=8.03 Hz, 2H), 7.07 (d, J=8.03 Hz, 1H), 7.3 (m, 2H), 7.47 (d, J=8.53 Hz, 2H), 7.69 (1, J=9.04 Hz, 1H), 8.03 (d, J=7.02 Hz, 1H).
  • Intermediate 11
  • 1-tert-Butyl 4-(4-{methyl[(4-methylphenyl)sulfonyl]amino)-1-naphthyl)-1-piperazinecarboxylate—1-tert-Butyl 4-(4-{[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylate (0.1 g, 0.2 mmol) was dissolved in DMSO (5 mL) and potassium carbonate (0.2 g) and methyl iodide (0.1 g) were added. The mixture was stirred and heated at 85° C. for 15 hours. The solution was poured into water (50 mL) and the product collected by filtration, washed with water and dried. Yield 0.078 g (78%) of a white solid. 1H NMR (400 MHz, CDCl3) δ 1.60 (s, 9H), 2.56 (s, 3H), 3.1 (br, 4H), 3.36 (s, 3H), 3.7 (br, 4H), 6.90 (AB, J=8.03 Hz, 1H), 6.97 (AB, J=8.03 Hz, 1H), 7.41 (d, J=8.03 Hz, 2H), 7.6 (m, 2H), 7.75 (d, J=8.29 Hz, 2H), 8.3 (m, 2H).
  • Intermediate 12
  • 5-Nitro-8-quinolinyl trifluoromethanesulfonate—To a solution of 5-nitro-8-quinolinol (1.89 g, 9.40 mmol) and Et3N (6.60 mL, 4.70 mmol) in CH2Cl2 (125 mL) was added N-phenyl-trifluoromethanesulfonimide (5.06 g, 14.1 mmol). The mixture was stirred at room temperature for 16 hours and then more of added N-phenyl-trifluoromethanesulfonimide (1.0 equiv.) was added and the mixture was stirred from another 16 hours. The reaction mixture was washed with 10% aqueous NaHCO3, dried with K2CO3, filtered and concentrated. The crude residue was triturated in MeOH to give 1.2 g (40%) of the pure product: 1H NMR (CDCl3) δ 9.20-9.18 (m, 1H), 9.11-9.07 (m, 1H), 8.48-8.45 (m, 1H), 7.83-7.79 (m, 1H), 7.76-7.72 (m, 1H); MS (posEI-DIP) m/z 321 (M+H).
  • Intermediate 13
  • 8-(4-Methyl-1-piperazinyl)-5-nitroquinoline—To a suspension of 5-nitro-8-quinolinyl trifluoromethanesulfonate (0.50 g, 1.56 mmol) and K2CO3 (0.43 g, 3.12 mmol) in CH3CN (6.0 mL) was added 1-methylpiperazine (0.19 mL, 1.71 mmol). The suspension was stirred at room temperature for 16 hours. The mixture was filtered and concentrated. Purification via flash column chromatography (SiO2, CHCl3/MeOH/NH3 9:1:0.4%) gave 0.509 g of the pure product: reversed phase HPLC>95% purity; MS (posESI) m/z 273 (M+H).
  • Intermediate 14
  • tert-Buyl (2R,6S)-2,6-dimethyl-4-(4-nitro-1-naphthyl)-1-piperazinecarboxylate—To a solution of cis-3,5-dimethyl-1-(4-nitro-1-naphthyl)piperazine (0.565 g, 1.98 mmol) and NaOH (0.198 g, 4.95 mmol) in THF:water (20 mL, 1:1) was added di-tert-butyl dicarbonate (1.30 g, 5.94 mmol) in THF (4 mL). The reaction mixture was stirred at room temperature for 4 hours followed by the addition of 3.0 equiv. of di-tert-butyl dicarbonate and 2.5 equiv. of NaOH. The mixture was stirred at room temperature for another 3 days. The mixture was concentrated and extracted with CHCl3 (3×20 mL). The combined organic phases were dried with K2CO3, filtered and concentrated. The crude residue was purified by column chromatography on silica using CHCl3 as eluent gave 0.200 g (26%) of the pure product as a solid brown solid: MS (posESI) m/z 386 (M+H).
  • Intermediate 15
  • tert-Butyl-2-methyl-4-(4-nitro-1-naphthyl)-1-piperazinecarboxylate was prepared from 3-methyl-1-(4-nitro-1-naphthyl)piperazine (0.436 g, 1.61 mmol) by the method described above: yield 0.552 g (92%) of the pure product as a yellow oil; 1H NMR (CDCl3) δ 8.73-8.70 (m, 1H), 8.34-8.30 (m, 1H), 8.28 (d, J=8.5 Hz, 1H), 7.74-7.69 (m, 1H), 7.63-7.58 (m, 1H), 7.02 (d, J=8.5 Hz, 1H), 4.50-4.442 (m, 1H), 4.10-4.03 (m, 1H), 3.52-3.39 (m, 2H), 3.32-3.27 (m, 1H), 3.08-3.03 (m, 1H), 2.89-2.82 (m, 1H), 1.53 (s, 3H), 1.51 (s, 9H); MS (posESI) m/z 372 (M+H).
    • Examples of Compounds According to the Invention Example 1 4-Methyl-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide, hydrochloride
  • 1-tert-Butyl 4-(4-{[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylate (intermediate 10) (0.4 g, 0.8 mmol) was dissolved in THF (20 mL) and treated with a 1N solution of HCl in diethyl ether (30 mL) for twelve hours. The product was collected as a pale pink solid. Yield 0.2 g (60%). mp 181° C. (dec); 1H NMR (DMSO-d6) δ 2.80 (s, 3H), 3.1 (br, 4H), 3.3 (br, 4H), 7.00 (q, J=8.06 Hz, 2H), 7.27 (ab, J=8.30 Hz, 2H), 7.4-7.5 (m, 2H), 7.53 (ab, J=8.30 Hz, 2H), 7.99 (d, J=8.06 Hz, 1H), 8.07 (d, J=7.57 Hz, 1H), 9.2 (br, 2H); MS (ESI+) for C21 H23 N3 O2 S Found m/z 381.1499 M+ Calc. 381.1611.
    • Example 2 3,4-Dimethoxy-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide, hydrochloride
  • tert-Butyl 4-(4-nitro-1-naphthyl)-1-piperazinecarboxylate (1 g, 2.8 mmol) in ethanol (200 mL) was hydrogenated at atmospheric pressure over Pd/C (10%, 0.2 g) for 3 hours after which time the uptake of hydrogen ceased. The solution was filtered and evaporated. The residue was dissolved in toluene (100 mL) and evaporated to give an off white solid. The solid was dissolved in acetonitrile (50 mL) containing 4-dimethylaminopyridine (0.73 g). This solution was divided into three portions. To one portion was added 3,4-dimethoxybenzene sulfonyl chloride (0.24 g). The mixture was stirred for 4 hours at 40° C. under nitrogen. Ethyl acetate (50 mL) was added and the solution washed with brine (2×100 mL). The organic phase was separated, dried over MgSO4 and evaporation. Purification by flash chromatography (SiO2, Petrol:Ethyl acetate 1:1) afforded the butoxycarbonyl protected product which was dissolved in methanol (2 mL) and treated with a 1N solution of HCl in ethyl acetate (25 mL) for three hours. The product was precipitated with ether (200 mL) and collected as a pale pink solid, 45 mg (12%). 1H NMR (DMSO-d6) δ 3.17 (br, 4H), 3.35 (br, 4H), 3.63 (s, 3H), 3.78 (s, 3H), 7.03 (d, J=8.55 Hz, 1H), 7.07 (ab, J=13.92, 8.06 Hz, 2H), 7.24 (dd, J=8.30, 2.19 Hz, 1H), 7.46 (m, 1H), 7.51 (m, 1H), 8.05 (d, J=7.57 Hz, 1H), 8.12 (d, J=7.56 Hz, 1H), 9.2 (br, 2H), 9.93 (s, 1H); MS (ESI+) for C22 H25 N3 O4 S m/z 427 (M+H)+.
    • Example 3 3,4-di-Fluoro-N-[4-(4-methyl-1,4-diazepan-1-yl)-1-naphthyl]benzenesulfonamide, hydrochloride
  • To a solution of (intermediate 2) 4-(4-methyl-1,4-diazepan-1-yl)-1-naphthylamine (0.173 g, 0.676 mmol) and pyridine (0.450 mL, 4.73 mmol) in CH2Cl2 (3 mL) was added a solution of 2,4-Di-fluorobenzenesulfonyl chloride (0.158 g, 0.743 mmol) in CH2Cl2 (2 mL). The mixture was stirred at room temperature for 16 hours and then concentrated. The crude mixture was purified by column chromatography chromatography (SiO2, CHCl3/MeOH/NH3 9:1:0.4%). The free base was converted to its HCl-salt and recrystallized from MeOH and ether to give 0.227 g (79%) of the salt: 1H NMR (DMSO-d6) δ 11.23 (br s, 1H), 10.49 (s, 1H), 8.21-8.17 (m, 1H), 7.72-7.65 (m, 1H), 7.55-7.46 (m, 3H), 7.19-7.10 (m, 3H), 3.65-3.35 (m, 6H), 3.30-3.15 (m, 2H), 2.85-2.82 (m, 3H), 2.33-2.10 (m, 2H); MS (posES-FIA) m/z 432 (M+H).
    • Example 4 3-Fluoro-N-[4-(4-methyl-1,4-diazepan-1-yl)-1-naphthyl]benzenesulfonamide, hydrochloride
  • To a solution of (intermediate 3 after reduction according to Method A) 4-(4-methyl-1,4-diazepan-1-yl)-1-naphthylamine (0.173 g, 0.676 mmol) and pyridine (450 μL, 4.73 mmol) in CH2Cl2 (3.0 mL) was added 3-fluorobenzenesulfonyl chloride (0.145 g, 0.743 mmol) in CH2Cl2 (1.0 mL). The solution was stirred at room temperature for 16 hours and the volatiles were evaporated. The crude product was purified by column chromatography (SiO2, CHCl3/MeOH/NH3 9:1:0.4%) to give 240 mg of the product as solid that was triturated with MeOH/ether to give 0.180 g (64%) of the free base which was converted to its HCl-salt: 1H NMR (DMSO-d6) δ 11.07 (br s, 1H), 10.28 (br s, 1H), 8.20-8.16 (m, 1H), 7.98-7.94 (m, 1H), 7.60-7.40 (m, 6H), 7.16-7.12 (m, 1H), 7.06-7.02 (m, 1H), 3.65-3.30 (m, partly obscured by solvent signal, HDO, 6H), 3.26-3.18 (m, 2H), 2.84 (s, 3H), 2.30-2.05 (m, 2H); MS (posES-FIA) m/z=414 (M+H).
    • Example 5 N-[4-(4-Ethyl-1-piperazinyl)-1-naphthyl]benzenesulfonamide, hydrochloride
  • The title compound was prepared from (intermediate 3 after reduction according to Method A) 4-(4-ethyl-1-piperazinyl)-1-naphthylamine (0.241 g, 0.945 mmol) and benzenesulfonyl chloride (0.121 mL, 0.945 mmol) by the method described above to yield HCl-salt 0.210 g (51%); 1H NMR (CD3OD) δ 8.19-8.15 (m, 1H), 7.94-7.90 (m, 1H), 7.70-7.66 (m, 2H), 7.56-7.46 (m, 2H), 7.44-7.36 (m, 3H), 7.19 (d, J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 3.75-3.40 (m, 6H), 3.34 (q, J=7.6 Hz, 2H), 3.25-3.10 (m, 2H), 1.43 (tr, J=7.6 Hz, 3H); MS (posEI) m/z 387 (M+).
    • Example 6 N-(4-Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl-1-naphthyl)-4-methylbenzenesulfonamide, hydrochloride
  • To a solution of (intermediate 6) 2-(4-nitro-1-naphthyl)octahydropyrrolo[1,2-a]pyrazine (0.160 g, 0.54 mmol) in 10 mL THF:EtOH (20 mL, 1:4) was added Raney-Ni (1.0 mL suspension in EtOH) followed by hydrazine hydrate (0.135 g, 2.70 mmol). The mixture was stirred vigorously at room temperature for 16 hours and then filtered through celite pretreated with water. The filtrate was concentrated and the residue was dissolved in CH2Cl2 (3 mL) and pyridine (0.35 mL, 3.78 mmol) and p-toluensulfonyl chloride (0.13 g, 0.54 mmol) were added to the solution. The reaction mixture was stirred at room temperature for 16 hours and then concentrated. The crude product was purified by column chromatography chromatography (SiO2, CHCl3/MeOH/NH3 9:1:0.4%) to give 0.217 g (95%) of the free base which was converted to its HCl-salt: 1H NMR (CD3OD) δ 8.21-8.14 (m, 1H), 7.97-7.93 (m, 1H), 7.58-7.47 (m, 3H), 7.43-7.37 (m, 1H), 7.25-7.10 (m, 4H), 4.12-4.02 (m, 1H), 3.80-3.0 (m, partly obscured by solvent signal, 8H), 2.45-2.10 (m, 3H), 2.35 (s, 3H), 1.87-1.75 (m, 1H); MS (posEI) m/z 421 (M+).
    • Example 7 N-(4-Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl-1-naphthyl)-3,4-dimethoxybenzenesulfonamide, hydrochloride
  • The title compound was prepared from (intermediate 6) 2-(4-nitro-1-naphthyl)octahydropyrrolo[1,2-a]pyrazine (0.133 g, 0.447 mmol) by the method described above: yield 0.160 g (76%) of the pure product as the free base which was converted to its HCl-salt; 1H NMR (CD3OD) δ 8.20-8.16 (m, 1H), 7.96-7.92 (m, 1H), 7.54-7.48 (m, 1H), 7.43-7.38 (m, 1H), 7.30-7.26 (m, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.09-7.07 (m, 1H), 6.95-6.92 (m, 1H), 3.83 (s, 3H), 3.82-3.0 (m, partly obscured by solvent signal, 10H), 3.62 (s, 3H), 2.50-2.10 (m, 2H); MS (posEI) m/z 467 (M+).
    • Example 8 N-[4-(4-Ethyl-1-piperazinyl)-1-naphthyl]-4-methylbenzenesulfonamide, hydrochloride
  • To a solution of (intermediate 3 after reduction according to Method A) 4-(4-ethyl-1-piperazinyl)-1-naphthylamine 0.241 g, 0.945 mmol) and pyridine (0.534 mL, 0.945 mmol) in CH2Cl2 (3.0 mL) was added p-toluenesulfonyl chloride (0.180 g, 0.945 mmol) in CH2Cl2 (2.0 mL). The mixture was stirred at room temperature for 16 hours followed by the addition of CH2Cl2 (15 mL). The reaction mixture was washed with saturated aqueous NaHCO3, dried with Na2SO4, filtered and concentrated. The crude residue was purified by column chromatography (SiO2. CHCl3→CHCl3/MeOH/NH3 9:1:0.4%) to give a solid which was converted to its HCl-salt: yield HCl-salt 0.372 g (88%); 1H NMR (CD3OD) δ 8.20-8.15 (m, 1H), 7.97-7.93 (m, 1H), 7.58-7.54 (m, 2H), 7.53-7.47 (m, 1H), 7.43-7.37 (m, 1H), 7.25-7.20 (m, 2H), 7.18 (d, J=8.0 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 3.80-3.10 (m, partly obscured by solvent signal, 10H), 2.35 (s, 3H), 1.43 (tr, J=7.3 Hz, 3H); MS (posEI) m/z 409 (M+).
    • Example 9 3,4-Dimethoxy-N-[4-(3-methyl-1-piperazinyl)-1-naphthyl]benzenesulfonamide, hydrochloride
  • The title compound was prepared from (intermediate 8 after reduction according to Method A) tert-butyl 4-(4-amino-1-naphthyl)-2-methyl-1-piperazinecarboxylate (0.189 g, 0.55 mmol) and 3,4-dimethoxybenzenesulfonyl chloride (0.130 g, 0.55 mmol) by the method described above: yield HCl-salt 0.068 g (26%); 1H NMR (CD3OD)
    • Example 10 4-Methyl-N-[4-(4-methyl-1-piperizinyl)-1-naphthyl]-1-benzenesulfonamide, hydrochloride
  • To a solution of 4-(4-methyl-1-piperazinyl)-1-naphthylamine (prepared according to methods A and B) (0.099 g, 0.409 mmol) and pyridine (231 μL, 2.86 mmol) in CH2Cl2 (3.0 mL) was added 4-methylbenzenesulfonyl chloride (0.078 g, 0.409 mmol) in CH2Cl2 (1.0 mL). The solution was stirred at room temperature for 16 hours and then washed with saturated aqueous NaHCO3, dried with Na2SO4, filtered and concentrated. The crude product was purified via column chromatography (SiO2, CHCl3→CHCl3/MeOH/NH3 9:1:0.4%) to give the pure base which was converted to its HCl-salt: yield 110 mg (62%); 1H NMR (DMSO-d6) δ 10.86 (br s, 1H), 10.02 (s, 1H), 8.11-8.03 (m, 2H), 7.60-7.56 (m, 2H), 7.55-7.44 (m, 2H), 7.33-7.30 (m, 2H), 7.09-7.06 (m, 1H), 7.04-7.01 (m, 1H), 3.55-3.32 (m, 6H), 3.19-3.10 (m, 2H), 2.86 (s, 3H), 2.34 (s, 3H); MS (posES-FIA) m/z=395.1665 (M+H)(calc 395.1667).
    • Example 11 4-Methyl-N-[4-(5-methyl-2,5-diazabicyclo[2,2,1]hept-2-yl]-naphtyl]benzenesulfonamide, hydrochloride
  • To a solution of 4-(5-methyl-2,5-diazabicyclo[2,2,1]hept-2-yl)-1-naphtylamine (0.210 g, 0.829 mmol) (prepared according to methods A and B), pyridine (468 μL, 5.80 mmol) in CH2Cl2 (3.0 mL) was added 4-methylbenzenesulfonyl chloride (0.158 g, 0.829 mmol) in CH2Cl2 (1.0 mL). The solution was stirred at room temperature for 16 hours and then concentrated. The crude product was purified via column chromatography (SiO2, CHCl3→CHCl3/MeOH/NH3 9:1:0.4%) to give the pure base which was converted to its HCl-salt: yield 160 mg (43%); 1H NMR (DMSO-d6) δ 10.78 (br s, 1H), 9.90-9.88 (m, 1H), 8.02-7.98 (m, 2H), 7.58-7.55 (m, 2H), 7.49-7.41 (m, 2H), 7.33-7.30 (m, 2H), 7.06-7.03 (m, 1H), 6.93-6.90 (m, 1H), 4.38-4.30 (m, 3H), 3.65-3.60 (m, 3H), 2.90-2.87 (m, 1H), 2.86-2.83 (m, 3H), 2.36 (br s, 2H), 2.35 (s, 3H); MS (posES-FIA) m/z=407.1655 (M+H)(calc 407.1667).
    • Example 12 4-Methyl-N-[4-(3-methyl-1-piperazinyl)-1-naphthyl]benzenesulfonamide, hydrochloride
  • To a solution of (intermediate 8 after resuction according to Method A) tert-butyl 4-(4-amino-1-naphthyl)-2-methyl-1-piperazinecarboxylate (0189 g, 0.55 mmol) and pyridine (0.311 mL, 3.85 mmol) in CH2Cl2 (3 mL) was added tolouenesulfonyl chloride (0.105 g, 0.55 mmol). The mixture was stirred at room temperature for 16 hours and then concentrated. The crude residue was purified by column chromatography (SiO2, EtOAc:pentane 3:7). The pure intermediate was dissolved in small amount of MeOH and de-protected using ether saturated with HCl-gas. The precipitate was collected by filtration and triturated with MeOH and ether: yield HCl-salt 0.047 g (19%); 1H NMR (CDCl3) δ 8.28-8.20 (m, 1H), 7.85-7.79 (m, 1H), 7.65-7.55 (m, 1H), 7.50-7.10 (m, partly obscured by solvent signal, 5H), 6.95-6.85 (m, 1H), 6.51 (br s, 1H), 4.50-4.25 (m, 1H), 4.05-3.85 (m, 1H), 3.52-3.33 (m, 1H), 3.28-3.05 (m, 2H), 2.97-2.85 (m, 1H), 2.82-2.67 (m, 1H), 2.85 (s, 3H), 1.52-1.47 (m, partly obscured by H2O signal, 3H); MS (pos-ES) m/z=395 (M+H).
    • Example 13 2-N-[4-(1-piperazinyl)-1-naphthyl]naphthalenesulfonamide, hydrochloride
  • To another portion of the solution of the reduced nitro compound was added 2-naphthalenesulfonyl chloride (0.23 g). The mixture was stirred for 4 hours at 40° C. under nitrogen and worked up as above. The product obtained was identified as 1-tert-butyl 4-(4-{bis[(2-naphthalene)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylate. This bis sulfonamide was refluxed for 3 hours in ethanol (10 mL) containing NaOH (0.1 g). This solution was added to a solution of HCl in ethyl acetate (1N, 100 mL) and stirred overnight. The solution was evaporated to give the crude product which was purified by preparative hplc (CH3CN:H2O 10% to 50% gradient). Yield 47 mg. 1H NMR (400 MHz, DMSO-d6) δ 3.05 (br, 4H), 3.3 (br, 4H), 7.0 (s, 2H), 7.2-7.5 (m, 2H), 7.55 (t, J=7.9 Hz, 1H), 7.62 (t, J=6.9 Hz, 1H), 7.76 (m, 1H), 7.9-8.1 (m, 5H), 8.21 (s, 1H), 8.7 (br, 2H)
    • Example 14
  • N,4-Dimethyl-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide, hydrochloride 1-tert-Butyl 4-(4-{methyl[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylate (intermediate 14 after reduction according to Method A) (75 mg, 0.15 mmol) was dissolved in methanol (5 mL) and treated with 1N HCl in ether (20 mL). After stirring overnight, the product precipitated and was collected by filtration, washed with ether and dried. Yield 60 mg (92%) of an off white solid.
    • Example 15 N-[4-(1,4-Diazepan-1-yl)-1-napthyl]-4-methylbenzenesulfonamide, hydrochloride
  • To a solution of (intermediate 7 after reduction according to Method A) 4-(1,4-diazepan-1-yl)-1-naphtylamine (0.399 g, 1.17 mmol), pyridine (661 μL, 8.19 mmol) and Et3N (329 μL, 2.34 mmol in CH2Cl2 (3.0 mL) was added 4-methylbenzenesulfonyl chloride (0.223 g, 1.17 mmol) in CH2Cl2 (1.0 mL). The solution was stirred at room temperature for 16 hours and then concentrated. The crude product was purified via column chromatography (SiO2, CHCl3→CHCl3/MeOH/NH3 9:1:0.4%) to give 0.360 g of the boc-protected compound. De-protection was accomplished by dissolving the intermediate in MeOH and then adding HCl-gas dissolved in ether. The precipitate was collected by filtration to give 0.143 g (28%) of the pure compound as the HCl-salt: 1H NMR (DMSO-d6) δ 10.00 (s, 1H), 9.28 (br s, 1H), 8.20-8.16 (m, 1H), 8.04-7.99 (m, 1H), 7.60-7.55 (m, 2H), 7.54-7.49 (m, 1H), 7.47-7.42 (m, 1H), 7.33-7.29 (m, 2H), 7.12 (d, J=8.16 Hz, 1H), 7.01 (d, J=8.16 Hz, 1H), 3.42-3.31 (m, 6H), 3.20.3.16 (m, 2H), 2.34 (s, 3H), 2.14-2.08 (m, 2); MS (posES-FIA) m/z=395.1667 (M+H) (calc 395.1667)
    • Example 16 N-[4-(1,4-Diazepan-1-yl)-1-napthyl]-2-methoxy-4-methylbenzenesulfonamide, hydrochloride
  • To a solution of (intermediate 7 after reduction according to Method A) 4-(1,4-diazepan-1-yl)-1-napthylamine (0.399 g, 1.17 mmol), pyridine (661 μL, 8.19 mmol) and Et3N (329 μL, 2.34 mmol in CH2Cl2 (3.0 mL) was added 2-methoxy-4-methylbenzenesulfonyl chloride (0.258 g, 1.17 mmol) in CH2Cl2 (1.0 mL). The solution was stirred at room temperature for 16 hours and then concentrated. The crude product was dissolved in EtOH and powdered KOH was added to the solution. The mixture was stirred at 70° C. for 16 hours. The suspension was concentrated and water was added. The solution was neutralized with 1N HCl and extracted with CH2Cl2 (2×20 mL). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated. Column chromatography (SiO2, CH2Cl2→CH2Cl2/MeOH (95:5) gave 0.432 g of a reddish brown solid. De-protection of the intermediate using MeOH ether saturated with HCl-gas gave brown solid which was collected by filtration. The product was re-crystallized from MeOH/ether to give 109 mg (20%) of product as its HCl-salt: 1H NMR (DMSO-d6) δ 9.74 (s, 1H), 9.36 (br s, 2H), 8.20-8.14 (m, 2H), 7.55-7.45 (m, 3H), 7.44-7.42 (m, 1H), 7.16-7.09 (m, 2H), 7.02-7.00 (m, 1H), 6.75-6.74 8 m, 1H), 3.85 (s, 3H), 3.42-3.27 (m, 6H), 3.18-3.14 (m, 2H), 2.31-(s, 3H), 2.14-2.07 (m, 2H); MS (posES-FIA) m/z=425.1768 (M+H)(calc 425.1774)
    • Example 17 N-(2-Methoxy-4-methylphenyl)-4-(3,5-trimethyl-1-piperazinyl)-1-naphthalenesulfonamide, hydrochloride
  • To a solution of (intermediate 4 after reduction according to Method A) 4-(2,6-dimethyl-1-piperazinyl)-1-naphthylamine (0.203 g, 0.563 mmol) and pyridine (322 μL, 3.99 mmol) in DCM (3.0 mL) was added 4-methylbenzenesulfonyl chloride (0.107 g, 0.563 mmol) in DCM (1.0 mL). The solution was stirred at room temperature for 16 hours and then washed with saturated aqueous NaHCO3, dried with Na2SO4, filtered and concentrated. The crude intermediate was purified via column chromatography on silica using CHCl3/CHCl3+10% MeOH+0.4% NH3 to give 0.230 g of the boc-protected intermediate. Removal of the boc-group was accomplished by dissolving the intermediate in MeOH and then adding ether saturated with HCl-gas. The crude product was dissolved in DCM and then purified via column chromatography on silica using CHCl3/CHCl3+10% MeOH+0.4% NH3 to give 156 mg (67%) of the pure base which was converted to its HCl-salt: 1H NMR (DMSO-d6) δ 10.01 (s, 1H), 9.86-9.78 (m, 1H), 9.14-9.00 (m, 1H), 8.13-8.10 (m, 1H), 8.05-8.02 (m, 1H), 7.58-7.55 (m, 2), 7.53-7.49 (m, 1H), 7.48-7.43 (m, 1H), 7.33-7.29 (m, 2H), 7.06 (d, J=7.85 Hz, 1H), 7.02 (d, J=8.17 Hz, 1H), 3.65-3.55 (m, 2H), 3.35-3.27 (m, 2H), 2.86-2.79 (m, 2H), 2.34 (s, 3H), 1.31 (d, J=6.60 Hz, 6H); MS (posES-FIA) m/z=409.1838 (M+H)(calc 407.1824)
    • Example 18 N-[4-(4-Isopropyl-1-piperizinyl)-1-naphthyl]-4-methylbenzenesulfonamide, hydrochloride
  • To a solution of 4-(4-isopropyl-1-piperazinyl)-1-naphthylamine (0.209 g, 0.776 mmol) (prepared according to Methods A and B) and pyridine (438 μL, 5.43 mmol) in CH2Cl2 (3.0 mL) was added 4-methylbenzenesulfonyl chloride (0.163 g, 0.850 mmol) in CH2Cl2 (1.0 mL). The solution was stirred at room temperature for 16 hours and the solid was collected by filtration as the HCl-salt to yield 0.236 g (66%); 1H NMR (DMSO-d6) δ 10.65 (br s, 1H), 9.95 (br s, 1H), 8.10-8.05 (m, 1H), 8.02-7.94 (m, 1H), 7.56-7.49 (m, 2H), 7.48-7.37 (m, 2H), 7.28-7.22 (m, 2H), 7.02-6.94 (m, 2H), 3.53-3.40 (m, 3H), 3.37-3.15 (m, 8H), 2.28 (s, 3H), 1.32-1.28 (m, 6H); MS (posES-FIA) m/z=423.1972 (M+H)(calc 423.1980).
    • Example 19 4-Bromo-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.21 (s, 1H), 9.12 (brs, 2H), 8.12 (d, J=8.48 Hz, 1H), 7.97 (d, J=8.16 Hz., 1H), 7.75-7.70 (m, 2H), 7.61-7.57 (m, 2H), 7.54-7.49 (m, 1H), 7.48-7.43 (m, 1H), 7.10-7.01 (M, 2h), 3.38-3.31 (M, 4H), 3.23-3.10 (M, 4H), MS (posESI) m/z=446 (M+H).
    • Example 20 2,5-Dichloro-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide, hydrochloride
  • 1H NMR (400 MHz, DMSO-d6) δ 3.2 (br, 4H), 3.4 (br, 4H), 7.09 (s, 2H), 7.54 (m, 2H), 7.70 (m, 3H), 8.10 (m, 2H); MS (ESI+) for C20 H19 Cl2 N3 O2 S m/z 436 (M+H)+.
    • Example 21 2-Chloro-4-fluoro-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide, hydrochloride
  • 1H NMR (400 MHz, DMSO-d6) δ 3.1 (br, 4H), 3.4 (br, 4H), 7.01 (AB, J=8.03 Hz, 1H), 7.04 (AB, J=8.03 Hz, 1H), 7.27 (dt, J=3.01, 8.53 Hz, 1H), 7.5 (m, 2H), 7.68 (dd, J=2.51, 9.03 Hz, 1H), 7.85 (dd, J=6.52, 9.03 Hz, 1H), 8.10 (d, J=7.03 Hz, 1H), 8.20 (d, J=7.03 Hz, 1H); MS (ESI+) for C20 H19 Cl F N3 O2 S m/z 420 (M+H)+.
    • Example 22 2,3-Dichloro-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide, hydrochloride
  • 1H NMR (400 MHz, DMSO-d6) δ 3.1 (br, 4H), 3.4 (br, 4H), 7.01 (AB, J=8.03 Hz, 1H), 7.03 (AB, J=8.03 Hz, 1H), 7.42 (t, J=7.78 Hz, 1H), 7.50 (m, 2H), 7.81 (dd, J=1.51, 8.03 Hz, 1H), 7.85 (dd, J=1.51, 8.03 Hz, 1H), 8.10 (dd, J=6.52, 2.0 Hz, 1H), 8.20 (dd, J=7.53, 2.01 Hz, 1H); MS (ESI+) for C20 H19 Cl2 N3 O2 S m/z 436 (M+H)+.
    • Example 23 2,4-Dichloro,5-methyl-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide, hydrochloride
  • 1H NMR (400 MHz, DMSO-d6) δ 2.27 (s, 3H), 3.15 (br, 4H), 3.4 (br, 4H), 7.07 (s, 2H), 7.54 (m, 2H), 7.79 (s, 1H), 7.85 (s, 1H), 8.13 (m, 1H), 8.19 (m, 1H); MS (ESI+) for C21 H21 Cl2 N3 O2 S m/z 450 (M+H)+.
    • Example 24 3-Trifluoromethyl-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide, hydrochloride
  • 1H NMR (400 MHz, DMSO-d6) δ 3.2 (br, 4H), 3.4 (br, 4H), 7.05 (AB, J=8.03 Hz, 1H), 7.10 (AB, J=8.03 Hz, 1H), 7.40 (t, J=7.53 Hz, 1H), 7.50 (t, J=7.53 Hz, 1H), 7.76 (t, J=8.03 Hz, 1H), 7.81 (s, 1H), 7.88 (d, J=8.53 Hz, 1H), 7.95 (d, J=8.03 Hz, 1H), 7.99 (d, J=8.03 Hz, 1H), 8.12 (d, J=8.54 Hz, 1H); MS (ESI+) for C21 H20 F3 N3 O2 S m/z 436 (M+H)+.
    • Example 25 2-Trifluoromethyl-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide, hydrochloride
  • 1H NMR (400 MHz, DMSO-d6) δ 3.0 (br, 4H), 3.4 (br, 4H), 6.93 (s, 2H), 7.36 (m, 1H), 7.41 (m, 1H), 7.64 (m, 2H), 7.85 (dd, J=2.01, 7.53 Hz, 1H), 7.90 (dd, J=2.01, 7.03 Hz, 1H), 8.02 (d, J=8.54 Hz, 2H).
    • Example 26 4-Bromo-N-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 9.12 (brs, 2H), 8.22-8.07 (m, 2H), 7.89 (d, J=8.44 Hz, 2H), 7.74-7.58 (m, 4H), 7.10 (d, J=7.91 Hz, 1H), 6.89 (d, 8.18 Hz, 1H), 3.50 (s, 3H), 3.43-3.27 (m, obscured in part by solvent signal), MS (posESI) m/z=460 (M+H).
    • Example 27 Naphthalene-1-sulfonic acid (4-piperazin-1-yl-naphthalen-1-yl)-amide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 9.00 (brs, 1H), 8.77-8.71 (m, 1H), 8.18 (d, J=8.44 Hz, 1H), 8.10-8.02 (m, 2H), 8.01-7.96 (m, 1H), 7.90 (d, J=8.18 Hz, 1H), 7.73-7.62 (m, 2H), 7.56-7.49 (m, 1H), 7.47-7.39 (m, 1H), 7.31-7.23 (m, 1H), 7.02-6.94 (m, 2H), 3.40-3.25 (m, obscured by solvent signal), 3.19-3.05 (m, 4H), MS (posESI) m/z=418 (M+H).
    • Example 28 2,5-Dichloro-thiophene-3-sulfonic acid (4-piperazin-1-yl-naphthalen-1-yl)-amide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.52 (brs, 1H), 9.02 (brs, 2H), 8.19-8.12 (m, 1H), 8.01-7.94 (m, 1H), 7.60-7.47 (m, 2H), 7.23-7.12 (m, 3H), 3.43-3.28 (m, obscured in part by solvent signal), 3.25-3.10 (m, m, 4H), MS (posESI) m/z=442 (M+H).
    • Example 29 4-Methoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 9.96 (s, 1H), 9.13 (brs, 1H), 8.15-8.08 (m, 1H), 8.06-7.99 (m, 1H), 7.65-7.57 (m, 2H), 7.55-7.42 (m, 2H), 7.12-6.97 (m, 4H), 3.43-3.29 (m, 4H), 3.24-3.10 (m, 4H), MS (posESI) m/z=398 (M+H).
    • Example 30 4-Chloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.25 (brs, 1H), 9.03 (brs, 1H), 8.16-8.09 (m, 1H), 8.00-7.94 (m, 1H), 7.71-7.41 (m, 6H), 7.13-7.01 (m, 2H), 3.40-3.26 (m, obscured in part by solvent signal), 3.24-3.08 (m, 4H), MS (posESI) m/z=402 (M+H).
    • Example 31 2-Chloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (CDCl3) δ; 8.24-8.12 (m, 2H), 7.90-7.83 (m, 1H), 7.60-7.43 (m, 3H), 7.32-7.27 (m, obscured in part by solvent signal, 1H), 7.09 (s, 1H), 7.04 (d, J=8.44 Hz, 1H), 6.87-6.79 (m, 1H), 3.90-3.40 (m, 4H), 3.12-2.80 (m, 4H), MS (posESI) m/z=402 (M+H).
    • Example 32 N-(4-piperazin-1-yl-naphthalen-1-yl)-4-trifluoromethyl-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.40 (brs, 1H), 9.03 (brs, 1H), 8.12 (d, J=7.65 Hz, 1H), 7.95-7.83 (m, 5H), 7.55-7.39 (m, 2H), 7.13-7.02 (m, 2H), 3.40-3.30 (m, obscured in part by solvent signal), 3.23-3.09 (m, 4H), MS (posESI) m/z=436 (M+H).
    • Example 33 4-Fluoro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.17 (brs, 1H), 9.18 (brs, 2H), 8.15-8.08 (m, 1H), 7.99-7.92 (m, 1H), 7.77-7.66 (m, 2H), 7.55-7.30 (m, 4H), 7.11-7.01 (m, 2H), 3.40-3.30 (m, obscured by solvent signal), 3.25-3.10 (m, 4H), MS (posESI) m/z=386 (M+H).
    • Example 34 5-Fluoro-2-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.27 (brs, 1H), 9.19 (brs, 2H), 8.16-8.10 (m, 1H), 8.03-7.96 (m, 1H), 7.58-7.33 (m, 5H), 7.12-6.98 (m, 2H), 3.40-3.30 (m, obscured by solvent signal) 3.24-3.10 (m, 4H), MS (posESI) m/z=400 (M+H).
    • Example 35 4-Phenoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.08 (s, 1H), 9.11 (brs, 2H), 8.18-8.07 (m, 1H), 7.98-7.89 (m, 1H), 7.67-7.60 (m, 2H), 7.57-7.40 (m, 4H), 7.28-7.20 (m, 1H), 7.11 (s, 2H), 7.07-6.98 (m, 1H), 7.11 (s, 2H), 7.07-6.98 (m, 4H), 3.40-3.30 (m, obscured by solvent signal), 3.24-3.10 (m, 4H), MS (posESI) m/z=460 (M+H).
    • Example 36 2-Bromo-4-iodo-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.45 (brs, 1H), 9.01 (brs, 2H), 8.28 (d, J=1.58 Hz, 1H), 8.18-8.09 (m, 2H), 7.88-7.83 (m, 1H), 7.59-7.50 (m, 3H), 7.07 (s, 2H), 3.40-3.30 (m, obscured by solvent signal), 3.23-3.10 (m, 4H), MS (posESI) m/z=572 (M+H).
    • Example 37 Thiophene-2-sulfonic acid (4-piperazin-1-yl-naphthalen-1-yl)-amide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.30 (s, 1H), 9.12 (brs, 1H), 8.17-8.09 (m, 1H), 8.00-7.92 (m, 1H), 7.89-7.85 (m, 1H), 7.56-7.38 (m, 3H), 7.18-7.06 (m, 3H), 3.40-3.30 (m, obscured by solvent signal), 3.25-3.15 (m, 4H), MS (posESI) m/z=374 (M+H).
    • Example 38 5-Chloro-thiophene-2-sulfonic acid (4-piperazin-1-yl-naphthalen-1-yl)-amide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.43 (brs, 1H), 9.11 (brs, 2H), 8.19-8.111 (m, 1H), 8.02-7.95 (m, 2H), 7.29 (d, J=3.95 Hz, 1H), 7.21-7.12 (m, 3H), 3.40-3.30 (m, obscured by solvent signal), 3.25-3.15 (m, 4H), MS (posESI) m/z=408 (M+H).
    • Example 39 3-Methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 8.14-8.07 (m, 1H), 8.04-7.97 (m, 1H), 7.55-7.35 (m, 6H), 7.07-6.97 (m, 2H), 3.30-2.98 (m, obscured in part by solvent signal, 8H), 2.29 (s, 3H), MS (posESI) m/z=442 (M+H).
    • Example 40 4-Butyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.05 (s, 1H), 9.20 (brs, 2H), 8.11 (d, J=7.91 Hz, 1H), 7.93 (d, J=8.18 Hz, 1H), 7.62-7.26 (m, 5H), 7.07 (s, 2H), 3.40-3.30 (m, obscured by solvent signal), 3.25-3.15 (m, 4H), 2.66-2.55 (m, obscured in part by solvent signal, 2H), 1.58-1.15 (m, 2H), 1.32-1.15 (m, 2H), 0.92-0.83 (m, 3H), MS (posESI) m/z=427 (M+H).
    • Example 41 2,4,6-Trimethyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 9.92 (brs, 1H), 9.01 (brs, 2H), 8.15-8.09 (m, 1H), 8.05-7.98 (m, 1H), 7.55-7.42 (m, 2H), 7.09-6.94 (m, 4H), 3.40-3.30 (m, obscured by solvent signal), 3.25-3.15 (m, 4H) 2.85 (s, 6H), 2.22 (s, 3H), MS (posESI) m/z=410 (M+H).
    • Example 42 2,4,5-Trichloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.68 (brs, 1H), 9.06 (brs, 1H), 8.22-8.08 (m, 2H), 8.18 (s, 1H), 7.88 (s, 1H), 7.61-7.52 (m, 2H), 7.09 (s, 2H), 3.40-3.30 (m, obscured by solvent signal), 3.25-3.15 (m, 4H), MS (posESI) m/z=470 (M+H).
    • Example 43 4-Iodo-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.22 (s, 1H), 9.06 (brs, 2H), 8.16-8.09 (m, 1H), 8.02-7.87 (m, 3H), 7.58-7.39 (m, 4H), 7.18-6.98 (m, 2H), 3.40-3.30 (m, 4H), 3.25-3.10 (m, 4H), MS (posESI) m/z=494 (M+H).
    • Example 44 2-Methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.13 (s, 1H), 9.15 (brs, 2H), 8.15-8.08 (m, 1H), 8.07-7.63 (m, 1H), 7.70-7.63 (m, 1H), 7.61-7.23 (m, 2H), 3.41-3.27 (m, 4H), 3.24-3.09 (m, 4H), 2.55 (s, obscured in part by solvent signal, 3H), MS (posESI) m/z=382 (M+H).
    • Example 45 3,4-Dichloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • MS (posESI) m/z=436 (M+H)
    • Example 46 5-Bromo-2-methoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.13 (s, 1H), 9.10 (brs, 2H), 8.16-8.07 (m, 2H), 7.78-7.71 (m, 1H), 7.59 (d, J=2.64 Hz, 1H), 7.57-7.46 (m, 2H), 7.22-7.06 (m, 3H), 3.19 (s, 3H), 3.40-3.30 (m, obscured by solvent signal), 3.24-3.09 (m, 4H), MS (posESI) m/z=476 (M+H).
    • Example 47 2-Bromo-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 9.37 (brs, 1H), 8.22-8.07 (m, 2H), 7.89-7.79 (m, 2H), 7.57-7.40 (m, 4H), 7.05 (s, 2H), 3.40-3.30 (m, obscured by solvent signal), 3.24-3.09 (m, 4H), MS (posESI) m/z=446 (M+H).
    • Example 48 3-Chloro-2-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 9.11 (brs, 1H), 8.17-8.09 (m, 1H)), 8.04-7.96 (m, 1H), 7.73-7.67 (m, 2H), 7.58-7.46 (m, 2H), 7.36-7.27 (m, 1H), 7.11-6.99 (m, 2H), 3.40-3.30 (m, obscured by solvent signal), 3.24-3.09 (m, 4H), 2.57 (s, 3H), MS (posESI) m/z=416 (M+H).
    • Example 49 2,6-Dichloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.60 (s, 1H), 9.08 (brs, 1H), 8.18-8.06 (m, 2H), 7.66-7.44 (m, 5H), 7.09 (s, 2H), 3.40-3.30 (m, obscured by solvent signal), 3.24-3.09 (m, 4H), MS (posESI) m/z=436 (M+H).
    • Example 50 3-Methoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.13 (s, 1H), 9.07 (brs, 2H), 8.15-8.08 (m, 1H), 8.02-7.95 (m, 1H), 7.56-7.36 (m, 3H), 7.28-7.22 (m, 1H), 7.19-7.02 (m, 4H), 3.69 (s, 3H), 3.40-3.30 (m, 4H), 3.24-3.10 (m, 4H), MS (posESI) m/z=398 (M+H).
    • Example 51 3-Chloro-4-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.20 (brs, 1H), 9.12 (brs, 2H), 8.16-8.10 (m, 1H), 8.04-7.97 (m, 1H), 7.65-7.61 (m, 1H), 7.58-7.43 (m, 4H), 7.12-6.99 (m, 2H), 3.40-3.30 (m, obscured by solvent signal), 3.24-3.09 (m, 4H), 2.36 (s, 3H), MS (posESI) m/z=416 (M+H).
    • Example 52 4-Bromo-2-fluoro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.59 (s, 1H), 9.17 (brs, 2H), 8.17-8.09 (m, 1H), 8.08-7.99 (m, 1H), 7.87-7.80 (m, 1H), 7.59-7.46 (m, 4H), 7.16-7.07 (m, 2H), 3.42-3.28 (, 4H), 3.24-3.08 (m, 4H), MS (posESI) m/z=464 (M+H).
    • Example 53 2,4-Dichloro-6-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 9.08 (brs, 2H), 8.18-8.04 (m, 2H), 7.73-7.69 (m, 1H), 7.60-7.42 (m, 3H), 7.14-7.04 (m, 2H), 3.40-3.30 (m, obscured by solvent signal), 3.24-3.09 (m, 4H), 2.80 (s, 3H), MS (posESI) m/z=450 (M+H).
    • Example 54 4-Bromo-2-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.24 (brs, 1H), 9.12 (brs, 2H), 8.17-8.10 (m, 1H), 8.05-7.98 (m, 1H), 7.68-7.65 (m, 1H), 7.58-7.46 (m, 4H), 7.10-6.96 (m, 2H), 3.40-3.30 (m, obscured by solvent signal), 3.24-3.09 (m, 4H), 2.53 (s, obscured in part by solvent signal, 3H), MS (posESI) m/z=450 (M+H).
    • Example 55 4,5-Dichloro-thiophene-2-sulfonic acid (4-piperazin-1-yl-naphthalen-1-yl)-amide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 8.97 (brs, 2H), 8.19-8.12 (m, 1H), 8.01-7.94 (m, 1H), 7.60-7.47 (m, 2h), 7.50 (S, 1H), 7.25-7.14 (m, 2H), 3.40-3.30 (m, obscured by solvent signal), 3.24-3.09 (m, 4H), MS (posESI) m/z=442 (M+H).
    • Example 56 N-Methyl-N-(4-bromo-2-methylphenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide, hydrochloride
  • 1H NMR (DMSO) δ 9.39 (br s, 2H), 8.23-8.13 (m, 1H), 8.09-7.99 (m, 1H), 7.75-7.56 (m, 5H), 7.13-7.02 (m, 2H), 3.41-3.18 (m, 8H), 3.26 (s, 3H), 2.25 (s, 3H); MS m/z (M+1) 475.
    • Example 57 N-Methyl-N-(5-fluoro-2-methylphenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide, hydrochloride
  • 1H NMR (DMSO) δ 9.21 (br s, 2H), 8.23-8.14 (m, 1H), 8.04-7.97 (m, 1H), 7.64-7.45 (m, 5H), 7.13-7.03 (m, 2H), 3.43-3.17 (m, 8H), 3.29 (s, 3H), 2.21 (s, 3H); MS m/z (M+1) 414.
    • Example 58 N-Methyl-N-(2-methylphenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide, hydrochloride
  • 1H NMR (CD3OD) δ 8.26-8.19 (m, 1H), 8.11-8.05 (m, 1H), 7.87-7.81 (m, 1H), 7.62-7.49 (m, 3H), 7.40-7.32 (m, 2H), 7.13-7.03 (m, 2H), 3.57-3.49 (m, 4H), 3.34-3.30 (m, 7H), 2.30 (s, 3H); MS m/z (M+1) 396.
    • Example 59 N-Methyl-N-(3-chloro-2-methylphenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide, hydrochloride
  • 1H NMR (DMSO) δ 9.52 (br s, 2H), 8.23-8.14 (m, 1H), 8.04-7.96 (m, 1H), 7.88-7.76 (m, 2H), 7.64-7.54 (m, 2H), 7.49-7.39 (m, 1H), 7.17-7.05 (m, 2H), 3.42-3.16 (m, 8H), 3.27 (s, 3H), 2.34 (s, 3H); MS m/z (M+1) 430.
    • Example 60 2,5-Dichlorothiophen-3-yl-Methyl-N-(2,5-dichlorothiophen-3-yl)-4-(1-pyperazinyl)-1-napthalenesulphonamide, hydrochloride
  • 1H NMR (DMSO) δ 9.49 (br s, 1H), 8.24-8.13 (m, 1H), 8.07-7.98 (m, 1H), 7.67-7.55 (m, 2H), 7.33 (s, 1H), 7.24-7.07 (m, 2H), 3.44-3.18 (m, 10H); MS m/z (M+1) 456.
    • Example 61 N-Methyl-N-(1-naphthyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide, hydrochloride
  • The compound was prepared 1-tert-butyl-4-(4-{bis[(2-naphthalene)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylate and potassium carbonate (120 mg, 0.87 mmol) in acetone (2 ml) was added iodomethane (44 μl, 0.7 mmol) and the mixture was stirred at room temperature over night. The mixture was diluted with acetonitrile, filtered and concentrated in vacuo. The residue was redissolved in DCM (3 ml) and treated with concentrated TFA (1 ml) at 0° C. for 30 min and then allowed to reach room temperature. Removal of the solvents in vacuo and purification by reversed phase HPLC. followed by treatment of the residue with an excess of 1M HCl in diethyl ether, gave the title compound (70 mg, 58%) as a solid. 1H NMR (DMSO) δ 9.28 (br s, 2H), 8.44 (s, 1H), 8.24-8.07 (m, 5H), 7.80-7.56 (m, 5H), 7.07-7.00 (m, 1H), 6.88-6.81 (m, 1H), 3.41-3.18 (m, 8H), 3.27 (s, 3H); MS m/z (M+1) 432.
    • Example 62 N-Methyl-N-(1-naphthyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide, hydrochloride
  • 1H NMR (DMSO) δ 9.25 (br s, 2H), 8.37-8.28 (m, 2H), 8.22-8.08 (m, 3H), 8.02-7.95 (m, 1H), 7.72-7.46 (m, 5H), 6.97 (s, 2H), 3.42-3.33 (m, 4H), 3.25 (s, 3H), 3.24-3.16 (m, 3H); MS m/z (M+1) 432.
    • Example 63 N-Methyl-N-(4-chlorophenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide, hydrochloride
  • 1H NMR (DMSO) δ 9.41 (br s, 2H), 8.23-8.05 (m, 2H), 7.73 (s, 4H), 7.67-7.56 (m, 2H), 7.13-7.03 (m, 1H), 6.92-6.85 (m, 1H), 3.42-3.19 (m, 8H), 3.22 (s, 3H); MS m/z (M+1) 416.
    • Example 64 N-Methyl-N-(4-methoxyphenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide, hydrochloride
  • 1H NMR (DMSO) δ 9.45 (br s, 2H), 8.22-8.11 (m, 2H), 7.69-7.57 (m, 4H), 7.21-7.14 (m, 2H), 7.09-7.03 (m, 1H), 6.86-6.81 (m, 1H), 3.87 (s, 3H), 3.41-3.19 (m, 8H), 3.16 (s, 3H); MS m/z (M+1) 412.
    • Example 65 5-Fluoro-2-methyl-N-{4-[(2R,5S)-2,5-dimethyl-1-]piperazin-1-yl-1-naphthyl}benzenesulfonamide, hydrochloride
  • Synthesis of (2R,5S)-Z 5-Dimethyl-1-(4-nitro-1-naphthyl)piperazine—A mixture of 1-chloro-4-nitronaphtalene (400 mg, 1.9 mmol), (2R,5S)-2,5-dimethylpiperazine (800 mg, 7 mmol) and potassium carbonate (1 g, 7 mmol) in DMSO (4 ml) was stirred at 100° C. over night followed by an additional 48 hours at room temperature. The reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with brine and 2M NaOH solution and then dried with potassium carbonate. The residue was purified on a silica column, using 10% methanol in chloroform as an eluent, to give the title compound (220 mg, 41%) as an oil. 1H NMR (CDCl3) δ 8.68-8.53 (m, 2H), 8.31-8.26 (m, 1H), 7.76-7.59 (m, 2H), 7.30-7.24 (m, 1H), 3.32-3.87 (m, 4H), 2.96-2.82 (m, 1H), 2.44-2.32 (m, 1H), 1.14-1.04 (m, 3H), 0.99-0.89 (m, 3H); MS m/z (M+1) 286.
  • Synthesis of tert-Butyl (2R,5S)-2,5-dimethyl-1-(4-nitro-1-naphthyl)piperazine-1-carboxylate—To a stirred solution of (2R,5S)-2,5-Dimethyl-1-(4-nitro-1-naphthyl)piperazine (220 mg, 0.77 mmol) in DCM (2 ml) was added, at 0° C., BOC-anhydride dissolved in DCM (2 ml). The solution was stirred for 15 min and was then allowed to reach room temperature. Water was added and the solution was extracted with DCM. The organic phase was separated and dried with potassium carbonate to give the title compound (300 mg, 100%) as an oil. 1H NMR (CDCl3) δ 8.75-8.67 (m, 1H), 8.30-8.17 (m, 2H), 7.70-7.55 (m, 2H), 6.93-6.86 (m, 1H), 4.60-4.50 (m, 1H), 3.97-3.65 (m, 4H), 2.90-2.73 (m, 1H), 1.49 (s, 9H), 1.41-1.36 (m, 3H), 0.99-0.87 (m, 3H); MS m/z (M+1) 386.
  • Synthesis of 5-Fluoro-2-methyl-N-(4-[(2R,5S)-2,5-dimethyl-1-]piperazin-1-yl-1-naphthyl}benzenesulfonamide hydrochloride salt—A mixture of tert-butyl (2R,5S)-2,5-dimethyl-1-(4-nitro-1-naphthyl)piperazine-1-carboxylate (300 mg, 0.78 mmol) and 10% Pd on carbon (approx. 0.1 mmol) in methanol (10 ml) was stirred in an hydrogen atmosphere over night. The mixture was filtered through a pad of Celite and the solvent evaporated. The crude aniline was dissolved in DCM (2 ml) and pyridine (0.5 ml) and 5-fluoro-2-methylbenzenesulfonyl chloride (97 μl, 0.67 mmol) was added slowly to the solution. After stirring for 2 hours water was added and the solution was extracted with DCM, the organic phase separated and dried using potassium carbonate. Removal of the solvents in vacuo gave a residue which was dissolved in DCM (3 ml) and treated with concentrated TFA (2 ml) at 0° C. The stirred solution was allowed to reach room temperature after which the solvents where removed in vacuo to give, after purification by reversed phase HPLC and treatment with an excess of 1M HCl in diethyl ether, the title compound (30 mg, 9%) as a solid. 1H NMR (CD3OD) δ 0.85 (d, J=6.07 Hz, 3H) 1.31 (d, J=6.60 Hz, 3H) 2.47 (s, 3H) 2.83 (m, 1H) 3.15 (m, 2H) 3.49 (m, 2H) 3.67 (m, 1H) 7.21 (m, 4H) 7.47 (m, 3H) 7.97 (m, J=7.92 Hz, 1H) 8.44 (d, J=8.44 Hz, 1H) MS m/z 428 (M+1).
    • Example 66 5-Fluoro-2-methyl-N-[4-(1,2,3,6-tetrahydropyridin-4-yl)-1naphthyl]benzenesulfonamide, hydrochloride
  • 5-Fluoro-2-methyl-N-[4-bromo-1-naphthyl]benzenesulfonamide—4-Bromo-1-naphthylamine (0.96 g, 4.33 mmol) was dissolved in DCM (10 mL) before pyridine (1 mL) was added. 5-Fluoro-2-methylbenzenesulfonyl chloride was added neat and the reaction mixture was stirred for 16 h. HCl (1 M, 1 mL) was added to the reaction mixture. The organic phase was filtered through a Silica plug using DCM as eluent. The solvent was evaporated. The obtained crude product was purified by flash-chromatography using MeOH (10%) in pentane, to give the desired product as a tar. To increase the purity, the product was purified by recrystallising (EtOAc/hexanes). This gave the product with a purity of 95%. 1H NMR (270 MHz, CDCl3) δ 8.22 (d, J=8.98 Hz, 1H), 7.92 (d, J=7.92 Hz, 1H), 7.64-7.51 (m, 4H), 7.25-7.23 (m, 1H), 7.21-7.05 (m, 2H), 6.84 (br.s, 1H, N—H), 2.55 (s, 3H); MS (ESI+) for C17 H13 Br F N O2 S m/z 394.263 (M+H)+.
  • MS (ESI−) for C17 H13 Br F N O2 S m/z 394.263 m/z (M−H)−.
  • 5-Fluoro-2-methyl-N-[4-(4-(tert-butoxycarbonyl)-1-hydroxypiperidin-1-yl)-1-naphthyl]benzenesulfonamide—5-Fluoro-2-methyl-N-[4-bromo-1-naphthyl]benzenesulfonamide (0.32 g, 0.812 mmol) was dissolved in dry THF (1 m mL) under N2(g). The reaction flask was cooled to −78° C. before n-BuLi (1.5 mL, 2.4 mmol) was added. The reaction mixture turned green. The reaction mixture was stirred for 5 minutes before a solution of tert-butyl 4-oxopiperidine-1-carboxylate (0.34 g, 1.7 mmol) was added during 10 s. The resulting reaction mixture was stirred and slowly reaching −30° C. after 3 h. Water dissolved in THF was added and the reaction flask was brought to RT. Brine and EtOAc was added. The phases were separated and the organic phase was dried (MgSO4). The obtained crude product was purified by reverse-phase (using the gradient 40→90). This gave 0.17 g of the desired product. Purity 95%. 1H NMR (270 MHz, CDCl3) δ 8.91-8.87 (m, 1H), 7.97-7.93 (m, 1H), 7.63-7.59 (m, 1H), 7.53-7.45 (m, 2H), 7.35 (d, J=8.1 Hz, 1H), 7.28-7.21 (m, 1H), 7.16-7.09 (m, 2H), 7.14 (br.s, 1H, N—H), 6.85 (br.s, 1H, O—H), 4.07-3.98 (m, 2H), 3.41-3.31 (m, 2H), 2.59 (s, 3H), 2.17-2.08 (m, 4H), 1.46 (s, 9H); MS (ESI+) for C27 H31 F N2 O5 S m/z 514.615 (M+H)+. Nothing; MS (ESI−) for C27 H31 F N2 O5 S m/z 514.615 (M−H)− 513.1.
  • The final product was obtained as following: 5-Fluoro-2-methyl-N-[4-(4-(tert-butoxycarbonyl)-1-hydroxypiperidin-1-yl)-1-naphthyl]benzenesulfonamide (0.022 g, 0.043 mmol) was dissolved in formic acid (5 mL) and stirred at RT for 24 h. HPLC showed complex reaction mixture. The reaction mixture was stirred at 100° C. for 4 h. One compound was seen on HPLC. The solvent was evaporated. The crude was transformed to the HCl salt (0.020 g) for the desired product, purity 98%. 1H NMR (270 MHz, CD3OD) δ 8.05-7.97 (m, 2H), 7.55-7.43 (m, 3H), 7.33-7.30 (m, 1H), 7.24-7.17 (m, 3H), 5.97 (br.s, 1H), 3.90-3.88 (m, 2H), 3.56-3.52 (m, 2H), 2.73-2.70 (m, 2H), 2.53 (s, 3H); MS (ESI+) for C22 H21 F N2 O2 S HCl m/z 396.13+35.98 (M+H)+ 397.2; MS (ESI−) C22 H21 F N2 O2 S HCl m/z 396.13+35.98 (M−H)−. 395.3.
    • Synthesis of Example in Table II Example 67 N-[4-(4-Methyl-1-piperazinyl)-2-naphthyl]benzenesulfonamide, hydrochloride
  • To a solution of 1-(4-dimethyl-1-piperazinyl)-3-naphthylamine (0.230 g, 0.951 mmol) and pyridine (537 μL, 6.66 mmol) in DCM (3.0 mL) was added benzenesulfonyl chloride (0.168 g, 0.951 mmol) in DCM (1.01 mL). The reaction mixture was stirred at room temperature for 16 hours and then and then concentrated. The crude intermediate was first purified via column chromatography on silica using CHCl3/CHCl3+10% MeOH+0.4% NH3 and then by preparative HPLC to give the pure base which was converted to its HCl-salt (yield 53% as HCl-salt): 1H NMR (DMSO-d6) δ 10.76 (br s, 1H), 10.50 (s, 1H), 7.98-7.94 (m, 1H), 7.85-7.81 (m, 2H), 7.76-7.73 (m, 1H), 7.60-7.56 (m, 1H), 7.55-7.51 (m, 2H), 7.30 (d, J=1.60 Hz, 1H), 6.99 (d, J=1.88 Hz, 1H), 3.58-3.48 (m, 2H), 3.42-3.25 (m, m, partly obscured by HDO signal, 4H), 3.12-3.00 (m, 2H), 2.86 (s, 3H); MS (posES-FIA) m/z=381.15 24 (M+H)(calc 381.1511)
    • Synthesis of Intermediates and Examples in Table III
  • Figure US20070066598A1-20070322-C00356
    In scheme 2, the following reagents are used: (i) Chlorosulphonic acid, trifluoroacetic acid; (ii) R1—NH2, pyridine (1:4); (iii) diamines of choice and DMSO.
    Intermediate 16
  • 4-Fluoro-naphthalene-1-sulfonyl chloride—An emulsion of 1-fluoronaphthalene (4.00 g, 27 mmol) in TFA (19.5 mL) was stirred on an ice-bath. Chlorosulfonic acid (4.33 mL, 65 mmol) was added dropwise over 30 min. The ice-bath was removed and the reaction slurry stirred at rt for 2 h. Pouring the reaction mixture on 29 mL ice-cold water gave a white precipitate, which was filtered and washed with cold water. After drying, 4.50 g of white solid (67%): 1H NMR (CDCl3, 400 MHz) δ 8.80 (d, 1H), 8.39 (dd, 1H), 8.28 (d, 1H), 7.88 (t, 1H), 7.76 (t, 1H), 7.26 (t, 1H); MS (EI) 244 (M). Purity (HPLC, Hichrom 200×4.6 mm I.D.)>98%.
  • General Method C
  • 4-Fluoro-naphthalene-1-sulfonic acid phenylamide, 4-fluoro-naphthalene-1-sulfonic acid (2-methoxy-phenyl)-amide and 4-fluoro-naphthalene-1-sulfonic acid (3-chloro-phenyl)-amide—Three reaction flasks with 4-fluoro-naphthalene-1-sulfonyl chloride (489 mg, 2.00 mmol) in CH2Cl2 (2 mL) were treated with aniline (224 mg, 2.40 mmol), o-anisidine (296 mg, 2.40 mmol) and m-chloroaniline (306 mg, 2.40 mmol), respectively. Pyridine (0.5 mL) was added and the reaction mixtures stirred for 3 h at rt. Dilution with ethyl acetate (50 mL) followed by washing with 1 M HCl (3×50 mL), drying (Na2SO4) and evaporation gave 586 mg of 4-fluoro-naphthalene-1-sulfonic acid phenylamide (97%), 629 mg of 4-fluoro-naphthalene-1-sulfonic acid (2-methoxy-phenyl)-amide (95%) and 656 mg of and 4-fluoro-naphthalene-1-sulfonic acid (3-chloro-phenyl)-amide (97%) as pink to red solids.
  • Intermediate 17
  • 4-Fluoro-naphthalene-1-sulfonic acid phenylamide: 1H NMR (CDCl3, 400 MHz) δ 8.66 (d, 1H), 8.20 (d, 1H), 8.15 (dd, 1H), 7.74 (t, 1H), 7.66 (t, 1H), 7.03-7.15 (m, 4H), 6.89 (d, 2H), 6.60 (bs, 1H); MS (CI) 299.8 (M−H)+; Purity (HPLC, Hichrom 200×4.6 mm I.D.)>98%.
  • Intermediate 18
  • 4-Fluoro-naphthalene-1-sulfonic acid (2-methoxy-phenyl)-amide: 1H NMR (CDCl3, 400 MHz) δ 8.70 (d, 1H), 8.16 (d, 1H), 8.12 (dd, 1H), 7.71 (t, 1H), 7.63 (t, 1H), 7.42 (d, 1H), 7.16 (bs, H), 7.06 (t, 1H), 6.95 (t, 1H), 6.83 (t, 1H), 6.56 (d, 1H), 3.30 (s, 3H); MS (CI) 330.2 (M−H)+; Purity (HPLC, Hichrom 200×4.6 mm I.D.)>98%.
    • Intermediate 19
  • 4-Fluoro-naphthalene-1-sulfonic acid (3-chloro-phenyl)-amide: 1H NMR (CDCl3, 400 MHz) δ 8.64 (d, 1H), 8.18-8.22 (m, 2H), 7.76 (t, 1H), 7.68 (t, 1H), 7.14 (dd, 1H), 7.06 (t, 1H), 7.02 (d, 1H), 6.97 (t, 1H), 6.78 (d, 1H), 6.67 (bs, 1H); MS (CI) 334.2 (M−H)+; Purity (HPLC, Hichrom 200×4.6 mm I.D.)>98%.
  • General Procedure D
  • General Procedure for Preparation of Compounds According to Examples 68-74:
  • Solutions of 4-fluoro-naphthalene-1-sulfonic acid (2-methoxy-phenyl)-amide (60 mg, 0.20 mmol), 4-fluoro-naphthalene-1-sulfonic acid (2-methoxy-phenyl)-amide (66 mg, 0.20 mmol) and 4-fluoro-naphthalene-1-sulfonic acid (3-chloro-phenyl)-amide (67 mg, 0.20 mmol) in DMSO (2 mL) were treated with piperazine (86 mg, 1.0 mmol), homopiperazine (100 mg, 1.0 mmol) and cis-2,6-dimethyl piperazine (114 mg, 1.0 mmol) in eight reaction combinations. The reaction mixtures were stirred at 100° C. for 3 h, diluted with ethyl acetate (50 mL), washed with sat. Na2CO3 (3×50 mL), dried (Na2SO4) and evaporated with an excess of HCl in ether, giving the hydrochlorides. No purification was necessary for compounds 20-23, while compounds 24-27 were purified with HPLC (YMC combiprep ODS-AQ, 50×20 mm I.D.).
    • Example 68 4-piperazin-1-yl-naphthalene-1-sulfonic acid phenylamide, hydrochloride
  • 86 mg (95% yield) of a white solid. 1H NMR (DMSO, 400 MHz) δ 9.52 (bs, 1H), 8.72 (d, 1H), 8.20 (d, 1H), 8.15 (d, 1H), 7.71 (t, 1H), 7.64 (t, 1H), 7.20 (d, 1H), 7.13 (t, 2H), 7.01 (d, 2H), 6.90 (t, 1H), 3.35 (bs, 4H), 3.30 (bs, 4H). 13C NMR (DMSO, 101 MHz) δ 153.3, 137.7, 137.6, 130.8, 129.2, 129.0, 128.9, 127.9, 126.5, 124.9, 124.5, 123.3, 118.7, 113.0, 49.1, 42.8; MS (CI) 368.0 (M+H)+, 366.4 (M−H)−; Purity (HPLC, Hichrom 200×4.6 mm I.D.) 90%.
    • Example 69 4-piperazin-1-yl-naphthalene-1-sulfonic acid (2-methoxy-phenyl)-amide, hydrochloride
  • 1H NMR (DMSO, 400 MHz) δ 9.59 (s, 1H), 8.76 (d, 1H), 8.23 (d, 1H), 7.93 (d, 1H), 7.64-7.70 (m, 2H), 7.14-7.19 (m, 2H), 7.05 (t, 1H), 6.82 (t, 1H), 6.76 (d, 1H), 3.39 (bs, 4H), 3.29 (bs, 4H), 3.11 (s, 3H). 13C NMR (DMSO, 101 MHz) δ 152.9, 152.5, 130.6, 129.7, 129.3, 127.9, 127.3, 126.5, 126.3, 125.7, 125.3, 125.2, 124.1, 120.2, 112.8, 111.6, 54.9, 49.2, 43.0. MS (CI) 398.2 (M+H)+, 396.2 (M−H)−; Purity (HPLC, Hichrom 200×4.6 mm I.D.) 96%.
    • Example 70 4-(cis-3,5-Dimethyl-piperazin-1-yl)-naphthalene-1-sulfonic acid (2-methoxy-phenyl)-amide, hydrochloride
  • 1H NMR (DMSO, 400 MHz) δ 9.75-9.81 (m, 1H), 9.60 (s, 1H), 9.03-9.12 (m, 1H), 8.76 (d, 1H), 8.23 (d, 1H), 7.93 (d, 1H), 7.64-7.71 (m, 2H), 7.05 (t, 1H), 6.82 (t, 1H), 6.76 (d, 1H), 3.63-3.71 (m, 2H), 3.47 (d, 2H), 3.13 (s, 3H), 2.89 (t, 2H), 1.32 (d, 6H). 13C NMR (DMSO, 101 MHz) δ 152.4, 152.3, 130.6, 129.8, 129.3, 127.9, 127.3, 126.5, 126.3, 125.3, 125.2, 125.1, 124.1, 120.2, 113.0, 111.6, 55.0, 54.9, 51.2, 15.5. MS (CD) 426.2 (M+H)+, 424.4 (M−H)−; Purity (HPLC, Hichrom 200×4.6 mm I.D.) 96%.
    • Example 71 4-(cis-3,5-Dimethyl-piperazin-1-yl)-naphthalene-1-sulfonic acid (3-chloro-phenyl)-amide, hydrochloride
  • 1H NMR (MeOD, 400 MHz) δ 8.80 (d, 1H), 8.32 (d, 1H), 8.27 (d, 1H), 7.79 (t, 1H), 7.73 (t, 1H), 7.28 (d, 1H), 7.12 (t, 1H), 7.07 (t, 1H), 6.95-7.00 (m, 2H); MS (CI) 430.2 (M+H)+, 428.4 (M−H)−; Purity (HPLC, Hichrom 200×4.6 mm I.D.) 98%.
    • Example 72 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (3-chloro-phenyl)-amide, hydrochloride
  • 1H NMR (MeOD, 400 MHz) δ 8.69 (d, 1H), 8.28 (d, 1H), 8.14 (d, 1H), 7.68 (t, 1H), 7.61 (t, 1H), 7.22 (d, 1H), 7.02 (t, 1H), 6.97 (bs, 1H), 6.86-6.89 (m, 2H), 3.57 (bs, 2H), 3.48 (bs, 4H), 3.33-3.37 (m, 2H), 2.20-2.24 (m, 2H); MS (CI) 416.0 (M+H)+, 414.2 (M−H)−; Purity (HPLC, Hichrom 200×4.6 mm I.D.) 88%.
    • Example 73 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid phenylamide, hydrochloride
  • 1H NMR (MeOD, 400 MHz) δ 8.57 (d, 1H), 8.13 (d, 1H), 7.96 (d, 1H), 7.44-7.55 (m, 2H), 7.04 (d, 1H), 6.90 (t, 2H), 6.72-6.82 (m, 3H), 3.39-3.43 (m, 2H), 3.32-3.36 (m, 4H), 3.17-3.21 (m, 2H), 2.05-2.10 (m, 2H); MS (CI) 382.2 (M+H)+, 380.4 (M−H)−; Purity (HPLC, Hichrom 200×4.6 mm I.D.) 94%.
    • Example 74 4-piperazin-1-yl-naphthalene-1-sulfonic acid (3-chloro-phenyl)-amide, hydrochloride
  • 1H NMR (MeOD, 400 MHz) δ 8.69 (d, 1H), 8.23 (d, 1H), 8.16 (d, 1H), 7.68 (t, 1H), 7.62 (t, 1H), 7.17 (d, 1H), 7.02 (t, 1H), 6.97 (t, 1H), 6.85-6.89 (m, 2H), 3.46-3.50 (m, 4H), 3.33 (bs, 4H); MS (CI) 402.2 (M+H)+, 400.0 (M−H)−; Purity (HPLC, Hichrom 200×4.6 mm I.D.) 98%.
    Figure US20070066598A1-20070322-C00357
  • 4-Fluoro-naphtalene-1-sulfonylchloride was dissolved in DCM. The amine (1.2 eq) was added followed by pyridine (3 eq). The mixture was stirred for 2 h at ambient temperature, diluted with DCM and washed 2 times with HCl (1M). The organic layer was filtered through a silica plug to afford the sulfonylamide.
    Figure US20070066598A1-20070322-C00358
  • The sulfonamide and the amine (5 eq) were dissolved in DMSO and stirred at 100° C. overnight. The DMSO solution was added dropwise to water to give a precipitate. After centrifugation, the solvent was decanted and the procedure was repeated. The residue was dissolved in MeOH and converted to HCl salt by adding HCl in ether (2 M) and evaporation.
    Figure US20070066598A1-20070322-C00359
  • To a solution of the sulfonamide in acetone, K2CO3 (3 eq) was added followed by MeI (1.2 eq). The mixture was stirred overnight, filtered through a short silica plug and evaporated to give the methylated sulfonamide.
    • Example 75 4-piperazin-1-yl-naphthalene-1-sulfonic acid (2-methylsulfanyl-phenyl)-amide, hydrochloride
  • N-(2-methylsulfanyl-phenyl)-4-fluorosulphonamide—Method E; Yield (84%)
  • 1H NMR (CDCl3) δ 8.74-8.70 (m, 1H), 8.29-8.24 (m, 1H), 8.17-8.14 (m, 1H ), 8.01 (br. s, 1H), 7.75-7.60 (m, 2H), 7.50-7.47 (m, 1H), 7.29-7.25 (m, 1H), 7.18-7.10 (m, 2H), 6.98-6.92 (m, 1H), 2.02 (s, 3H); MS (ESI+) for C17 H14 F N O2 S2 m/z 348 (M+H)+.
  • The final product was prepared according to Method F; Yield 0.77 g (53%)
  • 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 9.42 (br. s, 2H), 8.69-8.66 (m, 1H), 8.21-8.18 (m, 2H), 7.76-7.62 (m, 2H), 7.42-7.21 (m, 5H), 3.421-3.30 (m, 8H); MS (ESI+) for C21 H23 N3 O2 S2 m/z 414.2 (M+H)+.
    • Example 76 4-piperazin-1-yl-naphthalene-1-sulfonic acid methyl-naphthalen-1-yl-amide, hydrochloride
  • N-(1-naphthyl)-4-fluoronaqphthalensulphonamide—Method E; Yield (83%)
  • 1H NMR (CDCl3) δ 8.77-8.74 (m, 1H), 8.18-8.05 (m, 2H), 7.75-7.61 (m, 5H), 7.41-7.35 (m, 1H), 7.30-7.26 (m, 1H), 7.14-7.00 (m, 2H), 6.93 (br. s, 1H); MS (ESI+) for C20 H14 F N O2 S m/z 352 (M+H)+.
  • 4-Fluoro-1-naphthalene-1-sulfonic acid methyl-naphthalen-1-yl-amide—Methylation according to Method G, Yield (97%)
  • 1H NMR (DMSO-d6) δ 8.38-8.35 (m, 1H), 8.23-8.20 (m, 1H), 8.16 (dd, J=8.4, 5.5 Hz, 1H), 7.99-7.91 (m, 3H), 7.79-7.73 (m, 1H), 7.66-7.46 (m, 4H), 7.37-7.31 (m, 1H), 7.03 (dd, J=7.5, 1.2 Hz, 1H), 3.29 (s, 3H)
  • The final product was prepared according to Method F; Yield (36%)
  • 1H NMR (DMSO-d6) δ 9.33 (br. s, 1H), 8.40 (d, J=8.4 Hz, 1H), 8.25 (d, J=7.9 Hz, 1H), 8.09 (d, J=8.2 Hz, 1H), 7.98-7.91 (m, 3H), 7.68-7.62 (m, 1H), 7.58-7.43 (m, 3H), 7.40-7.34 (m, 1H), 7.24 (d, J=8.2 Hz, 1H), 7.13-7.10 (m, 1H), 3.44-3.39 (m, 4H), 3.29 (br. s, 4H), 3.25 (s, 3H); MS (ESI+) for C25 H25 N3 O2 S m/z 432 (M+H)+.
    • Example 77 4-piperazin-1-yl-naphthalene-1-sulfonic acid (2,3-dihydro-benzo[1,4]dioxin-6-yl)-methyl-amide, hydrochloride
  • N-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-4-sulphonamide—Method E; Yield (96%). 1H NMR (CDCl3) δ 8.66-8.63 (m, 1H), 8.22-8.09 (m, 2H), 7.77-7.63 (m, 2H), 7.10 (dd, J=8.2, 9.5 Hz, 1H), 6.58 (d, J=8.5 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.30 (dd, J=2.6, 8.7 Hz, 1H), 4.14 (s, 4H); MS (ESI+) for C18 H14 F N O4 S m/z 360 (M+H)+.
  • 4-Fluoro-Nl-naphthalene-1-sulfonic acid-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methyl-amide—Methylation according to Method G; Yield (100%). 1H NMR (DMSO-d6) δ 8.19-8.13 (m, 2H), 8.09 (dd, J=8.4, 5.5 Hz, 1H), 7.75-7.70 (m, 1H), 7.64-7.58 (m, 1H), 7.50 (dd, J=10.0, 8.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 6.55 (d, J=2.6 Hz, 1H), 6.51-6.47 (m, 1H), 4.20-4.15 (m, 4H), 3.10 (s, 3H)
  • The final product was prepared according to Method F; the product precipitates in MeOH; Yield (57%): 1H NMR (DMSO-d6) δ 9.29 (br. s, 2H), 8.23-8.16 (m, 2H), 8.01 (d, J=8.2 Hz, 1H), 7.64-7.49 (m, 2H), 7.25 (d, J=8.2 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 6.56-6.48 (m, 2H), 4.21-4.16 (m, 4H), 3.38-3.31 (m, 4H), 3.08 (s, 3H); MS (ESI+) for C23 H25 N3 O4 S m/z 440 (M+H)+.
    • Example 78 4-piperazin-1-yl-naphthalene-1-sulfonic acid (2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide, hydrochloride
  • The final product was prepared according to Method F; Yield (36%); 1H NMR (270 MHz, DMSO-D6) δ ppm 3.32 (m, 8H) 4.08 (m, 4H) 6.45 (m, 2H) 6.61 (d, J=8.44 Hz, 1H) 7.20 (d, J=8.18 Hz, 1H) 7.67 (m, 2H) 8.07 (d, J=7.92 Hz, 1H) 8.21 (d, J=8.71 Hz, 1H) 8.67 (d, J=8.44 Hz, 1H) 9.22 (s, 1H) 10.32 (s, 1H); MS (ESI+) for C22 H23 N3 O4 S m/z 426.2 (M+H)+.
    • Example 79 4-piperazin-1-yl-naphthalene-1-sulfonic acid methyl-(2-methylsulfanyl-phenyl)-amide, hydrochloride
  • 4-Fluoro-N-methyl-N-(2-methylsulfanyl-phenyl)-amide—Methylation according to Method G; Yield (97%); 1H NMR (DMSO-d6) δ 8.52-8.49 (m, 1H), 8.22-8.19 (m, 1H), 8.16 (dd, J=8.4, 5.5 Hz, 1H), 7.79-7.66 (m, 2H), 7.52 (dd, J=10.0, 8.4 Hz, 1H), 7.37-7.24 (m, 2H), 7.06-7.00 (m, 1H), 6.88 (dd, J=7.9, 1.3 Hz, 1H), 3.10 (s, 3H), 2.28 (s, 3H).
  • The final product was prepared according to Method F; Trituration with MeCN; Yield (65%) 1H NMR (DMSO-d6) δ 9.27 (br. s, 2H), 8.54-8.50 (m, 1H), 8.27-8.23 (m, 1H), 8.09 (d, J=8.2 Hz, 1H), 7.67-7.56 (m, 2H), 7.38-7.25 (m, 3H), 7.07-6.92 (m, 2H), 3.41-3.33 (m, 8H), 3.06 (s, 3H), 2.30 (s, 3H); MS (ESI+) for C22 H25 N3 O2 S2 m/z 428 (M+H)+.
    • Example 80 4-piperazin-1-yl-naphthalene-1-sulfonic acid methyl-(3-trifluoromethyl-phenyl)-amide, hydochloride
  • N-(3-trifluoromethylphenyl)-4-fluoronaphthalenesulphonamide—Method E; Yield (90%). 1H NMR (CDCl3) δ 8.65-8.62 (m, 1H), 8.23-8.18 (m, 2H), 7.78-7.65 (m, 2H), 7.31-7.17 (m, 2H), 7.16-7.08 (m, 3H); MS (ESI+) for C17 H11 F4 N O2 S m/z 370 (M+H)+. Methylation according to Method F; Yield (100%); 1H NMR (DMSO-d6) δ 8.19-8.11 (m, 2H), 8.01-7.98 (m, 1H), 7.73-7.62 (m, 2H), 7.57-7.44 (m, 4H), 7.35 (br. s, 1H), 3.21 (s, 3H).
  • The final product was prepared according to Method F; Trituration with MeCN; Yield 0.07 g (40%). 1H NMR (DMSO-d6) δ 9.35 (br. s, 2H), 8.21 (d, J=8.2 Hz, 1H), 8.06-8.02 (m, 2H), 7.63-7.42 (m, 5H), 7.28-7.24 (m, 2H), 3.39 (br. s, 8H), 3.21 (s, 3H), 2.06 (s, 3H); MS (ESI+) for C22 H22 F3 N3 O2 S m/z 450 (M+H)+.
    • Example 81 4-piperazin-1-yl-naphthalene-1-sulfonic acid (3-chloro-4-methyl-phenyl)-methyl-amide, hydrochloride
  • N-(3-Chloro-4-methylphenyl)-4-fluoronaphthalenesulphonamide—Method E; Yield (88%). 1H NMR (DMSO-d6) δ 10.86 (br. s, 1H), 8.74-8.71 (m, 1H), 8.22 (dd, J=8.3, 5.4 Hz, 1H), 8.19-8.16 (m, 1H), 7.89-7.75 (m, 2H), 7.47 (dd, J=10.0, 8.4 Hz, 1H), 7.12-7.09 (m, 1H), 7.00 (d, J=2.2 Hz, 1H), 6.86 (dd, J=8.3, 2.2 Hz, 1H), 2.11 (s, 3H);
  • 4-Fluoro-1-naphthalene-1-sulfonic acid (3-chloro-4-methyl-phenyl)-methyl-amide—Methylation according to Method G; Yield (100%). 1H NMR (DMSO-d6) δ 8.20-8.07 (m, 3H), 7.76-7.70 (m, 1H), 7.62-7.48 (m, 2H), 7.27-7.24 (m, 1H), 7.13 (d, J=2.4 Hz, 1H), 6.99 (dd, J=8.2, 2.4 Hz, 1H), 3.15 (s, 3H), 2.28 (s, 3H);
  • The final product was prepared according to Method F; Yield (28%). 1H NMR (DMSO-d6) δ 9.29 (br. s, 2H), 8.24-8.15 (m, 2H), 8.01 (d, J=8.2 Hz, 1H), 7.65-7.47 (m, 2H), 7.26 (dd, J=8.3, 4.6 Hz, 2H), 7.09-7.08 1H), 7.03-6.99 (m, 1H), 3.38-3.33 (m, 8H), 3.14 (s, 3H), 2.27 (s, 3H); MS (ESI+) for C22 H24 Cl N3 O2 S m/z 430 (M+H)+.
    • Example 82 4-piperazin-1-yl-naphthalene-1-sulfonic acid (3-ethyl-phenyl)-methyl-amide, hydrochloride
  • N-(3-ethylphenyl)-4-fluoronaphthalenesulphonamide—Method E; Yield (85%). 1H NMR (CDCl3) δ 8.66 (d, J=8.4 Hz, 1H), 8.20-8.14 (m, 2H), 7.75-7.62 (m, 2H), 7.10 (dd, J=9.5, 8.4 Hz, 1H), 7.02 (t, J=7.8 Hz, 1H), 6.88-6.85 (m, 1H), 6.72-6.68 (m, 3H), 2.45 (q, J=7.7 Hz, 2H), 1.03 (t, J=7.7 Hz, 3H)
  • 4-Fluoro-1-yl-naphthalene-1-sulfonic acid (3-ethyl-phenyl)-methyl-amide—Methylation according to Method G; Yield (100%); 1H NMR (DMSO-d6) δ 8.18-8.06 (m, 3 H), 7.72-7.66 (m, 1H), 7.54-7.48 (m, 2H), 7.21-7.16 (m, 1H), 7.10-7.08 (m, 1H), 6.96-6.92 (m, 1H), 6.81-6.80 (m, 1H), 3.16 (s, 3H), 2.41 (q, J=7.5 Hz, 2H), 0.93 (t, J=7.5 Hz, 3H)
  • The final product was prepared according to Method f; Trituration with MeCN; Yield (49%); 1H NMR (DMSO-d6) δ 9.21 (br. s, 2H), 8.21 (d, J=8.4 Hz, 1H), 8.13 (d, J=8.7 Hz, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.62-7.57 (m, 1H), 7.47-7.41 (m, 1H), 7.27-7.17 (m, 2H), 7.10-6.95 (m, 2H), 6.8 (br. s, 1H), 3.40-3.29 (m, 8H), 3.15 (s, 3H), 2.43 (q, J=7.6 Hz, 2H), 0.95 (t, J=7.6 Hz, 2H); MS (ESI+) for C23 H27 N3 O2 S m/z 410 (M+H)+.
    • Example 83 4-(3,5-Dimethyl-piperazin-1-yl)-naphthalene-1-sulfonic acid (2-isopropyl-phenyl)-amide, hydrochloride
  • The final product was prepared according to Method F; Yield (35%); 1H NMR (270 MHz, DMSO-D6) δ ppm 0.64 (d, J=6.86 Hz, 6H) 1.30 (d, J=6.60 Hz, 6H) 2.92 (m, 3H) 3.53 (m, 4H) 6.86 (d, J=7.65 Hz, 1H) 6.98 (m, 1H) 7.13 (m, 3H) 7.67 (m, 2H) 7.86 (d, J=7.92 Hz, 1H) 8.24 (m, 1H) 8.74 (m, 1H) 9.08 (m, 1H) 9.79 (m, 2H); MS (ESI+) for C25 H31 N3 O2 S m/z 438.01 (M+H)+.
    • Example 84 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (2-isopropyl-phenyl)-amide, hydrochloride
  • N-(2 isopropylphenyl)-4-fluoronaphthalensulphonamide—Method E; Yield (87%) 1H NMR (CDCl3) δ 8.67-8.64 (m, 1H), 8.22-8.18 (m, 1H), 8.12 (dd, J=8.3, 5.4 Hz, 1H), 7.71-7.62 (m, 2H), 7.15-6.97 (m, 5H), 2.84-2.73 (m, 1H), 0.85 (s, 3H), 0.82 (s, 3H)
  • The final product was prepared according to Method F; Yield (22%). 1H NMR (DMSO-d6) δ 9.83 (s, 1H), 9.37 (br. s, 2H), 8.74-8.70 (m, 1H), 8.27.8.24 (m, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.68-7.64 (m, 2H), 7.17-7.11 (m, 3H), 7.01-6.87 (m, 2H), 3.82 (br. s, 6H), 3.51-3.50 (m, 2H), 3.38-3.28 (m, 2H), 3.02-2.93 (m, 1H), 0.65 (s, 3H), 0.63 (s, 3H); MS (ESI+) for C24 H29 N3 O2 S m/z 424.02 (M+H)+.
    • Example 85 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (3-ethyl-phenyl)-amide, hydrochloride
  • The final product was prepared according to Method F; Yield (22%); 1H NMR (DMSO-d6) δ 10.53 (s, 1H), 9.24 (br. s, 2H), 8.68 (d, J=8.2 Hz, 1H), 8.20 (d, J=7.9 Hz, 1H), 8.14 (d, J=8.2 Hz, 1H), 7.72-7.60 (m, 2H), 7.22 (d, J=8.2 Hz, 1H), 7.01 (t, J=7.8 Hz, 1H), 6.83-6.72 (m, 3H), 3.33 (br. s, 6H), 2.39 (q, J=7.7 Hz, 2H), 2.12 (br. s, 2H), is 0.98 (t, J=7.5 Hz, 3H); MS (ESI+) for C23 H27 N3 O2 S m/z 410.03 (M+H)+.
    • Example 86 N-(2-Fluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide, hydrochloride
  • N-(2-Fluorophenyl)-4-fluoronaphthalensulphonamide—Method E; Yield (88%); 1H NMR (DMSO-d6) δ 10.41 (br. s, 1H), 8.76-8.69 (m, 1H), 8.20-8.17 (m, 1H), 8.08 (dd, J=8.0, 5.5 Hz, 1H), 7.82-7.75 (m, 2H), 7.41 (dd, J=10.0, 8.3 Hz, 1H), 7.20-7.01 (m, 4H); MS (ESI−) for C16 H11 F2 N O2 S m/z 318.2 (M−H)−.
  • The final product was prepared according to Method F; Yield (22%); 1H NMR (DMSO-d6) δ 10.41 (s, 1H), 9.35 (m, 2H), 8.72-8.68 (m, 1H), 8.24-8.20 (m, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.72-7.62 (m, 2H), 7.22-7.00 (m, 5H), 4.05 (d, J=1.3 Hz, 4H), 3.36 (s, 4H); MS (ESI+) for C20 H20 F N3 O2 S m/z 386 (M+H)+.
    • Example 87 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (3-trifluoromethyl-phenyl)-amide, hydrochloride
  • The final product was prepared according to Method F; Yield (21%); 1H NMR (DMSO-d6) δ 11.1 (s, 1H), 9.32 (br. s, 2H), 8.65 (d, J=8.2 Hz, 1H), 8.19 (t, J=8.6 Hz, 2H), 7.75-7.62 (m, 2H), 7.42-7.22 (m, 4H), 3.88 (br. s, 6H), 3.55-3.53 (m, 2H), 2.11 (m, 2H); MS (ESI+) for C22 H22 F3 N3 O2 S m/z 449.95 (M+H)+.
    • Example 88 N-(2,4-difluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide, hydrochloride
  • N-(2,4-di-Fluorophenyl)-4-fluoronaphthalensulphonamide—Method E; Yield (81%); 1H NMR (DMSO-d6) δ 10.44 (s, 1H), 8.73-8.69 (m, 1H), 8.21-8.18 (m, 1H), 8.02 (dd, J=8.4, 5.5 Hz, 1H), 7.85-7.76(m, 2H), 7.41 (dd, J=10.2, 8.3 Hz, 1H), 7.22-7.11 (m, 2H), 7.01-6.93 (m, 1H); MS (ESI−) for C16 H10 F3 N O2 S m/z 336.2 (M−H)−.
  • The final product was prepared according to Method F; Yield (27%); 1H NMR (DMSO-d6) δ 10.33 (s, 1H), 9.28 (br. s, 2H), 8.68-8.65 (m, 1H), 8.25-8.21 (m, 1H), 8.0 (d, J=8.2 Hz, 1H), 7.73-7.62 (m, 2H), 7.21-7.08 (m, 3H), 7.0-6.93 (m, 1H), 3.29 (br. s, 4H); MS (ESI+) for C20 H19 F2 N3 O2 S m/z 403.94 (M+H)+.
    • Example 89 4-piperazin-1-yl-naphthalene-1-sulfonic acid (2-trifluoromethoxy-phenyl)-amide, hydrochloride
  • N-(2-tri-Fluoromethoxyphenyl)-4-fluoronephthylsulphonamide—Method E; Yield (43%); 1H NMR (DMSO-d6) δ 10.58 (s, 1H), 8.80-8.76 (m, 1H), 8.20-8.17 (m, 1H), 8.08 (dd, J=8.3, 5.4 Hz, 1H), 7.84-7.74 (m, 2H), 7.42 (dd, J=10.2, 8.3 Hz, 1H), 7.32-7.18 (m, 4H).
  • The final product was prepared according to Method F; Yield (48%); 1H NMR (DMSO-d6) δ 10.49 (s, 1H), 9.27 (br. s, 2H), 8.75-8.72 (m, 1H), 8.24-8.21 (m, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.71-7.62 (m, 2H), 7.32-7.17 (m, 5H), 3.38 (br. s, 4H), 3.28 (br. s, 4H); S (ESI+) for C21 H20 F3 N3 O3 S m/z 451.9 (M+H)+.
    • Example 90 4-piperazin-1-yl-naphthalene-1-sulfonic acid (3-phenoxy-phenyl)-amide, hydrochloride
  • N-(3-phenyloxyphenyl)-4-fluoronephthylsulphonamide—Method E; Yield 0.64 g (100%); 1H NMR (DMSO-d6) δ 10.80 (br. s, 1H), 8.71-8.68 (m, 1H), 8.19-8.16 (m, 1H), 8.10 (dd, J=8.3, 5.4 Hz, 1H), 7.85-7.74 (m, 2H), 7.45 (dd, J=10.2, 8.3 Hz, 1H), 7.38-7.31 (m, 2′ H), 7.18-7.10 (m, 2H), 6.82-6.73 (m, 3H), 6.58-6.55 (m, 2H); MS (ESI−) for C22 H16 F N O3 S m/z 392.2 (M−H)−.
  • The final product was prepared according to Method F; Yield 0.08 g (31%); 1H NMR (DMSO-d6) δ 10.76 (s, 1H), 9.37 (br. s, 2H), 8.67-8.63 (m, 1H), 8.23-8.20 (m, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.73-7.62 (m, 2H), 7.41-7.35 (m, 2H), 7.20-7.09 (m, 3H), 6.84-6.73 (m, 3H), 6.60-6.52 (m, 2H), 3.47-3.37 (m, 8H); MS (ESI+) for C26 H25 N3 O3 S m/z 459.95 (M+H)+.
    • Example 91 4-piperazin-1-yl-naphthalene-1-sulfonic acid (3-trifluoromethoxy-phenyl)-amide, hydrochloride
  • N-(3-Trifluoromethoxyphenyl)-4-fluoronaphthalensulphonamide—Method E; Yield (35%); 1H NMR (DMSO-d6) δ 11.01 (br.s, 1H), 8.74-8.71 (m, 1H), 8.26 (dd, J=8.3, 5.3 Hz, 1H), 8.16 (d, J=9.0 Hz, 1H), 7.86-7.82 (m, 1H), 7.78-7.74 (m, 1H), 7.46 (dd, J=10.0, 8.5 Hz, 1H), 7.27 (t, J=8.3 Hz, 1H), 7.02-6.90 (m, 3H); MS (ESI−) for C17 H11 F4 N O3 S m/z 383.8 (M−H)−.
  • The final product was prepared according to Method F; Yield (35%); 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 9.63 (br. s, 1H), 9.31 (br. s, 1H), 8.66 (d, J=8.4 Hz, 1H), 8.21-8.18 (m, 2H), 7.75-7.62 (mil, 2H), 7.29-7.21 (m, 2H), 7.03-6.86 (m, 3H), 3.32-3.28 (m, 8H); MS (ESI+) for C26 H25 N3 O3 S m/z 451.94 (M+H)+.
    • Example 92 4-piperazin-1-yl-naphthalene-1-sulfonic acid (2-chloro-5-methyl-phenyl)-amide, hydrochloride
  • The final product was prepared according to method F: 1H NMR ((DMSO-d6) δ; 10.10 (brs, 1H), 9.25 (brs, 2H), 8.76-8.66 (m, 1H), 8.27-8.17 (m, 1H), 8.00-7.94 (m, 1H), 7.71-7.60 (m, 2H), 7.25-7.11 (m, 2H), 7.02 (s, 1H), 6.99-6.92 (m, 1H), 3.40-3.20 (m, obscured by solvent signal) 2.17 (s, 3H), MS (posESI) m/z=416 (M+H).
    • Example 93 4-piperazin-1-yl-naphthalene-1-sulfonic acid (4-isopropyl-phenyl)-amide, hydrochloride
  • The final product was prepared according to method F: 1H NMR ((DMSO-d6) δ; 10.52 (s, 1H), 9.26 (brs, 2H), 8.74-8.66 (m, 1H), 8.27-8.11 (m, 2H), 7.76-7.60 (m, 2H), 7.26.7.17 (m, 1H), 7.06-6.89 (m, 4H), 3.40-3.20 (m, obscured by solvent signal), 2.77-2.61 (m, 1H), 1.05 (d, J=6.87 Hz, 6H), MS (posESI) m/z=410 (M+H).
    • Example 94 N-(3,5-Difluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide, hydrochloride
  • The final product was prepared according to Method F using the crude N-(3,5-difluorophenyl)-4-fluoronaphthalene-1-sulfonamide (50 mg, 0.15 mmol) afforded the title compound (20 mg, 31%) as a yellow solid. 1H NMR (DMSO) δ 11.33 (s, 1H), 9.35 (br s, 2H), 8.69 (m, 1H), 8.30-8.18 (m, 2H), 7.80-7.61 (m, 2H), 7.30-7.21 (m, 1H), 6.84-6.62 (m, 3H), 3.45-3.24 (m, 8H); MS m/z (M+1) 404.
    • Example 95 1-[4-(3,4-Dihydroquinolin-1(2H)-ylsulfonyl)-1-naphthyl]piperazine, hydrochloride
  • 4-Fluoronaphthalene-1-sulfonyl chloride—To a stirred solution of 1-fluoronaphthalene (8.0 g, 55 mmol) in concentrated trifluoroacetic acid (40 ml), chlorosulfonic acid was added slowly (15 min) at 0° C. The mixture was stirred at room temperature for an additional 2 hours and then added slowly onto a stirred ice slurry. The formed precipitate filtered off, washed with cold water and dried in vacuo to give the title compound (7.3 g) as a white solid.
  • 1-[(4-Fluoro-1-naphthyl)sulfonyl]-1,2,3,4-tetrahydroquinoline—Method E: To a stirred solution of 4-fluoronaphthalene-1-sulfonyl chloride (200 mg, 0.82 mmol) in DCM (1 ml) was added 1,2,3,4-tetrahydroquinoline (123 μl, 0.98 mmol) followed by pyridine (0.25 ml). The reaction mixture was stirred over night, diluted with DCM and washed with 1M HCl (3×3 ml). Subsequent drying of the organic phase using MgSO4, and removal of the solvents in vacuo afforded the title compound (280 mg, 100%) as a white solid. 1H NMR (CDCl3) δ 8.24-8.10 (m, 3H), 7.68-7.62 (m, 1H), 7.58-7.51 (m, 1H), 7.42-7.34 (m, 1H), 7.23-7.04 (m, 3H), 6.96-6.89 (m, 1H), 3.84-3.74 (m, 2H), 2.39-2.28 (m, 2H), 1.63-1.49 (m, 1H); MS m/z (M+1) 342.
  • The final product was prepared according to Method F: A stirred solution of 1-[(4-fluoro-1-naphthyl)sulfonyl]-1,2,3,4-tetrahydroquinoline (50 mg, 0.15 mmol) and piperazine (80 mg, 0.9 mmol) in DMSO (1 ml) was heated at 95° C. over night. The reaction mixture was allowed to reach room temperature and was subsequently added dropwise into water. The formed solid was isolated, re-dissolved in MeOH and treated with an excess of 1M HCl in diethyl ether. Removal of the solvents in vacuo afforded the title compound (60 mg, 83%) as a white solid. 1H NMR (DMSO) δ 9.17 (br s, 2H), 8.23-8.06 (m, 3H), 7.61-7.55 (m, 1H), 7.48-7.38 (m, 2H), 7.29-7.23 (m, 1H), 7.19-7.12 (m, 1H), 7.09-6.98 (m, 2H), 3.78-3.71 (m, 2H), 3.44-3.30 (m, 8H), 2.42-2.32 (m, 2H), 1.57-1.48 (m, 2H); MS m/z (M+1) 408.
    • Example 96 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (3-nitro-phenyl)-amide, hydrochloride
  • The final product was prepared according to Method F: 1H NMR ((DMSO-d6) δ; 8.68-8.63 (m, 1H), 8.27-8.13 (m, 2H), 7.78 (s, 1H), 7.72-7.53 (m, 3H), 7.35-7.16 (m, 3H), 3.55-3.40 (m, 6H), 3.34-3.27 (m, obscured in part by solvent signal), 2.22-2.13 (m, 2H), MS (posESI) m/z=427 (M+H).
    • Example 97 4-piperazin-1-yl-naphthalene-1-sulfonic acid (3-nitro-phenyl)-amide, hydrochloride
  • The final product was prepared according to Method F: 1H NMR ((DMSO-d6) δ; 8.68-8.60 (m, 1H), 8.24-8.13 (m, 2H), 7.77 (s, 1H), 7.71-7.53 (m, 3H), 7.30-7.20 (m, 2H), 7.16-7.10 (m, 1H), 3.45-3.40 (m, 4H), 3.31-3.20 (m, 4H), MS (posESI) m/z=413 (M+H).
    • Example 98 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (3-nitro-phenyl)-methyl-amide, hydrochloride
  • The final product was prepared according to Method F: 1H NMR (DMSO-d6) δ; 8.21 (d, J=8.47 Hz, 1H), 8.12 (d, J=8.79 Hz, 1H), 8.01-7.95 (m, 2H), 7.64 (s, 1H), 7.54-7.39 (m, 3H), 7.34-7.28 (m, 1H), 7.23-7.18 (m, 1H), 3.60-3.30 (m, 8H), 3.17 (s, 3H), 2.24-2.16 (m, 2H), MS (posESI) m/z=441 (M+H).
    • Example 99 N-(4-Methylphenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide, hydrochloride
  • 4-Fluoro-N-(4-methylphenyl)naphthalene-1-sulfonamide—Method E: Use of 4-methylaniline afforded the title compound (500 mg, 95%) as an oil by the application of the general procedure A described above. 1H NMR (CDCl3) δ 8.82-8.75 (m, 1H), 8.22-8.13 (m, 2H), 7.73-7.58 (m, 2H), 7.44 (s, 1H), 7.11-7.02 (m, 1H), 6.93-6.80 (m, 4H), 2.17 (s, 3H); MS m/z (M+1) 316.
  • The final product was prepared according to Method E: Use of 4-fluoro-N-(4-methylphenyl)naphthalene-1-sulfonamide afforded the title compound (200 mg, 30%), after washing with methanol, as a yellow solid. 1H NMR (DMSO) δ 10.46 (s, 1H), 9.30 (br s, 2H), 8.76-8.65 (m, 1H), 8.25-8.06 (m, 2H), 7.78-7.59 (m, 2H), 7.25-7.14 (m, 1H), 6.98-6.83 (4H), 3.41-3.22 (m, 8H), 2.09 (s, 3H); MS m/z (M+1) 382.
    • Example 100 N-(3-Chloro-4-methylphenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide, hydrochloride
  • The final product was prepared according to Method E: yield 100%, purity 93% 1H NMR (500 MHz, DMSO-D6) δ ppm 2.26 (s, 3H), 2.74 (m, 4H), 3.54 (m, 4H), 7.23 (m, 4H), 7.83 (m, 2H), 8.31 (m, 2H), 8.81 (s, 1H), 9.11 (s, 1H, N—H), 10.86 (s, 1H, N—H); MS (ESI+) for C21 H22 Cl N3 O2 S HCl m/z (M+H)+. 416.1; MS (ESI−) for C21 H22 Cl N3 O2 S HCl m/z (M−H)−. 414.1.
    • Example 101 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (2,3-dimethyl-phenyl)-methyl-amide, hydrochloride
  • The final product was prepared according to Method F: 1H NMR (DMSO-d6) δ; 8.51-8.41 (m, 1H), 8.39-8.30 (m, 1H), 8.11-7.99 (m, 1H), 7.68-7.56 (m, 1H), 7.54-7.42 (m, 1H), 7.35-7.23 (m, 1H), 7.13-7.02 (M, 1H), 6.90-6.78 (m, 1H), 6.62-6.47 (m, 1H), 3.70-3.40 (m, 8H), 3.17 (s, 3H), 2.25 (s, 3H), 2.10 (s, 3H), MS (posESI) m/z=424 (M+H).
    • Example 102 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (4-isopropyl-phenyl)-amide, hydrochloride
  • The final product was prepared according to Method F: 1H NMR ((DMSO-d6) δ; 8.74 (d, J=8.16 Hz, 1H), 8.33 (d, J=8.48 Hz, 1H), 8.15-8.10 (m, 1H), 7.72-7.62 (m, 2H), 7.25-7.21 (m, 1H), 6.99-6.86 (m, 4H), 3.62-3.57 (m, 2H), 3.56-3.50 (m, 4H), 3.41-3.35 (m, 2H), 2.79-2.69 (m, 1H), 2.32-2.22 (m, 2H), 1.14-1.10 (m, 6H), MS (posESI) m/z=424 (M+H).
    • Example 103 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (4-isopropyl-phenyl)-methyl-amide, hydrochloride
  • The final product was prepared according to Method F: 1H NMR (DMSO-d6) δ; 8.13-8.07 (m, 1H), 8.01-7.93 (m, 1H), 7.51-7.41 (m, 1H), 7.38-7.15 (m, 2H), 7.00-6.95 (m, 2H), 6.89-6.85 (m, 2H), 3.59-3.28 (m, 8H), 3.09 (s, 3H), 2.81-2.71 (m, 1H), 1.11 (d, J=6.60 Hz, 6H), MS (posESI) m/z=438 (M+H).
    • Example 104 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (2,4-dimethyl-phenyl)-amide, hydrochloride
  • The final product was prepared according to Method F: 1H NMR ((DMSO-d6) δ; 8.70-8.61 (m, 1H), 8.30-8.20 (m, 1H), 7.91-7.78 (m, 1H), 7.60-7.51 (m, 2H), 7.14-7.06 (m, 1H), 6.76-6.59 (m, 3H), 3.64-3.40 (m, 6H), 3.35-3.30 (m, obscured in part by solvent signal), 2.24-2.13 (m, 2H), 2.07 (s, 3H), 1.76 (s, 3H), MS (posESI) m/z=410 (M+H).
    • Example 105 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (2-chloro-5-methyl-phenyl)-amide, hydrochloride
  • The final product was prepared according to Method F: 1H NMR ((DMSO-d6) δ; 8.67-8.61 (m, 1H), 8.24-8.19 (m, 1H), 7.95 (d, J=8.16 Hz, 1H), 7.57-7.56 (m, 2H), 7.21-7.18 (m, 1H), 7.12 (d, J=8.17 Hz, 1H), 6.89 (d, J=8.17 Hz, 1H), 6.78-6.75 (m, 1H), 3.52-3.47 8 m, 2H), 3.45-3.40 (m, 4H), 3.31-3.26 (m, 2H), 2.20-2.10 (m, 2H), 2.14 (s, 3H), MS (posESI) m/z=430 (M+H).
    • Example 106 4-piperazin-1-yl-naphthalene-1-sulfonic acid (2,5-dimethoxy-phenyl)-amide, hydrochloride
  • The final product was prepared according to Method F: 1H NMR ((DMSO-d6) δ; 8.80-8.72 (m, 1H), 8.27-8.19 (m, 1H), 7.98 (d, J=8.18 Hz, 1H), 7.74-7.60 (m, 2H), 7.17 (d, J=7.91. Hz, 1H), 6.76-6.75 (m, 2H), 6.62-6.55 (m, 1H), 3.60 (s, 3H), 3.40-3.20 (m, obscured by solvent signal), 3.12 (s, 3H), MS (posESI) m/z=428 (M+H).
    • Example 107 4-piperazin-1-yl-naphthalene-1-sulfonic acid (3-acetyl-phenyl)-amide; hydrochloride
  • The final product was prepared according to Method F: 1H NMR ((DMSO-d6) δ; 8.79-8.72 (m, 1H), 8.29-8.21 (m, 2H), 7.75-7.62 (m, 2H), 7.59-7.52 (m, 2H), 7.26-7.19 (m, 3H), 3.52-3.44 (m, 4H), 3.39-3.30 (m, obscured by solvent signal), 2.43 (s, 3H), MS (posESI) m/z=410 (M+H).
    • Example 108 4-piperazin-1-yl-naphthalene-1-sulfonic acid (2,4-dimethyl-phenyl)-amide, hydrochloride
  • The final product was prepared according to Method F: 1H NMR ((DMSO-d6) δ; 8.81-8.72 (m, 1H), 8.34-8.25 (m, 1H), 7.98 (d, J=8.18 hz, 1H), 7.71-7.60 (m, 2H), 7.14 (d, J=8.18 Hz, 1H), 6.81 (s, 1H), 6.76-6.72 (m, 2H), 3.58-3.47 (m, 4H), 3.44-3.30 (m, obscured in part by solvent signal), 2.16 (s, 3H), 1.84 (s, 3H), MS (posESI) m/z=396 (M+H).
    • Example 109 4-piperazin-1-yl-naphthalene-1-sulfonic acid (3-trifluoromethyl-phenyl)-amide, hydrochloride
  • The final product was prepared according to Method F: 1H NMR ((DMSO-d6) δ; 8.72-8.64 (m, 1H9, 82.7-8.16 (m, 2H), 7.81-7.62 (m, 2H), 7.45-7.19 (m, 5H), 3.40-3.20 (m, obscured by solvent signal), MS (posESI) m/z=436 (M+H).
    • Example 110 4-piperazin-1-yl-naphthalene-1-sulfonic acid biphenyl-2-ylamide, hydrochloride
  • The final product was prepared according to Method F: 1H NMR ((DMSO-d6) δ; 9.71 (s, 1H), 944 (brs, 2H), 8.51-8.42 (m, 1H), 8.24-8.15 (m, 1H), 7.83 (d, J=8.18 Hz, 1H), 7.66-7.49 (m, 2H), 7.29-6.98 (m, 10H), 3.50-3.30 (m, obscured by solvent signal), MS (posESI) m/z=444 (M+H).
    • Example 111 4-piperazin-1-yl-naphthalene-1-sulfonic acid (3-benzyloxy-phenyl)-amide
  • N-(3-phenyloxyphenyl)-4-fluoronaphthalensulphonamide—Method E; Yield 9.2 g (47%). 1H NMR (DMSO-d6) δ 10.75 (s, 1H), 8.75 (d, J=8.4 Hz, 1H), 8.23-8.14 (m, 2H), 7.87-7.73 (m, 2H), 7.44 (dd, J=10.2, 8.3 Hz, 1H), 7.34-7.29 (m, 5H), 7.03 (t, J=8.2 Hz, 1H), 6.66-6.56 (m, 3H), 4.93 (s, 2H); MS (ESI+) for C23 H18 F N O3 S m/z 407 (M+H)+.
  • The final product was prepared according to Method F: Yield 0.6 g (78%); 1H NMR (DMSO-d6) δ 10.67 (s, 1H), 9.30 (br. s, 2H), 8.69 (d, J=7.7 Hz, 1H), 8.21 (d, J=8.4 Hz, 1H), 8.13 (d, J=8.2 Hz, 1H), 7.75-7.61 (m, 2H), 7.35-7.30 (m, 5H), 7.19 (d, J=8.2 Hz, 1H), 7.03 (t, J=8.2 Hz, 1H), 6.68-6.54 (m, 3H), 4.93 (s, 2H), 3.36-3.29 (m, 8H); MS (ESI+) for C27 H27 N3 O3 S m/z 474 (M+H)+.
    • Example 112
  • N-(4-fluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide, hydrochloride-4-Fluoro-N-(4-fluorophenyl)naphthalene-1-sulfonamide—Method E: Use of 4-methoxyaniline afforded the title compound (475 mg, 86%) as an oil by the application of the general procedure A described above. 1H NMR (CDCl3) δ 8.79-8.71 (m, 1H), 8.23-8.10 (m, 2H), 7.75-7.59 (2H), 7.52-7.45 (m, 1H), 7.15-7.04 (m, 1H), 6.96-6.73 (m, 4H); MS m/z (M+1) 320.
  • The final product was prepared according to Method F: Use of 4-fluoro-N-(4-fluorophenyl)naphthalene-1-sulfonamide afforded the title compound (95 mg, 15%), after recrystallization from methanol, as a white solid by the application of the general procedure B described above. 1H NMR (DMSO) δ 10.60 (s, 1H), 9.37 (br s, 2H), 8.73-8.65 (m, 1H), 8.25-8.17 (m, 1H), 8.13-8.06 (m, 1H), 7.76-7.60 (m, 2H), 7.22-7.15 (m, 1H), 7.04-6.95 (m, 4H), 3.43-3.24 (m, 8H); MS m/z (M+1) 386.
    • Example 113 N-(3-Ethylphenyl)-4-piperazin.1.ylnaphthalene-1-sulphonamine, hydrochloride
  • N-(3-Ethylphenyl)-4-fluoronaphthalene-1-sulfonamide—Method E: yield 80%, purity 92%. 1H NMR (270 MHz, CDCl3) δ ppm 1.03 (t, J=7.52 Hz, 3H), 2.45 (q, J=7.65 Hz, 2H), 6.68-6.72 (m, 2H, N—H), 6.87 (d, J=7.13 Hz, 1H), 6.99-7.13 (m, 2H), 7.65-7.72 (m, 2H), is 8.13-8.20 (m, 2H), 8.65 (d, J=8.44 Hz, 1H); MS (ESI+) for C18 H16 F N O2 S m/z 329.393 (M+H)+. 330.0; MS (ESI−) for C18 H16 F N O2 S m/z 329.393 (M−H)−. 328.1
  • The final product was prepared according to Method F: yield 61%, purity 98%. 1H NMR (500 MHz, DMSO) δ 8.67-8.65 (m, 1H), 8.16-8.10 (m, 2H), 7.66-7.57 (m, 2H), 7.14 (d, J=8.56 Hz, 1H), 6.97-6.94 (m, 1H), 6.78-6.76 (m, 2H), 6-70-6.69 (m, 1H), 3.30-3.28 (m, 2H), 3.22-3.19 (m, 2H), 2.34 (q, J=17 Hz, 2H), 1.94 (tr, J=17 Hz, 3H); MS (ESI+) for C22 H25 N3 O2 S HCl m/z 431.98 (M−HCl+H)+. 396.1; MS (ESI−) for C22 H25 N3 O2 S HCl m/z (M−HCl−H)−. 394.1
    • Example 114 4-piperazinyl-N-[3-(trifluoromethyl)phenyl]naphthalene-1-sulfonamide, hydrochloride
  • The final product was prepared according to Method F: Use of 4-fluoro-N-(3-trifluoromethythiophenyl)naphthalene-1-sulfonamide afforded the title compound (0.08 g), gave 0.060 g of the desired product, yield 85%, purity 96%.
  • 1H NMR (270 MHz, CD3OD) δ 8.74-8.71 (m, 1H), 8.26-8.19 (m, 2H), 7.75-7.65 (m, 2H), 7.32 (br.s, 1H), 7.23-7.14 (m, 4H), 3.57-3.47 (m, 4H), 3.35-3.30 (m, 4H); MS (ESI+) for C21 H20 F3 N3 O2 S2 HCl m/z 467.09+35.46 (M+H)+ 468.0; MS (ESI+) for C21 H20 F3 N3 O2 S2 HCl m/z 467.09+35.46 (M−H)− 466.1.
    • Example 115 4-piperazinyl-N-[3-benzoylphenyl]naphthalene-1-sulfonamide, hydrochloride
  • The final product was prepared according to Method F: yield 25%, purity 97%. 1H NMR (270 MHz, CD3OD) δ 8.76-8.72 (m, 1H), 8.29-8.26 (m, 1H), 8.17 (d, J=8, 1 Hz, 1H), 7.73-7.60 (m, 3H), 7.55-7.44 (m, 4H), 7.34-7.28 (m, 4H), 7.18 (d, J=8, 1 Hz, 1H), 3.54-3.50 (m, 4H), 3.37-3.30 (m, 4H); MS (ESI+) for C27 H25 N3 O3 S HCl m/z 471.17+35.46 (M+H)+ 472.1; MS (ESI+)+) for C27 H25 N3 O3 S HCl m/z 471.17+35.46 (M−H)− 470.01.
    • Example 116 4-piperazinyl-N-[3-(4-bromo-1-methyl-1H-pyrazol-3-yl)phenyl]naphthalene-1-sulfonamide, hydrochloride
  • The final product was prepared according to Method F: yield 81%, purity 96%. 1H NMR (270 MHz, CD3OD) δ 8.78-8.74 (m, 1H), 8.27-8.24 (m, 1H), 8.19 (d, J=8, 1 Hz, 1H), 7.75-7.64 (m, 2H), 7.46 (s, 1H), 7.31-7.25 (m 1H), 7.19-7.16 (m, 2H), 7.02-6.96 (m, 2H), 3.57-3.49 (m, 4H), 3.52 (s, 3H), 3.35-3.30 (m, 4H); MS (ESI+) for C24 H24 Br N5 O2 S HCl m/z 525.08+35.46 (M+H)+ 526.0; MS (ESI+) C24 H24 Br N5 O2 S HCl m/z 525.08 +35.46 (M−H)− 524.1.
    • Example 117 4-piperazinyl-N-[3-biphenylphenyl]naphthalene-1-sulfonamide, hydrochloride
  • The final product was prepared according to Method F: yield 33%, purity 95%. 1H NMR (270 MHz, CD3OD) δ 8.83-8.80 (m, 1H), 8.26-8.22 (m, 2H), 7.79-7.68 (m, 2H), 7.39-7.35 (m, 5H), 7.23-7.19 (m, 4H), 7.03-6.99 (m, 1H), 3.52-3.47 (m, 4H), 3.35-3.30 (m, 4H); MS (ESI+) for C26 H25 N3 O2 S HCl m/z 443.17+36.45 (M+H)+ 444.1; MS (ESI−) for C26 H25 N3 O2 S HCl m/z 443.17+36.45 (M−H)− 442.2.
    • Synthesis of Examples and Intermediates in Table IV
  • General Method H
    • Example 118 N-[1-(4-Methyl-1-piperazinyl)-3-isoquinolinyl]benzenesulfonamide, hydrochloride
  • To a solution of 1-(4-methyl-1-piperazinyl)-3-isoquinolinylamine (commercially available; 0.26 g, 1.07 mmol) and pyridine (0.60 mL, 7.51 mmol) in CH2Cl2 (3.0 mL) was added benzenesulfonyl chloride (151 μL, 1.18 mmol) in CH2Cl2 (1 mL). The mixture was stirred at room temperature for 16 hours and left in the refrigerator for 24 hours. The precipitate was collected by filtration to give 0.255 g (57%) of the pure product as the HCl-salt: 1H NMR (DMSO-d6) δ 10.93 (s, 2H), 7.96-7.90 (m, 3H), 7.79-7.75 (m, 1H), 7.64-7.56 (m, 4H), 7.44-7.38 (m, 1H), 7.01 (s, 1H9, 3.70-3.15 (m, partly obscured by solvent signal, 8H), 2.79 (s, 3H); MS (posEI-DIP) m/z 382 (M+).
    • Example 119 2,4-di-Fluoro-N-[1-(4-methyl-1-piperazinyl)-3-isoquinolinyl]benzenesulfonamide, hydrochloride
  • The title compound was prepared from 1-(4-methyl-1-piperazinyl)-3-isoquinolinylamine (commercially available; 0.209 g, 0.862 mmol) using the method described in the example that follows: yield 0.152 g (65%); 1H NMR (DMSO-d6) δ; 11.35 (s, 1H), 11.09 (br s, 1H), 8.15-8.04 (m, 1H), 7.97-7.90 (m, 1H), 7.83-7.35 (m, 5H), 6.95 (s, 1H), 3.70-3.10 (m, 8H), 2.85-2.75 (m, 3H); MS (posESI) m/z 419 (M+H).
    • Example 120 4-Bromo-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 11.07 (s, 1H), 10.75 (br s, 1H), 7.98-7.75 (m, 5H), 7.66-7.58 (m, 1H), 7.52 (s, 1H), 7.47-7.37 (m, 1H), 7.00 (brs, 1H), 3.70-3.20 (obscured in part by solvent signal, 8H), 2.85-2.80 (m, 2H), MS (posESI) m/z=461 (M+H)
    • Example 121 5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonic acid [1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-amide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 11.47 (br s, 1H), 10.55 (br s, 1H), 8.14-8.07 (m, 1H), 8.01-7.98 (m, 1H), 7.96-7.98 (m, 1H), 7.82-7.76 (m, 1H), 7.67-7.52 (m, 2H), 7.47-7.39 (m, 1H), 7.06 (s, 1H), 3.80-3.65 (m, 2H), 3.60-3.25 (m, obscured by solvent signal), 2.80-2.73 (m, 3H)), MS (posESI) m/z=487 (M+H)
    • Example 122 3-Chloro-2-methyl-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 11.24 (br s, 1H), 10.56 (br s, 1H), 8.10-8.05 (m, 1H), 7.95-7.89 (m, 1H), 7.80-7.69 (m, 2H), 7.66-7.57 (m, 1H), 7.53-7.35 (m, 2H), 6.94 (s, 1H), 3.70-330 (m, obscured by solvent signal), 3.29-3.10 (m, 4H), 3.85-2.79 (m, 3H),), MS (posESI) m/z=431 (M+H).
    • Example 123 3,4-Dichloro-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 11.17 (s, 1H), 10.50 (br s, 1H), 8.16-8.14 (m, 1H), 7.98-7.93 (m, 1H), 7.91-7.89 (m, 2H), 7.85-7.80 (m, 1H), 7.68-7.60 (m, 1H), 7.49-7.41 (m, 1H), 7.04 (s, 1H), 3.85-3.20 (m, obscured by solvent signal), 2.87-2.83 (m, 3H),), MS (posESI) m/z=451 (M+H).
    • Example 124 4-Methyl-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.88 (m, brs, 1H), 7.95-7.88 (m, 1H), 7.85-7.74 (m, 3H), 7.65-7.56 (m, 1H), 7.51-7.34 (m, 4H), 7.14-7.09 (m, 1H), 6.99 (s, 1H), 3.75-3.45 (m, obscured by solvent signal, 4H), 3.35-3.15 (m, 4H), 2.84 (d, J=4.75 Hz, 3H), 2.33 (s, 3H)), MS posESI) m/z=397(M+H).
    • Example 125 3-Methoxy-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.93 (brs, 1H), 10.69 (brs, 1H), 7.93 (d, J=8.19 Hz, 1H), 7.79 (d, J=7.92 Hz, 1H), 7.65-7.57 (m, 1H), 7.52-7.37 (m, 4H), 7.24-7.13 (m, 1H), 7.03 (s, 1H), 3.78 (s, 3H), 3.75-3.20 (m, obscured by solvent signal, 8H), 2.81 (d, J=4.48 Hz, 3H), MS (posESI) m/z=413(M+H).
    • Example 126 5-Chloro-thiophene-2-sulfonic acid [1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-amide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 7.76-7.21 (m, 1H), 7.01-6.96 (m, 1H), 6.89-6.82 (m, 1H), 6.74-6.71 (m, 1H), 6.70-6.66 (m, 1H), 6.40 (brs, 1H), 6.22 (d, J=3.96 Hz, 1H), 3.20-3.10 (m, 2H), 2.87-2.75 (m, 2H), 2.70-2.50 (m, obscured in part by solvent signal, 4H), 2.19 (brs, 3H), MS (posESI) m/z=423(M+H).
    • Example 127 N-{2-Chloro-4-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-ylsulfamoyl]-phenyl}-acetamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.03 (s, 1H), 10.52 (brs, 1H), 7.93 (d, J=8.44 Hz, 1H), 7.78 (d, J=7.92 Hz, 1H), 7.71 (d, J=2.11 Hz, 1H), 7.65-7.57 (m, 1H), 7.57-7.51 (dd, J=2.11 and 8.44 Hz, 1H), 7.45-7.37 (m, 1H), 6.99 (s, 1H), 6.80 (d, 8.44 Hz, 1H), m3.82-3.71 (m, 2H), 3.60-3.20 (m, obscured by solvent signal) 2.84 (d, J=4.49 hz, 3H), MS (posESI) m/z=474(M+H).
    • Example 128 2,5-Dichloro-thiophene-3-sulfonic acid [1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-amide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 794-7.89 (m, 1H), 7.77-7.72 (m, 1H), 7.63-7.56 (m, 1H), 7.46 (s, 1H), 7.44-7.36 (m, 1H), 3.50-3.20 (m, obscured by solvent signal), 2.70-2.50 m, obscured by solvent signal), 2.32 (brs, 3H), MS (posESI) m/z=457(M+H).
    • Example 129 N-[1-(4-Methyl-piperazin-1-yl)-isoquinolin-3-yl]-3-trifluoromethyl-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 11.17 (s, 1H), 10.71 (brs, 1H), 8.27-8.17 (m, 2H), 8.07-8.01 (m, 1H), 7.97-7.79 (m, 3H), 7.67-7.60 (m, 1H), 7.48-7.40 (m, 1H), 7.06 (s, 1H), 3.70-3.40 (m, m, obscured by solvent signal), 3.31-3.14 (m, 4H), 2.82 (d, J=4.75 Hz, 3H), MS (posESI) m/z=451(M+H).
    • Example 130 N-[1-(4-Methyl-piperazin-1-yl)-isoquinolin-3-yl]-4-phenoxy-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.91 (s, 1H), 10.79 brs, 1H), 7.98-7.89 (m, 3H), 7.81-7.74 (m, 1H), 7.66-7.55 (m, 1H), 7.49-7.37 (m, 3H), 7.28-7.20 (m, 1H), 7.13-7.06 (m, 4H), 7.00 (s, 1H), 3.77-3.66 (m, 2H), 3.50-3.20 (m, 6H), 2.82 (d, J=4.49 Hz, 3H), MS (posESI m/z=475 (M+H).
    • Example 131 5-Bromo-2-methoxy-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.90 (s, 1H), 10.75 (brs, 1H), 7.99 (d, J=2.64 Hz, 1H), 7.91 (m, d, J=8.45 Hz, 1H), 7.80-7.73 (m, 2H), 7.65-7.57 (m, 1H), 7.45-7.37 (m, 1H), 7.14 (d, J=8.47 Hz, 1H), 3.82 (s, 3H), 3.68-3.55 (m, 2H), 3.52-3.38 (m, 2H), 3.35-3.20 (m, 4H), 2.84 (d, J=4.49 Hz, 3H), MS (posESI m/z=491(M+H).
    • Example 132 2-Methanesulphonyl-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide, hydrochloride
  • MS (posESI) m/z=461 (M+H).
    • Example 133 3,5-Dimethyl-isoxazole-4-sulfonic acid [1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-amide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 11.17 (s, 1H), 10.54 (s, 1H), 7.99 (d, J=8.45 Hz, 1H), 7.86 (d, J=7.92 Hz, 1H), 7.71-7.63 (m, 1H), 7.53-7.45 (m, 1H), 7.07 (s, 3H), 3.75-3.64 (m, 2H), 3.55-3.45 (m, 2H), 3.35-3.15 (m, 4H), 2.84 (d, J=4.49 Hz, 3H), 2.76 (s, 3H), 2.31 (s, 3H), MS (posESI) m/z=402 (M+H).
    • Example 134 2,4,6-Trimethyl-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide
  • 1H NMR (DMSO-d6) δ; 10.82 (s, 1H), 10.52 (brs, 1H), 7.92-7.87 (m, 1H), 7.76-7.70 (m, 1H), 7.64-7.56 (m, 1H), 7.43-7.36 (m, 1H), 7.00 (s, 2H), 6.88 (s, 1H), 6.74 (brs, 1H), 3.60-3.10 (m, 8H), 2.81 (d, J=4.75 Hz, 3H), 2.61 (s, 6H), 2.22 (s, 3H), MS (posESI) m/z=425 (M+H).
    • Example 135 3,4-Dimethoxy-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamide, hydrochloride
  • 1H NMR (DMSO-d6) δ; 10.75 (brs, 1H), 10.72 (s, 1H), 7.95-7.90 (m, 1H), 7.82-7.76 (m, 1H), 7.65-7.57 (m, 1H), 7.55-7.37 (m, 2H), 7.11 (d, J=8.71 Hz, 1H)m 7.05 (s, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 3.76-3.69 (m, obscured in part by —OMe), 3.51-3.19 (m, 6H), 2.82 (d, J=4.49 Hz, 3H), MS (posESI) m/z=443 (M+H).
    • Synthesis of Examples in Table V Example 136 N-[8-(4-Methyl-1-piperazinyl)-5-quinolinyl]benzenesulfonamide, hydrochloride
  • To a solution of 8-(4-methyl-1-piperazinyl)-5-nitroquinoline (0.379 g, 1.39 mmol) in THF:EtOH 1:4 solvent system was added Raney-Ni (1.0 mL suspension in EtOH) followed by hydrazine hydrate (0.348 g, 6.95 mmol). The mixture was stirred vigorously at room temperature for 16 hours and then filtered through celite pretreated with water. The filtrate was concentrated, and the residue was purified by column chromatography (SiO2, CHCl3/MeOH/NH3 9:1:0.4%) to give 0.337 g of 8-(4-methyl-1-piperazinyl)-5-quinolinylamine. The amine was dissolved in CH2Cl2 (6.0 mL) and pyridine (0.785 mL, 9.73 mmol) and benzenesulfonyl chloride (0.178 mL, 1.39 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours and then washed with saturated aqueous NaHCO3. The organic phase was dried with Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, CHCl3/MeOH/NH3 9:1:0.4%) to give 0.130 g of the free base which was converted to its HCl-salt: 1H NMR (DMSO-d6) δ; 11.09 (br s, 1H), 10.32 (s, 1H), 8.94-8.89 (m, 1H), 8.55-8.48 (m, 1H), 7.68-7.65 (m, 2H), 7.64-7.57 (m, 2H), 7.54-7.49 (m, 2H), 7.27-7.22 (m, 1H), 7.12-7.08 (m, 1H), 3.95-3.84 (m, 2H), 3.55-3.49 (m, 2H), 3.45-3.35 (m, 2H), 3.26-3.16 (m, 2H), 2.85-2.82 (m, 3); MS (posESI) m/z 383 (M+H).
    • Synthesis of Examples and Intermediates in Table VI
  • Figure US20070066598A1-20070322-C00360
    a) H2O2, CH3COOH, 100° C.; b) Me3SiCN, Toluene, (Me)2N—CO—Cl, 65° C.; c) HBr/CH3COOH, rt; d) Boc-piperazine, K2CO3, 90° C.; R—SO2Cl, py, rt.
    Intermediate 20
  • 3-Cyanomethylpyridine-N-oxide—Hydrogenperoxide (17 ml, 30% ww) was added to a mixture of 3-cyanomethylpyridine (11 g, 93 mmol) and glacial acetic acid (55 ml) and heated at 100° C. overnight. The mixture was diluted with water (70 ml) and MnO2 (5.0 g) was carefully added and stirred for 5 hours (check peroxide content with peroxide sticks), and only small amounts of peroxide was left. The mixture was concentrated in vacuo to 40 ml and diluted with methanol (40 ml), filtered through a short plug of silica, and washed with methanol (400 ml). The filtrate were concentrated and recrystallized from chloroform and hexane to give the title compound (9.5 g, 76%). 1H NMR (CDCl3) δ 8.16 (s, 2H), 7.32 (s, 2H), 3.73 (s, 2H); MS m/z (M+1) 135.
  • Intermediate 21
  • 3-(Cyanomethyl)pyridine-2-carbonitrile—Trimethylsilylcyanide (4.2 ml, 32 mmol) was added to a suspension of 3-cyanomethylpyridine-N-oxide (3.5 g, 26 mmol) in toluene (35 ml) and after 1 minute dimethylcarbamylchloride (2.4 ml, 26 mmol) was added and the reaction was stirred overnight at 65° C. EtOAc and 1N NaOH was added and the mixture was washed with water (2×). The organic phase was dried (MgSO4) and evaporated. The crude product was dissolved in ethanol (150 ml) and stirred overnight, filtered (remove byproduct) and concentrated (25 ml). After 30 min at 0° C. the yellow powder was filtered and washed with cold ethanol (1×) to give, after drying, the title compound (2.15 g, 57%). 1H NMR (CDCl3) δ 8.71 (m, 1H), 8.03 (d, J=8.03 Hz, 1H), 7.62 (dd, J=8.16, 4.64 Hz, 1H), 4.04 (s, 2H); MS m/z (M−1) 142.
  • Intermediate 22
  • 6-Amino-8-bromo-1,7-naphthyridine—3-(Cyanomethyl)pyridine-2-carbonitrile (4.0 g, 28 mmol) was added carefully to HBr in acetic acid (33%) (25 ml) at rt. The red suspension was stirred for 1.5 h and filtered. The red solid was washed with EtOAc (3×) and suspended in water. 1N NaOH was added dropwise until pH-8, and the suspension was stirred for 45 minutes and filtered. The red solid was washed with water (2×) and dried. The crude product was suspended in 5% MeOH in CH2Cl2 and filtered through a short plug of silica, washing with 5% MeOH in CH2Cl2. Subsequent concentration in vacuo afforded the title compound (3.85 g, 61%). 1H NMR (DMSO) δ 8.58 (dd, J=4.02, 1.51 Hz, 1H), 8.01 (dd, J=8.53, 1.51 Hz, 1H), 7.47 (dd, J=8.53, 4.02 Hz, 1H), 6.58 (s, 1H), 6.48 (s, 2H); MS m/z (M+1) 226.
  • Intermediate 23
  • tert-Butyl 4-(6-amino-1,7-naphthyridin-8-yl)piperazine-1-carboxylate—A mixture of 6-amino-8-bromo-1,7-naphthyridine (650 mg, 2.9 mmol), BOC-piperazine (1.1 g, 5.9 mmol), potassium carbonate (2 g, 15 mmol) in DMSO (1 ml) was stirred at 90° C. for 3 days. Chloroform was added, the mixture was filtered and the filtrate was washed with brine (3×100 ml). The organic phase was dried using potassium carbonate, filtered and concentrated in vacuo to give a yellow oil. The oil was triturated with diethyl ether and then eluted through a short silica plug using chloroform. Subsequent concentration of the residue in vacuo gave the title compound (700 mg, 74%) as a yellow oil. 1H NMR (CDCl3) δ 8.43 (dd, J=4.09, 1.72 Hz, 1H), 7.67 (dd, J=8.31, 1.72 Hz, 1H), 7.25-7.20 (m, 1H), 6.08 (s, 1H), 4.29 (s, 2H), 3.95-3.88 (m, 4H), 3.65-3-57 (m, 4H), 1.46 (s, 9H); MS m/z (M+1) 330.
  • General Procedure I
  • To a stirred solution of tert-butyl 4-(6-amino-1,7-naphthyridin-8-yl)piperazine-1-carboxylate (63 mg, 0.19 mmol) in anhydrous dichloromethane (0.5 ml) and pyridine (0.25 ml) was added p-toluenesulfonyl chloride (36 mg, 0.19 mmol). The reaction mixture was stirred at room temperature over night and then concentrated in vacuo. The residue was purified using reversed-phase preparative HPLC to give the corresponding tert-butoxycarbonyl protected piperazine intermediate. This was dissolved in dichloromethane (1.5 ml) and treated with concentrated TFA (1 ml) at room temperature for 1.5 hours.
    • Example 137 4-Methyl-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide, trifluoroacetic acid
  • The title compound was prepared following the general procedure I (61 mg, 65%) as a yellow solid. 1H NMR (CD3OD) δ 8.57-8.65 (m, 1H), 8.06-7.98 (m, 1H), 7.86-7.78 (m, 2H), 7.53-7.43 (m, 1H), 7.36-7.26 (m, 2H), 6.88 (s, 1H), 4.18-4.06 (m, 4H), 3.35-3.24 (m, 4H), 2.35 (s, 3H); MS m/z (M+1) 384.
    • Example 138 4-Bromo-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide, trifluoroacetic acid
  • The title compound was prepared following the general procedure I (14 mg, 13%). 1H NMR (CD3OD) δ 8.70-8.63 (m, 1H), 8.14-8.05 (m, 1H), 7.91-7.83 (m, 2H), 7.76-7.67 (m, 2H), 7.57-7.49 (m, 1H), 6.91 (s, 1H), 4.19-4.09 (m, 4H), 3.38-3.28 (m, 4H); MS m/z (M+1) 449.
    • Example 139 N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)naphthalene-1-sulfonamide, trifluoroacetic acid
  • The title compound was prepared following the general procedure I (66 mg, 65%). 1H NMR (CD3OD) δ 8.82-8.76 (m, 1H), 8.58-8.54 (m, 1H), 8.42-8.37 (m, 1H), 8.13-8.07 (m, 1H), 8.01-7.92 (m, 2H), 7.71-7.54 (m, 3H), 7.47-7.40 (m, 1H), 6.80 (s, 1H), 4.02-3.96 (m, 4H), 3.24-3.18 (m, 4H); MS m/z (M+1) 420.
    • Example 140 N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)butane-1-sulfonamide, trifluoroacetic acid
  • The title compound was prepared following the general procedure I (48 mg, 55%). 1H NMR-(CD3OD) δ 8.71-8.66 (m, 1H), 8.13-8.06 (m, 1H), 7.58-7.51 (m, 1H), 6.83 (s, 1H), 4.33-4.23 (m, 4H), 3.51-3.38 (m, 6H), 1.91-1.72 (m, 2H), 1.53-1.38 (m, 2H), 0.98-0.86 (m, 3H); MS m/z (M+2) 351.
    • Example 141 3-Trifluoromethyl-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide, trifluoroacetic acid
  • The title compound was prepared following the general procedure I (60 mg, 57%). 1H NMR (CD3OD) δ 8.70-8.63 (m, 1H), 8.28-8.17 (m, 2H), 8.13-8.05 (m, 1H), 7.96-7.87 (m, 1H), 7.80-7.69 (m, 1H), 7.58-7.48 (m, 1H), 6.93 (s, 1H), 4.18-4.07 (m, 4H), 3.39-3.27 (m, 4H); MS m/z (M+1) 438.
    • Example 142 3,4-Dimethoxy-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide, trifluoroacetic acid
  • The title compound was prepared following the general procedure 1 (65 mg, 63%). 1H NMR (CD3OD) δ 8.68-8.59 (m, 1H), 8.11-8.01 (m, 1H), 7.61-7.40 (m, 3H), 7.04-6.92 (m, 2H), 4.22-4.10 (m, 4H), 3.81 (s, 3H), 3.78 (s, 3H), 3.39-3.27 (m, 4H); MS m/z (M+1) 430.
    • Example 143 2,4-Dichloro-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide, trifluoroacetic acid
  • The title compound was prepared following the general procedure I (56 mg, 53%). 1H NMR (CD3OD) δ 8.66-8.61 (m, 1H), 8.25-8.20 (m, 1H), 8.06-8.00 (m, 1H), 7.65-7.61 (m, 1H), 7.57-7.47 (m, 2H), 6.76 (s, 1H), 4.13-4.06 (m, 4H), 3.36-3.28 (m, 4H); MS m/z (M+2) 439.
    • Example 144 N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)thiophene-2-sulfonamide, trifluoroacetic acid
  • The title compound was prepared following the general procedure I (57 mg, 61%). 1H NMR (CD3OD) δ 8.71-8.64 (m, 1H), 8.14-8.05 (m, 1H), 7.76-7.67 (m, 2H), 7.58-7.49 (m, 1H), 7.11-7.03 (m, 1H), 6.98 (s, 1H), 4.27-4.15 (m, 4H), 3.40-3.28 (m, 4H); MS m/z (M+1) 376.
    • Example 145 1-Phenyl-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)methanesulfonamide, trifluoroacetic acid
  • The title compound was prepared following the general procedure I (35 mg, 37%). 1H NMR (DMSO) δ 8.83 (br s, 1H), 8.52-8.40 (m, 2H), 7.47-7.41 (m, 1H), 7.29-7.10 (m, 6H), 6.87 (s, 1H), 4.52 (s, 2H), 4.39-4.31 (m, 4H), 3.30-3.22 (m, 4H); MS m/z (M+1) 384.
    • Synthesis of Examples and Intermediates in Table
  • Figure US20070066598A1-20070322-C00361
    Scheme 4 a) TMS-acethylene, Cu2O, Py, 80° C.; b) tBuO—Na, Pd2(dba)3, Xantphos, xilene, 120° C.; c) Raney-Ni, Hydrazine, THF/Ethanol; d) R—SO2-Cl, Py; e) HCl-diethyl ether.
    Intermediate 24
  • 7-Iodo-5-nitro-1-benzofuran—A mixture of 4-nitro-2,5-diiodophenol (7.68 g, 6.86 mmol), TMS-acetylene (0.67 g, 6.86 mmol) and Cu2O (0.59 g, 4.12 mmol) in pyridine (120 mL) was heated to 80 C for 48 h. The mixture was filtered through celite and the solvent was removed. Column chromatography DCM/heptane 1:1 gave 0.35 g (18%) of product.
  • 1H NMR (CD3OD) δ 8.60 (d, 1H, j=2.1 Hz), 8.51 (d, 1H, J=2.1 Hz), 7.84 (d, 1H, J=2.1 Hz), 7.04 (d, 1H, J=2.4 Hz); MS (ESI) 289.8 (M+H)+; Purity (HPLC, column X) 93%.
  • Intermediate 25
  • 1-Methyl-4-(5-Nitro-1-benzofuran-7-yl)-piperazine—A mixture of 7-iodo-5-nitro-1-benzofuran (94.5 mg, 0.327 mmol), Xanthpos (19 mg. 0.032 mmol), Pd2(dba)3 (7.4 mg, 0.025 mmol) and NaOt-Bu (44.0 mg, 0.458 mmol), methylpiperazine (39.3 mg, 0.392 mmol) in xylene (3 mL) was heated to 120° C. overnight. The mixture was diluted with DCM and filtered through silica. The product was eluted with DCM/MeOH×0.4% NH3. Flash chromatography (DCM/MeOH×0.4% NH3) gave 60 mg (70%) of BVT: 1H NMR (CD3OD) δ 8.07 (d, 1H, J=2.1 Hz), 7.70 (d, 1H, J=2.1 Hz), 7.58 (d, 1H, J=2.1 Hz), 6.84 (d, 1H, J=2.1 Hz), 3.44-3.40 (m, 4H), 2.65-2.62 (m, 4H), 2.36 (s, 3H); MS (ESI) 262.0 (M+H)+; Purity (HPLC, column X) 95%.
  • Intermediate 26
  • tert-Butyl 4-(5-nitro-1-benzofuran-7-yl)-piperazine-1-carboxylate—The title compound was prepared according to the same procedure used for Intermediate 25 using N-tert-butyl-piperazine carboxylate to afford 240 mg (64%) of a white solid: 1H NMR (CD3OD) δ 8.08 (d, 1H, J=2.1 Hz), 7.72 (d, 1H, J=2.1 Hz), 7.58 (d, 1H, J=2.1 Hz), 6.86 (d, 1H, J=2.1 Hz), 3.66-3.62 (m, 4H), 3.34-3.31 (m, 4H), 1.46 (s, 9H); MS (ESI) 370.0 (M+Na)+; Purity (HPLC, column X) 96%.
  • Intermediate 27
  • 1-Methyl-4-(5-amino-1-benzofuran-7-yl)-piperazine
  • Intermediate 28
  • tert-Butyl 4-(5-amino-1-benzofuran-7-yl)-piperazine-1-carboxylate—1-Methyl-4-(5-Nitro-1-benzofuran-7-yl)-piperazine (1 eq) and tert-butyl 4-(5-nitro-1-benzofuran-7-yl)-piperazine-1-carboxylate (1 eq) were reduced to aromatic amine with Raney-Ni and hydrazine (10 eq) in THF/Ethanol (1:4), 3 h at room temperature. The reaction mixture are filtered through celite pad, the volatiles are evaporated and the crude is used in the next reactions.
    • Example 146 3-Cyanophenyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
  • To a solution of tert-butyl 4-(5-amino-1-benzofuran-7-yl)-piperazine-1-carboxylate (43 mg 0.138 mmol) and pyridine (100 μL, 1.24 mmol) was added 3-cyanobenzenesulfonylchloride (33.4 mg, 0.166 mmol). After 2 h PS-Trisamin was added and the reaction was stirred overnight. Flash chromatography (DCM/Heptane/MeOH 5:4:1) gave 24.6 mg of a solid. The crude product was dissolved in MeOH (2 mL) and HCl/ether 2M (4 mL) was added. After 0.5 h the sample was concentrated to afford 19 mg (36%) of a white solid: 1HNMR (CD3OD) δ 8.02-7.88 (m, 3H), 7.72 (d, 1H, J=2.1 Hz), 7.76-7.61 (m, 1H), 6.92 (d, 1H, J=2.1 Hz), 6.74 (d, 1H, J=2.1 Hz), 6.60 (d, 1H, J=2.1 Hz), 3.52-3.41 (m, 8H); MS (ESI) 381.2 (M+H)+; Purity (HPLC, column X) 95%.
    • Example 147 4-Phenoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
  • The title compound was prepared according to the method used for the synthesis of Example 146 (21%) of a white solid: 1HNMR (CD3OD) δ 7.73 (d, 1H, J=2.1 Hz), 7.69-7.64 (m, 2H), 7.43-7.37 (m, 2H), 7.24-7.17 (m, 1H9, 7.04-6.94 (m, 4H), 6.88 (d, 1H, J=2.1 Hz), 6.74 (d, 1H, J=2.1 Hz), 6.70 (d, 1H, J=2.1 Hz), 3.53-3.41 (m, 8H); MS (ESI) 450.1 (M+H)+; Purity (HPLC, column X) 90%.
    • Example 148 1-Naphthyl-Phenoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
  • The title compound was prepared according to the method used for the synthesis of Example 146 (30%) of a white solid: 1HNMR (CD3OD) δ 8.65 (d, 1H, J=8.8 Hz), 8.03-7.86 (m, 3H), 7.58-7.49 (m, 3H9, 7.36-7.33 (m, 1H), 6.74 (d, 1H, J=2.2 Hz), 6.53 (d, 1H, J=2.2 Hz), 6.30 (d, 1H, J=2.2 Hz), 3.52-3.41 (m, 8H); MS (ESI) 408.1 (M+H)+; Purity (HPLC) 100%.
    • Example 149 N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
  • The title compound was prepared according to the method used for the synthesis of Example 146 (33%) of a white solid: 1HNMR (CD3OD) δ 7.72-7.69 (m, 3H), 7.57-7.51 (m, 1H), 7.47-7.41 (m, 2H), 6.92 (d, 1H, J=2.1 Hz), 6.72 (d, 1H, J=2.1 Hz), 6.58 (d, 1H, J=2.1), 3.49-3.39 (m, 8H); MS (ESI) 358.1 (M+H)+; Purity (HPLC) 96%.
    • Example 150 5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonic acid (7-piperazin-1-yl-benzofuran-5-yl)-amide, hydrochloride
  • The title compound was prepared according to the method used for the synthesis of Example 146 (9%) of a white solid: 1HNMR (CD3OD) δ 7.74-7.73 (m, 2H), 7.62 (d, 1H, J=2.2 Hz), 7.38-7.36 (m, 1H), 6.87 (d, 1H, J=1.8 Hz), 6.64 (d, 1H, J=2.2 Hz), 6.58 (d, 1H, J=1.8 Hz), 3.36-3.28 (m, 8H); MS (ESI) 398.2 (M+H)+; Purity (HPLC) 98%.
    • Example 151 N-[7-(4-methylpiperazin-1-yl)-1-benzofuran-5-yl]-benzenesulfonamide, hydrochloride
  • The title compound was prepared according to the method used for the synthesis of Example 146 using 1-Methyl-4-(5-Nitro-1-benzofuran-7-yl)piperazine (45%) of a white solid: 1HNMR (CD3OD) δ 7.74-7.283 (m, 6H), 6.82 (d, 1H, J=1.8 Hz), 6.62 (d, 1H, J=2.2 Hz), 6.48 (d, 1H, J=1.8 Hz), 3.82-2.95 (m, 8H), 2.87 (s, 3H); MS (ESI) 372.1 (M+H)+; Purity (HPLC, column X) 96%.
    • Example 152 4-Methyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
  • 4-(5-Amino-benzofuran-7-yl)-piperazine-1-carboxylic acid tert-butyl ester (44 mg, 0.139 mmol) in 3 ml dichloromethane was added to a tube containing p-toluenesulfonyl chloride (32 mg, 0.167 mmol) together with pyridine (100 μl, 1.25 mmol) and left on a shaker over weekend. After purification by preparative HPLC, the resulting Boc-material was treated with HCl in ether and left on a shaker until the salt had formed. The solution was centrifugated 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 to yield 10 mg of title product. HPLC purity=94%, m/z=372.3 (M+H). 1H NMR (270 MHz, methanol-d4) δ ppm 2.35 (s, 3H) 3.45 (m, 8H) 6.63 (d, J=1.85 Hz, 1H) 6.71 (d, J=2.11 Hz, 1H) 6.88 (d, J=1.85 Hz, 1H) 7.25 (m, 2H) 7.58 (m, 2H) 7.71 (d, J=2.11 Hz, 1H).
    • Example 153 3,4-Dimethoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
  • HPLC purity=92%, m/z=418.3 (M+H). 1H NMR (270 MHz, methanol-d4) δ ppm 3.45 (m, 8H) 3.70 (m, 3H) 3.81 (m, 3H) 6.62 (d, J=1.85 Hz, 1H) 6.73 (d, J=2.38 Hz, 1H) 6.94 (m, 2H) 7.17 (d, J=2.11 Hz, 1H) 7.29 (dd, J=8.44, 2.11 Hz, 1H) 7.72 (d, J=2.38 Hz, 1H).
    • Example 154 4-Bromo-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
  • HPLC purity=95%, m/z=436.2 (M+H). 1H NMR (270 MHz, methanol-d4) δ ppm 3.46 (m, 8H) 6.62 (d, J=1.85 Hz, 1H) 6.74 (d, J=2.38 Hz, 1H) 6.93 (d, J=1.85 Hz, 1H) 7.61 (m, 4H) 7.73 (d, J=2.11 Hz, 1H).
    • Example 155 2,3-Dichloro-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
  • HPLC purity=96%, m/z=426.2 (M+H). 1H NMR (270 MHz, methanol-d4) δ ppm 3.44 (m, 8H) 6.67 (d, J=1.85 Hz, 1H) 6.72 (d, J=2.11 Hz, 1H) 7.01 (d, J=1.85 Hz, 1H) 7.34 (t, J=8.18 Hz, 1H) 7.70 (m, 2H) 7.94 (dd, J=7.92, 1.58 Hz, 1H).
    • Example 156 2,4-Dichloro-5-methyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
  • HPLC purity=96%, m/z=440.2 (M+H). 1H NMR (270 MHz, methanol-d4) δ ppm 2.30 (s, 3H) 3.46 (m, 8H) 6.69 (d, J=1.85 Hz, 1H) 6.73 (d, J=2.11 Hz, 1H) 7.01 (d, J=1.85 Hz, 1H) 7.60 (s, 1H) 7.71 (d, J=2.11 Hz, 1H) 7.87 (s, 1H).
    • Example 157 4-Methoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
  • HPLC purity=93%, m/z=388.3 (M+H). 1H NMR (270 MHz, methanol-d4) δ ppm 3.45 (m, 8H) 3.79 (s, 3H) 6.72 (d, J=2.11 Hz, 1H) 6.93 (m, 3H) 7.63 (m, 3H) 7.71 (d, J=2.11 Hz, 1H).
    • Example 158 4-Chloro-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
  • HPLC purity=97%, m/z=392.3 (M+H). 1H NMR (270 MHz, methanol-d4) δ ppm 3.46 (m, 8H) 6.63 (d, J=1.85 Hz, 1H) 6.74 (d, J=2.38 Hz, 1H) 7.47 (m, 2H) 7.67 (m, 3H) 7.73 (d, J=2.11 Hz, 1H).
    • Example 159 N-(7-piperazin-1-yl-benzofuran-5-yl)-4-trifluoromethyl-benzenesulfonamide, hydrochloride
  • HPLC purity=91%, m/z=426.3 (M+H). 1H NMR (270 MHz, methanol-d4) δ ppm 3.47 (m, 8H) 6.64 (d, J=1.85 Hz, 1H) 6.74 (d, J=2.11 Hz, 1H) 6.92 (d, J=1.85 Hz, 1H) 7.73 (d, J=2.11 Hz, 1H) 7.84 (m, 4H).
    • Example 160 5-Fluoro-2-methyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide, hydrochloride
  • HPLC purity=94%, m/z=390.3 (M+H). 1H NMR (270 MHz, methanol-d4) δ ppm 2.57 (m, 3H) 3.46 (m, 8H) 6.63 (m, 1H) 6.74 (d, J=2.11 Hz, 1H) 6.91 (d, J=1.85 Hz, 1H) 7.20 (m, 1H) 7.34 (m, 1H) 7.56 (dd, J=8.71, 2.64 Hz, 1H) 7.73 (d, J=2.11 Hz, 1H).
    • Example 161 5-Chloro-thiophene-2-sulfonic acid (7-piperazin-1-yl-benzofuran-5-yl)-amide, hydrochloride
  • HPLC purity=94%, m/z=398.3 (M+H). 1H NMR (270. MHz, methanol-d4) δ ppm 3.48 (m, 8H) 6.68 (d, J=2.11 Hz, 1H) 6.79 (d, J=2.38 Hz, 1H) 6.97 (d, J=3.96 Hz, 1H) 7.01 (d, J=1.85 Hz, 1H) 7.25 (d, J=3.96 Hz, 1H) 7.76 (d, J=2.38 Hz, 1H).
  • Biological Tests
  • The ability of a compound according to the invention to bind a 5-HT6 receptor, and to be pharmaceutically useful, can be determined using in vivo and in vitro assays known in the art.
  • (a) 5-HT6 Intrinsic Activity Assay
  • Antagonists to the 5-HT6 receptor were characterized by measuring inhibition of 5-HT induced increase in cAMP in HEK 293 cells expressing the human 5-HT6 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 of 25,000/well and grown in DMEM (Dulbecco's Modified Eagle Medium) (without phenol-red) containing 5% dialyzed Foetal Bovine Serum for 48 h at 37° C. in a 5% CO2 incubator. The medium was 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 μl 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 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 Ki=IC50/(1+[5HT]/EC50).
  • The compounds in accordance with the invention have a selective affinity to 5-HT6 receptors with Ki values between 0.5 nM and 5 μM. The compounds show good selectivity for 5-HT1a, 5-HT2a, 5-HT2a, 5-HT2b, 5-HT2c.
  • (b) In Vivo Assay of Reduction of Food Intake
  • For a review on serotonin and food intake, see Blundell, J. E. and Halford, J. C. G. (1998) Serotonin and Appetite Regulation. Implications for the Pharmacological Treatment of Obesity. CNS Drugs 9:473-495.
  • 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 hours of infusion of compounds is recorded.
  • Male mice (obese C57BL/6JBom-Lepob and lean wild-type C57B1/6JBom; Bomholtsgaard, Denmark) 8-9 weeks with an average body weight of 50 g (obese) and 25 g (lean) are used in all the studies. The animals are housed singly in cages at 23±1° C., 40-60% 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 cyclodextrin, cyclodextrin/methane sulfonic acid, polyethylene glycol/methane sulfonic acid, saline. Fresh solutions are made for each study. Doses of 30, 50 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 μL/h) are used and loaded essentially as recommended by the Alzet technical information manual (Alza Scientific Products, 1997; Teeuwes and Yam, 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 only vehicle solution and maintained in vehicle pre-warmed to 37° C. (approx. 1 h). The minipumps are implanted subcutaneously in the neck/back region under short acting anesthesia (metofane/enflurane). This surgical procedure lasts approximately 5 min. It takes about 3 h to reach steady state delivery of the compound.
  • The weight of the food pellets are measured at 5 p.m. and at 8 p. m. for two days before (baseline) and one day after the implantation of the osmotic minipumps. The weigh-in is performed with a computer assisted Mettler Toledo PR 5002 balance. Occasional spillage is corrected for. At the end of the study the animals are killed by neck dislocation and trunk blood sampled for later analysis of plasma drug concentrations.
  • 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 (MRM with the transition m/z 316
    Figure US20070066598A1-20070322-P00900
    221). A linear regression analysis of the standards forced through 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 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-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 50-200 mg/kg.
    TABLE VI
    In vivo efficacy data on the effect of the compounds
    on Food Intake reduction
    In vivo efficacy - Food
    intake (15 h) in ob/ob
    mouse
    % Inhibition of Food Intake Free plasma concentration
    in ob/ob mice at of the compounds at steady
    EXAMPLES 50 mg/Kg/day, 15 h state (Css, u)
    48 23.8 0.008
    13 24.1 0.035
    53 25.7a ND
    34 51.4 0.078
    24 46.2 0.0076
    19 69.6 0.150
    27 68.9 0.008
    30 60.1 0.275
    29 71 0.33
    14 41b 0.23

    aThe effect on Food Intake reported in the table was obtained at the dose of 14.8 mg/kg/d

    bThe effect on Food Intake reported in the table was obtained at the dose of 100 mg/kg/d

Claims (14)

1. A compound of the formula V:
Figure US20070066598A1-20070322-C00362
or a pharmaceutically acceptable salt thereof, wherein:
P is
Figure US20070066598A1-20070322-C00363
P and R3 are bound to the same ring and are disposed in meta- or para-positions relative to each other;
R1 is
(a) C1-6 alkyl,
(b) C1-6 alkoxyalkyl,
(c) straight or branched C1-6 hydroxyalkyl,
(d) straight or branched C1-6 alkylhalides; or
(e) a group Ar;
Ar is
(a) phenyl,
(b) 1-naphthyl,
(c) 2-naphthyl,
(d) benzyl,
(e) cinnamoyl,
(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, or
(g) a bicyclic ring system comprising at least one heterocyclic ring according to (f).
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) C1-6 alkyl,
(c) C1-6 alkoxy,
(d) straight or branched C1-6 hydroxyalkyl, or
(e) straight or branched C1-6 alkylhalides;
or R1 and R2 are linked to form a group (CH2)4O;
One of R3 is a group
Figure US20070066598A1-20070322-C00364
X and Y are independently
(a) H,
(b) halogen,
(c) C1-6 alkyl,
(d) —CF3,
(e) hydroxy,
(f) C1-6 alkoxy,
(g) C1-4 alkenyl;
(h) phenyl;
(i) phenoxy,
(j) benzyloxy,
(k) benzoyl,
(l) —OCF3,
(m) —CN,
(n) straight or branched C1-6 hydroxyalkyl,
(o) straight or branched C1-6 alkylhalides,
(p) —NH2,
(q) —NHR4,
(r) —NR4R5,
(s) —NO2,
(t) —CONR4R5,
(u) —NHSO2R4,
(v) —NR4COR5,
(x) —SO2NR4R5,
(z) —C(═O)R4,
(aa) —CO2R4,
(ab) —S(O)nR4; wherein n is 0, 1, 2 or 3;
(ac) —S—(C1-6)alkyl, or
(ad) —SCF3;
R4 and R5 are independently
(a) H,
(b) C1-6 alkyl,
(c) C3-7 cycloalkyl, or
(d) Ar, as defined above for R1;
alternatively, R4 and R5 are linked to form a group (CH2)2O, (CH2)4O or (CH2)3-5; and
R6 is
(a) H, or
(b) straight of branched C1-6 alkyl.
2-6. (canceled)
7. The compound according to claim 1, wherein
R1 is
(a) C1-6 alkyl, or
(e) a group Ar;
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 X or Y; wherein X or Y is
(a) H,
(b) halogen,
(c) C1-6 alkyl,
(d) —CF3,
(f) C1-6 alkoxy,
(g) C1-4 alkenyl;
(l) —OCF3, or
(n) straight or branched C1-6 hydroxyalkyl.
R2 is
(a) H, or
(b) C1-3 alkyl, in particular methyl;
or R1 and R2 are linked to form a group (CH2)4O; and
R3 is
Figure US20070066598A1-20070322-C00365
wherein R6 is
(a) H, or
(b) C1-6 alkyl, in particular methyl.
8-10. (canceled)
11. The compound according to claim 1, wherein the compound is selected from the group consisting of:
4-Methyl-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide, trifluoroacetic acid;
4-Bromo-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide, trifluoroacetic acid;
N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)naphthalene-1-sulfonamide, trifluoroacetic acid;
N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)butane-1-sulfonamide, trifluoroacetic acid;
3-Trifluoromethyl-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide, trifluoroacetic acid;
3,4-Dimethoxy-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide, trifluoroacetic acid;
2,4-Dichloro-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide, trifluoroacetic acid;
N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)thiophene-2-sulfonamide, trifluoroacetic acid; and
1-Phenyl-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)methanesulfonamide, trifluoroacetic acid.
12. (canceled)
13. A process for the preparation of a compound according to claim 1, wherein P is
Figure US20070066598A1-20070322-C00366
said method comprising the steps of:
(a) nucleophilic aromatic substitution of the aromatic halogen atom in 1-chloro-3-nitronaphthalene or 1-chloro-4-nitronaphthalene with aliphatic or aromatic diamines;
(b) reduction of the nitro group in 1-diamine-3-nitronaphthalene or 1-diamine-4-nitronaphthalene obtained in step (a) to form 1-diamine-3-NH2-naphthalene or 1-diamine-4-NH2-naphthalene, respectively; and
(c) synthesis of a sulfonamide by reacting 1-diamine-3-NH2-naphthalene or 1-diamine-4-NH2-naphthalene obtained in step (b) with a suitable sulfonyl chloride.
14. The process of claim 13, wherein step (a) is by means of Palladium catalyzed nucleophilic substitution.
15. A process for the preparation of a compound according to claim 1, wherein P is
Figure US20070066598A1-20070322-C00367
said method comprising the steps of:
(a) nucleophilic aromatic substitution of the trifluoromethanesulfonate group in 2-trifluoromethansulfonate-5-nitroquinoline with aliphatic or aromatic diamines;
(b) reduction of the nitro group in 2-diamine-5-nitroquinoline obtained in step (a) to form 2-diamine-5-NH2-quinoline; and
(c) synthesis of a sulfonamide by reacting 2-diamine-5-NH2-quinoline obtained in step (b) with a suitable sulfonyl chloride.
16. A process for the preparation of a compound according to claim 1, wherein P is
Figure US20070066598A1-20070322-C00368
said method comprising the steps of:
(a) reacting a fluoronaphthalene and chlorosulfonic acid under acidic conditions, to introduce a sulfonyl chloride group in the para position to the carbon having the fluoro atom;
(b) reacting the product of step (a) with an aliphatic or aromatic primary amine to give a sulphonamide; and
(c) reaction of the product of step (b) with a diamine.
17. A pharmaceutical formulation containing a compound according to claim 1 as active ingredient, in combination with a pharmaceutically acceptable diluent or carrier.
18. A method for the treatment or prophylaxis of obesity, type II diabetes, and/or disorders of the central nervous system, which comprises administering to a mammal in need of such treatment an effective amount of a compound according to claim 1.
19. A method for reducing body-weight or reducing food intake, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1.
20. A method for modulating 5-HT6 receptor activity, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1.
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