HK1066790B

HK1066790B - Substituted sulfonamide compounds, process for their use as medicament for the treatment of cns disorders, obesity and type ii diabetes

Info

Publication number: HK1066790B
Application number: HK04109896.2A
Authority: HK
Inventors: K．贝尔莱恩; U.布雷姆伯格; P．考尔迪罗拉; A．詹马姆詹森; G.约翰森; A.莫特; L．特丹伯格; M.索尔
Original assignee: 比奥维特罗姆股份公开公司
Priority date: 2001-06-11
Filing date: 2002-06-11
Publication date: 2009-11-06

Description

Substituted sulfonamide compounds, process for their preparation and their use as medicaments for the treatment of CNS disorders, obesity and type II diabetes

Technical Field

The present invention relates to substituted sulfonamide compounds, pharmaceutical compositions comprising these compounds and to the use of these compounds for the prevention and treatment of medical disorders related to obesity, type II diabetes and CNS disorders.

Background

Obesity is a disease characterized by an increase in body fat content that results in overweight above an acceptable baseline. Obesity is the most important nutritional disorder in the western world and represents a major health problem in the industrialized countries used. This condition leads to increased mortality due to increased incidence of diseases such as cardiovascular disease, digestive disease, respiratory disease, cancer and type II diabetes. Studies of weight-reducing compounds have been conducted for decades. One of the routes of research is the activation of the 5-hydroxytryptamine energy system either by direct activation of the 5-hydroxytryptamine receptor subtype or by inhibition of 5-hydroxytryptamine reuptake. However, the exact receptor subtype distribution required is not known.

The key transmitter of the peripheral and central nervous systems, 5-hydroxytryptamine (serotonin or 5-HT), widely regulates physiological and pathological functions, including anxiety, sleep regulation, aggression, feeding, and depression. Various 5-hydroxytryptamine receptor subtypes have been identified and cloned. In 1993 one of the 5-HT was cloned from several groups₆Receptors (Ruat, M. et al (1993) communication of biochemistry and biophysics research (biochem. Biophys. Res. Commun.) 193: 268 + 276; Sebben, M. et al (1994) NeuroReport 5: 2553 + 2557). This receptor is positively coupled to adenylate cyclase and exhibits affinity for antidepressants such as clozapine. Recently 5-HT has been reported₆Antagonists and 5-HT₆The effect of antisense oligonucleotides in reducing rat feeding (Bentley, J.C. et al (1999) UK Pharmacology (suppl.) (Br J.Pharmac.suppl.)) 126, P66; Bentley, J.C. et al (1997) J.psychopharmacology (suppl.) (J.Psychopharmacol.suppl.)) A64, 255).

For example, in WO 00/34242 and Isaac, M. et al (2000) "6-bicyclic piperazinyl-1-arylsulfonyl indoles and 6-bicyclic piperidinyl-1-arylsulfonyl indoles derivatives as novel potent and selective 5-HT₆Receptor antagonists "-" communications of Bioorganic and pharmaco-organic chemistry (Bioorganic)&Medicinal Chemistry Letters) 10: 1719-₆Compounds with receptors having improved affinity and selectivity.

Information disclosure

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 are described in J.Med.chem.1970, 13(4), 592-598 as blood flukicides.

WO 99/42465 discloses the reaction of 5-HT₆Sulfonamide derivatives that bind to receptors and are useful for the treatment of CNS disorders, such asAnxiety, depression, epilepsy (epilexy), obsessive compulsive disorder, cognitive disorders, ADHD, anorexia and bulimia schizophrenia, substance abuse.

WO 01/32646A 1 discloses the reaction of 5-HT₆Compounds that bind to receptors and can be used for the treatment of CNS diseases and in particular can be used for the treatment of eating disorders.

WO 99/37623A 2 discloses the reaction of 5-HT₆Compounds that bind to receptors and can be used for the treatment of CNS diseases and in particular can be used for the treatment of eating disorders.

WO 99/42465A 3 discloses the reaction of 5-HT₆Compounds that bind to receptors and can be used for the treatment of CNS diseases and in particular can be used for the treatment of eating disorders.

EP 0815861A 1 discloses the reaction with 5-HT₆Compounds that bind to receptors and may be used in the treatment of CNS disorders.

WO 99/02502A 2 discloses the reaction of 5-HT₆Compounds that bind to receptors and can be used for the treatment of CNS diseases and in particular can be used for the treatment of eating disorders.

WO 98/27081A 1 discloses the reaction of 5-HT₆Compounds that bind to receptors and can be used for the treatment of CNS diseases and in particular can be used for the treatment of eating disorders.

Disclosure of the invention

It has surprisingly been found that compounds of formula (I) act as antagonists against 5-HT in the low nanomolar range₆The receptor exhibits affinity. The compounds of the invention and their pharmaceutically acceptable salts have 5-HT₆Receptor antagonist activity and their potential use in the treatment or prevention of obesity and I I type diabetes, and in the treatment or prevention of central nervous system disorders such as anxiety, depression, panic attacks, memory disorders, sleep disorders, migraine, anorexia, bulimia, mania (binge diso)rders), obsessive-compulsive disorders, psychosis, alzheimer's disease, parkinson's disease, huntington's chorea and/or schizophrenia, Attention Deficit Hyperactivity Disorder (ADHD), substance abuse.

Definition of

Unless otherwise stated or specified, the term "C_1-6Alkyl "refers to straight or branched chain alkyl groups having 1 to 6 carbon atoms. Examples of the lower alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and straight and branched pentyl and hexyl groups.

Unless otherwise stated or specified, the term "C_1-6Alkoxy "refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms. Examples of the lower alkyl group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and straight-and branched-chain pentoxy and hexoxy groups.

The term "halogen" shall mean fluorine, chlorine, bromine or iodine unless otherwise stated or specified.

The term "C_3-7Cycloalkyl "denotes a group having C₃-C₇Cycloalkyl of a large ring and a small ring. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, and cycloheptyl.

The term "heterocycle" refers to a hydrocarbon ring system containing from 4 to 8 membered rings with at least one heteroatom (e.g., S, N or O) as the ring moiety. It includes saturated, unsaturated, aromatic and non-aromatic heterocycles. Suitable heterocyclyl groups include thienyl, furyl, pyridyl, pyrrolidinyl, imidazolyl, pyrazolyl, piperidinyl, azepinyl, morpholinyl, pyranyl, dioxanyl, pyridazinyl, pyrimidinyl and piperazinyl.

The term "heteroaryl" refers to a hydrocarbon ring system containing at least one aromatic ring containing at least one heteroatom, such as O, N or S. Examples of heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, and indolyl.

A compound of the general formula I

In a first aspect, the present invention provides a compound having the general formula I:

wherein:

w is N and- (CH) -, provided that no more than 3W are N;

p is:

provided that P and R are³Can only be in the meta or para position relative to each other;

R¹the method comprises the following steps:

(a)C_1-6an alkyl group;

(b)C_1-6an alkoxyalkyl group;

(c) straight or branched C_1-6A hydroxyalkyl group;

(d) straight or branched C_1-6An alkyl halide; or

(e) A group Ar;

ar is:

(a) a phenyl group;

(b) 1-naphthyl;

(c) 2-naphthyl;

(d) a benzyl group;

(e) cinnamoyl;

(f)5-7 membered optionally aromatic, partially saturated or fully saturated heterocyclic ring containing 1-4 heteroatoms selected from oxygen, nitrogen and sulfur; or

(g) A bicyclic ring system containing at least one heterocycle of (f);

wherein the group Ar is substituted in one or more positions by:

(a) h, X or Y; or

(b)5-7 membered optionally aromatic, partially saturated or fully saturated mono-or bicyclic heterocycle each containing 1-4 heteroatoms selected from oxygen, nitrogen and sulfur;

R²the method comprises the following steps:

(a)H；

(b)C_1-6an alkyl group;

(c)C_1-6an alkoxyalkyl group;

(d) straight or branched C_1-6Hydroxyalkyl, or

(e) Straight or branched C_1-6An alkyl halide;

R³is the following group:

x and Y are independently:

(a)H；

(b) halogen;

(c)C_1-6an alkyl group;

(d)-CF₃；

(e) a hydroxyl group;

(f)C_1-6an alkoxy group;

(g)C_1-4an alkenyl group;

(h) a phenyl group;

(i) a phenoxy group;

(j) a benzyloxy group;

(k) a benzoyl group;

(l)-OCF₃；

(m)-CN；

(n) straight or branched C_1-6A hydroxyalkyl group;

(o) straight or branched C_1-6An alkyl halide;

(p)-NH₂；

(q)-NHR⁴；

(r)-NR⁴R⁵；

(s)-NO₂；

(t)-CONR⁴R⁵；

(u)-NHSO₂R⁴；

(v)-NR⁶COR⁵；

(x)-SO₂NR⁴R⁵；

(z)-C(＝O)R⁴；

(aa)-CO₂R⁴(ii) a Or

(ab)-S(O)_nR⁴(ii) a Wherein n is 0, 1, 2 or 3;

(ac)-S-(C_1-6) An alkyl group;

(ad)-SCF₃；

R⁴and R⁵Independently are:

(a)H；

(b)C_1-6an alkyl group;

(c)C₃-C₇a cycloalkyl group; or

(d) As to R¹Ar as defined;

or, R⁴And R⁵To the radical (CH)₂)₂O、(CH₂)₄O or (CH)₂)_3-5(ii) a And is

R⁶The method comprises the following steps:

(a) h; or

(b)C_1-6An alkyl group.

The invention features, in one aspect, a compound of formula (I):

wherein:

ring B isWherein D is a 5-membered heterocyclic or heteroaromatic ring, said ring containing 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 no more than 3 total W in rings A and B are N;

p is:

p and R³Are linked to the same ring and are arranged meta or para to each other;

R¹the method comprises the following steps:

(a)C_1-6an alkyl group;

(b)C_1-6an alkoxyalkyl group;

(c) straight or branched C_1-6A hydroxyalkyl group;

(d) straight or branched C_1-6An alkyl halide; or

(e) A group Ar;

ar is:

(a) a phenyl group;

(b) 1-naphthyl;

(c) 2-naphthyl;

(d) a benzyl group;

(e) cinnamoyl;

(g) A bicyclic ring system containing at least one heterocycle of (f);

wherein the group Ar is substituted in one or more positions by:

(a) h, X or Y; or

(b)5-7 membered optional aromatic, partially saturated or fully saturated heterocyclic rings each containing 1-4 heteroatoms selected from oxygen, nitrogen and sulfur;

R²the method comprises the following steps:

(a)H；

(b)C_1-6alkyl radical

(c)C_1-6An alkoxy group,

(d) straight or branched C_1-6Hydroxyalkyl, or

(e) Straight or branched C_1-6An alkyl halide;

or R¹And R²To the radical (CH)₂)₄O；

R³One of these is the following group:

x and Y are independently:

(a)H；

(b) halogen;

(c)C_1-6an alkyl group;

(d)-CF₃；

(e) a hydroxyl group;

(f)C_1-6an alkoxy group;

(g)C_1-4an alkenyl group;

(h) a phenyl group;

(i) a phenoxy group;

(j) a benzyloxy group;

(k) a benzoyl group;

(l)-OCF₃；

(m)-CN；

(n) straight or branched C_1-6A hydroxyalkyl group;

(o) straight or branched C_1-6An alkyl halide;

(p)-NH₂；

(q)-NHR⁴；

(r)-NR⁴R⁵；

(s)-NO₂；

(t)-CONR⁴R⁵；

(u)-NHSO₂R⁴；

(v)-NR⁴COR⁵；

(x)-SO₂NR⁴R⁵；

(z)-C(＝O)R⁴；

(aa)-CO₂R⁴(ii) a Or

(ab)-S(O)_nR⁴(ii) a Wherein n is 0, 1, 2 or 3;

(ac)-S-(C_1-6) An alkyl group;

(ad)-SCF₃；

R⁴and R⁵Independently are:

(a)H；

(b)C_1-6an alkyl group;

(c)C₃-C₇a cycloalkyl group; or

(d) As to R¹Ar as defined;

or, R⁴And R⁵Linkage forming group (CH)₂)₂O、(CH₂)₄O or (CH)₂)_3-5(ii) a And is

R⁶The method comprises the following steps:

(a) h; or

(b) Straight or branched C_1-6An alkyl group.

The present invention provides, in a preferred form, a naphthalene compound of formula (II), an isoquinoline compound of formula (III), a quinoline compound of formula (IV), a1, 7-naphthyridine compound of formula (V) and a benzofuran, benzothiophene or indole compound of formula (VI):

wherein R is³P, X and Y are as defined for formula (I); and wherein D in formula (VI) is a 5-membered heterocyclic or heteroaromatic ring, said ring containing one or two heteroatoms 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 may be attached to any unsubstituted carbon atom on D. When the heteroaromatic ring contains one or two nitrogen atoms, the radical R⁶May be attached to the secondary nitrogen.

Preferred compounds of the formulae (I), (II), (III) and (IV), (V), (VI) are those in which:

R¹the method comprises the following steps:

(a)C_1-6an alkyl group; or

(e) A group Ar;

ar is:

(a) a phenyl group;

(b) 1-naphthyl;

(c) 2-naphthyl; or

(f)5-7 membered partially saturated or fully saturated mono-or bicyclic heterocyclic ring each containing 1-4 heteroatoms selected from oxygen, nitrogen and sulfur;

wherein the group Ar is substituted in one or more positions by X or Y: wherein X or Y is:

(a)H；

(b) halogen;

(c)C_1-6an alkyl group;

(d)-CF₃；

(f)C_1-6an alkoxy group;

(g)C_1-4an alkenyl group;

(l)-OCF₃(ii) a Or

(m) straight or branched C_1-6A hydroxyalkyl group;

(n) phenoxy group

(o) benzyloxy group;

(ab)-S(O)_nR⁴(ii) a Wherein n is 0, 1, 2 or 3;

(ac)-S-(C_1-6) An alkyl group;

(ad)-SCF₃；

(v)-NR⁴COR⁵；

(x)-SO₂NR⁴R⁵；

(z)-C(＝O)R⁴

R²the method comprises the following steps:

(a) h; or

(b)C_1-3Alkyl, especially methyl;

or R¹And R²Linkage forming group (CH)₂)₄O；

R³The method comprises the following steps:

wherein R is⁶The method comprises the following steps:

(a) h; or

(b)C_1-6An alkyl group, a carboxyl group,in particular methyl;

x and Y are H; and/or

D is furyl.

Preferred compounds of the formula II are para-substituted naphthalene compounds in which P is

Wherein R is¹And R²As defined for formula (I); and X and Y are H, halogen, methyl, methoxy (see table I). Particularly preferred compounds of this type are those in which R is¹Is phenyl, methylphenyl, methoxyphenyl, dimethoxyphenyl, 1-naphthyl, 2-naphthyl, fluoromethylphenyl, chlorophenyl, dichlorophenyl, fluorochlorophenyl, dichlorothienyl, chlorothienyl, trifluoromethylphenyl or methoxymethylphenyl; r²Is H or methyl; and R is³Is piperazinyl or homopiperazinyl, 3, 5-dimethylpiperazinyl, 4-piperidine, 4- (4, 3) -dihydropyridine, 4- (1, 2, 3, 6) -tetrahydropyridine; r⁶Is H, methyl, ethyl, isopropyl.

Other preferred compounds of formula II are those containing P and R in the para position³The compound of (1).

Other preferred compounds of formula II are those containing P and R in the para position³Wherein P is

Wherein R is¹And R²As defined for general formula (I) (see table III); and X or Y is H, methyl, ethyl, isopropyl, methoxy, thiomethyl, 1-naphthyl, phenoxy, trifluoromethoxy, trifluorothienyl (see Table II). Particularly preferred compounds of this typeCompounds are those in which R is¹Is phenyl, 1-naphthyl, phenoxyphenyl, dimethoxyphenyl, dimethylphenyl, methylchlorophenyl, isopropylphenyl, fluorophenyl, 1(2H) -3, 4-dihydroquinoline, R²Is H or methyl, R³Is piperazinyl, and R⁶Is H.

Preferred compounds of the formula III are isoquinoline compounds, wherein P is

And in the 3-position of the ring, wherein R¹And R²As defined for formula (I); and X or Y is H, methyl, bromo, methoxy, acetylamino (acetylamino) (see table IV). Particularly preferred compounds of this type are those in which R is¹Is phenyl, bromophenyl, methylchlorophenyl, methylphenyl, methoxyphenyl, trimethylphenyl, dimethoxyphenyl, bromomethoxyphenyl; r²Is H or methyl; and R is³Is a methylpiperazinyl group.

Preferred compounds of the formula IV are quinoline compounds, wherein P is

And in the 5-position of the ring, wherein R¹And R²As defined for formula (I) and X or Y is H (see Table V). Particularly preferred compounds of this type are those in which R is¹Is phenyl; r²Is H or methyl; and R is³Is piperidinyl.

Preferred compounds of the formula V are 1, 7-naphthyridine compounds in which P is

And in the 8-position of the ring, wherein R¹And R²As defined for general formula (I) and X and Y are halogen, methoxy (see table V). Particularly preferred compounds of this type are those in which R is¹Is phenyl, dimethoxyphenyl, 1-naphthyl; r²Is H or methyl; and R is³Is piperidinyl.

Preferred compounds of the formula VI are benzofuran compounds in which P is

And in the 5-position of the ring, wherein R¹And R²As defined for formula (I); and wherein D in formula (VI) is a 5-membered heterocyclic or heteroaromatic ring, said ring containing one or two heteroatoms 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 may be attached to any unsubstituted carbon atom on D. When the heteroaromatic ring contains one or two nitrogen atoms, the radical R⁶May be attached to a secondary nitrogen; and X and Y are halogen, methoxy (see table V). Particularly preferred compounds of this type are those in which R is¹Phenyl, dichlorophenyl, bromophenyl, dichloromethylphenyl, 1-naphthyl, phenyl, methylphenyl, fluorophenyl, thiophenyl, chlorophenylthio; r²Is H or methyl; and R is³Is piperidinyl or N-methylpiperidinyl.

TABLE I

Para-substituted naphthalene compounds of the general formula II, where P isAnd X, Y is H:

TABLE II 3-substituted naphthalene compounds of the general formula II, where P isAnd X, Y is HH:

TABLE III 5-substituted naphthalene compounds of the general formula II, where P is

And X, Y and R⁴Is H:

TABLE IV

A meta-substituted isoquinoline compound of the general formula III wherein P isAnd X, Y is H:

TABLE V

5-substituted quinoline compounds of the general formula IV, wherein P isAnd X, Y is H:

TABLE VI

1, 7-naphthyridine compounds of the formula V wherein P is

R²And X, Y is H:

TABLE VII

5-substituted benzofuran compounds of the general formula VI in which P isR²And X, Y is H:

preparation method

Can pass throughWith selected diamines (R)³) The compounds of the present invention (tables I, II, IV, V, VI) were prepared starting from halonitro-substituted bicyclic aromatic rings by base (potassium carbonate) -catalyzed aromatic nucleophilic substitution of the halogen at the desired position on the central bicyclic ring. Reduction of the nitro group, suitably located on the central bicyclic ring, by Raney-Ni catalyzed reaction to give the aniline by reaction with selected alkyl-or aryl-sulfonyl chlorides (R)¹-SO₂-Cl) to further substitute it. Scheme 1 and scheme 3.

The compounds of the present invention (Table III) can be prepared starting from a fluorine substituted bicyclic aromatic ring, wherein the sulfonyl chloride functionality is introduced by acid catalyzed sulfonylation. Reacting the sulfonyl group further with selected anilines (R)¹-NH₂) And (4) reacting. Introduction of diamine groups (R) by base-catalyzed aromatic nucleophilic substitution³). Reaction scheme 2.

The compounds of the present invention can be prepared starting from an iodine-substituted bicyclic aromatic ring (Table VII). Introduction of diamine groups (R) by palladium-catalyzed nucleophilic substitution³). Reduction of the nitro group, suitably located on the central bicyclic ring, by Raney-Ni catalyzed reaction to give the aniline by reaction with selected alkyl-or aryl-sulfonyl chlorides (R)¹-SO₂-Cl) sulfonylation to further substitute it. Scheme 4.

The chemicals used in the above synthetic route may include: such as solvents, reagents, catalysts, protecting groups and deprotecting reagents. The above process may also include the step of adding or removing suitable protecting groups before or after the steps specifically described herein in order to finally synthesize the compound of general formula (I). In addition, various synthetic steps may be performed in an alternative order to obtain the desired compounds. Synthetic chemical transformations and protecting group methods (protection and deprotection) for synthesizing useful compounds are well known in the art and include: as described in the following documents, for example: larock, Integrated Organic Transformations (Comprehensive Organic Transformations), VCHPublishes (1989); greene and p.g.m.wuts, Protective Groups in Organic Synthesis, 2 nd edition, John Wiley and Sons (1991); fieser and m.fieser, Fieser and Fieser reagents for Organic Synthesis (Fieser and Fieser's reagent for Organic Synthesis), John Wiley and Sons (1994); and "Encyclopedia of reagents for Organic Synthesis" (Encyclopedia of reagents for Organic Synthesis), edited by Paquette, John Wiley and Sons (1995) and subsequent publications thereof.

Depending on the reaction conditions, the end product of the formula (I) is obtained in neutral or salt form. Both the free base and the salt of these end products are within the scope of the present invention.

The acid addition salts of the novel compounds can be converted into the free bases in a manner known per se using basic reagents such as alkali metals or by ion exchange. The resulting free base may also form salts with organic or inorganic acids.

In the preparation of the acid addition salt, it is preferred to use such acids which form suitable therapeutically acceptable salts. Examples of such acids are: a halogen acid; sulfuric acid; phosphoric acid; nitric acid; aliphatic, alicyclic, aromatic or heterocyclic carboxylic 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-hydroxybenzoic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, mandelic acid or naphthalenesulfonic acid.

In the context of the present description and the appended claims, a given chemical formula or name shall include all stereoisomers and optical isomers present and racemates thereof. All possible diastereomeric forms (pure enantiomers, tautomers, racemic mixtures and unequal mixtures of two enantiomers) are within the scope of the invention. Such compounds may also exist as cis-or trans-, E-or Z-double bond isomers. All isomeric forms are contemplated.

Pharmaceutical formulations are generally prepared by mixing the active substance or a pharmaceutically acceptable salt thereof with customary pharmaceutical excipients. The preparation can be further prepared by a known method such as granulation, compression, microencapsulation, spray coating and the like.

The present invention relates to methods of treating or preventing obesity, type II diabetes, and/or central nervous system disorders. The method includes the step of administering to a subject (e.g., a mammal, human, horse or cat) in need of such treatment an effective amount of one or more compounds of formula (I) as described above.

The invention also features methods of reducing body weight (e.g., treating a weight disorder). The method comprises the step of administering to a subject in need thereof an effective amount of a compound of formula (I). The term "weight disorders" as used herein refers to abnormal body weight (e.g. overweight) due to an imbalance between energy intake and energy expenditure. Such body weight disorders include obesity.

Also included within the scope of the invention are 5-HT₆Methods of modulating (e.g., inhibiting) receptor activity. The method comprises the step of administering to a subject in need thereof an effective amount of a compound of formula (I).

The methods described herein may further comprise the step of identifying a subject in need of treatment for obesity, type II diabetes, or disorders of the central nervous system, or in need of weight loss.

An "effective amount" refers to the amount of a compound that provides a therapeutic effect to the subject being treated. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject produces an indication or feels an effect). For clinical use, the compounds of the invention are formulated into pharmaceutical preparations for oral, rectal, parenteral or other mode of administration. The active compounds are usually used in an amount of 0.1 to 95% by weight of the preparation, preferably 0.2 to 20% by weight of the preparation for parenteral use and preferably 1 to 50% by weight of the preparation for oral administration.

The typical daily dosage of active substance varies within wide ranges and depends on various factors such as: such as the individual needs and route of administration of each patient. In general, the oral and parenteral dosage will be in the range of 5 to 1000 mg/day of active substance, preferably 50 to 150 mg/day.

The following specific examples are for illustrative purposes only and are not intended to limit the remainder of the disclosure in any way. Without further explanation, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. The entire disclosures of all publications cited herein are incorporated herein by reference in their entirety.

Examples

Synthesis of the examples and intermediates in Table I

Reaction scheme 1

In scheme 1, the following notation is used: (i) k₂CO₃DMF, selected diamines; (ii) h₂，

Raney-Ni or Pd/C, THF: ethanol; (iii) (BOC)₂O，NaOH；(iv)R¹-SO₂-Cl，Py，CH₂Cl₂(ii) a (v) Ethereal HCl; (vi) an alkyl halide. TfO ═ triflate.

General method A

Reduction of nitronaphthalene derivatives to naphthylamine derivatives

To a solution of the nitronaphthalene derivative (1 eq) in EtOH: THF (4: 1) was added Raney-Ni (. about.1.0 mL of EtOH suspension), followed by hydrazine monohydrate (6 eq). The compound was stirred vigorously for 3 hours and then filtered through celite, pretreated with water. The filtrate was concentrated, followed by addition of toluene. Purification by flash column chromatography (SiO)₂，CHCl₃/MeOH/NH₃9: 1: 0.4% and 2 parts of petroleum ether (light petroleum))A free base of a naphthylamine derivative.

General method B

Reaction of 4-nitro-chloronaphthalene with diamine

Diamines (1.2 equiv.) were added to chloronaphthalene derivatives (1 equiv.) and K₂CO₃(3.5) dissolving in DMF to obtain a suspension. The suspension was stirred at 65 ℃ for 16 hours and then filtered. The volatiles were removed to give a crude residue. Purification of the residue by flash chromatography (SiO)₂，CHCl₃→CHCl₃/10％MeOH/0.4％NH₃Water) to give the corresponding product as the free base.

(a) Intermediates for preparing the compounds of tables I, II, IV and V according to scheme 1

Intermediate 1

1-methyl-4- (4-nitro-1-naphthyl) -1, 4-diazepin: to 1-chloro-4-nitronaphthalene (1.0g, 4.82mmol) and K₂CO₃To a suspension of (2.0g, 14.46mmol) in DMF (10mL) was added 1-methyl-1, 4-diazepin (0.66g, 5.78 mmol). The suspension was stirred at 65 ℃ for 16 hours and then filtered. The volatiles were removed to give a crude residue. Purification of the residue by flash chromatography (SiO)₂，CHCl₃→CHCl₃/10％MeOH/0.4％NH₃Water) to yield 0.79g (57%) of the free base:

¹H NMR(CDCl₃)δ8.85-8.75(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)δ157.47，139.13，129.26，127.82，127.66，126.53，125.69，125.40，123.94，111.22，58.37，57.37，55.44，54.71，46.97，27.88；

MS (posES-FIA) m/z ═ measured value: 285.1463, calculated as: 285.1477.

intermediate 2

4- (4-methyl-1, 4-diazepin-1-yl) -1-naphthylamine: to a solution of 1-methyl-4- (4-nitro-1-naphthyl) -1, 4-diazepin (0.793g, 2.78mmol) in 40mL EtOH: THF (4: 1) was added Raney-Ni (. about.1.0 mL EtOH suspension), followed by hydrazine monohydrate (0.696g, 13.9 mmol). The compound was stirred vigorously for 3 hours and then filtered through celite, pretreated with water. The filtrate was concentrated, followed by addition of toluene. Purification by flash column chromatography (SiO)₂，CHCl₃/MeOH/NH₃9: 1: 0.4% and 2 parts of petroleum ether) to yield 0.441g (62%) of the free base:

¹H NMR(CDCl₃)δ8.37-8.29(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 1-chloro-4-nitronaphthalene (0.794g, 3.82mmol) and K₂CO₃To the resulting mixture (0.791g, 5.73mmol) in DMF (3mL) was added N-ethylpiperazine (0.486mL, 3.82 mmol). The mixture was heated in a 100W microwave oven for 1 minute. The reaction mixture was cooled and the procedure was repeated 5 times. The mixture was filtered and concentrated. The crude product was purified by column chromatography (SiO)₂，CHCl₃/MeOH/NH₃9: 1: 0.4%) to yield 0.950g (87%) of a light reddish-brown solid:

¹H NMR(CDCl₃)δ；8.75-8.70(m，1H)，8.30(d，J＝8.4Hz，1H)，8.24-8.20(m，1H)，7.72-7.66(m，1H)，7.60-7.54(m，1H)，7.02(d，J＝8.4Hz，1H)，3.32-3.24(m，4H)，2.85-2.70(m，4H)，2.54(q，J＝7.3Hz，2H)，1.17(tr，J＝7.3Hz，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 (0.481g, 2.32mmol) and cis-2, 6-dimethylpiperazine (0.481g, 2.32mmol) by the above method to give 0.554g (84%) of the pure product as a pale reddish brown solid;

¹H NMR(CDCl₃)δ；8.76-8.71(m，1H)，8.30(d，J＝8.4Hz，1H)，8.23-8.14(m，1H)，7.72-7.66(m，1H)，7.61-7.55(m，1H)，7.0(d，J＝8.4Hz，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 (0.395g, 1.90mmol) and 2-methylpiperazine (0.395g, 1.90mmol) by the above method to give 0.470g (84%) of the pure product as a solid;¹HNMR(CDCl₃)δ8.75-8.70(m，1H)，8.29(d，J＝8.55Hz，1H)，8.24-8.20(m，1H)，7.72-7.65(m，1H)，7.61-7.55(m，1H)，7.00(d，J＝8.55Hz，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＝6.4Hz，3H))；MS(EI)m/z 271(M⁺).

intermediate 6

2- (4-Nitro-1-naphthyl) octahydropyrrolo [1, 2-a)]Pyrazine: from 1-chloro-4-nitronaphthalene (0.306g, 1.47mmol) and octahydropyrrolo [1, 2a ] by the above method]Pyrazine (0.185g, 1.47mmol) prepared this compound to give 0.332g (76%) of the pure product as a yellow oil;¹H NMR(CDCl₃)δ8.75-8.71(m，1H)，8.29(d，J＝8.5Hz，1H)，8.23-8.20(m，1H)，7.72-7.67(m，1H)，7.60-7.55(m，1H)，7.05(d，J＝8.5Hz，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-diazepan: to 1-chloro-4-nitronaphthalene (0.971g, 4.68mmol) and K₂CO₃(0.973g, 7.10mmol) in CH₃CN (5.0mL) to the resulting solution was added homopiperazine (0.711g, 7.10 mmol). The reaction mixture was heated in a sealed container in a microwave oven at 120 ℃ for 10 minutes. The suspension was filtered and concentrated. Purification by column chromatography (SiO)₂，CHCl₃→CHCl₃MeOH 9: 1) to give 0.952g of pure product;

¹H NMR(CDCl₃)δ8.80-8.74(m，1H)，8.29(d，J＝8.5Hz，1H)，8.25-8.19(m，1H)，7.71-7.63(m，1H)，7.57-7.49(m，1H)，7.03(d，J＝8.5Hz，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

4- (4-nitro-1-naphthyl) -1-piperazinecarboxylic acid tert-butyl ester: 1-chloro-4-nitronaphthalene (2.7g, 13mmol), tert-butyl-1-piperazinecarboxylate (2.4g, 13mmol) and potassium carbonate (2g) were heated together in DMSO (100mL) at 90 ℃ overnight. The solution was cooled to room temperature and poured into water (500 mL). The product was collected by filtration and recrystallized from methanol/water to yield 2.8g (60%) of the title compound;

¹H NMR(CDCl₃)δ1.52(s，9H)，3.2(br，4H)，3.75(br，4H)，7.04(d，J＝8.53Hz，1H)，7.62(t，J＝7.02Hz，1H)，7.73(t，J＝7.02Hz，1H)，8.25(d，J＝8.53Hz，1H)，8.3(d，J＝8.54Hz，1H)，8.73(d，J＝8.53Hz，1H).

intermediate 9

4- (4- { bis [ (4-methylphenyl) sulfonyl group)]Amino } -1-naphthyl) -1-piperazinecarboxylic acid 1-tert-butyl ester: tert-butyl 4- (4-nitro-1-naphthyl) -1-piperazinecarboxylate (1g, 2.8mmol) in ethanol (200mL) was hydrogenated using Pd/C (10%, 0.2g) at atmospheric pressure for 3 hours, after which the uptake of hydrogen was stopped. The solution was filtered and evaporated. The residue was dissolved in toluene (100mL) and evaporated to an off-whiteA colored solid. This solid was dissolved in acetonitrile (50mL) containing 4-dimethylaminopyridine (0.73 g). Tosyl chloride (1.14g, 6mmol) was added and the mixture was stirred at 35 ℃ overnight. Brine was added and the product was extracted into ethyl acetate (2x100 mL). With MgSO₄The organic extract was dried and evaporated to give a light brown solid which was recrystallized from ethanol. Yield 1.04g (58%) as a white solid.

Mp 176-178；¹H NMR(400MHz，CDCl₃)δ1.40(s，9H)，2.36(s，6H)，3.0(br，4H)，3.6(br，4H)，6.81(AB，J＝8.03Hz，1H)，6.89(AB，J＝8.03Hz，1H)，7.17(m，1H)，7.19(d，J＝7.53Hz，4H)，7.32(m，1H)，7.45(d，J＝8.53Hz，1H)，7.70(d，J＝8.54Hz，4H)，8.03(d，J＝8.03Hz，1H).

Intermediate 10

4- (4- { [ (4-methylphenyl) sulfonyl ] amino } -1-naphthyl) -1-piperazinecarboxylic acid 1-tert-butyl ester: 4- (4- { bis [ (4-methylphenyl) sulfonyl ] amino } -1-naphthyl) -1-piperazinecarboxylic acid 1-tert-butyl ester (1g, 1.6mmol) was dissolved in ethanol (50 mL). Potassium hydroxide (85%, 0.54g) was added and the solution refluxed for 12 hours. The solution was poured into water (100mL) and acidified with acetic acid (0.6 mL). The product precipitated and was collected by filtration, washed with water and dried. The yield was 0.81 g;

¹H NMR(400MHz，CDCl₃)δ1.36(s，9H)，2.22(s，3H)，2.8(br，4H)，3.5(br，4H)，6.47(s，1H)，6.79(d，J＝8.03Hz，1H)，7.03(d，J＝8.03Hz，2H)，7.07(d，J＝8.03Hz，1H)，7.3(m，2H)，7.47(d，J＝8.53Hz，2H)，7.69(1，J＝9.04Hz，1H)，8.03(d，J＝7.02Hz，1H).

intermediate 11

4- (4- { methyl [ (4-methylphenyl) sulfonyl ] amino } -1-naphthyl) -1-piperazinecarboxylic acid 1-tert-butyl ester: 1-tert-butyl 4- (4- { [ (4-methylphenyl) sulfonyl ] amino } -1-naphthyl) -1-piperazinecarboxylate (0.1g, 0.2mmol) was dissolved in DMSO (5mL) and potassium carbonate (0.2g) and methyl iodide (0.1g) were added. The mixture was stirred and heated at 85 ℃ for 15 hours. The solution was poured into water (50 mL). The product precipitated and was collected by filtration, washed with water and dried. Yield 0.078g (78%) as a white solid.

¹H NMR(400MHz，CDCl₃)δ1.60(s，9H)，2.56(s，3H)，3.1(br，4H)，3.36(s，3H)，3.7(br，4H)，6.90(AB，J＝8.03Hz，1H)，6.97(AB，J＝8.03Hz，1H)，7.41(d，J＝8.03Hz，2H)，7.6(m，2H)，7.75(d，J＝8.29Hz，2H)，8.3(m，2H).

Intermediate 12

Trifluoromethanesulfonic acid 5-nitro-8-quinolinate: to 5-nitro-8-quinolinol (1.89g, 9.40mmol) and Et₃N (6.60mL, 4.70mmol) in CH₂Cl₂To the resulting solution (125mL) was added N-phenyl-trifluoromethanesulfonimide (5.06g, 14.1 mmol). The mixture was stirred at room temperature for 16 hours and then additional N-phenyltrifluoromethanesulfonimide (1.0 eq) was added and the mixture was stirred for a further 16 hours. The reaction mixture was washed with 10% NaHCO₃Washing with aqueous solution, using K₂CO₃Dilute, filter and concentrate. The crude residue was triturated in MeOH to give 1.2g (40%) of the pure product:

¹H NMR(CDCl₃)δ9.20-9.18(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 trifluoromethanesulfonic acid 5-nitro-8-quinolinate (0.50g, 1.56mmol) and K₂CO₃(0.43g, 3.12mmol) in CH₃CN (6.0mL) to the resulting suspension was added 1-methylpiperazine (0.19mL, 1.71 mmol). The suspension was stirred at room temperature for 16 hours. The mixture was filtered and concentrated and purified by flash column chromatography (SiO)₂，CHCl₃/MeOH/NH₃9: 1: 0.4%) to yield 0.509g of pure product: reverse phase HPLC > 95% purity; MS (posESI) M/z 273(M + H).

Intermediate 14

(2R, 6S) -2, 6-dimethyl-4- (4-nitro-1-naphthyl) -1-piperazinecarboxylic acid tert-butyl ester to a solution of cis-3, 5-dimethyl-1- (4-nitro-1-naphthyl) piperazine (0.565g, 1.98mmol) and NaOH (0.198g, 4.95mmol) in THF: water (20mL, 1: 1) was added a solution of di-tert-butyl dicarbonate (1.30g, 5.94mmol) in THF (4 mL). The reaction mixture was stirred at room temperature for 4 hours, followed by the addition of 3.0 equivalents of di-tert-butyl dicarbonate and 2.5 equivalents of NaOH. The mixture was stirred at room temperature for another 3 days. The mixture was concentrated and taken up in CHCl₃(3 × 20 mL). By K₂CO₃The combined organic phases were dried, filtered and concentrated. The crude residue was purified by column chromatography using CHCl₃As eluent, 0.200g (26%) of pure product was thus obtained as a 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 (0.436g, 1.61mmol) by the above method: 0.552g (92%) of the pure product was produced as a yellow oil;

¹H NMR(CDCl₃)δ8.73-8.70(m，1H)，8.34-8.30(m，1H)，8.28(d，J＝8.5Hz，1H)，7.74-7.69(m，1H)，7.63-7.58(m，1H)，7.02(d，J＝8.5Hz，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 the Compounds of the invention

Example 1

4-methyl-N- [4- (1-piperazinyl) -1-naphthyl ] benzenesulfonamide hydrochloride

Coupling 4- (4- { [ (4-methylphenyl) sulfonyl]Amino } -1-naphthyl) -1-piperazinecarboxylic acid 1-tert-butyl ester (intermediate 10) (0.4g, 0.8mmol) was dissolved in THF (20mL) and dissolved with 1N HCl in ether (30mL)The treatment was carried out for 12 hours. The product was collected as a pale pink solid. Yield 0.2g (60%). mp181 ℃ (decomposition);¹H NMR(DMSO-d₆)δ2.80(s，3H)，3.1(br，4H)，3.3(br，4H)，7.00(q，J＝8.06Hz，2H)，7.27(ab，J＝8.30Hz，2H)，7.4-7.5(m，2H)，7.53(ab，J＝8.30Hz，2H)，7.99(d，J＝8.06Hz，1H)，8.07(d，J＝7.57Hz，1H)，9.2(br，2H)；

MS (ESI +): to C₂₁H₂₃N₃O₂Measured value of S M/z 381.1499M⁺Calculated 381.1611.

Example 2

3, 4-dimethoxy-N- [4- (1-piperazinyl) -1-naphthyl ] benzenesulfonamide hydrochloride

Tert-butyl 4- (4-nitro-1-naphthyl) -1-piperazinecarboxylate (1g, 2.8mmol) in ethanol (200mL) was hydrogenated with Pd/C (10%, 0.2g) at atmospheric pressure for 3h, after which the uptake of hydrogen was stopped. The solution was filtered and evaporated. The residue was dissolved in toluene (100mL) and evaporated to an off-white solid. This solid was dissolved in acetonitrile (50mL) containing 4-dimethylaminopyridine (0.73 g). The solution was divided into 3 portions. To one portion was added 3, 4-dimethoxybenzenesulfonyl chloride (0.24 g). The mixture was stirred at 40 ℃ for 4 hours under nitrogen. Ethyl acetate (50mL) was added and the solution was washed with brine (2 × 100 mL). Separating the organic phase with MgSO₄Dried and evaporated. Purification by flash chromatography (SiO)₂Petroleum ether (petroleum): ethyl acetate 1: 1) to give the butoxycarbonyl protected product, which was dissolved in methanol (2mL) and treated with 1N HCl in ethyl acetate (25mL) for 3 hours. The product was precipitated with diethyl ether (200mL) and collected as a pale pink solid 45mg (12%).

¹H NMR(DMSO-d₆)δ3.17(br，4H)，3.35(br，4H)，3.63(s，3H)，3.78(s，3H)，7.03(d，J＝8.55Hz，1H)，7.07(ab，J＝13.92，8.06Hz，2H)，7.24(dd，J＝8.30，2.19Hz，1H)，7.46(m，1H)，7.51(m，1H)，8.05(d，J＝7.57Hz，1H)，8.12(d，J＝7.56Hz，1H)，9.2(br，2H)，9.93(s，1H)；

MS (ESI +): to C₂₂H₂₅N₃O₄S m/z 427(M+H)⁺。

Example 3

3, 4-bis-fluoro-N- [4- (4-methyl-1, 4-diazepin-1-yl) -1-naphthyl ] benzenesulfonamide hydrochloride

To (intermediate 2)4- (4-methyl-1, 4-diazepin-1-yl) -1-naphthylamine (0.173g, 0.676mmol) and pyridine (0.450mL, 4.73mmol) in CH₂Cl₂(3mL) to the resulting solution was added 2, 4-di-fluorobenzenesulfonyl chloride (0.158g, 0.743mmol) in CH₂Cl₂(2mL) of the resulting solution. The mixture was stirred at room temperature for 16 hours and then concentrated. The crude mixture (SiO) was purified by column chromatography₂，CHCl₃/MeOH/NH₃9: 1: 0.4%). The free base was converted to its HCl-salt and recrystallized from MeOH and ether to give 0.227g (79%) of the salt:

¹H NMR(DMSO-d6)δ11.23(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-diazepin-1-yl) -1-naphthyl ] benzenesulfonamide hydrochloride

To (intermediate 3 after reduction according to general procedure A) 4- (4-methyl-1, 4-diazepin-1-yl) -1-naphthylamine (0.173g, 0.676mmol) and pyridine (450. mu.L, 4.73mmol) in CH₂Cl₂(3.0mL) to the resulting solution was added 3-fluorobenzenesulfonyl chloride (0.145g, 0.743mmol) in CH₂Cl₂(1.0mL) of the solution. The solution was stirred at room temperature for 16 hours and the volatiles were evaporated. The crude product was purified by column chromatography (SiO)₂，CHCl₃/MeOH/NH₃9: 1: 0.4%) to yield 240mg of solid productTrituration with MeOH/ether afforded 0.180g (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, partially masked 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 by the above method from (intermediate 3 after reduction according to general procedure a) 4- (4-ethyl-1-piperazinyl) -1-naphthylamine (0.241g, 0.945mmol) and benzenesulfonyl chloride (0.121mL, 0.945mmol) to give HCl-salt 0.210g (51%);

¹H NMR(CD₃OD)δ8.19-8.15(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＝8.0Hz，1H)，7.11(d，J＝8.0Hz，1H)，3.75-3.40(m，6H)，3.34(q，J＝7.6Hz，2H)，3.25-3.10(m，2H)，1.43(tr，J＝7.6Hz，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 (intermediate 6)2- (4-nitro-1-naphthyl) octahydropyrrolo [1, 2 a)]To a solution of piperazine (0.160g, 0.54mmol) in 10mL THF/EtOH (20mL, 1: 4) was added Raney-Ni (1.0mL EtOH suspension), followed by hydrazine monohydrate (0.135g, 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(3mL) and to this solution were added pyridine (0.35mL, 3.78mmol) and p-toluenesulfonyl chloride (0.13g, 0.54mmol)l). The reaction mixture was stirred at room temperature for 16 hours and then concentrated. The crude product was purified by column chromatography (SiO)₂，CHCl₃/MeOH/NH₃9: 1: 0.4%) to yield 0.217g (95%) of the free base, which was converted into its HCl-salt:

¹H NMR(CD₃OD) Δ 8.21 to 8.14(m, 1H), 7.97 to 7.93(m, 1H), 7.58 to 7.47(m, 3H), 7.43 to 7.37(m, 1H), 7.25 to 7.10(m, 4H), 4.12 to 4.02(m, 1H), 3.80 to 3.0(m, partially masked by a solvent signal, 8H), 2.45 to 2.10(m, 3H), 2.35(s, 3H), 1.87 to 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 (0.133g, 0.447mmol) by the above method: yield 0.160g (76%) of pure product, its free base, which was converted into 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 ═ 8.0Hz, 1H), 7.16(d, J ═ 8.0Hz, 1H), 7.09-7.07(m, 1H), 6.95-6.92(m, 1H), 3.83(s, 3H), 3.82-3.0(m, partially masked by the 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 (intermediate 3 after reduction according to general procedure A) 4- (4-ethyl-1-piperazinyl) -1-naphthylamine (0.241g, 0.945mmol) and pyridine (0.534mL, 0.945mmol) in CH₂Cl₂(3.0mL) to the resulting solution was added p-toluenesulfonyl chloride (0.180g, 0.945mmol) in CH₂Cl₂(2.0mL) solution. Will be provided withThe mixture was stirred at room temperature for 16 hours, followed by addition of CH₂Cl₂(15 mL). The reaction mixture was washed with saturated NaHCO₃Washing with aqueous solution and adding Na₂SO₄Dried, filtered and concentrated. The crude residue was purified by column chromatography (SiO)₂，CHCl₃→CHCl₃/MeOH/NH₃9: 1: 0.4%) to give a solid, which is converted into its HCl-salt: HCl-salt 0.372g (88%) was produced;

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 ═ 8.0Hz, 1H), 7.10(d, J ═ 8.0Hz, 1H), 3.80-3.10(m, partially solvent masked, 10H), 2.35(s, 3H), 1.43(tr, J ═ 7.3Hz, 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 (0.189g, 0.55mmol) and 3, 4-dimethoxybenzenesulfonyl chloride (0.130g, 0.55mmol) by the above method: HCl-salt 0.068g (26%) was produced; 1H NMR (CD)₃OD)

Example 10

4-methyl-N- [4- (4-methyl-1-piperazinyl) -1-naphthyl ] -1-benzenesulfonamide hydrochloride

To 4- (4-methyl-1-piperazinyl) -1-naphthylamine (prepared according to methods A and B) (0.099g, 0.409mmol) and pyridine (231. mu.L, 2.86mmol) were dissolved in CH₂Cl₂(3.0mL) to the resulting solution was added 4-methylbenzenesulfonyl chloride (0.078g, 0.409mmol) in CH₂Cl₂(1.0mL) of the solution. The solution was stirred at room temperature for 16 hours and then with saturated NaHCO₃Washing with aqueous solution and adding Na₂SO₄Dried, filtered and concentrated. The crude product was purified by column chromatography (SiO)₂，CHCl₃→CHCl₃/MeOH/NH₃9: 1: 0.4%) to give soda ash, which is converted into its HCl-salt: yield 110mg (62%);¹h NMR (DMSO-d6) delta 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) (calculated 395.1667).

Example 11

4-methyl-N- [4- (5-methyl-2, 5-diazabicyclo [2, 2, 1] hept-2-yl ] -naphthyl ] benzenesulfonamide hydrochloride

To 4- (5-methyl-2, 5-diazabicyclo [2, 2, 1]]Hept-2-yl) -1-naphthylamine (0.210g, 0.829mmol) (prepared as in methods A and B), pyridine (468uL, 5.80mmol) dissolved in CH₂Cl₂(3.0mL) to the resulting solution was added 4-methylbenzenesulfonyl chloride (0.158g, 0.829mmol) in CH₂Cl₂(1.0mL) of the solution. The solution was stirred at room temperature for 16 hours and then concentrated. The crude product was purified by column chromatography (SiO)₂，CHCl₃→CHCl₃/MeOH/NH₃9: 1: 0.4%) to give soda ash, which is converted into its HCl-salt: yield 160mg (43%);

¹h NMR (DMSO-d6) delta 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) (calculated 407.1667).

Example 12

4-methyl-N- [4- (3-methyl-1-piperazinyl) -1-naphthyl ] benzenesulfonamide hydrochloride

To (intermediate 8)4- (4-amino-1-naphthyl) -2-methyl-1-piperazinecarboxylic acid tert-butyl ester after reduction according to method AThe ester (0.189g, 0.55mmol), pyridine (0.311mL, 3.85mmol) were dissolved in CH₂Cl₂To the resulting solution (3mL) was added tosyl chloride (0.105g, 0.55 mmol). The solution was stirred at room temperature for 16 hours and then concentrated. The crude product was purified by column chromatography (SiO)₂EtOAc: pentane 3: 7). The pure intermediate was dissolved in a small amount of MeOH and deprotected using HCl gas saturated ether. The precipitate was collected by filtration and triturated with MeOH and ether: HCl-salt 0.047g (19%) was produced;

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, partially masked 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, partially H)₂O signal masking, 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 reduced nitro compound was added 2-naphthalenesulfonyl chloride (0.23 g). The mixture was stirred at 40 ℃ for 4 hours under nitrogen and worked up as described above. The resulting product was identified as 4- (4- { bis [ (2-naphthalene) sulfonyl group]Amino } -1-naphthyl) -1-piperazinecarboxylic acid 1-tert-butyl ester. This disulfonamide was refluxed in ethanol (10ml) containing NaOH (0.1g) for 3 hours. This solution was added to a solution of HCl in ethyl acetate (1N, 100mL) and stirred overnight. The solution was evaporated to give the crude product, which was purified by preparative hplc (CH)₃CN∶H₂O10% -50% gradient). The yield was 47 mg.

¹H NMR(400MHz，DMSO-d₆)δ3.05(br，4H)，3.3(br，4H)，7.0(s，2H)，7.2-7.5(m，2H)，7.55(t，J＝7.9Hz，1H)，7.62(t，J＝6.9Hz，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-14- (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) (75mg, 0.15mmol) was dissolved in methanol (5mL) and treated with a 1N HCl in ether (20 mL). After stirring overnight the product precipitated and was collected by filtration, washed with ether and dried. 60mg (92%) of an off-white solid were produced.

Example 15

N- [4- (1, 4-diazepin-1-yl) -1-naphthyl ] -4-methylbenzenesulfonamide hydrochloride

To (intermediate 7 after reduction according to method A) 4- (1, 4 diazepin-1-yl) -1-naphthylamine (0.399g, 1.17mmol), pyridine (661 uL, 8.19mmol) and Et₃N (329. mu.L, 2.34mmol) in CH₂Cl₂(3.0mL) to the resulting solution was added 4-methylbenzenesulfonyl chloride (0.223g, 1.17mmol) in CH₂Cl₂(1.0mL) of the solution. The solution was stirred at room temperature for 16 hours and then concentrated, and the crude product (SiO) was purified by column chromatography₂，CHCl₃→CHCl₃/MeOH/NH₃9: 1: 0.4%) to yield 0.360g of boc-protected compound. Deprotection was performed by dissolving the intermediate in MeOH and then adding HCl-gas dissolved in ether. The precipitate was collected by filtration to give 0.143g (28%) of the pure compound as 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 ═ 8.16Hz, 1H), 7.01(d, J ═ 8.16Hz, 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) (calculated 395.1667)

Example 16

N- [4- (1, 4-diazepin-1-yl) -1-naphthyl ] -2-methoxy-4-methylbenzenesulfonamide hydrochloride

To (intermediate 7 after reduction according to method A) 4- (1, 4 diazepin-1-yl) -1-naphthylamine (0.399g, 1.17mmol), pyridine (661 uL, 8.19mmol) and Et₃N (329. mu.L, 2.34mmol) in CH₂Cl₂(3.0mL) to the resulting solution was added 2-methoxy-4-methylbenzenesulfonyl chloride (0.258g, 1.17mmol) in CH₂Cl₂(1.0mL) of the solution. 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 ℃ for 16 hours. The suspension was concentrated and water was added. Neutralize the solution with 1N HCl and use CH₂Cl₂(2x20 mL). The combined organic phases were washed with brine, washed with Na₂SO₄Dried and concentrated. Performing column chromatography (SiO)₂，CH₂Cl₂→CH₂Cl₂MeOH (95: 5) to give 0.432g of a light reddish-brown solid. Deprotection with MeOH ether saturated with HCl-gas afforded a brown solid, which was collected by filtration. The product was recrystallized from MeOH/ether to give 109mg (20%) of the product as its HCl-salt:

¹h NMR (DMSO-d6) delta 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), 6.75-6.748 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) (calculated 425.1774)

Example 17

N- (2-methoxy-4-methylphenyl) -4- (3, 5-trimethyl-1-piperazinyl) -1-naphthalenesulfonamide hydrochloride

To a solution of 4- (2, 6-dimethyl-1-piperazinyl) -1-naphthylamine (intermediate 4 after reduction according to method A) (0.203g, 0.563mmol) and pyridine (322. mu.L, 3.99mmol) in DCM (3.0mL) was added a solution of 4-methylbenzenesulfonyl chloride (0.107g, 0.563mmol) in DCM (1.0 mL). The solution was stirred at room temperature for 16 hours and then usedSaturated NaHCO₃Washing with aqueous solution and adding Na₂SO₄Dried, filtered and concentrated. By using CHCl₃/CHCl₃+10％MeOH+0.4％NH₃The crude intermediate was purified by column chromatography on silica gel to give 0.230g of boc-protected intermediate. The boc-group was removed by dissolving the intermediate in MeOH and then adding ether saturated with HCl-gas. The crude product was dissolved in DCM and then passed through the use of CHCl₃/CHCl₃+10％ MeOH+0.4％ NH₃Purification by silica gel column chromatography to give 156mg (67%) of soda ash, 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 ═ 7.85Hz, 1H), 7.02(d, J ═ 8.17Hz, 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, 6H); MS (posES-FIA) M/z 409.1838(M + H) (calculated 407.1824)

Example 18

N- [4- (4-isopropyl-1-piperazinyl) -1-naphthyl ] -4-methylbenzenesulfonamide hydrochloride

To 4- (4-isopropyl-1-piperazinyl) -1-naphthylamine (0.209g, 0.776mmol) (prepared according to methods A and B) and pyridine (438 μ L, 5.43mmol) were dissolved in CH₂Cl₂(3.0mL) to the resulting solution was added 4-methylbenzenesulfonyl chloride (0.163g, 0.850mmol) in CH₂Cl₂(1.0mL) of the solution. The solution was stirred at room temperature for 16 hours and the solid was collected by filtration to give 0.236g of HCl-salt (66%);

¹h NMR (DMSO-d6) delta 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) (calculated 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＝8.48Hz，1H)，7.97(d，J＝8.16Hz，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(400MHz，DMSO-d₆)δ3.2(br，4H)，3.4(br，4H)，7.09(s，2H)，7.54(m，2H)，7.70(m，3H)，8.10(m，2H)；

C₂₀H₁₉C₁₂N₃O₂S MS (ESI +) M/z 436(M + H)⁺。

Example 21

2-chloro-4-fluoro-N- [4- (1-piperazinyl) -1-naphthyl ] benzenesulfonamide hydrochloride

¹H NMR(400MHz，DMSO-d₆)δ3.1(br，4H)，3.4(br，4H)，7.01(AB，J＝8.03Hz，1H)，7.04(AB，J＝8.03Hz，1H)，7.27(dt，J＝3.01，8.53Hz，1H)，7.5(m，2H)，7.68(dd，J＝2.51，9.03Hz，1H)，7.85(dd，J＝6.52，9.03Hz，1H)，8.10(d，J＝7.03Hz，1H)，8.20(d，J＝7.03Hz，1H)；

C₂₀H₁₉ClFN₃O₂S MS (ESI +) M/z 420(M + H)⁺。

Example 22

2, 3-dichloro-N- [4- (1-piperazinyl) -1-naphthyl ] benzenesulfonamide hydrochloride

¹H NMR(400MHz，DMSO-d₆)δ3.1(br，4H)，3.4(br，4H)，7.01(AB，J＝8.03Hz，1H)，7.03(AB，J＝8.03Hz，1H)，7.42(t，J＝7.78Hz，1H)，7.50(m，2H)，7.81(dd，J＝1.51，8.03Hz，1H)，7.85(dd，J＝1.51，8.03Hz，1H)，8.10(dd，J＝6.52，2.0Hz，1H)，8.20(dd，J＝7.53，2.01Hz，1H)；

C₂₀H₁₉Cl₂N₃O₂S MS (ESI +)436(M + H)⁺。

Example 23

2, 4-dichloro, 5-methyl-N- [4- (1-piperazinyl) -1-naphthyl ] benzenesulfonamide hydrochloride

¹H NMR(400MHz，DMSO-d₆)δ2.27(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)；C₂₁H₂₁Cl₂N₃O₂S MS (ESI +) M/z 450(M + H)⁺。

Example 24

3-trifluoromethyl-N- [4- (1-piperazinyl) -1-naphthyl ] benzenesulfonamide hydrochloride

¹H NMR(400MHz，DMSO-d₆)δ3.2(br，4H)，3.4(br，4H)，7.05(AB，J＝8.03Hz，1H)，7.10(AB，J＝8.03Hz，1H)，7.40(t，J＝7.53Hz，1H)，7.50(t，J＝7.53Hz，1H)，7.76(t，J＝8.03Hz，1H)，7.81(s，1H)，7.88(d，J＝8.53Hz，1H)，7.95(d，J＝8.03Hz，1H)，7.99(d，J＝8.03Hz，1H)，8.12(d，J＝8.54Hz，1H)；

C₂₁H₂₀F₃N₃O₂S MS (ESI +) M/z 436(M + H)⁺。

Example 25

2-trifluoromethyl-N- [4- (1-piperazinyl) -1-naphthyl ] benzenesulfonamide hydrochloride

¹H NMR(400MHz，DMSO-d₆)δ3.0(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＝2.01，7.53Hz，1H)，7.90(dd，J＝2.01，7.03Hz，1H)，8.02(d，J＝8.54Hz，2H).

Example 26

4-bromo-N-methyl-N- (4-piperazin-1-yl-naphthalen-1-yl) -benzenesulfonamide hydrochloride

¹H NMR (DMSO-d6) delta; 9.12(brs, 2H), 8.22-8.07(M, 2H), 7.89(d, J ═ 8.44Hz, 2H), 7.74-7.58(M, 4H), 7.10(d, J ═ 7.91Hz, 1H), 6.89(d, 8.18Hz, 1H), 3.50(s, 3H), 3.43-3.27(M, masked by the 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) delta; 9.00(brs, 1H), 8.77-8.71(M, 1H), 8.18(d, J ═ 8.44Hz, 1H), 8.10-8.02(M, 2H), 8.01-7.96(M, 1H), 7.90(d, J ═ 8.18Hz, 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, masked by a 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) delta; 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, partially masked by the 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) delta; 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, masked by the 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, partially masked by the solvent signal, 1H), 7.09(s, 1H), 7.04(d, J ═ 8.44Hz, 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) delta; 10.40(brs, 1H), 9.03(brs, 1H), 8.12(d, J ═ 7.65Hz, 1H), 7.95-7.83(M, 5H), 7.55-7.39(M, 2H), 7.13-7.02(M, 2H), 3.40-3.30(M, partially masked by the 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, masked 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) delta; 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, masked by the 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) delta; 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, 4H), 3.40-3.30(M, masked by a 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) delta; 10.45(brs, 1H), 9.01(brs, 2H), 8.28(d, J ═ 1.58Hz, 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, masked by the 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) delta; 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, masked by the 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) delta; 10.43(brs, 1H), 9.11(brs, 2H), 8.19-8.111(M, 1H), 8.02-7.95(M, 2H), 7.29(d, J ═ 3.95Hz, 1H), 7.21-7.12(M, 3H), 3.40-3.30(M, masked by the 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) delta; 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, partially masked by the 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) -benzenesulfonylamine hydrochloride:

¹h NMR (DMSO-d6) delta; 10.05(s, 1H), 9.20(brs, 2H), 8.11(d, J ═ 7.91Hz, 1H), 7.93(d, J ═ 8.18Hz, 1H), 7.62 to 7.26(M, 5H), 7.07(s, 2H), 3.40 to 3.30(M, masked by a solvent signal), 3.25 to 3.15(M, 4H), 2.66 to 2.55(M, partially masked by a solvent signal, 2H), 1.58 to 1.15(M, 2H), 1.32 to 1.15(M, 2H), 0.92 to 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) delta; 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, masked by the 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) delta; 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, masked by the 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) delta; 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, partially masked by the 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) delta; 10.13(s, 1H), 9.10(brs, 2H), 8.16-8.07(M, 2H), 7.78-7.71(M, 1H), 7.59(d, J ═ 2.64Hz, 1H), 7.57-7.46(M, 2H), 7.22-7.06(M, 3H), 3.19(s, 3H), 3.40-3.30(M, masked by the 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) delta; 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, masked by the 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) delta; 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, masked by the 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) delta; 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, masked by the 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) delta; 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, masked by the solvent signal), 3.24-3.09(M, 4H), 2.36(s, 3H), ms (pos esi) 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) delta; 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, masked by the 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) delta; 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, obsxed basic signal), 3.24-3.09(M, 4H), 2.53(s, masked by a 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) delta; 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, masked by the 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-piperazinyl) -1-naphthalenesulfonamide hydrochloride

¹H NMR(DMSO)δ9.39(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-piperazinyl) -1-naphthalenesulfonamide hydrochloride

¹H NMR(DMSO)δ9.21(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-piperazinyl) -1-naphthalenesulfonamide hydrochloride

¹H NMR(CD₃OD)δ8.26-8.19(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-piperazinyl) -1-naphthalenesulfonamide hydrochloride

¹H NMR(DMSO)δ9.52(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-dichlorothien-3-yl-methyl-N- (2, 5-dichlorothien-3-yl) -4- (1-piperazinyl) -1-naphthalenesulfonamide hydrochloride

¹H NMR(DMSO)δ9.49(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-piperazinyl) -1-naphthalenesulfonamide hydrochloride

To the compound prepared from 1-tert-butyl-4- (4- { bis [ (2-naphthalene) sulfonyl ] amino } -1-naphthyl) -1-piperazinecarboxylate and potassium carbonate (120mg, 0.87mmol) in acetone (2ml) was added iodomethane (44 μ l, 0.7mmol) and the mixture was stirred at room temperature overnight. The mixture was diluted with acetonitrile, filtered and concentrated in vacuo. The residue was redissolved in DCM (3ml) and treated with concentrated TFA (1ml) at 0 ℃ for 30 min and then the system was allowed to reach room temperature. The solvent was removed in vacuo and purified by reverse phase HPLC, then the residue was treated with excess 1M HCl in ether to give the title compound (70mg, 58%) as a solid.

¹HNMR(DMSO)δ9.28(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

¹H NMR(DMSO)δ9.25(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-piperazinyl) -1-naphthalenesulfonamide hydrochloride

¹H NMR(DMSO)δ9.41(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-piperazinyl) -1-naphthalenesulfonamide hydrochloride

¹H NMR(DMSO)δ9.45(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) -2, 5-dimethyl-1- (4-nitro-1-naphthyl) piperazine: a mixture of 1-chloro-4-nitronaphthalene (400mg, 1.9mmol), (2R, 5S) -2, 5-dimethylpiperazine (800mg, 7mmol) and potassium carbonate (1g, 7mmol) dissolved in DMSO (4ml) was stirred overnight at 100 ℃ and subsequently at room temperature for a further 48 hours. The reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with brine and 2M NaOH solution and then dried over potassium carbonate. The residue was purified by silica gel column using 10% methanol in chloroform as eluent, to give the title compound (220mg, 41%) as an oil.

¹H NMR(CDCl₃)δ8.68-8.53(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 solution of (2R, 5S) -2, 5-dimethyl-1- (4-nitro-1-naphthyl) piperazine (220mg, 0.77mmol) in DCM (2ml) at 0 ℃ was added BOC-anhydride dissolved in DCM (2 ml). The solution was stirred for 15 minutes and then the system was allowed to reach room temperature. Water was added and the solution was extracted with DCM. The organic phase was separated and dried over potassium carbonate to give the title compound (300mg, 100%) as an oil.

¹HNMR(CDCl₃)δ8.75-8.67(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: the resulting mixture of (2R, 5S) -2, 5-dimethyl-1- (4-nitro-1-naphthyl) piperazine-1-carboxylic acid tert-butyl ester (300mg, 0.78mmol) and 10% Pd/carbon (ca. 0.1mmol) dissolved in methanol (10ml) was stirred overnight under a hydrogen atmosphere. The mixture was filtered through a pad of celite and the solvent was evaporated. The crude aniline was dissolved in DCM (2ml) and pyridine (0.5ml) and 5-fluoro-2-methylbenzenesulfonyl chloride (97. mu.l, 0.67mmol) was slowly added to the solution. After stirring for 2 hours water was added and the solution was extracted with DCM, the organic phase was separated and dried with potassium carbonate. The solvent was removed in vacuo to give a residue, which was dissolved in DCM (3ml) and treated with concentrated TFA (2ml) at 0 ℃. The stirred solution was brought to room temperature, after which the solvent was removed in vacuo and the title compound (30mg, 9%) was obtained after purification by reverse phase HPLC and treatment with excess 1M HCl in ether as a solid.

1H

NMR(CD₃OD)δ0.85(d，J＝6.07Hz，3H)1.31(d，J＝6.60Hz，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＝7.92Hz，1H)8.44(d，J＝8.44Hz，1H)MS m/z 428(M+1).

Example 66

5-fluoro-2-methyl-N- [4- (1, 2, 3, 6-tetrahydropyridin-4-yl) -1-naphthyl ] benzenesulfonamide hydrochloride

5-fluoro-2-methyl-N- [4- (bromo-1-naphthyl)]Benzenesulfonamide: 4-bromo-1-naphthylamine (0.96g, 4.33mmol) was dissolved in DCM (10mL) and pyridine (1mL) was added thereafter. 5-fluoro-2-methylbenzenesulfonyl chloride was added singly and the reaction mixture 1 was stirred for 16 hours. To the reaction mixture was added HCl (1M, 1 mL). The organic phase was filtered through a plug of silica gel using DCM as eluent. The solvent was evaporated. The crude product obtained was purified by flash chromatography using MeOH (10%) in pentane to give the desired product as tar. To increase the purity, the product was purified by recrystallization (EtOAc/hexanes). This procedure gave a product with 95% purity.¹HNMR(270MHz，CDCl₃)δ8.22(d，J＝8.98Hz，1H)，7.92(d，J＝7.92Hz，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+)forC17 H13 Br FN O2 S m/z 394.263(M+H)⁺.

C₁₇H₁₃BrFNO₂S MS (ESI +) M/z 394.263(M + H)₊。

To C₁₇H₁₃BrFNO₂MS (ESI-) M/z 394.263M/z (M-H) of S^-。

In N₂(g) Reacting 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 (0.32g, 0.812mmol) was dissolved in dry THF (1m mL). The reaction flask was cooled to-78 ℃ after which n-BuLi (1.5mL, 2.4mmol) was added. The reaction mixture turned green. The reaction mixture was stirred for 5 minutes, after which 4-oxopiperidine-1-carboxylic acid tert-butyl ester (0.34g, 1.7mmol) was added in the course of 10 seconds. The resulting reaction mixture was stirred and allowed to slowly reach-30 ℃ after 3 hours. Water dissolved in THF was added and the temperature of the reaction flask was brought to RT. Brine and EtOAc were added. The phases were separated and the organic phase was dried (MgSO₄). The resulting crude product was purified by reverse phase (using gradient 40 → 90). This procedure gave 0.17g of the desired product. The purity is 95%.¹H NMR(270MHz，CDCl₃)δ8.91-8.87(m，1H)，7.97-7.93(m，1H)，7.63-7.59(m，1H)，7.53-7.45(m，2H)，7.35(d，J＝8.1Hz，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)；

C₂₇H₃₁FN₂O₅S MS (ESI +) M/z 514.615(M + H)⁺. None; c₂₇H₃₁FN₂O₅MS (ESI-) M/z 514.615(M-H) of S^-513.1。

The final product was obtained as follows: 5-fluoro-2-methyl-N- [4- (4- (tert-butoxycarbonyl) -1-hydroxypiperidin-1-yl) -1-naphthyl ] benzenesulfonamide (0.022g, 0.043mmol) was dissolved in formic acid (5mL) and stirred at RT for 24 hours. HPLC showed the reaction mixture to be complex. The reaction mixture was stirred at 100 ℃ for 4 hours. One compound was observed on HPLC. The solvent was evaporated. The crude product was converted to the HCl salt of the desired product (0.020g) in 98% purity.

¹H NMR(270MHz，CD₃OD)δ8.05-7.97(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)；

C₂₂H₂₁FN₂O₂MS of S (ESI +)

HCl m/z 396.13+35.98(M+H)⁺397.2；MS(ESI-)C₂₂H₂₁FN₂O₂SHCI m/z 396.13+35.98(M-H)^-.395.3。

Synthesis of the examples 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 (0.230g, 0.951mmol) and pyridine (537. mu.L, 6.66mmol) in DCM (3.0mL) was added a solution of benzenesulfonyl chloride (0.168g, 0.951mmol) in DCM (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours and then concentrated. Preferably by using CHCl₃/CHCl₃+10％MeOH+0.4％NH₃And then purifying the crude intermediate using preparative HPLC to give soda ash, which is converted to its HCl-salt (53% yield 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 ═ 1.60Hz, 1H), 6.99(d, J ═ 1.88Hz, 1H), 3.58-3.48(m, 2H), 3.42-3.25(m, m, partially masked by HDO signals, 4H), 3.12-3.00(m, 2H), 2.86(s, 3H); MS (posES-FIA) M/z 381.1524 (M + H) (calc 381.1511)

Synthesis of intermediates and examples in Table III

Reaction scheme 2

In scheme 2, the following reagents were used: (i) chlorosulfonic acid, trifluoroacetic acid; (ii) r¹-NH₂Pyridine (1: 4); (iii) selected diamines and DMSO.

Intermediate 16

4-fluoro-naphthalene-1-sulfonyl chloride: the resulting emulsion of 1-fluoronaphthalene (4.00g, 27mmol) in TFA (19.5mL) was stirred on an ice bath. Chlorosulfonic acid (4.33mL, 65mmol) was added dropwise over 30 minutes. The ice bath was removed and the reaction slurry was stirred at rt for 2 hours. The reaction mixture was poured onto 29mL of ice-cold water to give a white precipitate, which was filtered and washed with cold water. After drying, 4.50g of a white solid (67%) are obtained:

¹H NMR(CDCl₃，400MHz)δ8.80(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 × 4.6mm 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: CH containing 4-fluoro-naphthalene-1-sulfonyl chloride (489mg, 2.00mmol) was treated with aniline (224mg, 2.40mmol), o-anisidine (296mg, 2.40mmol), and m-chloroaniline (306mg, 2.40mmol), respectively₂Cl₂(2mL) solution in three reaction flasks. Pyridine (0.5mL) was added and the reaction mixture was stirred at rt for 3 hours. Diluted with ethyl acetate (50mL), then washed with 1M HCl (3 × 50mL), dried (Na)₂SO₄) And evaporated to give 586mg of 4-fluoro-naphthalene-1-sulfonic acid phenylamide (97%), 629mg of 4-fluoro-naphthalene-1-sulfonic acid (2-methoxy-phenyl) -amide (95%) and 656mg of 4-fluoronaphthalene-1-sulfonic acid (3-chloro-phenyl) -amide (97%) as a pink to red solid.

Intermediate 17

4-fluoro-naphthalene-1-sulfonic acid phenylamide:¹H NMR(CDCl₃，400MHz)δ8.66(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 × 4.6mm i.d.) > 98%.

Intermediate 18

4-fluoro-naphthalene-1-sulfonic acid (2-methoxy-phenyl) -amide:

¹H NMR(CDCl₃，400MHz)δ8.70(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 × 4.6mm i.d.) > 98%.

Intermediate 19

4-fluoro-naphthalene-1-sulfonic acid (3-chloro-phenyl) -amide:

¹H NMR(CDCl₃，400MHz)δ8.64(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 × 4.6mm i.d.) > 98%.

General procedure D

General preparation procedure for the Compounds of examples 68-74:

treatment of 4-fluoro-naphthalene-1-sulfonic acid (2-methoxy-phenyl) -amide (60mg, 0.20mmol), 4-fluoro-naphthalene-1-sulfonic acid (2-methoxy-phenyl) -amide (66mg, 0.20mmol), and 4-fluoro-naphthalene-1-sulfonic acid (3-chloro-phenyl) -amide (67mg, 0.20mmol) in DMSO (2mL) with piperazine (86mg, 1.0mmol), homopiperazine (100mg, 1.0mmol), and cis-2, 6-dimethylpiperazine (114mg, 1.0mmol) in 8 reaction combinationsAnd (4) liquid. The reaction mixture was stirred at 100 ℃ for 3 hours, diluted with ethyl acetate (50mL), and saturated Na₂CO₃(3X50mL) washed and dried (Na)₂SO₄) And evaporated with excess HCl in ether to give the hydrochloride salt. It was not necessary to purify compound 20-23, but compound 24-27 was purified by HPLC (YMCcomp preprop ODS-AQ, 50X20mm I.D.).

Example 68

4-piperazin-1-yl-naphthalene-1-sulfonic acid phenylamide hydrochloride

86mg (yield 95%) of a white solid.

¹H NMR(DMSO，400MHz)δ9.52(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，101MHz)δ153.3，137.7，137.6，130.8，129.2，129.0，128.9，127.9，126.5，124.9，124.5，123.3，118.7，113.0，49.1，42.8；MS(CI)368.0(M+H)⁺，366.4(M-H)^-；

Purity (HPLC, Hichrom 200 × 4.6mm i.d.) 90%.

Example 69

4-piperazin-1-yl-naphthalene-1-sulfonic acid (2-methoxy-phenyl) -amide hydrochloride

¹H NMR(DMSO，400MHz)δ9.59(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，101MHz)δ152.9，152.5，130.6，129.7，129.3，127.9，127.3，126.5，126.3，125.7，125.3，125.2，124.1，120.2，112.8，111.6，54.9，49.2，43.0.MS(CI)398.2(M+H)⁺，396.2(M-H)^-；

Purity (HPLC, Hichrom 200 × 4.6mm 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，400MHz)δ9.75-9.81(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，101MHz)δ152.4，152.3，130.6，129.8，129.3，127.9，127.3，126.5，126.3，125.3，125.2，125.1，124.1，120.2，113.0，111.6，55.0，54.9，51.2，15.5.MS(CI)426.2(M+H)⁺，424.4(M-H)^-；

Purity (HPLC, Hichrom 200 × 4.6mm 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，400MHz)δ8.80(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 × 4.6mm i.d.) 98%.

Example 72

4- [1, 4] diazepin-1-yl-naphthalene-1-sulfonic acid (3-chloro-phenyl) -amide hydrochloride

¹H NMR(MeOD，400MHz)δ8.69(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 × 4.6mm i.d.) 88%.

Example 73

4- [1, 4] diazepin-1-yl-naphthalene-1-sulfonic acid phenylamide hydrochloride

¹H NMR(MeOD，400MHz)δ8,57(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 × 4.6mm i.d.) 94%.

Example 74

4-piperazin-1-yl-naphthalene-1-sulfonic acid (3-chloro-phenyl) -amide hydrochloride

¹H NMR(MeOD，400MHz)δ8.69(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 × 4.6mm i.d.) 98%.

General method E

4-fluoro-naphthalene-1-sulfonyl chloride was dissolved in DCM. Amine (1.2 eq) was added followed by pyridine (3 eq). The mixture was stirred at ambient temperature for 2 hours, diluted with DCM and washed 2 times with HCl (1M). The organic layer was filtered through a plug of silica gel to give the sulfonylamide.

General procedure F

Sulfonamide and amine (5 equivalents) were dissolved in DMSO and stirred overnight at 100 ℃. The DMSO solution was added dropwise to water to generate a precipitate. After centrifugation the solvent was decanted and the procedure repeated. The residue was dissolved in MeOH and converted to HCl salt by addition of HCl in ether (2M) and evaporated.

General method G

Adding K to a solution of sulfonamide in acetone₂CO₃(3 equiv.) followed by addition of MeI (1.2 equiv.). The mixture was stirred overnight, filtered through a short plug of silica gel and evaporated to give the methylated sulfonamide.

Example 75

4-piperazin-1-yl-naphthalene-1-sulfonic acid (2-methylsulfanyl-phenyl) -amide hydrochloride

N- (2-methylsulfanylphenyl) -4-fluorosulfonamide-method E; yield (84%)

¹H NMR(CDCl₃)δ8.74-8.70(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)；

C₁₇H₁₄FNO₂S₂MS (ESI +) M/z 348(M + H)⁺。

Preparing the final product according to method F; yield 0.77g (53%)

¹H NMR(DMSO-d₆)δ11.13(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)；

C₂₁H₂₃N₃O₂S₂MS (ESI +) 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-fluoronaphthalene sulfonamide-method E; yield (83%)

¹H NMR(CDCl₃)δ8.77-8.74(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)；

C₂₀H₁₄FNO₂S MS (ESI +) 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)δ8.38-8.35(m，1H)，8.23-8.20(m，1H)，8.16(dd，J＝8.4，5.5Hz，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＝7.5，1.2Hz，1H)，3.29(s，3H)

Preparing the final product according to method F; yield (36%)

¹H NMR(DMSO-d₆)δ9.33(br.s，1H)，8.40(d，J＝8.4Hz，1H)，8.25(d，J＝7.9Hz，1H)，8.09(d，J＝8.2Hz，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＝8.2Hz，1H)，7.13-7.10(m，1H)，3.44-3.39(m，4H)，3.29(br.s，4H)，3.25(s，3H)；

C₂₅H₂₅N₃O₂S MS (ESI +) 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-sulfonamide: method E; yield (96%).¹HNMR(CDCl₃)δ8.66-8.63(m，1H)，8.22-8.09(m，2H)，7.77-7.63(m，2H)，7.10(dd，J＝8.2，9.5Hz，1H)，6.58(d，J＝8.5Hz，1H)，6.46(d，J＝2.4Hz，1H)，6.30(dd，J＝2.6，8.7Hz，1H)，4.14(s，4H)；

C₁₈H₁₄FNO₄S MS (ESI +) 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)δ8.19-8.13(m，2H)，8.09(dd，J＝8.4，5.5Hz，1H)，7.75-7.70(m，1H)，7.64-7.58(m，1H)，7.50(dd，J＝10.0，8.4Hz，1H)，6.71(d，J＝8.4Hz，1H)，6.55(d，J＝2.6Hz，1H)，6.51-6.47(m，1H)，4.20-4.15(m，4H)，3.10(s，3H)

Preparing the final product according to method F; the product was precipitated in MeOH; yield (57%):

¹H NMR(DMSO-d₆)δ9.29(br.s，2H)，8.23-8.16(m，2H)，8.01(d，J＝8.2Hz，1H)，7.64-7.49(m，2H)，7.25(d，J＝8.2Hz，1H)，6.72(d，J＝8.4Hz，1H)，6.56-6.48(m，2H)，4.21-4.16(m，4H)，3.38-3.31(m，4H)，3.08(s，3H)；

C₂₃H₂₅N₃O₄s MS (ESI +) 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

Preparing the final product according to method F; yield (36%);¹H NMR(270MHz，DMSO-D6)δppm 3.32(m，8H)4.08(m，4H)6.45(m，2H)6.61(d，J＝8.44Hz，1H)7.20(d，J＝8.18Hz，1H)7.67(m，2H)8.07(d，J＝7.92Hz，1H)8.21(d，J＝8.71Hz，1H)8.67(d，J＝8.44Hz，1H)9.22(s，1H)10.32(s，1H)；

C₂₂H₂₃N₃O₄MS (ESI +) M/z 426.2(M + H) of S⁺。

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-methylated according to method G; yield (97%);¹H NMR(DMSO-d₆)δ8.52-8.49(m，1H)，8.22-8.19(m，1H)，8.16(dd，J＝8.4，5.5Hz，1H)，7.79-7.66(m，2H)，7.52(dd，J＝10.0，8.4Hz，1H)，7.37-7.24(m，2H)，7.06-7.00(m，1H)，6.88(dd，J＝7.9，1.3Hz，1H)，3.10(s，3H)，2.28(s，3H).

preparing the final product according to method F; grinding with MeCN; yield (65%)

¹H NMR(DMSO-d₆)δ9.27(br.s，2H)，8.54-8.50(m，1H)，8.27-8.23(m，1H)，8.09(d，J＝8.2Hz，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)；

C₂₂H₂₅N₃O₂S₂MS (ESI +) M/z 428(M + H)⁺。

Example 80

4-piperazin-1-yl-naphthalene-1-sulfonic acid methyl- (3-trifluoromethyl-phenyl) -amide hydrochloride

N- (3-trifluoromethylphenyl) -4-fluoronaphthalene sulfonamide-method E; yield (90%).

¹H NMR(CDCl₃)δ8.65-8.62(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)；

C₁₇H₁₁F₄NO₂S MS (ESI +) M/z 370(M + H)⁺。

Methylation according to method F; yield (100%);

¹H NMR(DMSO-d₆)δ8.19-8.11(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).

preparing the final product according to method F; grinding with MeCN; yield 0.07g (40%).

¹H NMR(DMSO-d₆)δ9.35(br.s，2H)，8.21(d，J＝8.2Hz，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)；

C₂₂H₂₂F₃N₃O₂S MS (ESI +) 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-fluoronaphthalenesulfonamide-method E; yield (88%).

¹H NMR(DMSO-d₆)δ10.86(br.s，1H)，8.74-8.71(m，1H)，8.22(dd，J＝8.3，5.4Hz，1H)，8.19-8.16(m，1H)，7.89-7.75(m，2H)，7.47(dd，J＝10.0，8.4Hz，1H)，7.12-7.09(m，1H)，7.00(d，J＝2.2Hz，1H)，6.86(dd，J＝8.3，2.2Hz，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)δ8.20-8.07(m，3H)，7.76-7.70(m，1H)，7.62-7.48(m，2H)，7.27-7.24(m，1H)，7.13(d，J＝2.4Hz，1H)，6.99(dd，J＝8.2，2.4Hz，1H)，3.15(s，3H)，2.28(s，3H)；

Preparing the final product according to method F; yield (28%).¹H NMR(DMSO-d₆)δ9.29(br.s，2H)，8.24-8.15(m，2H)，8.01(d，J＝8.2Hz，1H)，7.65-7.47(m，2H)，7.26(dd，J＝8.3，4.6Hz，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)；

C₂₂H₂₄ClN₃O₂S MS (ESI +) 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-fluoronaphthalene sulfonamide-method E; yield (85%).

¹H NMR(CDCl₃)δ8.66(d，J＝8.4Hz，1H)，8.20-8.14(m，2H)，7.75-7.62(m，2H)，7.10(dd，J＝9.5，8.4Hz，1H)，7.02(t，J＝7.8Hz，1H)，6.88-6.85(m，1H)，6.72-6.68(m，3H)，2.45(q，J＝7.7Hz，2H)，1.03(t，J＝7.7Hz，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)δ8.18-8.06(m，3H)，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＝7.5Hz，2H)，0.93(t，J＝7.5Hz，3H)

preparing the final product according to method f; grinding with MeCN; yield (49%);

¹H NMR(DMSO-d₆)δ9.21(br.s，2H)，8.21(d，J＝8.4Hz，1H)，8.13(d，J＝8.7Hz，1H)，8.02(d，J＝8.2Hz，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＝7.6Hz，2H)，0.95(t，J＝7.6Hz，2H)；

C₂₃H₂₇N₃O₂s MS (ESI +) M/z 410(M + H)⁺。

Example 83

4- (3, 5-dimethyl-piperazin-1-yl) -naphthalene-1-sulfonic acid (2-isopropyl-phenyl) amide hydrochloride

Preparing the final product according to method F; yield (35%);¹H NMR(270MHz，DMSO-D6)δppm 0.64(d，J＝6.86Hz，6H)1.30(d，J＝6.60Hz，6H)2.92(m，3H)3.53(m，4H)6.86(d，J＝7.65Hz，1H)6.98(m，1H)7.13(m，3H)7.67(m，2H)7.86(d，J＝7.92Hz，1H)8.24(m，1H)8.74(m，1H)9.08(m，1H)9.79(m，2H)；

C₂₅H₃₁N₃O₂(ESI +) M/z 438.01(M + H) for S MS⁺。

Example 84

4- [1, 4] diazepin-1-yl-naphthalene-1-sulfonic acid (2-isopropyl-phenyl) -amide hydrochloride

N- (2-isopropylphenyl) -4-fluoronaphthalene sulfonamide-method E; yield (87%)

¹H NMR(CDCl₃)δ8.67-8.64(m，1H)，8.22-8.18(m，1H)，8.12(dd，J＝8.3，5.4Hz，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)

Preparing the final product according to method F; yield (22%).

¹H NMR(DMSO-d6)δ9.83(s，1H)，9.37(br.s，2H)，8.74-8.70(m，1H)，8.27.8.24(m，1H)，7.84(d，J＝7.9Hz，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)；

C₂₄H₂₉N₃O₂S MS (ESI +) M/z 424.02(M + H)⁺。

Example 85

4- [1, 4] diazepin-1-yl-naphthalene-1-sulfonic acid (3-ethyl-phenyl) -amide hydrochloride

Preparing the final product according to method F; yield (22%);¹H NMR(DMSO-d₆)δ10.53(s，1H)，9.24(br.s，2H)，8.68(d，J＝8.2Hz，1H)，8.20(d，J＝7.9Hz，1H)，8.14(d，J＝8.2Hz，1H)，7.72-7.60(m，2H)，7.22(d，J＝8.2Hz，1H)，7.01(t，J＝7.8Hz，1H)，6.83-6.72(m，3H)，3.33(br.s，6H)，2.39(q，J＝7.7Hz，2H)，2.12(br.s，2H)，0.98(t，J＝7.5Hz，3H)；

C₂₃H₂₇N₃O₂s MS (ESI +) M/z 410.03(M + H)⁺。

Example 86

N- (2-fluorophenyl) -4-piperazin-1-ylnaphthalene-1-sulfonamide hydrochloride

N- (2-fluorophenyl) -4-fluoronaphthalene sulfonamide-method E; yield (88%);

¹HNMR(DMSO-d₆)δ10.41(br.s，1H)，8.76-8.69(m，1H)，8.20-8.17(m，1H)，8.08(dd，J＝8.0，5.5Hz，1H)，7.82-7.75(m，2H)，7.41(dd，J＝10.0，8.3Hz，1H)，7.20-7.01(m，4H)；

C₁₆H₁₁F₂NO₂MS (ESI-) M/z 318.2(M-H) of S^-。

Preparing the final product according to method F; yield (22%);¹H NMR(DMSO-d₆)δ10.41(s，1H)，9.35(m，2H)，8.72-8.68(m，1H)，8.24-8.20(m，1H)，8.02(d，J＝7.9Hz，1H)，7.72-7.62(m，2H)，7.22-7.00(m，5H)，4.05(d，J＝1.3Hz，4H)，3.36(s，4H)；

C₂₀H₂₀FN₃O₂s MS (ESI +) M/z 386(M + H)⁺。

Example 87

4- [1, 4] diazepin-1-yl-naphthalene-1-sulfonic acid (3-trifluoromethyl-phenyl) -amide hydrochloride

Preparing the final product according to method F; yield (21%);¹H NMR(DMSO-d6)δ11.1(s，1H)，9.32(br.s，2H)，8.65(d，J＝8.2Hz，1H)，8.19(t，J＝8.6Hz，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)；

C₂₂H₂₂F₃N₃O₂s MS (ESI +) 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-fluoronaphthalene sulfonamide-method E; yield (81%);

¹H NMR(DMSO-d₆)δ10.44(s，1H)，8.73-8.69(m，1H)，8.21-8.18(m，1H)，8.02(dd，J＝8.4，5.5Hz，1H)，7.85-7.76(m，2H)，7.41(dd，J＝10.2，8.3Hz，1H)，7.22-7.11(m，2H)，7.01-6.93(m，1H)；

C₁₆H₁₀F₃NO₂MS (ESI-) M/z 336.2(M-H) of S^-。

Preparing the final product according to method F; yield (27%);¹H NMR(DMSO-d6)δ10.33(s，1H)，9.28(br.s，2H)，8.68-8.65(m，1H)，8.25-8.21(m，1H)，8.0(d，J＝8.2Hz，1H)，7.73-7.62(m，2H)，7.21-7.08(m，3H)，7.0-6.93(m，1H)，3.29(br.s，4H)；

C₂₀H₁₉F₂N₃O₂s MS (ESI +) M/z 403.94(M + H)⁺。

Example 89

4-piperazin-1-yl-naphthalene-1-sulfonic acid (2-trifluoromethoxy-phenyl) -amide hydrochloride

N- (2-tris-fluoromethoxyphenyl) -4-fluoronaphthalenylsulfonamide-method E; yield (43%);

¹H NMR(DMSO-d₆)δ10.58(s，1H)，8.80-8.76(m，1H)，8.20-8.17(m，1H)，8.08(dd，J＝8.3，5.4Hz，1H)，7.84-7.74(m，2H)，7.42(dd，J＝10.2，8.3Hz，1H)，7.32-7.18(m，4H).

preparing the final product according to method F; yield (48%);¹H NMR(DMSO-d6)δ10.49(s，1H)，9.27br.s，2H)，8.75-8.72(m，1H)，8.24-8.21(m，1H)，8.02(d，J＝7.9Hz，1H)，7.71-7.62(m，2H)，7.32-7.17(m，5H)，3.38(br.s，4H)，3.28(br.s，4H)；

C₂₁H₂₀F₃N₃O₃(ESI +) M/z 451.9(M + H) of S⁺。

Example 90

4-piperazin-1-yl-naphthalene-1-sulfonic acid (3-phenoxy-phenyl) -amide hydrochloride

N- (3-phenoxyphenyl) -4-fluoronaphthalene sulfonamide-method E; yield 0.64g (100%);

¹H NMR(DMSO-d₆)δ10.80(br.s，1H)，8.71-8.68(m，1H)，8.19-8.16(m，1H)，8.10(dd，J＝8.3，5.4Hz，1H)，7.85-7.74(m，2H)，7.45(dd，J＝10.2，8.3Hz，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)；

C₂₂H₁₆FNO₃MS (ESI-) M/z 392.2(M-H) of S^-。

Preparing the final product according to method F; yield 0.08g (31%);

¹H NMR(DMSO-d6)δ10.76(s，1H)，9.37(br.s，2H)，8.67-8.63(m，1H)，8.23-8.20(m，1H)，8.02(d，J＝8.2Hz，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)；

C₂₆H₂₅N₃O₃s MS (ESI +) 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-fluoronaphthalene sulfonamide-method E; yield (35%);

¹H NMR(DMSO-d6)δ11.01(br.s，1H)，8.74-8.71(m，1H)，8.26(dd，J＝8.3，5.3Hz，1H)，8.16(d，J＝9.0Hz，1H)，7.86-7.82(m，1H)，7.78-7.74(m，1H)，7.46(dd，J＝10.0，8.5Hz，1H)，7.27(t，J＝8.3Hz，1H)，7.02-6.90(m，3H)；

C₁₇H₁₁F₄NO₃MS (ESI-) M/z 383.8(M-H) of S^-。

Preparing the final product according to method F; yield (35%);

¹H NMR(DMSO-d6)δ11.07(s，1H)，9.63(br.s，1H)，9.31(br.s，1H)，8.66(d，J ＝8.4Hz，1H)，8.21-8.18(m，2H)，7.75-7.62(m，2H)，7.29-7.21(m，2H)，7.03-6.86(m，3H)，3.32-3.28(m，8H)；

C₂₆H₂₅N₃O₃MS of S(ESI+)m/z 451.94(M+H)⁺。

Example 92

4-piperazin-1-yl-naphthalene-1-sulfonic acid (2-chloro-5-methyl-phenyl) -amide hydrochloride

Preparation of the final product according to procedure 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, masked 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

Preparation of the final product according to procedure 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, masked by solvent signal), 2.77-2.61(M, 1H), 1.05(d, J ═ 6.87Hz, 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 crude N- (3, 5-difluorophenyl) -4-fluoronaphthalene-1-sulfonamide (50mg, 0.15mmol) to give the title compound (20mg, 31%) as a yellow solid.

¹H NMR(DMSO)δ11.33(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 (8.0g, 55mmol) in concentrated trifluoroacetic acid (40ml) at 0 deg.C was slowly added chlorosulfonic acid (15 min). The reaction mixture was stirred at room temperature for an additional 2 hours and then slowly added to the stirred ice slurry. The precipitate formed was filtered off, washed with cold water and dried in vacuo to give the title compound (7.3g) as a white solid.

1- [ (4-fluoro-1-naphthyl) sulfonyl group]1, 2, 3, 4-tetrahydroquinoline-method E: to a stirred solution of 4-fluoronaphthalene-1-sulfonyl chloride (200mg, 0.82mmol) in DCM (1ml) was added 1, 2, 3, 4-tetrahydroquinoline (123. mu.l, 0.98mmol) followed by pyridine (0.25 ml). The reaction mixture was stirred overnight, diluted with DCM and washed with 1M HCl (3 × 3 ml). Followed by MgSO₄The organic phase was dried and the solvent was removed in vacuo to give the title compound (280mg, 100%) as a white solid.

¹H NMR(CDCl₃)δ8.24-8.10(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.

Preparation of the final product according to procedure F: a stirred solution of 1- [ (4-fluoro-1-naphthyl) sulfonyl ] -1, 2, 3, 4-tetrahydroquinoline (50mg, 0.15mmol) and piperazine (80mg, 0.9mmol) dissolved in DMSO (1ml) was heated overnight at 95 ℃. The reaction mixture was allowed to reach room temperature and then added dropwise to water. The solid formed was isolated, redissolved in MeOH and treated with excess 1M HCl in ether. The solvent was removed in vacuo to give the title compound (60mg, 83%) as a white solid.

¹H NMR(DMSO)δ9.17(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] diazepin-1-yl-naphthalene-1-sulfonic acid (3-nitro-phenyl) -amide hydrochloride

Preparation of the final product according to procedure 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, partially masked by the 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

Preparation of the final product according to procedure 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] diazepin-1-yl-naphthalene-1-sulfonic acid (3-nitro-phenyl) -methyl-amide hydrochloride

Preparation of the final product according to procedure F:

¹H NMR(DMSO-d6)δ；8.21(d，J＝8.47Hz，1H)，8.12(d，J＝8.79Hz，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: the title compound (500mg, 95%) was obtained as an oil using 4-methylaniline and applying general procedure a above.

¹H NMR(CDCl₃)δ8.82-8.75(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)；MSm/z(M+1)316.

Preparation of the final product according to method E: use of 4-fluoro-N- (4-methylphenyl) naphthalene-1-sulfonamide gave the title compound (200mg, 30%) as a yellow solid after washing with methanol.

¹H NMR(DMSO)δ10.46(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

Preparation of the final product according to method E: the yield is 100 percent, and the purity is 93 percent

¹H NMR(500MHz，DMSO-D6)δppm 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)；

C₂₁H₂₂ClN₃O₂MS (ESI +) M/z (M + H) of S HCl⁺.416.1；C₂₁H₂₂ClN₃O₂MS (ESI-) M/z (M-H) -.414.1 for SHCl.

Example 101

4- [1, 4] diazepin-1-yl-naphthalene-1-sulfonic acid (2, 3-dimethyl-phenyl) -methyl-amide hydrochloride

Preparation of the final product according to procedure 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] diazepin-1-yl-naphthalene-1-sulfonic acid (4-isopropyl-phenyl) -amide hydrochloride

Preparation of the final product according to procedure F:

¹H NMR((DMSO-d6)δ；8.74(d，J＝8.16Hz，1H)，8.33(d，J＝8.48Hz，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] diazepin-1-yl-naphthalene-1-sulfonic acid (4-isopropyl-phenyl) -methyl-amide hydrochloride

Preparation of the final product according to procedure 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＝6.60Hz，6H)，MS(posESI)m/z＝438(M+H).

example 104

4- [1, 4] diazepin-1-yl-naphthalene-1-sulfonic acid (2, 4-dimethyl-phenyl) -amide hydrochloride

Preparation of the final product according to procedure 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, partially masked by a 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] diazepin-1-yl-naphthalene-1-sulfonic acid (2-chloro-5-methyl-phenyl) -amide hydrochloride

Preparation of the final product according to procedure F:

¹H NMR((DMSO-d6)δ；8.67-8.61(m，1H)，8.24-8.19(m，1H)，7.95(d，J＝8.16Hz，1H)，7.57-7.56(m，2H)，7.21-7.18(m，1H)，7.12(d，J＝8.17Hz，1H)，6.89(d，J＝8.17Hz，1H)，6.78-6.75(m，1H)，3.52-3.47 8m，2H)，3.45-3.40(m，4H)，331-3.26(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

Preparation of the final product according to procedure F:

¹h NMR ((DMSO-d6) δ; 8.80-8.72(M, 1H), 8.27-8.19(M, 1H), 7.98(d, J ═ 8.18Hz, 1H), 7.74-7.60(M, 2H), 7.17(d, J ═ 7.91Hz, 1H), 6.76-6.75(M, 2H), 6.62-6.55(M, 1H), 3.60(s, 3H), 3.40-3.20(M, masked by the 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

Preparation of the final product according to procedure 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, masked by the 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

Preparation of the final product according to procedure F:

¹h NMR ((DMSO-d6) δ; 8.81-8.72(M, 1H), 8.34-8.25(M, 1H), 7.98(d, J ═ 8.18Hz, 1H), 7.71-7.60(M, 2H), 7.14(d, J ═ 8.18Hz, 1H), 6.81(s, 1H), 6.76-6.72(M, 2H), 3.58-3.47(M, 4H), 3.44-3.30(M, masked by the 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

Preparation of the final product according to procedure 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, masked by the solvent signal), ms (posesi) M/z 436(M + H).

Example 110

4-piperazin-1-yl-naphthalene-1-sulfonic acid biphenyl-2-ylamide hydrochloride

Preparation of the final product according to procedure 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 ═ 8.18Hz, 1H), 7.66-7.49(M, 2H), 7.29-6.98(M, 10H), 3.50-3.30(M, masked by the 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-phenoxyphenyl) -4-fluoronaphthalene sulfonamide-method E; yield 9.2g (47%).

¹H NMR(DMSO-d₆)δ10.75(s，1H)，8.75(d，J＝8.4Hz，1H)，8.23-8.14(m，2H)，7.87-7.73(m，2H)，7.44(dd，J＝10.2，8.3Hz，1H)，7.34-7.29(m，5H)，7.03(t，J＝8.2Hz，1H)，6.66-6.56(m，3H)，4.93(s，2H)；

C₂₃H₁₈FNO₃S MS (ESI +) M/z 407(M + H)⁺。

Preparation of the final product according to procedure F: yield 0.6g (78%)¹H NMR(DMSO-d₆)δ10.67(s，1H)，9.30(br.s，2H)，8.69(d，J＝7.7Hz，1H)，8.21(d，J＝8.4Hz，1H)，8.13(d，J＝8.2Hz，1H)，7.75-7.61(m，2H)，7.35-7.30(m，5H)，7.19(d，J＝8.2Hz，1H)，7.03(t，J＝8.2Hz，1H)，6.68-6.54(m，3H)，4.93(s，2H)，3.36-3.29(m，8H)；

C₂₇H₂₇N₃O₃S MS (ESI +) 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: the title compound (475mg, 86%) was obtained as an oil using 4-methoxyaniline and applying the above-described general procedure a.

¹H NMR(CDCl₃)δ8.79-8.71(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.

Preparation of the final product according to procedure F: using 4-fluoro-N- (4-fluorophenyl) naphthalene-1-sulfonamide and applying general procedure B above, the title compound (95mg, 15%) was obtained as a white solid after recrystallization from methanol.

¹H NMR(DMSO)δ10.60(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-sulfonamide hydrochloride

N- (3-ethylphenyl) -4-fluoronaphthalene-1-sulfonamide-method E: yield 80% and purity 92%.

¹H NMR(270MHz，CDCl₃)δppm 1.03(t，J＝7.52Hz，3H)，2.45(q，J＝7.65Hz，2H)，6.68-6.72(m，2H，N-H)，6.87(d，J＝7.13Hz，1H)，6.99-7.13(m，2H)，7.65-7.72(m，2H)，8.13-8.20(m，2H)，8.65(d，J＝8.44Hz，1H)；

C₁₈H₁₆FNO₂MS (ESI +) M/z 329.393(M + H) +.330.0 for S;

C₁₈H₁₆FNO₂MS (ESI-) M/z 329.393(M-H) of S^-.328.1

Preparation of the final product according to procedure F: yield 61%, purity 98%.

¹H NMR(500MHz，DMSO)δ8.67-8.65(m，1H)，8.16-8.10(m，2H)，7.66-7.57(m，2H)，7.14(d，J＝8.56Hz，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＝17Hz，2H)，1.94(tr，J＝17Hz，3H)；

C₂₂H₂₅N₃O₂MS (ESI +) M/z 431.98(M-HCl + H) of S HCl⁺.396.1；C₂₂H₂₅N₃O₂MS (ESI-) M/z of S HCl (M-HCl-H)^-.394.1

Example 114

4-piperazinyl-N- [3- (trifluoromethyl) phenyl ] naphthalene-1-sulfonamide hydrochloride

Preparation of the final product according to procedure F: the title compound (0.08g) was obtained using 4-fluoro-N- (3-trifluoromethylsulfanyl) naphthalene-1-sulfonamide to give 0.060g of the desired product in 85% yield and 96% purity.

¹H NMR(270MHz，CD₃OD)δ8.74-8.71(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)；

C₂₁H₂₀F₃N₃O₂S₂MS (ESI +) M/z 467.09+35.46(M + H) of HCl⁺468.0；C₂₁H₂₀F₃N₃O₂S₂MS (ESI +) M/z 467.09+35.46(M-H) of HCl^-466.1。

Example 115

4-piperazinyl-N- [ 3-benzoylphenyl ] naphthalene-1-sulfonamide hydrochloride

Preparation of the final product according to procedure F: the yield is 25%, and the purity is 97%.

¹H NMR(270MHz，CD₃OD)δ8.76-8.72(m，1H)，8.29-8.26(m，1H)，8.17(d，J＝8,1Hz，1H)，7.73-7.60(m，3H)，7.55-7.44(m，4H)，7.34-7.28(m，4H)，7.18(d，J＝8,1Hz，1H)，3.54-3.50(m，4H)，3.37-3.30(m，4H)；

C₂₇H₂₅N₃O₃MS (ESI +) M/z 471.17+35.46(M + H) of S HCl⁺472.1；C₂₇H₂₅N₃O₃MS (ESI +) M/z 471.17+35.46(M-H) of S HCl^-470.01。

Example 116

4-piperazinyl-N- [3- (4-bromo-1-methyl-1H-pyrazol-3-yl) phenyl ] naphthalene-1-sulfonamide hydrochloride

Preparation of the final product according to procedure F: yield 81% and purity 96%.

¹H NMR(270MHz，CD₃OD)δ8.78-8.74(m，1H)，8.27-8.24(m，1H)，8.19(d，J＝8,1Hz，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)；

C₂₄H₂₄BrN₅O₂MS (ESI +) M/z 525.08+35.46(M + H) of S HCl⁺526.0；MS(ESI+)C₂₄H₂₄BrN₅O₂S HCl m/z 525.08+35.46(M-H)^-524.1。

Example 117

4-piperazinyl-N- [ 3-biphenylphenyl ] naphthalene-1-sulfonamide hydrochloride

Preparation of the final product according to procedure F: yield 33% and purity 95%.

¹H NMR(270MHz，CD₃OD)δ8.83-8.80(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)；

C₂₆H₂₅N₃O₂MS (ESI +) M/z 443.17+36.45(M + H) of S HCl⁺444.1；C₂₆H₂₅N₃O₂MS (ESI-) M/z 443.17+36.45(M-H) of S HCl^-442.2。

Synthesis of the examples and intermediates in Table IV

General method H

Example 118

N- [1- (4-methyl-1-piperazinyl) -3-isoquinolinyl ] benzenesulfonamide hydrochloride

To 1- (4-methyl-1-piperazinyl) -3-isoquinolinamine (commercially available; 0.26g, 1.07mmol) and pyridine (0.60mL, 7.51mmol) were dissolved in CH₂Cl₂(3.0mL)To the resulting solution was added benzenesulfonyl chloride (151. mu.L, 1.18mmol) in CH₂Cl₂(1mL) of the solution. The mixture was stirred at room temperature for 16 hours and stored in a refrigerator for 24 hours. The precipitate was collected by filtration to give 0.255g (57%) of pure product as HCl salt:

¹h NMR (DMSO-d6) delta 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, partially masked by solvent signal, 8H), 2.79(s, 3H); MS (posEI-DIP) M/z 382(M, I-DIP)⁺).

Example 119

2, 4-bis-fluoro-N- [1- (4-methyl-1-piperazinyl) -3-isoquinolinyl ] benzenesulfonamide hydrochloride

The title compound was prepared from 1- (4-methyl-1-piperazinyl) -3-isoquinolylamine (commercially available; 0.209g, 0.862mmol) using the method described in the example: yield 0.152g (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) delta; 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(br, 1H), 3.70-3.20 (partially masked 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) delta; 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, masked 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) delta; 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, masked by the 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) delta; 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, masked by the 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) delta; 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, masked by the solvent signal, 4H), 3.35-3.15(M, 4H), 2.84(d, J ═ 4.75Hz, 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) delta; 10.93(brs, 1H), 10.69(brs, 1H), 7.93(d, J ═ 8.19Hz, 1H), 7.79(d, J ═ 7.92Hz, 1H), 7.65 to 7.57(M, 1H), 7.52 to 7.37(M, 4H), 7.24 to 7.13(M, 1H), 7.03(s, 1H), 3.78(s, 3H), 3.75 to 3.20(M, masked by a solvent signal, 8H), 2.81(d, J ═ 4.48Hz, 3H), ms (pos esi) 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) delta; 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 ═ 3.96Hz, 1H), 3.20-3.10(M, 2H), 2.87-2.75(M, 2H), 2.70-2.50(M, partially masked by the solvent signal, 4H), 2.19(brs, 3H), ms (possesi) 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) delta; 10.03(s, 1H), 10.52(brs, 1H), 7.93(d, J ═ 8.44Hz, 1H), 7.78(d, J ═ 7.92Hz, 1H), 7.71(d, J ═ 2.11Hz, 1H), 7.65-7.57(M, 1H), 7.57-7.51(dd, J ═ 2.11 and 8.44Hz, 1H), 7.45-7.37(M, 1H), 6.99(s, 1H), 6.80(d, 8.44Hz, 1H), M3.82-3.71(M, 2H), 3.60-3.20(M, masked by a solvent signal) 2.84(d, J ═ 4.49Hz, 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) delta; 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, masked by the solvent signal), 2.70-2.50M, masked by the 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) delta; 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, masked by solvent signals), 3.31-3.14(M, 4H), 2.82(d, J ═ 4.75Hz, 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＝4.49Hz，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＝2.64Hz，1H)，7.91(m，d，J＝8.45Hz，1H)，7.80-7.73(m，2H)，7.65-7.57(m，1H)，7.45-7.37(m，1H)，7.14(d，J＝8.47Hz，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＝4.49Hz，3H)，MS(posESI)m/z＝491(M+H).

Example 132

2-methanesulfonyl-N- [1- (4-methyl-piperazin-1-yl) -isoquinolin-3-yl ] -benzenesulfonamide hydrochloride

MS(posESI)m/z＝461(M+H).

Example 133

3, 5-dimethyl-isoxazolyl-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＝8.45Hz，1H)，7.86(d，J＝7.92Hz，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＝4.49Hz，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＝4.75Hz，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) delta; 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 ═ 8.71Hz, 1H) m 7.05(s, 1H), 3.78(s, 3H), 3.76-3.69(m, masked by-OMe), 3.51-3.19(m, 6H), 2.82(d, J ═ 4.49Hz, 3H), MS (po)sESI)m/z＝443(M+H).

Synthesis of the 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 (0.379g, 1.39mmol) in a THF: EtOH 1: 4 solvent system was added Raney-Ni (1.0mL EtOH suspension), followed by hydrazine hydrate (0.348g, 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 (SiO)₂，CHCl₃/MeOH/NH₃9: 1: 0.4%) and 0.337g of 8- (4-methyl-1-piperazinyl) -5-quinolinylamine. Dissolving the amine in CH₂Cl₂(6.0mL) and pyridine (0.785mL, 9.73mmol) and benzenesulfonyl chloride (0.178mL, 1.39mmol) were added. The reaction mixture was stirred at room temperature for 16 hours and then with saturated NaHCO₃And (4) washing with an aqueous solution. With Na₂SO₄The organic phase was dried, filtered and concentrated. The crude product was purified by column chromatography (SiO)₂，CHCl₃/MeOH/NH₃9: 1: 0.4%) to yield 0.130g of the free base, which is converted into 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 the examples and intermediates in Table VI

Reaction scheme 3

a)H₂O₂，CH₃COOH，100℃；b)Me₃SiCN, toluene, (Me)₂N-CO-Cl，65℃；c)HBr/CH₃COOH, rt; d) boc-piperazine, K₂CO₃，90℃；R-SO₂Cl，py，rt。

Intermediate 20

3-cyanomethylpyridine-N-oxide-hydrogen peroxide (17ml, 30% w) was added to a mixture of 3-cyanomethylpyridine (11g, 93mmol) and glacial acetic acid (55ml) and heated at 100 ℃ overnight. The mixture was diluted with water (70ml) and MnO carefully added₂(5.0g) and stirred for 5 hours (peroxide content checked with peroxide bar) and only a small amount of peroxide remained. The mixture was concentrated in vacuo to 40ml and diluted with methanol (40ml), filtered through a short silica gel plug and washed with methanol (400 ml). The filtrate was concentrated and recrystallized from chloroform and hexane to give the title compound (9.5g, 76%).

¹H NMR(CDCl₃)δ8.16(s，2H)，7.32(s，2H)，3.73(s，2H)；MS m/z(M+1)135.

Intermediate 21

3- (cyanomethyl) pyridine-2-carbonitrile trimethylsilylcyanide (4.2ml, 32mmol) was added to a suspension of 3-cyanomethylpyridine-N-oxide (3.5g, 26mmol) in toluene (35ml) and after 1 min dimethylcarbamoyl chloride (2.4ml, 26mmol) was added and the reaction stirred at 65 ℃ overnight. EtOAc and 1N NaOH were added and the mixture was washed with water (2 ×). The organic phase was dried (MgSO)₄) And evaporated. The crude product was dissolved in ethanol (150ml) and stirred overnight, filtered (to remove by-products) and concentrated (25 ml). After 30 min at 0 ℃ the yellow powder was filtered and washed with cold ethanol (1 ×) to yield the title compound after drying (2.15g, 57%).

¹H NMR(CDCl₃)δ8.71(m，1H)，8.03(d，J＝8.03Hz，1H)，7.62(dd，J＝8.16，4.64Hz，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 (4.0g, 28mmol) was added carefully to a solution of HBr in acetic acid (33%) (25ml) at room temperature. The red suspension was stirred for 1.5 hours and filtered. The red solid was washed with EtOAc (3 ×) and suspended in water. 1N NaOH was added dropwise to 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 CH₂Cl₂Neutralized and filtered through a short plug of silica gel, CH with 5% MeOH₂Cl₂And (4) washing the solution. Subsequent concentration in vacuo afforded the title compound (3.85g, 61%).

¹H NMR(DMSO)δ8.58(dd，J＝4.02，1.51Hz，1H)，8.01(dd，J＝8.53，1.51Hz，1H)，7.47(dd，J＝8.53，4.02Hz，1H)，6.58(s，1H)，6.48(s，2H)；MS m/z(M+1)226.

Intermediate 23

4- (6-amino-1, 7-naphthyridin-8-yl) piperazine-1-carboxylic acid tert-butyl ester: a mixture of 6-amino-8-bromo-1, 7-naphthyridine (650mg, 2.9mmol), BOC-piperazine (1.1g, 5.9mmol), potassium carbonate (2g, 15mmol) dissolved in DMSO (1ml) was stirred at 90 ℃ 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 over potassium carbonate and concentrated in vacuo to give a yellow oil. The oil was triturated with ether and then eluted through a short silica gel plug using chloroform. The residue was then concentrated in vacuo to give the title compound (700mg, 74%) as a yellow oil.

¹H NMR(CDCl₃)δ8.43(dd，J＝4.09，1.72Hz，1H)，7.67(dd，J＝8.31，1.72Hz，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 (63mg, 0.19mmol) in anhydrous dichloromethane (0.5ml) and pyridine (0.25ml) was added p-toluenesulfonyl chloride (36mg, 0.19 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was purified using reverse phase preparative HPLC to give the corresponding tert-butoxycarbonyl protected piperazine intermediate. This was dissolved in dichloromethane (1.5ml) and treated with concentrated TFA (1ml) at room temperature for 1.5 h.

Example 137

4-methyl-N- (8-piperazin-1-yl-1, 7-naphthyridin-6-yl) benzenesulfonamide trifluoroacetic acid

The title compound (61mg, 65%) was prepared as a yellow solid according to general procedure I.

¹H NMR(CD₃OD)δ8.57-8.65(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 (14mg, 13%) was prepared as a yellow solid according to general procedure I.

¹H NMR(CD₃OD)δ8.70-8.63(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 (66mg, 65%) was prepared according to general procedure I.

¹H NMR(CD₃OD)δ8.82-8.76(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) but-1-sulfonamide trifluoroacetic acid

The title compound (48mg, 55%) was prepared according to general procedure I.

¹H NMR(CD₃OD)δ8.71-8.66(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 (60mg, 57%) was prepared according to general procedure I.

¹H NMR(CD₃OD)δ8.70-8.63(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 (65mg, 63%) was prepared according to general procedure I.

¹H NMR(CD₃OD)δ8.68-8.59(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 (56mg, 53%) was prepared according to general procedure I.

¹H NMR(CD₃OD)δ8.66-8.61(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 (57mg, 61%) was prepared according to general procedure I.

¹H NMR(CD₃OD)δ8.71-8.64(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 (35mg, 37%) was prepared according to general procedure I.

¹HNMR(DMSO)δ8.83(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 the examples and intermediates in the tables

Reaction scheme 4

Reaction scheme 4a) TMS-acetylene, Cu₂O，Py，80℃；b)tBuO-Na，Pd₂(dba)₃Xanthphos, xylene (xilene), 120 ℃; c) raney-Ni, hydrazine, THF/ethanol; d) R-SO₂Cl, Py; e) HCl-diethyl ether.

Intermediate 24

7-iodo-5-nitro-1-benzofuran: 4-Nitro-2, 5-diiodophenol (7.68g, 6.86mmol), TMS-acetylene (0.67g, 6.86mmol) and Cu were mixed together₂The resulting mixture of O (0.59g, 4.12mmol) in pyridine (120mL) was heated to 80 ℃ for 48 hours. The mixture was filtered through celite and the solvent was removed. Column chromatography in DCM/heptane 1: 1 gave 0.35g (18%) of the product.

¹H NMR(CD₃OD)δ8.60(d，1H，j＝2.1Hz)，8.51(d，1H，J＝2.1Hz)，7.84(d，1H，J＝2.1Hz)，7.04(d，1H，J＝2.4Hz)；MS(ESI)289.8(M+H)⁺；

Purity (HPLC, column X) 93%.

Intermediate 25

1-methyl-4- (5-nitro-1-benzofuran-7-yl) -piperazine: mixing 7-iodo-5-nitro-1-benzofuran (94.5mg, 0.327mmol), Xanthpos (19mg.0.032mmol), Pd₂(dba)₃A mixture of (7.4mg, 0.025mmol) and NaOt-Bu (44.0mg, 0.458mmol), methylpiperazine (39.3mg, 0.392mmol) in xylene (3mL) was heated to 120 ℃ overnight. The mixture was diluted with DCM and filtered through silica gel. With DCM/MeOH x 0.4% NH₃The product was eluted. Flash chromatography (DCM/MeOH X0.4% NH)₃) To give 60mg (70%) of BVT:

¹H NMR(CD₃OD)δ8.07(d，1H，J＝2.1Hz)，7.70(d，1H，J＝2.1Hz)，7.58(d，1H，J＝2.1Hz)，6.84(d，1H，J＝2.1Hz)，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

4- (5-nitro-1-benzofuran-7-yl) -piperazine-1-carboxylic acid tert-butyl ester: the title compound was prepared following the same procedure as for intermediate 25 using N-tert-butyl-piperazinecarboxylate to yield 240mg (64%) of a white solid:

¹H NMR(CD₃OD)δ8.08(d，1H，J＝2.1Hz)，7.72(d，1H，J＝2.1Hz)，7.58(d，1H，J＝2.1Hz)，6.86(d，1H，J＝2.1Hz)，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

4- (5-amino-1-benzofuran-7-yl) -piperazine-1-carboxylic acid tert-butyl ester: 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 the aromatic amine over 3 hours at room temperature with Raney-Ni and hydrazine (10 eq) in THF/ethanol (1: 4). The reaction mixture was filtered through a pad of celite, the volatiles were evaporated and the crude product was used for the next reaction.

Example 146

3-cyanophenyl-N- (7-piperazin-1-yl-benzofuran-5-yl) -benzenesulfonamide hydrochloride

To a solution of 4- (5-amino-1-benzofuran-7-yl) -piperazine-1-carboxylic acid tert-butyl ester (43mg0.138mmol) and pyridine (100 μ L, 1.24mmol) was added 3-cyanobenzenesulfonyl chloride (33.4mg, 0.166 mmol). After 2 hours PS-Trisamin was added and the reaction was stirred overnight. Flash chromatography (DCM/heptane/MeOH 5: 4: 1) afforded 24.6mg of a solid. The crude product was dissolved in MeOH (2mL) and HCl/ether 2M (4mL) was added. After 0.5 h the sample was concentrated to give 19mg (36%) of a white solid:

¹H NMR(CD₃OD)δ8.02-7.88(m，3H)，7.72(d，1H，J＝2.1Hz)，7.76-7.61(m，1H)，6.92(d，1H，J＝2.1Hz)，6.74(d，1H，J＝2.1Hz)，6.60(d，1H，J＝2.1Hz)，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 (21%) was prepared as a white solid according to the method used for the synthesis of example 146:

¹H NMR(CD₃OD)δ7.73(d，1H，J＝2.1Hz)，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＝2.1Hz)，6.74(d，1H，J＝2.1Hz)，6.70(d，1H，J＝2.1Hz)，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 (30%) was prepared as a white solid according to the method used for the synthesis of example 146:

¹H NMR(CD₃OD)δ8.65(d，1H，J＝8.8Hz)，8.03-7.86(m，3H)，7.58-7.49(m，3H9，7.36-7.33(m，1H)，6.74(d，1H，J＝2.2Hz)，6.53(d，1H，J＝2.2Hz)，6.30(d，1H，J＝2.2Hz)，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 (33%) was prepared as a white solid according to the method used for the synthesis of example 146:¹H NME(CD₃OD)δ7.72-7.69(m，3H)，7.57-7.51(m，1H)，7.47-7.41(m，2H)，6.92(d，1H，J＝2.1Hz)，6.72(d，1H，J＝2.1Hz)，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 (9%) was prepared as a white solid according to the method used for the synthesis of example 146:

¹H NMR(CD₃OD)δ7.74-7.73(m，2H)，7.62(d，1H，J＝2.2Hz)，7.38-7.36(m，1H)，6.87(d，1H，J＝1.8Hz)，6.64(d，1H，J＝2.2Hz)，6.58(d，1H，J＝1.8Hz)，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 (45%) was prepared as a white solid according to the method for the synthesis of example 146 using 1-methyl-4- (5-nitro-1-benzofuran-7-yl) piperazine:

¹H NMR(CD₃OD)δ7.74-7.283(m，6H)，6.82(d，1H，J＝1.8Hz)，6.62(d，1H，J＝2.2Hz)，6.48(d，1H，J＝1.8Hz)，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 (44mg, 0.139mmol) dissolved in 3ml dichloromethane was added to a test tube containing p-toluenesulfonyl chloride (32mg, 0.167mmol) and pyridine (100. mu.l, 1.25mmol) and kept on a shaker for 1 week. After purification by preparative HPLC, the resulting Boc-material was treated with HCl in ether and kept on a shaker until salt formation. The solution was centrifuged and the supernatant removed. Diethyl ether was added, then centrifuged and decanted (repeated 3 times) to remove excess HCl. Finally the remaining ether was evaporated in a SpeedVAc concentrator to give 10mg of the title product. HPLC purity 94%, M/z 372.3(M + H).1H NMR (270MHz, methanol-d 4) δ ppm 2.35(s, 3H)3.45(M, 8H)6.63(d, J1.85 Hz, 1H)6.71(d, J2.11 Hz, 1H)6.88(d, J1.85 Hz, 1H)7.25(M, 2H)7.58(M, 2H)7.71(d, J2.11 Hz, 1H).

Example 153

3, 4-dimethoxy-N- (7-piperazin-1-yl-benzofuran-5-yl) -benzenesulfonamide hydrochloride

The HPLC purity is 92 percent,

m/z 418.3(M + H).1H NMR (270MHz, methanol-d 4) δ ppm3.45(M, 8H)3.70(M, 3H)3.81(M, 3H)6.62(d, J ═ 1.85Hz, 1H)6.73(d, J ═ 2.38Hz, 1H)6.94(M, 2H)7.17(d, J ═ 2.11Hz, 1H)7.29(dd, J ═ 8.44, 2.11Hz, 1H)7.72(d, J ═ 2.38Hz, 1H).

Example 154

4-bromo-N- (7-piperazin-1-yl-benzofuran-5-yl) -benzenesulfonamide hydrochloride

The purity of HPLC is 95 percent,

m/z 436.2(M + H).1H NMR (270MHz, methanol-d 4) δ ppm3.46(M, 8H)6.62(d, J1.85 Hz, 1H)6.74(d, J2.38 Hz, 1H)6.93(d, J1.85 Hz, 1H)7.61(M, 4H)7.73(d, J2.11 Hz, 1H).

Example 155

2, 3-dichloro-N- (7-piperazin-1-yl-benzofuran-5-yl) -benzenesulfonamide hydrochloride

The purity of HPLC is 96 percent,

m/z 426.2(M + H).1H NMR (270MHz, methanol-d 4) δ ppm3.44(M, 8H)6.67(d, J ═ 1.85Hz, 1H)6.72(d, J ═ 2.11Hz, 1H)7.01(d, J ═ 1.85Hz, 1H)7.34(t, J ═ 8.18Hz, 1H)7.70(M, 2H)7.94(dd, J ═ 7.92, 1.58Hz, 1H).

Example 156

2, 4-dichloro-5-methyl-N- (7-piperazin-1-yl-benzofuran-5-yl) -benzenesulfonamide hydrochloride

The purity of HPLC is 96 percent,

m/z 440.2(M + H).1H NMR (270MHz, methanol-d 4) δ ppm2.30(s, 3H)3.46(M, 8H)6.69(d, J1.85 Hz, 1H)6.73(d, J2.11 Hz, 1H)7.01(d, J1.85 Hz, 1H)7.60(s, 1H)7.71(d, J2.11 Hz, 1H)7.87(s, 1H).

Example 157

4-methoxy-N- (7-piperazin-1-yl-benzofuran-5-yl) -benzenesulfonamide hydrochloride

The HPLC purity is 93 percent,

m/z 388.3(M + H).1H NMR (270MHz, methanol-d 4) δ ppm3.45(M, 8H)3.79(s, 3H)6.72(d, J2.11 Hz, 1H)6.93(M, 3H)7.63(M, 3H)7.71(d, J2.11 Hz, 1H).

Example 158

4-chloro-N- (7-piperazin-1-yl-benzofuran-5-yl) -benzenesulfonamide hydrochloride

The purity of HPLC is 97%,

m/z 392.3(M + H).1H NMR (270MHz, methanol-d 4) δ ppm3.46(M, 8H)6.63(d, J1.85 Hz, 1H)6.74(d, J2.38 Hz, 1H)7.47(M, 2H)7.67(M, 3H)7.73(d, J2.11 Hz, 1H).

Example 159

N- (7-piperazin-1-yl-benzofuran-5-yl) -4-trifluoromethyl-benzenesulfonamide hydrochloride

The HPLC purity is 91 percent,

m/z 426.3(M + H).1H NMR (270MHz, methanol-d 4) δ ppm3.47(M, 8H)6.64(d, J ═ 1.85Hz, 1H)6.74(d, J ═ 2.11Hz, 1H)6.92(d, J ═ 1.85Hz, 1H)7.73(d, J ═ 2.11Hz, 1H)7.84(M, 4H).

Example 160

5-fluoro-2-methyl-N- (7-piperazin-1-yl-benzofuran-5-yl) -benzenesulfonamide hydrochloride

The HPLC purity is 94 percent,

m/z 390.3(M + H).1H NMR (270MHz, methanol-d 4) δ ppm2.57(M, 3H)3.46(M, 8H)6.63(M, 1H)6.74(d, J ═ 2.11Hz, 1H)6.91(d, J ═ 1.85Hz, 1H)7.20(M, 1H)7.34(M, 1H)7.56(dd, J ═ 8.71, 2.64Hz, 1H)7.73(d, J ═ 2.11Hz, 1H).

Example 161

5-chloro-thiophene-2-sulfonic acid (7-piperazin-1-yl-benzofuran-5-yl) -amide hydrochloride

The HPLC purity is 94 percent,

m/z 398.3(M + H).1H NMR (270MHz, methanol-d 4) δ ppm3.48(M, 8H)6.68(d, J2.11 Hz, 1H)6.79(d, J2.38 Hz, 1H)6.97(d, J3.96 Hz, 1H)7.01(d, J1.85 Hz, 1H)7.25(d, J3.96 Hz, 1H)7.76(d, J2.38 Hz, 1H).

Biological assay

Compounds of the invention can be assayed for 5-HT using in vivo and in vitro assays well known in the art₆The binding capacity of the receptor.

(a)5-HT₆Intrinsic Activity test

Expression of human 5-HT by determination of 5-HT₆Inhibition of receptor induction of cAMP increase in HEK293 cells characterises 5-HT₆Receptor antagonists (see Boess et al (1997) Neuropharmacology 36: 713-720). Briefly, HEK293/5-HT₆Cells were seeded at 25,000/well density on polylysine coated 96-well plates and allowed to stand at 37 ℃ and 5% CO₂Growth was carried out in DMEM (Dulbecco's modified Eagle's Medium) containing 5% dialyzed fetal bovine serum (without phenol red) in an incubator for 48 hours. The medium was then aspirated and replaced with 0.1ml of assay medium (Hanks balanced salt solution containing 20mM HEPES, 1.5mM isobutylmethylxanthine and 1mg/ml bovine serum albumin). After addition of 50. mu.l of test substance in the assay medium, the cells were incubated at 37 ℃ and 5% CO₂Incubate for 10 minutes in the incubator. The medium was again aspirated and the cAMP content was determined using a radioactive cAMP kit (Amersham Pharmacia Biotech, BIOTRAK RPA 559). 5-HT, which caused a cAMP increase, was 50% inhibited by assay (in [ 5-HT)]2.8 times EC₅₀Time) to quantify the potency of the antagonist using equation K_i＝IC₅₀/(1+[5HT]/EC₅₀)。

Compound of the present invention para 5-HT₆The receptor has selective affinity, K_iThe value was 0.5nM to 5. mu.M. Furthermore, these compounds show a 5-HT profile_1a、5-HT_2a、5-HT_2a、5-HT_2b、5-HT_2cGood selectivity.

(b) In vivo test for reducing food intake

For reviews on 5-hydroxytryptamine and food intake, see Blundell, j.e. and Halford, j.c.g. (1998): 5-hydroxytryptamine and appetite regulation. Meaning of Pharmacological Treatment for Obesity "(Serotonin and empirical regulation. injections for the Pharmacological Treatment of Obesity.) -" CNS drugs (CNSDrugs) 9: 473-495.

Obese (ob/ob) mice were selected as the primary animal model for screening because such mutant mice consume large amounts of food and produce high signal-to-noise ratios. To further confirm and compare efficacy data, the effect of the compounds on food consumption was also studied in wild type (C57BL/6J) mice. The amount of food consumed during the 15 hour infusion of the compound was recorded.

8-9 week male mice (obese C57BL/6 JBom-Lep) with average body weights of 50g (obese) and 25g (lean)^obAnd lean wild type C57B1/6 JBom; bomholtsgaard, Denmark) were used for all studies. Animals were housed individually in cages at 23 + -1 deg.C, 40-60% humidity and were provided with ad libitum access to water and standard laboratory food. Set 12/12-hour light/dark to cancel light at 5 pm. Animals were maintained in this condition for at least 1 week, after which the study was initiated.

The test compounds are dissolved in a solvent suitable for each particular compound, such as cyclodextrin, cyclodextrin/methanesulfonic acid, polyethylene glycol/methanesulfonic acid, saline. Fresh solutions were prepared for each study. 30, 50 and 100mgkg were used^-1Sky^-1The dosage of (a). The purity of the test compound was analytical grade.

Animals were weighed at the start of the study and randomly grouped based on body weight. An Alzet mini-osmotic pump (Model 2001D; infusion rate 8. mu.l/hr) was used and loaded essentially as recommended by the Alzet technical information handbook (Alza Scientific Products, 1997; Teeuwes and Yam, 1976). A continuous subcutaneous infusion was used for a period of 24 hours. The micro osmotic pump was loaded with different concentrations of test compound dissolved in the vehicle and vehicle solution alone and maintained at a pre-warmed to 37 c (about 1 hour). The micro-osmotic pump was implanted subcutaneously under short-term anesthetic (methoxyflurochloroethane/aminoflurane). This procedure lasts about 5 minutes. It takes about 3 hours to achieve steady state delivery of the compound.

The weight of the food pellets was measured 2 days before implantation of the mini osmotic pump (baseline) and 1 day after implantation at 5 pm and 8 pm. Weighing was carried out using a computer-assisted Mettler Toledo PR 5002 balance. The calibration is performed for occasional spills. At the end of the study, animals were sacrificed by cervical dislocation and trunk blood samples were taken for subsequent blood concentration analysis.

Proteins in plasma samples were precipitated with methanol, centrifuged and the supernatant transferred to HPLC vials and injected into a liquid chromatography/mass spectrometry system. The mass spectrometer was set to electrospray positive ion mode and multiple reaction monitoring (MRM m/z 316 with switching > 221). Linear regression analysis of the standards forced through the origin was used to calculate the concentration of the unknown samples.

Food consumption values were determined for 15 hours on 3 consecutive days and the percentage of baseline level values were derived for each animal on the day before and after treatment. Values are expressed as mean ± SD and ± SEM from 8 animals/dose group. Statistical evaluation was performed by Kruskal-Wallis one-way ANOVA using baseline percentage values. The Mann Whitney U-test was performed on the statistical comparison between the control and treatment groups if the statistical significance reached a level of p < 0.05.

The compounds of the invention show effects in the range of 50-200 mg/kg.

TABLE VI in vivo efficacy data relating to the effect of compounds on reduction of food intake

Examples	In vivo efficacy-ob/ob mouse food intake (15 hours)
Examples	In vivo efficacy-ob/ob mouse food intake (15 hours)			Produced at 50 mg/Kg/day in ob/ob miceRaw food intake inhibition% for 15 hours	Free plasma concentration of the Compound at Steady State (Css, μ)
48	23.8	0.008
48	23.8	0.008	13	24.1	0.035
53	25.7	ND	13	24.1	0.035
53	25.7	ND	34	51.4	0.078
24	46.2	0.0076	34	51.4	0.078
24	46.2	0.0076	19	69.6	0.150
27	68.9	0.008	19	69.6	0.150
27	68.9	0.008	30	60.1	0.275
29	71	0.33	30	60.1	0.275
29	71	0.33	14	41	0.23

^aThe effect on food intake as reported in the table was obtained at a dose of 14.8 mg/kg/d.

^bThe effect on food intake as reported in the table was obtained at a dose of 100 mg/kg/d.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof,

wherein:

ring B isWherein D is a 5-membered heterocyclic or heteroaromatic ring, said ring containing oneOr 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 no more than 3 total W are N;

p is:

R¹the method comprises the following steps:

(a)C_1-6an alkyl group;

(b)C_1-6an alkoxyalkyl group;

(c) straight or branched C_1-6A hydroxyalkyl group;

(d) straight or branched C_1-6An alkyl halide; or

(e) A group Ar;

ar is:

(a) a phenyl group;

(b) 1-naphthyl;

(c) 2-naphthyl;

(d) a benzyl group;

(e) cinnamoyl;

(g) Bicyclic ring system containing at least one heterocycle according to (f);

wherein the group Ar is substituted in one or more positions by:

(a)5-7 membered optionally aromatic, partially saturated or fully saturated heterocyclic ring each containing 1-4 heteroatoms selected from oxygen, nitrogen or sulfur;

(b) halogen;

(c)C_1-6an alkyl group;

(d)-CF₃；

(e) a hydroxyl group;

(f)C_1-6an alkoxy group;

(g)C_1-4an alkenyl group;

(h) a phenyl group;

(i) a phenoxy group;

(j) a benzyloxy group;

(k) a benzoyl group;

(l)-OCF₃；

(m)-CN；

(n) straight or branched C_1-6A hydroxyalkyl group;

(o) straight or branched C_1-6An alkyl halide;

(r)-NR⁴R⁵；

(s)-NO₂；

(t)-CONR⁴R⁵；

(u)-NHSO₂R⁴；

(v)-NR⁴COR⁵；

(x)-SO₂NR⁴R⁵；

(z)-C(＝O)R⁴；

(aa)-CO₂R⁴(ii) a Or

(ab)-S(O)_nR⁴(ii) a Wherein n is 0, 1, 2 or 3;

(ac)-S-(C_1-6) An alkyl group;

(ad)-SCF₃；

R²the method comprises the following steps:

(a)H；

(b)C_1-6alkyl radical

(c)C_1-6An alkoxy group,

(d) straight or branched C_1-6Hydroxyalkyl, or

(e) Straight or branched C_1-6An alkyl halide;

or R¹And R²Linkage forming group (CH)₂)₄O；

R³Is the following group:

x and Y are independently:

(a)H；

(b) halogen;

(c)C_1-6an alkyl group;

(d)-CF₃；

(e) a hydroxyl group;

(f)C_1-6an alkoxy group;

(g)C_1-4an alkenyl group;

(h) a phenyl group;

(i) a phenoxy group;

(j) a benzyloxy group;

(k) a benzoyl group;

(l)-OCF₃；

(m)-CN；

(n) straight or branched C_1-6A hydroxyalkyl group;

(o) straight or branched C_1-6An alkyl halide;

(r)-NR⁴R⁵；

(s)-NO₂；

(t)-CONR⁴R⁵；

(u)-NHSO₂R⁴；

(v)-NR⁴COR⁵；

(x)-SO₂NR⁴R⁵；

(z)-C(＝O)R⁴；

(aa)-CO₂R⁴(ii) a Or

(ab)-S(O)_nR⁴(ii) a Wherein n is 0, 1, 2 or 3;

(ac)-S-(C_1-6) An alkyl group;

(ad)-SCF₃；

R⁴and R⁵Independently are:

(a)H；

(b)C_1-6an alkyl group;

(c)C₃-C₇a cycloalkyl group; or

(d) As to R¹Ar as defined;

R⁶The method comprises the following steps:

(a) h; or

(b) Straight or branched C_1-6An alkyl group.

2. The compound of claim 1 of formula VI:

wherein R is³P, X and Y are as defined for formula (I); and wherein D is a 5-membered heterocyclic or heteroaromatic ring, said ring containing 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 a heteroaryl group, and when the heteroaromatic ring contains one or two nitrogen atoms, the group R⁶Attached to a secondary nitrogen, wherein R⁶As defined in claim 1.

3. The compound of claim 1, wherein

R¹The method comprises the following steps:

(a)C_1-6an alkyl group; or

(e) A group Ar;

ar is:

(a) a phenyl group;

(b) 1-naphthyl;

(c) 2-naphthyl; or

(f)5-7 membered optionally aromatic, partially saturated or fully saturated heterocyclic ring containing 1-4 heteroatoms selected from oxygen, nitrogen and sulfur;

wherein the group a is substituted in one or more positions by X or Y; wherein X or Y is:

(a)H；

(b) halogen;

(c)C_1-6an alkyl group;

(d)-CF₃；

(f)C_1-6an alkoxy group;

(g)C_1-4an alkenyl group;

(l)-OCF₃(ii) a Or

(n) straight or branched C_1-6A hydroxyalkyl group;

R²the method comprises the following steps:

(a) h; or

(b)C_1-3An alkyl group;

or R¹And R²To the radical (CH)₂)₄O；

R³The method comprises the following steps:

wherein R is⁶The method comprises the following steps:

(a) h; or

(b)C_1-6An alkyl group;

x and Y are H; and/or

D is pyrrolyl, thienyl or furyl.

4. The compound of claim 1, wherein R⁶Is methyl.

5. The compound of claim 1, which is the following:

3-cyanophenyl-N- (7-piperazin-1-yl-benzofuran-5-yl) -benzenesulfonamide hydrochloride;

4-phenoxy-N- (7-piperazin-1-yl-benzofuran-5-yl) -benzenesulfonamide hydrochloride;

1-naphthyl-N- (7-piperazin-1-yl-benzofuran-5-yl) -benzenesulfonamide hydrochloride;

n- (7-piperazin-1-yl-benzofuran-5-yl) -benzenesulfonamide hydrochloride;

5-chloro-3-methyl-benzo [ b ] thiophene-2-sulfonic acid (7-piperazin-1-yl-benzofuran-5-yl) amide hydrochloride;

n- [7- (4-methylpiperazin-1-yl) -1-benzofuran-5-yl ] -benzenesulfonamide hydrochloride.

6. A pharmaceutical formulation comprising a compound according to claim 1 as active ingredient in association with a pharmaceutically acceptable diluent or carrier.

7. Having a 5-HT₆Use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof, having receptor antagonist activity, for the manufacture of a medicament for the treatment or prevention of obesity, type II diabetes and/or mania,

wherein:

w is N or- (CH) -, provided that no more than 3 total W are N;

p is:

R¹the method comprises the following steps:

(a)C_1-6an alkyl group;

(b)C_1-6an alkoxyalkyl group;

(c) straight or branched C_1-6A hydroxyalkyl group;

(d) straight or branched C_1-6An alkyl halide; or

(e) A group Ar;

ar is:

(a) a phenyl group;

(b) 1-naphthyl;

(c) 2-naphthyl;

(d) a benzyl group;

(e) cinnamoyl;

(g) Bicyclic ring system containing at least one heterocycle according to (f);

wherein the group Ar is substituted in one or more positions by:

(b) halogen;

(c)C_1-6an alkyl group;

(d)-CF₃；

(e) a hydroxyl group;

(f)C_1-6an alkoxy group;

(g)C_1-4an alkenyl group;

(h) a phenyl group;

(i) a phenoxy group;

(j) a benzyloxy group;

(k) a benzoyl group;

(l)-OCF₃；

(m)-CN；

(n) straight or branched C_1-6A hydroxyalkyl group;

(o) straight or branched C_1-6An alkyl halide;

(r)-NR⁴R⁵；

(s)-NO₂；

(t)-CONR⁴R⁵；

(u)-NHSO₂R⁴；

(v)-NR⁴COR⁵；

(x)-SO₂NR⁴R⁵；

(z)-C(＝O)R⁴；

(aa)-CO₂R⁴；

(ab)-S(O)_nR⁴(ii) a Wherein n is 0, 1, 2 or 3;

(ac)-S-(C_1-6) An alkyl group; or

(ad)-SCF₃；

R²The method comprises the following steps:

(a)H；

(b)C_1-6alkyl radical

(c)C_1-6An alkoxy group,

(d) straight or branched C_1-6Hydroxyalkyl, or

(e) Straight or branched C_1-6An alkyl halide;

or R¹And R²Linkage forming group (CH)₂)₄O；

R³Is the following group:

x and Y are independently:

(a)H；

(b) halogen;

(c)C_1-6an alkyl group;

(d)-CF₃；

(e) a hydroxyl group;

(f)C_1-6an alkoxy group;

(g)C_1-4an alkenyl group;

(h) a phenyl group;

(i) a phenoxy group;

(j) a benzyloxy group;

(k) a benzoyl group;

(l)-OCF₃；

(m)-CN；

(n) straight or branched C_1-6A hydroxyalkyl group;

(o) straight or branched C_1-6An alkyl halide;

(r)-NR⁴R⁵；

(s)-NO₂；

(t)-CONR⁴R⁵；

(u)-NHSO₂R⁴；

(v)-NR⁴COR⁵；

(x)-SO₂NR⁴R⁵；

(z)-C(＝O)R⁴；

(aa)-CO₂R⁴(ii) a Or

(ab)-S(O)_nR⁴(ii) a Wherein n is 0, 1, 2 or 3;

(ac)-S-(C_1-6) An alkyl group;

(ad)-SCF₃；

R⁴and R⁵Independently are:

(a)H；

(b)C_1-6an alkyl group;

(c)C₃-C₇a cycloalkyl group; or

(d) As to R¹Ar as defined;

R⁶The method comprises the following steps:

(a) h; or

(b) Straight or branched C_1-6An alkyl group.