JP2003513085A - New compound - Google Patents

Abstract

  (57) [Summary] The present invention relates to novel sulfonamide compounds having CNS activity, processes for their preparation, compositions containing them and their use as medicaments.

Description

Detailed Description of the Invention

The present invention relates to novel sulfonamide compounds having pharmacological activity, a process for their preparation, compositions comprising sulfonamide compounds and their use in the treatment of CNS disorders. WO98 / 27081, WO99 / 37623 and WO / 9942465 has a 5-HT ₆ antagonist activity discloses sulfonamide compounds as claims to be useful in the treatment of various CNS disorders. WO94 /
Both 21619 and EP0701819 disclose systems of naphthalene derivatives which are claimed to be 5-HT _1A receptor ligands.

It has also now been discovered that a series of structurally different compounds exhibit 5-HT ₆ receptor antagonist activity. Therefore, in the first aspect of the present invention, the formula (
I):

[Chemical 4] (I)

[0003] [In the formula,   P is one to three selected from phenyl, naphthyl, oxygen, nitrogen and sulfur.
5- or 6-membered heteroaryl rings containing heteroatoms or oxygen, nitrogen and sulfur
Bicyclic or tricyclic heteroaryl containing 1 to 3 heteroatoms selected from yellow
Is a ring of rings;   A is a single bond, C_1-6Alkylene or C_2-6An alkenylene group;   R¹Is substituted with halogen, one or more halogen atoms,
Good C_1-6Alkyl, C_3-6Cycloalkyl, phenyl, COC_1-6A
Rukiru, C_1-6Alkoxy, OCF_Three, Hydroxy, hydroxy C_1-6Al
Kill, hydroxy C_1-6Alkoxy, C_1-6Alkoxy C_1-6Alkoxy
, Nitro, amino, C_1-6Alkylamino or di-C_1-6With alkylamino
Yes;   n is 0, 1, 2, 3, 4 or 5;   R^TwoIs hydrogen, C_1-6Alkyl or R^ThreeTogether with- (CR⁶R⁷) _p -Forms here and R⁶And R⁷Are independently hydrogen or C_1-6Archi
And p is 2, 3 or 4;   R^ThreeIs C optionally substituted by one or more halogen atoms_{1 -6} Alkyl, halogen, C_1-6Alkoxy or R^TwoTogether with the above
Same meaning- (CR⁶R⁷)_p-Forms;   m is 0, 1 or 2;   R^FourIs -X-R⁵Where X is a single bond, CH_Two, O, NH or
N-C_1-6Alkyl and R⁵Is 1 selected from nitrogen, sulfur or oxygen
~ 5-7 membered optionally substituted heterocyclic containing ~ 3 heteroatoms
A ring or a bicyclic heterocyclic ring;   Q is a phenyl ring or a 6-membered heteroaryl containing 1 or 2 nitrogen atoms
It is a ring] And a pharmaceutically acceptable salt thereof.

The C _1-6 alkyl group, alone or as part of another group, may be a straight chain or branched chain. The term “halogen” as used herein, unless otherwise indicated,
It is a group selected from fluorine, chlorine, bromine or iodine. When P is naphthyl, this represents a naphth-1-yl and naphth-2-yl group. When P is a 5 or 6 membered heteroaryl ring, suitable examples include thienyl, furyl, pyrrolyl, triazolyl, diazolyl, oxazolyl, thioazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl and pyrazinyl. When P is a bicyclic heteroaryl ring, suitable examples include indolyl, benzofuryl, benzothienyl, quinolinyl and isoquinolinyl. When P is a tricyclic heteroaryl ring, a preferred example is dibenzofuryl. The heteroaryl ring can be attached to the residue of the molecule via any suitable carbon atom, or nitrogen atom if present. Preferred P is phenyl, naphthyl, benzofuryl or benzothienyl. Preferred A is a single bond, a methylene or ethylene group or a -CH = CH- group. The most preferred A is a single bond.

When n is greater than 1, the R ¹ groups can be the same or different. Preferred R ¹ is halogen (especially chloro or bromo) or a C _1-6 alkyl group which may be substituted with one or more halogen atoms, such as methyl, ethyl, isopropyl, t-butyl or trifluoromethyl. Is. Preferred n is 0, 1, 2 or 3, especially 1 or 2. _{^{(CR 6 R 7) p -}} - R 2 is further taken together with ^{R 3} groups when forming a group, both ^{R 6} and ^{R 7} groups are preferably hydrogen, p is preferably 2 is there. R ² is preferably hydrogen. The substituent R ³ can be attached to any unsubstituted carbon atom in the fused ring. When m is greater than 1, the R ³ groups can be the same or different. If the R ² / R ³ groups can be joined together, the R ³ group must be attached to one of the carbon atoms of the fused ring, ortho to the sulfonamide bond. Preferably m is 0. The R ⁴ group can be attached to any unsubstituted carbon atom in ring Q. When R ⁵ is a 5- or 7-membered heterocyclic ring, suitable examples include piperazinyl, piperidinyl, pyrrolidinyl and morpholinyl. The 5-7 membered heterocyclic ring can be attached to the residue of the molecule through the carbon atom or, if present, the appropriate nitrogen atom. When X is O, NH or N—C _1-6 alkyl, the 5-7 membered heterocyclic ring must be attached to the residue of the molecule via a carbon atom. Preferably, X is a single bond (i.e., ^R 4 ⁼ R ⁵⁾ is a heterocyclic ring of 5 to 7 membered, is combined with the residue of the molecule via a suitable nitrogen atom.

When R ⁵ is a bicyclic heterocyclic ring, X is preferably a single bond (ie R ⁴ = R ⁵ ) and suitable examples of these groups are:

[Chemical 5] Is.

Optional substituents on the ring as defined for R ⁵ that may be present on a carbon and / or nitrogen atom include C _1-6 alkyl, especially methyl. Most preferred R ⁴ is unsubstituted piperazine or N-methylpiperazine, which is attached to the residue of the molecule via a suitable nitrogen atom. Suitable Q is a phenyl ring or a 6 membered heteroaryl ring containing one or two nitrogen atoms. Preferably Q is taken together with the phenyl ring to which it is fused to form a quinoline ring, the substituent R ⁴ being in the 4-position, ie of formula (A)
:

[Chemical 6] It is a group represented by (A).

Particularly preferred compounds of the present invention include: 5-chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid (4- [
4-Methylpiperazin-1-yl] -quinolin-6-yl) -amide; 5-chloro-naphthalene-2-sulfonic acid (4- [4-methyl-piperazin-
1-yl] -quinolin-6-yl) -amide; 4-bromo-N- [4- (4-methyl-piperazin-1-yl) -quinolin-
6-yl] -benzenesulfonamide; 3,5-dichloro-N- [4- (4-methyl-piperazin-1-yl) -quinolin-6-yl] -benzenesulfonamide; 5-chloro-3-methyl -Benzo [b] thiophene-2-sulfonic acid (4- [
3,5-Dimethylpiperazin-1-yl] -quinolin-6-yl) -amide; 5-chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid [4- (
4-Methyl-piperazin-6-yl] -quinazolin-6-yl) amide; 5-chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid (4-piperazin-1-yl-quinolin-6- Yl) -amide; 3,5-dichloro-N- (4-piperazin-1-yl-quinolin-6-yl)
-Benzenesulfonamide; 5-chloro-3-methyl-benzofuran-2-sulfonic acid (4-piperazine-
1-yl-quinolin-6-yl) amide;

5,7-Dichloro-3-methyl-benzo [b] thiophene-2-sulfonic acid (
4-Piperazin-1-yl-quinolin-6-yl) -amide; 5-chloro-naphthalene-2-sulfonic acid (4-piperazin-1-yl-quinolin-6-yl) -amide; 5-chloro-naphthalene -1-Sulfonic acid (4-piperazin-1-yl-quinolin-6-yl) -amide; 5-chloro-2-methyl-benzo [b] thiophen-3-sulfonic acid (4-piperazin-1-yl- Quinolin-6-yl) -amide; 2-dibenzofuran-sulfonic acid (4-piperazin-1-yl-quinolin-6)
-Yl) -amide; 5-chloro-3,7-dimethyl-benzo [b] thiophene-2-sulfonic acid (
4-Piperazin-1-yl-quinolin-6-yl) -amide; 7-chloro-2-methyl-benzo [b] thiophen-3-sulfonic acid (4-piperazin-1-yl-quinolin-6-yl) -Amide; 4,6-dichloro-2-methyl-benzo [b] thiophene-3-sulfonic acid (
4-piperazin-1-yl-quinolin-6-yl) -amide; 5,7-dichloro-2-methyl-benzo [b] thiophen-3-sulfonic acid (
4-Piperazin-1-yl-quinolin-6-yl) -amide; Biphenyl-4-sulfonic acid (4-piperazin-1-yl-quinolin-6-yl) -amide; 4-tert-butyl-N- ( 4-Piperazin-1-yl-quinolin-6-yl) -benzenesulfonamide; 5-Bromo-3-methyl-benzo [b] thiophen-2-sulfonic acid (4-piperazin-1-yl-quinolin-6- 4-n-butyl-N- (4-piperazin-1-yl-quinolin-6-yl)-
Benzenesulfonamide; 4-chloro-2,5-dimethyl-N- (4-piperazin-1-yl-quinolin-6-yl) -benzenesulfonamide; 5-chloro-3-ethyl-benzo [b] thiophene- 2-Sulfonic acid (4-piperazin-1-yl-quinolin-6-yl) -amide; 5-chloro-3-isopropyl-benzo [b] thiophene-2-sulfonic acid (
4-piperazin-1-yl-quinolin-6-yl) -amide; 4-iodo-N- (4-piperazin-1-yl-quinolin-6-yl) -benzenesulfonamide; 1- (5-chloro- 3-methyl-benzo [b] thiophene-2-sulfonyl)
-8- (4-Methyl-piperazin-1-yl) -2,3-dihydro-1H-pyrrolo [2,3-g] quinoline; 5-chloro-naphthalene-2-sulfonic acid (2-methyl-4- Piperazine-1
-Yl-quinolin-6-yl) amide; 5-chloro-3-methyl-benzo [b] thiophen-2-sulfonic acid (2-methyl-4-piperazin-1-yl-quinolin-6-yl) amide; 5-chloro-3-methyl-benzofuran-2-sulfonic acid (2-methyl-4-
Piperazin-1-yl-quinolin-6-yl) amide; 5-chloro-naphthalene-2-sulfonic acid (3-methyl-4-piperazine-1)
-Yl-quinolin-6-yl) amide;

5-chloro-3-methyl-benzo [b] thiophen-2-sulphonic acid (3-methyl-4-piperazin-1-yl-quinolin-6-yl) amide; 5,7-dichloro-3- Methyl-benzo [b] thiophene-2-sulfonic acid (
3-Methyl-4-piperazin-1-yl-quinolin-6-yl) amide; 5-chloro-3-methyl-benzofuran-2-sulfonic acid (3-methyl-4-
Piperazin-1-yl-quinolin-6-yl) amide; 4-tert-butyl-N- [4- (S-hexahydro-pyrrolo [1,2-a
] Pyrazin-2-yl) -quinolin-6-yl-benzenesulfonamide; 5-chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid [4- (
S-Hexahydro-pyrrolo [1,2-a] pyrazin-2-yl) -quinoline-6
-Yl] amide; 5-chloro-2-methyl-benzo [b] thiophene-3-sulfonic acid (4- [
3,5-Dimethylpiperazin-1-yl] -quinolin-6-yl) -amide; 5-chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid [4-((
S) -3-Methyl-piperazin-1-yl) -quinolin-6-yl] -amide; 5-chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid [4-((
R) -3-Methyl-piperazin-1-yl) -quinolin-6-yl] -amide; 5-chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid [4-((
R) -3-Isopropyl-piperazin-1-yl) -quinolin-6-yl]-
Amide; 5-chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid [4- (
Trans-2,5-Di-methyl-piperazin-1-yl) -quinolin-6-yl] -amide; 5-chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid [8- (
4-Methyl-piperazin-1-yl) -naphthalen-2-yl] -amide; or a pharmaceutically acceptable salt thereof.

The compound represented by the formula (I) is, for example, a conventional pharmaceutically acceptable acid such as maleic acid, enoic acid, hydrobromic acid, phosphoric acid, acetic acid, fumaric acid, salicylic acid, citric acid, lactic acid. , Can form acid addition salts with mandelic acid, tartaric acid and methanesulfonic acid. The compounds of formula (I) are also capable of forming solvates, eg hydrates, and these forms are within the scope of the invention. The term "compound of formula (I)" as referred to herein also includes these forms. Certain compounds of formula (I) are capable of existing in stereoisomeric forms, including diastereomers and enantiomers, and the present invention includes their individual stereoisomeric forms and mixtures thereof, including racemates. Is also a range. The different stereoisomeric forms can be separated one from the other by conventional methods, or certain isomers can be obtained by stereospecific or asymmetric synthesis. The invention also covers any tautomers and mixtures thereof.

The present invention also provides a method for producing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, which comprises the formula (II):

[Chemical 7] (II) [wherein R ¹ , n, P and A have the same meanings as described in formula (I), and L is a leaving group], and a compound of formula (III):

[0013]

[Chemical 8] (III) [wherein Q, m, R ² , R ³ and R ⁴ have the same meaning as described in formula (I)] or a protected derivative thereof, and then: Any protecting group may be removed, and a pharmaceutically acceptable salt may be formed.

Suitable leaving groups include halogen, especially chloro. Formulas (II) and (III)
The reaction of the compound of formula (I) is carried out by mixing the two reagents together and optionally in an inert solvent such as dichloromethane or acetone. The reaction can be carried out in the presence of a base. One of ordinary skill in the art will appreciate that there is a need to protect certain groups. Suitable protecting groups and methods for their attachment and removal are conventional in the field of organic chemistry, for example Green TW "Protecting groups in organic synthesis" New York, Wi.
The method described in ley (1981). A suitable protecting group for the piperazine group is BO
C, COCCl ₃ , COCF ₃ and methyl, the latter of which can be removed by treatment with 1-chloroethyl chloroformate according to standard methods. N-substituted piperazines can be prepared by acylation or alkylation of the appropriate NH-piperazine compounds according to standard methods. The compounds of formulas (II) and (III) are commercially available and can be prepared by known methods or methods analogous thereto according to the methods described herein. The pharmaceutically acceptable salts can be conveniently prepared by reaction with the appropriate acid or acid derivative.

The compounds of formula (I) and their pharmaceutically acceptable salts have 5HT ₆ receptor antagonist activity and are associated with certain CNS disorders such as anxiety, depression, epilepsy,
Obsessive-compulsive disorder, migraine, cognitive memory disorders (eg age-related cognitive decline and / or Alzheimer's disease), Parkinson's disease, ADHD (attention deficit / hyperdisease), sleep disorders (including circadian rhythm disorders) Eating disorders such as anorexia and bulimia, panic attacks, withdrawal symptoms of substance abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and diseases related to spinal cord injury and / or head injury, such as hydrocephalus It is considered to have potential use in the treatment of illness. The compounds of the invention are also expected for use in the treatment of certain GI (gastrointestinal) disorders, such as IBS (irritable bowel syndrome). Therefore, the present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for the treatment or prevention of the above diseases, as a therapeutic substance. In particular, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for treating or preventing schizophrenia, ADHD, cognitive memory disorders, anxiety and / or depression. . Furthermore, the present invention relates to a method for treating or preventing the above-mentioned diseases in mammals including humans, wherein a safe or therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient. The present invention provides a method comprising administering to

In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of the above diseases. The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
And a pharmaceutical composition comprising a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention, which can be prepared by mixing, suitably at ambient temperature and atmospheric pressure, are generally suitable for oral, parenteral or rectal administration, for example tablets, capsules, oral liquid preparations, powders, granules, It may be in the form of lozenges, reconstituted powders, injection or infusion solutions or suspensions. Orally administrable compositions are generally preferred. Tablets and capsules for oral administration may be in unit dosage form and may contain conventional excipients such as binders, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. . The tablets may be coated according to methods well known in standard pharmaceutical practice. Oral liquid formulations may be, for example, in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or in the form of dry formulations which are reconstituted with water or a suitable vehicle before use. May be. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavors or A colorant may be included. For parenteral administration, fluid unit dosage forms are prepared utilizing a compound of the invention or a pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. In preparing solutions, the compound is dissolved in the infusion solution, sterilized by filtration, filled in a suitable bottle or ampoule, and sealed. Advantageously, auxiliary substances, such as local anesthetics, preservatives and buffers, are dissolved in the vehicle. For increased stability, the composition is frozen after filling into bottles and the water removed under reduced pressure. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active ingredient, depending on the method of administration.

Dosages of compounds used to treat the aforementioned disorders will typically vary with the severity of the disorder, the weight of the patient and other similar factors. However, as a general guide, a suitable unit dose is 0.05 to 1000 mg, more suitably 0.05 to 20.0 m
g, for example 0.2-0.5 mg; such a unit dose is once or more than once a day,
For example, twice or three times daily, the daily dose is administered in the range of about 0.5-100 mg; such treatment may be for weeks or months. It is expected that the compounds of the invention will have no unacceptable toxic effects when administered in accordance with the invention. The following description and examples illustrate the preparation of compounds of this invention.

Description 1 6-Nitroquinoline-1-oxide (D1) m-chloroperoxybenzoic acid (57-8 in dichloromethane (800 ml)
6%, 37.5 g) solution over 15 hours in dichloromethane (500 ml)
6-Nitroquinoline (25 g, 0.14 mmol) in was added to a stirred ice-cold solution. The mixture was stirred at room temperature for a further 18 hours, then washed with 5% sodium metabisulfite (1 l), saturated K ₂ CO ₃ solution (1 l), dried (Na ₂ SO ₄ ), filtered and the filtrate reduced in vacuo. Concentrate under to give the title compound (25 g, 91%) as a yellow solid (
D1) was obtained. MH ⁺ 191

Description 2 4-Chloro-6-nitroquinoline (D2) 6-Nitroquinoline-1-oxide (24.5 g, 0.13 mmol) was added dropwise to ice-cooled stirred phosphorus oxychloride (150 ml). Then, the mixture was heated under reflux for 3 hours under an argon atmosphere to form a precipitate. After cooling the mixture to room temperature, stirred ice (
1.5 Kg), then neutralized with cold 40% NaOH solution, the solid precipitate obtained was filtered and washed with water (6 × 200 ml). The solid was dried under reduced pressure at 60 ° C. to give a crude material which was subjected to column chromatography on silica gel eluting with dichloromethane to give the following isomeric compound: 4-chloro-6-nitroquinoline (D2 ): Yellow solid (12.0 g, 45%)
, MH ⁺ 209/211, 3-chloro-6-nitroquinoline: white solid (2.6 g, 10%), MH ⁺ 2.
09/211, 2-chloro-6-nitroquinoline: yellow solid (1.4 g, 5%), MH ⁺ 20.
9/211.

Description 3 4- (4-Methylpiperazin-1-yl) -6-nitroquinoline (D3) 4-Chloro-6-nitroquinoline (D) in N-methylpiperazine (30 ml).
2) (3.0 g, 14.4 mmol) was stirred at 60 ° C. for 24 hours under an argon atmosphere. The solution was concentrated under reduced pressure, the oil was dissolved in dichloromethane (100 ml) and washed with water (3 x 100 ml). The organic phase was dried (Na ₂ SO ₄ ) and concentrated to give the title compound (D3) as a yellow solid (3.8 g, 97%). MH ⁺ 273

Description 4 6-Amino-4- (4-methylpiperazin-1-yl) quinoline (D4) 4- (4-methylpiperazin-1-yl) -6 in ethanol (100 ml)
-Nitroquinoline (D3) (3.8 g, 14.0 mmol) 5% Pd / in solution
A suspension of C (0.3g) was stirred under a hydrogen atmosphere for 24 hours. The mixture is filtered,
Concentration under reduced pressure gave the title compound (D4) as a solid (3.3.g, 97%). MH ⁺ 243

Description 5 6-Nitro-4- (piperazin-1-yl) quinoline (D5) 4-chloro-6-nitroquinoline (D2) (5.
A solution of 0 g, 24.0 mmol) and piperazine (8.3 g, 96 mmol) was heated to reflux under an argon atmosphere for 24 hours. The solution was concentrated under reduced pressure, the residue was dissolved in dichloromethane (150 ml), washed with water (3 × 200 ml), dried (Na ₂ SO ₄ ) and concentrated to an orange solid (6.0 g, 98%). To give the title compound (D5). MH ⁺ 259

Description 6 4- (4-tert-Butoxycarbonylpiperazin-1-yl) -6-nitroquinoline (D6) Water (80 ml) over 5 minutes at room temperature in tetrahydrofuran (80 ml).
6-Nitro-4- (piperazin-1-yl) quinoline (D5) in 6.0 g (6.0 g)
, 23.4 mmol) was added to the stirred solution. Tetrahydrofuran (
Di-tert-butyldicarboxylate (5.1 g, 23.4 mm) in 20 ml).
ol) over 0.5 hour and then potassium carbonate (3.4 g, 24.
6 mmol) was added in portions. The mixture was stirred for 3 days, then the organic solvent was removed under reduced pressure and the remaining aqueous residue was extracted with dichloromethane (4 x 150 ml).
The extract was dried (Na ₂ SO ₄ ), concentrated to an oil and crystallized in diethyl ether / hexane (1: 1) to give the title compound (D6) (7.7 g, 92%).
MH ⁺ 359

Description 7 6-amino-4- (4-tert-butoxycarbonylpiperazin-1-yl) quinoline (D7) 4- (4-tert-butoxycarbonylpiperazin-1-yl) -6-nitroquinoline (D6 ) (7.7 g, 21.5 mmol) was hydrogenated as described 4 to give the title compound (D7) as a yellow solid (7.1 g, 100%). MH ⁺ 3
29

Description 8 1-Benzyl-5-nitroindoline (D8) 5-nitroindoline (50 g, 0.30 mol) in acetone (500 ml)
Anhydrous potassium carbonate (55.3 g, 0.40 mol) was added to the stirred solution of), and then benzyl bromide (42 ml, 0.35 mol) was added dropwise over 45 minutes. The mixture was stirred at room temperature for 24 hours. Further benzyl bromide (10.0 ml, 0
． 08 mol) and potassium carbonate (12.0 g, 0.09 mol) were added and the mixture was heated to reflux for 3 days. Upon cooling, the mixture was filtered and the filtrate evaporated under reduced pressure to a dark red oil. The oil was triturated with hexane to give the title compound (D8) as an orange crystalline solid (79.0g, 100%). ¹ H NMR (250 MHz, CDCl ₃ ) δ (ppm): 8.05 (d, 1H), 7.91 (s, 1H), 7.25-7.40 (m
, 5H), 6.35 (d, 1H), 4.35 (s, 2H), 3.63 (t, 2H), 3.09 (t, 2H) .MS: m / z
= 255 (MH ⁺ )

[0026]   Description 9   5-amino-1-benzylindoline (D9)   1-benzyl-5-nitroindoline (description 8) in methanol (400 ml)
20.0 g, 0.08 mol), tin (II) chloride (60.0 g, 0.32 m)
ol) and concentrated HCl (40 ml) were heated to reflux for 16 hours. Cool down
And concentrate the mixture into a red oil, CH_TwoCl_TwoAnd partition with water, 40% Na
Basify with OH solution, remove insoluble tin residue by filtration and dry (Na_TwoSO _Four ) And concentrated under reduced pressure to give the title compound as a dark green oil (10.5 g, 60%).
The product (D9) was obtained.¹ H NMR (250MHz, CDCl₃) δ (ppm): 7.23-7.41 (m, 5H), 6.58 (s, 1H), 6.45 (dd
, 1H), 6.37 (d, 1H), 4.13 (s, 2H), 3.31 (br s, 2H), 3.18 (t, 2H), 2.87 (
t, 2H) .MS: m / z = 225 (MH⁺)

Description 10 Methyl diethyl (1-benzylindoline-5-yl-amino) malonate (D
10) Diethyl was replaced with methyl malonate (9.45 ml, 0.05 mol) with toluene (5
5-amino-1-benzylindoline (description 9; 10.5 g, 0 in 00 ml)
． (05 mol) solution and the mixture was heated to reflux for 1.5 hours under an argon atmosphere. Upon cooling, the solvent was removed under reduced pressure to give a brown oil, 19.6 g. Flash chromatography of oil (eluent, hexane: EtOAc 70:30)
And the title compound (D1 as a yellow crystalline solid (14.3 g, 77%).
0) was obtained. ¹ H NMR (250 MHz, CDCl ₃ ) δ (ppm): 8.42 (d, 1H), 7.28-7.38 (m, 5H), 6.93 (s
, 1H), 6.83 (dd, 1H), 6.44 (d, 2H), 4.17-4.33 (m, 6H), 3.36 (t, 2H), 2.9
9 (t, 2H), 1.25-1.40 (m, 6H). NH not observed. MS: m / z = 395 (MH ⁺ ).

Description 11 Ethyl 1-benzyl-8-chloro-2,3-dihydropyrrolo [2,3-g] quinoline-7-carboxylate (D11) Diethyl (1-benzyl) in phosphorus oxychloride (40 ml) Methyl indoline-5-yl-amino) malonate (description 10; 10.0 g, 25.3 mmol)
The mixture was heated under reflux for 2.5 hours under an argon atmosphere. The mixture was concentrated under reduced pressure and the remaining oil was treated with 10% Na ₂ CO ₃ solution until it became basic. Extraction with CH ₂ Cl ₂ gave a red gum, which was subjected to column chromatography (eluent hexane:
Purification by EtOAc 70:30) gave the title compound (D11) as a yellow crystalline solid (6.3 g, 68%). ¹ H NMR (250 MHz, CDCl ₃ ) δ (ppm): 8.81 (s, 1H), 7.69 (s, 1H), 7.27-7.40 (m
, 5H), 7.02 (s, 1H), 4.51 (s, 2H), 4.46 (q, 2H), 3.59 (t, 2H), 3.24 (t,
2H), 1.44 (t, 3H) .MS: m / z = 367 (MH ⁺ ).

[0029]   Description 12   Ethyl 1-benzyl-8- (4-methyl-1-piperazinyl) -2,3-dihi
Doropyrrolo- [2,3-g] quinoline-7-carboxylate (D12)   Ethyl 1-benzyl-8-chloro-2,3-dihydro in DMF (50 ml)
Pyrrolo [2,3-g] quinoline-7-carboxylate (Description 11; 5.5 g, 15
． 0 mmol) and N-methylpiperazine (5.0 ml, 45.0 mmol)
Triethylamine (6.3 ml, 45.0 mmol) was added to the solution of
Was heated at 90 ° C. for 16 hours under an argon atmosphere. DMF was removed under reduced pressure and the residue
CH the residue_TwoCl_TwoAnd partitioned between water. The organic matter is separated and the aqueous solution is further CH _Two Cl_TwoExtracted with (1 ×). Dry the combined organics (Na_TwoSO_Four) And under reduced pressure
Evaporate to an orange oil with and triturate with ethyl acetate (2x) to give a yellow solid.
The title compound (D12) was obtained as (4.83 g, 75%).¹ H NMR (250MHz, CDCl₃) δ (ppm): 8.54 (s, 1H), 7.67 (s, 1H), 7.29-7.41 (m
, 5H), 6.76 (s, 1H), 4.45 (s, 2H), 4.41 (q, 2H), 3.60 (t, 2H), 3.17-3.25
 (m, 6H), 2.40 (br s, 4H), 2.30 (s, 3H), 1.40 (t, 3H) .MS: m / z = 431 (M
H⁺)

Description 13 1-Benzyl-8- (4-methyl-1-piperazinyl) -2,3-dihydropyrrolo- [2,3-g] quinoline-7-carboxylate (D13) in ethanol (100 ml) Ethyl 1-benzyl-8- (4-methyl-1-)
Piperazinyl) -2,3-dihydropyrrolo- [2,3-g] quinoline-7-carboxylate (description 12; 4.8 g, 11.1 mmol) in sodium hydroxide (0.89 g) in water (20 ml). , 22.2 mmol) solution and the mixture was heated to reflux under an argon atmosphere for 16 hours. The ethanol was removed under reduced pressure, the residue diluted with water and triturated with 1M HCl solution (pH 7). The yellow precipitate was filtered, dried under reduced pressure and identified as the title compound (D13, 4.5 g, 100%). ¹ H NMR (250 MHz, d ₆ DMSO) δ (ppm): 8.35 (s, 1H), 7.56 (s, 1H), 7.39-7.55 (
m, 5H), 6.73 (s, 1H), 4.50 (s, 2H), 3.56 (t, 2H), 3.34 (br s, 4H), 3.16
(t, 2H), 2.87 (br s, 4H), 2.61 (s, 3H). OH is not observed. MS: m / z = 403
(MH ⁺ )

[0031]   Description 14   1-benzyl-8- (4-methyl-1-piperazinyl) -2,3-dihydropi
Lolo- [2,3-g] quinoline (D14)   1-benzyl-8- (4-methyl-1-piperazinyl) -2,3-dihydropi
Lolo- [2,3-g] quinoline-7-carboxylic acid salt (Description 13; 4.46 g, 1
1.1 mmol) in small portions and carefully (lower the air condenser)
Add to nyl ether (100 ml) at 250 ° C. over 15 minutes. The mixture
The mixture was heated to 250 to 270 ° C for 10 minutes and cooled to 35 ° C. Then add the solution
Poured into hexane (200 ml) and extracted into 2M HCl solution. Acidic extract
Wash with hexane (4x) to remove diphenyl ether and remove 10% Na_TwoCO _Three Basified with solution. Extract with ethyl acetate (3x) to give a yellow crystalline solid (4.0
(g, 100%) to give the title compound (D14).¹ H NMR (250MHz, CDCl₃) δ (ppm): 8.42 (d, 1H), 7.68 (s, 1H), 7.28-7.42 (
m, 5H), 6.73 (d, 1H), 6.61 (s, 1H), 4.42 (s, 2H), 3.57 (t, 2H), 3.20 (t,
 2H), 3.08 (br s, 4H), 2.42 (br s, 4H), 2.36 (s, 3H) .MS: m / z = 359 (MH ⁺ ).

Description 15 8- (4-Methyl-1-piperazinyl) -2,3-dihydropyrrolo- [2,3
-G] quinoline (D15) 1-benzyl-8- (4-methyl-1-piperazinyl) -2,3-dihydropyrrolo- [2,3-g] quinoline in ethanol (50 ml) (description 14; 3. 9
8 g, 11.1 mmol) and concentrated HCl (4.0 ml) were hydrogenated with 10% palladium on carbon at 50 psi (344.8 KPa) / room temperature for 30 hours. The mixture was filtered through Celite and basified with solid K ₂ CO ₃ . Evaporation gave an off-white solid, which was dissolved in CH ₂ Cl ₂ and the inorganics filtered. The filtrate was evaporated under reduced pressure and combined with a yellow solid (1.8g, 74%) to give the title compound (D15). ¹ H NMR (250 MHz, CDCl ₃ ) δ (ppm): 8.46 (d, 1H), 7.72 (s, 1H), 6.96 (s, 1H)
, 6.77 (d, 1H), 4.14 (br s, 1H), 3.68 (t, 2H), 3.23 (t, 2H), 3.19 (br s,
4H), 2.68 (br s, 4H), 2.41 (s, 3H). MS: m / z = 269 (MH ⁺ ).

Description 16 5,7-Dichloro-3-methylbenzo [b] thiophene (D16) The compound, MS: m / z MH ⁺ 217, was prepared from the appropriate thiophenol derivative as described in the references below. . 1. NB Chapman, K. Clarke, and B. Iddon, J. Chem. Soc., 774, 1965. NB Chapman, K. Clark, and N. Sawhney, J. Chem. Soc. (C), 2747, 1
968.

Description 17 5-Chloro-3,7-dimethylbenzo [b] thiophene (D17) This compound, MS: m / z MH ⁺ 197, was prepared as described in Description 26.

Description 18 5-chloro-3,7-dimethylbenzo [b] thiophene-2-sulfonyl chloride (D18) 5-chloro-3,7-dimethylbenzo [b] thiophene (D18) in chloroform.
17) (1.5 g, 7.6 mmol) in a solution of chlorosulfonic acid (1.3 ml, 19 mmol) was added dropwise at -10 ° C, and the resulting reaction mixture was stirred at -10 ° C for 2.
The mixture was stirred for 5 hours and then at room temperature for 1 hour. Mix the mixture with dichloromethane and cold water (
100 ml: 30 ml). The aqueous phase is dichloromethane (2 x 50 ml)
It was extracted with. The combined dichloromethane extracts were dried (Na ₂ SO ₄ ) and the solvent removed to give the title compound (D18) as a tan solid (1.2g, 53%).
δ _H (250 MHz, CDCl ₃ -d ₆ ), 2.56 (3H, s), 2.8 (3H, s), 7.38 (1H, s), 7.75
(1H, s).

[0036]   Description 19   5,7-Dichloro-3-methylbenzo [b] thiophene-2-sulfonyl chloride
(D19)   The compound was prepared as described in Description 18 with a yield of 87%. δ_H (250 MHz, CDCl ₃ -d₆), 2.8 (3H, s), 7.6 (1H, d, J = 1.6 Hz), 7.83 (1H, d, J = 1.6 Hz).

Description 20 7-Chloro-2-methylbenzo [b] thiophene (D20) The compound, MS: M ⁺ 182, was prepared from the appropriate thiophenol derivative as described in the following references. WK Anderson, EJ LaVoie, and JC Bottaro, J. Chem. Soc. Perkin I
, 1, 1976.

Description 21 4,6-Dichloro-2-methyl-benzo [b] thiophene (D21) This compound, MS: M ⁺ 216, was prepared as described in Description 20.

Description 22 7-Chloro-2-methylbenzo [b] thiophene-3-sulfonyl chloride (D2
2) Benzo [b] thiophene (D20
) Manufactured from. δ _H (250 MHz, CDCl ₃ -d ₆ ), 2.97 (3H, s), 7.47 (2H, m,), 8.
21 (1H, m). The compound was used in the coupling step without purification.

Description 23 4,6-dichloro-2-methylbenzo [b] thiophene 3-sulfonyl chloride (
D23) This compound was prepared by converting the compound into the corresponding benzo [b] thiophene (D2) as described in 18.
Manufactured from 1). Yield 94%. δ _H (250 MHz, CDCl ₃ -d ₆ ), 2.94 (3H, s), 7.
59 (1H, d, J = 1.7), 7.69 (1H, d, J = 1.7).

Description 24 5-Chloro-3-methyl [b] benzofuran-2-sulfonyl chloride (D24) 5-Chloro-3-methyl [b] benzofuran (T. Suzuki, T. Horaguchi) in diethyl ether (30 ml). , T. Shimizu, T. Abe, Bull. Chem. Soc. Jpn., 2
762, 1983) (3.7 g, 22 mmol) at −70 ° C. under argon atmosphere, a 2.0 M solution of lithium diisopropylamide in hexane / tetrahydrofuran (15 ml) was added dropwise. After stirring at this temperature for 30 minutes, anhydrous sulfur dioxide was introduced onto the surface of the reaction mixture 1 hour before the reaction. Mixture for an additional hour at -70 ° C
Stirred at, warmed to room temperature and diluted with diethyl ether (100 ml). The resulting tan precipitate was collected and dried under reduced pressure at room temperature to remove sulfur dioxide. This solid (2.8g) was dissolved in dichloromethane (200ml) and cooled to -50. N-chlorosuccinimide (1.57 g, 1 in dichloromethane (10 ml)
1.8 mmol) was added dropwise over 10 minutes. The mixture at -50 ° C for 3 hours,
Stirred at room temperature for 1 hour. The solid was filtered and washed with dichloromethane (200ml). The combined filtrate was concentrated and the residue was purified by column chromatography on silica gel (eluting with hexane-dichloromethane (9: 1, v / v)) to give the title compound (D24) as an orange solid; (24% yield). Got δ _H (250 MHz, CDCl ₃ ),
2.61 (3H, s), 7.55 (1H, m), 7.68 (1H, m).

Description 25 5-Chloro-2-methylbenzo [b] thiophene-3-sulfonyl chloride (D2
5) Sulfuryl chloride (0.75 ml, 9.3 mmol) was added to DMF (0.85 ml)
Was added to the stirred solution of at 0 ° C. After stirring at this temperature for 20 minutes, 5-chloro-2-methylbenzo [b] thiophene (1.0 g, 5.5 mmol) in DMF (2 ml).
To the solution was added and the mixture was heated at 85 ° C. with stirring for 2.5 hours. The cooled mixture was poured into cold water (100 ml) and the mixture was extracted into ethyl acetate (100 ml). The organic phase is dried and concentrated under reduced pressure to give the title compound (D25
) Was obtained and used without purification. δ _H (250 MHz, CDCl ₃ ), 2.95 (3H, s), 7.45 (1H
, m), 7.70 (1H, m), 8.30 (1H, m).

Description 26 4- (3,5-Dimethylpiperazin-1-yl) -6-nitroquinoline (D2
6) The title compound (D26, yield 80%, MH ⁺ 287/288) was added to 4-chloro-6.
Prepared from -nitroquinoline (D2) and 2,6-dimethylpiperazine in a similar manner as described in 3.

Description 27 6-amino-4- (3,5-dimethylpiperazin-1-yl) quinoline (D2
7) The title compound (D27, 96% yield, MH + 257/258) was prepared as described in 4- (3,5-dimethylpiperazin-1-yl) -6-nitroquinoline (D26).
) Was hydrogenated.

[0045]   Description 28   4- (4-Methyl-piperazin-1-yl) -6-nitro-quinazoline (D2
8)   N-methylpiperazine (13 ml, 0.17 mol) dry dichloromethane (6
4-chloro-6-nitroquinazoline (0 ml) (Yakugaku Zasshi, 1974, 94 (
4), 417-423) (2.44 g, 11.6 mmol) was added dropwise to the stirred solution. At room temperature
After stirring for 1 hour, the mixture was washed with water (3 x 30 ml) and the organic extract was dried (Na _Two SO_Four) And concentrated under reduced pressure to give the title compound as a solid (2.8 g, 90%) (
D28) was obtained. δ_H (250 MHz, CDCl₃) 2.39 (3H, s), 2.64 (4H, t), 3.98 (4H, t), 7.96 (1H,
 d), 8.48 (1H, dd), 8.78 (1H, s), 8.97 (1H, d).

Description 29 6-Amino-4- (4-methyl-piperazin-1-yl) quinazoline (D29
) 4- (4-Methyl-piperazin-1-yl) -6-nitro-quinazoline (D2
8) (3.18 g, 11.6 mmol) was hydrogenated as described 4 to give the title compound (D29) as a solid (2.72 g, 97%). MH ⁺ 244.

Description 30 5,7-Dichloro-2-methylbenzo [b] thiophene (D30) This compound, MH ⁺ 217, was synthesized as described in Description 16.

Description 31 5,7-Dichloro-2-methylbenzo [b] thiophene-3-sulfonyl chloride (D31) This compound was prepared as 5,7-dichloro-2-methylbenzo [b] thiophene (D30).
Prepared as described.

Description 32 5-Chloro-3-ethyl-benzo [b] thiophene (D32) The compound was prepared by converting 1- (4-chloro-phenylsulfanyl) -butan-2-one (C
him. Ther. 1973, 8, 536-544). δ _H (250 MHz, CDCl ₃ ), 1.36 (3H, t), 2.84 (2H, q), 7.13 (1H, s), 7.29 (1H
, dd, J = 2, 8.5Hz), 7.70-7.76 (2H, m).

Description 33 5-chloro-3-ethyl-benzo [b] thiophene-2-sulfonyl chloride (D
33) This compound was prepared as described in description 18 from 5-chloro-3-ethyl-benzo [b] thiophene (D32). δ _H (250 MHz, CDCl ₃ ), 1.39 (3H, t), 3.30 (2H, q), 7.54-7.91 (3H, m).

Description 34 5-Chloro-3-isopropyl-benzo [b] thiophene (D34) This compound was prepared from 1- (4-chloro-phenylsulfanyl) -3-methyl-butan-2-one (Chim Ther. 1973, 8, 536-544). δ _H (250 MHz, CDCl ₃ ), 1.37 (6H, d), 3.22 (1H, quin), 7.27 (1H, dd, J = 2
, 10.5Hz), 7.71-7.75 (2H, m).

Description 35 5-Chloro-3-isopropyl-benzo [b] thiophene-2-sulfonyl chloride (D35) The present compound was prepared using 5-chloro-3-isopropyl-benzo [b] thiophene (D34).
) Was prepared as described in 18). δ _H (250 MHz, CDCl ₃ ), 1.57 (6H, d), 4.26 (1H, quin), 7.52 (1H, dd, J = 1
.9, 8.7Hz), 7.81 (1H, d J = 8.7Hz), 8.14 (1H, d, J = 1.8Hz).

Description 36 5-Bromo-3-methyl-benzo [b] thiophene-2-sulfonyl chloride (D
36) This compound was treated with 5-bromo-3-methyl-benzo [b] thiophene (J. Het. Chem,
1988, 25, 1271-1272). δ _H (250 MHz, CDCl ₃ ), 2.81 (3H, s), 7.67-7.78 (2H, m), 8.05 (1H, d).

Description 37 2-Methyl-6-nitro-4- (piperazin-1-yl) quinoline (D37) 4-chloro-2-methyl-6-nitroquinoline (J.
Amer. ChemSoc., 1964, 29, 3548) (3.3 g, 14.8 mmol) and piperazine (5.1 g, 59.1 mmol) under stirring under argon atmosphere.
The mixture was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was diluted with dichloromethane (1
00 ml) and the solution was washed with water (2 x 100 ml). Dry the organic phase (N
a ₂ SO _4), filtered, and the filtrate was concentrated under reduced pressure, a solid (3.8 g, was obtained as 95%) the title compound (D37). MS, MH ⁺ 273.

Description 38 4- (4-tert-Butoxycarbonylpiperazin-1-yl) -2-methyl-6-nitroquinoline (D38) Water (50 ml) in tetrahydrofuran (THF) (50 ml) 2-methyl- 6-Nitro-4- (piperazin-1-yl) quinoline (D37) (3.8 g,
14 mmol) slowly and then di-,-in THF (13 ml).
A solution of tert-butyl dicarbonate (3.06 g, 14 mmol) was added over 10 minutes. Potassium carbonate (2.03 g, 14.7 mmol) was added portionwise and the reaction mixture was allowed to come to room temperature for 60 minutes. The reaction mixture was concentrated under reduced pressure, THF
Was removed and the resulting aqueous mixture was extracted with dichloromethane (2 x 100 ml). The combined organic phases were washed with water (2 × 100 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give a foam which was diethyl ether / hexane (1: 1) (1: 1).
(00 ml) and the mixture was stirred to give the title compound (D38) as an insoluble solid (4.6 g, 88%). MS MH ⁺ 373.

Description 39 6-Amino-4- (4-tert-butoxycarbonylpiperazin-1-yl) -2-methylquinoline (D39) Title compound (D39), MS: MH ⁺ 343, 4- (4- tert-Butoxycarbonylpiperazin-1-yl) -2-methyl-6-nitroquinoline (D3
Prepared as described in 4) from 8) using ethanol / dioxane (1: 1) as solvent.

Description 40 3-Methyl-6-nitro-4- (piperazin-1-yl) quinoline (D40) Title compound (D40), MS: MH ⁺ 273, 4-chloro-3-methy
Prepared from l-6-nitroquinoline (J. Chem. Soc., 1950, 2092, 2094) as described 37 in 54% yield.

Description 41 4- (4-Tert-butoxycarbonylpiperazin-1-yl) -3-methyl-6-nitroquinoline (D41) Title compound (D41), M.I. S. MH ⁺ 373 to 3-methyl-6-nitro-4
-(Piperazin-1-yl) quinoline (D40) as described in 38,
It was produced in a yield of 98%.

Description 42 6-Amino-4- (4-tert-butoxycarbonylpiperazin-1-yl) -3-methylquinoline (D42) The title compound (D42), M.I. S. MH ⁺ 343 was added to 4- (4-tert-butoxycarbonylpiperazin-1-yl) -3-methyl-6-nitroquinoline (D
41) to 39) in a yield of 98%.

Description 43 4- (S-hexahydro-pyrrolo [1,2-a] pyrazin-2-yl) -6-
Nitroquinoline (D43) 4-chloro-6-nitroquinoline (D2) (860) in toluene (18 ml).
mg, 4.1 mmol) and (S) -octahydro-pyrrolo [1,2-a] pyrazine (571 mg, 4.5 mmol) (J. Med. Chem., 1993, 36, 2311-2320).
The suspension was heated to reflux under an argon atmosphere for 40 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with dichloromethane / methanol to give the title compound (D4 as a foam (315 mg, 26%)).
3) was obtained. MS MH ⁺ 299.

Description 44 6-Amino-4- (S-hexahydro-pyrrolo [1,2-a] pyrazine-2-
Il) -quinoline (D44) The title compound (D44), M.I. S. , MH ⁺ 269 was prepared from 4- (S-hexahydr-pyrrolo [1,2-a] pyrazin-2-yl) -6-nitroquinoline (D43) as described 4.

Description 45 4-((S) -3-Methyl-piperazin-1-yl) -6-nitroquinoline (
D45) The title compound (D45, MH ⁺ 273/274, yield 98%) was prepared as described in 5.

Description 46 4- (4-tert-Butoxycarbonyl-((S) -3-methyl-piperazin-1-yl) -6-nitroquinoline (D46) Title compound (D46, MH ⁺ 373/374, yield (99%) Production was carried out in the same manner as described in 6.

Description 47 6-Amino-4- (4-tert-butoxycarbonyl-((S) -3-methyl-piperazin-1-yl) quinoline (D47) 4- (4-tert-butoxycarbonyl- (S ) -Methyl-piperazine-1
Hydrogenation of -yl) -6-nitroquinoline (D46) as described in 4 gave the title compound (D47) in 11% yield. MH ⁺ 343/344.

Description 48 4-((R) -3-methyl-piperazin-1-yl) -6-nitroquinoline (
D48) The title compound (D48, MH ⁺ 273/274, 73% yield) was prepared as described in 5.

Description 49 4- (4-Tert-butoxycarbonyl- (R) -3-methyl-piperazin-1-yl) -6-nitroquinoline (D49) Title compound (D49, MH ⁺ 373/374, yield 99%) was prepared as described 6.

Description 50 6-Amino-4- (4-tert-butoxycarbonyl-((R) -3-methyl-piperazin-1-yl) quinoline (D50) 4- (4-tert-butoxycarbonyl- (R ) -Methyl-piperazine-1
-Yl) -6-nitroquinoline (D49) was hydrogenated as described 4, yield 45
The title compound (D50) was obtained in%. MH ⁺ 343/344.

Description 51 4- (trans-2,5-Dimethyl-piperazin-1-yl) -6-nitroquinoline (D51) trans-2,5-dimethylpiperazine (in 51 ml 1-methyl-2-pyrrolidinone (7 ml) 0.12 g, 1.06 mmol), 4-chloro-6-nitroquinoline (
D2) (0.1 g, 0.48 mmol) and potassium fluoride (42 mg, 0.
72 mmol) was stirred under an argon atmosphere for 24 hours. The solvent was removed and the residue was co-evaporated with toluene (1 x 10 ml). The product was purified by silica gel column chromatography eluting with a dichloromethane-methanol gradient to give the title compound (D51) as a tan oil (50 mg, 36%). MH + 287/288.

Description 52 4- (4-tert-butoxycarbonyl-trans-2,5-dimethyl-piperazin-1-yl) -6-nitroquinoline (D52) compound (D52, MH ⁺ 387/388, yield 99) %) Was prepared in an analogous manner to Description 6.

Description 53 6-amino-4- (4-tert-butoxycarbonyl-trans-2,5-
Dimethyl-piperazin-1-yl) quinoline (D53) 4- (4-tert-butoxycarbonyl-trans-2,5-dimethyl-piperazin-1-yl) in saturated aqueous ammonium chloride solution (15 ml) and methanol (10 ml). -6-Nitroquinoline (D52) (0.32 g) and iron (
0.23 g) was heated to reflux for 2.5 hours. Cold mix the Celite (Diatom
aceous Earth), the celite was washed with methanol (6 × 10 ml) and the combined filtrates were evaporated to a small volume. Then the product was extracted with dichloromethane (5 × 30ml), The combined extracts were dried _(Na 2 SO _4), and the solvent removed. The product was purified by silica gel column chromatography eluting with a dichloromethane-ethyl acetate / dichloromethane-methanol gradient to give a tan solid (0.23 g, 77).
%) To give the title compound (D53). MH ⁺ 357/358.

Description 54 (R) -3-Isopropylpiperazine (D54) (R) -3-Isopropyl-2,5-piperazinedione (2.5 g, 16 mmol) and borane-tetrahydrofuran complex (tetrahydrofuran in tetrahydrofuran (50 ml). A 1M solution in water, 64 ml) was heated to reflux under an argon atmosphere for 24 hours. The solvent was removed, the residue was dissolved in tetrahydrofuran-6M aqueous hydrochloric acid solution (100 ml: 40 ml), and then heated under reflux for 5 hours. Upon cooling, the mixture was concentrated to a small volume, diluted with water (200 ml), basified with 40% aqueous NaOH and extracted with dichloromethane (3 x 100 ml). The organic extract was dried (Na ₂ SO ₄ ) and the solvent removed to give a pale oil which was treated with diethyl ether (200 ml) at 5 ° C. to give the title compound (D54 as a colorless solid).
) (0.4 g, 19%) was obtained. MH + 129/130.

Description 55 4-((R) -3-Isopropyl-piperazin-1-yl) -6-nitroquinoline (D55) The title compound (D55, MH ⁺ 301/302, yield 43%) is described in Description 51. As manufactured.

Description 56 4- (4-Tert-butoxycarbonyl- (R) -3-isopropyl-piperazin-1-yl) -6-nitroquinoline (D56) Title compound (D56, MH ⁺ 402/403, yield 90%) was prepared in the same manner as described in 6.

Description 57 6-Amino-4- (4-tert-butoxycarbonyl- (R) -3-isopropyl-piperazin-1-yl) quinoline (D57) Title compound (D57) MH ⁺ 371/372, yield 54%) was prepared by a method as described in 53.

Example 1 5-Chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid (4- [
4-Methylpiperazin-1-yl] -quinolin-6-yl) -amide hydrochloride (E
1) 5-Chloro-3-methyl-benzo [b] thiophene-2-sulfonyl chloride (115 mg, 0.41 mmol) and 6-amino-4- (4-methylpiperazin-1-yl) in dichloromethane (5 ml). Quinoline (D4) (100 mg, 0
． 41 mmol) solution was stirred under argon atmosphere for 24 hours. The precipitated solid was filtered and recrystallized from ethanol / diethyl ether to give a white solid (163 m
(g, 76%) to give the title compound (E1). MH ⁺ -HCl 487/489 The following hydrochloride compounds (E2-E6) (Table 1) were used as described in Example 1 with the appropriate sulfonyl chloride derivative and 6-amino-4- (4-methylpiperazine-1-). Ill)
Prepared by reaction with quinoline (D4) or the appropriate quinoline. The compound of Example 5 was purified by silica gel column chromatography eluting with a dichloromethane-methanol gradient. The aminoquinoline used to prepare the compound of Example 5 was prepared as described in 26 and 27. The aminoquinoline used to prepare the compound of Example 6 was prepared as described 28 and 29.

[0076]

[Table 1]

Example 7 5-Chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid (4-piperazin-1-yl-quinolin-6-yl) -amide hydrochloride (E7) dichloromethane (5 ml) 5-Chloro-3-methyl-benzo [b] thiophene-2-sulfonyl chloride (285 mg, 1.0 mmol), 6-amino-4-in
(4-tert-Butoxycarbonylpiperazin-1-yl) quinoline (D7)
(300 mg, 0.92 mmol) and pyridine (0.15 ml, 1.8 mm)
ol) solution was stirred under an argon atmosphere for 24 hours. The solution is 1M hydrochloric acid (5 ml
) Then washed with water (5 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give a residue. The residue was dissolved in tetrahydrofuran (5 ml) and concentrated hydrochloric acid (1 ml), and the solution was heated under reflux for 1.5 hours. The solution was concentrated and the residue was stirred with acetone to give the title compound (E7) as a white solid (182 mg, 39%). MH ⁺ -HCl 473/475. The following hydrochloride compound (E8-E26) (Table 2) was prepared as in Example 7 with the appropriate sulfonyl chloride derivative and 6-amino-4- (4-tert-butoxycarbonylpiperazine. Prepared by reaction with -1-yl) quinoline (D7). The sulfonyl chloride used in Example 9 is described in Description 24. Other sulfonyl chlorides were prepared as shown in Example 10. (D16 and D19), E13 (D25
), E15 (D17 and D18), E16 (D20 and D22), E17 (
D21 and D23), E18 (D30 and D31), E21 (D36), E
24 (D32 and D33), E25 (D34 and D35)

[0078]

[Table 2]

Example 27 1- (5-chloro-3-methyl-benzo [b] thiophene-2-sulfonyl)
-8- (4-Methyl-piperazin-1-yl) -2,3-dihydro-1H-pyrrolo [2,3-g] quinoline hydrochloride (E27) 5-chloro-3- in 1,2-dichloroethane Methyl-benzothiophene-2
-Sulfonyl chloride (75 mg, 0.27 mmol) and 8- (4-methyl-piperazin-1-yl) -2,3-dihydro-1H-pyrrolo [2,3-g] quinoline (D17) (72 mg, 0. 27 mmol) was refluxed under an argon atmosphere for 5 hours. The cold reaction mixture was washed with 0.1 M aqueous potassium hydroxide solution, dried (Na ₂ SO ₄ ), concentrated to a solid and purified by silica gel column chromatography eluting with methanol / dichloromethane (1: 9) to give a solid. Which was treated with 1M ethereal hydrochloric acid to give the title compound (E27) (80 mg, 54%). MH ⁺
513/515. The following hydrochloride compounds (E28-E30) (Table 3) were used as in Example 7 with the appropriate sulfonyl chloride derivative and 6-amino-4- (4-tert-butoxycarbonylpiperazine-1- Prepared by reaction with yl) -2-methylquinoline (D39).

[0080]

[Table 3] The following hydrochloride compounds (E31-E34) (Table 4) were treated with the appropriate sulfonyl chloride derivative and 6-amino-4- (4-tert-butoxycarbonylpiperazin-1-yl) -3-methyl as in Example 7. Prepared by reaction with quinoline (D42). The sulfonyl chlorides used in Example 33 are described in description D19 and D16.

[0081]

[Table 4]

Example 35 4-tert-butyl-N- [4- (S-hexahydro-pyrrolo [1,2-a
] Pyrazin-2-yl) -quinolin-6-yl-benzenesulfonamide hydrochloride (E35) 4-tert-butyl-benzenesulfonyl chloride (112 mg, 0.48 mm
6-amino-4- (S-hexahydro-pyrrolo [1,2-a] pyrazin-2-yl) -quinoline (D44) (117) in dry dichloromethane (5 ml).
mg, 0.44 mmol) at room temperature and the solution was stirred for 24 hours. The reaction mixture was concentrated under reduced pressure and purified by chromatography on silica gel eluting with a gradient of dichloromethane / methanol to give the title compound (E35) (39 mg, 19%).
Got MS: MH ⁺ 465. Hydrochloride compounds (E36, E37) (Table 5) were prepared by reaction with the appropriate sulfonyl chloride and quinoline derivatives as described in Example 35. Hydrochloride compound (
E38-E41) were prepared as described in Example 7 and, where appropriate, compounds were purified by column chromatography. A description of the preparation of quinoline derivatives used in the derivation of some examples is given by: E36 (D44), E37 (D
27), E38 (D47), E39 (D50), E40 (D57), E41 (D
53).

[0083]

[Table 5]

Example 42 5-Chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid [8- (
4-Methyl-piperazin-1-yl) -naphthalen-2-yl] -amide hydrochloride (E42) 2-Amino-8- (4-methyl-piperazin-1-yl) -naphthalene in dry dichloromethane (3 ml). (EP701819) (68 mg, 0.28 mmo
l) was added to 5-chloro-3-methyl-benzo [b] thiophene-2-sulfonyl chloride (87 mg, 0.31 mmol) and the solution was stirred for 24 hours. The solid that precipitated was collected and purified by silica gel column chromatography eluting with a gradient of ethyl acetate / ethanol / water to give the title compound (E42, 58 mg, 40%). MS: MH ⁺ 486/488

Medical Data Compounds can be tested by the methods set forth in WO 98/27081. All compounds are human clone 5-HT ₆ receptors with p values in the range of 7.1 to 9.5.
Having a value of Ki, it showed good binding to the 5-HT ₆ receptor.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 19/08 A61P 19/08 25/06 25/06 25/08 25/08 25/18 25/18 25 / 22 25/22 25/24 25/24 25/28 25/28 25/30 25/30 43/00 114 43/00 114 C07D 333/62 C07D 333/62 405/12 405/12 409/12 409 / 12 409/14 409/14 471/04 102 471/04 102 487/04 140 487/04 140 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, G, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS , JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Steven・ Mark Bromidge, CM 59.5 ADA, Essec, UK , Harlow, Third Avenue, New Frontiers Science Park South, Smith Cline Beecham Pharmaceuticals (72) Inventor Harina Teresa Serafinosuka, CM 19.5 ADB, England , Essex, Harlow, Third Avenue, New Frontiers Science Park South, Smith Line Beecham Pharmaceuticals F-Term (reference) 4C031 LA01 4C050 AA01 BB04 CC08 EE02 FF05 GG01 HH04 4C063 AA01 AA03 BB02 BB07 CC76 CC94 DD14 DD31 EE01 4C065 AA04 AA19 BB04 CC01 DD02 EE02 HH01 JJ09 KK01 LL08 PP05 PP15 QQ04 4C086 AA01 AA02 AA03 AA04 BC50 CB05 GA02 GA04 GA07 ZA05 ZA12 ZA05 ZA12 ZA05 ZA12 ZA05 ZA12 ZA05 ZA12 ZA05 ZA12 ZA05 ZA12 ZA05 ZA12 ZA05 ZA12

Claims (10)

[Claims] 1. Formula (I): [Chemical 1]                 (I) [In the formula,   P is one to three selected from phenyl, naphthyl, oxygen, nitrogen and sulfur.
A 5- or 6-membered heteroaryl ring containing a heteroatom or oxygen, nitrogen and
Bicyclic or tricyclic heteroaryl containing 1 to 3 heteroatoms selected from sulfur
A reel ring;   A is a single bond, C_1-6Alkylene or C_2-6An alkenylene group;   R¹Is substituted with halogen, one or more halogen atoms,
Good C_1-6Alkyl, C_3-6Cycloalkyl, phenyl, COC_1-6A
Rukiru, C_1-6Alkoxy, OCF_Three, Hydroxy, hydroxy C_1-6Al
Kill, hydroxy C_1-6Alkoxy, C_1-6Alkoxy C_1-6Alkoxy
, Nitro, amino, C_1-6Alkylamino or di-C_1-6With alkylamino
Yes;   n is 0, 1, 2, 3, 4 or 5;   R^TwoIs hydrogen, C_1-6Alkyl or R^ThreeTogether with- (CR⁶R⁷) _p -Forms here and R⁶And R⁷Are independently hydrogen or C_1-6Archi
And p is 2, 3 or 4;   R^ThreeIs C optionally substituted by one or more halogen atoms_{1 -6} Alkyl, halogen, C_1-6Alkoxy or R^TwoTogether with the above
Same meaning- (CR⁶R⁷)_p-Forms;   m is 0, 1 or 2;   R^FourIs -X-R⁵Where X is a single bond, CH_Two, O, NH or
N-C_1-6Alkyl and R⁵Is 1 selected from nitrogen, sulfur or oxygen
~ 5-7 membered optionally substituted heterocyclic containing ~ 3 heteroatoms
A ring or a bicyclic heterocyclic ring;   Q is a phenyl ring or a 6-membered heteroaryl containing 1 or 2 nitrogen atoms
It is a ring] Or a salt thereof. 2. The compound according to claim 1, wherein P is phenyl, naphthyl, benzofuryl or benzothienyl. 3. The compound according to claim 1 or 2, wherein R ¹ is halogen or C _1-6 alkyl optionally substituted by one or more halogen atoms. 4. The compound according to claim 1, wherein R ⁴ is a piperazine ring optionally substituted by C _1-6 alkyl. 5. A compound according to any one of the preceding claims, wherein Q together with its fused phenyl group forms a quinoline, isoquinoline or quinazoline ring. 6. A compound according to claim 1 selected from Examples E1-E42 or pharmaceutically acceptable salts thereof. 7. A method for producing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, which comprises the formula (II): (II) [wherein R ¹ , n, P and A have the same meanings as described in formula (I), and L is a leaving group], and a compound of formula (III): Chemical 3] (III) [wherein Q, m, R ² , R ³ and R ⁴ have the same meaning as described in formula (I)] or a protected derivative thereof, and then: Any protecting group may be removed, and a pharmaceutically acceptable salt may be formed. 8. A compound according to any one of claims 1 to 6 for use in therapy. 9. A compound according to any one of claims 1 to 6 for use in the treatment of anxiety, depression, cognitive memory disorders, schizophrenia or ADHD. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier or excipient.