EA010298B1 - Novel benzofuran derivatives, which can be used in prophylaxis or treatment of 5-htreceptor-related disorder - Google Patents

Abstract

The present invention relates to compounds of formula (I): wherein P, R<3>, W1, and W2 are as described herein, to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds for the preparation of a medicament against 5-HT6 receptor-related disorders.

Description

FIELD OF THE INVENTION

The present invention relates to new compounds, pharmaceutical compositions containing these compounds, methods for their preparation, as well as to the use of these compounds for the preparation of drugs used against disorders associated with the 5-HT ₆ receptor.

BACKGROUND OF THE INVENTION

Obesity is a condition characterized by an increase in body fat mass, resulting in overweight above generally accepted standards. Obesity is the most important nutritional disorder in the Western world and is a major health problem in all industrialized countries. This disorder leads to an increase in mortality due to increasing cases of diseases such as cardiovascular disease, digestive tract disease, respiratory disease, cancer and type 2 diabetes. For many decades, the search continues for compounds that reduce body weight. A number of studies relate to the activation of serotonergic systems either by directly activating subtypes of the serotonin receptor or by inhibiting the reuptake of serotonin. The exact receptor subtype of the desired profile is, however, unknown.

Serotonin (5-hydroxytryptamine or 5-HT), a key mediator of peripheral and central nervous systems, modulates a wide range of physiological and pathological functions, including fear, sleep regulation, aggression, nutrition and depression. Numerous subtypes of serotonin receptor are identified and cloned. One of them, the 5-HT ₆ receptor, was cloned by individual research groups in 1993 (Kia! M. et al., (1993), Wüssjös. Vyuruyz. Vez. Soships., 193: 268-276; 8eBep M. et al., (1994), HeshoKeroP, 5: 2553-2557). This receptor is undoubtedly associated with adenylyl cyclase and exhibits affinity for antidepressants, such as clozapine. The effects of a 5-HT6 antagonist have recently been reported. and 5-HT ₆ antisense oligonucleotides to reduce food intake in rats (Vepyeu 1.S. et al., (1999), B. I. Ryagshaso1. 8irp1., 126, P66; Wepbeu 1.S. et al., (1997), I. Rzusyoryagshaso1. 8irr1., A64, 255; Aoo11eu M. B. et al., (2001), Heigoryagshasodu, 41: 210-219).

Compounds with increased affinity and selectivity for the 5-HT ₆ receptor have been identified, for example, as described in AO 00/34242 and M.A. az poee1 ro1ep! Apb Ze1esyue 5-HT ₆ Geser! Oh ap! Adotz. Vyuoguds & Meb1sta Siyesh1z1gu Beyegs, 10: 1719-1721 (2000), Vyuuguds & Meb1sta1 (SkheshzPu Beyegs, 13: 3355-3359 (2003), Exp! Oryop Tiegareijs Ra1ep1z, 12 (4), 513-527 (2002).

It has been unexpectedly found that the compounds of the present invention exhibit affinity for the 5-HT6 receptor as antagonists in the nanomolar range. The compounds of the present invention and their pharmaceutically acceptable salts possess 5-HT6 receptor antagonist, agonist and partial agonist activity and are believed to be useful for treating or preventing obesity and type 2 diabetes, achieving weight loss and weight gain, as well as treatment and prevention of central nervous system disorders such as fear, depression, panic attacks, memory impairment, cognitive impairment, epilepsy, sleep disturbances, migraine, anorexia, bulimia, eating disorders properties after an abundant table, obsessive-compulsive disorders, psychosis, Alzheimer's disease, Parkinson's disease, Huntington’s chorea and / or schizophrenia, attention deficit disorder in hyperactive disorder (ΑΌΗΌ), drug discontinuation (drug abusus), neurodegenerative diseases characterized by a slowdown in neuronal growth, and pain. Weight loss and weight gain (for example, treatment of body weight disorders) are achieved, among other things, by reducing food intake. As used here, the term "violation of body weight" refers to violations caused by the imbalance between energy consumption and energy consumption, resulting in an abnormal (eg, excessive) body weight. Such weight loss disorders include obesity.

Description of the invention

An object of the present invention is a compound of formula (I)

where P is selected from the substituents of the formulas (ΙΙ) - (ΥΙΙ)

- 1 010298

(V)

or

where x, y and _ |, each independently, are selected from 0, 1 and 2;

where the dashed lines show that P and K ³ , respectively, can be attached to either the A or B ring on any carbon atom that can be substituted, provided that P and K ³ are both not simultaneously attached to ring B ;

K ^{1 is} selected from the group consisting of:

(a) C _1-6 alkyl, (b) C _1-6 alkoxy-C _1-6 alkyl, (c) C _3-6 alkenyl, (ά) hydroxy-C _1-6 alkyl, (e ) halogen-C _1-6 -alkyl, (ί) aryl, (e) arylcarbonylmethyl, (11) aryl-C _3-6 -alkenyl, (ι) aryl-C _1-6 -alkyl,

Щ C _3-7 -cycloalkyl, (k) heteroaryl, (l) 4-piperidinyl, (t) Ν-substituted 4-piperidinyl, where the substituents are selected from C _1-6 -alkyl and aryl-C _1-6 -alkyl, (o) heteroaryl-C _1-6 -alkyl, where any heteroaryl or aryl residue, one or as part of another group, may be independently substituted at one or more positions with a substituent selected from:

(a) hydrogen, (b) halogen, (c) C _1-6 alkyl, (ά) hydroxy, (e) C _1-6 alkoxy, (ί) C2-6 alkenyl, (e) C _{2- 3-} alkynyl, (1) phenyl, (1) phenoxy,

Щ benzyloxy, (k) benzoyl, (l) benzyl, (t) -ОСР3, (p) -СЧ, (о) hydroxy-С _1-6 -alkyl, (r) С _1-6- alkoxy-С _{1- 6} -alkyl, (ς) halogen-С _1-6 -alkyl, (g) -CHK ⁹ K ⁹ , (8) -ΝΟ2, (ΐ) -KNOW ⁹ K ⁹ , (and) -KHK ⁷ SOK ¹⁰ , ( ν) -С (= О) К ¹⁰ , (х) С _1-6- alkoxycarbonyl, (у) С _1-6- alkylthio, (ζ) -8СР3, (aa) -СИР = SI2, (ab) methylsulfonyl or (ac) -COOH,

- 2 010298, provided that when the substituent of the above aryl or heteroaryl residue selected from the group consisting of phenyl, phenoxy, benzyloxy, benzoyl and benzyl, it may be a phenyl ring optionally substituted with one or more halogen atoms, C1 _-4 -alkyl, C1 _-4- alkylthio, C1 _-4- alkoxy, cyano or trifluoromethyl;

K ^{2 is} selected from the group consisting of:

(a) hydrogen, (b) C _1-6 alkyl, (c) C _1-6 alkoxy-C _2-6 alkyl, (ά) hydroxy-C _2-6 alkyl, (e) - (CH ₂ ) _t -CH ₂ -G, where t is 2-4, (ί) 3,3,3-trifluoropropyl or (d) C _1-4 -alkylsulfonyl, provided that P is selected from the substituents of formula (V);

and ^ ₂ each independently selected from the group consisting of:

(a) hydrogen, (b) halogen, (c) C1-6 alkyl, (ά) hydroxy, (e) C1-6 alkoxy, (ί) C _1-6 alkylthio, (e) C _2-6 alkenyl, (11) phenyl, (ΐ) phenoxy, (Ϊ) benzyloxy, (k) benzoyl, (l) benzyl, (t) -OHCH, (p) -ΌΝ, (o) hydroxy-C1-6-alkyl, (p) C _1-6 -alkoxy-C _1-6 -alkyl, (ς) halogen-C _1-6 -alkyl, (g) -СЫЫК ⁹ К ⁹ , (8) -С (= О) К ¹⁰ , (ΐ) C _1-6 alkoxycarbonyl, (i) -8CG ₃ or (ν) -CNG = CH2, provided that when ^ ₁ and ^ ₂ are selected from the group consisting of phenyl, phenoxy, benzoyl, benzyloxy and benzyl their phenyl rings may optionally be substituted with one or more halogen atoms, C _1-4 alkyl, C _1-4 alkoxy, cyan o or trifluoromethyl; and under the following condition, when and ^ 2 do not choose a group consisting of methoxy, methyl and halogen, at least one of and 'means hydrogen;

K ³ means H when P means a substituent of formula (II), where K ¹ means Ν-substituted 4 piperidinyl, or K ³ means a group selected from

- 3 010298

K ³ may also be a group selected from

and then a group selected from -Ο- (Ο = ΝΗ) ΝΚ ¹¹ Κ ¹¹ or - (0Η ₂ ) _η -Θ-ΝΗ (0 = ΝΗ) -ΝΚ ¹¹ Κ ¹¹ ;

where η = 0, 1, 2 or 3, g, each independently, means 0, 1 or 2, o = 1, 2 or 3, p, each independently, means 1 or 2, = 2 or 3, ΐ = 0 or 1, ΐ ₁ = 1 or 2, ΐ ₂ = 0 or 1,

- 4 010298 £ = 1, 2, 3 or 4, and £ v = 1, 2 or 4, provided that when ί ₁ and p simultaneously mean 1, r does not mean 0;

X is selected from O, ΝΚ ⁷ and 8;

X _{I is} selected from ΝΚ ⁷ and 8;

X _{2 is} selected from O, ΝΚ ⁷ and 8, provided that X2 is selected from ΝΚ ⁷ and 8 when ί2 = 0;

X _{3 is} selected from ΝΚ ⁷ and 8, provided that X ₃ means 8 when r = 1;

X _{4 is} selected from O, ΝΚ ⁷ and 8, provided that X _{4 is} selected from ΝΚ ⁷ and 8, when £ is selected from 2, 3 and 4;

selected from CH ₂ , 8O ₂ and oxygen, provided that when 9 is 8O ₂ or oxygen, p is 1;

Ζ choose from 8O ₂ and oxygen;

when P means a group selected from substituents of the formulas (Y) - (UP), K ³ , in addition, are selected from the following groups:

·!

where η = 0, 1, 2 or 3, r = 0, 1 or 2, o = 1, 2 or 3, p = 1 or 2, = 2 or 3, and £ = 1, 2, 3 or 4;

K ^{4 is} selected from the group consisting of (a) hydrogen, (b) C _1-6 alkyl, (c) 2-cyanoethyl, (i) hydroxy-C _2-6 alkyl, (e) C _3-6 - alkenyl, (£) C _3-6 alkynyl, (e) C _3-7 cycloalkyl, (I) C _3-7 cycloalkyl-C _1-4 alkyl, (ΐ) C _1-6 alkoxy-C _2-6 alkyl

(]) -С- ^ КЩ-М-К ¹¹ ^ ¹¹ , (k) - ^^ Ο ^ Ν-Κ ¹¹ ^ ¹ , (l) -СН ^ СО-И-К ¹¹ ^ ¹ or (t) 3 , 3,3-trifluoropropyl;

K ^{5 is} selected from the group consisting of (a) hydrogen, (b) C _1-4 alkyl, (c) hydroxy-C _1-4 alkyl, (i) C _1-4 alkoxymethyl, (e) halogen C _1-4 alkyl, (ί) -ΝΡ. ¹¹ ^ ¹ , (e) -CO-IR ¹¹ ^ ¹ , (I) a hydroxyl group, provided that the above hydroxyl group is not attached to a carbon atom adjacent to the ring nitrogen atom, or (ΐ) fluorine, provided that the above fluorine atom is not attached to a carbon atom adjacent to the nitrogen atom of the ring;

K ^{6 is} selected from the group consisting of (a) hydrogen, (b) C _1-4 alkyl, (c) hydroxy-C _1-4 alkyl,

- 5 010298 (b) C1_4-alkoxy-C1_4-alkyl, (f) hydroxyl group, provided that the above hydroxyl group is not attached to the carbon atom adjacent to the nitrogen atom of the heterocycle, and under the further condition that the above heterocycle is not substituted by an oxo group ;

(D) fluorine, provided that the above fluorine atom is not attached to a carbon atom adjacent to the nitrogen atom of the ring; or (e) halo-C _1-4 alkyl;

In ⁷ , each independently, is selected from the group consisting of:

(a) hydrogen, provided that B ⁷ does not mean hydrogen when g is simultaneously present and the above g means 1 or 2, (b) C _1-4 alkyl, (c) hydroxy-C _2-4 alkyl, or ( b) methoxy-C _2-4 alkyl;

At ⁸ , each independently, is selected from:

(a) hydrogen or (b) C _1-4 alkyl, and when both B ^{8 are} C _1-4 alkyl simultaneously, the above C _1-4 alkyls may be attached to the same or different carbon atoms, or, when two groups are at the same carbon atom, they can together form a cyclopropane ring;

At ⁹ , each independently, is selected from:

(a) hydrogen, (b) C _1-6 alkyl, (c) C _3-7 cycloalkyl, or where two B ⁹ groups together with the nitrogen atom to which they are attached form a heterocycle; and provided that when two B ⁹ groups form a piperazine ring, the nitrogen atom of the above piperazine ring, which may be substituted, is substituted with C _1-4 alkyl; and provided that when two B ⁹ groups form a piperidine ring, any carbon atom in the above piperidine ring may optionally be substituted with methyl;

At ¹⁰ choose from:

(a) C _1-6 alkyl, (c) aryl, or (b) heteroaryl, where heteroaryl or aryl can be substituted at one or more positions with substituents selected from a halogen atom, C _1-4 alkyl, C _1-4 alkoxy, cyano, trifluoromethyl;

At ¹¹ , each independently, is selected from:

(a) hydrogen, (b) methyl, or (c) ethyl, provided that B ¹¹ is in group B ⁴ or B ²⁶ meaning —CH ₂ —CO — S — B ¹¹ B ¹¹ ;

^{12 is} selected from the group consisting of:

(a) hydrogen, (b) C _1-6 -alkyl, (c) aryl, (b) aryl-C _1-6 -alkyl, (f) C3-7-cycloalkyl, (ί) C _3-7 -cycloalkyl -C _1-4 -alkyl, (e) heteroaryl or (11) heteroaryl-C _1-6 -alkyl, where any heteroaryl or aryl residue, one or as part of another group, is optionally independently substituted in one or more positions by substituents selected from the group consisting of:

(a) hydrogen, (b) halogen, (c) C _1-6 alkyl, (b) hydroxy, (e) C _1-6 alkoxy, (ί) C _2-6 alkenyl, (e) C2- 6-alkynyl, (1) phenyl, (ί) phenoxy, (ί) benzyloxy, (k) benzoyl, (l) benzyl,

- 6 010298 (t) -ОСО3, (η) -ΟΝ, (o) hydroxy-С _1-6 -alkyl, (p) С _1-6- alkoxy-С _1-6 -alkyl, (p. |) Halogen -C _1-6 -alkyl, (g) -hick, (8) -ΝΟ ₂ , (ΐ) -СОХК'К.

(i) -NK. ⁷ SOK ¹⁰ , (ν) -С (= О) К ¹⁰ , (х) С _1-6- alkoxycarbonyl, (у) С _1-6 -alkylthio, (ζ) -8CEz, (aa) -0ΗΕ = 0Η ₂ , (ab) methylsulfonyl or (ac) -COOH.

with the proviso that when the substituent of the aryl or heteroaryl residue indicated above is selected from the group consisting of phenyl, phenoxy, benzyloxy, benzoyl and benzyl, its phenyl ring may optionally be substituted with one or more halogen atoms, C _1-4 alkyl, C _{1- 4-} alkoxy, cyano or trifluoromethyl;

K ^{13 is} selected from the group consisting of:

(a) C _1-6 alkyl, (b) C _3-6 cycloalkyl, (c) aryl, (b) heteroaryl, (e) aryl-C _1-2 alkyl or (ί) heteroaryl-C _{1- 2-} alkyl, where any heteroaryl or aryl residue can be substituted in one or more positions by substituents selected from a halogen atom, C1-4 alkyl, C1-4 alkoxy, cyano, trifluoromethyl and acetyl;

K ^{14 is} selected from the group consisting of:

(a) aryl, (b) heteroaryl, (c) aryl-C _1-3 -alkyl, or (b) heteroaryl-C _1-3 -alkyl, where any heteroaryl or aryl residue can be substituted in one or more positions by substituents, selected from a halogen atom, C _1-4 alkyl, C _1-4 alkoxy, cyano and trifluoromethyl;

K ¹⁵ choose from:

(a) fluorine; or (b) hydroxy;

K ^{16 is} selected from the group consisting of:

(a) hydrogen, provided that r = 0, (b) amino, (c) dimethylamino, (b) E or (e) OH;

K ¹⁷ choose from:

(a) hydrogen, (b) C _1-4 alkyl, (c) hydroxyl group, provided that the above hydroxyl group is not attached to a carbon atom adjacent to the nitrogen atom of the ring;

K ^{18 is} selected from:

(a) hydrogen or (b) fluorine;

K ^{19 is} selected from the group consisting of:

(a) hydrogen, (b) methyl, (c) trifluoromethyl, or (b) C _1-2 alkoxymethyl;

and provided that at least one of K ¹⁹ and K ¹¹ , when they are both present simultaneously, does not mean hydrogen; and also provided that when K ^{19 is} selected from trifluoromethyl or C _1-2 alkoxymethyl, each K ¹¹ means hydrogen;

- 7 010298

K ^{20 is} selected from the group consisting of:

(a) hydrogen, (b) S1_ ₄ alkyl, (c) hydroxy-C _1-4 alkyl, (b) C _{1. 4-} alkoxy-C ₁ . _4- alkyl or (e) fluoromethyl;

provided that when 1 ₂ means 1, K ²⁰ means N; K ²¹ and

To ²² , each independently, is selected from:

(a) hydrogen or (b) methyl,

11 21 22 with the proviso that when at least two of K, K and K are present simultaneously with K, they are hydrogen; K ^{23 is} selected from the group consisting of:

(a) hydroxy-C1-4 alkyl, (b) C _1-4 alkoxymethyl, (c) halogen-C _1-4 alkyl, or (b) -CO-NOK ^P K ^P , provided that K ⁴ do not choose from - ^^ ΝΗ ^ Ν-Η ¹¹ ^ ¹ , -С- ^ О ^ -К ¹¹ ^ ¹ and -CH ₂ СО-М-К ^П К ^П ;

K ²⁴ choose from:

(a) hydroxymethyl, (b) methoxymethyl or (c) fluoromethyl;

To ²⁵ , each independently, is selected from the group consisting of:

(a) hydrogen, (b) C1-4 alkyl, (c) hydroxy-C1-4 alkyl, (b) C _1-4 alkoxy-C _1-4 alkyl, or (e) fluoromethyl;

with the proviso that when simultaneously both K ^{25 are} C 1-4 alkyl, the aforementioned C 1-4 alkyls may be attached to the same or different carbon atoms; and also provided that when one K ^{25 is} selected from hydroxy-C _1-4 alkyl, C _1-4 alkoxy-C _1-4 alkyl and fluoromethyl, the other K ²⁵ is hydrogen; and

K ^{26 is} selected from the group consisting of:

(a) 2-cyanoethyl, (b) C3-6 alkenyl, (c) C3-6 alkynyl, (b) C _3-7 cycloalkyl, (e) C _3-7 cycloalkyl C _1-4 - alkyl, (ί) -C11; -COAA K or (d) 3,3,3-trifluoropropyl;

provided that K ² and K ¹² in the formula (III) do not simultaneously mean hydrogen; and also provided that the above K ² and K ¹² together can form a heterocycle selected from piperidine, pyrrolidine, morpholine, piperazine, thiomorpholine, and provided that when K ² and K ¹² together form a piperazine ring, a peripheral nitrogen atom in piperazine, optionally substituted with C _1-4 alkyl or aryl, and wherein the above aryl is substituted in one or more positions with substituents selected from a halogen atom, C _1-4 alkyl, C _1-4 alkoxy, cyano, trifluoromethyl; or K ² and K ¹² together form a heteroaromatic ring of formula (VIII):

where ν means 0, 1 or 2; and also provided that when K ¹⁵ is hydroxy, K ¹⁸ is hydrogen; and its pharmaceutically acceptable salts, hydrates, solvates, geometric isomers, tautomers, optical isomers and prodrug forms.

Preferred is a compound of formula @ b):

where P is selected from the substituents of the formulas (Π) - (νΠ)

- 8 010298

(V)

(Vi) or

where x, y and each independently, are selected from 0, 1 and 2;

where dashed lines indicate that K ³ can be attached to either the A or B ring at any carbon atom that can be substituted;

K ^{1 is} selected from the group consisting of:

(a) C _1-6 alkyl, (b) C _1-6 alkoxy-C _2-6 alkyl, (c) C3-6 alkenyl, (ά) hydroxy-C2-6 alkyl, (e) halogen-C _1-6 -alkyl, (ί) aryl, (e) arylcarbonylmethyl, (1) aryl-C3-6-alkenyl, (ι) aryl-C _1-6 -alkyl,

(]) C _3-7 -cycloalkyl, (k) heteroaryl, (o) heteroaryl-C _1-6 -alkyl, where any heteroaryl or aryl residue, one or as part of another group, may be optionally independently substituted, in one or more provisions, substituents selected from the group consisting of:

(b) halogen, (c) C _1-6 alkyl, (ά) hydroxy, (e) C _1-6 alkoxy, (ί) C2-6 alkenyl, (e) C2-3 alkynyl, (l ) phenyl, (ι) phenoxy, (ί) benzyloxy, (k) benzoyl, (l) benzyl, (t) -ОСРе, (p) -СЧ, (о) hydroxy-С _1-6 -alkyl, (p) C _1-6 -alkoxy-C _1-6 -alkyl, (ен) halogen-С _1-6 -alkyl, (g) -CHK ⁹ K ⁹ , (8) -CHO2, (ΐ) -SOK ⁹ K ⁹ , (i) -CHK ⁷ SOK ¹⁰ , (ν) -С (= О) К ¹⁰ , (х) С _1-6- alkoxycarbonyl, (у) С _1-6- alkylthio, (ζ) -8СРэ, (aa) -CHP = CH2, (ab) methylsulfonyl, or (ac) -COOH, provided that when the substituent of the above aryl or heteroaryl residue is knocked out

- 9 010298 rayut from the group consisting of phenyl, phenoxy, benzyloxy, benzoyl and benzyl, it may be a phenyl ring optionally substituted with one or more halogen, C1 _-4 alkyl, C1 _-4 alkylthio, C1 _-4 alkoxy, cyano or trifluoromethyl;

K ^{2 is} selected from the group consisting of:

(a) hydrogen, (b) C1 _-6 alkyl, (c) C1 _-6 alkoxy-C _2-6 alkyl, (ά) hydroxy-C _2-6 alkyl, (e) - (CH ₂ ) _t -CH ₂ -P, where t is 2-4, or (d) C1 _-4- alkylsulfonyl, with the proviso that P is selected from the substituents of formula (V);

and ^ ₂ each independently selected from the group consisting of:

(a) hydrogen, (b) halogen, (c) _C1-6 alkyl, (ά) hydroxy, (e) _C1-6 alkoxy, (ί) _C1-6 alkylthio, (e) C2-6 alkenyl , (t) -OSR3, (n) -rm, (o) hydroxy-C1 _-6 -alkyl, (p) C _1-6 alkoxy-C _1-6 alkyl, (c |) halo-C _{1- 6-} alkyl, (g) -СОККК ⁹ , (8) -С (= О) К ¹⁰ , (ΐ) С _1-6- alkoxycarbonyl, (i) -8СР ₃ or (ν) -СНР = СН2, provided that when ^ ₁ and ^ _{2 are} not selected from the group consisting of hydroxy, methoxy, methyl and a halogen atom, at least one of ^ ₁ and ^ ₂ means hydrogen;

K ³ is a group selected from:

- 10 010298 where η = 0, 1, 2 or 3, r = 0, 1 or 2, o = 1, 2 or 3, p = 1 or 2, = 2 or 3, ΐ = 0 or 1, ΐ ₂ = 0 OR 1, £ = 1, 2, 3 or 4, and £ ι = 1, 2 or 4;

X1 is selected from ΝΚ ⁷ and 8;

X _{2 is} selected from O, ΝΚ ⁷ and 8, provided that when ΐ ₂ = 0 and 8 = 2, then X _{2 is} selected from ΝΚ ⁷ and 8;

X _{3 is} selected from ΝΚ ⁷ and 8, provided that X ₃ means 8 when r = 1;

X _{4 is} selected from O, ΝΚ ⁷ and 8, provided that X4 is selected from ΝΚ ⁷ and 8 when £ is selected from 2 and 3, and K ^{6 is} simultaneously selected from hydrogen and C 1-4 alkyl;

when P means a group selected from substituents of the formulas (ν) - (νΐΐ), K ³ , in addition, are selected from the following groups:

where r = 0, 1 or 2, o = 1, 2 or 3, p, each independently, means 1 or 2, = 2 or 3, and £ = 1, 2, 3 or 4;

K ^{4 is} selected from the group consisting of:

(a) hydrogen, (b) C1 _-6 alkyl, (c) 2-cyanoethyl, (b) hydroxy-C _2-6 -alkyl, (e) C _3-6 alkenyl, (£) S3-6- alkynyl, (e) C _3-7 -cycloalkyl, (I) C _3-7 -cycloalkyl-C _1-4 -alkyl, (1) C _1-6 -alkoxy-C _2-6 -alkyl, (1) - SI ^ SO-M-K ¹¹ ^ ¹ or (t) 3,3,3-trifluoropropyl;

K ^{5 is} selected from the group consisting of:

(a) hydrogen, (b) C _1-4 alkyl, (c) hydroxy-C1-4 alkyl, (b) C _1-4 alkoxymethyl, (e) halogen-C _1-4 alkyl, (£ ) -ΝΕ ¹¹ Ε ¹¹ , (I) a hydroxyl group, provided that the above hydroxyl group is not attached to the carbon atom adjacent to the nitrogen atom of the ring, or (1) fluorine, provided that the above fluorine atom is not attached to the carbon atom adjacent to the nitrogen atom of the ring;

K ^{6 is} selected from the group consisting of:

(a) hydrogen, (b) C _1-4 alkyl, (c) hydroxy-C1-4 alkyl, (b) C _1-4 alkoxy-C _1-4 alkyl,

- 11 010298 (e) hydroxyl group, provided that the above hydroxyl group is not attached to the carbon atom adjacent to the nitrogen atom of the heterocycle;

(1) fluorine, provided that the above fluorine atom is not attached to a carbon atom adjacent to the nitrogen atom of the ring; or (e) halo-C _1-4 alkyl;

I ⁷ , each independently, are selected from the group consisting of:

(a) hydrogen, provided that I ⁷ does not mean hydrogen when g is simultaneously present and the above g means 1 or 2, (b) C _1-4 alkyl, (c) hydroxy-C _2-4 alkyl, or ( b) methoxy-C _2-4 alkyl;

I am ⁸ , each independently, choose from:

(a) hydrogen or (b) C _1-4 alkyl, and provided that when both I ⁸ simultaneously mean C _1-4 alkyl, where the above C _1-4 alkyls may be attached to the same or different carbon atoms, or when two groups are on the same carbon atom, they can together form a cyclopropane ring; I am ⁹ , each independently, choose from:

(a) hydrogen, (b) C _1-6 -alkyl, (c) C _3-7 -cycloalkyl, or where two I ⁹ groups together with the nitrogen atom to which they are attached form a heterocycle; and provided that when two R ⁹ groups form a piperazine ring, the nitrogen atom of the above piperazine ring, which may be substituted, may optionally be substituted with C1-4 alkyl; and also provided that when two R ⁹ groups form a piperidine ring, any carbon atom in the above piperidine ring may optionally be substituted with methyl;

I ¹⁰ choose from:

(a) C _1-6 alkyl, (c) aryl, or (b) heteroaryl, where heteroaryl or aryl may optionally be substituted at one or more positions with substituents selected from a halogen atom, C1-4 alkyl, C1-4- alkoxy, cyano, trifluoromethyl;

I am ¹¹ , each independently, choose from:

(a) hydrogen, (b) methyl, or (c) ethyl, provided that I ¹¹ is in the group I ⁴ or I ²⁶ , meaning —CH ₂ —CO — S — I ¹¹ I ¹¹ ;

I am ¹² selected from the group consisting of:

(a) hydrogen, (b) C _1-6 alkyl, (c) aryl, (b) aryl C _1-6 alkyl, (e) C3-7 cycloalkyl, (I) C _3-7 cycloalkyl -C _1-4 -alkyl, (e) heteroaryl or (II) heteroaryl-C _1-6 -alkyl, where any heteroaryl or aryl residue, one or as part of another group, may be optionally independently substituted, in one or more positions , substituents selected from the group consisting of:

(b) halogen, (c) C _1-6 alkyl, (b) hydroxy, (e) C _1-6 alkoxy, (1) C _2-6 alkenyl, (e) C2-3 alkynyl, ( 1) phenyl, (ί) phenoxy, (ί) benzyloxy, (k) benzoyl, (l) benzyl, (t) -ОСО ₃ , (п) -СЫ,

- 12 010298 (o) hydroxy-C1 _-6- alkyl, (p) C1 _-6- alkoxy-C1 _-6- alkyl, (c.) Halogen-C1 _-6- alkyl, (g) -XK / 'K ⁹ , (h) -ΝΟ ₂ , (!) -SOKHK'K ', (and) -KHK SOK.

(ν) -C (= O) To a ^10, (x) C1 _-6 -alkoxycarbonyl, (y) C1 _-6 alkylthio, (ζ) -8SE _3, (aa) -SNE = CH2, (ab) or methylsulfonyl (ac) -COOH, with the proviso that when the substituent of the above aryl or heteroaryl residue selected from the group consisting of phenyl, phenoxy, benzyloxy, benzoyl and benzyl, it may be a phenyl ring optionally substituted with one or more halogen atoms, a C1 _-4 - alkyl, C1 _-4 alkoxy, cyano or trifluoromethyl;

K ^{13 is} selected from the group consisting of:

(a) C _1-6 alkyl, (b) C _3-6 cycloalkyl, (c) aryl, (b) heteroaryl, (e) aryl-C _1-2 alkyl or (ί) heteroaryl-C _{1- 2-} alkyl, where any heteroaryl or aryl residue may be optionally substituted in one or more positions by substituents selected from a halogen atom, C _1-4 alkyl, C _1-4 alkoxy, cyano, trifluoromethyl and acetyl;

K ^{14 is} selected from the group consisting of:

(a) aryl, (b) heteroaryl, (c) aryl-C _1-3 -alkyl, or (b) heteroaryl-C _1-3 -alkyl, where any heteroaryl or aryl residue can be substituted in one or more positions by substituents, selected from a halogen atom, C _1-4 alkyl, C _1-4 alkoxy, cyano and trifluoromethyl;

To ²⁰ , each independently, is selected from:

(a) hydrogen, (b) methyl, provided that when ΐ ₂ means 1, K ²⁰ means H;

K ²¹ and K ²² , each independently, are selected from:

(a) hydrogen or (b) methyl,

11 21 22 with the proviso that when at least two of K, K and K are present simultaneously with K, they are hydrogen; K ^{23 is} selected from the group consisting of:

(a) hydroxy-C _1-4 alkyl, (b) C1-4 alkoxymethyl or (c) halogen-C _1-4 alkyl;

To ²⁵ , each independently, is selected from the group consisting of:

(a) hydrogen, (b) C _1-4 alkyl, (c) hydroxy-C _1-4 alkyl, (b) C _1-4 alkoxy-C _1-4 alkyl, or (e) fluoromethyl;

with the proviso that when simultaneously both K ^{25 are} C 1-4 alkyl, the aforementioned C 1-4 alkyls may be attached to the same or different carbon atoms; and also provided that when one K ^{25 is} selected from hydroxy-C _1-4 alkyl, C _1-4 alkoxy-C _1-4 alkyl and fluoromethyl, the other K ²⁵ is hydrogen;

K ^{26 is} selected from the group consisting of:

(a) 2-cyanoethyl, (b) C3-6-alkenyl, (c) C3-6-alkynyl, (b) C3-7-cycloalkyl,

- 13 010298 (f) C _3-7 -cycloalkyl-C _1-4 -alkyl, (ί) -CH ₂ -CO-ChK ¹¹ K ¹¹ or (e) 3,3,3-trifluoropropyl;

provided that K ² and K ¹² in the formula (III) do not simultaneously mean hydrogen; and also provided that the above K ² and K ¹² together can form a heterocycle selected from piperidine, pyrrolidine, morpholine, piperazine, thiomorpholine, and provided that when K ² and K ¹² together form a piperazine ring, a peripheral nitrogen atom in piperazine, may optionally be substituted with C _1-4 alkyl or aryl, and wherein the above aryl may be optionally substituted in one or more positions with substituents selected from a halogen atom, C _1-4 alkyl, C _1-4 alkoxy, cyano, trifluoromethyl; or K ² and K ¹² together form a heteroaromatic ring of formula (VIII):

Ί (ΟΗ ₂ ) ν

(VIII) where ν is 0 or 1.

It is further preferred that:

P is selected from substituents of the formulas (Π) - (ν):

I ¹ ₂ I ² —Ν ^ / / to ¹² η Ν-Κ ² K O>' Ά ^{8 |} Ήβ, at OR (P) (W) (Iv) (V)

where x is 2, y is 0 and | means 1;

K ^{1 is} selected from the group consisting of:

(ί) aryl, (ΐ) aryl-C _1-3 -alkyl, (k) heteroaryl, (o) heteroaryl-C1-3-alkyl, where any heteroaryl or aryl residue, one or as part of another group, may be optional independently substituted, in one or more positions, by substituents selected from the group consisting of:

(b) halogen, (c) C _1-4 -alkyl, (b) hydroxy, (e) C _1-4 -alkoxy, (t) -OCP3, (p) -CH, (o) hydroxy-C _{1- 4-} alkyl, (r) C _1-2 -alkoxy-C _1-2 -alkyl, (c) halogen-C _1-3 -alkyl, (g) -CHK ⁹ K ⁹ , (l) -NUMBER ⁹ K ⁹ , (i) -CHK ⁷ SOK ¹⁰ , (ν) -С (= О) К ¹⁰ , (х) С _1-3- alkoxycarbonyl, (у) С _1-3 -alkylthio or (аb) methylsulfonyl;

K ^{2 is} selected from the group consisting of:

(a) hydrogen; (b) C _1-4 alkyl;

and ^ 2 each independently selected from the group consisting of:

(a) hydrogen, (b) halogen, (c) C _1-4 alkyl, (b) hydroxy, (e) C _1-4 alkoxy, (ί) C _1-4 alkylthio, (t) -OCP3 , (p) -MF,

- 14 010298 (o) hydroxy-C _1-2 -alkyl, (p) C ₁ . _2- alkoxy-C ₁ . _2- alkyl, (h) -Crz, (g) -CHOCK ⁹ , (h) acetyl, (ΐ) C _1-4 -alkoxycarbonyl, or provided that when W ₁ and W _{2 are} not selected from the group consisting of hydroxy, methoxy, methyl and a halogen atom, at least one of W ₁ and W ₂ means hydrogen;

K ³ is a group selected from:

where η = 0, 1, 2 or 3, r means 0, 1 or 2, o = 1, 2 or 3, p means 1 or 2, s = 2 or 3, ΐ = 0 or 1, ΐ ₂ = 0 or 1, and £ = 1, 2, 3, or 4;

X _{1 is} selected from ΝΚ ⁷ and 8;

X _{2 is} selected from O, ΝΚ ⁷ and 8, provided that when X _{2 is} selected from ΝΚ ⁷ and 8, then ΐ = 0 and s = 2;

X _{3 is} selected from ΝΚ ⁷ and 8, provided that X ₃ means 8 when r = 1;

X _{4 is} selected from O, ΝΚ ⁷ and 8, provided that X4 is selected from ΝΚ ⁷ and 8 when £ is selected from 2 and 3, and K ^{6 is} simultaneously selected from hydrogen and C 1-4 alkyl; or when P means a group selected from substituents of the formula (ν), where) = 1, and K ³ also means the following group:

- 15 010298 t

K ⁷

In ⁴ choose from the group consisting of:

(a) hydrogen, (b) C1-4 alkyl, (b) hydroxy-C2-4-alkyl, (e) C3-6-cycloalkyl, (1) C _3-6 -cycloalkyl-C _1-4 -alkyl , (ί) C _1-4 alkoxy-C _2-4 alkyl, or (t) 3,3,3-trifluoropropyl;

In ⁵ choose from the group consisting of:

(a) hydrogen, (b) C _1-4 alkyl, (c) hydroxy-C _1-4 alkyl, (b) C _1-4 alkoxymethyl, (e) halogen C _1-4 alkyl, ( D) -IR ¹¹ B ¹¹ , (1) a hydroxyl group, provided that the above hydroxyl group is not attached to the carbon atom adjacent to the ring nitrogen atom, or (ί) fluorine, provided that the above fluorine atom is not attached to the atom carbon adjacent to the ring nitrogen atom;

In ⁶ choose from the group consisting of:

(a) hydrogen, (b) C _1-4 alkyl, (c) hydroxy-C _1-4 alkyl, (b) C _1-4 alkoxy-C _1-4 alkyl, (e) hydroxyl group, provided that the above hydroxyl group is not attached to a carbon atom adjacent to the nitrogen atom of the heterocycle;

(D) fluorine, provided that the above fluorine atom is not attached to a carbon atom adjacent to the nitrogen atom of the ring; or (e) halo-C _1-4 alkyl;

In ⁷ , each independently, is selected from the group consisting of:

(a) hydrogen, provided that B ⁷ does not mean hydrogen when g is simultaneously present and the above g means 1 or 2, (b) C _1-4 alkyl, (c) hydroxy-C2-4 alkyl, or (b a) methoxy-C2-4 alkyl;

At ⁸ , each independently, is selected from:

(a) hydrogen or (b) C _1-4 alkyl, and provided that when both B ^{8 are} C _1-4 alkyl at the same time, the above C _1-4 alkyl may be attached to the same or different carbon atoms, or when two groups are on the same carbon atom, they can together form a cyclopropane ring;

At ⁹ , each independently, is selected from:

(a) hydrogen, (b) C _1-6 alkyl, or where two B ⁹ groups together with the nitrogen atom to which they are attached form a heterocycle; and provided that when the two B ⁹ groups form a piperazine ring, the nitrogen atom of the above piperazine ring which may be substituted is optionally substituted with C1-4 alkyl;

At ¹⁰ choose from:

(a) C _1-6 alkyl, (c) aryl, or (b) heteroaryl, where heteroaryl or aryl may optionally be substituted at one or more positions with substituents selected from a halogen atom, C1-4 alkyl, C1-4- alkoxy, cyano, trifluoromethyl;

At ¹¹ , each independently, is selected from:

(a) hydrogen, (b) methyl, or (c) ethyl, provided that B ¹¹ is in group B ²⁶ meaning —CH ₂ —CO — IR ¹¹ B ¹¹ ;

^{12 is} selected from the group consisting of:

(a) hydrogen,

- 16 010298 (c) aryl, (ά) aryl-C _1-3 -alkyl, (e) heteroaryl or (1) heteroaryl-C _1-3 -alkyl, where any heteroaryl or aryl residue, one or as part of another group may optionally be independently substituted, in one or more positions, by substituents selected from the group consisting of:

(b) halogen, (c) C _1-4 -alkyl, (ά) hydroxy, (e) C _1-4 -alkoxy, (t) -ОСО ₃ , (p) -СЧ, (о) hydroxy-С _{1 -3-} alkyl, (r) C _1-3 -alkoxy-C _1-3 -alkyl, (cf halogen-C _1-4 -alkyl, (g) -hKK ⁹ , (ΐ) -NUMBER ⁹ K ⁹ , ( i) -CHK SOK, (ν) -C (= O) K ¹⁰ , (x) C1-3-alkylthio or (a) methylsulfonyl;

To ¹³ choose from:

(c) aryl, (ά) heteroaryl, (e) aryl-C _1-2 -alkyl or (ί) heteroaryl-C _1-2 -alkyl, where any heteroaryl or aryl residue may be optionally substituted in one or more positions with substituents selected from a halogen atom, C _1-4 alkyl, C _1-4 alkoxy, cyano, trifluoromethyl and acetyl;

To ¹⁴ choose from:

(a) aryl, (b) heteroaryl, (c) aryl-C _1-3 -alkyl or (ά) heteroaryl-C _1-3 -alkyl, where any heteroaryl or aryl residue may be optionally substituted in one or more positions with substituents selected from a halogen atom, C _1-4 alkyl, C _1-4 alkoxy, cyano and trifluoromethyl;

K ²⁰ choose from:

(a) hydrogen or (b) methyl, provided that when ΐ2 means 1,

K ²⁰ means H;

K ²¹ and K ²² , each independently, are selected from:

(a) hydrogen or (b) methyl,

11 21 22 with the proviso that when at least two of K, K and K are present simultaneously with K, they are hydrogen; K ²³ choose from:

(a) hydroxy-C _1-4 alkyl, (b) C _1-4 alkoxymethyl or (c) halogen C _1-4 alkyl;

K ^{25 is} selected from the group consisting of:

(a) hydrogen, (b) C _1-4 alkyl, (c) hydroxy-C _1-4 alkyl, (ά) C _1-4 alkoxy-C _1-4 alkyl, or (e) fluoromethyl;

with the proviso that when both K ^{25 are} simultaneously C 1-4 alkyl, the aforementioned C 1-4 alkyls may be attached to the same or different carbon atoms; and also provided that when one K ^{25 is} selected from hydroxy-C _1-4 alkyl, C _1-4 alkoxy-C _1-4 alkyl and fluoromethyl, the other K ²⁵ is hydrogen;

K ^{26 is} selected from the group consisting of:

(e) C _3-7 cycloalkyl-C _1-4 alkyl,

- 17 010298 (ί) -СНг-СО-ЫЖ'К. ¹¹ or (d) 3,3,3-trifluoropropyl;

provided that K ² and K ¹² in the formula (III) do not simultaneously mean hydrogen; and provided that the above K ² and K ¹² together can form a heterocycle selected from piperidine, pyrrolidine, morpholine, piperazine, thiomorpholine, and provided that when K ² and K ¹² together form a piperazine ring, the peripheral nitrogen atom in piperazine may optionally be substituted with C _1-4 alkyl or aryl, and wherein the above aryl is optionally substituted in one or more positions with substituents selected from a halogen atom, C _1-4 alkyl, C _1-4 alkoxy, cyano, trifluoromethyl; or K ² and K ¹² together form a heteroaromatic ring of formula (VIII)

where ν means 0 or 1.

A group of preferred compounds according to this invention are compounds corresponding to General formula (XII)

where ^ ₁ , ^ 2, P and K ³ mean, as described above for formula D).

Further preferred compounds of formula (XII) are those wherein

P is selected from the substituents of the formulas (Ή ^^ ν);

x is 2 and y is 0;

K ^{1 is} selected from aryl and heteroaryl, wherein any heteroaryl or aryl residue may optionally be independently substituted at one or more positions with substituents selected from a halogen atom, C _1-4 alkyl, C _1-4 alkoxy, and trifluoromethyl;

K ² means hydrogen;

No. 1 and Ж mean hydrogen;

K ³ means a group selected from

- 18 010298 where p = 1 or 2,

K ³ choose from:

(a) hydrogen or (b) C _1-4 alkyl;

To ¹¹ , each independently, is selected from:

(a) hydrogen, (b) methyl, or (c) ethyl, provided that K ¹¹ is in the K ²⁶ group meaning —CH ₂ —CO — IK ¹¹ K ¹¹ ;

K ¹² and K ¹³ each independently selected from aryl and heteroaryl;

where any heteroaryl or aryl residue may be optionally substituted, independently, in one or more positions, with a substituent selected from a halogen atom,

C _1-4 alkyl, C _1-4 alkoxy and CP ₃ ;

K ²⁵ choose from:

(a) hydrogen or (b) C _1-4 alkyl; To ²⁶ choose from:

(e) C _3-7 -cycloalkyl-C _1-4 -alkyl, (ί) -CH ₂ -CO-IR ^P K ^P or (d) 3,3,3-trifluoropropyl.

In more preferred compounds of formula (XII)

P is selected from substituents of formula (ΙΙ) - (ΐν);

x is 2 and y is 0;

K ¹ , K ^12, and K ¹³ each independently selected from phenyl or substituted phenyl selected from the group consisting of 2-methoxy-5-methylphenyl, 2-methylphenyl, 4-methylphenyl, 4-fluorophenyl, 3,4dimethoxyphenyl, 2 -chlorophenyl, 2-trifluoromethylphenyl, 2,6-dichlorophenyl, 3-chloro-4-methylphenyl, 3methylphenyl, 3,6-dichloro-2-methylphenyl and 2-chloro-5-fluorophenyl; or selected from heteroaryl or substituted heteroaryl selected from 2-thienyl, 5-chloro-2-thienyl, 5-chloro and 1,3-dimethyl-1H-pyrazole-

4-yl;

K ² means hydrogen;

(a) hydrogen or (b) methyl;

To ¹¹ , each independently, is selected from:

(a) hydrogen or (b) methyl;

_To ²⁵ _, each independently, is selected from:

(a) hydrogen; or (b) methyl.

A further group of preferred compounds according to this invention are compounds corresponding to the general formula (XIII):

(Xx)

- 19 010298 where ^ 2, P and K ³ mean, as described above for formula (1b).

Also preferred compounds of formula (XIII) are those wherein:

P is selected from substituents of the formulas (ΙΙ) - (ΐν);

x is 2, and y is 0;

K ^{1 is} selected from aryl and heteroaryl, wherein any heteroaryl or aryl residue may optionally be independently substituted, at one or more positions, with a substituent selected from a halogen atom, C1-4 alkyl, trifluoromethoxy, C1-4 alkoxy;

K ² means hydrogen;

Where

To ⁴ , each independently, is selected from:

(a) hydrogen or (b) C _1-4 alkyl;

To ²⁵ , each independently, is selected from:

(a) hydrogen or (b) C _1-4 alkyl, provided that when both K ²⁵ are C _1-4 alkyl, the above C _1-4 alkyls may be attached to the same or different carbon atoms ;

K ¹² and K ¹³ are each independently selected from aryl and heteroaryl, where any heteroaryl or aryl residue may optionally be independently substituted at one or more positions with a substituent selected from a halogen atom, C _1-4 alkyl, trifluoromethyl and C _{1 -4-} alkoxy.

In more preferred compounds of formula (XIII),

P is selected from a substituent of formula (II);

K ¹ is 2-methoxy-5-methylphenyl;

K ² means hydrogen;

and mean hydrogen;

K ³ means a group selected from:

To ⁴ , each independently, is selected from:

(a) hydrogen or (b) methyl;

To ²⁵ , each independently, is selected from:

(a) hydrogen; or (b) methyl.

Preferred compounds are: ^ (7- {methyl [3- (methylamino) propyl] amino} -1-benzofuran-5-yl) benzenesulfonamide hydrochloride, No. (7-piperidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide ,

4-fluoro-L- (7-piperidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide,

3.4-dimethoxy-L- (7-piperidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride,

3.4- dimethoxy-L- (7-pyrrolidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide, ^ (7-pyrrolidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide, 4-fluoro-L - (7-pyrrolidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride, 4-fluoro-L- (7-morpholin-4-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride, ^ (7-morpholin -4-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride,

3.4- dimethoxy-L- (7-morpholin-4-yl-1-benzofuran-5-yl) benzenesulfonamide, 2-methoxy-5-methyl-L- (7-pyridin-4-yl-1-benzofuran-5- il) benzenesulfonamide, No. (7-pyridin-3-yl-1-benzofuran-5-yl) benzenesulfonamide trifluoroacetate,

2-methoxy-5-methyl-L- (7-pyridin-3-yl-1-benzofuran-5-yl) benzenesulfonamide trifluoroacetate, ^ (7-pyrazin-2-yl-1-benzofuran-5-yl) benzene sulfonamide trifluoroacetate, No. (7-pyrimidin-5-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride and

- 20 010298

W [7- (1-azabicyclo [2.2.2] oct-2-en-3-yl) benzofuran-5-yl] -2-methoxy-5-methylbenzenesulfonamide hydrochloride,

2- [4- (5 - {[(2-chlorophenyl) sulfonyl] amino} -1-benzofuran-7-yl) piperazin-1-yl] -Ν, Ν-diethylacetamide hydrochloride, ^ Shdiethyl-2- [4- ( 5- {[(2-methoxy-5-methylphenyl) sulfonyl] amino} -1-benzofuran-7-yl) piperazin-1yl] acetamide hydrochloride,

Ш [7- (1-azabicyclo [2.2.2] oct-3-yloxy) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride,

N- [7- (1-azabicyclo [2.2.2] oct-3-yloxy) -1-benzofuran-5-yl] -2-chlorobenzenesulfonamide hydrochloride,

N- [7- (1-azabicyclo [2.2.2] oct-3-yloxy) -1-benzofuran-5-yl] -2-methoxy-5-benzenesulfonamide hydrochloride,

W {7 - [(2-morpholin-4-yl-ethyl) amino] -1-benzofuran-5-yl} -benzenesulfonamide hydrochloride,

2-methoxy-5-methyl-Y- {7 - [(2-morpholin-4-yl-ethyl) amino] -1-benzofuran-5-yl} -benzenesulfonamide hydrochloride, No. {7 - [(2-morpholin-4-yl-ethyl) amino] -1-benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide hydrochloride,

2,6-dichloro-Y- {7 - [(2-morpholin-4-yl-ethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride, No. (7 - {[2- (dimethylamino) ethyl] amino} - 1-benzofuran-5-yl) -2-methoxy-5-benzenesulfonamide hydrochloride,

2-chloro-Y- (7- {2- (dimethylamino)} - 1-benzofuran-5-yl) benzenesulfonamide hydrochloride,

Ш [7- (pyridin-4-ylamino) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride,

2-chloro-Y- [7- (pyridin-4-ylamino) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride,

2-methoxy-5-methyl-Y- [7- (pyridin-4-ylamino) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride,

2-methoxy-5-methyl-Y- [7- (piperazin-1-ylcarbonyl) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride,

2-methoxy-5-methyl-Y- [7- (piperazin-1-ylmethyl) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride, No. {7 - [(3-aminopyrrolidin-1-yl) methyl] -1- benzofuran-5-yl} -2-methoxy-5-methylbenzenesulfonamide hydrochloride,

Ш [7- (6,6-dioxohexahydrothieno [3,4-b] pyrazin-1- (2H) -yl) -1-benzofuran-5-yl] -2-methoxy-5methylbenzenesulfonamide hydrochloride,

W [7- (6,6-dioxohexahydrothieno [3,4-b] pyrazin-1- (2H) -yl) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride,

W {7 - [(2-pyrrolidin-1-ethylethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride,

2- methoxy-5-methyl-Y- {7 - [(2-pyrrolidin-1-yl-ethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride,

W {7 - [(2-pyrrolidin-1-yl-ethyl) amino] -1-benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide hydrochloride,

3- chloro-4-methyl-Y- {7 - [(2-pyrrolidin-1-ethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride,

2- methoxy-5-methyl-Y- {7 - [(3-morpholin-4-ylpropyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride, No. {7 - [(3-morpholin-4-ylpropyl) amino] -1-benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide hydrochloride,

3- chloro-4-methyl-Y- {7 - [(3-morpholin-4-ylpropyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride,

M- [7 - ({[(2K) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride,

M- [7 - ({[(2K) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -2-methoxy-5methylbenzenesulfonamide hydrochloride,

M- [7 - ({[(2K) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -2- (trifluoromethyl) benzenesulfonamide hydrochloride,

Ν- [7 - ({[(2K) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -3-methylbenzenesulfonamide hydrochloride, No. [7 - ({[(2K) -1 ethyl pyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] thiophen-2-sulfonamide hydrochloride,

5-chloro-Y- [7 - ({[((2K) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] thiophen-2-sulfonamide hydrochloride,

5-chloro-Y- [7 - ({[((2K) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -1,3-dimethyl-1Npyrazol-4-sulfonamide hydrochloride,

Ν- (7- {[3 - (2-methylpiperidin-1-yl) propyl] amino} -1-benzofuran-5-yl) benzenesulfonamide hydrochloride,

- 21 010298

2-methoxy-5-methyl-N- (7 - {[3- (2-methylpiperidin-1-yl) propyl] amino} -1-benzofuran-5-yl) benzenesulfonamide hydrochloride,

Ν- (7- {[3 - (2-methylpiperidin-1-yl) propyl] amino} -1-benzofuran-5-yl) -2- (trifluoromethyl) benzenesulfonamide hydrochloride,

5-chloro-1,3-dimethyl-N- (7 - {[3- (2-methylpiperidin-1-yl) propyl] amino} -1-benzofuran-5-yl) -1 Npyrazol-4-sulfonamide hydrochloride,

N- [7- (6-aminopyridin-3-yl) -1-benzofuran-5-yl] -2-methoxy-5-methylbenzenesulfonamide,

Ν- {7- [4- (cyclopropylmethyl) piperazin-1-yl] -1-benzofuran-5-yl} -2-methoxy-5-methylbenzenesulfonamide hydrochloride,

2-methoxy-5-methyl-N- {7- [4- (3,3,3-trifluoropropyl) piperazin-1-yl] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride,

2-methoxy-5-methyl-N- {7- [3- (trifluoromethyl) piperazin-1-yl] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride,

N- [7- (aminopiperidin-1-yl) -1-benzofuran-5-yl] -2- (trifluoromethyl) benzenesulfonamide hydrochloride,

N- [7- (aminopiperidin-1-yl) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride,

N- [7- (aminopiperidin-1-yl) -1-benzofuran-5-yl] -2-chlorobenzenesulfonamide hydrochloride,

N- [7- (aminopiperidin-1-yl) -1-benzofuran-5-yl] -2-methoxy-5-methylbenzenesulfonamide hydrochloride,

N- (7 - {[cis-3-fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl) -2-methoxy-5-methylbenzenesulfonamide hydrochloride,

N- (7 - {[trans-3-fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl) -2-methoxy-5-methylbenzenesulfonamide hydrochloride,

N- (7 - {[cis-3-fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl) -2- (trifluoromethyl) benzenesulfonamide hydrochloride,

N- (7 - {[trans-3-fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl) -2- (trifluoromethyl) benzenesulfonamide hydrochloride,

2-chloro-N- (7 - {[trans-3-fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl) benzenesulfonamide hydrochloride,

N- (7 - {[trans-3-fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl) -3-methylbenzenesulfonamide hydrochloride,

3, b-dichloro-N- (7 - {[trans-3-fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl) -2-methylbenzenesulfonamide hydrochloride,

2-chloro-5-fluoro-N- (7 - {[trans-3-fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl) benzenesulfonamide hydrochloride,

N- (2-methoxy-5-methylphenyl) -7 - [(3-methylpiperazin-1-yl) methyl] -1-benzofuran-5-sulfonamide hydrochloride,

N- (2-methylphenyl) -7- (piperazin-1-ylmethyl) -1-benzofuran-5-sulfonamide trifluoroacetate,

7 - [(3,5-dimethylpiperazin-1-yl) methyl] -N- (2-methylphenyl) -1-benzofuran-5-sulfonamide trifluoroacetate,

N- (2-methylphenyl) -7 - [(3-methylpiperazin-1-yl) methyl] - 1-benzofuran-5-sulfonamide trifluoroacetate, 7- (1,4-diazepan-1-ylmethyl) -N- (2- methylphenyl) -1-benzofuran-5-sulfonamide trifluoroacetate, 7 - {(trans-2,5-dimethylpiperazin-1-yl) methyl} -N- (2-methylphenyl) -1-benzofuran-5-sulfonamide trifluoroacetate,

N- (2-methylphenyl) -7 - {[((2Κ) -2-methylpiperazin-1-yl] methyl} -1-benzofuran-5-sulfonamide trifluoroacetate,

N- (2-methoxy-5-methylphenyl) -7 - [(3-methylpiperazin-1-yl) methyl] -1-benzofuran-5-sulfonamide trifluoroacetate,

7- (1,4-diazepan-1-ylmethyl) -N- (2-methoxy-5-methylphenyl) -1-benzofuran-5-sulfonamide trifluoroacetate,

N- (2-methoxy-5-methylphenyl) -7- (piperazin-1-ylmethyl) -1-benzofuran-5-sulfonamide trifluoroacetate, 7 - {(cis-3,5-dimethylpiperazin-1-yl) methyl} -N - (2-methoxy-5-methylphenyl) -1-benzofuran-5-sulfonamide trifluoroacetate,

7 - {[trans-2,5-dimethylpiperazin-1-yl] methyl} -N- (2-methoxy-5-methylphenyl) -1-benzofuran-5-sulfonamide trifluoroacetate,

7 - [(18.48) -2,5-diazabicyclo [2.2.1] hept-2-ylmethyl] -N- (2-methoxy-5-methylphenyl) -1-benzofuran-5sulfonamide trifluoroacetate,

N- (2-methoxy-5-methylphenyl) -7 - [(2-methylpiperazin-1-yl) methyl] -1-benzofuran-5-sulfonamide trifluoroacetate,

2-chloro-H- [7- (piperazin-1-methylmethyl) -1-benzofuran-5-yl] benzenesulfonamide dihydrochloride,

2-methyl-N- [7- (piperazin-1-ylmethyl) -1-benzofuran-5-yl] benzenesulfonamide dihydrochloride,

Ν- [7- (piperazin-1-ylmethyl) -1-benzofuran-5-yl] thiophen-2-sulfonamide dihydrochloride,

- 22 010298

2-χΛορ-Ν- [7- (1,4-diazepan-1-methyl) -1-benzofuran-5-yl] benzenesulfonamide dihydrochloride,

M- [7- (1,4-diazepan-1-ylmethyl) -1-benzofuran-5-yl] -2-methylbenzenesulfonamide dihydrochloride, No. [7- (1,4-diazepan-1-ylmethyl) -1-benzofuran- 5-yl] thiophen-2-sulfonamide dihydrochloride,

2-methoxy-5-methyl-No. {7 - [(2-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide dihydrochloride,

2-methyl-No. {7 - [(2-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide dihydrochloride,

2,5-dichloro-No. {7 - [(2-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} thiophen-3-sulfonamide dihydrochloride,

2-methoxy-5-methyl-No. {7 - [(3-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide dihydrochloride,

Ν- {7 - [(3-methylpiperazin-1-yl) methyl] - 1-benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide dihydrochloride,

2-chloro-No. {7 - [(3-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide dihydrochloride, No. {7 - [(18,48) -2,5-diazabicyclo [2, 2,1] hept-2-ylmethyl] -1-benzofuran-5-yl} -2-methoxy-5-methylbenzenesulfonamide dihydrochloride, No. {7 - [(18.48) -2,5-diazabicyclo [2.2.1 ] hept-2-ylmethyl] -1-benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide dihydrochloride, No. {7 - [(18,48) -2,5-diazabicyclo [2.2.1] hept-2 -ylmethyl] -1-benzofuran-5-yl} -2-methylbenzenesulfonamide dihydrochloride,

2-methoxy-5-methyl-No. {7 - [(trans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide bistrifluoroacetate,

2-methyl-No. {7 - [(trans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide bistrifluoroacetate,

2-chloro-No. {7 - [(trans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide bistrifluoroacetate,

- ({5 - [(2-methoxy-5-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) piperazine trifluoroacetate,

1- {[5- (phenylsulfonyl) -1-benzofuran-7-yl] methyl} piperazine trifluoroacetate,

- ({5 - [(4-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) piperazine trifluoroacetate,

- ({5 - [(2-methoxy-5-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) -1,4-diazepantrifluoroacetate,

1- {[5- (phenylsulfonyl) -1-benzofuran-7-yl] methyl} -1,4-diazepantrifluoroacetate,

- ({5 - [(4-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) -1,4-diazepantrifluoroacetate,

- ({5 - [(2-methoxy-5-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) -2-methylpiperazine trifluoroacetate,

- ({5 - [(2-methoxy-5-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) -3-methylpiperazine trifluoacetate, No. (2-methylphenyl) -7 - {[(3K) -pyrrolidine- 3-ylamino] methyl} -1-benzofuran-5-sulfonamide trifluoroacetate, No. (2-methylphenyl) -7- (piperidin-4-ylmethyl) -1-benzofuran-5-sulfonamide trifluoroacetate, No. (2-methylphenyl) -7- ( pyrrolidin-3-ylmethyl) -1-benzofuran-5-sulfonamide trifluoroacetate, No. (2-methylphenyl) -7- (piperidin-3-ylmethyl) -1-benzofuran-5-sulfonamide trifluoroacetate,

2- methoxy-5-methyl-No. [7- (piperidin-4-ylmethyl) -1-benzofuran-5-yl] benzenesulfonamide trifluoroacetate,

- ({5 - [(4-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) pyrrolidine trifluoroacetate,

2-methoxy-5-methyl-No. [5- (piperidin-4-ylmethyl) -1-benzofuran-7-yl] benzenesulfonamide trifluoacetate,

2-methoxy-5-methyl-No. {5 - [(3-methylpiperazin-1-yl) methyl] -1-benzofuran-7-yl} benzenesulfonamide bistrifluoroacetate,

2-methoxy-5-methyl-No. [5- (piperidin-4-ylmethyl) -1-benzofuran-7-yl] benzenesulfonamide trifluoroacetate.

Another object of the present invention is a method for producing the above compounds, comprising the following stages:

(a) halogenating 4-nitrophenol to obtain a dihalogenated 4-nitrophenol; (b) cyclizing the dihalogenated 4-nitrophenol using trimethylsilylacetylene to obtain halogenated nitrobenzofuran; nitrobenzofuran to obtain a BOC-protected amino-substituted nitrobenzofuran, (f) reduction of a BOC-protected amino-substituted nitrobenzofuran to obtain

- 23 010298 protected aminosubstituted aminobenzofuran, (ί) binding halogenated nitrobenzofuran with tributilstannilgeterotsiklicheskim, tributilstannilgeteroarilnym compound or heteroarylboronic acid or ester heteroarylboronic acid to give heterocycle-substituted or heteroaryl-nitrobenzofuran, (d) reducing the heterocycle-substituted or aryl-substituted nitrobenzofuran to obtain heterocycle-substituted or heteroaryl-aminobenzofuran ( 1) arylsulfonylation of heterocytes lzameschennogo or heteroaryl-aminobenzofuran to give a heterocycle-substituted or heteroaryl-arilsulfonilaminobenzofurana, (ί) arilsulfonilirovanie BOC-protected amino-substituted aminobenzofuran to give the BOC-protected amino-substituted arilsulfonilaminobenzofurana, (ί) removing the BOC-protecting group from the BOC-protected amino-substituted arilsulfonilaminobenzofurana, (k) benzylation of the BOC-protected amino-substituted aminobenzofuran to obtain a BOC-protected amino-substituted benzylamine benzofuran, (l) removal of the BOC-protecting group from the BOC-protected benzene-aminobenzofuran, (t) benzoylation of the BOC-protected amino-substituted aminobenzofuran to obtain a BOC-protected amino-substituted benzoylaminobenzofuran, (p) removal of the BOC-protecting group from BOC-protected benzene-aminosin o) reacting the BOC-protected amino-substituted aminobenzofuran with an arylisocyanate to produce a BOC-protected amino-substituted phenylaminocarbonylaminobenzofuran, and (p) removing the BOC-protecting groups from the BOC-protected amino-substituted phenylaminocarbonylaminobenzofuran.

Additional synthesis steps for preparing the compounds of the present invention are shown in Schemes 7-14.

Another object of the present invention is the use of the above compounds in therapy, in particular for the treatment or prevention of disorders associated with the 5-HT ₆ receptor, to achieve weight loss and weight gain.

Another object of the present invention is a pharmaceutical composition containing the above compound as an active ingredient, in combination with a pharmaceutically acceptable diluent or carrier, in particular for the treatment or prevention of disorders associated with the 5-HT6 receptor, to achieve weight loss and increase in weight.

Another object of the present invention is a method of treating a person or animal suffering from a disorder associated with the 5-HT ₆ receptor, to achieve weight loss and weight gain. The method may include administering to a subject (eg, a human or animal, dog, cat, horse, cow) the necessary effective amount of one or more compounds of any of the formulas indicated herein, their salts, or compositions containing these compounds or salts.

The methods described may also include the step of identifying that the subject needs to treat a disorder associated with the 5-HT ₆ receptor to achieve weight loss and weight gain. The identification of a subject in need of such treatment can be carried out by deciding the subject or professional health care, and it can be subjective (for example, a specialist’s opinion) or objective (for example, determined using testing or a diagnostic method).

Another object of the present invention is a method of treating or preventing a disorder associated with a 5-HT ₆ receptor in order to achieve weight loss and weight gain, comprising administering to a subject in need of such treatment an effective amount of the above compound.

Another object of the present invention is a method of modulating (for example, inhibiting or stimulating) the activity of a 5-HT ₆ receptor, comprising administering to a subject in need of such treatment an effective amount of the above compound.

Another object of the present invention is the use of the aforementioned compounds for the manufacture of a medicament for use in the prophylaxis or treatment of a disorder associated with the 5-HT ₆ receptor, in order to achieve a reduction in body weight and weight gain.

The above compounds may be agonists, partial agonists or antagonists of the 5HT ₆ receptor. Preferably, the compounds act as partial agonists or antagonists of the 5HT6 receptor.

Another object of the present invention is a cosmetic composition containing the above compound as an active ingredient in combination with a cosmetically acceptable diluent or carrier, in particular for use in the prevention or treatment of disorders associated with the 5-HT ₆ receptor, to achieve weight loss and weight gain.

Examples of disorders associated with the 5-HT ₆ receptor are obesity; type II diabetes; naru

- 24 010298 diseases of the central nervous system, such as fear, depression, panic attacks, memory impairment, cognitive impairment, epilepsy, sleep disturbances, migraines, anorexia, bulimia, eating disorders after a plentiful table, obsessive-compulsive disorders, psychoses, Alzheimer's disease , Parkinson’s disease, Huntington’s chorea, schizophrenia, attention deficit hyperactive disorder (ΑΌΗΌ), drug discontinuation, neurodegenerative diseases characterized by slower neural growth, and pain.

The compounds and compositions are useful in treating disorders in order to achieve weight loss and weight gain. Disorders include obesity; type II diabetes; disorders of the central nervous system, such as fear, depression, panic attacks, memory impairment, cognitive impairment, epilepsy, sleep disturbances, migraine, anorexia, bulimia, eating disorders after a plentiful table, obsessive-compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease , Huntington's chorea, schizophrenia, attention deficit hyperactive disorder (ΑΌΗΌ), drug discontinuation, neurodegenerative diseases characterized by a slowdown in neural growth, and pain. In one aspect, the invention relates to a method for treating or preventing the aforementioned disease, comprising administering to a subject in need of such treatment an effective amount of a compound or composition described in this context.

Definitions of terms

The following definitions of terms are used throughout the description of the invention and the attached claims.

Unless otherwise specified or indicated, the term "C _{] -6} alkyl" means a linear or branched alkyl group containing 1-6 carbon atoms. Examples of the above C _1-6 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, linear and branched pentyl, and hexyl. With regard to parts of the range of meanings of the term “C _1-6 alkyl”, all its subgroups are considered, such as C _1-5 alkyl, C _1-4 alkyl, C _1-3 alkyl, C _1-2 alkyl, C _{2 -6} alkyl, C _2-5 alkyl, C _2-4 alkyl, C _2-3 alkyl, C _3-6 alkyl, C _4-5 alkyl, etc. The term “halo-C _1-6 alkyl” means a C _1-6 alkyl group substituted with one or more halogen atoms. Examples of the above halo-C _1-6 alkyl include 2-fluoroethyl, fluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl. Similarly, the term "aryl-C _1-6 -alkyl" oznachaetS _1-6 alkyl group substituted by one or more aryl groups.

Unless otherwise specified or indicated, the term “hydroxy-C _1-6 -alkyl” means a linear or branched alkyl group, the hydrogen atom of which is substituted by OH. Examples of the above hydroxy-C _1-6 alkyl include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl and 2hydroxy-2-methylpropyl.

Unless otherwise specified or indicated, the term “C1-6 alkoxy” means a linear or branched alkoxy group containing 1-6 carbon atoms. Examples of the above C _1-6 alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, linear and branched pentoxy and hexoxy. With respect to parts of the range of meanings of the term “C _1-6 alkoxy”, all subgroups thereof are considered, such as C _1-5 alkoxy, C _1-4 alkoxy, C _1-3 alkoxy, C _1-2 alkoxy, C _2-6 alkoxy, C _2-5 alkoxy, C _2-4 alkoxy, C _2-3 alkoxy, C _3-6 alkoxy, C _4-5 alkoxy, etc.

Unless otherwise specified or indicated, the term “C1-6 alkoxy-C1-6 alkyl” means a linear or branched alkoxy group containing 1-6 carbon atoms attached to an alkyl group containing 1-6 carbon atoms. Examples of the above C _1-6 alkoxy C _1-6 alkyl include methoxymethyl, ethoxymethyl, isopropoxymethyl, n-butoxymethyl, tert-butoxymethyl and linear and branched pentoxymethyl. With regard to parts of the range of meanings of the term “C _1-6 alkoxy-C _1-6 alkyl”, all subgroups thereof are considered, such as C _1-5 alkoxy-C _1-6 alkyl, C _1-4 alkoxy-C _1-6 -alkyl, C _1-3 -alkoxy-C _1-6 -alkyl, C _1-2 -alkoxy-C _1-6 -alkyl, C _2-6 -alkoxy-C _1-6 -alkyl, C _{2 -5} -alkoxy-C _{1- 6} -alkyl, C _2-4 -alkoxy-C _1-6 -alkyl, C _2-3 -alkoxy-C _1-6 -alkyl, C _3-6 -alkoxy-C _{1- 6} -alkyl, C _4-5 ^- alkoxy-C _1-6 -alkyl, C _1-6 -alkoxy-C _1-5 -alkyl, C _1-6 -alkoxy-C _1-4 -alkyl etc.

Unless otherwise specified or indicated, the term “C _2-6 alkenyl” means a linear or branched alkenyl group containing 2-6 carbon atoms. Examples of the above C2-6 alkenyl include vinyl, allyl, 2,3-dimethylallyl, 1-butenyl, 1-pentenyl and 1-hexenyl. With regard to parts of the range of meanings of the term “C2-6 alkenyl”, all its subgroups are considered, such as C2-5 alkenyl, C _2-4 alkenyl, C _2-3 alkenyl, C _3-6 alkenyl, C _4-5 alkenyl etc. Similarly, the term “aryl C2-6 alkenyl” means a C2-6 alkenyl group substituted with one or more aryl groups. Examples of the above aryl-C2-6-alkenyl include styryl and cinnamyl.

The term “oxo group” means

Unless otherwise stated or indicated, the term “C2-6 alkynyl” means a linear or branched alkynyl group containing 2-6 carbon atoms. Examples of the above C2-6 alkynyl include ethynyl, 1-propynyl, 1-butynyl and 1-hexynyl. For parts of the range

- 25 010298 meanings of the term “C _2-6 alkynyl” consider all its subgroups, such as C _2-5 alkynyl, C _2-4 alkynyl, C _2-3 alkynyl, C _3-6 alkynyl, C _{4- 5-} alkynyl, etc.

Unless otherwise specified or indicated, the term "C _3- 7 cycloalkyl" means a cyclic alkyl group containing 3-7 carbon atoms in the ring. Examples of the above cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl and cyclopentyl. With respect to the range of values of portions of the term "C _3- 7 cycloalkyl" treat all subgroup thereof, such as C _3-6 -cycloalkyl, C _3-5 -cycloalkyl, C _3-4 -cycloalkyl, C _4-7 -cycloalkyl, C _4-6 cycloalkyl, C _4-5 cycloalkyl, C _5-7 cycloalkyl, C _6-7 cycloalkyl, etc.

Unless otherwise stated or indicated, the term “aryl” refers to a hydrocarbon ring system having at least one aromatic ring. Examples of aryl are phenyl, indenyl, indanyl, 1,2,3,4-tetrahydronaphthyl, 1-naphthyl, 2-naphthyl and fluorenyl.

Similarly, the term “aryloxy” refers to an aryl group bonded to an oxygen atom.

The term “heteroaryl” refers to a mono- or bicyclic aromatic ring system, with only one ring being aromatic and the above heteroaryl radical can be linked to the rest of the molecule via a carbon or nitrogen atom in any ring containing 5-10 atoms (mono- or a bicyclic) ring, wherein one or more ring atoms are other than carbon, such as nitrogen, sulfur, oxygen and selenium. Examples of such heteroaryl rings include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, chromanyl, quinazolinyl, indolinyl, isoindino, isoindino, isoindino, , 2,3-dihydrobenzofuranyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, benzodioxolyl, benzodioxinyl, ben otienilnye, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl and 2,1,3-benzoxadiazolyl group. If the bicyclic heteroaryl is substituted, then it can be substituted at any position of the rings.

Unless otherwise specified or indicated, the term “heterocyclyl” refers to a non-aromatic (ie, partially or fully saturated) mono- or bicyclic ring system containing 4-10 atoms in a ring with at least one heteroatom, such as O, Ν or 8, and the remaining atoms in the ring are carbon. Examples of heterocyclic groups include piperidyl, tetrahydropyranyl, tetrahydrofuranyl, azepinyl, azetidinyl, pyrrolidinyl, morpholinyl, imidazolinyl, thiomorpholinyl, pyranyl, dioxanyl, piperazinyl, octahydrofuro [3,4-azibi-2,6-azyl-pyrazinyl] 2, 2, 2-azinyl-pyrazinyl] 2, 2-azinyl-2-azibi-2,6-azlycylobenzyl-2,6-azyl-pyridinyl] 2-en-3-yl groups. When present, the sulfur atom may be in oxidized form (i.e., 8 = 0 or 0 = 8 = 0). Examples of heterocyclic groups containing a sulfur atom in an oxidized form include octahydrothieno [3,4-b] pyrazin-6,6-dioxide and thiomorpholine-1,1-dioxide.

Unless otherwise specified or indicated, the term “halogen” means fluoro, chloro, bromo or iodo.

The term “-8 (0) _x ” in formula (IV), where x is 0, 1 or 2, has the meaning as illustrated by formulas (1X) - (X1)

FE (X) (XI)

The term “leaving group” refers to a group that must be cleaved from the molecule during the nucleophilic substitution reaction. Examples of leaving groups are iodide, bromide, chloride, methanesulfonate, hydroxy, methoxy, thiomethoxy, tosyl or their suitable protonated forms (e.g., H ₂ O, MeOH), especially bromide and methanesulfonate.

The term “optional” or “optional” means that a case or circumstance subsequently described may take place, but does not occur unnecessarily, and that the description includes examples where such a case or circumstance takes place, and examples in which this does not occur.

The term "pharmaceutically acceptable" means the suitability for obtaining a pharmaceutical composition, that is, as a rule, safe, non-toxic and neither biologically nor otherwise undesirable, and includes suitability for veterinary use, as well as for pharmaceutical use.

The term "treatment", as used here, includes the prevention of the aforementioned violation or condition, or reducing the intensity or elimination of the once established violation.

The term "effective amount" refers to the amount of a compound that provides a therapeutic effect in the subject being treated. The therapeutic effect can be objective (that is, determined using any test or marker) or subjective (that is, the subject discovers a sign of the effect or feels it).

- 26 010298

The term "prodrug forms" means a pharmacologically acceptable derivative, such as an ester or amide, which is biotransformed in the body into the form of an active drug. The reference is made to Sooytai and Sytai'k, Thieu Ryagtasoododsa1 Baak οί Tyegareiysk, 8th ed., Ms-Sga ^ -NSh, Y11. Her., 1992, Vu1gai8 £ ogta1uui o £ Igidk, ss. 13-15; and Thie Ogdashs SyetShgu o £ Aegis Ie81di apy Aegid Asyop. Shsyagy V., 8Shegtap., Chapter 8, p. 352. (Asayetu Rgekk, Sch., 1992, ΚΒΝ 0-12643730-0).

The following abbreviations are used:

VSAR means 2,2'-bis (diphenylphosphino) -1,1-binaphthyl,

BOC means tert-butyloxycarbonyl,

CV means coefficient of variation,

ISM means dichloromethane,

IME means 1,2-dimethoxyethane,

IM8O (DMSO) means dimethyl sulfoxide,

EITL (EDTA) means ethylenediaminetetraacetic acid,

JUN means ethanol,

ESAc means ethyl acetate,

ECTA means ethylenebis (hydroxyethylene nitrile) tetraacetic acid,

HEPE8 (HEPES) means 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid,

HPLC (HPLC) means high performance liquid chromatography,

L8I means lysergic acid diethylamide,

MeCN means acetonitrile,

8PA means scintillation proximal analysis,

1-ViOK means potassium tert-butylate,

TEM means triethylamine,

TEA (TFA) means trifluoroacetic acid,

TUE (THF) means tetrahydrofuran, and

Hai1ryo§ (xanthos) means 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene.

All possible isomeric forms (pure enantiomers, diastereomers, tautomers, racemic mixtures and unequal mixtures of two enantiomers) of the described compounds are included in the scope of this invention. Such compounds may also be in cis or trans, in the E or Ζ isomeric forms at the double bond. All isomeric forms are considered.

The compounds of formula (I) can be used as such or, respectively, in the form of their pharmacologically acceptable salts (acid addition salts or bases). The above pharmacologically acceptable addition salts are meant to include therapeutically active non-toxic addition salts and bases which the compounds are capable of forming. Compounds that have basic properties can be converted into their pharmaceutically acceptable acid addition salts by treating the base form with a suitable acid. Examples of acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, , succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamic acid, benzoic acid, ascorbic acid etc. Examples of base addition salt forms are sodium, potassium, calcium salts, and salts of pharmaceutically acceptable amines, such as, for example, ammonia, alkylamines, benzathine, and amino acids, such as, for example, arginine and lysine.

For example, sulfonamide derivatives of formula (I), where P is selected from substituents of formulas (II) and (III) and where K ² is hydrogen, can be converted to their corresponding potassium, sodium or calcium salts, or salts of other alkali metals or alkali land metals. The term “addition salt”, as used here, also includes solvates that are capable of forming compounds and their salts, such as, for example, hydrates, alcoholates, and the like.

For clinical use, pharmaceutical compositions for oral, rectal, parenteral administration or other route of administration are prepared from the compounds of this invention. Pharmaceutical compositions are usually prepared by mixing the active substance or its pharmaceutically acceptable salt with standard pharmaceutical excipients. Examples of excipients are water, gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silicon dioxide, and the like. Such compositions may also contain other pharmacologically active agents and standard additives, such as stabilizers, wetting agents, emulsifiers, flavors, buffers, and the like. Typically, the amount of active compounds is 0.1-95 wt.%, Based on the weight of the drug, preferably 0.2-20 wt.%, In preparations for parenteral use

- 27 010298 and more preferably 1-50 wt.% In preparations for oral administration.

The pharmaceutical compositions can further be prepared by known methods, such as granulation, compression, microencapsulation, spray coating, etc. Compositions can be obtained by standard methods in the form of such a dosage form as tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections. Liquid pharmaceutical compositions can be prepared by dissolving or suspending the active substance in water or another suitable solvent. Tablets and granules can be coated according to standard procedures.

In a further aspect, this invention relates to methods for producing compounds of any of the formulas specified herein, comprising reacting any one or more compounds of the formulas described herein, including any of the methods described herein. Compounds of the above formula (Ι) can be prepared by standard methods or by analogy with standard methods.

The above methods can be carried out to obtain the compounds according to this invention in the form of a free base or in the form of an acid addition salt. A pharmaceutically acceptable acid addition salt may be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with standard procedures for preparing acid addition salts from basic compounds. Examples of forming acid addition salts are indicated above.

The compounds of formula (Ι) can have one or more chiral carbon atoms and, therefore, can be obtained in the form of optical isomers, for example, as a pure enantiomer or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers. The separation of mixtures of optical isomers to obtain pure enantiomers is well known in the art and can, for example, be achieved by fractional crystallization of salts with optically active (chiral) acids or by chromatographic separation on chiral columns.

The chemicals used in the syntheses described herein may include, for example, solvents, reagents, catalysts and reagents to protect groups, and reagents to deprotect groups. The methods described above may also additionally include steps carried out either before or after the specific steps described herein, for attaching or removing suitable protecting groups in order to ultimately facilitate the synthesis of the compounds. In addition, the various stages of the synthesis can be performed in alternating sequence or in order to obtain the desired compounds. Chemical transformations in the synthesis and methodology for the protecting group (protecting and deprotecting) suitable for the synthesis of suitable compounds are known in the art and include, for example, those described by K. Lagosk, Sotrge Nezpš Ог Ogdasz TgaizGogtaGuiz, ed. USN (1989); TA. Sgeeie and R.S.M. AIgz, RGGesGke Sgoirz ίη Ogdashs 8uyGyezz, 3rd ed., 1st and APeu aib 8oiz (1999); B. Ezeg and M. Ezeg, Ezeg Aib Ezeg'z Keadei Gz Gog Oddash 8yuGyez1z, 1Oi APeu aib 8oiz (1994); and b. Raschepe, eds., Jesus Christ of the Fathers, Gog Ogdashs, 8th, 8th, 1th, and 6th, (1995), and its subsequent editions.

The necessary starting materials for the preparation of compounds of formula (I) are either known or can be prepared by analogy with the preparation of known compounds. The dosage level and dosage frequency of an individual compound varies depending on various factors, including the effectiveness of the individual compound used, metabolic stability and duration of action of this compound, patient age, body weight, general health, gender, diet, method and time of administration, excretion rate , a combination of drugs, the severity of the condition being treated and the therapy the patient is undergoing. The daily dose may, for example, range from about 0.001 mg to about 100 mg per kg of body weight, administered singly or in multiple doses, for example, from about 0.01 mg to about 25 mg each. Typically, such a dose is administered orally, but parenteral administration can also be chosen.

The invention will be further illustrated by the following non-limiting examples of protection.

The individual examples illustrated below are provided only as illustrative and not limiting the rest of the disclosure of the present invention in any direction whatsoever. Without further elaboration, it will become apparent to a person skilled in the art after considering the description given herein, or may be clarified by the full application of the present invention. All publications cited herein are hereby incorporated by reference in their entireties.

Methods ¹ H-Nuclear Magnetic Resonance (NMR) and ¹³ C-NMR are recorded on Vgikeg Αbνaise ERX 400, Vgikeg ECX 500, DEOI GHM-EX 270 spectrometers or on Wapai MEXICU p1iz, 400 MHz. All spectra are recorded using residual solvent or tetramethylsilane (TM8) as an internal standard. Spectra according to mass spectrometry (M8) with spray ionization are obtained on a Regkt-E1teg AP1 150EX mass spectrometer. Preparative HPLC with mass spectrometry (HPLC / M8) was performed using the AaGegs / Mugotazz R1aGGogt Ζρ system equipped with system A: column

- 28 010298

ACE 5 C8 (19x50 mm), or system B: X1egg M8 C18 column, 5 μm (19x50 mm). For subsequent HPLC systems, they also use: System C: Syzop / UMS Ar C18, 150x30 mm; system Ώ: Sysop Ethernet / column UMS OE8-AR, 5 μm (20x50 mm); system E: Supso! esI NRES-IU 8Υ8-2; Ace C8 column, 5 μm (21x50 mm); and the system E: Supso! esI NRS-TsU 8Υ8-2; Ace C8 column, 5 μm (30x150 mm). Eluents used for system A, C-E: MESA in Meyr water with 0.1% TFA. The eluents used for system B are: Meyr water, MESY and UN ₄ NSO ₃ (100 mm). Analytical HPLC was performed on an Adyep instrument! 1100, column ACE 3 C8 (system A) or column: ΥΜС ОЭ8-АР (system B) or column: SIgoto1iI C18 (50x4.6 mm) (system C); eluents: water M1Shr / 0.1% TFUK and MESA. Preparative flash chromatography was performed using silica gel Megsk 60 (230-400 mesh). Reactions carried out under controlled microwave energy are carried out in a Regzop1 SIETDGU8TiI SgeaUg microwave oven using 0.5-2 ml, 2-5 ml or 20 ml tubes for the Smith method, equipped with aluminum covers and partitions.

Table 1

Etc. R KZ one Ν- (7- {Methyl [3- (methylamino) propyl] amino} -1benzofuran-5-yl) benzenesulfonamide hydrochloride O- ^ O ΝΗ -one- ΝΗ / 2 Ν- (7-Piperidin-1-yl-1-benzofuran-5yl) benzenesulfonamide o o = x = o ΝΗ D- -4o 3 4-Φτορ-Ν- (7-piperidin-1-yl-1-benzofuran-5yl) benzenesulfonamide οψο ΝΗ --1- about

- 29 010298

4 3,4-Dimethoxy-Y- (7-piperidin-1-yl-1-benzofuran- 5-yl) benzenesulphonamide hydrochloride o ά ⁰ '0 = 1 = 0 ό 5 3,4-Dimethoxy-Y- (7-pyrrolidin-1-yl-1benzofuran-5-yl) benzenesulfonamide (A p ⁰ '0 = 1 = 0. one κι o b Ν- (7-Pyrrolidine ~ 1-yl-1-benzofuran-5yl) benzenesulfonamide about ΝΗ 7- ά 7 4-Fluoro-Ν- (7-pyrrolidin-1-yl-1-benzofuran-5yl) benzenesulfonamide hydrochloride o, -H-V_N N ό R 8 4-Φτορ-Ν- (7-morpholin-4-yl-1-benzofuran-5yl) benzenesulfonamide hydrochloride OAGO ^- O '- ό nine Ν- (7-Morpholin-4-yl-1-benzofuran-5- silt) benzenesulfonamide hydrochloride about n 0 10 3,4-Dimethoxy-Ν- (7-morpholin-4-yl-1-benzofuran- 5-yl) benzenesulfonamide o -4 \\ .ΝΗ o ^ | ό BUT, eleven Ν- (3,5-Dimethylbenzyl) -7-piperazin-1-yl-1benzofuran-5-amine hydrochloride Δα ό Η 12 Ν- (3,4-difluorobenzyl) -7-piperazin-1-yl-1benzofuran-5-amine hydrochloride 6 Η thirteen Ν- (3,5-Dimethoxybenzyl) -7-piperazin-1-yl-1benzofuran-5-amine hydrochloride Yes ό Η 14 Ν-Benzyl-7-piperazin-1-yl-1-benzofuran-5-amine hydrochloride Sic ό Η

- 30 010298

fifteen Ν- (7-piperazin-1-yl-1-benzofuran-5yl) benzamide hydrochloride 6 Η sixteen 4-Methoxy-y- (7-piperazin-1-yl-1-benzofuran-5yl) benzamide hydrochloride 0 ό Ν Η 17 2-Bromo-5-methoxy-Y- (7-piperazin-1-yl-1benzofuran-5-yl) benzamide hydrochloride 6 Η eighteen 3-Methyl-Ν- (7-piperazin-1-yl-1-benzofuran-5yl) benzamide hydrochloride 0 -4— ο Η nineteen Ν- (7-piperazin-1-yl-1-benzofuran-5-yl) -3- (trifluoromethyl) benzamide hydrochloride ο, Αλ 0 ’4” ο Ν Η twenty 2,4-Dichloro-Y- (7-piperazin-1-yl-1-benzofuran-5yl) benzamide hydrochloride C1 8 ό Η 21 3,5-Dimethoxy-Y- (7-piperazin-1-yl-1-benzofuran- 5-yl) benzamide hydrochloride 0 ο Η 22 Ν- (3,5-Dimethoxyphenyl) -Ν '- (7piperazin-1-yl-1-benzofuran-5-yl) urea hydrochloride \> ώ _Ν Α _Ν . \ n A 6 Η 23 Ν- (2,4-Dichlorophenyl) -Ν '- (7piperazin-1-yl-1-benzofuran-5-yl) urea hydrochloride α n n 6 Η 24 Ν- (2-Methoxyphenyl) -Ν '- (7-piperazin1-yl-1-benzofuran-5-yl) urea hydrochloride / 0  Η Ο Η 25 Ν-φθΗππ-Ν 'hydrochloride - (7-piperazin-1-yl-1 benzofuran-5-yl) urea 6 Η 26 Ν- (3-Fluorophenyl) -Ν '- (7-piperazin-1yl-1-benzofuran-5-yl) urea hydrochloride -4-ο Η 27 Ν- (7-piperazin-1-yl-1-benzofuran-5yl) -Ν '- [(trifluoromethyl) phenyl] urea hydrochloride Ε 6 Η 28 2-Methoxy-5-methyl-I- (7-pyridin-4-yl-1Rarr'ZGybh / gae pg’hlpigbgly d hyatl p - η, o = p ΙχΙΗ 6 Ν 29th Ν- (7-Pyridin-3-yl-1-benzofuran-5- il) benzenesulfonamide trifluoroacetate £ .G ό

- 31 010298

thirty 2-Methoxy-5-methyl-Y- (7-pyridin-3-yl-1- benzofuran-5-yl) benzenesulfonamide trifluoroacetate V "' ο = έ = ο 1 | N ό 31 Ν- (7-Pyrazin-2-yl-1-benzofuran-5yl) benzenesulfonamide trifluoroacetate V | ЧН fd 32 Ν- (7-Pyrimidin-5-yl-1-benzofuran-5yl) benzenesulfonamide hydrochloride 0 ΝΗ x 33 Ν- [7- (1-Azabicyclo [2.2.2] οκτ-2-en-Zyl) benzofuran-5-yl] -2-methoxy-5methylbenzenesulfonamide hydrochloride ΝΗ 34 2- [4- (5 - {[(2-Chlorophenyl) sulfonyl] amino} -1benzofuran-7-yl) piperazin-1-yl] -Ν, Ν diethylacetamide hydrochloride 0 Oh ^ | SU ABOUT N 35 Ν, Y-Diethyl-2- [4 - (5- {[(2-methoxy-5methylphenyl) sulfonyl] amino} -1-benzofuran-7yl) piperazin-1-yl] acetamide hydrochloride o -Ί-- \\, ΝΗ 0 *? 0 + -H ” ABOUT N 38 Ν- [7- (1-Azabicyclo [2.2.2] oct-3-yloxy) -1benzofuran-5-yl] benzenesulfonamide hydrochloride it-- Hmn b 39 Ν- [7- (1-Azabicyclo [2.2.2] oct-3-yloxy) -1benzofuran-5-yl] -2- chlorobenzenesulfonamide hydrochloride 0 -g_U ' ^NN (U 40 Ν- [7- (1-Azabicyclo [2.2.2] oct-3-yloxy) -1benzofuran-5-yl] -2-methoxy-5benzenesulfonamide hydrochloride Bw about ^t / 41 Ν- {7 - [(2-Morpholin-4-yl-ethyl) amino] -1-benzofuran- 5-yl} benzenesulfonamide hydrochloride it-- \\ mn of O Η N U h f 42 2-Methoxy-5-methyl-Y- {7 - [(2-morpholin-4 yl-ethyl) amino] -1-benzofuran-5yl} benzenesulfonamide hydrochloride Bw o / ΗΝ-U h f

- 32 010298

Ν— {7 - [(2-Morpholin-4-yl-ethyl) amino] -1-benzofuran-5-yl} -2 (trifluoromethyl) benzenesulfonamide hydrochloride

2,6-Dichloro-Ν- {7 - [(2-morpholin-4-yl ethyl) amino] -1benzofuran-5-yl} benzenesulfonamide hydrochloride

2-Methoxy-5-methyl-Y- [7- (2-morpholin-4-ylethoxy) 1-benzofuran-5-yl] benzenesulfonamide hydrochloride

6 3-Methyl-Ν- [7- (2-morpholin-4-yl-ethoxy) -1benzofuran-5-yl] benzenesulfonamide hydrochloride

3-Chloro-4-methyl-Ν- [7- (2-morpholin-4-ylethoxy) -1benzofuran-5-yl] benzenesulfonamide hydrochloride

Ν- (7— {[2- (Dimethylamino) ethyl] amino} -1benzofuran-5-yl) -2-methoxy-5benzenesulfonamide hydrochloride

2-Methoxy-5-methyl-M- [7- (piperazin-1ylcarbonyl) -1-benzofuran-5yl] benzenesulfonamide hydrochloride

2-Methoxy-5-methyl-Y- [7- (pyridin-4-ylamino) -1benzofuran-5-yl] benzenesulfonamide hydrochloride

- 33 010298

54 2-Methoxy-5-methyl-Y- [7- (piperazin-1-ylmethyl) -1benzofuran-5-yl] benzenesulfonamide hydrochloride about ¹ / Oh oh 55 Ν- {7 - [(3-Aminopyrrolidin-1-yl) methyl] -1benzofuran-5-yl} -2-methoxy-5- methylbenzenesulfonamide hydrochloride o --1- Α -ΝΗ ⁰ h ΝΗ ₂ 56 Ν- [7- (6,6-dioxohexahydrotieno [3,4- B] pyrazin-1- (2H) -yl) -1-benzofuran-5-yl] -2methoxy-5-methylbenzenesulfonamide hydrochloride , ΝΗ / M 57 Ν- [7- (6,6-dioxohexahydrotieno [3,4-b] pyrazin-1- (2Н) -yl) -1-benzofuran-5yl] benzenesulfonamide hydrochloride it-- \\ ^ ΝΗ ABOUT bh 58 N- {7 - [(2-Pyrrolidin-1-yl-ethyl) amino] -1benzofuran-5-yl} benzenesulfonamide hydrochloride about h \\, ΝΗ ъ f 59 2-Methoxy-5-methyl-Y- {7- [(2-pyrrolidin-1ylethyl) amino] -1-benzofuran-5yl} benzenesulfonamide hydrochloride about h- A-MI 60 Ν- {7 - [(2-Pyrrolidin-1-yl-ethyl) amino] -1benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide hydrochloride o Ch- Λ ' ^ΝΗ P 61 3-Chloro-4-methyl-Ν- {7- [(2-pyrrolidin-1-ethyl) amino] -1-benzofuran-5yl) benzenesulfonamide hydrochloride about. H- Α-ΝΗ ABOUT 62 2-Methoxy-5-methyl-Y- {7 - [(3-morpholin-4ylpropyl) amino] -1-benzofuran-5yl} benzenesulfonamide hydrochloride + ’1m do about 63 Ν- {7 - [(3-Morpholin-4-ylpropyl) amino] -1benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide hydrochloride D '™ p 64 Z-Chloro-4-methyl-Y- {7 - [(Z-morpholin-4ylpropyl) amino] -1-benzofuran-5tl π 1 (lsioppchch / pi. <+ »Gchi and kl 0. h ~ Α-ΝΗ o *! at / g * 65 Ν- [7- ({[(2B.) -1-Ethylpyrrolidin-2yl] methyl} amino) -1-benzofuran-5yl] benzenesulfonamide hydrochloride ABOUT \\, ΝΗ ъ h

- 34 010298

Ν- [7 - ({[(2B) -1-Ethylpyrrolidin-2yl] methyl} amino) -1-benzofuran-5-yl] -2-methoxy-5methylbenzenesulfonamide hydrochloride

yl] methyl} amino) -1-benzofuran-5-yl] thiophen-2sulfonamide hydrochloride

Ν- [7- ({[(2B.) -1-Ethylpyrrolidin-2-benzofuran-5-yl] -2Ν- [7 - ({[((2B) -1-Ethylpyrrolidin-2methyl} amino) -1-benzofuran -5-yl] -3Ν- [7- ({[((213) -1-Ethylpyrrolidin-2yl] methyl} amino) -1-benzofuran-5-yl] thiophen-2sulfonamide hydrochloride

5-Chloro-Y- [7 - ({[(2B.) - 1-ethylpyrrolidin-2yl] methyl} amino} -1-benzofuran-5-yl] -1,3-dimethyl1H-pyrazol-4-sulfonamide hydrochloride

Ν- (7 - {[3- (2-Methylpiperidin-1-yl) propyl] amino) benzofuran-5-yl) benzenesulfonamide hydrochloride

2-Methoxy-5-methyl-b- (7 - {[3- (2-methylpiperidin-1yl) propyl] amino} -1-benzofuran-5benzenesulfonamide hydrochloride

Ν- (7 - {[3- (2-Methylpiperidin-1-yl) propyl] amino} 1-benzofuran-5-yl) -2 (trifluoromethyl) benzenesulfonamide hydrochloride

5-Chloro-1, 3-dimethyl-Ν- (7 - {[3- (2-methylpiperidin1-yl) propyl] amino} -1-benzofuran-5-yl) -1Npyrazole-4-sulfonamide hydrochloride

Ν- [7- (6-Aminopyridin-3-yl) -1-benzofuran-5-yl] 2-methoxy-5-methylbenzenesulfonamide

Ν- {7- [4 - (Cyclopropylmethyl) piperazin-1-yl] -1benzofuran-5-yl} -2-methoxy-5methylbenzenesulfonamide hydrochloride

- 35 010298

78 2-Methoxy-5-methyl-Y- {7- [4- (3,3,3 trifluoropropyl) piperazin-1-yl] -1-benzofuran-5yl} benzenesulfonamide hydrochloride > ___, Oh Oh oh ^x '/ δ GTT R 79 2-Methoxy-5-methyl-Y- {7- [3- (trifluoromethyl) piperazin-1-yl] -1-benzofuran-5yl} benzenesulfonamide hydrochloride o Α ^ΝΗ Λ A. n ³ 80 Ν- [7- (Aminopiperidin-1-yl) -1-benzofuran-5-yl] - 2- (trifluoromethyl) benzenesulfonamide hydrochloride o chΛ ' ^ΝΗ R DD 2 81 Ν- [7- (Aminopiperidin-1-yl) -1-benzofuran-5yl] benzenesulfonamide hydrochloride o A, ΝΗ ⁰ X $ m Νπ _? 82 Ν- [7- (Aminopiperidin-1-yl) -1-benzofuran-5-yl] - 2-chlorobenzenesulfonamide hydrochloride θθ ^ ΝΗ δ _C | & 83 Ν- [7- (Aminopiperidin-1-yl) -1-benzofuran-5-yl] - 2-methoxy-5-methylbenzenesulfonamide hydrochloride 0¾ about ¹ / 84 Ν- (7- {[cis-Z-Fluoropiperidin-4-yl] oxy} -1benzofuran-5-yl) -2-methoxy-5methylbenzenesulfonamide hydrochloride B about ³ '/ about-\ N 85 Ν- (7- {[trans-3-Fluoropiperidin-4-yl] oxy} -1benzofuran-5-yl) -2-methoxy-5methylbenzenesulfonamide hydrochloride about CHU -ΝΗ OL & ⁴ Ν N 86 Ν- (7 - {[cis-Z-Fluoropiperidin-4-yl] oxy} -1benzofuran-5-yl) -2- (trifluoromethyl) benzenesulfonamide hydrochloride 0 h Α ^ΝΗ P 0 ^ o ^l , 0 ⁴ Ν N 87 Ν- (7 - {[trans-3-Fluoropiperidin-4-yl] oxy} -1benzofuran-5-yl) -2- (trifluoromethyl) benzenesulfonamide hydrochloride 0 W- 'Ο ^ΝΗ P 0- ^{> g} ΟΛ & n 88 2-Chloro-Y- (7 - {[trans-3-fluoropiperidin-4-yl] oxy} - 1-benzofuran-5-yl) benzenesulfonamide hydrochloride ____, about Od about OA N N 89 Ν- (7- {[trans-3-Fluoropiperidin-4-yl] oxy} -1benzofuran-5-yl) -3methylbenzenesulfonamide hydrochloride ΝΗ ° l OD to I T V n

- 36 010298

90 3, b-Dichloro-Ν- (7- {[trans-3-fluoropiperidin-4yl] oxy} -1-benzofuran-5-yl) -2 methylbenzenesulfonamide hydrochloride o-nHmm 0 * 1 Xt ol Η 91 2-Χπορ-5-φτορ-Ν- (7 - {[trans-Z-fluoropiperidin-4- silt] oxy} -1-benzofuran-5- silt) benzenesulfonamide hydrochloride ABOUT X xn 0 * 1, ιΧ οχ & Η 92 Ν- (2-Methoxy-5-methylphenyl) -7 - [(3methylpiperazin-1-yl) methyl] -1-benzofuran-5sulphonamide hydrochloride 'z'^{; o} ΗΝ 'Ό X ”- α 93 Ν- (2-Methylphenyl) -7- (piperazin-1-ylmethyl) -1benzofuran-5-sulfonamide trifluoroacetate II ό Ν 94 7 - [(3, 5-Dimethylpiperazin-1-yl) methyl] -Ν- (2 methylphenyl) -1-benzofuran-5sulfonamide trifluoroacetate 0 N 1 Α 95 Ν- (2-Methylphenyl) -7- [(3-methylpiperazin-1yl) methyl] -1-benzofuran-5sulfonamide trifluoroacetate π Ζ4, 0 Η 1 ι-5 ' 96 7- (1, 4-diazepan-1-ylmethyl) -Ν- (2-methylphenyl) -1benzofuran-5-sulfonamide trifluoroacetate , Н (¢ 4] 0 Н ¹ ό \ -Ν 97 7 - {(trans-2,5-dimethylpiperazin-1-yl) methyl} -Νί 2-methylphenyl) -1-benzofuran-5sulfonamide trifluoroacetate , ° ΐί ^ ι 0 Н ¹ Α 98 Ν- (2-Methylphenyl) -7- {[((2B.) -2-methylpiperazin-1yl] methyl} -1-benzofuran-5sulfonamide trifluoroacetate θ ' Η 99 Ν- (2-Methoxy-5-methylphenyl) -7 - [(3methylpiperazin-1-yl) methyl] -1-benzofuran-5sulfonamide trifluoroacetate 0 H 0. Ρ Η one hundred 7- (1,4-Diazepan-1-ylmethyl) -Ν- (2-methoxy-5methylphenyl) -1-benzofuran-5sulfonamide trifluoroacetate it. η Ν Η 101 Ν- (2-Methoxy-5-methylphenyl) -7- (piperazin-1ylmethyl) -1-benzofuran-5sulfonamide trifluoroacetate it. Α ό Ν Η 102 7 - {(cis-3,5-dimethylpiperazin-1-yl) methyl} -Ν- (2methoxy-5-methylphenyl) -1-benzofuran-5sulfonamide trifluoroacetate it. Λ Η

- 37 010298

103 7 - {[trans-2,5-dimethylpiperazin-1-yl] methyl) -Ν (2-methoxy-5-methylphenyl) -1-benzofuran-5sulfonamide trifluoroacetate 0 N SC Oh Υ1 N 104 7- (2,5-Diazabicyclo [2.2, 1] hept-2-ylmethyl] -Ν- (2methoxy-5-methylphenyl) -1-benzofuran-5sulfonamide trifluoroacetate 0 N SC N N 105 Ν- (2-Methoxy-5-methylphenyl) -7 - [(2methylpiperazin-1-yl) methyl] -1-benzofuran-5sulfonamide trifluoroacetate 0 n SK Th γ N N 106 2-Chloro-Ch- [7- (piperazin-1-ylmethyl) -1-benzofuran- 5-yl] benzenesulfonamide dihydrochloride Ayu a ^{s |} '6 0 A N 107 2-Methyl-k1- [7- (piperazin-1-ylmethyl) -1benzofuran-5-yl] benzenesulfonamide dihydrochloride 0 0 A n 108 Ν- [7- (Piperazin-1-ylmethyl) -1-benzofuran-5yl] thiophen-2-sulfonamide dihydrochloride W ° N [0 A N 109 2-Chloro-Y- [7- (1,4-diazepan-1-ylmethyl) -1benzofuran-5-yl] benzenesulfonamide dihydrochloride Ayu 'r 0 Ν- ⁷ N 110 Ν- [7- (1,4-Diazepan-1-ylmethyl) -1-benzofuran-5 yl] -2-methylbenzenesulfonamide dihydrochloride A * 9 0 b 0 N 111 Ν- [7- (1,4-Diazepan-1-ylmethyl) -1-benzofuran-5yl] thiophen-2-sulfonamide dihydrochloride 3 '? No. 0 N 112 2-Methoxy-5-methyl-Y- {7 - [(2-methylpiperazin-1- il) methyl] -1-benzofuran-5- il) benzenesulfonamide dihydrochloride AI 'a ° - N SU ^H | \ G n 113 2-Methyl-Y- {7 - [(2-methylpiperazin-1-yl) methyl] -1benzofuran-5-yl} benzenesulfonamide dihydrochloride AJ and 1 about g * 'SU n 114 2, 5-Dichloro-Y- {7 - [(2-methylpiperazin-1-yl) methyl] 1-benzofuran-5-yl) thiophen-3sulfonamide dihydrochloride νΤο TA b u to n 115 2-Methoxy-5-methyl-M- {7- [(3-methylpiperazin-1- il) methyl] -1-benzofuran-5- silt} benzenesulfonamide dihydrochloride Ay 'a ° - sous n

- 38 010298

116 N- {7 - [(3-Methylpiperazin-1-yl) methyl] -1benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide dihydrochloride N OA D ^SR 3 0 ³ 4 p L ' ⁴ n 117 2-Chloro-Y- {7 - [(3-methylpiperazin-1-yl) methyl] -1benzofuran-5-yl} benzenesulfonamide dihydrochloride BJ 0 ^{C |} with η Η 118 Ν- [7- (2, 5-Diazabicyclo [2.2.1] hept-2-ylmethyl) -1benzofuran-5-yl] -2-methoxy-5- methylbenzenesulfonamide dihydrochloride L | 4 '° - Ν Η 119 Ν- [7- (2,5-Diazabicyclo [2.2.1] hept-2-ylmethyl) -1benzofuran-5-yl] -2- (trifluoromethyl) benzenesulfonamide dihydrochloride BJ n CE, 0 ³ 4 Η 120 Ν- [7- (2,5-Diazabicyclo [2.2.1] hept-2-ylmethyl) -1benzofuran-5-yl] -2- methylbenzenesulfonamide dihydrochloride 'and 1 0 ⁴ Ν Η 121 2-Methoxy-5-methyl-Y- {7 - [(trans-2,5dimethylpiperazin-1-yl) methyl] -1-benzofuran-5yl} benzenesulfonamide bistrifluoroacetate L% 0 '° °' Η 122 2-Methyl-Y- {7 - [(trans-2,5-dimethylpiperazin-1yl) methyl] -1-benzofuran-5- silt} benzenesulfonamide bistrifluoroacetate N 'AI 0 Η 123 2-Χπορ-Ν- {7 - [(trans-2,5-dimethylpiperazin-1yl) methyl] -1-benzofuran-5- silt} benzenesulfonamide bistrifluoroacetate f one* Η 124 1 - ({5 - [(2-Methoxy-5-methylphenyl) sulfonyl] -1 benzofuran-7-yl} methyl) piperazine trifluoroacetate 4-f ό Ν 125 1 - {[5- (Phenylsulfonyl) -1-benzofuran-7yl] methyl} piperazine trifluoroacetate 4-0 ’II 0 Κ 0 Ν 126 1 - ({5 - [(4-Methylphenyl) sulfonyl] -1-benzofuran-7yl} methyl) piperazine trifluoroacetate 4-l  II 0 Κ 0 127 1 - ({5 - [(2-Methoxy-5-methylphenyl) sulfonyl] -1 benzofuran-7-yl} methyl) -1,4 diazepantrifluoroacetate 4 ^ 'II 0o κ 0 V Η 128 1 - {[5- (Phenylsulfonyl) -1-benzofuran-7- sludge] methyl} -1,4-diazepantrifluoroacetate 4-0 'II 0 κ ό V Η

- 39 010298

129 1 - ({5 - [(4-Methylphenyl) sulfonyl] -1 ~ benzofuran-7yl) methyl) -1,4-diazepantrifluoroacetate L-σ ' ¹ II 0 to 0 Th n 130 1 - ({5 - [(2-Methoxy-5-methylphenyl) sulfonyl] -1 benzofuran-7-yl] methyl) -2 methylpiperazine trifluoroacetate IT-. k ' V n 131 1 - ({5 - [(2-Methoxy-5-methylphenyl) sulfonyl] -1 benzofuran-7-yl} methyl) -3 methylpiperazine trifluoroacetate it. CK A n 134 Ν- (2-Methylphenyl) -7 - {[(ZK) -pyrrolidin-3ylamino] methyl} -1-benzofuran-5sulfonamide trifluoroacetate about n ¹ 6 n 135 Ν- (2-Methylphenyl) -7- (piperidin-4-ylmethyl) -1benzofuran-5-sulfonamide trifluoroacetate pn-p 0 n ¹ / n 136 Ν- (2-Methylphenyl) -7- (pyrrolidin-3-ylmethyl) -1benzofuran-5-sulfonamide trifluoroacetate about n ¹ / n 137 Ν- (2-Methylphenyl) -7- (piperidin-3-ylmethyl) -1benzofuran-5-sulfonamide trifluoroacetate 0 N ¹ No. n 138 2-Methoxy-5-methyl-Y- [7- (piperidin-4-ylmethyl) -1benzofuran-5-yl] benzenesulfonamide trifluoroacetate IT-. n 139 3 - ({5 - [(4-Methylphenyl) sulfonyl] -1-benzofuran-7yl} methyl) pyrrolidine trifluoroacetate ’II 0 ό n

table 2

Etc. K ⁷ to ² 36 Ν- [2- (1-Azabitsyklo [2.2.2] οκτ-2-en-Z-yl) -1benzofuran-7-yl] benzenesulfonamide hydrochloride 37 Ν- [2- (1-Azabicyclo [2.2.2] oct-2-en-3-yl) -1benzofuran-7-yl] -2-methoxy-5methylbenzenesulfonamide hydrochloride ν-

Table 3

Etc. K ⁷ to ⁵ 132 2-Methoxy-5-methyl-M- [5- (piperidin-4-ylmethyl) -1- benzofuran-7-yl] benzenesulfonamide trifluoroacetate 0 b 133 2-Methoxy-5-methyl-Y- {5 - [(3-methylpiperazin-1yl) methyl] -1-benzofuran-7- silt} benzenesulfonamide bistrifluoroacetate 10. 140 2-Methoxy-5-methyl-14- [5- (piperidin-4-ylmethyl) -1benzofuran-7-yl] benzenesulfonamide trifluoroacetate ^ΗΝ ? ^Σ ί

- 40 010298

The preparation of the compounds of formula (I) according to the examples can, in particular, be illustrated by the following schemes 1-6, where stages (a) to (h) are described in detail below.

Experimental details are given for each of the individual synthesis examples. Schemes 1-6 illustrate only a few methods by which the compounds of the present invention can be synthesized, and various modifications of these reaction synthesis schemes can be made. Any nitrogen atom of a primary or secondary amine, if present, in K ³ may optionally be protected with a nitrogen protecting group, such as tert-butoxycarbonyl (tert-BOC) or benzyl, in reactions aimed at preparing a compound of formula (Ι). Subsequent deprotection of nitrogen is carried out by standard methods, such as those described in Proceedings of the United States of America and the United States of America, United States and the United States, 1991.

Scheme 1

where K = H or 81Me ₃ , Na1 = C1, Br or I,

K ³ has the meaning indicated for formula (Ι). Scheme 2

where K = H or 81Me ₃ ,

Na1 = C1, Br or I,

Not! = heteroaryl group or heterocyclic group in the framework of K ³ as described for formula (I). Typical heteroaryl or heterocyclic groups are selected from 3-pyridyl, 4-pyridyl, pyrazinyl, 5-pyrimidyl and 1-azabicyclo [2.2.2] oct-3-en-2-yl,

K ¹ has the meaning indicated for formula (I).

Scheme 3

where Na1 = C1, Br or I,

K ³ and K ¹² have the meanings indicated for formula (I).

Scheme 4

where K = H or 81Me ₃ ,

K ³ and K ¹⁴ have the meanings indicated for formula (I) Scheme 5

where K = H or 81Me ₃ ,

K ³ and K ¹⁴ have the meanings indicated for formula (I).

- 41 010298

Scheme 6

where K = H or 81Me ₃ ,

molecules through a nitrogen atom. Typical At groups are depicted in FIG. 1. FIG. one

where K ¹¹ each independently selected from hydrogen or methyl. Scheme 8

where K ¹² has the meaning indicated for formula (I) and the At group is attached to the rest of the molecule via a nitrogen atom. Typical At groups are depicted in FIG. one.

Scheme 9

Where

K ¹² has the meaning indicated for formula (I) and the At group is attached to the rest of the molecule via a nitrogen atom. Typical At groups are depicted in FIG. one.

- 42 010298

Pattern 10

where K ¹² has the meaning indicated for formula (I), P means a suitable protecting group, such as tert-BOC, and ζ = 0, 1 or 2.

where K ¹ has the meaning indicated for formula (I), P means a suitable protecting group, such as tert-BOC, and ζ = 0, 1 or 2.

Pattern 12

where K ¹ has the meaning indicated for formula (I) and the At group is attached to the rest of the molecule via a nitrogen atom. Typical At groups are depicted in FIG. one.

- 43 010298 where K ¹ has the meaning indicated for formula (I) and the At group is attached to the rest of the molecule via a nitrogen atom. Typical At groups are depicted in FIG. one.

Scheme 14

where K ¹² has the meaning indicated for formula (I) and the At group is attached to the rest of the molecule via a nitrogen atom. Typical At groups are depicted in FIG. one.

Intermediate 1.

N, N'-Dimethyl-N- (5-nitro-1-benzofuran-7-yl) propyl-1,3-diamine.

To a mixture of 7-iodo-5-nitro-1-benzofuran (obtained according to the following methods: Ca§1go CE., Merjepz K.E., B. Ogd. SЬt., 1963, 28, 2163; and Eoab Θ.6.8. , Vag11gor TA., Reiu SM., O \\ sp T.C., Te1gayebgop Lel., 1989, 30, 1597-1598) (300 mg, 1.0 mmol), Hapfiosis (xanthosa) (60 mg, 0.1 mmol), Pb ₂ (ba) ₃ (23 mg, 25 mmol), sodium tert-butylate (125 mg, 1.3 mmol) in xylene (10 ml) add Ν, Ν '-dimethylpropane1,3-diamine (540 μl 5 mmol). The mixture was stirred at 120 ° C. for 2 hours, followed by cooling and filtration through a pad of celite. The filtrate was concentrated in vacuo to give the crude title compound.

M8, t / ζ = 264 (M + H) ⁺ .

Intermediate 2. tert-Butyl-3 - [(5-amino-1-benzofuran-7-yl) (methyl) amino] propyl (methyl) carbamate.

Crude N, N'-dimethyl-N- (5-nitro-1-benzofuran-7-yl) propyl-1,3-diamine (intermediate 1) was dissolved in an ESM (10 ml) and di-tert-butyl dicarbonate ( 327 mg, 1.5 mmol) in an ESM (5 ml) at 0 ° C. The mixture was stirred at 0 ° C for 15 minutes, after which the ice bath was removed and the mixture was stirred for 2 hours at room temperature. Add water. The organic substance was extracted with chloroform (2 times), the combined organic layers were dried (MgSO4 and filtered. Volatiles were evaporated to give a yellow oil, which was filtered through silica gel, eluting with EuAc. Volatiles were evaporated and the crude material tert-butyl methyl [3- (methyl {5 {5 -nitro-1-benzofuran-7-yl} amino) propyl] carbamate is dissolved in E1OH and excess Raney nickel is added as a suspension in E1OH (4 ml) followed by hydrazine hydrate (300 μl, 6 mmol). The reaction mixture is stirred at room temperature for 2 hours, followed by filtration through a pre-treated celite pad, the celite pad was washed with MeOH and the filtrate was concentrated in vacuo to give the crude title compound (250 mg), which was used directly in the next step.

Intermediate 3.

tert-Butylmethyl [3- (methyl {5 - [(phenylsulfonyl) amino] -1-benzofuran-7-yl} amino) propyl] carbamate.

Benzene sulfonyl chloride (115 μl, 0.9 mmol) is added to a mixture of tert-butyl-3 - [(5-amino-1-benzofuran-7-yl) (methyl) amino] propyl (methyl) carbamate (intermediate 2; 250 mg, 0 , 75 mmol) in an ESM (2 ml) followed by the addition of pyridine (1 ml). The reaction mixture was stirred at room temperature for 4 hours. Volatiles were evaporated in vacuo and the resulting residue was purified using reverse phase HPLC (O11zop / UMS Ar C18; 150x30 mm) to obtain the title compound as beige oil (202 mg, yield 43% in 4 stages); HPLC: 93%, K _T : 2.49 min (system A); 95%, K _T : 2.27 min (system B); ¹ H NMR (SES _{1 3} ) δ ppm 1.41 (s, 9H), 1.60-1.75 (m, 2.74 (s, 3H), 2.93 (s, 3H), 3.13-3.25 (m, 2H) 3.42-3.53 (m, 2H), 6.19-6.69 (m, 2H), 6.87-7.06 (m, 1H), 7.337.58 (m, 4H), 7 , 71-7.79 (m, 2H); M8, t / ζ = 474 (M + H) ⁺ .

Example 1. Ν- (7- {Methyl [3- (methylamino) propyl] amino} -1-benzofuran-5-yl) benzenesulfonamide hydrochloride.

tert-Butylmethyl [3- (methyl {5 - [(phenylsulfonyl) amino] -1-benzofuran-7-yl} amino) propyl] carbamate (intermediate 3; 202 mg, 0.4 3 mmol) in an ESM (2 ml ) treated with TFA (2 ml) at a temperature of 0 ° C for 10 min and additionally stirred for 30 min at room temperature. After concentration in vacuo, the residue was redissolved in MeOH and treated with an excess of 1 M HC1 in diethyl ether. Removal of the solvents gave the title compound (173 mg, 98% yield) as a white solid; HPLC: 100%, CT = 1.65 min (system A); 100%, K _T = 0.630 min (system B); ¹ H NMR (methanol-b ₄ ) δ ppm 1.85-2.00 (m, 2H), 2.67 (s, 3H), 3.04-3.17 (m, 5H), 3.64-3.73 (m, 2H), 6, 81-6.84 (m, 1H), 6.95-6.98 (m, 1H), 7.06-7.09 (m, 1H), 7.43-7.60 (m, 3H), 7.72-7.78 (m, 2H); 7.81-7.85 (m, 1H); M8, t / ζ = 374 (M + H) ⁺ .

Intermediate 4.

1- (5-Nitro-1-benzofuran-7-yl) piperidine.

- 44 010298

Stage 1. 2-Bromo-6-iodo-4-nitrophenol.

A solution of 4-nitrophenol (130 g, 0.96 mol) in acetonitrile (500 ml) is cooled to a temperature of 0 ° C. While maintaining the temperature below 5 ° C, chlorosulfonic acid (120 g, 1.03 mol) is added. The resulting mixture was stirred for 30 minutes at a temperature of 0-5 ° C. Ν-Bromosuccinimide (181 g, 1.01 mol) was added portionwise to the mixture over a period of 7 hours, keeping the temperature below 8 ° C. The reaction mixture was then quenched by adding a solution of NaH8O ₃ (250 g, 2.4 mol) in water (600 ml) at a temperature maintained below 20 ° C. The aqueous phase is removed and the remaining organic phase is concentrated to 300 ml by distillation. The residue was diluted with acetic acid (381 ml, 6.6 mol) and potassium acetate (212 g, 2.16 mol) was added. Set the temperature at 50 ° C and add isophthaloyl chloride DS1) (152 g, 0.936 mol), maintaining the temperature at 50-80 ° C. When the addition is complete, the product is precipitated by the addition of water (1000 ml). After cooling to a temperature of 10 ° C, the product is isolated by filtration, with a yield of 290 g (90%) of 2-bromo-6-iodo-4-nitrophenol. ¹ H NMR (270 MHz, SIS1 ₃ ) δ ppm 6.53 (s, 1H), 8.42 (d, 1 = 2.72 Hz, 1H), 8.58 (d, 1 = 2.72 Hz, 1H).

Stage 2. 7-Bromo-5-nitro-2- (trimethylsilyl) benzofuran.

To a solution of 2-bromo-6-iodo-4-nitrophenol (200 g, 581.56 mmol; obtained in step 1) in acetonitrile (2800 ml) are added CU (2.22 g, 11.63 mmol) and E1 ^ ( 117.70 g, 1163.12 mmol). It is placed in a nitrogen atmosphere and PbC12 (Pbb3) 2 (4.08 g, 5.82 mmol) is added, followed by slow addition of (trimethylsilyl) acetylene (59.98 g, 610.64 mmol) over 2 hours. The reaction mixture is stirred in overnight until complete formation of the intermediate 2-bromo-4-nitro-6 - [(trimethylsilyl) ethynyl] phenol and then heated at 85 ° C for 8 hours. The mixture was diluted with acetonitrile (1500 ml) and activated carbon was added (6 g) followed by the addition of water (600 ml). The resulting suspension is heated to a temperature of 85 ° C and activated carbon is removed by filtration. The volume was adjusted to 1950 ml by distillation, followed by the addition of water (1600 ml). The product is obtained as an oily precipitate, which solidifies upon cooling. The liquid is decanted and the solid residue is dissolved in acetonitrile (500 ml). Volatiles were removed to give 149.7 g (82% yield) of 7-bromo-5-nitro-2- (trimethylsilyl) benzofuran. ¹ H NMR (270 MHz, SIS1 ₃ ) δ ppm 0.39 (s, 9H), 7.12 (s, 1H), 8.38 (d, 1 = 2.23 Hz, 1H), 8.42 (d, 1 = 2.23 Hz, 1H).

Step 3.1: 1- (5-Nitro-1-benzofuran-7-yl) piperidine.

A mixture of 7-bromo-5-nitro-2- (trimethylsilyl) benzofuran (1.57 g, 5 mmol; obtained in stage 2), piperidine (0.47 g, 5.5 mmol), Pb (OAc) ₂ (56 mg, 0.25 mmol), VSHAR (0.31 g, 0.5 mmol) and No. 10Bi (0.96 g, 10 mmol) in xylene (15 ml) was stirred at 110 ° C for 6 hours. Chilled the mixture was filtered through celite and concentrated to give an oil which was taken up in ₂ occupies 8 column and eluted with E1OAs / hexane (25:75) to give 1- (5-nitro-1-benzofuran-7-yl) piperidine. Yield: 650 mg (53%). ^! H NMR (400 MHz, COC1 ₃ ) δ ppm 1.62-1.70 (m, 2H), 1.77-1.85 (m, 4H), 3.36 (t, 4H), 6.86 (d, 1H), 7.64 (d, 1H), 7.73 (d, 1H), 8.09 (d, 1H); SS-M8 (EN) [gas chromatography - mass spectrometry (EN ·)] for C _; 1 Ι ΝΌ _; . t / ζ: 246 (M) ⁺ .

Intermediate 5.

4- (5-Nitro-1-benzofuran-7-yl) morpholine.

Receive in accordance with the methodology for obtaining intermediate product 4 (stage 3), based on morpholine. Yield: 460 mg (37%). ¹ H NMR (400 MHz, SIS1 ₃ ) δ ppm 3.40-3.45 (m, 4H), 3.94-3.98 (m, 4H), 6.90 (d, 1H), 7.64 (d, 1H), 7.74 (d, 1H), 8.15 (d, 1H); CC-M8 (E! +) For C1 ₂ H ₁₂ ^ O ₄ , m / z: 248 (M) ⁺ .

Intermediate 6.

7-piperidin-1-yl-1-benzofuran-5-amine.

1- (5-Nitro-1-benzofuran-7-yl) piperidine (630 mg, 2.56 mmol; intermediate 4) was dissolved in ESAc (50 ml), Ryu _{2 was} added and the mixture was stirred under a hydrogen atmosphere for 36 h Filter through celite and concentrate the filtrate to give 7-piperidin-1-yl-1-benzofuran-5amine. Yield: 540 mg (98%). ^! H NMR (400 MHz, CHC _{1 3} ) δ ppm 1.59-1.65 (m, 2H), 1.71-1.83 (m, 4H), 3.213.26 (m, 4H), 3.55 (br s, 2H), 6.19 ( d, 1H), 6.45 (d, 1H), 6.56 (d, 1H), 7.51 (d, 1H); CC-M8 (ΒΣ +) for С1 ₃ Н ₁₆ ^ О, t / ζ: 216 (М) ⁺ .

Intermediate 7. 7-Morpholin-4-yl-1-benzofuran-5-amine.

Receive in accordance with the methodology for the preparation of intermediate product 6, starting from 4- (5 nitro-1-benzofuran-7-yl) morpholine (intermediate product 5). Yield: 520 mg (98%). ¹ H NMR (400 MHz, CHC _{1 3} ) δ ppm 3.28-3.32 (m, 4H), 3.56 (br s, 2H), 3.91-3.95 (m, 4H), 6.17 (d, 1H), 6.50 ( d, 1H), 6.58 (d, 1H), 7.50 (d, 1H); CC-M8 (ΒΈ +) for C ^ H ^ O ^ t / ζ: 218 (M) ⁺ .

Example 2. No. (7-Piperidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide.

The synthesis is carried out in accordance with the procedure for the preparation of intermediate 3, starting from 7-piperidin-1-yl-1-benzofuran-5-amine (intermediate 6). Yield: 70 mg (39%). ¹ H NMR (400 MHz, CHC _{1 3} ) δ ppm 1.57-1.62 (m, 2H), 1.70-1.78 (m, 4H), 3.16 (t, 4H), 6.39 (br s, 1H), 6.41 ( d, 1H), 6.63 (d, 1H), 6.83 (d, 1H), 7.37-7.43 (m, 2H), 7.49-7.54 (m, 1H), 7 57 (d, 1H); 7.68-7.72 (m, 2H); M8 +) for C11 ₃ ΝΟΑ. t / ζ: 357 (M + H) ⁺ ; HPLC: 97% (system A).

Example 3. 4-Fluoro ^ - (7-piperidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide.

- 45 010298

The synthesis is carried out in accordance with the procedure for the preparation of intermediate 3, starting from 7-piperidin-1-yl-1-benzofuran-5-amine (intermediate 6). Yield: 55 mg (29%). ¹ H NMR (400 MHz, SEGH) δ ppm 1.56-1.65 (m, 2H), 1.70-1.79 (m, 4H), 3.19 (t, 4H), 6.43 (d, 1H), 6.48 (br. s, 1H), 6.63 (d, 1H), 6.81 (d, 1H), 7.04-7.10 (m, 2H), 7.58 (d, 1H), 7.68-7 74 (m, 2H); ¹³ C NMR (100 MHz, GHSB) δ 24.30, 25.88, 50.90, 107.00, 108.11, 108.42, 115.96, 116.19, 128.67, 130.01, 131.52, 134.89, 138.76, 144.80, 145.16, 163.85, 166.39; M8 (E81 +) for С ₁₉ Н ₁₉ ЕЫ ₂ О ₃ 8, t / ζ: 375 (М + Н) ⁺ ; HPLC 100% (system A).

Example 4. 3,4-Dimethoxy-Y- (7-piperidin-1-yl-1-benzofuran-5-yl) benzene sulfonamide hydrochloride.

The synthesis is carried out in accordance with the procedure for the preparation of intermediate 3, starting from 7-piperidin-1-yl-1-benzofuran-5-amine (intermediate 6). Yield: 100 mg (48%). ¹ H NMR (400 MHz, HSSG) δ ppm 1.52-1.57 (m, 2H), 1.62-1.66 (m, 4H), 3.09-3.15 (m, 4H), 3.69 (s, 3H), 3, 75 (s, 3H), 6.50-6.55 (m, 1H), 6.82 (d, 1H), 6.88 (d, 1H), 7.01 (d, 1H), 7.20 -7.26 (m, 2H), 7.87 (d, 1H), 9.80 (br s, 1H); M8 (E81 +) for C ₂₁ H ₂₄ N ₂ O ₅ 8, t / ζ: 417 (M + H) ⁺ ; HPLC: 100% (system A).

Intermediate 8. 1- (5-Nitro-1-benzofuran-7-yl) pyrrolidine.

The synthesis is carried out as described for the preparation of intermediate product 4 (step 3). Yield: 26%. ¹ H NMR (400 MHz, COC1 _; ) δ ppm 2.03-2.08 (m, 4H), 3.66-3.72 (m, 4H), 6.82 (d, 1H), 7.23 (d, 1H), 7.67 (d, 1H), 7.81 (d, 1H); 6C-M8 (E1 +) for C ^ H ^ Oe, m / z: 232 (M) ⁺ .

Intermediate 9. 7-Pyrrolidin-1-yl-1-benzofuran-5-amine.

The synthesis is carried out as described for intermediate product 6. Yield: 48%.

M8 (E81 +) for C ₁₂ H ₁₄ N ₂ O, t / ζ: 203 (M + H) ⁺ .

Example 5. 3,4-Dimethoxy-Y- (7-pyrrolidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide.

The title compound was prepared according to the procedure for the preparation of intermediate 3, starting from 7-pyrrolidin-1-yl-1-benzofuran-5-amine (intermediate 9). Yield: 70 mg (43%). ^! H NMR (400 MHz, COC1;) δ ppm 1.88-1.93 (m, 4H), 3.38-3.43 (m, 4H), 3.71 (s, 3H), 3.75 (s, 3H), 6.16 (d, 1H), 6.60 (d, 1H), 6.75 (d, 1H), 7.01 (d, 1H), 7.24-7.29 (m, 2H), 7.80 (d, 1H) ), 9.71 (s, 1H); ¹³ NMR (100 MHz, DMSO-b6): δ 24.72, 48.82, 55.62, 55.71, 100.66, 101.57, 106.96, 109.54, 110.91, 120, 58, 128.29, 131.10, 134.01, 134.58, 140.65, 145.37, 148.33, 151.89; M8 (E81 +) for C ₂₀ H ₂₂ N ₂ O ₅ 8, t / ζ: 403 (M + H) ⁺ ; HPLC: 98% (system A).

Example 6. Y- (7-Pyrrolidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide.

The title compound was prepared according to the procedure for the preparation of intermediate 3, starting from 7-pyrrolidin-1-yl-1-benzofuran-5-amine (intermediate 9). Yield: 30 mg (22%). ^! H NMR (400 MHz, DMSO-b6) δ ppm 1.86-1.93 (m, 4H), 3.36-3.43 (m, 4H), 6.13 (broad s, 1H), 6.59 (broad s, 1H), 6, 73 (d, 1H), 7.45-7.60 (m, 3H), 7.73 (d, 2H), 7.79 (d, 1H), 9.92 (s, 1H); ¹³ C NMR (100 MHz, DMSO-b6) δ ppm 24.73, 48.79, 100.68, 101.51, 106.97, 126.74, 128.33, 129.05, 132.58, 133.70, 134.62, 139.67, 140, 68, 145.40; M8 (E81 +) for С18Н ₁₈ Н ₂ О ₃ 8, t / ζ: 343 (М + Н) ⁺ ; HPLC: 95% (system A).

Example 7. 4-Fluoro-Y- (7-pyrrolidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure for the preparation of intermediate 3, starting from 7-pyrrolidin-1-yl-1-benzofuran-5-amine (intermediate 9).

Yield: 65 mg (41%). ^! H NMR (400 MHz, DMSO-b6) δ ppm 1.87-1.94 (m, 4H), 3.38-3.44 (m, 4H), 6.13 (d, 1H), 6.58 (d, 1H), 6.75 (d, 1H), 7.34-7.40 (m, 2H), 7.74-7.80 (m, 2H), 7.81 (d, 1H), 9.94 (s, 1H); ¹³ C NMR (100 MHz, DMSO-b6) δ 24.73.48.85, 100.97, 101.73, 106.99, 116.13, 116.36, 128.38, 129.71, 129, 80, 133.51, 134.59, 135.99, 140.77, 145.48, 162.88, 165.38; M8 (E81 +) for С18Н ₁₇ ЕЫ ₂ О ₃ 8, t / ζ: 361.0 (М + Н) ⁺ ; HPLC: 98%.

Example 8. 4-Fluoro-Y- (7-morpholin-4-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure for preparing intermediate 3, starting from intermediate 7. Yield: 100 mg (53%). 'H NMR (400 MHz, DMSO-b ₆ ) δ ppm 3.08-3.14 (m, 4H), 3.72-3.78 (m, 4H), 6.47 (d, 1H), 6.83 (d, 1H), 6.88 (d, 1H), 7.32-7.40 (m, 2H), 7.74-7.78 (m, 2H), 7.88 (d, 1H), 10.07 (s, 1H); ¹³ C NMR (100 MHz, DMSO-b ₆ ) δ ppm 49.31, 65.98, 105.45, 106.13, 107.14, 116.20, 116.43, 128.52, 129.85, 133.24, 135.70, 137.00, 143, 09, 145.74, 162.96, 165.46; M8 (E81 +) for С1 ₈ Н ₁₇ ЕЫ ₂ О ₄ 8, t / ζ: 377.2 (М + Н) ⁺ ; HPLC: 100%.

Example 9. Y- (7-Morpholin-4-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure for preparing intermediate 3, starting from intermediate 7. Yield: 75 mg (42%). ¹ H NMR (400 MHz, DMSO-b6) δ ppm 3.06-3.12 (m, 4H), 3.71-3.78 (m, 4H), 6.46 (d, 1H), 6.82 (d, 1H), 6.88 (d, 1H), 7.48-7.54 (m, 2H), 7.54-7.60 (m, 1H), 7.71 (d, 2H), 7.87 (d, 1H), 10.03 (s, 1H); ¹³ C NMR (100 MHz, DMSO-b6) δ 49.29, 65.98, 105.30, 105.90, 107.10, 126.75, 128.46, 129.11, 132.71, 133, 40, 136.93, 139.37, 142.99, 145.67; M8 (E81 +) for C1 ₈ H ₁₈ S ₂ O ₄ 8, t / ζ: 359.2 (M + H) ⁺ ; HPLC: 97%.

Example 10. 3,4-Dimethoxy-L- (7-morpholin-4-yl-1-benzofuran-5-yl) benzenesulfonamide.

The title compound was prepared according to the procedure for preparing intermediate 3, starting from intermediate 7. Yield: 45 mg (21%). ¹ H NMR (400 MHz, COC1 _; ) δ ppm 3.23-3.28 (m, 4H), 3.75 (s, 3H), 3.89 (s, 3H), 3.89-3.93 (m, 4H), 6.53 (br. s, 1H), 6.65 (d, 1H),

- 46 010298

6.76 (broad s, 1H), 6.82 (d, 1H), 6.89 (broad s, 1H), 7.18 (d, 1H), 7.35 (dd, 1H), 7 57 (d, 1H); M8 (Ε8Ι +) for C ₂ .11. L O. 8. t / ζ: 419.0 (M + H) ⁺ ; HPLC: 88%.

Intermediate 10.

tert-Butyl-4- (5-amino-1-benzofuran-7-yl) piperazine-1-carboxylate.

tert-Butyl-4- (5-nitro-1-benzofuran-7-yl) piperazine-1-carboxylate * (1 g, 2.9 mmol) was dissolved in a mixture of THF / E1OH (1: 4). An excess of Raney nickel (suspension in ethanol) was added followed by hydrazine hydrate (0.58 g, 11.5 mmol). The reaction mixture was stirred at room temperature overnight. Filter and evaporate to give 1.19 g of the title product, which is used in the next step without further purification. HPLC purity 93%, R _t = 1.71 min (System A, 10-97% MeCN over 3 min).

* Previously described in \ UO 2002100822.

General Procedure A. Alkylation of tert-butyl 4- (5-amino-1-benzofuran-7-yl) piperazine-1 carboxylate.

To the corresponding benzyl bromide (0.378 mmol) was added a basic solution of tert-butyl 4- (5 amino-1-benzofuran-7-yl) piperazine-1-carboxylate (0.12 g, 0.378 mmol; intermediate 10) in acetonitrile together with K ₂ CO ₃ (52 mg, 0.378 mmol). The mixture was shaken at room temperature for 3 hours. The progress of the reaction was monitored using BS-M8 (liquid chromatography - mass spectrometry). Processing: filtration and purification using preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid. Deprotection of nitrogen is carried out in accordance with the procedure of example 1 and the target hydrochloride is obtained by subsequent processing with a 2 M solution of HC1 in diethyl ether.

Example 11. N- (3,5-Dimethylbenzyl) -7-piperazin-1-yl-1-benzofuran-5-amine hydrochloride.

Prepared according to General Procedure A from 1- (bromomethyl) -3,5-dimethylbenzene (75 mg, 0.378 mmol). Yield: 8 mg (6%). HPLC: 93%, R _t = 1.240 min (System A, 10-97% MeCN over 3 min). 'H NMR (270 MHz, methanol-6 ₄ ) δ ppm 2.30 (s, 6H), 3.47-3.64 (m, 8H), 4.52 (s, 2H), 6.86-6.95 (m, 2H), 7.08-7 09 (m, 3H); 7.32 (s, 1H); 7.93 (s, 1H). BS-M8: 336 (M + H) ⁺ .

Example 12. No. (3,4-Difluorobenzyl) -7-piperazin-1-yl-1-benzofuran-5-amine hydrochloride.

Prepared according to General Procedure A from 4- (bromomethyl) -1,2-difluorobenzene (78 mg, 0.378 mmol). Yield: 6 mg (5%). HPLC: 97%, R _t = 1.499 min (System A, 10-97% MeCN over 3 min). 'H NMR (270 MHz, methanol-6 ₄ ) δ ppm 3.46-3.63 (m, 8H), 4.73 (s, 2H), 6.86-6.94 (m, 2H), 7.36 (s, 1H), 7.49-7, 64 (m, 2H), 7.91-8.00 (m, 2H). BS-M8: 344 (M + H) ⁺ .

Example 13. N- (3,5-Dimethoxybenzyl) -7-piperazin-1-yl-1-benzofuran-5-amine hydrochloride.

Prepared according to General Procedure A from 1- (bromomethyl) -3,5-dimethoxybenzene (87 mg, 0.378 mmol). Yield: 8 mg (6%). HPLC: 93%, R _t = 1.355 min (System A, 10-97% MeCN over 3 min). 'H NMR (270 MHz, methanol-6 ₄ ) δ ppm 3.47-3.65 (m, 8H), 3.76 (s, 6H), 4.56 (s, 2H), 6.54 (s, 1H), 6.64 (s, 2H), 6 89 (s, 1H) 6.95 (s, 1H) 7.35 (s, 1H); 7.92 (s, 1H). BS-M8: 368 (M + H) ⁺ .

Example 14. No. Benzyl-7-piperazin-1-yl-1-benzofuran-5-amine hydrochloride.

To benzyl bromide (65 mg, 0.378 mmol) was added a basic solution of tert-butyl 4- (5-amino-1-benzofuran-7-yl) piperazine-1-carboxylate (0.12 g, 0.378 mmol; intermediate 10) in acetonitrile together with K2CO3 (52 mg, 0.378 mmol). The mixture was shaken at room temperature for 3 hours. The reaction progress was monitored using BS-M8, filtered and purified by preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid. Deprotection of nitrogen and conversion to hydrochloride is carried out by treating with a 2 M solution of HC1 in diethyl ether. Yield: 19 mg (16.4%). HPLC 92%, R _t = 1.240 min (System A, 10-97% MeCN over 3 min). '11 NMR (270 MHz, methanol-6 ₄ ) δ ppm 3.56 (d, 8H), 4.65 (s, 2H), 6.94 (s, 2H), 7.43 (s, 6H), 7.92 (s, 1H). BS-M8: 308 (M + H) ⁺ .

General Procedure B. Amidation of tert-butyl 4- (5-amino-1-benzofuran-7-yl) piperazine-1 carboxylate.

Pyridine (274 μl, 3.40 mmol) and a basic solution of tert-butyl 4- (5-amino-1-benzofuran-7-yl) piperazine-1-carboxylate (0.12 g) are added to the corresponding benzoyl chloride (0.454 mmol). 0.378 mmol; intermediate 10) in an ESM (2 ml). The mixture was shaken at room temperature for 2 hours. Products were monitored with BS-M8 and the solvent was removed. Purification of the products is carried out using preparative HPLC using gradients of acetonitrile - water containing 0.1% trifluoroacetic acid. The final products are obtained by subsequent deprotection of nitrogen in accordance with the procedure of Example 1 and converted into the corresponding hydrochloride by treatment with a 2 M solution of HCl in diethyl ether.

Example 15. No. (7-Piperazin-1-yl-1-benzofuran-5-yl) benzamide hydrochloride.

Prepared according to General Procedure B from tert-butyl 4- (5-amino-1-benzofuran-7-yl) piperazine-1 carboxylate (64 mg, 0.454 mmol; intermediate 10). Yield: 3 mg (3%). HPLC: 94%, R _t = 1.534 min (System A, 10-97% MeCN over 3 min). 'H NMR (270 MHz, methanol-6 ₄ ) δ ppm 3.46-3.61 (m, 8H), 6.85 (d, 1 = 2.23 Hz, 1H), 7.28 (d, 3 = 1.24 Hz, 1H), 7.52-7 59 (m, 4H), 7.78 (d, 1M, 98 Hz, 1H), 7.95 (d, 1 = 6.68 Hz,

- 47 010298

2H). L-M8: 322 (M + H) ⁺ .

Example 16. 4-Methoxy-X- (7-piperazin-1-yl-1-benzofuran-5-yl) benzamide hydrochloride.

Prepared according to General Procedure B from 4-methoxybenzoyl chloride (77 mg, 0.454 mmol). Yield: 2 mg (1.5%). HPLC: 99%, K = 1.568 min (system A; 10-97% MeCX for 3 min). ¹ H NMR (270 MHz, methanol-b ₄ ) δ ppm 3.44-3.61 (m, 8H), 3.87 (s, 2H), 6.84 (d, 1 = 2.23 Hz, 1H), 7.04 (d, 1 = 8.91 Hz) , 2H), 7.27 (d, 1 = 1.48 Hz, 1H), 7.52 (d, 1 = 1.73 Hz, 1H), 7.77 (d, 1 = 1.98 Hz, 1H ), 7.93 (d, 1 = 8.91 Hz, 2H). L-M8: 352 (M + H) ⁺ .

Example 17. 2-Bromo-5-methoxy-X- (7-piperazin-1-yl-1-benzofuran-5-yl) benzamide hydrochloride.

Prepared according to General Procedure B from 2-bromo-5-methoxybenzoyl chloride (113 mg, 0.454 mmol). Yield: 10 mg (6.2%). HPLC: 85%, K _T = 1.685 min (system A; 10-97% MeCX for 3 min). ¹ H NMR (270 MHz, methanol-b ₄ ) δ ppm 3.46-3.48 (m, 4H), 3.59-3.61 (m, 4H), 3.84 (s, 3H), 6.84 (d, 1 = 1.98 Hz, 1H) 6.97 (dd, 1 = 8.66, 2.72 Hz, 1H), 7.10 (d, 1 = 2.97 Hz, 1H), 7.23 (s, 1H), 7.54- 7.59 (m, 2H); 7.78 (d, 1 = 1.98 Hz, 1H). Bsm8: 430 (M + H) ⁺ .

Example 18. 3-Methyl-X- (7-piperazin-1-yl-1-benzofuran-5-yl) benzamide hydrochloride.

Prepared according to General Procedure B from 3-methylbenzoyl chloride (70 mg, 0.454 mmol). Yield: 14 mg (11.1%). HPLC: 93%, K = 1.666 min (system A; 10-97% MeCX for 3 min). ^! H NMR (270 MHz, methanol-b ₄ ) δ ppm 2.43 (s, 3H), 3.46-3.62 (m, 8H), 6.84 (d, 1 = 1.73 Hz, 1H), 7.39 (d, 1 = 4.21 Hz) , 2H), 7.76 (d, 1 = 10.14 Hz, 3H). L-M8: 336 (M + H) ⁺ .

Example 19. X- (7-piperazin-1-yl-1-benzofuran-5-yl) -3- (trifluoromethyl) benzamide hydrochloride.

Prepared according to General Procedure B from 3- (trifluoromethyl) benzoyl chloride (95 mg, 0.454 mmol). Yield: 12 mg (8.2%). HPLC: 88%, K _T = 1.799 min (system A; 10-97% MeCX for 3 min). ¹ H NMR (270 MHz, methanol-b ₄ ) δ ppm 3.45-3.63 (m, 8H), 6.86 (d, 1 = 2.23 Hz, 1H), 7.31 (d, 1 = 1.73 Hz, 1H), 7.58 (s , 1H), 7.75-7.79 (m, 2H), 7.92 (s, 1H), 8.24 (m, 2H). L-M8: 390.1 (M + H) ⁺ .

Example 20. 2,4-Dichloro-X- (7-piperazin-1-yl-1-benzofuran-5-yl) benzamide hydrochloride.

Prepared according to General Procedure B from 2,4-dichlorobenzoyl chloride (95 mg, 0.454 mmol). Yield: 19 mg (12.9%). HPLC: 93%, K = 1.803 min (system A; 10-97% MeCX for 3 min). ^! H NMR (270 MHz, methanol-b ₄ ) δ ppm 3.47-3.62 (m, 8H), 6.84 (d, 7 = 2.23 Hz, 1H), 7.21 (d, 1 = 2.23 Hz, 1H), 7.44-7 78 (m, 5H). L-M8: 390 (M + H) ⁺ .

Example 21. 3,5-Dimethoxy-X- (7-piperazin-1-yl-1-benzofuran-5-yl) benzamide hydrochloride.

Prepared according to General Procedure B from 3,5-dimethoxybenzoyl chloride (91 mg, 0.454 mmol). Yield: 18.3 mg (12.7%). HPLC: 91%, K _T = 1.666 min (system A; 10-97% MeCX for 3 min). ¹ H NMR (270 MHz, methanol-b ₄ ) δ ppm 2.76-7.82 (m, 8H), 3.04 (s, 6H), 5.87 (s, 1H), 6.02 (d, 1 = 1.57 Hz, 1H), 6.30 (d, 1 = 1.57 Hz, 2H), 6.41-6.49 (m, 1H), 6.78-6.79 (m, 1H), 6.98-6.69 (m, 1H ) L-M8: 382 (M + H) ⁺ .

General Procedure C. Synthesis of urea derivatives from tert-butyl 4- (5-amino-1-benzofuran-7yl) piperazine-1-carboxylate.

Method A.

To the corresponding aryl isocyanate (0.416 mmol) was added a basic solution of tert-butyl 4- (5 amino-1-benzofuran-7-yl) piperazine-1-carboxylate (0.12 g, 0.378 mmol; intermediate 10) in acetonitrile (2 ml ) and pyridine (27 4 μl, 3.4 mmol). The mixture was shaken at room temperature overnight. The progress of the reaction is monitored with bC-M8. Processing: filtration and purification using preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid. The final products are obtained by subsequent deprotection of nitrogen in accordance with the procedure of Example 1 and are converted to hydrochloride by treatment with a 2 M solution of HCl in diethyl ether.

Example 22. X- (3,5-Dimethoxyphenyl) -X '- (7-piperazin-1-yl-1-benzofuran-5-yl) urea hydrochloride.

Prepared according to General Procedure C (Method A) from 1-isocyanato-3,5-dimethoxybenzene (75 mg, 0.416 mmol). Yield: 11 mg (8%). HPLC: 100%, K.! = 1.673 min (system A; 10-97% MeCX for 3 min). H NMR (270 MHz, methanol-b ₄ ) δ ppm 3.44-3.46 (m, 4H), 3.56-3.57 (m, 4H), 3.75 (s, 6H), 6.78 (d, 1 = 1.98, Hz, 2H ), 7.03 (s, 2H), 7.27 (d, 1 = 1.48 Hz, 1H), 7.72 (d, 1 = 1.98 Hz, 2H). L-M8: 397 (M + H) ⁺ .

Example 23. X- (2,4-Dichlorophenyl) -X '- (7-piperazin-1-yl-1-benzofuran-5-yl) urea hydrochloride.

Prepared according to General Procedure C (Method A) from 2,4-dichloro-1-isocyanatobenzene (78 mg, 0.416 mmol). Yield: 9 mg (6%). HPLC: 100%, K _T = 1.775 min (system A; 10-97% MeCX for 3 min). ¹ H NMR (270 MHz, methanol-b ₄ ) δ ppm 3.46-3.47 (m, 4H), 3.58-3.59 (m, 4H), 6.80 (d, 1 = 1.98 Hz, 1H), 7.06-7.07 ( m, 1H), 7.26 (d, 1 = 2.23 Hz, 1H), 7.29 (d, 1 = 2.47 Hz, 1H), 7.46 (d, 1 = 2.47 Hz, 1H), 7.74 (d, 1 = 1.98 Hz, 1H), 8.13 (d, 1 = 8.91 Hz, 1H). L-M8: 405 (M + H) ⁺ .

General Procedure C. Synthesis of urea derivatives from tert-butyl 4- (5-amino-1-benzofuran-7yl) piperazine-1-carboxylate.

Method B. To a corresponding isocyanate (0.416 mmol) was added a basic solution of tert-butyl 4- (5-amino-1-benzofuran-7-yl) piperazine-1-carboxylate (0.12 g, 0.378 mmol; intermediate 10) in acetonitrile together with triethylamine (158 μl, 1.13 mmol). The mixture was shaken at room temperature overnight. The progress of the reaction is monitored with bC-M8. Processing: filtering and

- 48 010298 purification by preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid. The final products are obtained by subsequent deprotection of nitrogen in accordance with the procedure of Example 1 and converted into the corresponding hydrochloride by treatment with a 2 M solution of ΗΟΊ in diethyl ether.

Example 24. No. (2-Methoxyphenyl) -Y ′ - (7-piperazin-1-yl-1-benzofuran-5-yl) urea hydrochloride.

Prepared according to the general procedure described above (method B) from 1-isocyanato-2-methoxybenzene (60 mg, 0.416 mmol). Yield: 33 mg (23.8%). HPLC: 93%, R _t = 1.673 min (System A, 10-97% MeCN over 3 min). ¹ Η NMR (270 MHz, methanol-b ₄ ) δ ppm 3.44-3.60 (m, 8Η), 3.92 (s, 3Η), 6.79-6.99 (m, 5Η), 7.127.21 (m, 1Η), 7.73 (d, 1 = 2.23 Hz, 1Η), 8.05 (d, 1 = 7.67 Hz, 1Η). L-M8: 367.1 (M + H) ⁺ .

Example 25. No. Phenyl-L '- (7-piperazin-1-yl-1-benzofuran-5-yl) urea hydrochloride.

Prepared according to the general procedure described above (method B) from isocyanatobenzene (50 mg, 0.416 mmol). Yield: 31 mg (24.4%). HPLC: 93%, R _t = 1.583 min (System A, 10-97% MeCN over 3 min). ¹ Η NMR (270 MHz, methanol-b ₄ ) δ ppm 3.43-3.47 (m, 4Η), 3.56-3.60 (m, 4Η), 6.80 (d, 1 = 2.23 Hz, 1Η), 7.09-7.21 ( m, 2Η), 7.22-7.31 (m, 3Η), 7.43 (d, 1 = 8.41 Hz, 2Η), 7.74 (d, 1 = 2.23 Hz, 1Η). L-M8: 337 (M + H) ⁺ .

Example 26. No. (3-Fluorophenyl) -Y ′ - (7-piperazin-1-yl-1-benzofuran-5-yl) urea hydrochloride.

Prepared according to the general procedure described above (method B) from 1-fluoro-3-isocyanatobenzene (57 mg, 0.416 mmol). Yield: 5 mg (3.7%). HPLC: 93%, R _t = 1.700 min (System A, 10-97% MeCN over 3 min). ¹ Η NMR (270 MHz, methanol-b ₄ ) δ ppm 3.46-3.47 (m, 4Η), 3.57-3.60 (m, 4Η), 6.77-6.81 (m, 2Η), 7.08-7.09 (m, 2Η) ), 7.22-7.28 (m, 2Η), 7.42-7.47 (m, 1Η), 7.74 (d, 1 = 1.98 Hz, 1Η). L-M8: 355 (M + H) ⁺ .

Example 27. Hydrochloride No. (7-piperazin-1-yl-1-benzofuran-5-yl) -Y '- [(trifluoromethyl) phenyl] urea.

Prepared according to the general procedure described above (method B) from 1-isocyanato-3 (trifluoromethyl) benzene (78 mg, 0.416 mmol). Yield: 27 mg (17.7%). HPLC: 91%, R _t = 1.932 min (System A, 10-97% MeCN over 3 min). ¹ Η NMR (270 MHz, methanol-b ₄ ) δ ppm 3.44-3.47 (t; 4Η), 3.57-3.61 (m, 4Η), 6.81 (d, 1 = 2.23 Hz, 1Η), 7.12-7.30 ( m, 3Η), 7.51 (m, 2Η), 7.74 (d, 1 = 2.23 Hz, 1Η), 7.96 (s, 1Η). L-M8: 405 (M + H) ⁺ .

Intermediate 11.

4- (5-Nitro-1-benzofuran-7-yl) pyridine.

In a 50 ml tube, 7-iodo-5-nitrobenzofuran (2.00 g, 0.00692 mol), 4-tributylstannylpyridine (2.80 g, 0.00761 mol), copper-D iodide (132 mg, 0.692) are introduced mmol) and dichlorobis (triphenylphosphine) palladium (II) (49 mg, 0.0692 mmol) followed by the addition of DMF (20 ml). The mixture is heated at a temperature of 100 ° C. overnight at 81 eB1osk. After cooling to room temperature, an aqueous sodium hydroxide solution (2 M solution, 4 ml) was added and the solution was stirred for 15 minutes. Chloroform (20 ml) was added and the mixture was filtered through celite. The aqueous layer was then extracted with chloroform (3 times) and the combined organic phases were evaporated. The residue was then triturated with diethyl ether and the precipitate was dried in vacuo overnight to give a light brown solid. Yield: 686 mg (41%); HPLC (system A): purity = 99%, t / ζ = 241 (M + H) ⁺ . ¹ Η NMR (270 MHz, DMSO-b ₆ ) δ ppm 7.33 (d, 1 = 2.23 Hz, 1Η), 7.98 (m, 2Η), 8.38 (d, 1 = 2.23 Hz, 1Η), 8.50 (d, 1 = 2 , 47 Hz, 1Η), 8.75 (d, 1 = 2.23 Hz, 1Η), 8.79 (m, 2Η).

Intermediate 12.

3- (5-Nitro-1-benzofuran-7-yl) pyridine.

The title compound was prepared according to the procedure described above for the preparation of intermediate 11, starting from 3-tributylstannylpyridine. Yield: 145 mg (35%); HPLC (system A): purity = 97%, t / ζ = 241 (M + H) ⁺ . '11 NMR (270 MHz, DMSO-b ₆ ) δ ppm 7.32 (d, 1 = 2.23 Hz, 1Η), 7.63 (dd, 1 = 7.79, 4.82 Hz, 1Η), 8.33 (m, 1Η), 8.36 (d , 1-2.23 Hz, 1Η), 8.44 (d, 1 = 2.47 Hz, 1Η), 8.72 (m, 2Η), 9.14 (d, 1 = 1.73 Hz, 1Η )

Intermediate 13.

2- (5-Nitro-1-benzofuran-7-yl) pyridine.

The title compound was prepared according to the procedure described above for the preparation of intermediate 11, starting from 2-tributylstannylpyridine. Yield: 282 mg (42%); HPLC (system A): purity = 98%, t / ζ = 241 (M + H) ⁺ . ¹ Η NMR (270 MHz, DMSO-b ₆ ) δ ppm 7.33 (d, 1 = 2.23 Hz, 1Η), 7.53 (m, 1Η), 8.06 (m, 1Η) , 8.41 (m, 2Η), 8.72 (d, 1 = 2.47 Hz, 1Η), 8.84 (m, 1Η), 8.99 (d, 1 = 2.47 Hz, 1Η) .

Intermediate 14.

2- (5-Nitro-1-benzofuran-7-yl) pyrazine.

The title compound was prepared according to the procedure described above for the preparation of intermediate 11, starting from 2-tributylstannylpyrazine. Yield: 238 mg (57%); HPLC (system A): purity = 97%, t / ζ = 242 (M + H) ⁺ . '11 NMR (270 MHz, DMSO-b ₆ ) δ ppm 7.35 (d, 1 = 2.23 Hz, 1Η), 8.43 (d, 1 = 2.23 Hz, 1Η), 8.78 (m, 2Η), 8.92 (m, 2Η), 9.58 (s, 1Η).

Intermediate 15.

2- (5-Nitro-1-benzofuran-7-yl) pyrimidine.

- 49 010298

The title compound was prepared according to the procedure described above for the preparation of intermediate 11, starting from 2-tributylstannylpyrimidine. Yield: 219 mg (52%); HPLC (system A): purity = 97%, t / ζ = 242 (M + H) ⁺ . ¹ H NMR (270 MHz, DMSO-b ₆ ) δ ppm 7.32 (d, 1 = 2.23 Hz, 1H), 7.61 (t, 1 = 4.95 Hz, 1H), 8.40 (d, 1 = 2.23 Hz, 1H), 8, 81 (d, 1 = 2.47 Hz, 1H), 9.07 (m, 3H).

Intermediate 16.

4- (5-amino-1-benzofuran-7-yl) pyridine.

4- (5-Nitro-1-benzofuran-7-yl) pyridine (125 mg, 0.520 mmol; intermediate 11) was dissolved in 1,4-dioxane (15 ml). After adding ethanol (20 ml), Raney nickel (suspension in ethanol, 2 ml) and hydrazine hydrate (4 ml), the mixture was allowed to stir at room temperature overnight. The product is used directly in the next reaction after filtration through celite and evaporation of the solvent.

Example 28. 2-Methoxy-5-methyl-Y- (7-pyridin-4-yl-1-benzofuran-5-yl) benzenesulfonamide.

4- (5-amino-1-benzofuran-7-yl) pyridine (55 mg, 0.260 mmol; intermediate 16) and 6 methoxy-m-toluenesulfonyl chloride (69 mg, 0.312 mmol) were dissolved in dichloromethane (5 ml). Triethylamine (73 μl, 0.520 mmol) was added and the mixture was shaken for 2 hours. After concentration, the residue was triturated with cold acetonitrile and the precipitate was collected and dried in vacuo. Yield: 56 mg (55%). HPLC (system A): purity = 98%, t / ζ = 395 (M + H) ⁺ . '11 NMR (270 MHz, DMSO-b ₆ ) δ ppm 2.21 (s, 3H), 3.87 (s, 3H), 7.09 (m, 2H), 7.35 (dd, 1 = 8.54, 2.10 Hz, 1H), 7.56 (m, 2H), 8.14 (d, 1 = 2.23 Hz, 1H), 8.25 (d, 1 = 6.68 Hz, 2H), 8.98 (d, 1 = 6.68 Hz , 2H), 10.13 (s, 1H).

Example 29. W (7-Pyridin-3-yl-1-benzofuran-5-yl) benzenesulfonamide trifluoroacetate.

The title compound was prepared according to the procedure described for Example 28 above starting from 3- (5-amino-1-benzofuran-7-yl) pyridine * and purified by preparative HPLC. Yield: 63 mg (51%); HPLC (system A): purity = 95%, t / ζ = 351 (M + H) ⁺ . 'H NMR (270 MHz, methanol ₄ ) δ ppm 6.90 (d, 1 = 2.23 Hz, 1H), 7.49 (m, 5H), 7.74 (m, 2H), 7.89 (d, 1 = 2.23 Hz, 1H), 8.01 (m, 1H), 8.77 (m, 2H), 9.19 (d, 1 = 1.73 Hz, 1H).

* Obtained in accordance with the procedure for the preparation of intermediate 16, starting from 3- (5 nitro-1-benzofuran-7-yl) pyridine (intermediate 12).

Example 30. 2-Methoxy-5-methyl-X- (7-pyridin-3-yl-1-benzofuran-5-yl) benzenesulfonamide trifluoroacetate.

The title compound was prepared according to the procedure described for Example 28 above starting from 3- (5-amino-1-benzofuran-7-yl) pyridine * and purified by preparative HPLC (system Ό). Yield: 67 mg (50%); HPLC (system A): purity = 97%, t / ζ = 395 (M + H) ⁺ . 'H NMR (270 MG c, methanol-b ₆ ) δ ppm

2.1ν (s, 3H), 3.95 (s, 3H), 6.88 (d, 1 = 2.23 Hz, 1H), 7.01 (d, 1 = 8.41 Hz, 1H), 7.29 (m, 1H), 7.48 (d, 1 = 2.23 Hz, 2H), 7.54 (m, 1H), 7.86 (d, 1 = 2.23 Hz, 1H), 8.10 (m, 1H), 8.84 (m, 2H), 9.24 (d, 1 = 1, 98 Hz, 1H).

* Obtained in accordance with the procedure for the preparation of intermediate 16, starting from 3- (5 nitro-1-benzofuran-7-yl) pyridine (intermediate 12).

Example 31. W (7-Pyrazin-2-yl-1-benzofuran-5-yl) benzenesulfonamide trifluoroacetate.

The title compound was prepared according to the procedure described for Example 28 above starting from 2- (5-amino-1-benzofuran-7-yl) pyrazine * and purified by preparative HPLC (system Ό). Yield: 20 mg (17%); HPLC (system A): purity = 98%, t / ζ = 352 (M + H) ⁺ . 'H NMR (270 MHz, DMSO-b ₆ ) δ ppm 7.07 (d, 1 = 2.23 Hz, 1H), 7.53 (m, 3H), 7.76 (m, 2H), 7.91 (d, 1 = 1.98 Hz, 1H), 8.14 (d, 1 = 2.23 Hz, 1H), 8.67 (d, 1 = 2.47 Hz, 1H), 8.82 (m, 1H), 9.45 (d, 1 = 1 , 73 Hz, 1H); 10.39 (s, 1H).

* Obtained in accordance with the procedure for the preparation of intermediate 16, starting from 2- (5 nitro-1-benzofuran-7-yl) pyrazine (intermediate 14).

The intermediate product 17.

5- (5-Nitro-1-benzofuran-7-yl) pyrimidine.

To 7-iodo-5-nitro-1-benzofuran (1.00 g, 3.45 mmol) was added Rb (PPE ₃ ) ₄ (240 mg, 209 mmol) in 1,2 dimethoxyethane (OME) (11 ml) and the resulting the mixture is stirred for 10 minutes The color changes from dark red to mustard yellow. Pyrimidine-5-boronic acid (0.24 g, 0.21 mmol) and a 1 M solution of Ш ₂ СО ₃ (5 ml) are added and the reaction mixture is refluxed at 100 ° С for 2.5 hours. The mixture concentrated in vacuo and the residue was dissolved in 1 M HC1 solution (50 ml) and washed with diethyl ether (50 ml). The aqueous layer was alkalinized (pH = 8) by adding K ₂ CO ₃ and extracted with chloroform (3 times). The combined organic layers were dried over K ₂ CO ₃ , filtered and concentrated to give 0.4 to 55 g (55% yield) of a yellow solid. HPLC: 100%, K _T = 1.870 min (system A; 10-97% MeCN for 3 min). 'H NMR (270 MHz, COC1 _; ) δ ppm 7.06 (d, 1 = 2.47 Hz, 1H), 7.90 (d, 1 = 2.23 Hz, 1H), 8.45 (d, 1 = 2.23 Hz, 1H), 8, 63 (d, 1 = 2.23 Hz, 1H), 9.28-9.31 (m, 3H). BS-M8: 242 (M + H) ⁺ .

The intermediate product.

7-Pyrimidin-5-yl-1-benzofuran-5-amine.

To 5- (5-nitro-1-benzofuran-7-yl) pyrimidine (0.455 g, 1.87 mmol; intermediate 17)

- 50 010298 ethanol / THF mixtures (100 ml: 25 ml), Raney nickel (suspension in ethanol, 2 ml) and hydrazine (0.378 g, 7.55 mmol) are added. The mixture was stirred at room temperature for 3 hours, filtered through celite and concentrated in vacuo to give 0.317 g (8% yield) of the title compound as a yellow solid. HPLC 100%, R _t = 0.957 min (System A, 10-97% MeSCh for 3 min). ¹ H NMR (270 MHz, methanol-f) δ ppm 6.77 (d, 1 = 2.23 Hz, 1H), 7.05 (q, 1 = 2.23 Hz, 2H), 7.76 (d, 1 = 2.23 Hz, 1H), 9 14 (s, 1H); 9.26 (s, 2H); YC-M8 212 (M + H) ⁺ . JS-M8: 212 (M + H) ⁺ .

Example 32. H- (7-Pyrimidin-5-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride.

To 7-pyrimidin-5-yl-1-benzofuran-5-amine (0.100 g, 0.473 mmol; intermediate 18) in dichloromethane (2 ml), benzenesulfonyl chloride (0.093 g, 0.524 mmol) and pyridine (347 μl, 430 mmol) are added. ) The mixture was shaken at room temperature for 1 h and the solvent was removed. The crude product is purified by preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid and then converted to the hydrochloride salt by treatment with a 2 M solution of HCl in diethyl ether. Obtain 0.071 g (yield 43%) of the title compound as a yellow solid. HPLC: 97%, R _t = 1.863 min (System A, 10-97% MeSCh for 3 min). ¹ H NMR (500 MHz, DMSO-F ₆ ) δ ppm 6.98 (d, 1 = 2.20 Hz, 1H), 7.34 (d, 1 = 2.20 Hz, 1H), 7.50-7.54 (m, 3H), 7.58-7 60 (m, 1H), 7.80-7.82 (m, 1H), 7.97 (d, 1 = 2.20 Hz, 1H), 9.10 (s, 2H), 9.20 ( s, 1H); 9.87 (s, 1H). SSM8: 351 (M ⁺ ).

Example 33. H- [7- (1-Azabicyclo [2.2.2] oct-2-en-3-yl) benzofuran-5-yl] -2-methoxy-5-methylbenzenesulfonamide hydrochloride.

To a mixture of 7-iodo-5-nitrobenzofuran (0.52 g, 1.79 mmol) and Ρά (ΡΡ1 ₃ ) ₄ (0.206 g, 0.17 mmol) in DMF (10 ml) was added 3-tributylstannyl-1-azabicyclo [2,2,2] oct-2-ene (2.14 g, 5.36 mmol; obtained according to the method of Wuogd, Meά. Siet. Ley., 1994, 4, 2837-2840). The mixture is heated at a temperature of 160 ° C. for 10 min in a closed reaction vessel using controlled microwave energy.

The reaction mixture was diluted with CHC13 and then filtered through a pad of celite and concentrated under reduced pressure. The residue was purified by repeated chromatography on silica gel using gradient elution (CHC1 ₃ CHC1 ₃ + 10% MeOH + 0.4% CH ₃ ), then using CHC ₃ + 10% MeOH + 0.4% CH ₃ , to obtain 399, 5 mg of 3- (5-nitrobenzofuran-7-yl) -1-azabicyclo [2.2.2] oct-2-ene. This intermediate was dissolved in a mixture of solvents of EUN: THF (4: 1, 20 ml) and Raney nickel (~ 1.0 ml of suspension in EUN) was added, followed by hydrazine monohydrate (6 eq.). The mixture was vigorously stirred for 3 hours and then filtered through celite pretreated with water. The filtrate was concentrated, followed by the addition of toluene and evaporated again to give 340 mg of a crude intermediate (7- (1-azabicyclo [2.2.2] oct-2-en-3yl) benzofuran-5-ylamine). Most of this substance (325 mg, 1.35 mmol) is dissolved in an ESM (5 ml). Pyridine (1.05 ml) was added followed by 2-methoxy-5-methylbenzenesulfonyl chloride (267 mg, 1.20 mmol). The resulting mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using gradient elution (CHCl ₃ CHC _{1 3} + 10% MeOH + 0.4% CH ₃ ) to give 230 mg of the free base of the title compound. The free base is dissolved in MeOH and a 1 M solution of HCl in diethyl ether is added to the solution. More diethyl ether was added and the precipitate was collected by filtration to obtain 182 mg of HC1 salt. The product was dissolved in a mixture of CH ₃ MF: MeOH (2: 1) and then purified using preparative reverse phase HPLC. Pure HPLC fractions were combined and then concentrated to give the TFA salt of the final product. The TFA salt is converted to the HCl salt: 100 mg of Ch- [7- (1-azabicyclo [2.2.2] oct-2-en-3yl) benzofuran-5-yl] -2-methoxy-5-methylbenzenesulfonamide hydrochloride is obtained. 'H NMR (27 0 MHz, DMSO-F ₆ ) δ ppm 1.57-1.76 (m, 2H), 2.00-2.20 (m, 3H), 2.21 (s, 3H), 3.00-3.17 (m, 2H), 3, 27-3.66 (m, partially hidden (unclear) signal of the solvent, 3H), 3.86 (s, 3H), 6.99-7.09 (m, 2H), 7.20-7.42 (m , 4H), 7.53-7.60 (m, 1H), 8.05-8.10 (m, 1H), 9.98 (m, s, 1H); SS-M8 (E1 +) for C ₂₃ H ₂₄ H ₂ O ₄ 8, t / ζ: 425 (M) ⁺ .

Intermediate 19. tert-Butyl-4- (5 - {[((2-chlorophenyl) sulfonyl] amino} -1-benzofuran-7-yl) piperazine-1-carboxylate. tert-Butyl-4- (5-amino-1-benzofuran-7-yl) piperazine-1-carboxylate (0.59 g, 1.87 mmol; intermediate 10) was dissolved in an ESM. 2-Chlorobenzenesulfonyl chloride (0.59 g, 2.8 mmol) was added, followed by pyridine (0.45 ml, 5.6 mmol). The reaction mixture was stirred at room temperature overnight. Filter through a layer of silica to give 0.66 g (72% yield) of the title product. HPLC: 92% purity, R _t = 2.56 min (System A, 10-97% MeSCh for 3 min). Ή NMR (400 MHz, SES1 ₃ ) δ ppm 1.48 (s, 9H), 3.07-3.21 (m, 4H), 3.51-3.65 (m, 4H), 6.51 (d, 1 = 2.0 Hz, 1H) 6.62 (d, 1 = 2.3 Hz, 1H), 6.93 (d, 1 = 2.0 Hz, 1H), 7.00 (s, 1H), 7.18-7.31 ( m, 2H), 7.36-7.47 (m, 1H), 7.47-7.57 (m, 2H), 7.90 (dd, 1 = 7.9.1.6 Hz, 1H) . M8 (E81 +), t / ζ: 492.2 (M + H) ⁺ .

Intermediate 20.

2-Chloro-Ch- (7-piperazin-1-yl-1-benzofuran-5-yl) benzenesulfonamide. tert-Butyl-4- (5 - {[((2-chlorophenyl) sulfonyl] amino} -1-benzofuran-7-yl) piperazine-1-carboxylate.

51 010298 (0.66 g, 1.34 mmol; intermediate 19) was dissolved in an ESM (5 ml) and TFA (30% solution of TFA in an ESM; 5 ml) was added and the mixture was stirred for 30 minutes. The solvents are evaporated. The residue was dissolved in water, the pH was adjusted to 8 and extracted with EAUc. The organic layer was dried and evaporated to give 0.41 g (80% yield) of the title product, which was used in the next step without further purification. HPLC: purity = 93%, K _T = 1.61 min (system A; 10-97% MeCX for 3 min).

Intermediate 21.

1- (5-Nitro-1-benzofuran-7-yl) piperazine.

Removal of the X-1-BOC group from tert-butyl-4- (5-nitro-1-benzofuran-7-yl) piperazine-1-carboxylate * is carried out in accordance with the procedure for intermediate 20 to obtain 2.3 g ( 80% yield) of the title compound as a yellow solid. HPLC: purity = 94%, K _T = 1.37 min (system A; 10-97% MeCX for 3 min).

* Previously described in AO 2002100822.

Intermediate 22.

X, X-Diethyl-2 - [4- (5-nitro -1-benzofuran-7-yl) piperazin-1-yl] acetamide.

A mixture of 1- (5-nitro-1-benzofuran-7-yl) piperazine (0.4 g, 1.6 mmol; intermediate 21) and 2 chloro-X, X-diethylacetamide (0.48 g, 3.2 mmol ) in the presence of K ₂ CO ₃ (0.45 g, 3.2 mmol) in DMF is heated at 225 ° C for 5 min using controlled microwave energy. The solvent was evaporated and the residue was triturated with MeCX to give 0.31 g (54% yield) of the title compound as a yellow solid. HPLC: purity = 80%, K _T = 1.63 min (system A; 10-97% MeCX for 3 min). ¹ H NMR (400 MHz, DMSO-b ₆ ) δ ppm 1.02 (t, 1 = 7.0 Hz, 3H), 1.14 (t, 1 = 7.0 Hz, 3H), 2.58-2.77 (m, 4H), 3.14-3 50 (m, 10H), 7.14 (d, 1 = 2.3 Hz, 1H), 7.53 (d, 1 = 2.3 Hz, 1H), 8.18 (dd, 1 = 12, 5, 2.3 Hz, 2H).

Intermediate 23.

2- [4- (5-amino-1-benzofuran-7-yl) piperazin-1-yl] -X, X-diethylacetamide.

The reduction of the nitro group in X, X-diethyl-2- [4- (5-nitro-1-benzofuran-7-yl) piperazin-1-yl] acetamide (0.3 g, 0.83 mmol; intermediate 22) is carried out in accordance with the procedure for the preparation of intermediate 10. Yield: 0.19 g (70%). This substance is used in the next step without further purification.

M8 (EZN), t / ζ: 331.2 (M + H) ⁺ .

Example 34. 2- [4- (5 - {[(2-Chlorophenyl) sulfonyl] amino} -1-benzofuran-7-yl) piperazin-1-yl] -X, diethylacetamide hydrochloride.

2- [4- (5-amino-1-benzofuran-7-yl) piperazin-1-yl] -X, X-diethylacetamide (0.095 g, 0.29 mmol; intermediate 23) is reacted with 2-chlorobenzenesulfonyl chloride in in accordance with the method for obtaining the intermediate product 19. Yield: 0.0 6 g (41%) after purification by preparative HPLC (system E; 20-50% MeCX). ¹ H NMR (400 MHz, DMSO-b ₆ ) δ ppm 1.08 (t, 1 = 6.9 Hz, 3H), 1.15 (t, 1 = 6.9 Hz, 3H), 3.09-3.43 (m, 7H), 3.55-3 65 (m, 2H), 3.67-3.76 (m, 2H), 4.39 (s, 2H), 6.62 (d, 1 = 1.0 Hz, 1H), 6.86 ( d, 1 = 1.3 Hz, 1H), 6.93 (d, 1 = 1.5 Hz, 1H), 7.47 (t, 1 = 7.0 Hz, 1H), 7.60 (q. , 1 = 7.7 Hz, 2H), 7.91 (d, 1 = 1.3 Hz, 1H), 8.01 (d, 1 = 7.8 Hz, 1H), 10.08 (s, 1H ), 10.46 (s, 1H). HPLC: purity = 92%, K _T = 1.85 min (system A; 10-97% MeCX for 3 min). M8 (EM +), t / ζ: 505.2 (M + H) ⁺ .

Example 35. X, X-Diethyl-2- [4- (5 - {[(2-methoxy-5-methylphenyl) sulfonyl] amino} -1-benzofuran-7-yl) piperazin-1-yl] acetamide hydrochloride.

The reaction of 2- [4- (5-amino-1-benzofuran-7-yl) piperazin-1-yl] - X, X-diethylacetamide (0.095 g, 0.29 mmol; intermediate 23) with 2-methoxy 5-methylphenylsulfonyl chloride in accordance with the procedure for the preparation of intermediate product 19. Yield: 0.05 g (33%) after purification by preparative HPLC (system P; 10-50% MeCX). HPLC: purity = 93%, K _T = 1.87 min (system A; 10-97% MeCX for 3 min). ¹ H NMR (400 MHz, DMSO-b ₆ ) δ ppm 1.08 (t, 1 = 1.0 Hz, 3H), 1.16 (t, 1 = 7.0 Hz, 3H), 2.20 (s, 3H), 3.08-3.45 (m , 7H), 3.58-3.73 (m, 4H), 3.87 (s, 3H), 4.40 (s, 2H), 6.61 (d, 1 = 1.8 Hz, 1H) 6.85 (d, 1 = 2.0 Hz, 1H), 6.93 (d, 1 = 1.8 Hz, 1H), 7.04 (d, 1 = 8.5 Hz, 1H), 7 32 (dd, 1 = 8.8, 2.0 Hz, 1H), 7.52 (d, 1 = 1.8 Hz, 1H), 7.89 (d, 1 = 2.3 Hz, 1H) 9.75 (s, 1H); 10.07 (s, 1H). M8 (EM +), t / ζ: 515.4 (M + H) ⁺ .

Intermediate 24.

3- (7-Bromo-1-benzofuran-2-yl) quinuclidin-3-ol.

Stage 1. 3 - [(Trimethylsilyl) ethynyl] quinuclidin-3-ol.

A mixture of 3-quinuclidinone hydrochloride (24.12 g, 0.149 mol) and Xa ₂ CO ₃ (27 g, 0.25 mol) in water (500 ml) was extracted with dichloromethane (500 ml). The organic phase is evaporated to dryness. The residue was dissolved in THF (200 g) and slowly added to a solution of TMS-Y-acetylide (1.1 eq.) In THF (200 g) at a temperature of 0-5 ° C. When the addition is complete, add a solution of HaNSO ₃ in water (500 ml). The organic phase was washed with additional water (500 ml) and evaporated to dryness to give 20.8 9 g (63%) of the title compound as a white solid. ¹ H NMR (270 MHz, SES 1333) δ ppm 0.15 (s, 9H), 1.27-1.46 (m, 1H), 1.47-1.73 (m, 1H), 1.80-2.14 (m, 3H), 2, 61-3.02 (m, 5H), 3.17 (dd, 1 = 13.86, 1.73

- 52 010298

Hz, 1H), 4.14 (br s, 1H).

Stage 2. 3- (7-Bromo-1-benzofuran-2-yl) quinuclidin-3-ol.

Into a round-bottom flask, 2, 6-dibromonitrophenol (3.0 g, 0.0119 mol), 3 - [(trimethylsilyl) ethynyl] quinuclidin-3-ol (2.66 g, 0.0119 mol; introduced in stage 1) are introduced; , Cu ₂ O (1.70 g, 0.0119 mol) and pyridine (200 ml). The resulting mixture was heated at reflux overnight, filtered through celite and the solvent was evaporated. The residue was purified by silica gel chromatography using ethyl acetate (250 ml) and methanol (500 ml) as eluents. The methanol fraction was evaporated, yielding 1.12 g (29%) of the title compound. HPLC: purity = 90%, t / ζ: 322 (M + H) ⁺ .

Intermediate 25.

3- (7-Bromo-1-benzofuran-2-yl) -1-azabicyclo [2.2.2] oct-2-ene.

3- (7-Bromo-1-benzofuran-2-yl) quinuclidin-3-ol (600 mg, 1.86 mmol; intermediate 24, step 2) was dissolved in methanol (2 ml) and formic acid ( 40 ml). The resulting mixture was heated at reflux overnight. Concentrate in vacuo to give 562 mg (99% yield) of the title product. HPLC: purity = 90%, t / ζ: 305 (M + H) ⁺ .

Intermediate 26.

[2- (1-Azabicyclo [2.2.2] oct-2-en-3-yl) -1-benzofuran-7-yl] amine.

3- (7-Bromo-1-benzofuran-2-yl) -1-azabicyclo [2.2.2] oct-2-ene (300 mg, 0.986 mmol; intermediate 25) was dissolved in methanol (2 ml). A concentrated aqueous solution of ammonia (25%, 10 ml) and CuCl ₂ (15 mg) were added and the resulting mixture was heated at 120 ° C for 48 hours. The mixture was passed through a layer of silica using a methanol / ammonia solution (9: 1) as an eluent. Concentrate in vacuo to give 236 mg of the crude title product. This substance is used directly in the following experiments.

Example 36. No. [2- (1-Azabicyclo [2.2.2] oct-2-en-3-yl) -1-benzofuran-7-yl] benzenesulfonamide hydrochloride.

[2- (1-Azabicyclo [2.2.2] oct-2-en-3-yl) -1-benzofuran-7-yl] amine (118 mg, 0.493 mmol; intermediate 26), benzenesulfonyl chloride (104 mg 0.592 mmol) and triethylamine (137 μl, 0.986 mmol) are dissolved in ethanol (5 ml). The mixture is shaken for 2 hours. Purification is carried out using preparative HPLC (gradient: 20-90% acetonitrile / TFA-water). Evaporate to give 47 mg of the TFA salt, which is converted to the HC1 salt by stirring with HC1 / diethyl ether. Yield: 37 mg (18%). HPLC: purity = 99%, t / ζ: 381 (M + H) ⁺ . 'H NMR (270 MHz, methanol-6 ₆ ) δ ppm 1.74-1.91 (m, 2H), 2.10-2.26 (m, 2H), 3.15-3.29 (m, 2H), 3.49-3.57 (m, 1H ), 3.64-3.78 (m, 2H), 6.97-7.01 (m, 1H), 7.13-7.28 (m, 3H), 7.387.57 (m, 4H), 7.70-7.76 (m, 2H).

Example 37. No. [2- (1-Azabicyclo [2.2.2] oct-2-en-3-yl) -1-benzofuran-7-yl] -2-methoxy-5-methylbenzenesulfonamide hydrochloride.

The title compound was prepared according to a similar procedure as in Example 36. Yield: 56 mg (25%). HPLC: purity = 99%, t / ζ: 425 (M + H) ⁺ . 'H NMR (270 MHz, δ ppm 1.77-

1.96 (m, 2H), 2.06-2.20 (m, 2H), 2.22 (s, 3H), 3.14-3.32 (m, 2H), 3.39-3, 48 (m, 1H), 3.55-3.71 (m, 2H), 3.97 (s, 3H), 6.89-6.95 (m, 2H), 7.06-7.29 ( m, 5H), 7.41 (dd, 1 = 7.92, 0.99 Hz, 1H).

Example 38. No. [7- (1-Azabicyclo [2.2.2] oct-3-yloxy) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride.

Stage 1. 3 - [(5-Nitro-1-benzofuran-7-yl) oxy] quinuclidine.

7-Iodine-5-nitro-1-benzofuran (1.00 g, 3.46 mmol), quinuclidin-3-ol (1.10 g, 8.65 mmol), 1.10 phenanthroline (0.25 g, 1 , 38 mmol), Cu1 (0.13 g, 0.69 mmol) and toluene (20 ml) are mixed together and heated at 140 ° C overnight. The solvent was removed in vacuo and the crude product was purified by flash chromatography (eluent: hexane / chloroform: MeOH: triethylamine, 9: 0.9: 0.1) to obtain

3 - [(5-nitro-1-benzofuran-7-yl) oxy] quinuclidine (3.46 mmol).

Step 2. 7- (1-Azabicyclo [2.2.2] oct-3-yloxy) -1-benzofuran-5-amine.

3 - [(5-Nitro-1-benzofuran-7-yl) oxy] quinuclidine (1.38 g, 4.79 mmol; obtained in step 1) was dissolved in ethanol: THF (100 ml: 25 ml) and added Raney Nickel (suspension in ethanol, 6 ml) and hydrazine (891 μl, 0.18 mmol). The mixture was stirred at room temperature for 3 hours and then filtered through celite and the solvent was removed in vacuo. The crude product is purified using flash chromatography [eluent: ESM: methanol (6: 1) and chloroform: MeOH: triethylamine (9: 1: 0.1)] to give 7- (1-azabicyclo [2.2, 2] oct-3-yloxy) -1-benzofuran-5-amine (500 mg, yield 4 0%).

Step 3. Ν- [7- (1-Azabicyclo [2.2.2] oct-3-yloxy) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride.

To 7- (1-azabicyclo [2.2.2] oct-3-yloxy) -1-benzofuran-5-amine (0.50 g, 0.194 mmol; obtained in step 2), benzenesulfonyl chloride is added in an ESM (2 ml) (30 μl, 0.232 mmol) and pyridine (141 μl, 1.74 mmol). The mixture was shaken at room temperature for 2 hours and then the solvent was removed in vacuo. Purification of the product is carried out using preparative HPLC using gradient

- 53 010298 mer acetonitrile - water containing 0.1% trifluoroacetic acid. The obtained TFA salt is converted to the hydrochloride by treatment with a 2 M solution of HCl in diethyl ether. Yield: 11.0 mg (11.8%). HPLC: 100%, K _T = 1.680 min (system B; 10-97% MeCN for 3 min). ¹ H NMR (270 MHz, methanol ₆ δ ppm 0.91 (t, 1 = 7.05 Hz, 1H), 1.31 (m, 1H), 1.89-2.36 (m 5H), 3.32-3.46 (m, 4H), 3.77-3.87 (m, 1H), 6.68-6.74 (m, 2H), 6.94 (s, 1H ), 7.43-7.56 (m, 3H), 7.68-7.73 (m, 3H). L-M8: 399 (M + H) ⁺ .

Example 39. Ν- | 7- (1-Azabicyclo [2.2.2] oct-3-yloxy) -1-benzofuran-5-yl] -2-chlorobenzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure for Example 38, step 3, starting from 7- (1-azabicyclo [2.2.2] oct-3-yloxy) -1-benzofuran-5-amine (obtained in Example 38, stage 2) and 2chlorobenzenesulfonyl chloride (0.49 g, 0.232 mmol). Yield: 55 mg (54%). HPLC: 100%, K _T = 1.760 min (system B; 10-97% MeCN for 3 min). ¹ H NMR (270 MHz, methanol ₆ ) δ ppm 1.80-2.35 (m, 5H), 2.18 (d, 1 = 7.42 Hz, 1H), 2.25 (s, 1H), 3.29-3.30 (m, 2H) 3.41 (t, 1 = 8.04 Hz, 2H); 3.83 (dd, 1 = 13.61; 7.92 Hz, 1H),

3.97 (s, 1H), 6.73-6.76 (m, 2H), 6.99-7.05 (m, 2H), 7.33-7.36 (m, 1H), 7, 50-7.54 (m, 1H), 7.70 (t, 1 = 2.60 Hz, 1H), 7.96 (d, 1 = 7.67 Hz, 1H). L-M8: 433 (M + H) ⁺ .

Example 40. No. [7- (1-Azabicyclo [2.2.2] oct-3-yloxy) -1-benzofuran-5-yl] -2-methoxy-5-methylbenzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure for Example 38, step 3, starting from 7- (1-azabicyclo [2.2.2] oct-3-yloxy) -1-benzofuran-5-amine (obtained in Example 38, step 2) and 2 methoxy-5-methylbenzenesulfonyl chloride (0.51 g, 0.232 mmol). Yield: 80 mg (77%). HPLC: 100%, K _T = 1.794 min (system B; 10-97% MeCN for 3 min). ¹ H NMR (270 MHz, methanol ₄ ) δ ppm 0.92 (d, 1 = 7.92 Hz, 1H), 1.28-1.37 (m, 1H), 1.99 (d, 1 = 11.13 Hz, 3H), 2.21 (s , 3H), 2.36 (s, 1H), 3.46-3.48 (m, 4H), 3.85 (d, 1 = 1.18 Hz, 1H), 3.96 (s, 3H) 5.02-5.04 (m, 1H), 6.73-6.77 (m, 2H), 6.96 (s, 1H), 7.03 (d, 1 = 8.41 Hz, 1H ),

7.32 (d, 1 = 7.42 Hz, 1H), 7.49 (s, 1H), 7.70 (d, 1 = 1.48 Hz, 1H). L-M8: 443 (M + H) ⁺ .

Intermediate 27.

(2-Morpholin-4-yl-ethyl) (5-nitro-1-benzofuran-7-yl) -amine.

7-Iodine-5-nitrobenzofuran (1.00 g, 3.46 mmol), 4- (2-aminoethyl) morpholine (0.54 g, 4.15 mmol), No. 1O1Vi (0.47 g, 0.00484 mol), xanthos (0.20 g, 0.346 mmol) and Pb ₂ (ba) ₃ (80 mg, 0.08 65 mol) are heated in xylene (20 ml) at a temperature of 120 ° C for 1.5 hours. the mixture was filtered through celite and the solvent was evaporated. The residue was passed through a silica layer using dichloromethane (ISM) and then, in a ratio of 90: 9: 1, an ESM / MeOH ^ H mixture (25% aqueous solution) as an eluent. The product containing fractions were concentrated to give 0.978 g (97% yield) of the title compound as a dark yellow oil. HPLC: purity = 97%, t / ζ: 292 (M + H) ⁺ . ¹ H NMR (270 MHz, COC _{1 3} ) δ ppm 2.44-2.61 (m, 4H), 2.75 (t, 1 = 5.81 Hz, 2H), 3.31-3.43 (m, 2H), 3.69-3.82 ( m, 4H), 6.85 (d, 1 = 1.98 Hz, 1H), 7.36 (d, 1 = 1.98 Hz, 1H), 7.70 (d, 1 = 1.98 Hz, 1H), 7.90 (d, 1 = 2.23 Hz, 1H).

Intermediate 28.

^ - (2-Morpholin-4-yl-ethyl) -1-benzofuran-5,7-diamine.

(2-Morpholin-4-yl-ethyl) (5-nitro-1-benzofuran-7-yl) -amine (450 mg, 1.545 mmol; intermediate 27) was dissolved in TTF (5 ml). After adding ethanol (100 ml), Raney nickel (cat.) And hydrazine hydrate (2 ml), the mixture was allowed to stir at room temperature for 2 hours. The product was used directly in the next reaction after filtration through celite and evaporation of the solvent.

Intermediate 29.

4- {2 - [(5-Nitro-1-benzofuran-7-yl) oxy] ethyl} morpholine.

7-iodo-5-nitrobenzofuran (1.0 g, 0.00346 mol), 4- (2-hydroxyethyl) morpholine (0.91 g, 0.00692 mol), cesium carbonate (2.25 g, 0.00692 mol), 1.10-phenanthroline (0.25 g, 0.00138 mol) and CU (130 mg, 0.692 mmol). Toluene (15 ml) was added and the solution was heated at 81 eB1osk for 72 hours. After filtration through celite, the crude material was purified by flash chromatography (EULAc / ISM; 1: 1). Yield: 32%, HPLC: purity = 90%, t / ζ: 293 (M + H) ⁺ .

Intermediate 30.

[7- (2-Morpholin-4-yl-ethoxy) -1-benzofuran-5-yl] -amine.

The title compound was prepared according to a similar procedure for the preparation of intermediate 28, starting from intermediate 29. The product was used directly in the next reaction (Example 45).

Example 41

No. {7 - [(2-Morpholin-4-yl-ethyl) amino] -1-benzofuran-5-yl} -benzenesulfonamide hydrochloride.

To a solution of ^ - (2-morpholin-4-yl-ethyl) -1-benzofuran-5,7-diamine (58 mg, 0.221 mmol; intermediate 28) in dichloromethane (2 ml) was added triethylamine (62 μl, 0.4 42 mmol) and benzenesulfonyl chloride (39 mg, 0.221 mmol). The mixture was stirred at room temperature for 1 h and evaporated. The residue was purified by preparative HPLC (system Ό), the pure fractions were evaporated, and the resulting TFA salt was converted to the HC1 salt. Yield: 32%. HPLC: purity = 100%, t / ζ: 402 (M + H) ⁺ . ^! H NMR (270 MHz, methanol ₄ ) δ ppm 3.43 (t, 1 = 6.06 Hz, 2H), 3.40-3.61 (m, 1 = 6.06, 6.06 Hz, 4H), 3.68 (t,

- 54 010298

1 = 6.06 Hz, 2H), 3.75-4.14 (m, 4H), 6.48-6.55 (m, 2H), 6.64 (d, 1 = 2.23 Hz, 1H ), 7.41-7.59 (m, 3H), 7.65-7.74 (m, 3H).

Example 42. 2-Methoxy-5-methyl-Y- {7 - [(2-morpholin-4-yl-ethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure for Example 41. Yield: 37%. HPLC: purity = 100%, t / ζ: 446 (M + H) ⁺ . ¹ H NMR (270 MHz, methanol-b ₄ ) δ ppm 2.18-2.24 (s, 3H), 3.353.60 (m, 4H), 3.43 (t, 1 = 5.94 Hz, 2H), 3.67 (t, 1 = 5.94 Hz , 2H), 3.74-4.07 (m, 4H), 3.94-3.99 (m, 3H), 6.51 (d, 1 = 1.98 Hz, 1H), 6.63 ( dd, 1 = 4.08, 2.10 Hz, 2H), 7.03 (d, 1 = 8.41 Hz, 1H), 7.32 (dd, 1 = 8.78, 2.60 Hz, 1H ), 7.49 (d, 1 = 2.23 Hz, 1H), 7.64 (d, 1 = 2.23 Hz, 1H).

Example 43. Y- {7 - [(2-Morpholin-4-yl-ethyl) amino] -1-benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure for Example 41. Yield: 38%. HPLC: purity = 100%, t / ζ: 470 (M + H) ⁺ . '11 NMR (270 MHz, methanol-b ₄ ) δ ppm 3.15-3.63 (m, 4H), 3.43 (t, 1 = 5.94 Hz, 2H), 3.67 (t, 1 = 6.06 Hz, 2H), 3.72-4 14 (m, 4H), 6.49 (d, 1 = 1.73 Hz, 1H), 6.64 (dd, 1 = 7.42, 1.98 Hz, 2H), 7.60-7, 75 (m, 3H), 7.88-7.94 (m, 1H), 8.00-8.04 (m, 1H).

Example 44. 2,6-Dichloro-Y- {7 - [(2-morpholin-4-yl-ethyl) amino] -1-benzofuran-5-yl} -benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure for Example 41. Yield: 19%. HPLC: purity = 100%, t / ζ: 470 (M + H) ⁺ . '11 NMR (270 MHz, methanol-b ₄ ) δ ppm 3.22-3.60 (m, 4H), 3.45 (t, 1 = 5.94 Hz, 2H), 3.69 (t, 1 = 5, 94 Hz, 2H), 3.72-4 13 (m, 4H), 6.58 (d, 1 = 1, 98 Hz, 1H), 6.67 (dd, 1 = 9.65, 1.98 Hz, 2H), 7.33-7, 41 (m, 1H), 7.45-7.52 (m, 2H), 7.66 (d, 1 = 1.98 Hz, 1H).

Example 45. 2-Methoxy-5-methyl-Y- [7- (2-morpholin-4-yl-ethoxy) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure for Example 41 starting from [7 (2-morpholin-4-yl-ethoxy) -1-benzofuran-5-yl] -amine (intermediate 30). Yield: 32%. HPLC: purity = 99%, t / ζ: 447 (M + H) ⁺ . Ή NMR (270 MHz, methanol-b ₄ ) δ ppm 2.20 (s, 3H), 3.26-3.74 (m, 4H), 3.663.72 (m, 2H), 3.75-4.15 (m, 4H), 3.96 (s, 3H), 4.49-4.57 (m, 2H), 6.73 (d, 1 = 2.23 Hz, 1H), 6.85 (d, 1 = 1.98 Hz, 1H), 6, 96 (d, 1 = 1.98 Hz, 1H), 6.99-7.04 (m, 1H), 7.27-7.34 (m, 1H), 7.51 (d, 1 = 2, 23 Hz, 1H), 7.70 (d, 1 = 2.23 Hz, 1H).

Example 46. 3-Methyl-Y- [7- (2-morpholin-4-ylethoxy) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure for Example 41 starting from [7 (2-morpholin-4-yl-ethoxy) -1-benzofuran-5-yl] -amine (intermediate 30). Yield: 28%. HPLC: purity = 98%, t / ζ: 417 (M + H) ⁺ . 'H NMR (270 MHz, methanol-b ₄ ) δ ppm 2.28-2.36 (m, 3H), 3.24-3.69 (m, 4H), 3.67-3.73 (m, 2H), 3.76-4.17 (m, 4H) ), 4.51-4.59 (m, 2H), 6.74 (d, 1 = 2.23 Hz, 1H), 6.82 (d, 1 = 1.98 Hz, 1H), 6.89 (d, 1 = 1.98 Hz, 1H), 7.27-7.40 (m, 2H), 7.46-7.57 (m, 2H), 7.73 (d, 1 = 2.23 Hz, 1H).

Example 47. 3-Chloro-4-methyl-Y- [7- (2-morpholin-4-yl-ethoxy) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure for Example 41 starting from [7 (2-morpholin-4-yl-ethoxy) -1-benzofuran-5-yl] -amine (intermediate 30). Yield: 11%. HPLC: purity = 99%, t / ζ: 451 (M + H) ⁺ . '11 NMR (270 MHz, methanol-C1 ₄ ) δ ppm 2.36-2.39 (m, 3H), 3.31-3.71 (m, 4H), 3.68-3.74 (m, 2H), 3.75-4.22 (m, 4H) ), 4.54-4.61 (m, 2H), 6.77 (d, 1 = 1.98 Hz, 1H), 6.87 (q, 1 = 1.98 Hz, 2H), 7, 35-7.40 (m, 1H), 7.48-7.54 (m, 1H), 7.66 (d, 1 = 1.73 Hz, 1H), 7.75 (d, 1 = 1, 98 Hz, 1H).

Intermediate 31.

[2- (Dimethylamino) ethyl] (5-nitro-1-benzofuran-7-yl) amine.

To 7-iodo-5-nitro-1-benzofuran (1.00 g, 3.46 mmol), L, L-dimethylethane-1,2-diamine (0.37 g, 4.15 mmol), Rb ₂ ( ba) ₃ (0.08 g, 0.87 mmol), xanthos (0.20 g, 0.35 mmol) and Cg ₂ CO ₃ (1.59 g, 4.84 mmol) add xylene (75 ml) . The mixture was stirred at 120 ° C. overnight, filtered through celite and the solvent was removed in vacuo. The crude product was purified by flash chromatography [eluent: ESM: MeOH (6: 1) and ESM: MeOH: E1 ₃ S (9: 1: 0.1)] to give 0.37 8 g (44% yield) of the title connections. HPLC: 90%, _W = 1.430 min (System A, 10-97% Mesa for 3 min). Ή NMR (270 MHz, methanol-b ₄ ) δ ppm 2.44 (d, 1 = 3.22 Hz, 6H), 2.81 (t, 1 = 6.56 Hz, 2H), 3.52 (t, 1 = 6.56 Hz, 2H), 6, 97 (d, 1 = 2.23 Hz, 1H), 7.40 (d, 1 = 2.23 Hz, 1H), 7.89 (t, 1 = 1.98 Hz, 2H), L-M8 250 (M + H) ⁺ . L-M8: 250 (M + H) ⁺ .

Example 48. Ν- (7- {[2- (Dimethylamino) ethyl] amino} -1-benzofuran-5-yl) -2-methoxy-5-benzenesulfonamide.

Stage 1. N ⁷ - [2- (Dimethylamino) ethyl] -1-benzofuran-5,7-diamine.

To [2- (dimethylamino) ethyl] (5-nitro-1-benzofuran-7-yl) amine (0.378 g, 1.52 mmol; intermediate 31) in a mixture of ethanol (100 ml) and THF (25 ml) Raney Nickel (suspension in ethanol, 2 ml) and hydrazine (295 μl, 6.08 mmol). The reaction mixture was stirred at room temperature for 2 hours. An additional amount of Raney nickel (suspension in ethanol, 2 ml) and hydrazine were added.

55 010298 (295 μl, 6.08 mmol) and stirred overnight. The mixture was filtered through celite and the solvent was removed. The crude product is used in the next step without further purification.

Step 2. I- (7- {[2- (Dimethylamino) ethyl] amino} -1-benzofuran-5-yl) -2-methoxy-5-benzenesulfonamide.

To I ⁷ - [2- (dimethylamino) ethyl] -1-benzofuran-5,7-diamine (0.120 g, 0.547 mmol; from step 1), 2-methoxy-5-methylbenzenesulfonyl chloride (0.145 g) was added to an ESM (1 ml) 0.657 mmol) and pyridine (398 μl, 4.93 mmol). The mixture was shaken at room temperature for 1 h, the solvent was removed in vacuo and the product was purified by preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid. The resulting TFA salt was converted to the hydrochloride by treatment with a 2 M solution of HCl in diethyl ether to give 13.3 mg (6% yield) of the title product. HPLC: 99%, CT = 1,692 min (system A; 10-97% MeCI for 3 min). ¹ H NMR (270 MHz, methanol-a4) δ ppm 2.21 (s, 3H), 2.94 (s, 6H), 3.40 (t, 1 = 5.69 Hz, 2H), 3.60-3.64 (m, 2H), 3.97 (s, 3H), 6.52 (s, 1H), 6.64 (t, 1 = 2.10 Hz, 1H), 7.03 (d, 1 = 8.41 Hz, 1H), 7.32 (d, 1 = 6.19 Hz, 1H), 7.50 (d, 1 = 1, 98 Hz, 1H), 7.65 (d, 1 = 2.23 Hz, 2H). L-M8: 404 (M + H) ⁺ .

Example 49. 2-Chloro-I- (7- {2- (dimethylamino)} - 1-benzofuran-5-yl) benzenesulfonamide hydrochloride.

To I ⁷ - [2- (dimethylamino) ethyl] -1-benzofuran-5,7-diamine (0.120 g, 0.547 mmol; example 48, step 1), 2-chlorobenzenesulfonyl chloride (0.139 g, 0.657) was added to an ESM (1 ml) mmol) and pyridine (398 μl, 4.93 mmol). The mixture was shaken at room temperature for 1 h, the solvent was removed in vacuo and the product was purified by preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid. The resulting TFA salt was converted to the hydrochloride by treatment with a 2 M solution of HCl in diethyl ether to give 22.8 mg (10% yield) of the title product. HPLC: 99%, CT = 1.651 min (system A; 10-97% MeCI for 3 min). ¹ H NMR (270 MHz, methanol-a4) δ ppm 2.94 (s, 6H), 3.40 (s, 2H), 3.65 (d, 1 = 1.48 Hz, 2H), 6.65 (d, 1 = 1.73 Hz, 1H), 7.36 (t, 1 = 1.18 Hz, 2H), 7.50-7.56 (m, 3H), 7.66 (d, 1 = 1.73 Hz, 1H), 7.97 (d , 1 = 7.67 Hz, 1H). L-M8: 394 (M + H) ⁺ .

Intermediate 32.

I- (5-Nitro-1-benzofuran-7-yl) pyridin-4-ylamine.

A mixture of 7-iodo-5-nitro-1-benzofuran (1.00 g, 3.46 mmol), 4-aminopyridine (0.39 g, 4.15 mmol), xanthos (0.20 g, 0.36 mmol ), Ra ₂ (aBa) ₃ (0.08 g, 0.09 mmol), ΝαΟίΒιι (0.47 g, 4.84 mmol) in xylene (200 ml) are heated at 120 ° C overnight. The reaction mixture was filtered through celite and a yellow precipitate formed, which was collected by filtration to obtain 0.52 g (60% yield) of the title product. HPLC: 96%, R _t = 1.344 min (System A, 10-97% impurity for 3 min). ¹ H NMR (270 MHz, methanol-a ₄ ) δ ppm 6.91-7.12 (m, 4H), 8.00 (d, 1 = 2.23 Hz, 1H), 8.15-8.24 (m, 2H), 8.37 (d, 1 = 2.23 Hz, 1H). L-M8: 256 (M + H) ⁺ .

Intermediate 33.

(5 - amino-1-benzofuran-7-yl) pyridin-4-ylamine.

To I- (5-nitro-1-benzofuran-7-yl) pyridin-4-ylamine (0.52 g, 2.08 mmol; intermediate

32) Raney nickel (suspension in ethanol, 2 ml) and hydrazine (404 μl, 8.33 mmol) are added to a mixture of ethanol (40 ml) and THF (10 ml). The mixture was stirred at room temperature for 3 hours, filtered through celite and the solvent was removed in vacuo to give 0.27 g (53% yield) of the title product. HPLC: 96%, R _t = 0.964 min (System A, 10-97% impurity for 3 min). ¹ H NMR (270 MHz, methanol-a ₄ ) δ ppm 6.69 (d, 1 = 2.23 Hz, 1H), 6.72 (d, 1 = 2.23 Hz, 1H), 6.77 (d, 1 = 1.98 Hz, 1H), 6, 83 (dd, 1 = 4.95, 1.48 Hz, 2H), 7.62 (d, 1 = 1.98 Hz, 1H), 8.08-8.10 (m, 2H). L-M8: 226 (M + H) ⁺ .

Example 50. I- [7- (Pyridin-4-ylamino) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride.

K (5-amino-1-benzofuran-7-yl) pyridin-4-ylamine (90 mg, 0.40 mmol; intermediate

33) benzenesulfonyl chloride (65 μl, 0.48 mmol) and pyridine (289 μl, 3.58 mmol) are added to the ESM (2 ml). The mixture was heated at 40 ° C. for 10 minutes, shaken at room temperature for 1 hour, and the solvent was removed in vacuo. The residue was purified by preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid. The resulting TFA salt was converted to the hydrochloride by treatment with a 2 M solution of HCl in diethyl ether to give 7 8.7 mg (yield 4 5%) of the title product. HPLC 100%, R _t = 1.560 min (System A, 10-97% impurity for 3 min). ¹ H NMR (270 MHz, methanol-a ₄ ) δ ppm 6.91 (s, 1H), 7.04 (d, 1 = 2.23 Hz, 2H), 7.36 (d, 1 = 1.98 Hz, 1H), 7.51-7.65 (m , 3H), 7.74-7.77 (m, 2H), 8.03 (d, 1 = 1.98 Hz, 1H), 8.32 (d, 1 = 6.93 Hz, 2H), 10 43 (s, 1H); 10.84 (s, 1H). L-M8: 366 (M + H) ⁺ .

Example 51. 2-Chloro-I- [7- (pyridin-4-ylamino) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride.

Obtained by a similar procedure as for the preparation of I- [7- (pyridin-4-ylamino) -1-benzofuran-

5-yl] benzenesulfonamide hydrochloride (Example 50), starting from 2-chlorobenzenesulfonyl chloride (101 mg, 0.48 mmol). The result is 60.3 mg (32% yield) of 2-chloro-I- [7- (pyridin-4-ylamino) -1benzofuran-5-yl] benzenesulfonamide hydrochloride. HPLC 100%, R _t = 1.639 min (System A, 10-97% impurity for 3 min). ^! H NMR (270 MHz, methanol-a ₄ ) δ ppm 6.92 (s, 1H), 7.03 (d, 1 = 2.23 Hz, 1H), 7.09 (d, 1 = 1.98 Hz, 1H), 7.36 (d, 1 = 2 , 23 Hz, 1H), 7.48-7.53 (m, 1H), 7.60-7.68 (m, 2H), 8.02-8.06 (m, 2H), 8.33 ( d, 1 = 7.18 Hz, 2H), 10.74 (s, 1H), 10.86 (s, 1H). L-M8: 400 (M + H) ⁺ .

- 56 010298

Example 52. 2-Methoxy-5-methyl-Y- [7- (pyridin-4-ylamino) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride.

Obtained by a similar procedure as for obtaining No. [7- (pyridin-4-ylamino) -1-benzofuran5-yl] benzenesulfonamide hydrochloride (Example 50), starting from 2-methoxy-5-methylbenzenesulfonyl chloride (105 mg, 0.48 mmol) . The result is 50.9 mg (26% yield) of 2-methoxy-5-methyl-Y- [7 (pyridin-4-ylamino) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride. HPLC 100%, R _t = 1.692 min (System A, 10-97% MeCN over 3 min). 'Η NMR (270 MHz, methanol-b ₄ ) δ ppm 2.21 (s, 3Η), 3.86 (s, 3Η), 6.91 (s, 1Η), 7.02-7.09 (m, 3Η), 7.33-7.38 (m, 2Η), 7.55 (d, 1 = 1.73 Hz, 1Η), 8.00 (d, 1 = 1, 98 Hz, 1Η),

8.32 (d, 1 = 6.93 Hz, 2Η), 10.04 (s, 1Η), 10.78 (s, 1Η). BS-M8: 410 (M + H) ⁺ .

Example 53. 2-Methoxy-5-methyl-Y- [7- (piperazin-1-ylcarbonyl) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride.

Stage 1. 7-Bromo-2-trimethylsilanylbenzofuran-5-ylamine.

7-Bromo-5-nitro-2-trimethylsilylbenzofuran (5.0 g, 15.9 mmol; intermediate 4, step 2) was reduced with P1O ₂ (363 mg, 1.6 mmol) in ESAc (100 ml) in hydrogen atmosphere at a pressure of 2.5 bar overnight. The resulting mixture was filtered through wet celite to give 4.5 g (quantitative yield) of 7-bromo-2-trimethylsilanylbenzofuran-5-ylamine.

Stage 2. No. (7-Bromo-2-trimethylsilanylbenzofuran-5-yl) -2-methoxy-5-methylbenzenesulfonamide.

The amine coupling reaction (4.5 g, 15.9 mmol) of step 1 is carried out with 2-methoxy-5-methylphenylsulfonyl chloride (3.5 g, 15.9 mmol) in dichloromethane (200 ml) using pyridine as the base ( 3.2 ml, 4 0 mmol) for 2.5 hours at ambient temperature. The resulting mixture was washed with water, dried and concentrated to give 7.4 g (100% yield) No. (7-bromo-2-trimethylsilanylbenzofuran-5-yl) -2-methoxy-5-methylbenzenesulfonamide as a dark orange solid.

Stage 3. 4- [5- (2-Methoxy-5-methylbenzenesulfonylamino) benzofuran-7carbonyl] piperazine-1-carboxylic acid tert-butyl ester.

Shsk carbonylation is carried out under controlled microwave irradiation, heating at a temperature of 150 ° C for 15 minutes by mixing the above bromide (168 mg, 0.36 mmol) from step 2, (tert-butoxycarbonyl) piperazine (134 mg, 0.72 mmol), Mo (CO) ₆ (48 mg, 0.18 mmol), trans-di (acetate) bis [o- (di-o-tolulfosphino) benzyl] dipalladium- (P) (Herrmann catalyst, 36 mg, 0 , 04 mmol), an aqueous solution of K ₂ CO ₃ (4 M; 300 μl, 1.3 mmol) and diglyme (1 ml). About 50% of the product is obtained with residual 1M8 (tetramethylsilane) (4- [5- (2-methoxy-5methylbenzenesulfonylamino) -2-trimethylsilanylbenzofuran-7-carbonyl] piperazine-1-carboxylic acid tert-butyl ester) and about 7% of the product without GM8, that is, the title of the product. Both products are isolated in pure form using preparative HPLC (Οί18οη; using a gradient of 30-70%

MESX). Yield of tM8 product: 53 mg (24%), yellow oil. HPLC 100%, R _t = 2.06 min (System C; 2-95% MeCN over 2 min). The BM8 group is removed by stirring with 1-Βι.ιΝΈ ^- (0.5 ml, 1 M solution in THF) in THF (3 ml) at ambient temperature for 1 h 20 min. Purify using preparative HPLC (gradient 30-70% MeC #) to give the additional title product as a yellow oil.

Step 4. 2-Methoxy-5-methyl-Y- [7- (piperazin-1-ylcarbonyl) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride.

Deprotection of the Ν-ΐ-BOC group in 4- [5- (2-methoxy-5-methylbenzenesulfonylamino) benzofuran-7-carbonyl] piperazine-1-carboxylic acid tert-butyl ester (step 3) is carried out by adding ΗC1 / diethyl ether to a solution of the above substrate in ethyl acetate and stirring overnight at ambient temperature. By concentrating the solution, the title product is obtained as a white solid. Yield: 31 mg. HPLC: 96%, R _t = 2.73 min (System A, 30-80% MeCN over 3 min); 1.05 min (system C; 2-95% MeCN for 2 min). 'Η NMR (400 MHz, methanol-b ₄ ) δ ppm 2.17 (s, 3Η), 3.19 (m, 2Η), 3.34 (m, 2Η), 3.49 (m, 2Η), 3.91 (s, 3Η), 4.01 (m , 2Η) 6.80 (d, 1 = 2.2 Hz, 1Η), 6.99 (d, 1 = 8.6 Hz, 1Η), 7.20 (d, 1 = 2.2 Hz, 1Η) , 7.28 (dd, 1 = 8.6, 2.0 Hz, 1Η), 7.45 (d, 7 = 2.2 Hz, 1Η), 7.49 (d, 1 = 2.0 Hz, 1Η), 7.76 (d, 1 = 2.0 Hz, 1Η), ¹³ С NMR (400 Hz, MeOShb ₄ ) δ ppm 19.15, 55.60, 94.55, 106.86, 112.31, 116.62, 118.32, 118.44, 125.90, 129.07, 129.89, 130.51, 133, 47, 135.37, 140.33, 147.22, 147.92, 154.75, 166.24 (C = O). M8 (EM) for t / ζ: 430 (M + H) ⁺ .

Example 54. 2-Methoxy-5-methyl-Y- [7- (piperazin-1-ylmethyl) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride.

To a solution of 4- [5- (2-methoxy-5-methylbenzenesulfonylamino) -2-trimethylsilanylbenzofuran-7-carbonyl] piperazine-1-carboxylic acid tert-butyl ester (94 mg, 0.16 mmol; obtained in Example 53, step 3) LABAH ₄ (22 mg, 0.56 mmol) was added to THF and allowed to mix overnight at 80 ° C (only 50% conversion to bisamine with removed β-BOC and tM8 after 3 hours). The solution is neutralized by adding an aqueous 1 M solution ΗΟ and extracted with ethyl acetate, but with a small amount of product in the organic phase. Therefore, the resulting aqueous phase is acidified and then concentrated. Purification was carried out using preparative HPLC (Οί18οη; gradient: 20-50%

- 57 010298

MESA) to obtain 14 mg of pure product as a TFA salt. Conversion to the HC1 salt is carried out using a 6 M aqueous HC1 solution. Upon concentration, the final product is obtained in the form of a white solid. Yield: 15 mg. HPLC: 100%, I _t = 2.51 min (system A; 30-80% MECA for 3 min); 0.94 min (system C; 2-95% MECA for 2 min). ¹ H NMR (400 Hz, MeOH-b ₄ ) δ ppm 2.14 (s, 3H),

2.98 (s, 3H), 3.66 (broad m, 9H), 4.69 (s, 2H), 6.80 (d, 1 = 8.3 Hz, 1H), 6.82 (d , 1 = 2.2 Hz, 1H), 7.14 (dd, 1 = 8.3, 2.2 Hz, 1H), 7.38 (d, 1 = 2.0 Hz, 1H), 7.40 (d, 1 = 2.0 Hz, 1H), 7.52 (d, 1 = 2.2 Hz, 1H), 7.82 (d, 1 = 2.2 Hz, 1H). M8 (E81) for С21Н25Ы3О48, t / ζ: 416 (M + H) ⁺ .

Example 55. Y- {7 - [(3-Aminopyrrolidin-1-yl) methyl] -1-benzofuran-5-yl} -2-methoxy-5-methylbenzenesulfonamide hydrochloride.

To a solution of {1- [5- (2-methoxy-5-methylbenzenesulfonylamino) -2-trimethylsilanylbenzofuran-7-carbonyl] pyrrolidin-3-yl} carbamic acid * (84 mg, 0.14 mmol) in THF 1A1N added ₄ (22 mg, 0.56 mmol) and the resulting mixture was allowed to stir for 4 hours at 80 ° C. Ethyl acetate was added and the mixture was washed with 1 M aqueous HC1 and then with water, dried and concentrated to obtain 37 mg of mono-Boc-protected diamine. (According to HPLC, 34% is recovered in the furan ring). Purification was carried out using preparative HPLC (Schop; gradient: 40-80% MeCY) to obtain pure Boc-protected diamine. Deprotection of nitrogen is carefully carried out overnight in a 6 M aqueous solution of HC1 (mixing with a solution of HC1 in diethyl ether at 60 ° C during the night gives only 25% of the product plus some by-products) to obtain, after evaporation, the product as yellow solid. Yield: 16 mg. HPLC: 92%, I _t = 1.30 min (system A; 30-80% MECA for 3 min); 1.03 min (system C; 2-95% MECA for 2 min). The peaks in the proton NMR spectrum are broadened due to the conformational flexibility of the pyrrolidine ring. ¹ H NMR (400 MHz, methanol-b ₄ ) δ ppm 1.44 (broad s, 1H), 2.17 (s, 3H), 2.38 (broad s, 1H), 3.37-3.83 (broad m, 4H), 3.97 ( s, 3H), 4.08-4.73 (br.m, 3H), 6.82 (br s, 1H), 7.03 (m, 1H), 7.22-7.34 (br. m, 5H), 7.48 (m, 3H), 7.81 (br s, 1H). M8 (E81) for C ₂ 1H ₂₅ N ₃ O ₄ 8, t / ζ: 416 (M + H) ⁺ .

* Obtained from pyrrolidin-3-yl-carbamic acid tert-butyl ester in accordance with the procedure of Example 53 (step 3).

The intermediate product 34.

Octahydrothieno [3,4-b] pyrazine-6,6-dioxide *.

To ethane-1,2-diamine (10.4 g, 173.0 mmol) in dioxane (25 ml) was added dropwise cis-3,4-dichlorotetrahydrothiophen-1,1-dioxide (5.0 g, 26.0 mmol) in dioxane (40 ml) at a temperature of 0 ° C. The mixture was heated at 100 ° C. for 3 hours, followed by cooling to room temperature and stirring continued overnight. Two layers are separated and the lower layer containing ethylenediamine and amine salt is washed twice with dioxane. The dioxane layers were combined and the solvent was removed in vacuo. The crude product was recrystallized from toluene to give 2.7 g (59% yield) of the title compound as white crystals. HPLC: 98%, I _t = 0.292 min (system B; 1097% MECA for 3 min). ^! H NMR (270 MHz, methanol-b ₄ ) δ ppm 2.67-2.76 (m, 2H), 2.86-2.96 (m, 2H), 3.13-3.20 (m, 2H), 3.33-3.44 (m, 2H) ), 3.63-3.70 (m, 2H). L-M8: 177 (M + H) ⁺ .

* Previously described in US patent 3882122.

Intermediate 35.

1- (5-Nitro-1-benzofuran-7-yl) octahydrothieno [3,4-b] pyrazin-6,6-dioxide.

To 7-iodo-5-nitro-1-benzofuran (1.00 g, 3.46 mmol), octahydrothieno [3,4-b] pyrazine-6,6-dioxide (0.73 g, 4.15 mmol; intermediate 34), Pb ₂ (ba) ₃ (0.08 g, 0.87 mmol), xanthos (0.20 g, 0.35 mmol) and Cg ₂ CO ₃ (1.59 g, 4.84 mmol) xylene (150 ml) was added. The resulting mixture was stirred at 120 ° C. overnight, filtered through celite and the solvent was removed in vacuo. The crude product was purified by flash chromatography [eluent: ESM and ESM: MeOH (1: 1)] and then recrystallized from MeOH to give 0.354 g (8% yield) of the title product. HPLC: 90%, I _m = 1.390 min (system A; 10-97% MECA for 3 min). ^! H NMR (270 MHz, SIS) δ ppm 2.85 (dd, 1 = 12.62, 7.42 Hz, 1H), 3.16-3.49 (m, 6H), 3.71 (t, 1 = 11.63 Hz, 1H), 4 , 02-4.05 (m, 1H), 5.17-5.25 (m, 1H), 6.93 (d, 1 = 2.23 Hz, 1H), 7.62 (t, 1 = 2 , 72 Hz, 1H), 7.77 (d, 1 = 1.98 Hz, 1H), 8.19 (d, 1 = 1.98 Hz, 1H). HM8: 338 (M + H) ⁺ .

Intermediate 36.

7- (6,6-dioxohexahydrothieno [3,4-b] pyrazin-1 (2H) -yl-1-benzofuran-5-amine.

To 1- (5-nitro-1-benzofuran-7-yl) octahydrothieno [3,4-b] pyrazin-6,6-dioxide (0.354 g, 1.05 mmol; intermediate 35) in a mixture of THF (20 ml ) and E1OH (80 ml) are added Raney Nickel (suspension in ethanol, 2 ml) and hydrazine (204 ml, 4.20 mmol). The resulting mixture was stirred at room temperature overnight, and then more Raney Nickel (suspension in ethanol, 2 ml) and hydrazine (204 ml, 4.20 mmol) were added and stirred overnight. The mixture was filtered through celite and the solvent was removed in vacuo to give 0.338 g (quantitative yield). HPLC: 90%, I _t = 0.782 min (system A; 10-97% MECA for 3 min). Ί1 NMR (270 MHz, methanol-b ₄ ) δ ppm 2.79 (dd, 1 = 12.49, 7.30 Hz, 1H), 2.90-3.25 (m, 4H), 3.43-3.64 (m, 3H), 3.91- 3.94 (m, 1H), 5.01-5.07 (m, 1H), 6.33 (d, 1 = 1, 98 Hz, 1H), 6.61 (dd,

- 58 010298

1 = 12.99, 2.10 Hz, 2H), 7.62 (d, 1 = 1.98 Hz, 1H). BS-M8: 308 (M + H) ⁺ .

Example 56. S- [7- (6,6-Dioxohexahydrotieno [3,4-b] pyrazin-1 (2H) -yl) -1-benzofuran-5-yl] -2methoxy-5-methylbenzenesulfonamide hydrochloride.

To 7- (6,6-dioxohexahydrothieno [3,4-b] pyrazin-1 (2H) -yl-1-benzofuran-5-amine (0.110 g, 0.357 mmol; intermediate 36) in an ESM (1 ml) 2-methoxy-5-methylbenzenesulfonyl chloride (0.094 g, 0.428 mmol) and pyridine (259 μl, 3.21 mmol). The mixture was shaken at room temperature for 1 h, the solvent was removed in vacuo and the residue was purified by preparative HPLC using gradients acetonitrile - water containing 0.1% trifluoroacetic acid The obtained TFA salt is converted into hydrochloride by treatment with a 2 M solution of HCl in diethyl ether to give iem 20.0 mg (yield 11%) of the titled product by HPLC: 98%, RT = 1.483 min (System A, 10-97% MeCN over 3 min) '11 NMR (270 MHz, methanol-b _4.. ) δ ppm 3.08-3.12 (m, 2H), 3.37-3.79 (m, 6H), 3.96 (s, 3H), 4.55 (d, 1 = 3 , 96 Hz, 1H), 6.77 (d, 1 = 2.23 Hz, 1H), 6.84 (d, 1 = 1.98 Hz, 1H), 7.03 (d, 1 = 8.41 Hz, 1H), 7.12 (d, 1 = 1.98 Hz, 1H), 7.31 (dd, 1 = 8.78, 1.86 Hz, 1H), 7.51 (d, 1 = 1 , 73 Hz, 1H), 7.74 (d, 1 = 2.23 Hz, 1H). BS-M8: 492 (M + H) ⁺ .

Example 57. W [7- (6,6-dioxohexahydrothieno [3,4-b] pyrazin-1 (2H) -yl) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride.

To 7- (6,6-dioxohexahydrothieno [3,4-b] pyrazin-1 (2H) -yl-1-benzofuran-5-amine (0.110 g, 0.357 mmol; intermediate 36) in an ESM (1 ml) benzenesulfonyl chloride (0.076 g, 0.428 mmol) and pyridine (259 ml, 3.21 mmol). The mixture was shaken at room temperature for 1 h, the solvent was removed in vacuo and the residue was purified by preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid The resulting TFA salt is converted to the hydrochloride by treatment with a 2 M solution of HCl in diethyl ether to give 27.0 mg (yield 17%) of the title product HPLC: 99%, K1 = 1.556 min (system A; 1097% MeCN for 3 min). '11 NMR (270 MHz, methanol-b ₄ ) δ ppm 3.17 (d, 1 = 6.68 Hz, 2H), 3.47-3.85 (m, 6H), 4.52-4.56 (m, 1H), 4.95-4.99 (m, 1H ), 6.77-6.79 (m, 2H), 7.07 (d, 1 = 1.98 Hz, 1H), 7.42-7.54 (m, 3H), 7.697.77 (m, 3H). BS-M8: 448 (M + H) ⁺ .

Example 58. No. {7 - [(2-Pyrrolidin-1-yl-ethyl) amino] -1-benzofuran-5-yl} -benzenesulfonamide hydrochloride.

To a test tube containing benzenesulfonyl chloride (42 mg, 0.235 mmol), a solution of Ν ⁷ - (2pyrrolidin-1-yl-ethyl) -1-benzofuran-5,7-diamine * (48 mg, 0.195 mmol) in dichloromethane (3 ml) was added. After the addition of triethylamine (55 μl, 0.391 mmol), the mixture was shaken for 1 h and then concentrated. The residue was purified by preparative HPLC. The resulting TFA salt was treated with a solution of HCl in diethyl ether and evaporated to give the title compound. Yield: 5%. HPLC: purity = 99%, t / ζ = 386 (M + H) ⁺ . '11 NMR (270 MHz, methanol-b ₄ ) δ ppm 1.95-2.26 (m, 4H), 3.03-3.24 (m, 2H), 3.38-3.47 (m, 2H), 3.58-3.65 (m, 2H) ), 3.64-3.77 (m, 2H), 6.45-6.48 (m, 1H), 6.55-6.57 (m, 1H), 6.65 (d, 1 = 2 , 23 Hz, 1H), 7.40-7.59 (m, 3H), 7.67 (d, 1 = 2.23 Hz, 1H), 7.68-7.73 (m, 2H).

* Obtained in two stages, starting from 2-pyrrolidin-1-yl-ethylamine: ί) amination on a RBcatalyst of 7-iodo-5-nitrobenzofuran in accordance with the procedure for obtaining intermediate product 31 to obtain (5-nitrobenzofuran-7-yl) - ( 2-pyrrolidin-1-yl-ethyl) amine and ίί) reduction of the nitro group of (5-nitrobenzofuran-7-yl) - (2-pyrrolidin-1-yl-ethyl) amine to give A- (2-pyrrolidin-1-yl-ethyl) -1-benzofuran- 5,7-diamine in accordance with the procedure of example 48 (stage 1).

Example 59. 2-Methoxy-5-methyl-Y- {7 - [(2-pyrrolidin-1-yl-ethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure described in Example 58. Yield: 18%. HPLC: purity = 98%, t / ζ = 430 (M + H) ⁺ . 'H NMR (500 MHz, DMSO-b ₆ ) δ ppm 1.81-1.92 (m, 2H), 1.96-2.08 (m, 2H), 2.18-2.22 (m, 3H), 3.00-3.12 (m, 2H) ), 3.31-3.37 (m, 2H), 3.39-3.45 (m, 2H), 3.55-3.63 (m, 2H), 3.87-3.90 (m , 3H), 6.34-6.37 (m, 1H), 6.59-6.63 (m, 1H), 6.77 (d, 1 = 2.20 Hz, 1H), 7.03- 7.07 (m, 1H),

7.32 (m, 1H), 7.48-7.50 (m, 1H), 7.83 (d, 1 = 1.88 Hz, 1H).

Example 60. No. {7 - [(2-Pyrrolidin-1-yl-ethyl) amino] -1-benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure described in Example 58. Yield: 31%. HPLC: purity = 99%, t / ζ = 454 (M + H) ⁺ . '11 NMR (270 MHz, methanol-b ₄ ) δ ppm 1.92-2.26 (m, 4H), 3.07-3.22 (m, 2H), 3.39-3.48 (m, 2H), 3.56-3.64 (m, 2H) ), 3.61-3.75 (m, 2H), 6.49 (d, 1 = 1.98 Hz, 1H), 6.63 (d, 1 = 1, 98 Hz, 1H), 6.66 (d, 1 = 2.23 Hz, 1H), 7.60-7.76 (m, 3H), 7.88-7.95 (m, 1H), 7.99-8.05 (m, 1H) )

Example 61. 3-Chloro-4-methyl-Y- {7 - [(2-pyrrolidin-1-ethylethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure described in Example 58. Yield: 32%. HPLC: purity = 99%, t / ζ = 433 (M + H) ⁺ . ¹ H NMR (270 MHz, methanol-b ₄ ) δ ppm 1.93-2.25 (m, 4H), 2.35-2.40 (m, 3H), 3.11-3.24 (m, 2H), 3.42-3.50 (m, 2H) ), 3.61-3.68 (m, 2H), 3.65-3.76 (m, 2H), 6.47-6.50 (m, 1H), 6.56-6.60 (m , 1H), 6.67 (d, 1 = 2.23 Hz, 1H), 7.35-7.40 (m, 1H), 7.48-7.54 (m, 1H), 7.67 ( d, 1 = 1.98 Hz, 1H); 7.68 (d, 1 = 1.98 Hz, 1H).

- 59 010298

Example 62. 2-Methoxy-5-methyl-Ch- {7 - [(3-morpholin-4-ylpropyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure described in Example 58 based on H ⁷ - (3-morpholin-4-ylpropyl) benzofuran-5,7-diamine *. Yield: 5%. HPLC: purity = 98%, t / ζ = 460 (M + H) ⁺ . '11 NMR (270 MHz, methanol-b ₄ ) δ ppm 1.99-2.15 (m, 2Η), 2.18-2.27 (m, 3Η), 3.17-3.40 (m, 6Η), 3.61-4.05 (m, 6Η) ), 3.94-3.98 (m, 3Η), 6.46 (d, 1 = 1.73 Hz, 1Η), 6.53-6.57 (m, 1Η), 6.61 (d, E = 2.23 Hz, 1Η), 6.997.06 (m, 1Η), 7.27-7.34 (m, 1Η), 7.47-7.52 (m, 1Η), 7.60 (d , E = 2.23 Hz, 1Η).

* Obtained in two stages, starting from 3-morpholin-4-ylpropylamine: ί) amination on a RBcatalyst 7-iodo-5-nitrobenzofuran in accordance with the procedure for obtaining intermediate product 31 to obtain (3-morpholin-4-ylpropyl) - ( 5-nitrobenzofuran-7-yl) amine and ίί) reduction of the nitro group of (3-morpholin-4-ylpropyl) - (5-nitrobenzofuran-7-yl) amine to obtain Ν ⁷ - (3morpholin-4-ylpropyl) benzofuran-5, 7-diamine in accordance with the procedure of example 48 (stage 1).

Example 63. H- {7 - [(3-Morpholin-4-ylpropyl) amino] -1-benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure described in Example 58 based on H ⁷ - (3-morpholin-4-ylpropyl) benzofuran-5,7-diamine. Yield: 13%. HPLC: purity = 99%, t / ζ = 484 (M + H) ⁺ . '11 NMR (270 MHz, methanol-b ₄ ) δ ppm 1.99-2.15 (m, 2Η), 3.03-3.38 (m, 6Η), 3.38-3.57 (m, 2Η), 3.62-3.85 (m, 2Η) ), 3.89-4.14 (m, 2Η), 6.44 (d, 1 = 1.98 Hz, 1Η), 6.53 (d, 1 = 1, 98 Hz, 1Η), 6.62 (d, 1 = 2.23 Hz, 1Η), 7.60-7.75 (m, 3Η), 7.89-7.94 (m, 1Η), 7.99-8.05 (m, 1Η )

Example 64. 3-Chloro-4-methyl-Ch- {7 - [(3-morpholin-4-ylpropyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure described in Example 58 based on H ⁷ - (3-morpholin-4-ylpropyl) benzofuran-5,7-diamine. Yield: 15%. HPLC: purity = 99%, t / ζ = 464 (M + H) ⁺ . '11 NMR (270 MHz, methanol-b ₄ ) δ ppm 2.04-2.18 (m, 2Η), 2.35-2.40 (m, 3Η), 3.06-3.24 (m, 2Η), 3.27-3.41 (m, 4Η ), 3.44-3.57 (m, 2Η), 3.65-3.81 (m, 2Η), 3.98-4.13 (m, 2Η), 6.43-6.49 (m , 2Η), 6.63 (d, 1 = 1.98 Hz, 1Η), 7.34-7.40 (m, 1Η), 7.47-7.52 (m, 1Η), 7.65 ( d, 1 = 1.98 Hz, 1Η), 7.66 (d, 1 = 1.98 Hz, 1Η).

Intermediate 37.

{[((2K) -1-Ethylpyrrolidin-2-yl] methyl} (5-nitro-1-benzofuran-7-yl) amine.

The title compound was prepared according to the procedure described for preparing intermediate 27, starting from (K) -2-aminomethyl-1-ethylpyrrolidine. Yield: 100%. HPLC: purity = 90%, t / ζ = 290 (M + H) ⁺ .

Intermediate 38.

Part ⁷ - {[(2K) -1-Ethylpyrrolidin-2-yl] methyl} -1-benzofuran-5,7-diamine.

The title compound was prepared according to the procedure described for preparing intermediate 28, starting from {[(2K) -1-ethylpyrrolidin-2-yl] methyl} (5-nitro-1-benzofuran-7yl) amine (intermediate 37). The resulting product is directly used in the next reaction.

Example 65. Ν- [7 - ({[((2K) -1-Ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure described in Example 41 based on H ⁷ - {[(2K) -1-ethylpyrrolidin-2-yl] methyl} -1-benzofuran-5,7-diamine. Yield: 7 mg (8%). HPLC: purity = 95%, t / ζ = 400 (M + H) ⁺ . '11 NMR (270 MHz, methanol-b ₄ ) δ ppm 1.29 (t, 1 = 7.30 Hz, 3Η), 1.83-2.39 (m, 4Η), 3.05-3.28 (m, 2Η), 3.37-3.54 ( m, 1Η), 3.54-3.61 (m, 1 = 6.06, 3.34 Hz, 2Η), 3.63-3.77 (m, 2Η), 6.47 (d, 1 = 1.73 Hz, 1Η), 6.57 (d, 1 = 1.98 Hz, 1Η), 6.65 (d, 1 = 2.23 Hz, 1Η), 7.39-7.59 (m, 3Η), 7.65-7.73 (m, 3Η).

Example 66. H- [7 - ({[(2K) -1-Ethylpyrrolidin-2-yl] methyl} amino} -1-benzofuran-5-yl] -2-methoxy-5methylbenzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure described in Example 41 based on H ⁷ - {[(2K) -1-ethylpyrrolidin-2-yl] methyl} -1-benzofuran-5,7-diamine. Yield: 16 mg (17%). HPLC: purity = 97%, t / ζ = 444 (M + H) ⁺ . '11 NMR (270 MHz, methanol-b ₄ ) δ ppm 1.27 (t, 1 = 7.18 Hz, 3Η), 1.85-2.20 (m, 2Η), 2.19-2.23 (s, 3Η), 2.24-2.42 ( m, 1Η), 3.01-3.28 (m, 3Η), 3.38-3.53 (m, 1Η), 3.54-3.60 (m, 2Η), 3.63-3, 81 (m, 2Η), 3.94-3.98 (s, 3Η), 6.53 (d, 1 = 1.73 Hz, 1Η), 6.64 (dd, 1 = 3.84, 1, 86 Hz, 2Η), 7.00-7.06 (m, 1Η), 7.28-7.35 (m, 1Η), 7.45-7.51 (m, 1Η), 7.64 (d , 1 = 1.98 Hz, 1Η).

Example 67. Ν- [7 - ({[(2K) -1-Ethylpyrrolidin-2-yl] methyl} amino} -1-benzofuran-5-yl] -2- (trifluoromethyl) benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure described in Example 41 based on X ⁷ - {| (2P) -1-ethylpyrrolidin-2-yl | methyl; -1-benzofuran-5.7-diamine. Yield: 21 mg (21%). HPLC: purity = 99%, t / ζ = 468 (M + H) ⁺ . '11 NMR (270 MHz, methanol-b ₄ ) δ ppm 1.29 (t, 1 = 7.30 Hz, 3Η), 1.82-2.39 (m, 4Η), 3.05-3.28 (m, 2Η), 3.40-3.53 ( m, 1Η), 3.53-3.61 (m, 2Η), 3.63-3.78 (m, 2Η), 6.50 (d, 1 = 1, 98 Hz, 1Η), 6.66 (dd, 1 = 5.57, 2.10 Hz, 2Η), 7.58-7.77 (m, 3Η), 7.88-7.95 (m, 1Η), 7.97-8.05 (m, 1Η).

Example 68. N- [7 - ({[(2K) -1-Ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -3-methylbenzenesulfonamide hydrochloride.

- 60 010298

The title compound was prepared according to the procedure described in Example 41 based on ^ - {[(2K) -1-ethylpyrrolidin-2-yl] methyl} -1-benzofuran-5,7-diamine. Yield: 15 mg (16%). HPLC: purity = 96%, t / ζ = 414 (M + H) ⁺ . Ή NMR (270 MHz, methanol-6 ₄ ) δ ppm 1.29 (t, 1 = 7.30 Hz, 3H),

1.81-2.38 (m, 4H), 2.30-2.34 (s, 3H), 3.02-3.27 (m, 2H), 3.39-3.54 (m, 1H), 3.54-3.61 (m, 2H), 3.64-3.79 (m, 2H), 6.47 (d, 1 = 1.98 Hz, 1H), 6.57 (d, 1 = 1.73 Hz, 1H), 6.66 (d, 1 = 2.23 Hz, 1H), 7.26-7.41 (m, 2H), 7.44-7.55 (m, 2H), 7.67 (d, 1 = 1.98 Hz, 3H).

Example 69. Ν- [7 - ({[((2K) -1-Ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] thiophen-2-sulfonamide hydrochloride.

The title compound was prepared according to the procedure described in Example 41 based on ^ - {[(2K) -1-ethylpyrrolidin-2-yl] methyl} -1-benzofuran-5,7-diamine. Yield: 17 mg (19%). HPLC: purity = 99%, t / ζ = 406 (M + H) ⁺ . Ή NMR (270 MHz, methanol-6 ₄ ) δ ppm 1.30 (t, 1 = 7.30 Hz, 3H),

1.82- 2.42 (m, 4H), 3.02-3.28 (m, 2H), 3.39-3.57 (m, 1H), 3.57-3.64 (m, 2H), 3.64-3.82 (m, 2H), 6.49-6.54 (m, 1 = 1.98 Hz, 1H), 6.64 (d, 1 = 1.98 Hz, 1H), 6 69 (d, 1 = 1.98 Hz, 1H), 7.04 (dd, 1 = 4.95, 3.71 Hz, 1H), 7.43 (dd, 1 = 3.71, 1.24 Hz, 1H); 7.63-7.72 (m, 2H).

Example 70. 5-Chloro-I- [7 - ({[(2K) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] thiophene-2-sulfonamide hydrochloride.

The title compound was prepared according to the procedure described in Example 41 based on ^ - {[(2K) -1-ethylpyrrolidin-2-yl] methyl} -1-benzofuran-5,7-diamine. Yield: 5 mg (5%). HPLC: purity = 99%, t / ζ = 440 (M + H) ⁺ . 'H NMR (270 MHz, methanol-6 ₄ ) δ ppm 1.32 (t, 1 = 7.30 Hz, 3H), 1.84-2.42 (m, 4H), 3.06-3.28 (m, 2H), 3.44-3.58 ( m, 1H), 3.59-3.65 (m, 2H), 3.65-3.82 (m, 2H), 6.52 (d, 1 = 1.73 Hz, 1H), 6.68 (d, 1 = 1.98 Hz, 1H), 6.73 (d, 1 = 2.23 Hz, 1H), 6.95-6.99 (m, 1H), 7.22-7.26 ( m, 1H), 7.72 (d, 1 = 2.23 Hz, 1H).

Example 71. 5-Chloro-I- [7 - ({[((2K) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -1,3dimethyl-1H-pyrazol-4 -sulfonamide hydrochloride.

The title compound was prepared according to the procedure described in Example 41 based on ^ - {[(2K) -1-ethylpyrrolidin-2-yl] methyl} -1-benzofuran-5,7-diamine. Yield: 12 mg (12%). HPLC: purity = 98%, t / ζ = 452 (M + H) ⁺ . Ή NMR (270 MHz, methanol-6 ₄ ) δ ppm 1.33 (t, 1 = 7.30 Hz, 3H), 1.87-2.41 (m, 4H), 2.17-2.20 (m, 3H), 3.07-3.28 ( m, 2H), 3.44-3.65 (m, 3H), 3.66-3.82 (m, 2H), 3.70-3.73 (m, 3H), 6.53 (d, 1 = 1.98 Hz, 1H), 6.64 (d, 1 = 1.98 Hz, 1H), 6.70 (d, 1 = 1.98 Hz, 1H), 7.70 (d, 1 = 2.23 Hz, 1H).

Example 72. Ν- (7- {[3- (2-Methylpiperidin-1-yl) propyl] amino} -1-benzofuran-5-yl) benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure described in Example 58 based on ^ - [3- (2-methylpiperidin-1-yl) propyl] benzofuran-5,7-diamine *. Yield: 9%. HPLC: purity = 97%, t / ζ = 428 (M + H) ⁺ . 'H NMR (270 MHz, methanol-6 ₄ ) δ ppm 1.29 (d, 1 = 6.43 Hz, 0, 3H, rotamers) 1.32 (d, 1 = 6.43 Hz, 3H), 1.45-2.17 (m, 8H), 2, 91-3.07 (m, 1H), 3.13-3.27 (m, 3H), 3.35 (t, 1 = 6.43 Hz, 2H), 3.39-3.56 (m, 1H), 6.43-6.49 (m, 2H), 6.61 (d, 1 = 2.23 Hz, 1H), 7.40-7.58 (m, 3H), 7.63 (d , 1 = 1.98 Hz, 1H); 7.68-7.74 (m, 2H).

* Obtained in two stages, starting from 3- (2-methylpiperidin-1-yl) propylamine: ί) amination on a P6 catalyst of 7-iodo-5-nitrobenzofuran in accordance with the procedure for obtaining intermediate product 31 to obtain [3- (2- methylpiperidin-1-yl) propyl] - (5-nitrobenzofuran-7-yl) amine and ίί) reduction of the nitro group (3-morpholin-4-ylpropyl) - (5-nitrobenzofuran-7-yl) amine to obtain Ν ⁷ [3 - (2-methylpiperidin-1-yl) propyl] benzofuran-5,7-diamine according to the procedure for Example 48 (step 1).

Example 73. 2-Methoxy-5-methyl-H- (7 - {[3- (2-methylpiperidin-1-yl) propyl] amino} -1-benzofuran-5yl) benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure described in Example 58 based on ^ - [3- (2-methylpiperidin-1-yl) propyl] benzofuran-5,7-diamine. Yield: 7%. HPLC: purity = 98%, t / ζ = 472 (M + H) ⁺ . '11 NMR (270 MHz, methanol-6 ₄ ) δ ppm 1.29 (d, 1 = 6.43 Hz, 0.3H, rotamers) 1.31 (d, 7 = 6.43 Hz, 3H), 1.48-2.16 (m, 8H), 2, 18-2.22 (m, 3H), 2.88-3.05 (m, 1H), 3.11-3.27 (m, 3H), 3.31-3.39 (m, 2H), 3.38-3.55 (m, 1H), 3.94-3.98 (m, 3H), 6.46-6.49 (m, 1H), 6.58 (d, 7 = 1.98 Hz, 1H), 6.61 (d, 7 = 1.98 Hz, 1H), 6.997.05 (m, 1H), 7.27-7.34 (m, 1H), 7.48-7.52 (m, 1H), 7.60 (d, 7 = 1.98 Hz, 1H).

Example 74. No. (7 - {[3- (2-Methylpiperidin-1-yl) propyl] amino} -1-benzofuran-5-yl) -2- (trifluoromethyl) benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure described in Example 58 based on ^ - [3- (2-methylpiperidin-1-yl) propyl] benzofuran-5,7-diamine. Yield: 1%. HPLC: purity = 97%, t / ζ = 496 (M + H) ⁺ . Ή NMR (270 MHz, methanol-6 ₄ ) δ ppm 1.29 (d, 1 = 6.43 Hz, 0.3H, rotamers) 1.33 (d, 7 = 6.43 Hz, 3H), 1.45-2.20 (m, 8H), 2, 94-3.08 (m, 1H), 3.12-3.28 (m, 3H), 3.32-3.39 (m, 2H), 3.44-3.59 (m, 1H), 6.46-6.49 (m, 1H), 6.53 (d, 1 = 1.98 Hz, 1H), 6.63 (d, 7 = 2.23 Hz, 1H), 7.60-7 76 (m, 3H); 7.88-7.94 (m, 1H); 7.998.06 (m, 1H).

Example 75. 5-Chloro-1,3-dimethyl-I- (7 - {[3 - (2-methylpiperidin-1-yl) propyl] amino} -1-benzofuran-5yl) -1H-pyrazole-4-sulfonamide hydrochloride .

- 61 010298

The title compound was prepared according to the procedure described in Example 58 based on L ⁷ - [3- (2-methylpiperidin-1-yl) propyl] benzofuran-5,7-diamine. Yield: 10%. HPLC: purity = 97%, t / ζ = 480 (M + H) ⁺ . ¹ H NMR (270 MHz, methanol-b ₄ ) δ ppm 1.30 (d, 1 = 6.43 Hz, 0.4H, rotamers) 1.35 (d, 1 = 6.43 Hz, 3H ), 1.50-2.16 (m, 8H), 2.17-2.21 (m, 3H), 2.93-3.08 (m, 1H), 3.15-3.27 (m , 3H), 3.38 (t, 1 = 6.43 Hz, 2H), 3.41-3.58 (m, 1H), 3.70-3.73 (m, 3H), 6.46- 6.49 (m, 1H), 6.56 (d, 1 = 1.73 Hz, 1H), 6.66 (d, 1 = 1.98 Hz, 1H), 7.66 (d, 1 = 1 , 98 Hz, 1H).

Intermediate 39.

5- (5-Nitrobenzofuran-7-yl) pyridin-2-ylamine.

Together with dioxane (4 ml), 7-iodo-5-nitrobenzofuran (28 9 mg, 1.0 mmol), pinacolborane (192 mg, 1.5 mmol) and PbCl ₂ (brrH) -ECM are added to the test tube. Triethylamine (304 mg, 3.0 mmol) was carefully added to the solution, and the mixture was heated at 81 ° B1osk at 70 ° C overnight to form ίη Shi 5-nitro-7- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1-benzofuran. Then add 2 amino-5-iodopyridine (220 mg, 1.0 mmol) and an aqueous solution of barium hydroxide (1 ml, 2 M). The resulting mixture was stirred at 70 ° C. overnight and then filtered through celite and evaporated. The residue was extracted with chloroform / water and evaporated to give the title product. Yield: 82%. HPLC: purity = 82%, t / ζ = 256 (M + H) ⁺ .

Intermediate 40.

5- (5-amino-1-benzofuran-7-yl) pyridin-2-amine.

The title compound was prepared from 5- (5-nitrobenzofuran-7-yl) pyridin-2-ylamine (intermediate 39) according to the procedure for the preparation of intermediate 28. The product was directly used in the next reaction.

Example 76. N- [7- (6-Aminopyridin-3-yl) -1-benzofuran-5-yl] -2-methoxy-5-methylbenzenesulfonamide.

The title compound was prepared from 5- (5-amino-1-benzofuran-7-yl) pyridin-2-amine (intermediate 40) according to the procedure for Example 41, except for the purification step using flash chromatography (eluent : 30% EJAc in hexane). Yield: 7%. HPLC: purity = 93%, t / ζ = 410 (M + H) ⁺ . ¹ H NMR (270 MHz, methanol-b ₄ ) δ ppm 2.20 (s, 3H), 3.96 (s, 3H), 6.84 (d, 1 = 2.23 Hz, 1H), 6.99-7.05 (m, 1 = 8.41 Hz) , 1H), 7.10-7.17 (m, 1 = 9.90 Hz, 1H), 7.27-7.36 (m, 3H), 7.51-7.55 (m, 1H), 7.82 (d, 1 = 2.23 Hz, 1H), 8.27-8.34 (m, 2H).

Intermediate 41.

2-Methoxy-5-methyl-Y- (7-piperazin-1-yl-1-benzofuran-5-yl) benzenesulfonamide. tert-Butyl-4- (5 - {[((2-methoxy-5-methylphenyl) sulfonyl] amino} -1-benzofuran-7-yl) piperazine-1 carboxylate * (1.5 g, 2.99 mmol) is added into the reaction in accordance with the procedure for the preparation of intermediate product 20, and this product is used in the next step without further purification. Yield: 1.2 g (100%). HPLC: purity = 99%, _W = 1.60 min (System A, 10-97% Mesa for 3 min).

* Obtained from tert-butyl-4- (5-amino-1-benzofuran-7-yl) piperazine-1-carboxylate (intermediate 10) in accordance with the procedure for the preparation of intermediate 19.

Example 77. Y- {7- [4- (Cyclopropylmethyl) piperazin-1-yl] -1-benzofuran-5-yl} -2-methoxy-5-methylbenzenesulfonamide hydrochloride.

To a solution of 2-methoxy-5-methyl-Y- (7-piperazin-1-yl-1-benzofuran-5-yl) benzenesulfonamide (0.1 g, 0.25 mmol; intermediate 41) in methanol is added cyclopropanecarbaldehyde ( 0.087 g, 1.25 mmol). After stirring at room temperature for 5 minutes, sodium cyanoborohydride (0.156 g, 2.5 mmol) was added and the resulting mixture was stirred at room temperature for 5 days. The precipitate formed from the reaction mixture was collected by filtration to obtain the free base of the title compound (0.063 g, 55% yield). The free base is dissolved in MeOH and treated with a mixture of a 1 M solution of HCl in diethyl ether to give the title compound. Yield: 0.029 g (43%). HPLC: 100% B _t = 1.82 min (System A, 10-97% Mesa for 3 min). '11 NMR (400 MHz, DMSO-b ₆ ) δ ppm 0.37-0.48 (m, 2H), 0.59-0.72 (m, 2H), 1.09-1.22 (m, 1H), 2.20 (s, 3H), 3, 03 (dd, 1 = 6.7, 5.4 Hz, 2H), 3.12-3.26 (m, 4H), 3.59-3.75 (m, 4H), 3.87 (s, 3H), 6.59 (d, 1 = 1.8 Hz, 1H), 6.85 (d, 1 = 2.0 Hz, 1H), 6.95 (d, 1 = 1.8 Hz, 1H) 7.03 (d, 1 = 8.5 Hz, 1H), 7.32 (dd, 1 = 8.4, 2.1 Hz, 1H), 7.51 (d, 1 = 2.0 Hz, 1H), 7.89 (d, 1 = 2.3 Hz, 1H), 9.74 (s, 1H). M8 (E81 +) for C ₂₄ H ₂₉ N ₃ O ₄ 8, t / ζ: 456.2 (M + H) ⁺ .

Example 78. 2-Methoxy-5-methyl-Y- {7- [4- (3,3,3-trifluoropropyl) piperazin-1-yl] -1-benzofuran-5yl} benzenesulfonamide hydrochloride.

The title compound was obtained from 2-methoxy-5-methyl-Y- (7-piperazin-1-yl-1 benzofuran-5-yl) benzenesulfonamide (0.1 g, 0.25 mmol; intermediate 41) and 3, 3.3 trifluoropropanal in accordance with the procedure of Example 77. The precipitate formed from the reaction mixture was collected by filtration to obtain the free base of the title compound (0.075 g, 60% yield). The free base is dissolved in MeOH and treated with a mixture of a 1 M solution of HCl in diethyl ether to give the title compound. Yield: 0.078 g (96%). HPLC: 98%, _W = 1.84 min (System A, 10-97% Mesa for 3 min). 'H NMR (400 MHz, DMSO-b ₆ ) δ ppm 2.20 (s, 3H), 2.93-3.10 (m, 2H), 3.15 (s, 2H), 3.16-3.30 (m, 4H), 3.36-3, 50 (m, 2H), 3.60-3.77 (m, 3H), 3.87 (s, 3H),

- 62 010298

6.58 (d, 1 = 1.8 Hz, 1H), 6.85 (d, 1 = 2.3 Hz, 1H), 6.95 (d, 1 = 1.8 Hz, 1H), 7, 03 (d, 1 = 8.5 Hz, 1H), 7.25 (s, 2H), 7.31 (dd, 1 = 8.5, 2.3 Hz, 1H), 7.38 (s, 2H ), 7.51 (s, 3H), 7.89 (d, 1 = 2.3 Hz, 1H), 9.74 (s, 1H). M8 (Ε8Ι +) for С ₂₃ Н ₂₆ Е ^ ₃ 0 ₄ 8, t / ζ: 498.2 (М + Н) ⁺ .

Intermediate 42.

3.3-Dibromo-1,1,1-trifluoroacetone *.

1,1,1-Trifluoropropanone (50.0 g, 446.2 mmol) was dissolved in concentrated sulfuric acid (250 g). Br ₂ (81.69 g, 510.1 mmol) was added dropwise at room temperature for 2 hours and the mixture was stirred overnight. After that, an additional amount of Br ₂ (40.85 g, 255.6 mmol) was added and the mixture was stirred overnight. Two phases are separated, which are formed after the mixture is left standing, and the lower layer is distilled to obtain 3,3-dibromo-1,1,1-trifluoroacetone as a yellow oil (10.37 g, 8.6%). Ή-NMR (270 MHz, SES1 ₃ ): δ ppm 6.23 (s, 1H).

* Previously described in Kay. Tgat. Sat. Rouse-Vaz, 1995, 114, 97-102.

Intermediate 43.

3.3.3- Trifluoro-2-oxopropanal *.

3.3- Dibromo-1,1,1-trifluoroacetone (10.37 g, 38.43 mmol; intermediate 42) was dissolved in water (51.85 g). No. 10Le (12.61 g, 153.72 mmol) was added and the resulting mixture was stirred at 100 ° C. overnight. The mixture was extracted with EyAc (50 ml) and the solvents were evaporated from the organic phase. The residue was redissolved in EJAc (20 ml) and filtered to give 3.3,3-trifluoro-2-oxo-propanal (1.35 g, 24%).

* Previously described in Kes. Τιαν. Sat. Rouse-Vaz, 1995, 114, 97-102.

Intermediate 44.

1- Benzyl-3 - (trifluoromethyl) piperazine *.

A solution of 3,3,3-trifluoro-2-oxopropanal (0.31 g, 2.3 mmol; intermediate 43) in DMF (10 ml) is cooled to 0 ° C. and a solution of No. benzyl ethane-1,2-diamine is added (0.37 g, 2.72 mmol) in DMF (10 ml). Then it was stirred at room temperature overnight and the mixture was concentrated in vacuo. The residue was redissolved in THF (5 ml) and citrate buffer (5.3 ml, 0.4 M solution) was added, followed by the addition of NaBH ₃ CN (0.31 g, 4.9 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was alkalinized (pH 8) with an aqueous solution of # YUN (8 ml, 1 M) and the aqueous layer was extracted twice with ESM (15 ml). The combined organic layers are dried (No. 80 ₄ ) and concentrated. The residue was purified using preparative BS-M8 to give 1-benzyl-3- (trifluoromethyl) piperazine (66 mg, 12% yield). HPLC: 94%, R _t = 1.25 min (System A / 10-97% MeCN over 3 min). Ή NMR (270 MHz, SES1 ₃ ) δ ppm 2.77 (s, 2H), 3.17-3.31 (m, 1H), 3.32-3.64 (m, 3H), 3.83-4.02 (m, 1H), 4, 13-4.31 (m, 2H), 6.68 (s, 1H), 7.30-7.55 (m, 5H). M8 (Ε8Ι +), t / ζ: 245 (M + H) ⁺ .

* Previously described in Kes. Tgat. Sat. Rouse-Vaz, 1995, 114, 97-102.

Intermediate 45.

2- (Trifluoromethyl) piperazine *.

1-Benzyl-3- (trifluoromethyl) piperazine (0.74 g, 3.0 mmol; intermediate 44) was dissolved in acetic acid (70 ml) and water (5 ml). Add Rb, 5% on activated carbon, (0.074 g) and carry out hydrogenation at a pressure of 3 bar and a temperature of 70 ° C overnight. The reaction mixture was filtered through celite, the layer of which was washed with water (5 ml). Solvents were removed in vacuo, toluene (20 ml) was added to the residue, followed by re-concentration in vacuo to remove residual water. The desired product is sublimated in an evaporator and 0.15 g (32% yield) is collected as a white powder. Ή-NMR (270 MHz, methanol-b ₄ ): δ ppm 2.67-2.87 (m, 3H), 2.91-3.05 (m, 2H), 3.12-3.21 (m , 1H). M8 (Ε8Ι +), t / ζ: 155 (M + H) ⁺ .

* Previously described in Kes. Thau. Sat. Rouse-Vaz, 1995, 114, 97-102.

Intermediate 46.

1- (5-Nitro-1-benzofuran-7-yl) -3- (trifluoromethyl) piperazine.

The following substances are added to 7-iodo-5-nitro-1-benzofuran (231.4 mg, 0.08 mmol): xanthos (92.6 mg, 0.16 mmol), Pb ₂ (ba) ₃ (36.6 mg, 0.04 mmol), sodium tert-butylate (215.4 mg, 2.24 mmol), 2 (trifluoromethyl) piperazine (148.1 mg, 0.96 mmol; intermediate 45) and xylene (23 ml) . The resulting mixture was stirred at a temperature of 100 ° C for 3 days. It is filtered through celite and purified by flash chromatography using EJAc: heptane (1: 1) as an eluent, resulting in 1- (5-nitro-1-benzofuran-7-yl) -3- (trifluoromethyl) piperazine ( 112 mg, 44% yield). HPLC: 90%, K _T = 1.648 min (system A; 10-97% MeCN for 3 min).

M8 (Ε8Ι +), t / ζ: 316 (M + H) ⁺ .

Intermediate 47.

7- [3 - (trifluoromethyl) piperazin-1-yl] -1-benzofuran-5-amine.

1- (5-Nitro-1-benzofuran-7-yl) -3- (trifluoromethyl) piperazine (96.6 mg, 0.31 mmol; intermediate 46) was dissolved in THF (6 ml) and Εΐ0H (25 ml) . Raney nickel (suspension in ethanol, 1 ml) and ΧΝΝΧ (61.4 mg, 1.23 mmol) are added and the mixture is stirred at room temperature overnight. From

- 63 010298 was filtered through celite and concentrated to give 7- [3- (trifluoromethyl) piperazin-1-yl] -1 benzofuran-5-amine (55 mg, 63% yield). This substance is used in the next reaction without further purification.

Example 79. 2-Methoxy-5-methyl-Y- {7- [3- (trifluoromethyl) piperazin-1-yl] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride.

A mixture of 7- [3- (trifluoromethyl) piperazin-1-yl] -1-benzofuran-5-amine (59 mg, 0.19 mmol; intermediate 47), pyridine (155 μl, 1.93 mmol) and 6- methoxy-m-toluenesulfonyl chloride (42.6 mg, 0.19 mmol) in an ESM (2 ml) was stirred at room temperature overnight. Volatiles are removed in vacuo. The residue was redissolved in MeOH (1.5 ml) and the solution was filtered. MeOH (100 μl), a solution of HCl in diethyl ether (500 μl), and diethyl ether (500 μl) were added, followed by removal of solvents in vacuo to give 2-methoxy-5-methyl-Y- {7- [3- (trifluoromethyl) ) piperazin-1-yl] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride as a brown oil (44.1 mg, 47% yield). HPLC 100%, R _t = 1.861 min (System A, 10-97% MeCN over 3 min). ¹ H NMR (270 MHz, methanol-b ₄ ) δ ppm 2.23 (s, 3H), 2.28 (s, 1H), 2.98-3.24 (m, 1H), 3.46-3.71 (m, 2H), 3.85 (s, 1H), 3.96 (s, 3H), 4.09-4.19 (ha, 1H), 4.56-4.70 (m, 1H), 6.75 (d, 1 = 1.98 Hz) , 2H), 6.98 (d, 1 = 1.73 Hz, 1H), 7.02 (s, 1H), 7.05 (s, 1H), 7.33 (dd, 1 = 8.04, 2.60 Hz, 1H), 7.52 (d, 1 = 1.73 Hz, 1H), 7.73 (d, 1 = 2.23 Hz, 1H), 8.10-8.19 (m, 1H), 8.64-8.74 (m, 1H), 8.90 (d, 1 = 5.20 Hz, 1H). M8 (Ε8Ι +), t / ζ: 470 (M + H) ⁺ .

Intermediate 48. Tert-Butyl [1- (5-nitro-1-benzofuran-7-yl) piperidin-4-yl] carbamate.

To 7-iodo-5-nitro-1-benzofuran (2.78 g, 9.61 mmol), tert-butylpiperidin-4-ylcarbamate (2.31 g, 12.0 mmol), Pb ₂ (ba) s ( 0.22 g, 0.24 mmol), xanthol (200 ml) was added to xanthos (0.56 g, 0.96 mmol) and sodium tert-butylate (1.29 g, 13.0 mmol). The mixture was heated at 120 ° C. with stirring for 16 hours. The reaction mixture was allowed to stand at room temperature, filtered through a pad of celite and concentrated in vacuo. The crude product was purified by flash chromatography using an ESM as the eluent to give 1.03 g (84% yield) of the title product. HPLC: 94%, R _t = 2.770 min (System B, 10-97% MeCN over 3 min). ¹ H NMR (270 MHz, methanol-b ₄ ) δ ppm 1.45 (s, 9H), 1.62-1.72 (m, 2H), 1.75-2.03 (m, 2H), 2.94-3.02 (m, 2H), 3, 55-3.57 (m, 1H), 3.88-3.93 (m, 2H), 7.01 (d, 1 = 2.23 Hz, 1H), 7.64 (d, 1 = 2, 23 Hz, 1H), 7.93 (d, 1 = 2.23 Hz, 1H), 8.13 (d, 1 = 2.23 Hz, 1H). BS-M8: 362 (M + H) ⁺ .

Intermediate 49. Tert-Butyl [1- (5-amino-1-benzofuran-7-yl) piperidin-4-yl] carbamate.

To tert-butyl [1- (5-nitro-1-benzofuran-7-yl) piperidin-4-yl] carbamate (1.03 g, 2.85 mmol; intermediate 48) in a mixture of THF (50 ml) and ethanol (150 ml) add hydrazine (1.038 ml, 28 mmol) and Raney nickel (suspension in ethanol, 10 ml). The mixture was stirred at room temperature for 16 hours, filtered through a pad of celite and concentrated in vacuo to give 1.02 g (quantitative yield) of the title product. HPLC: 95%, R _t = 1.746 min (System A, 10-97% MeCN over 3 min). Ή NMR (270 MHz, methanol-b ₄ ) δ ppm 1.45 (s, 9H), 1.65-1.69 (m, 2H), 1.72-1.96 (m, 2H), 2.76-2.85 (m, 2H), 3, 50-3.54 (m, 1H), 3.76 (d, 1 = 12.62 Hz, 2H), 6.33 (d, 1 = 1, 98 Hz, 1H), 6.54 (d, 1H , 98 Hz, 1H), 6.60 (d, 1 = 2.23 Hz, 1H), 7.59 (d, 1 = 1.98 Hz, 1H). BS-M8: 332 (M + H) ⁺ .

Example 80. Ν- [7- (Aminopiperidin-1-yl) -1-benzofuran-5-yl] -2- (trifluoromethyl) benzenesulfonamide hydrochloride.

To tert-butyl [1- (5-amino-1-benzofuran-7-yl) piperidin-4-yl] carbamate (100.0 mg, 0.30 mmol; intermediate 49) in an ESM (1 ml), 2 - (trifluoromethyl) benzenesulfonyl chloride (89.0 mg, 0.36 mmol) and pyridine (219 ml). The mixture was shaken at room temperature for 1 h, the solvent was removed in vacuo and the residue was purified by preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid. Deprotection of nitrogen and conversion to hydrochloride is carried out by treating with a 2 M solution of HC1 in diethyl ether. The result is 76.1 mg (57% yield) of the title product. HPLC: 100%, CT = 1.834 min (system A; 10-97% MeCN for 3 min). Ή NMR (500 MHz, DMSO-b ₆ ) δ ppm 1.70-1.72 (m, 2H), 2.002.02 (m, 2H), 2.78 (t, 1 = 11.30 Hz, 2H), 3.21 (s, 1H), 3.71 (d, 1 = 12.56 Hz, 2H), 6.60 (d, 1 = 1.88 Hz, 1H), 6.83 (d, 1 = 2.20 Hz, 1H), 6.85-6 91 (m, 1 = 1.88 Hz, 1H), 7.80-7.81 (m, 2H), 7.88-7.89 (m, 1H), 7.96-7.98 (m , 1H), 8.088.10 (m, 4H), 10.40 (s, 1H). BS-M8: 440 (M + H) ⁺ .

Example 81. Ν- [7- (Aminopiperidin-1-yl) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride.

To tert-butyl [1- (5-amino-1-benzofuran-7-yl) piperidin-4-yl] carbamate (100.0 mg, 0.30 mmol; intermediate 49) in an ESM (1 ml) benzene sulfonyl chloride is added (64.0 mg, 0.36 mmol) and pyridine (219 μl). The mixture was shaken at room temperature for 1 h, the solvent was removed in vacuo and the residue was purified by preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid. Deprotection of nitrogen and conversion to hydrochloride is carried out by treating with a 2 M solution of HC1 in diethyl ether. The result is 31.3 mg (28% yield) of the title product. HPLC 100%, R _t = 1.612 min (System A, 10-97% MeCN over 3 min). Ή NMR (500 MHz, DMSO-b ₆ ) δ ppm 1.69-1.70 (m, 2H), 2.00-2.01 (m, 2H), 2.76 (t,

- 64 010298

1 = 11.30 Hz, 2H), 3.18-3.26 (m, 1H), 6.54 (d, 1 = 1.88 Hz, 1H), 6.82 (d, 1 = 2.20 Hz, 1H), 6.86 (d, 1 = 1.88 Hz, 1H), 7.52 (t, 1 = 7.54 Hz, 2H), 7.57-7.68 (m, 1H), 7.71-7.72 (m, 2H), 7.88 (d, 1 = 2.20 Hz, 1H), 8.14 (s, 3H), 10.03 (s, 1H). L-M8: 372 (M + H) ⁺ .

Example 82. Ch- [7- (Aminopiperidin-1-yl) -1-benzofuran-5-yl] -2-chlorobenzenesulfonamide hydrochloride.

To tert-butyl [1- (5-amino-1-benzofuran-7-yl) piperidin-4-yl] carbamate (100.0 mg, 0.30 mmol; intermediate 49) in an ESM (1 ml), 2 -chlorobenzenesulfonyl chloride (76.0 mg, 0.36 mmol) and pyridine (219 ml). The mixture was shaken at room temperature for 1 h, the solvent was removed in vacuo and the residue was purified by preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid. Deprotection of nitrogen and conversion to hydrochloride is carried out by treating with a 2 M solution of HC1 in diethyl ether. The result is 60.6 mg (50% yield) of the title product. HPLC 100%, R _t = 1.702 min (System A, 10-97% MeSCh for 3 min). Ή NMR (500 MHz, DMSO-F ₆ ) δ ppm 1.69-1.72 (m, 2H), 2.01-2.02 (m, 2H), 2.76 (t, 1 = 11.62 Hz, 2H), 3.21 (s, 1H) 3.68 (d, 1 = 12.56 Hz, 2H), 6.58 (s, 1H), 6.82 (d, 1 = 2.20 Hz, 1H), 6.88 (s, 1H) 7.47 (t, 1 = 7.54 Hz, 1H), 7.62-7.63 (m, 2H), 7.87 (d, 1 = 1.88 Hz, 1H), 7.99 ( d, 1 = 7.54 Hz, 1H), 8.23 (s, 3H), 10.33 (s, 1H). L-M8: 406 (M + H) ⁺ .

Example 83. Ch- [7- (Aminopiperidin-1-yl) -1-benzofuran-5-yl] -2-methoxy-5-methylbenzenesulfonamide hydrochloride.

To tert-butyl [1- (5-amino-1-benzofuran-7-yl) piperidin-4-yl] carbamate (100.0 mg, 0.30 mmol; intermediate 49) in an ESM (1 ml), 2 methoxy-5-methylbenzenesulfonyl chloride (80.0 mg, 0.36 mmol) and pyridine (219 ml). The mixture was shaken at room temperature for 1 h, the solvent was removed in vacuo and the residue was purified by preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid. Deprotection of nitrogen and conversion to hydrochloride is carried out by treating with a 2 M solution of HC1 in diethyl ether. The result is 59.0 mg (47% yield) of the title product. HPLC 100%, R _t = 1.731 min (System A, 10-97% MeSCh for 3 min). ^! H NMR (400 MHz, DMSO-F ₆ ) δ ppm 1.70-1.76 (m, 2H), 2.05 (d, 1 = 10.05 Hz, 2H), 2.20 (s, 3H), 2.76 (t, 1 = 11.46 Hz , 2H), 3.19-3.21 (m, 1H), 3.65 (d, 1 = 12.56 Hz, 2H), 3.87 (s, 3H), 6.58 (d, 1 = 1.88 Hz, 1H), 6.81 (d, 1 = 2.20 Hz, 1H), 6.89 (d, 1 = 1.88 Hz, 1H), 7.04 (d, 1 = 8, 48 Hz, 1H), 7.32 (dd, 1 = 8.48, 2.20 Hz, 1H), 7.51 (d, 1 = 2.20 Hz, 1H), 7.86 (d, 1 = 1.88 Hz, 1H), 8.35 (d, 1 = 3.45 Hz, 3H), 9.65 (s, 1H). L-M8: 416 (M + H) ⁺ .

Intermediate 50. Tert-Butyl-cis-3-fluoro-4 - [(5-nitro-1-benzofuran-7-yl) oxy] piperidine-1-carboxylate. Intermediate 51.

tert-Butyl-trans-3-fluoro-4 - [(5-nitro-1-benzofuran-7-yl) oxy] piperidine-1-carboxylate.

7-Iodo-5-nitrobenzofuran (2.0 g, 6.9 mmol), tert-butyl-3-fluoro-4-hydroxypiperidin-1 carboxylate * (3.8 g, 17.3 mmol; mixture of cis / trans isomers) , 1,10-phenanthroline (0.50 g,, 28 mmol), Cu1 (0.26 g, 1.4 mmol) and C8 ₂ CO ₃ (4.5 g, 13.8 mmol) are heated in toluene (20 ml) at a temperature of 120 ° C for 72 hours. The reaction mixture was filtered through celite and evaporated. The resulting diastereomers were separated by flash chromatography using heptane / EULS [(4: 1) ^ (2: 1)] to give 255 mg of the cis isomer and 919 mg of the trans isomer.

Cis isomer (intermediate 50): yield: 10%; HPLC: purity = 70%; t / ζ = 381 (M + H) ⁺ . Trans isomer (intermediate 51): yield: 35%; HPLC: purity = 94%; t / ζ = 381 (M + H) ⁺ . * Obtained in accordance with the procedure described in \ UO 2001085728.

Intermediate 52. Tert-Butyl-cis-4 - [(5-amino-1-benzofuran-7-yl) oxy] -3-fluoropiperidin-1-carboxylate.

To a solution of tert-butyl-cis-3-fluoro-4 - [(5-nitro-1-benzofuran-7-yl) oxy] piperidine-1-carboxylate (200 mg, 0.526 mmol; intermediate 50) in THF (10 ml) and ethanol (40 ml), Raney nickel (as a suspension in ethanol) and hydrazine hydrate (0.2 ml) are added. The mixture was stirred at room temperature for 30 minutes and then filtered through celite and evaporated. The residue was redissolved in toluene and evaporated again. This substance is used directly in the next experiment.

Intermediate 53.

tert-Butyl-trans-4- [(5-amino-1-benzofuran-7-yl) oxy] -3-fluoropiperidin-1-carboxylate.

The title compound was prepared from intermediate 51 in accordance with a procedure for the preparation of intermediate 52 and was used directly in the next experiment.

Example 84. H- (7- {[cis-3-Fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl] -2-methoxy-5-methylbenzenesulfonamide hydrochloride.

To a solution of tert-butyl cis-4 - [(5-amino -1-benzofuran-7-yl) oxy] -3-fluoropiperidin-1-carboxylate (92 mg, 0.263 mmol; intermediate 52) in dichloromethane (3 ml ) 6-methoxy-mtoluenesulfonyl chloride (70 mg, 0.315 mmol) and triethylamine (73 μl, 0.525 mmol) are added. Shake the mixture

- 65 010298 at room temperature for 1 h and then evaporated. Purify by preparative HPLC (gradient: 50-85% GeCN in a TFA / water mixture). The residue was dissolved in methanol (0.5 ml) and a solution of HC1 in diethyl ether (2 ml). Then the solution was stirred for 2 hours, the solvent was evaporated to obtain the title compound. Yield: 25 mg (20%). HPLC: purity = 95%, t / ζ = 435 (M + H) ⁺ . ¹ H NMR (270 MHz, methanol ₄ ) δ ppm 1.90-2.37 (m, 2H), 2.16-2.26 (m, 3H), 3.14-3.46 (m, 2H), 3.48-3.74 (m, 2H) ), 3.92-3.98 (m, 3H), 4.73-4.88 (m, 1H), 4.89-5.12 (m, 1H), 6.72 (d, 1 = 2 , 23 Hz, 0.2H, rotamers) 6.75 (d, 1 = 1, 98 Hz, 1H), 6.80 (d, 1 = 1, 98 Hz, 0.2H, rotamers) 6.87 (d , 1 = 1, 98 Hz, 1H), 6.95 (d, 1 = 1, 98 Hz, 0.2H, rotamers) 6.98-7.05 (m, 2H), 7.27-7.35 (m, 1H), 7.50-7.53 (m, 1H), 7.72 (d, 1 = 2.23 Hz, 1H).

Example 85. Ν- (7- {[trans-3-Fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl] -2-methoxy-5-methylbenzenesulfonamide hydrochloride.

The title compound was prepared according to a similar procedure to Example 84, starting from tert-butyl-trans-4 - [(5-amino-1-benzofuran-7-yl) oxy] -3-fluoropiperidin-1-carboxylate (intermediate 53) and 6-methoxy-m-toluenesulfonyl chloride. Yield: 8 mg (5%). HPLC: purity = 92%, t / ζ = 435 (M + H) ⁺ . ¹ H NMR (270 MHz, methanol ₄ ) δ ppm 2.12-2.30 (m, 2H), 2.21 (s, 3H), 3.14-3.34 (m, 2H), 3.37-3.53 (m, 1H), 3, 63-3.79 (m, 1H), 3.95 (s, 3H), 4.72-4.83 (m, 1H), 4.95-5.20 (m, 1H), 6.73 ( d, 1 = 2.23 Hz, 1H), 6.84 (d, 1 = 1.73 Hz, 1H), 6.99 (d, 1 = 1.98 Hz, 1H), 7.00-7, 05 (m, 1H), 7.28-7.35 (m, 1H), 7.50 (d, 1 = 1.98 Hz, 1H), 7.70 (d, 1 = 1.98 Hz, 1H )

Example 86. N- (7 - {[cis-3-Fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl] -2- (trifluoromethyl) benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure described in Example 84 based on 2- (trifluoromethyl) benzenesulfonyl chloride. Yield: 27 mg (21%). HPLC: purity = 100%, t / ζ = 459 (M + H) ⁺ . ¹ H NMR (270 MHz, methanol ₄ ) δ ppm 1.94-2.37 (m, 2H), 3.14-3.49 (m, 3H), 3.53-3.70 (m, 1H), 4.78-5.16 (m, 2H) ), 6.74 (d, 1 = 2.23 Hz, 0.3H, rotamers) 6.77 (d, 1 = 2.23 Hz, 1H), 6.79 (d, 1 = 1, 98 Hz, 0.3N, rotamers) 6.87 (d, 1 = 1, 98 Hz, 1H), 6.95 (d, 1 = 1, 98 Hz, 0.3H, rotamers) 7.02 (d, 1 = 1 , 98 Hz, 1H), 7.61-7.74 (m, 3H), 7.75 (d, 1 = 2.23 Hz, 1H), 7.88-7.95 (m, 1H), 7 98-8.06 (m, 1H).

Example 87. Ν- (7 - {[trans-3-Fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl] -2- (trifluoromethyl) benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure described in Example 84 based on tert-butyl-trans-4 - [(5-amino-1-benzofuran-7-yl) oxy] -3-fluoropiperidin-1-carboxylate ( intermediate 53) and 2- (trifluoromethyl) benzenesulfonyl chloride. Yield: 49 mg (25%). HPLC: purity = 100%, t / ζ = 459 (M + H) ⁺ . '11 NMR (270 MHz, methanol ₄ ) δ ppm 2.13-2.31 (m, 2H), 3.15-3.56 (m, 3H), 3.64-3.79 (m, 1H), 4.77-4.97 (m, 1H ), 5.00-5.24 (m, 1H), 6.75 (d, 1 = 1.98 Hz, 1H), 6.81-6.84 (m, 1H), 6.99 (d, 1 = 1.73 Hz, 1H), 7.60-7.77 (m, 3H), 7.87-7.95 (m, 1H), 7.98-8.05 (m, 1H).

Example 88. 2-Chloro-N- (7 - {[trans-3-Fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl] benzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure described in Example 84 based on tert-butyl-trans-4 - [(5-amino-1-benzofuran-7-yl) oxy] -3-fluoropiperidin-1-carboxylate ( intermediate 53) and 2-chlorobenzenesulfonyl chloride. Yield: 40 mg (22%). HPLC: purity = 100%, t / ζ = 425 (M + H) ⁺ . '11 NMR (270 MHz, methanol ₄ ) δ ppm 2.09-2.35 (m, 2H), 3.10-3.57 (m, 3H), 3.623.79 (m, 1H), 4.73-4.96 (m, 1H), 4, 97-5.23 (m, 1H), 6.74 (d, 1 = 2.23 Hz, 1H), 6.85 (d, 1 = 1.98 Hz, 1H), 7.05 (d, 1 = 1.73 Hz, 1H), 7.31-7.40 (m, 1H), 7.45-7.58 (m, 2H), 7.71 (d, 1 = 2.23 Hz, 1H) 7.96 (dd, 1 = 7.79, 1.61 Hz, 1H).

Example 89. Ν- (7 - {[trans-3-Fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl) -3-methylbenzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure described in Example 84 based on tert-butyl trans-4 - [(5-amino-1-benzofuran-7-yl) oxy] -3-fluoropiperidin-1-carboxylate ( intermediate 53) and 3-methylbenzenesulfonyl chloride. Yield: 47 mg (27%). HPLC: purity = 100%, t / ζ = 405 (M + H) ⁺ . 'H NMR (270 MHz, methanol ₄ ) δ ppm 2.12-2.34 (m, 2H), 2.28-2.34 (m, 3H), 3.153.57 (m, 3H), 3.64-3.78 (m, 1H), 4, 73-4.97 (m, 1H), 4.98-5.21 (m, 1H), 6.71-6.79 (m, 2H), 7.25-7.57 (m, 4H), 7.70-7.74 (m, 1H).

Example 90

3,6-Dichloro-N- (7 - {[trans-3-fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl) -2-methylbenzenesulfonamide hydrochloride.

The title compound was prepared according to the procedure described in Example 84 based on tert-butyl-trans-4 - [(5-amino-1-benzofuran-7-yl) oxy] -3-fluoropiperidin-1-carboxylate ( intermediate 53) and 3,6-dichloro-2-methylbenzenesulfonyl chloride. Yield: 39 mg (19%). HPLC: purity = 98%, t / ζ = 473 (M + H) ⁺ . '11 NMR (270 MHz, methanol ₄ ) δ ppm 2.11-2.34 (m, 2H), 2.472.54 (m, 3H), 3.14-3.56 (m, 3H), 3.63-3.79 (m, 1H), 4, 76-4.97 (m, 1H), 4.97-5.22 (m, 1H), 6.77 (d, 1 = 1, 98 Hz, 1H), 6.83 (d, 1 = 1, 73 Hz, 1H), 7.06 (d, 1 = 1, 98 Hz, 1H), 7.26 (d, 1 = 1.98 Hz, 1H), 7.50 (d, 1 = 1.98 Hz , 1H); 7.74 (d, 1 = 2.23 Hz, 1H).

Example 91. 2-Chloro-5-fluoro-N- (7 - {[trans-3-fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl) benzenesulfonamide hydrochloride.

- 66 010298

The title compound was prepared according to the procedure described in Example 84 based on tert-butyl-trans-4 - [(5-amino-1-benzofuran-7-yl) oxy] -3-fluoropiperidin-1-carboxylate ( intermediate 53) and 2-chloro-5-fluorobenzenesulfonyl chloride. Yield: 34 mg (18%). HPLC: purity = 100%, t / ζ = 443 (M + H) ⁺ . ^! H NMR (270 MHz, methanol-b ₄ ) δ ppm 2.11-2.36 (m, 2H), 3.15-3.58 (m, 3H), 3.63-3.81 ( m, 1H), 4.77-4.98 (m, 1H), 5.00-5.24 (m, 1H), 6.75 (d, 1 = 2.23 Hz, 1H), 6.85 (d, 1 = 1.98 Hz, 1H), 7.05 (d, 1 = 1.98 Hz, 1H), 7.09-7.20 (m, 1H), 7.42 (dd, 1 = 8.66, 2.47 Hz, 1H), 7.72 (d, 1 = 2.23 Hz, 1H), 7.97-8.06 (m, 1H).

Intermediate 54.

2,3-dihydrobenzofuran-5-sulfonyl chloride.

Chlorosulfonic acid (43.4 g, 0.366 mol) in an ESM (10 ml) is added to a cold solution (temperature 5 ° C) of 2,3-dihydrobenzofuran (20 g, 0.166 mol) in an ESM (200 ml). After addition, the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was quenched with water (150 ml), keeping the temperature below 10 ° C. The organic phase is separated and washed with an aqueous solution of HaNCO3 (13.9 g, dissolved in 150 ml of water). The organic solvents were evaporated to give the title compound as a solid in an amount of 3.3 g (23%). ΊI NMR (270 MHz, COC1 ₃ ) δ ppm 3.32 (t, 1 = 8.91 Hz, 2H), 4.75 (t, 1 = 8.91 Hz, 2H), 6.90 (d, 1 = 9.15 Hz, 1H), 7, 78-7.90 (m, 2H).

Intermediate 55.

7-Iodo-2,3-dihydrobenzofuran-5-sulfonyl chloride.

To a solution of 2,3-dihydrobenzofuran-5-sulfonyl chloride (5 g, 23 mmol; intermediate 54) in an ESM (100 ml) was added dropwise a solution of Yu (7.7 g, 47 mmol) in an ESM (100 ml) at a temperature boiling under reflux in a nitrogen atmosphere. The reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature and acetonitrile (50 ml) was added. The resulting mixture was washed with a saturated HaHCO3 solution and the organic phase was separated, followed by removal of volatiles in vacuo, to give 8 g of a brown oil, which was used in the next step without further purification. ¹ H NMR (270 MHz, SEGH) δ ppm 3.45 (t, 1 = 8.91 Hz, 2H), 4.82 (t, 1 = 8.91 Hz, 2H), 7.79 (d, 1 = 1.48 Hz, 1H), 8, 16 (d, 1 = 1.98 Hz, 1H).

Intermediate 56.

7-Iodo-1-benzofuran-5-sulfonyl chloride.

Azobisisobutyronitrile (AGHC (270 mg, 1.3 mmol) and X-bromosuccinimide (XB8) (2.5 g, 14 mmol) are added to 7-iodo-2,3-dihydrobenzofuran-5-sulfonyl chloride (4.4 g, 13 mmol; intermediate 55) in chlorobenzene (30 ml) at a temperature of 70 ° C. One hour after the addition, the heating was stopped. Acetonitrile (30 ml) was added and the organic phase was washed with sodium sulfite in water. The organic phase was separated and the volatiles were evaporated with 4 g (90% yield) of the title compound as yellow crystals ¹ H NMR (270 MHz, SES _{1 3} ) δ ppm 7.07 (d, 1 = 2.2 3 Hz, 1H), 7.90 (d, 1 = 2.23 Hz, 1H), 8.29-8.37 (m, 1H).

Intermediate 57.

7-Iodo-X- (2-methoxy-5-methylphenyl) -1-benzofuran-5-sulfonamide.

To a solution of 7-iodo-1-benzofuran-5-sulfonyl chloride (10.75 g, 31 mmol; intermediate 56) in dichloromethane (200 ml) was added 5-methyl-2-methoxyaniline (4.25 g, 31 mmol) and pyridine (7.4 ml, 93 mmol) and allowed to stir at room temperature overnight. The dark red solution is washed with water, separated, dried and filtered through a layer of silica to remove most of the red impurity and, finally, concentrated. Yield: 13.51 g (99% yield) of a red solid. HPLC: 90%, K _T = 2.58 min (system A; 30-80% MeCX for 3 min), 1.75 min (system C; 2-95% MeCX for 2 min). ¹ H NMR (400 MHz, SEGH) δ ppm 2.23 (m, 3H), 3.52 (s, 3H), 6.54 (d, 1 = 8.30 Hz, 1H), 6.79 (dd, 1 = 8.42, 1.59 Hz , 1H), 6.86 (d, 1 = 2.20 Hz, 1H), 6.96 (s, 1H), 7.31 (d, 1 = 1.71 Hz, 1H), 7.71 (d , 1 = 2.20 Hz, 1H), 7.95 (d, 1 = 1.71 Hz, 1H), 8.04 (d, 1 = 1.71 Hz, 1H). M8 (EZC for С ₁₆ Н ₁₄ ГХО ₄ 8, t / ζ: 444 (М + Н).

Example 92. X- (2-Methoxy-5-methylphenyl) -7 - [(3-methylpiperazin-1-yl) methyl] - 1-benzofuran-5-sulfonamide hydrochloride.

Stage 1. 7- (3-Methylpiperazine-1-carbonyl) benzofuran-5-sulfonic acid (2-Methoxy-5-methylphenyl) amide.

To 7-iodo-X- (2-methoxy-5-methylphenyl) -1-benzofuran-5-sulfonamide (100 mg, 0.23 mmol; intermediate 57), 2-methylpiperazine (45 mg, 0.46 mmol) was added , Hermann's catalyst (25 mg, 0.02 mmol), Mo (CO) ₆ (30 mg, 0.12 mmol) and K ₂ CO ₃ (112 mg, 0.81 mmol) in diglyme (3 ml) and heated in 81 eatB1osk at a temperature of 120 ° C. After 20 minutes, the mixture was filtered, diluted with ethyl acetate and washed with water. After concentration, the crude mixture was purified by preparative HPLC (Sysoy; gradient 3070% MeXX) to obtain, after alkalization with XAOH and washing with water, the title amide. Yield: 36 mg (36%). HPLC: 88%, K _T = 1.09 min (system C; 2-95% MeCX for 2 min). M8 (E8C for C ₂₂ H ₂₅ X ₃ O ₅ 8, t / ζ: 444 (M + H).

Stage 2. X- (2-Methoxy-5-methylphenyl) -7 - [(3-methylpiperazin-1-yl) methyl] -1-benzofuran-5-sulfo

- 67 010298 namidhydrochloride.

To the obtained (2-methoxy-5-methylphenyl) amide of 7- (3-methylpiperazine-1-carbonyl) benzofuran-5sulfonic acid (30 mg, 0.07 mmol; stage 1), L1A1H ₄ (9.0 mg, 0, 24 mmol) in anhydrous THF (4 ml) and the mixture was heated at the boiling point under reflux. After 1 h, HPLC analysis showed 15% of the product and the remaining impurities. To the mixture was added 2 M HC1, concentrated and purified by preparative HPLC (Schl; gradient of 30-70% MeSC). Pure fractions were stripped, a solution of HCl in diethyl ether was added and concentrated to give the title compound as a colorless solid. Yield: 1.3 mg (5%). HPLC: 90%, CT = 1.17 min (system A; 30-80% MeCN for 3 min), 1.13 min (system C; 2-95% MeCN for 2 min). ¹ H NMR (400 MHz, methanol ₄ ) δ ppm 1.29 (d, 1 = 7.0 Hz, 2H), 2.21 (s, 3H), 2.72 (m, 1H), 2.86 (m, 1H), 3.38 (s, 4H) ), 3.433.64 (m, 4H), 4.30 (d, 1 = 6.59 Hz, 2H), 6.62 (d, 1 = 8.30 Hz, 1H), 6.81-6.88 (m, 1H), 6.99 (d, 1 = 2.44 Hz, 1H), 7.25 (d, 1 = 1, 95 Hz, 1H), 7.76 (broad s, 1H), 7 94 (d, 1 = 2.20 Hz, 1H); 8.08 (d, 1 = 1.71 Hz, 1H). M8 (E8C for C ₂₂ H ₂₇ ^ O ₄ 8, m / z: 430 (M + H).

Intermediate 58.

7-Iodine-No. (2-methylphenyl) -1-benzofuran-5-sulfonamide.

7-Iodo-1-benzofuran-5-sulfonyl chloride (10 g, 29.2 mmol; intermediate 56) and 2 methylaniline (3.43 ml, 32.1 mmol) were dissolved in dichloromethane (150 ml) and pyridine was added (3, 53 ml, 43.8 mmol). The solution was stirred overnight and washed with 1 M HCl (2 times 100 ml), dried over sodium sulfate and evaporated to give a crude solid, which was recrystallized from methanol. Yield: 5.32 g (44%) of a beige solid. ¹ H NMR (400 MHz, SIS1 ₃ ) δ ppm 2.05 (s, 3H), 6.36 (s, 1H), 6.95 (d, 1 = 2.3 Hz, 1H), 7.11-7.19 (m, 3H), 7.28 (d, 1 = 7.5 Hz, 1H), 7.81 (d, 1 = 2.3 Hz, 1H), 7.99 (d, 1 = 1.8 Hz, 1H), 8.08 (d , 1 = 1.8 Hz, 1H).

Intermediate 59.

No. (2-Methylphenyl) -7-vinyl-1-benzofuran-5-sulfonamide.

7-Iodine-No. (2-methylphenyl) -1-benzofuran-5-sulfonamide (0.41 g, 1 mmol; intermediate 58), tributyl vinyltin (0.32 ml, 1.1 mmol), bis (triphenylphosphine) palladium diacetate (10 mg) and acetonitrile (3 ml) are heated for 5 min at a temperature of 180 ° C under irradiation with microwaves. The mixture was cooled, filtered and evaporated. The resulting oil was washed with hexane (2 times 50 ml), dissolved in diethyl ether (50 ml), filtered and evaporated to give a crude product, which was crystallized from ethanol: water (3: 1). Yield: 0.19 g (61%) of an off-white solid. ¹ H NMR (400 MHz, DMSO _6th ) δ ppm 1.93 (s, 3H), 5.57 (dd, 1 = 1 1.3, 1.0 Hz, 1H), 6.12 (dd, 1 = 17.8, 1.0 Hz, 1H), 6.84-7.07 (m, 6H), 7.62 (d, 1 = 1.8 Hz, 1H), 7.84 (d, 1 = 1.8 Hz, 1H), 8.14 (d , 1 = 2.3 Hz, 1H); 9.43 (s, 1H).

Intermediate 60.

7-Formyl-No. (2-methylphenyl) -1-benzofuran-5-sulfonamide.

No. (2-Methylphenyl) -7-vinyl-1-benzofuran-5-sulfonamide (1.03 g, 3.3 mmol; intermediate 59) was dissolved in dioxane (30 ml) and 2,6-lutidine (0.8 ml). Osmium tetroxide (84 mg, 0.33 mmol) was added, followed by stirring with a solution of sodium periodate (2.82 g, 13.2 mmol) in water (10 ml). After stirring for 90 minutes, 1 M HC1 (40 ml) was added, then water (200 ml). The precipitated product is obtained by filtration, washed with water and dried in vacuo.

Yield: 0.95 g (91%) of an off-white solid. ¹ H NMR (400 MHz, SIS1 ₃ ) δ ppm 2.05 (s, 3H), 6.38 (s, 1H), 6.95 (d, 1 = 2.3 Hz, 1H), 7.11 (dd, 1 = 5.1, 1.1 Hz , 2H), 7.13-7.19 (m, 2H), 7.91 (d, 1 = 2.3 Hz, 1H), 8.25 (dd, 1 = 15.8, 1.8 Hz, 2H), 10.42 (s, 1H).

Example 93. No. (2-Methylphenyl) -7- (piperazin-1-ylmethyl) -1-benzofuran-5-sulfonamide trifluoroacetate.

7-Formyl-No. (2-methylphenyl) -1-benzofuran-5-sulfonamide (20 mg, 0.06 mmol; intermediate 60), No. (tert-butoxycarbonyl) piperazine (13 mg, 0.07 mmol), acetic acid (36 μl, 0.63 mmol), sodium triacetoxyborohydride (27 mg, 0.13 mmol) are mixed with anhydrous tetrahydrofuran (3 ml) and heated for 5 min at 130 ° C under microwave irradiation. The solution was cooled, filtered and evaporated. The residue was dissolved in methanol (3 ml) and treated with concentrated hydrochloric acid (0.3 ml). This solution is heated for 5 min at a temperature of 100 ° C under irradiation with microwaves. The solvent was evaporated, yielding a crude product, which was purified by preparative HPLC (Soy system equipped with an ACE 5 C8 column (30 mm x 150 mm), flow rate: 35 ml / min. Eluent: gradient 15-40% MeCN in 0.1% TFA in water IIEP). Yield: 16 mg (50%). Analytical HPLC was performed on an AdPep instrument! 1100, column: ACE 3 C8 (system A) or column: UMS-Rask (system B); eluents: MP1 | O / 0.1% TFA and MeSC HPLC: 99%, K _T = 1.48 min (system A; 10-97% MeCN for 3 min), 99%, K _T = 1.31 min (system B; 10-90% of MeSC for 3 min). M8 (Eg [+) for C ₂₀ H ₂₃ K ₃ O ₃ 8, t / ζ: 386 (M + 1). ^! H NMR (400 MHz, methanol ₄ ) δ ppm 1.89 (s, 3H), 2.65-2.72 (m, 4H), 3.103.17 (m, 4H), 3.95 (s, 2H), 6.92 (d, 1 = 2, 3 Hz, 1H), 6.96-6.99 (m, 2H), 6.99-7.02 (m, 1 = 3.2, 1.8, 1.8 Hz, 2H), 7.51 (d, 1 = 1.8 Hz, 1H), 7.87 (d, 1 = 2.3 Hz, 1H), 7.96 (d, 1 = 1.8 Hz, 1H).

Example 94. 7 - [(3,5-Dimethylpiperazin-1-yl) methyl] -K- (2-methylphenyl) -1-benzofuran-5-sulfonamide trifluoroacetate.

- 68 010298

The title compound was prepared according to the procedure described in Example 93 using 7-formyl-Y- (2-methylphenyl) -1-benzofuran-5-sulfonamide (40 mg, 0.12 mmol; intermediate 60) and 3.5 -dimethylpiperazine (16 mg, 0.14 mmol) [note: without the stage of deprotection using HC1]. Yield: 21.5 mg (40%). HPLC: 97%, K _t = 1.57 min (system A; 10-97% МеСЫ for 3 min), 99%, K _t = 1.39 min (system B; 10-90% МеСЫ for 3 min ) M8 (E81 +) for C ₂₂ H ₂₇ N ₃ O ₃ 8, t / ζ: 414 (M + 1). Ή NMR (400 MHz, methanol-6 ₄ ) δ ppm 1.19 (d, 1 = 6.8 Hz, 6H), 1.91 (s, 3H), 2.11 (dd, 1 = 12.7, 11.4 Hz, 2H), 2.96 (dd , 1 = 12.9, 2.4 Hz, 2H), 3.27 (ddd, 1 = 11.1, 6.7, 3.3 Hz, 2H), 3.91 (s, 2H), 6, 90 (d, 1 = 2.3 Hz, 1H), 6.95-7.03 (m, 4H), 7.57 (d, 1 = 1.5 Hz, 1H), 7.86 (d, 1 = 2.3 Hz, 1H), 7.91 (d, 1 = 1.8 Hz, 1H).

Example 95. Y- (2-Methylphenyl) -7 - [(3-methylpiperazin-1-yl) methyl] - 1-benzofuran-5-sulfonamide trifluoroacetate.

The title compound was prepared according to the procedure described in Example 93 using 7-formyl-Y- (2-methylphenyl) -1-benzofuran-5-sulfonamide (40 mg, 0.12 mmol; intermediate 60) and 2-methylpiperazine (14 mg, 0.14 mmol) [note: no stage of deprotection with HC1]. Yield: 31.6 mg (59%). HPLC: 97%, K _t = 1.50 min (system A; 10-97% МеСЫ for 3 min), 99%, K _t = 1.33 min (system B; 10-90% МеСЫ for 3 min ) M8 (E81 +) for C _2! H ₂₅ S ₃ O ₃ 8, t / ζ: 400 (M + 1). ^! H NMR (400 MHz, methanol-6 ₄ ) δ ppm 1.20 (d, 1 = 6.8 Hz, 3H), 1.90 (s, 3H), 2.33 (dd, 1 = 12.7, 10.7 Hz, 1H), 2.47 ( 16, 1 = 12.4, 3.1 Hz, 1H), 2.87-2.94 (m, 1 = 12.8 Hz, 1H), 3.00-3.09 (m, 2H), 3 26-3.34 (m, 1 = 10.0, 6.8, 6.8, 3.0 Hz, 2H), 3.94-4.04 (m, 2H), 6.92 (d, 1 = 2.3 Hz, 1H), 6.97 (61, 1 = 5.0, 2.2 Hz, 2H), 7.01 (td, 1 = 3.6, 2.0 Hz, 2H), 7.55 (d, 1 = 1.8 Hz, 1H), 7.87 (d, 1 = 2.0 Hz, 1H), 7.95 (d, 1 = 1.8 Hz, 1H).

Example 96. 7- (1,4-Diazepan-1-ylmethyl) -Y- (2-methylphenyl) -1-benzofuran-5-sulfonamide trifluoroacetate.

The title compound was prepared according to the procedure described in Example 93 using 7-formyl-Y- (2-methylphenyl) -1-benzofuran-5-sulfonamide (40 mg, 0.12 mmol; intermediate 60) and Y- ( tert-butoxycarbonyl) homopiperazine (28 mg, 0.14 mmol). Yield: 21.0 mg (31%). HPLC: 99%, R _t = 1.34 min (System A, 10-97% Mesa for 3 min), 99%, R _t = 1.18 min (System B, 10-90% Mesa for 3 min ) M8 (E81 +) for С ₂ 1Н ₂₅ Н ₃ О ₃ 8, t / ζ: 400 (М + 1). ¹ H NMR (400 MHz, methanol-6 ₄ ) δ ppm 1.94 (s, 3H), 2.10-2.17 (m, 2H), 3.28-3.35 (m, 4H), 3.49-3.59 (m, 4H), 4, 60 (s, 2H), 6.92-7.04 (m, 5H), 7.72 (d, 1 = 1.8 Hz, 1H), 7.94 (d, 1 = 2.3 Hz, 1H ), 8.09 (d, 1 = 1.8 Hz, 1H).

Example 97. 7 - {(trans-2,5-Dimethylpiperazin-1-yl) methyl} -Y- (2-methylphenyl) -1-benzofuran-5-sulfonamide trifluoroacetate.

The title compound was prepared according to the procedure described in Example 93 using 7-formyl-Y- (2-methylphenyl) -1-benzofuran-5-sulfonamide (80 mg, 0.24 mmol; intermediate 60) and trans-2 , 5-dimethylpiperazine (58 mg, 0.48 mmol) [note: without the deprotection step using HC1]. Yield: 32.2 mg (30%). HPLC: 99%, K _t = 1.58 min (system A; 10-97% МеСЫ for 3 min), 99%, К _t = 1.40 min (system B; 10-90% МеСЫ for 3 min ) M8 (E81 +) for C ₂₂ H ₂₇ N ₃ O ₃ 8, t / ζ: 414 (M + 1). Ή NMR (400 MHz, methanol-6 ₄ ) δ ppm 1.12 (d, 1 = 6.5 Hz, 3H), 1.22 (d, 1 = 5.8 Hz, 3H), 1.91 (s, 3H), 2.23 (dd, 1 = 13 , 1, 11.3 Hz, 1H), 2.75-2.86 (m, 3H), 3.14-3.21 (m, 1H), 3.27 (dd, 1 = 12.2, 2 4 Hz, 1H), 3.72 (d, 1 = 14.3 Hz, 1H), 4.37 (d, 1 = 14.3 Hz, 1H), 6.91 (d, 1 = 2.3 Hz, 1H), 6.97-7.03 (m, 4H), 7.58 (d, 1 = 1.8 Hz, 1H), 7.86 (d, 1 = 2.3 Hz, 1H), 7.91 (d, 1 = 1.8 Hz, 1H).

Example 98. Y- (2-Methylphenyl) -7 - {[((2K) -2-methylpiperazin-1-yl] methyl} -1-benzofuran-5-sulfonamide trifluoroacetate.

The title compound was prepared according to the procedure described in Example 93 using 7-formyl-Y- (2-methylphenyl) -1-benzofuran-5-sulfonamide (40 mg, 0.12 mmol; intermediate 60) and (3K) -3-methyl-1-tritylpiperazine (48 mg, 0.14 mmol). Yield: 22.8 mg (35%). HPLC: 96%, R _t = 1.49 min (System A, 10-97% Mesa for 3 min), 96%, R _t = 1.31 min (System B, 10-90% Mesa for 3 min ) M8 (E81 +) for С ₂ 1Н ₂₅ Н ₃ О ₃ 8, t / ζ: 400 (М + 1). ¹ H NMR (400 MHz, methanol-6 ₄ ) δ ppm 1.32 (d, 1 = 6.3 Hz, 3H), 1.90 (s, 3H), 2.58-2.66 (m, 1H), 2.87-2.97 (m, 2H) , 2.99-3.08 (m, 2H), 3.24-3.27 (m, 1H), 3.33 (61, 1 = 11.9, 1.8 Hz, 1H), 3.91 (d, 1 = 14.1 Hz, 1H), 4.50 (d, 1 = 14.1 Hz, 1H), 6.94 (d, 1 = 2.3 Hz, 1H), 6.96-6 99 (m, 2H), 7.01 (dd, 1 = 4.0, 2.8 Hz, 2H), 7.56 (d, 1 = 1.8 Hz, 1H), 7.88 (d, 1 = 2.0 Hz, 1H); 7.99 (d, 1 = 1.8 Hz, 1H).

The intermediate product 61.

Y- (2-Methoxy-5-methylphenyl) -7-vinyl-1-benzofuran-5-sulfonamide.

Five batches, each consisting of a mixture of Y- (2-methoxy-5-methylphenyl) -7-iodo-1-benzofuran-5sulfonamide (443 mg, 1.0 mmol; intermediate 57), tributyl (vinyl) tin (350 mg, 1.1 mmol) and bis (triphenylphosphine) palladium diacetate (15 mg, 0.02 mmol) in acetonitrile (3 ml), heated for 5 minutes at 180 ° C in a 8ιηί11ι Сgeа1ог microwave oven. The combined reaction mixtures were filtered and concentrated, yielding 2.0 g of crystalline crude material, which was passed through a column of 81O ₂ using an ethyl acetate / hexane mixture (gradient 5:95 25:75) as eluent to obtain 1.3 g (yield 75 %) off-white crystalline product. ¹ H NMR (400 MHz, COC1 _; ) 6 2.26 (s, 3H), 3.53 (s, 3H), 5.56 (dd, 1H), 6.16 (dd, 1H), 6.57 (d, 1H), 6.79-6.98 (m, 4H), 7.38 (d, 1H), 7.71-7.74 (m, 2H), 7.94 (d, 1H); M8 (E81 +) for С ₁₈ Н ₁₇ НО ₄ 8, t / ζ: 344 (М + Н) ⁺ .

Intermediate 62.

- 69 010298

7-Formyl-K- (2-methoxy-5-methylphenyl) -1-benzofuran-5-sulfonamide.

Osmium tetroxide (84 mg, 0.33 mmol) is added to a solution of K- (2-methoxy-5-methylphenyl) -7-vinyl-1 benzofuran-5-sulfonamide (1.25 g, 3.3 mmol; intermediate 61) and lutidine (0.71 g, 6.6 mmol) in dioxane (30 ml). With stirring, a solution of sodium periodate (2.82 g, 13.2 mmol) in water (10 ml) is added. After 90 minutes, an aqueous HC1 solution (2 M; 40 ml) was added to give a clear solution. The addition of water (200 ml) causes precipitation, which is collected by filtration. This material was washed with water and dried, yielding 1.12 g (88% yield) of the title product. ¹ H NMR (400 MHz, SES1 ₃ ) δ 2.27 (s, 3H), 3.55 (s, 3H), 6.57 (d, 1H), 6.80-6.85 (m, 1H) 6.92 (d, 1H), 7.02 (br s, 1H), 7.38 (d, 1H), 7.85 (d, 1H), 8.22 (d, 1H), 8, 28 (d, 1H), 10.38 (s, 1H).

Example 99. N- (2-Methoxy-5-methylphenyl) -7 - [(3-methylpylpiperazin-1-yl) methyl] -1-benzofuran-5 sulfonamide trifluoroacetate.

Mixture of 7-formyl-No (2-methoxy-5-methylphenyl) -1-benzofuran-5-sulfonamide (100 mg, 0.29 mmol; intermediate 62), 2-methylpiperazine (32 mg, 0.32 mmol) and sodium triacetoxyborohydride (245 mg, 1.16 mmol) in 1.2 dichloromethane (3 ml) was stirred overnight. By filtration and concentration, 100 mg of crude material is obtained, which is purified by preparative HPLC to obtain, after concentration, 30 mg (19% yield) of the title compound. 'H NMR (400 MHz, methanol-b ₄ ) δ 1.27 (d, 3H), 2.24 (s, 3H), 2.33-2.40 (m, 1H), 2.46-2, 55 (m, 1H), 2.91-2.98 (m, 1H), 3.05-3.17 (m, 2H), 3.32-3.38 (m, 1H), 3.39 ( s, 3H), 3.96-4.08 (m, 2H), 6.64 (d, 1H), 6.87 (dd, 1H), 6.97 (d, 1H), 7.28 (d , 1H); 7.66 (d, 1H); 7.91 (d, 1H); 8.04 (d, 1H); M8 +) for С ₂₂ Н ₂₇ ЩО ₄ 8, t / ζ: 430 (М + Н) ⁺ ;

HPLC: 99%, K _t = 1.66 min (system A; 10-97% MeCN for 3 min), 99%, K _t = 1.46 min (system B; 10-97% MeCN for 3 min )

Example 100. 7- (1,4-Diazepan-1-ylmethyl) -№ (2-methoxy-5-methylphenyl) -1-benzofuran-5-sulfonamide trifluoroacetate.

The title compound was prepared according to the procedure for Example 99. Yield: 55 mg (69%). ¹ H NMR (400 MHz, methanol-b4) δ 2.16-2.23 (m, 2H), 2.23 (s, 3H), 3.35-3.42 (m, 4H), 3.39 (s, 3H), 3.58-3.67 (m, 4H), 4.66 (s, 2H), 6.64 (d, 1H), 6.88 (dd, 1H), 7.05 ( d, 1H), 7.28 (d, 1H), 7.84 (d, 1H), 7.98 (d, 1H), 8.18 (d, 1H); M8 (Ε8I +) for С22Н27ЩО48, t / ζ: 430 (M + H) ⁺ ; HPLC: 99%, Cr = 1.50 min (System A, 10-97% MeCN over 3 min), 99%, R _t = 1.33 min (System B, 10-97% MeCN over 3 min) .

Example 101. No. (2-Methoxy-5-methylphenyl) -7- (piperazin-1-ylmethyl) -1-benzofuran-5-sulfonamide trifluoroacetate.

The title compound was prepared according to the procedure for EXAMPLE 99. Yield: 26 mg (34%). ¹ H NMR (400 MHz, methanol-b4) δ 2.24 (s, 3H), 2.91-2.96 (m, 4H), 3.26-3.32 (m, 4H), 3.38 (s, 3H), 4.17 (s, 2H), 6.63 (d, 1H), 6.87 (dd, 1H), 6.99 (d, 1H), 7.28 (d, 1H), 7 68 (d, 1H); 7.92 (d, 1H); 8.08 (d, 1H); M8 +) for С21Н25ЩО48, t / ζ: 416 (M + H) ⁺ ; HPLC: 99%, Cr = 1.58 min (System A, 10-97% MeCN over 3 min), 99%, R _t = 1.39 min (System B, 10-97% MeCN over 3 min) .

Example 102. 7 - {(cis-3,5-dimethylpiperazin-1-yl) methyl} -№ (2-methoxy-5-methylphenyl) -1-benzofuran-5-sulfonamide trifluoroacetate.

The title compound was prepared according to the procedure for Example 99. Yield: 39 mg (48%). ¹ H NMR (400 MHz, methanol-b4) δ 1.26 (d, 6H), 2.20-2.28 (m, 2H), 2.23 (s, 3H), 3.03-3.08 (m, 2H), 3.32-3.39 (m, 2H), 3.41 (s, 3H), 4.01 (s, 2H), 6.65 (d, 1H), 6.86 ( dd, 1H), 6.96 (d, 1H), 7.27 (d, 1H), 7.69 (d, 1H), 7.90 (d, 1H), 8.02 (d, 1H); M8 +) for С23Н29ЩО48, t / ζ: 4 44 (M + H) ⁺ ; HPLC: 99% Cr 0 = 1.7 min (System A, 10-97% MeCN over 3 min), 99%, R _t = 1.50 min (System B, 10-97% MeCN over 3 min )

Example 103. 7 - {[trans-2,5-Dimethylpiperazin-1-yl] methyl} -№ (2-methoxy-5-methylphenyl) -1-benzofuran-5-sulfonamide trifluoroacetate.

The title compound was prepared according to the procedure for EXAMPLE 99. Yield: 11 mg (13%). ¹ H NMR (4 00 MHz, methanol-b ₄ ) δ 1.17 (d, 3H), 1.26 (d, 3H), 2.16-2.24 (m, 1H), 2.24 (s , 3H), 2.72-2.78 (m, 1H),

2.82-2.91 (m, 2H), 3.19-3.25 (m, 1H), 3.30-3.35 (m, 1H), 3.41 (s, 3H), 3, 71 (d, 1H), 4.36 (d, 1H), 6.66 (d, 1H),

6.87 (dd, 1H), 6.97 (d, 1H), 7.29 (d, 1H), 7.67 (d, 1H), 7.91 (d, 1H), 8.02 (d , 1H); M8 +) for С ₂₃ Н ₂₉ ЩО ₄ 8, t / ζ: 444 (М + Н) ⁺ ; HPLC: 99%, K _t = 1.70 min (system A; 10-97% MeCN for 3 min), 99%, K _t = 1.49 min (system B; 10-97% MeCN for 3 min )

Example 104. 7 - [(18.48) -2,5-Diazabicyclo [2.2.1] hept-2-ylmethyl] -№ (2-methoxy-5-methylphenyl) -1benzofuran-5-sulfonamide trifluoroacetate.

The title compound was prepared according to the procedure for Example 99. Yield: 46 mg (73%). ¹ H NMR (400 MHz, C1O1)) δ 2.20 (d, 1H), 2.23 (s, 3H), 2.54 (d, 1H), 3.38 (s, 3H), 3.44 -3.50 (m, 2H), 3.56 (dd, 1H), 3.78 (dd, 1H), 4.28 (broad s, 1H), 4.54 (broad s, 1H), 4.61 (d, 1H), 4.71 (d, 1H), 6.64 (d, 1H), 6.88 (dd, 1H), 7.04 (d, 1H), 7.28 (d , 1H); 7.83 (d, 1H); 7.97 (d, 1H); 8.16 (d, 1H); M8 +) for C ^ H ^ OA m / z: 428 (M + H) ⁺ ; HPLC: 99%, K _t = 1.50 min (system A; 10-97% MeCN for 3 min), 99%, K _t = 1.32 min (system B; 10-97% MeCN for 3 min )

Example 105. No. (2-Methoxy-5-methylphenyl) -7 - [(2-methylpiperazin-1-yl) methyl] -1-benzofuran-5sulfonamide trifluoroacetate.

The title compound was prepared according to the procedure for Example 99. Yield: 31 mg (49%).

- 70 010298 ^! H NMR (400 MHz, methanol-a4) δ 1.35 (d, 3H), 2.24 (s, 3H), 2.56-2.65 (m, 1H), 2.87-3.11 ( Oueg1arrshd t, 4H), 3.25-3.28 (m, 1H), 3.33-3.37 (m, 1H), 3.38 (s, 3H), 3.88 (d, 1H), 3.48 (d, 1H), 6.64 (d, 1H), 6.87 (dd, 1H), 6.98 (d, 1H), 7.29 (d, 1H), 7.66 (d , 1H); 7.92 (d, 1H); 8.07 (d, 1H); M8 +) for C22H27I3O48, t / ζ: 430 (M + H) ⁺ ; HPLC: 99%, Cr = 1.58 min (System A, 10-97% impurity for 3 min), 99%, R _t = 1.40 min (System B, 10-97% impurity for 3 min) .

Intermediate 63.

7-Methyl-5-nitro -1-benzofuran.

7-Iodine-5-nitrobenzofuran (6.5 g, 22.1 mmol), Ra (OAc) ₂ (1 g, 3.9 mmol), P (o-tolyl) ₃ (5.5 g, 18.2 mmol), (CH ₃ ) ₄ 8p (8.05 g, 42 mmol) and (C ₂ H ₅ ) ₃ I (3.16 ml, 20.4 mmol) are dissolved in dimethylformamide (40 ml) and divided into parts, placed in 13 tubes, and each tube is heated for 10 min at a temperature of 100 ° C, using controlled microwave energy. The reaction mixtures were combined and filtered, and the solvent was evaporated. The crude material is purified using flash chromatography (using an isohexane gradient of 10% ethyl acetate in isohexane). Yield: 2.82 g (70%) of 7-methyl-5-nitro-1-benzofuran. ^! H NMR (400 MHz, δ ppm, 2.51-2.64 (m, 3H), 6.90 (d, 1 = 2.3

Hz, 1H), 7.77 (d, 1 = 2.3 Hz, 1H), 8.04 (d, 1 = 1.3 Hz, 1H), 8.37 (d, 1 = 2.3 Hz, 1H); HPLC: 96%, R _t = 2.31 min (System A, 10-97% impurity for 3 min, Column ACE). M8 (Ε8I +) for С ₉ Н ₇ ИО ₃ , t / ζ: 173 (М + Н) ⁺ .

Intermediate 64.

7- (Bromomethyl) -5-nitrobenzofuran.

7-Methyl-5-nitrobenzofuran (2.1 g, 12 mmol; intermediate 63) was dissolved in CC1 ₄ and heated to a temperature of 80 ° C. Benzoyl peroxide (0.43 g, 1.6 mmol) was added, followed by I-bromosuccinimide (IV8) (2.1 g, 12 mmol), which was added in small portions. The reaction mixture was refluxed overnight with stirring. Additional benzoyl peroxide (0.08 mmol) and IV8 (0.2 mmol) were added and the reaction mixture was stirred for one additional night. After this time, the mixture is filtered and concentrated. The crude product is redissolved in dichloromethane and washed with water. The organic solvent was dried (MD8O ₄ ) and evaporated. The residue was purified using preparative HPLC with a gradient of 45-70% MeCI. Obtain 0.7 g (yield 22%) of 7- (bromomethyl) -5-nitrobenzofuran as a solid. ¹ H NMR (400 MHz, δ ppm, 4.78 (s, 2H), 6.96 (d, 1 = 2.3 Hz, 1H), 7.84 (d, 1 = 2.3 Hz, 1H), 8.28 (d, 1 = 2.3 Hz, 1H), 8.49 (d, 1 = 2.3 Hz, 1H). HPLC: K _t = 1.9 min (system A; 30- 80% MeCI for 3 min, ACE column).

Example 106. 2-Chloro-I- [7- (piperazin-1-ylmethyl) -1-benzofuran-5-yl] benzenesulfonamide dihydrochloride.

Step 1. Tert-Butyl-4 - [(5-nitro-1-benzofuran-7-yl) methyl] piperazine-1-carboxylate.

7- (Bromomethyl) -5-nitro-1-benzofuran (145 mg, 70 mol% of purity, 0.44 mmol; intermediate 64), K ₂ CO ₃ (181 mg, 1.31 mmol) and 1-BOC Piperazine (98 mg, 0.53 mmol) was mixed in anhydrous MeCI (5 ml) and heated with stirring for 2 hours at a temperature of 80 ° C using 81etB1osk. The solvent was evaporated under reduced pressure and the residue was partitioned between water and dichloromethane (2 times). The organic layers were combined, dried (IA ₂ 8O ₄ ) and purified using a flash column (10% MeOH in dichloromethane). The title product (123 mg, 78% yield) was obtained as a pale yellow solid. HPLC: 98%, K _t = 1.70 min (system A; 10-97% MeCI for 3 min), 99%, K _t = 1.55 min (system B; 10-97% MeCI for 3 min ); M8 (Ε8I +) for С1 ₈ Н ₂₃ И ₃ О ₅ , t / ζ: 362 (М + Н) ⁺ .

Step 2: 4- (5-aminobenzofuran-7-ylmethyl) piperazine-1-carboxylic acid tert-butyl ester.

Raney Nickel (suspension in ethanol) and hydrazine hydrate (66 μl, 1.36 mmol) are added to tert-butyl 4 - [(5-nitro-1-benzofuran-7-yl) methyl] piperazine-1-carboxylate (123 mg, 0 , 34 mmol; obtained in stage 1) in a mixture of ethanol: THF (4: 1; 10 ml). The mixture was stirred at room temperature for 1 hour. There was still an unreacted starting material, and with continuous stirring for 1 hour, additional Raney nickel and hydrazine hydrate (33 μl, 0.68 mmol) were added. The mixture is filtered through a pad of celite, which is washed several times with ethanol. After evaporation of the solvent, 119 mg (quantitative yield) of the title amine is obtained in the form of a thick green oil, which is used directly in the next step.

Step 3: 2-Chloro-I- [7- (piperazin-1-methyl) -1-benzofuran-5-yl] benzenesulfonamide dihydrochloride.

Anhydrous pyridine (20 μl, 0.24 mmol) and 2-chlorobenzenesulfonyl chloride (25 μl, 0.18 mmol) are added to the solution of 4- (5-aminobenzofuran-7-ylmethyl) piperazine-1-carboxylic acid tert-butyl ester (40 mg, 0.12 mmol; obtained in stage 2) in a mixture of anhydrous dichloromethane: TTF (2: 1; 3 ml). The resulting mixture was stirred for 3 hours and the volatiles were then evaporated. The product was purified using a flash column (15% MeOH in dichloromethane). The residue was dissolved in a mixture of TFA: water (9: 1; 2 ml) and the mixture was stirred at room temperature for 30 minutes to remove the I-tert-BOC group. The reaction mixture was made basic by adding a saturated aqueous solution of Ia2CO3 (pH 8-9) and extracted with dichloromethane (2 times). The organic layers are combined, dried

71 010298 (Na ₂ 8 O ₄ ) and concentrated. The crude product is purified by preparative HPLC (system A; 10-40% MECA). Pure fractions are combined and concentrated. The resulting TFA salt was dissolved in methanol and a 1 M solution of HCl in diethyl ether was added, then concentrated to obtain the title compound (10 mg, 18% yield) as a light yellow solid. HPLC: 100%, I _t = 1.38 min (System A, 10-97% Mesa for 3 min), 100%, Yat = 1.23 min (System B, 10-90% Mesa for 3 min) . ^! H NMR (400 MHz, methanol-b ₄ ) δ ppm 2.86-2.92 (m, 4H), 3.25-3.28 (m, 4H), 4.04-4.08 (m, 2H), 6.73 (d, 1 = 2.26 Hz, 1H), 7.15 (d, 4 = 2.01 Hz, 1H), 7.26-7.31 (m, 1H), 7.32 (d, 1 = 2.26 Hz, 1H), 7.42-7.47 (m, 1H), 7.477.52 (m, 1H), 7.70 (d, 1 = 2.26 Hz, 1H), 7.90 (dd, 1 = 8.03, 1.51 Hz, 1H). M8 (E81 +) for С1 ₉ Н ₂₀ СЫЫ ₃ О ₃ 8, t / ζ: 406 (М + Н).

Example 107. 2-Methyl-Y- [7- (piperazin-1-ylmethyl) -1-benzofuran-5-yl] benzenesulfonamide dihydrochloride.

The title compound was prepared according to the procedure for Example 106, Step 3, starting from 4- (5-aminobenzofuran-7-ylmethyl) piperazine-1-carboxylic acid tert-butyl ester (40 mg, 0.12 mmol; obtained in Example 106, step 2) and 2-methylbenzenesulfonyl chloride (26 μl, 0.18 mmol). The crude product is purified by preparative HPLC (system B; 10-40% MECA). The title compound (10 mg, 19% yield) was obtained as a colorless solid. HPLC: 99%, I _t = 1.41 min (system A; 10-97% MECA for 3 min), 99%, I _t = 1.26 min (system B; 10-90% MECA for 3 min ) ¹ H NMR (400 MHz, methanol-b ₄ ) δ ppm 2.66 (s, 3H), 3.50-3.65 (m, 8H), 4.67 (s, 2H), 6.86 (d, 1 = 2.01 Hz, 1H), 7.22 -

7.29 (m, 1H), 7.30-7.37 (m, 2H), 7.40-7.48 (m, 2H), 7.81-7.90 (m, 2H). M8 (E81 +) for C ₂₀ H ₂₃ N ₃ O ₃ 8, t / ζ: 386 (M + H) ⁺ .

Example 108. Y- [7- (Piperazin-1-ylmethyl) -1-benzofuran-5-yl] thiophen-2-sulfonamide dihydrochloride.

The title compound was prepared according to the procedure for Example 106, Step 3, starting from 4- (5-aminobenzofuran-7-ylmethyl) piperazine-1-carboxylic acid tert-butyl ester (40 mg, 0.12 mmol; obtained in Example 106, stage 2) and 2-thiophenesulfonyl chloride (33 mg, 0.18 mmol). With continuous stirring for 1 h, an additional amount of 2-thiophenesulfonyl chloride (10 mg, 0.05 mmol) was added. The crude product is purified by preparative HPLC (system B; 10-40% MECA). The title compound (3 mg, 6% yield) was obtained as a colorless solid. HPLC: 95%, I _t = 1.25 min (system A; 10-97% MECA for 3 min), 95%, I _t = 1.11 min (system B; 10-90% MECA for 3 min ) ^! H NMR (400 MHz, methanol-b ₄ ) δ ppm 3.43-3.49 (m, 4H), 3.50-3.57 (m, 4H), 4.59 (s, 2H), 6.90 (d, 1 = 2.26 Hz, 1H) 7.05 (dd, 1 = 5.02, 3.76 Hz, 1H), 7.35 (d, 1 = 2.26 Hz, 1H), 7.45-7.50 (m, 2H), 7.70 (dd, 1 = 5.02, 1.51 Hz, 1H); 7.88 (d, 1 = 2.26 Hz, 1H). M8 (E81 +) for C1 ₇ H ₁₉ N ₃ O ₃ 8 ₂ , t / ζ: 378 (M + H) ⁺ .

Example 109. 2-Chloro-Y- [7- (1,4-diazepan-1-ylmethyl) -1-benzofuran-5-yl] benzenesulfonamide dihydrochloride.

Stage 1. tert-Butyl-4 - [(5-nitro-1-benzofuran-7-yl) methyl] - 1,4-diazepan-1-carboxylate.

The title compound, obtained as a pale yellow solid, was prepared according to the procedure for Example 106, Step 1, starting from 1-BOC-homopiperazine (103 μl, 0.53 mmol). Yield: 109 mg (66%).

HPLC: 98%, I _t = 1.73 min (system A; 10-97% MECA for 3 min), 100%, I _t = 1.57 min (system B; 10-97% MECA for 3 min ) M8 (E81 +) for С1 ₉ Н ₂₅ Н ₃ О5, t / ζ: 376 (М + Н) ⁺ .

Stage 2. 4- (5-aminobenzofuran-7-ylmethyl) -1,4-diazepan-1-carboxylic acid tert-butyl ester

The title compound was prepared according to the procedure for Example 106, step 2, starting from tert-butyl-4 - [(5-nitro-1-benzofuran-7-yl) methyl] -1,4-diazepan-1-carboxylate (obtained from stage 1).

Step 3. 2-Chloro-Y- [7- (1,4-diazepan-1-methyl) -1-benzofuran-5-yl] benzenesulfonamide dihydrochloride.

The title compound was prepared according to the procedure for Example 106, Step 3, starting from 4- (5-aminobenzofuran-7-ylmethyl) -1,4-diazepan-1-carboxylic acid tert-butyl ester (36 mg, 0.10 mmol; obtained in step 2) and 2-chlorobenzenesulfonyl chloride (21 μl, 0.16 mmol). The crude material is purified by preparative HPLC (system B; 10-40% MECA). The title compound (16 mg, 33% yield) was obtained as a colorless solid. HPLC: 95%, I _m = 1.31 min (system A; 1097% MECA for 3 min), 96%, I _m = 1.17 min (system B; 10-97% MECA for 3 min). ¹ H NMR (400 MHz, methanol-b ₄ ) 5 ppm 2.25-2.37 (m, 2H), 3.41-3.48 (m, 2H), 3.48-3.59 (m, 1 = 4.52 Hz, 2H), 3.69- 3.75 (m, 1 = 3.51 Hz, 2H), 3.74-3.83 (m, 2H), 4.70 (s, 2H), 6.86 (d, 1 = 2.26 Hz) , 1H), 7.36-7.41 (m, 1H), 7.42 (d, 1 = 2.01 Hz, 1H), 7.51-7.59 (m, 3H), 7.35 ( d, 1 = 2.01 Hz, 1H), 8.00-8.04 (m, 1 = 1, 91, 1.13 Hz, 1H). M8 (E81 +) for С ₂₀ Н ₂₂ С1Ы ₃ О ₃ 8, t / ζ: 420 (М + Н) ⁺ .

Example 110. Y- [7- (1,4-Diazepan-1-ylmethyl) -1-benzofuran-5-yl] -2-methylbenzenesulfonamide dihydrochloride.

The title compound was prepared according to the procedure for Example 106, Step 3, starting from 4- (5-aminobenzofuran-7-ylmethyl) -1,4-diazepan-1-carboxylic acid tert-butyl ester (36 mg, 0.10 mmol; obtained according to example 109, step 2) and 2-methylbenzenesulfonyl chloride (23 μl, 0.16

- 72 010298 mmol). The title compound (13 mg, 28% yield) was obtained as a colorless solid. HPLC: 99%, K _t = 1.35 min (system A; 10-97% MeCN for 3 min), 100%, K _t = 1.22 min (system B; 10-97% MeCN for 3 min ) 'Η NMR (400 MHz, methanol-b ₄ ) δ ppm 2.26-2.32 (m, 2Η), 2.66 (s, 3Η), 3.40-3.60 (m, 4Η), 3.69-3.83 (m, 4Η), 4, 69 (s, 2Η), 6.86 (d, 1 = 2.26 Hz, 1Η), 7.23-7.29 (m, 1Η), 7.32-7.38 (m, 2Η), 7 41-7.46 (m, 1Η), 7.47 (d, 1 = 2.26 Hz, 1Η), 7.84-7.90 (m, 2Η). M8 +) for ΑΗ ^ ΝΑδ, t / ζ: 400 (M + H) ⁺ .

Example 111. No. [7- (1,4-Diazepan-1-ylmethyl) -1-benzofuran-5-yl] thiophen-2-sulfonamide dihydrochloride.

The title compound was prepared according to the procedure for Example 106, Step 3, starting from 4- (5-aminobenzofuran-7-ylmethyl) -1,4-diazepan-1-carboxylic acid tert-butyl ester (36 mg, 0.10 mmol; obtained according to example 109, step 2) and 2-thiophenesulfonyl chloride (29 mg, 0.16 mmol). With continuous stirring for 1 h, an additional amount of 2 thiophenesulfonyl chloride (10 mg, 0.06 mmol) was added. The title compound (10 mg, 22% yield) was obtained as a colorless solid. HPLC: 100%, K _t = 1.20 min (system A; 10-97% MeCN for 3 min), 100%, K _t = 1.06 min (system B; 10-97% MeCN for 3 min ) 'Η NMR (400 MHz, methanol-b ₄ ) δ ppm 2.20-2.29 (m, 2Η), 3.34-3.41 (m, 2Η), 3.41-3.55 (m, 2Η), 3.63-3.69 (m, 2Η) ), 3.69-3.77 (m, 2Η), 4.66 (s, 2Η), 6.84 (d, 1 = 2.26 Hz, 1Η), 6.98 (dd, 1 = 5, 02, 3.76 Hz, 1Η), 7.32 (d, 1 = 2.01 Hz, 1Η), 7.42 (dd, 1 = 3.76, 1.25 Hz, 1Η), 7.47 ( d, 1 = 2.26 Hz, 1Η), 7.63 (dd, 1 = 5.02, 1.25 Hz, 1Η), 7.82 (d, 1 = 2.26 Hz, 1Η). M8 (E8I +) for С18Η21NзΟз82, t / ζ: 392 (М-Η) '.

Example 112. 2-Methoxy-5-methyl-Y- {7 - [(2-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide dihydrochloride.

Step 1. Tert-Butyl-3-methyl-4 - [(5-nitro -1-benzofuran-7-yl) methyl] piperazin-1-carboxylate.

A mixture of 7- (bromomethyl) -5-nitro-1-benzofuran (120 mg, 70 mol%, 0.39 mmol; intermediate 64), K ₂ CO ₃ (162 mg, 1.17 mmol) and tert butyl 3-methylpiperazine-1-carboxylate (94 mg, 0.47 mmol) in anhydrous MeCN (5 ml) was heated with stirring for 1 h 45 min at a temperature of 80 ° C using 81etB1osk. The solvent was evaporated under reduced pressure and the residue was partitioned between water and dichloromethane (2 times). The organic layers were combined, dried (Na ₂ 8 O ₄ ) and purified using a flash column (10% methanol in dichloromethane). The title product (115 mg, 78% yield) was obtained as a pale yellow thick oil. HPLC: 99%, K _t = 2.47 min (system A; 5-60% MeCN for 3 min), 99%, K _t = 2.27 min (system B; 5-60% MeCN for 3 min ); M8 (E8H) for C ^ A, m / z: 376 (M + H) ⁺ .

Step 2. Tert-Butyl-4 - [(5-amino-1-benzofuran-7-yl) methyl] -3-methylpiperazin-1-carboxylate.

Raney Nickel (suspension in ethanol) and hydrazine hydrate (97 μl, 2.0 mmol) are added to tert-butyl 3-methyl-4 - [(5-nitro-1-benzofuran-7-yl) methyl] piperazine-1-carboxylate ( 115 mg, 0.31 mmol; obtained in step 1) in a mixture of ethanol: THF (4: 1; 5 ml). The resulting mixture was stirred at room temperature for 1.5 hours, then filtered through celite. The celite layer is washed several times with ethanol. The solvent was evaporated to give a crude product (136 mg) as a light green solid. This substance is used in the next step without further purification.

HPLC: 98%, K _t = 1.77 min (system A; 5-60% MeCN for 3 min), 100%, K _t = 1.50 min (system B; 5-60% MeCN for 3 min ); M8 (E8I +) for CA ^ Oz, m / z: 346 (M + H) ⁺ .

Step 3. 2-Methoxy-5-methyl-Y- {7 - [(2-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide dihydrochloride.

Pyridine (17 μl, 0.20 mmol) and 6-methoxy-m-toluenesulfonyl chloride (34 mg, 0.15 mmol) are added to a solution of tert-butyl-4 - [(5-amino-1-benzofuran-7-yl) methyl] -3-methylpiperazine-1-carboxylate (45 mg of crude material, 0.10 mmol; obtained in step 2) in an anhydrous mixture of dichloromethane: THF (2: 1; 3 ml). The reaction mixture was stirred at room temperature for 2 hours and the solvent was evaporated under reduced pressure, then purified using a flash column (15% MeΟΗ in dichloromethane). The residue was dissolved in a mixture of TFA: water (9: 1; 4.5 ml) and the mixture was stirred at room temperature for 1 h to remove the трет-tert-BOC group. The reaction mixture was diluted with dichloromethane (10 ml) and an aqueous saturated solution of NaCO _{3 was} added until a pH of 89 (about 15 ml) was reached. The phases are separated using "phase separator" filters and the organic phase is concentrated. The crude product is purified by preparative HPLC (system B; 10-40% MeC #). Pure fractions were combined and concentrated to give the product as a free base, which was dissolved in methanol and a 1 M solution of ΗΟ1 in diethyl ether (200 μl, 0.2 mmol) was added. The solvent was evaporated to give the title compound (19 mg, 38% yield) as an off-white solid. HPLC: 99%, K _t = 1.46 min (system A; 10-97% MeCN for 3 min), 100%, K _t =

1.29 min (system B; 10-97% MeCN for 3 min). 'Η NMR (400 MHz, methanol-b ₄ ) δ ppm 1.72 (d, 1 = 6.53 Hz, 3Η), 2.20 (s, 3Η), 3.39-3.62 (m, 5Η), 3.67-3.74 (m, 1Η) , 3.87-3.96 (m, 1Η), 3.98 (s, 3Η), 4.60 (d, 1 = 13.55 Hz, 1Η), 4.93 (d, 1 = 13.80 Hz, 1Η), 6.87 (d, 1 = 2.26 Hz, 1Η), 7.04 (d, 1 = 8.53 Hz, 1Η), 7.28-7.37 (m, 2Η), 7.52 (d, 1 = 2.26 Hz, 1Η), 7.54 (d, 1 = 2.01 Hz, 1Η), 7.85 (d, 1 = 2.01 Hz, 1Η). M8 (E8H) for ^ Η ^ ΝΑδ, t / ζ: 430 (M + H) ⁺ .

- 73 010298

Example 113. 2-Methyl-Y- {7 - [(2-methylpiperazin-1-yl) methyl] - 1-benzofuran-5-yl} benzenesulfonamide dihydrochloride.

The title compound was prepared according to the procedure for Example 112, Step 3, starting from tert-butyl-4 - [(5-amino-1-benzofuran-7-yl) methyl] -3-methylpiperazine-1-carboxylate (45 mg of crude material) , 0.10 mmol; obtained in Example 112, step 2) and o-toluenesulfonyl chloride (22 μl, 0.15 mmol). The title compound (17 mg, 35% yield) was obtained as an off-white solid. HPLC: 99%, K _T = 1.42 min (system A; 10-97% MeCN for 3 min), 100%, K _T = 1.26 min (system B; 10-97% MeCN for 3 min ) 'H NMR (400 MHz, methanol-b ₄ ) δ ppm 1.69-1.74 (m, 3H), 2.67 (s, 3H), 3.37-3.62 (m, 5H), 3.67-3.75 (m, 1H), 3, 84-3.95 (m, 1H), 4.57-4.65 (m, 1H), 4.90-4.97 (m, 1 = 13.55 Hz, 1H), 6.86 (d, 1 = 2.26 Hz, 1H), 7.23-7.29 (m, 1 = 7.65, 7.65 Hz, 1H), 7.31 (d, 1 = 2.01 Hz, 1H), 7.32-7.36 (m, 1H), 7.407.46 (m, 1H), 7.50 (d, 1 = 2.01 Hz, 1H), 7.85-7.90 (m, 2H) . M8 (E8T +) for t / ζ: 400 (M + H) ⁺ .

Example 114. 2,5-Dichloro-Y- {7 - [(2-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} thiophen-3sulfonamide dihydrochloride.

The title compound was prepared according to the procedure for Example 112, Step 3, starting from tert-butyl-4 - [(5-amino-1-benzofuran-7-yl) methyl] -3-methylpiperazine-1-carboxylate (45 mg of crude material) , 0.10 mmol; obtained in Example 112, step 2) and 2,5-dichlorothiophen-3-sulfonyl chloride (38 mg, 0.15 mmol). The title compound (23 mg, 43% yield) was obtained as an off-white solid. HPLC: 98%, K _T = 1.61 min (system A; 10-97% MeCN for 3 min), 100%, K _T = 1.43 min (system B; 10-100% MeCN for 3 min ) 'H NMR (400 MHz, methanol-b ₄ ) δ ppm 1.53 (d, 1 = 6.27 Hz, 3H), 2.87-3.02 (m, 1H), 3.14-3.27 (m, 2H), 3.39-3.47 ( m, 1H), 3.47-3.54 (m, 1H), 4.12-4.24 (m, 1H), 4.62-4.71 (m, 1H), 6.89 (d, 1 = 2.26 Hz, 1H), 7.13 (s, 1H), 7.30-7.32 (m, 1 = 1.76 Hz, 1H), 7.45 (d, 1 = 2.26 Hz, 1H), 7.85 (d, 1 = 2.26 Hz, 1H).

* Two hydrogen atoms in the spectrum are invisible. Probably “hidden” behind the H ₂ O and MeOH signals. M8 (Е§ [+) for С18Н1 ₉ С12ШО3§2, t / ζ: 460 (М + Н) ⁺ .

Example 115. 2-Methoxy-5-methyl-Y- {7 - [(3-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide dihydrochloride.

Step 1. 3-Methyl-1 - [(5-nitro-1-benzofuran-7-yl) methyl] piperazine.

The title compound was prepared according to the procedure for Example 112, Step 1, starting from 7 (bromomethyl) -5-nitro-1-benzofuran (120 mg, 70 mol%, 0.39 mmol; intermediate 64) and 2 methylpiperazine (196 mg , 1.95 mmol.). The crude product is purified by flash chromatography (eluent: 4% MeOH, 1% AL ₂ H ₅ ) ₃ in dichloromethane). The title compound (102 mg, 87% yield) was obtained as a pale yellow thick oil.

HPLC: 99%, K _T = 1.60 min (system A; 5-60% MeCN for 3 min), 100%, K _T = 1.40 min (system B; 5-60% MeCN for 3 min )

M8 (Е8Т +) for С1 ₄ Н ₁₇ No., О ₃ , t / ζ: 276 (М + Н) ⁺ .

Step 2. Tert-Butyl-2-methyl-4 - [(5-nitro -1-benzofuran-7-yl) methyl] piperazine-1-carboxylate.

Di-tert-butyl dicarbonate (89 mg, 0.41 mmol) in anhydrous dichloromethane (2 ml) was added with a syringe, in an atmosphere of Ν ₂ , to 3-methyl-1 - [(5-nitro-1-benzofuran-7- il) methyl] piperazine (102 mg, 0.37 mmol; obtained in step 1) and AH ₂ H ₅ ) ₃ (77 μl, 0.77 mmol) in anhydrous dichloromethane (5 ml) at 0 ° C. The resulting mixture was allowed to stand until room temperature was reached and stirred for 1.5 hours. The reaction mixture was diluted with dichloromethane and a saturated aqueous solution of N.C. O _{3 was} added. The organic layer was dried (№ ₂ 8o ₄₎ and concentrated followed by purification using flash chromatography (eluent: 1.5% MeOH in dichloromethane). The title compound (124 mg, yield 8–9%) was obtained as a white foam.

HPLC: 90%, K _T = 2.53 min (system A; 5-60% MeCN for 3 min), 90%, K _T = 2.35 min (system B; 5-60% MeCN for 3 min )

M8 (E8T +) for C2d3C3O3, m / z: 376 (M + H) ⁺ .

Step 3. Tert-Butyl-4 - [(5-amino -1-benzofuran-7-yl) methyl] -2-methyl-piperazin-1-carboxylate.

The title compound was prepared according to the procedure for Example 112, step 2, using tert-butyl-2-methyl-4 - [(5-nitro-1-benzofuran-7-yl) methyl] piperazine-1-carboxylate (124 mg, 0 33 mmol; obtained in step 2). The title crude compound (124 mg) was obtained as a light green solid. This substance is used in the next step without further purification. HPLC: 100%, K _T = 1.82 min (system A; 5-60% MeCN for 3 min), 100%, K _T = 1.57 min (system B; 5-60% MeCN for 3 min ) M8 (E8H) for C _1E H ₂₇ ^ O ₃ , m / z: 346 (M + H) ⁺ .

Step 4. 2-Methoxy-5-methyl-Y- {7 - [(3-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide dihydrochloride.

tert-Butyl-4 - [(5-amino-1-benzofuran-7-yl) methyl] -2-methyl-piperazine-1-carboxylate (41 mg of crude starting material, 0.11 mmol; obtained in step 3) is dissolved in an anhydrous mixture of dichloromethane: THF (2: 1; 3 ml). Pyridine (18 μl, 0.22 mmol) and 6-methoxy-m-toluenesulfonyl chloride (36 mg, 0.17 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours and the solvent was evaporated under reduced pressure, then purification was carried out using a flash column.

74 010298 (11% MeOH in dichloromethane). The residue was dissolved in a mixture of TFA: water (9: 1; 4.5 ml) and the mixture was stirred at room temperature for 1 h to remove the H-tert-BOC group. The reaction mixture was diluted with dichloromethane (10 ml) and a saturated aqueous solution of ChaCO3 was added to reach a pH of 8-9 (about 15 ml). The phases are separated using phase separator filters and the organic phase is concentrated. The crude product is purified by preparative HPLC (system B; 10-40% MeSCh). Pure fractions were combined and concentrated to give the product as a free base, which was dissolved in MeOH and a 1M solution of HCl in diethyl ether (200 μl, 0.2 mmol) was added. The solvent was evaporated to give the title compound (16 mg, 29% yield) as an off-white solid. HPLC: 99%, K _t = 1.48 min (system A; 10-97% MeSCh for 3 min), 100%, K _t =

1.30 min (system B; 10-97% MeSCh for 3 min). ¹ H NMR (400 MHz, methanol-ά / ΐ) δ ppm 1.38-1.45 (m, 1 = 6.53 Hz, 3H), 2.20 (s, 3H), 3.34-3.42 (m, 1 = 13.30 Hz, 1H), 3 46-3.78 (m, 5H), 3.79-3.91 (m, 1H), 3.98 (s, 3H), 4.7.1 (s, 2H), 6.87 (d , 1 = 2.26 Hz, 1H), 7.04 (d, 1 = 8.53 Hz, 1H), 7.29-7.34 (m, 1 = 8.78, 2.01 Hz, 1H) 7.37 (d, 1 = 2.26 Hz, 1H), 7.51-7.53 (m, 1 = 2.01 Hz, 1H), 7.54 (d, 1 = 2.26 Hz, 1H), 7.85 (d, 1 = 2.01 Hz, 1H). M8 (E81 +) for C ₂₂ H ₂₇ H ₃ O ₄ 8, t / ζ: 430 (M + H) ⁺ .

Example 116. H- {7 - [(3-Methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide dihydrochloride.

The title compound was prepared according to the procedure for Example 115, step 4, starting from tert-butyl-4 - [(5-amino-1-benzofuran-7-yl) methyl] -2-methylpiperazine-1-carboxylate (41 mg of crude starting material). substances, 0.11 mmol; obtained in Example 115, step 3) and 2- (trifluoromethyl) benzenesulfonyl chloride (25 μl, 0.17 mmol). The title compound (24 mg, 44% yield) was obtained as an off-white solid. HPLC: 98%, K _t = 1.56 min (system A; 10-97% MESC for 3 min), 97%, K _t = 1.37 min (system B; 10-97% MEC for 3 min ) ¹ H NMR (400 MHz, methanol-ά / ΐ) δ ppm 1.41 (d, 1 = 6.53 Hz, 3H), 3.36-3.44 (m, 1 = 13.30, 12.05 Hz, 1H), 3.47-3.78 (m, 5H), 3.81-3.94 (m, 1H), 4.74 (s, 2H), 6.88 (d, 1 = 2.26 Hz, 1H), 7.41 (d, 1 = 2 , 01 Hz, 1H), 7.53 (d, 1 = 2.26 Hz, 1H), 7.68-7.76 (m, 2H), 7.88 (d, 1 = 2.01 Hz, 1H ), 7.90-7.95 (m, 1 = 6.90, 2.13 Hz, 1H), 8.09-8.13 (m, 1H). M8 (E81 +) for C ₂ 1H ₂₂ E ₃ H ₃ O ₃ 8, t / ζ: 454 (M + H) ⁺ .

Example 117. 2-Chloro-Ch- {7 - [(3-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzene sulfonamide dihydrochloride.

The title compound was prepared according to the procedure for Example 115, step 4, starting from tert-butyl-4 - [(5-amino-1-benzofuran-7-yl) methyl] -2-methylpiperazine-1-carboxylate (41 mg of crude starting material). substances, 0.11 mmol; obtained in Example 115, step 3) and 2-chlorobenzenesulfonyl chloride (22 μl, 0.17 mmol). The title compound (21 mg, 39% yield) was obtained as an off-white solid. HPLC 100%, R _t = 1.42 min (System A, 10-97% MeSCh for 3 min), 100%, R _t = 1.26 min (System B, 10-97% MeSCh for 3 min ) ¹ H NMR (400 MHz, methanol-ά / ΐ) δ ppm 1.41 (d, 1 = 6.53 Hz, 3H), 3.32-3.37 (m, 1H), 3.45-3.59 (m, 2H), 3.63-3.76 ( m, 3H), 3.78-3.89 (m, 1H), 4.70 (s, 2H), 6.86 (d, 1 = 2.26 Hz, 1H), 7.36-7.41 (m, 1H), 7.42 (d, 1 = 2.01 Hz, 1H), 7.49-7.54 (m, 1H), 7.54-7.58 (m, 2H), 7, 86 (d, 1 = 2.01 Hz, 1H), 8.02 (dd, 1 = 7.91.1.63 Hz, 1H). M8 (E81 +) for С ₂₀ Н ₂₂ С1Ч ₃ О ₃ 8, t / ζ: 420 (М + Н) ⁺ .

Example 118. H- {7 - [(18,48) -2,5-Diazabicyclo [2.2.1] hept-2-ylmethyl] -1-benzofuran-5-yl} -2-methoxy5-methylbenzenesulfonamide dihydrochloride.

Step 1. Tert-Butyl (18.48) -5 - [(5-nitro-1-benzofuran-7-yl) methyl] -2,5-diazabicyclo [2.2.1] heptane2-carboxylate.

The title compound was prepared according to the procedure for Example 112, Step 1, starting from 7 (bromomethyl) -5-nitro-1-benzofuran (120 mg, 7 0 mol%, 0.39 mmol; intermediate 64) and tert-butyl- ( 18.48) - (-) - 2,5-diazabicyclo (2.2.1) -heptane-2-carboxylate (93 mg, 0.47 mmol). The title compound (115 mg, 7% 9% yield) was obtained as a pale yellow thick oil. HPLC: 99%, Cr = 2.34 min (System A; 5-60% MeSCh for 3 min), 99%, R _t = 2.15 min (System B, 5-60% MeSCh for 3 min) . M8 (E81 +) for C1 ₉ H ₂₃ H ₃ O ₅ , t / ζ: 374 (M + H) ⁺ .

Step 2. Tert-Butyl- (18.48) -5 - [(5-amino-1-benzofuran-7-yl) methyl] -2,5-diazabicyclo [2.2.1] heptane2-carboxylate.

The title compound was prepared according to the procedure for EXAMPLE 112 Step 2 using tert-butyl- (18,48) -5 - [(5-nitro-1-benzofuran-7-yl) methyl] -2,5-diazabicyclo [2 , 2.1] heptane-2-carboxylate (116 mg, 0.31 mmol; obtained in step 1). The title compound (133 mg) was obtained as a pale green solid. This substance is used in the next step without further purification. HPLC: 99%, R _t = 1.69 min (System A; 5-60% MeSCh for 3 min), 100%, R _t = 1.45 min (System B, 5-60% MeSCh for 3 min ) M8 (E81 +) for C1 ₉ H ₂₅ H ₃ O ₃ , t / ζ: 344 (M + H) ⁺ .

Step 3. H- {7 - [(18,48) -2,5-Diazabicyclo [2.2.1] hept-2-ylmethyl] -1-benzofuran-5-yl} -2-methoxy-5methylbenzenesulfonamide dihydrochloride.

The title compound was prepared according to the procedure for Example 112, Step 3, starting from tert-butyl- (18,48) -5 - [(5-amino-1-benzofuran-7-yl) methyl] -2,5-diazabicyclo [ 2,2,1] heptane-2-carboxylate (44 mg of crude starting material, 0.10 mmol; obtained in step 2) and 6-methoxy-m-toluenesulfonyl chloride (34 mg, 0.15 mmol). The title compound (11 mg, 20% yield) was obtained as

- 75 010298 off-white solid. HPLC: 100%, K _T = 1.39 min (system A; 10-97% MeCN for 3 min), 100%, K _T = 1.24 min (system B; 10-97% MeCN for 3 min ) ¹ H NMR (400 MHz, methanol-b ₄ ) δ ppm 2.20 (s, 3H), 2.28-2.34 (m, 1 = 12.80 Hz, 1H), 2.61-2.70 (m, 1H), 3.52-3.58 ( m, 1 = 13.80.2.76 Hz, 1H), 3.643.72 (m, 1 = 13.30, 2.51 Hz, 1H), 3.85-3.93 (m, 1H), 3 98 (s, 3H), 4.48 (s, 1H), 4.65 (s, 1H), 4.70-4.76 (m, 1H), 4.77-4.82 (m, 2H) ), 6.87 (d, 1 = 2.01 Hz, 1H), 7.04 (d, 1 = 8.53 Hz, 1H), 7.30-7.34 (m, 1 = 8.53, 2.26 Hz, 1H), 7.41 (d, 1 = 2.26 Hz, 1H), 7.50 (d, 1 = 2.01 Hz, 1H), 7.51-7.53 (m, 1 = 2.26 Hz, 1H); 7.85 (d, 1 = 2.26 Hz, 1H). M8 (Ε8Ι +) for C ₂₂ H ₂₅ No., 0 ₄ 8, t / ζ: 428 (M + H) ⁺ .

Example 119. Ν- {7 - [(18,48) -2,5-Diazabicyclo [2.2.1] hept-2-ylmethyl] -1-benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide- dihydrochloride.

The title compound was prepared according to the procedure for Example 112, Step 3, starting from tert-butyl- (18,48) -5 - [(5-amino-1-benzofuran-7-yl) methyl] -2,5-diazabicyclo [ 2,2,1] heptane-2-carboxylate (44 mg of crude starting material, 0.10 mmol; obtained in Example 118, step 2) and 2- (trifluoromethyl) benzenesulfonyl chloride (24 μl, 0.15 mmol). The title compound (18 mg, 34% yield) was obtained as an off-white solid. HPLC: 99%, K _T = 1.46 min (system A; 10-97% MeCN for 3 min), 100%, K _T = 1.29 min (system B; 10-97% MeCN for 3 min ) ¹ H NMR (400 MHz, methanol-b ₄ ) δ ppm 2.31-2.37 (m, 1 = 13.05 Hz, 1H), 2.65-2.78 (m, 1 = 6.27 Hz, 1H), 3.53-3.60 (m, 1 = 13.43, 2.89 Hz, 1H), 3.67-3.76 (m, 1H), 3.88-3.96 (m, 1 = 12.80 Hz, 1H), 4.51 (s, 1H), 4.66 (s, 1H), 4.72-4.79 (m, 1H), 4.84 (d, 2H), 6.88 (d, 1 = 2.01 Hz, 1H), 7.46 (d, 1 = 2.01 Hz, 1H), 7.51 (d, 1 = 2.01 Hz, 1H), 7.68-7.75 (m, 2H), 7, 88 (d, 1 = 2.26 Hz, 1H), 7.89-7.94 (m, 1H), 8.09-8.13 (m, 1H). M8 (Ε8Ι +) for С ₂₁ Н ₂₀ Е№0 ₃ 8, t / ζ: 452 (М + Н) ⁺ .

Example 120. Ν- {7 - [(18,48) -2,5-Diazabicyclo [2.2.1] hept-2-ylmethyl] -1-benzofuran-5-yl} -2-methylbenzenesulfonamide dihydrochloride.

The title compound was prepared according to the procedure for Example 112, Step 3, starting from tert-butyl- (18,48) -5 - [(5-amino-1-benzofuran-7-yl) methyl] -2,5-diazabicyclo [ 2,2,1] heptane-2-carboxylate (44 mg of crude starting material, 0.10 mmol; obtained in Example 118, step 2) and otoluenesulfonyl chloride (22 μl, 0.15 mmol). The title compound (15 mg, 31% yield) was obtained as an off-white solid. HPLC: 98%, K _T = 1.37 min (system A; 10-97% MeCN for 3 min), 97%, K _T = 1.21 min (system B; 10-97% MeCN for 3 min ) ¹ H NMR (400 MHz, methanol-b ₄ ) δ ppm 2.28-2.34 (m, 1H), 2.66 (s, 3H), 2.67-2.72 (m, 1H), 3.52-3.59 (m, 1 = 13.68 , 2.64 Hz, 1H), 3.63-3.76 (m, 1H), 3.85-3.93 (m, 1 = 12.80 Hz, 1H), 4.45-4.51 ( m, 1H), 4.65 (s, 1H), 4.69-4.78 (m, 1H), 4.784.83 (m, 2H), 6.86 (d, 1 = 2.26 Hz, 1H ), 7.23-7.29 (m, 1H), 7.31-7.36 (m, 1 = 7.53 Hz, 1H), 7.37-7.46 (m, 2H), 7, 48 (d, 1 = 2.26 Hz, 1H), 7.84-7.88 (m, 2H). M8 (Ε8Ι +) for C11 _{; 3} \ ₃ 0 ₃ 8. t / ζ: 398 (M + H) ⁺ .

Example 121. 2-Methoxy-5-methyl-H- {7 - [(trans-2,5-dimethylpiperazin-1-yl) methyl] 1-benzofuran-5yl} benzenesulfonamide bis (trifluoroacetate).

Step 1. Trans-2,5-Dimethyl-1 - [(5-nitro-1-benzofuran-7-yl) methyl] piperazine.

The title compound was prepared according to the procedure for Example 112, Step 1, starting from 7 (bromomethyl) -5-nitro-1-benzofuran (0.16 g, 0.6 mmol) and trans-2,5-dimethylpiperazine (0.36 g, 3.1 mmol). As a result, the title compound (0.11 g, 60% yield) was obtained as a pale yellow solid. HPLC: 98%, K _T = 1.26 min (system A; 10-97% MeCN for 3 min). Ή NMR (400 MHz, C1) C1 ₃ ) δ ppm 0.93 (d, 1 = 6.3 Hz, 3H), 1.17 (d, 1 = 6.0 Hz, 3H), 1, 48 (broad s, 1H), 1.79 (dd, 1 = 11.0, 10.3 Hz, 1H), 2.29-2.41 (m, 1H), 2.63-2.75 ( m, 2H), 2.80-2.89 (m, 1H), 2.93 (dd, 1 = 12.0, 3.3 Hz, 1H), 3.61 (d, 1 = 14.6 Hz , 1H), 4.28 (d, 1 = 14.3 Hz, 1H), 6.91 (d, 1 = 2.3 Hz, 1H), 7.76 (d, 1 = 2.3 Hz, 1H ), 8.29 (d, 1 = 2.3 Hz, 1H), 8.41 (d, 1 = 2.3 Hz, 1H). M8 (Ε8Ι +), t / ζ: 290.1 (M + H) ⁺ .

Stage 2. Tert-Butyl-trans-2,5-dimethyl-4 - [(5-nitro-1-benzofuran-7-yl) methyl] piperazine-1 carboxylate.

trans-2,5-Dimethyl-1 - [(5-nitro-1-benzofuran-7-yl) methyl] piperazine (0.11 g, 0.4 mmol; obtained in step 1) is dissolved in Me0H. BOC anhydride (0.114 g, 0.5 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with a solution of citric acid. The organic layer was dried (MD80 ₄ ) and evaporated, yielding 0.135 g (91% yield) of the title compound. HPLC: 96%, K _T = 1.79 min (system A; 10-97% MeCN for 3 min). ¹ H NMR (400 MHz, SES1 ₃ ) δ ppm 1.07 (d, 1 = 6.5 Hz, 3H), 1.27 (d, 1 = 6.8 Hz, 3H), 1.46 (s, 9H), 2.18-2.27 (m , 1H), 2.82 (dd, 1 = 11.5, 4.3 Hz, 1H), 2.98-3.06 (m, 1H), 3.37 (dd, 1 = 13.1, 3 5 Hz, 1H), 3.65-3.75 (d, 1 = 13.1 Hz, 1H), 3.83-3.95 (m, 2H), 4.16-4.27 (m, 1H), 6.91 (d, 1 = 2.3 Hz, 1H), 7.76 (d, 1 = 2.3 Hz, 1H), 8.25-8.55 (m, 2H). M8 (Ε8Ι +), t / ζ: 390.2 (M + H) ⁺ .

Stage 3. tert-Butyl-trans-4 - [(5-amino-1-benzofuran-7-yl) methyl] -2,5-dimethylpiperazine-1 carboxylate.

tert-Butyl-trans-2,5-dimethyl-4 - [(5-nitro-1-benzofuran-7-yl) methyl] piperazine-1-carboxylate (0.14 g, 0.35 mmol; obtained in step 2 ) dissolved in a mixture of THF: ethanol (4: 1; 5 ml). Raney nickel is added in excess (suspension in ethanol), then hydrazine hydrate (0.07 g, 1.39 mmol). The reaction mixture was stirred overnight at room temperature. After filtering off and evaporating the solvent, crude oil (0.11 g, 87% yield) is obtained, which is used in the next step without further purification. HPLC: 86%, K _T = 1.15 min (system B; 10-97% MeCN for 3 min). M8 (Ε8Ι +). t / ζ:

- 76 010298

360.2 (M + H) ⁺ .

Step 4. Tert-Butyl-trans-4 - [(5 - {[(2-methoxy-5-methylphenyl) sulfonyl] amino} -1-benzofuran-7yl) methyl] -2,5-dimethylpiperazine-1-carboxylate.

tert-Butyl-trans-4 - [(5-amino-1-benzofuran-7-yl) methyl] -2,5-dimethylpiperazine-1-carboxylate (0.037 g, 0.1 mmol; obtained in stage 3) is dissolved in dichloromethane and is reacted with 2 methoxy-5-methylbenzenesulfonyl chloride (0.045 g, 0.2 mmol) and pyridine (0.024 g, 0.3 mmol) overnight. The mixture was washed with 1 M HC1 and the organic layer was dried (MgO ₄ ) and evaporated. The crude product was purified using a flash column (10% MeOH in dichloromethane) to give the title product (0.026 g, 48% yield). HPLC: 93%, _W = 2.01 min (System A, 10-97% Mesa for 3 min); 93% B _t = 1.85 min (System B, 10-97% Mesa for 3 min). M8 (E81 +), t / ζ: 544.2 (M + H) ⁺ .

Step 5. 2-Methoxy-5-methyl-Y- {7 - [(trans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5yl} benzenesulfonamide bis (trifluoroacetate).

A solution of tert-butyl-trans-4 - [(5 - {[((2-methoxy-5-methylphenyl) sulfonyl] amino} -1-benzofuran-7yl) methyl] -2,5-dimethylpiperazine-1-carboxylate (0.026 g , 0.047 mmol; obtained in stage 4) in a mixture of TFA: water (9: 1) was stirred at room temperature for 1 h. The solvent was evaporated and the residue was purified by preparative HPLC (system A; 20-40% MeCSA). Pure fractions were combined and concentrated to give the title compound as a colorless TFA salt (0.020 mg, 63% yield). HPLC: 100% B _t = 1.52 min (System A, 10-97% Mesa for 3 min), 100% B _t = 1.25 min (System B, 10-97% Mesa for 3 min ) 'H NMR (400 MHz, methanol-b ₄ ) δ ppm 1.24 (d, 4 = 6.53 Hz, 3H),

1.48 (d, 1 = 6.27 Hz, 3H), 2.20 (s, 3H), 2.61 (dd, 1 = 13.30, 11.54 Hz, 1H), 3.05-3.23 (m, 3H), 3.39-3.47 (m, 1H),

3.50 (dd, 1 = 12.92, 2.64 Hz, 1H), 3.97 (s, 3H), 4.07 (d, 1 = 13.80 Hz, 1H), 4.60 (d , 1 = 13.80 Hz, 1H), 6.80 (d, 1 = 2.26 Hz, 1H), 7.03 (d, 1 = 8.53 Hz, 1H), 7.24 (d, 1 = 2.01 Hz, 1H), 7.29-7.33 (m, 1 = 8.78, 2.01 Hz, 1H), 7.35 (d, 1 = 2.01 Hz, 1H), 7 48-7.51 (m, 1 = 1.51 Hz, 1H); 7.76 (d, 1 = 2.01 Hz, 1H). M8 (E81 +) for C ₂₃ H ₂₉ N ₃ O ₄ 8, t / ζ: 444 (M + H) ⁺ .

Example 122. 2-Methyl-Y- {7 - [(trans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide bis (trifluoroacetate).

Step 1. Tert-Butyl-trans-2,5-dimethyl-4 - [(5 - {[(2-methylphenyl) sulfonyl] amino} -1-benzofuran-7yl) methyl] piperazine-1-carboxylate.

The title product was obtained according to the procedure for Example 121, step 4, starting from tert-butyl trans-4 - [(5-amino -1-benzofuran-7-yl) methyl] -2,5-dimethylpiperazin-1-carboxylate (obtained in Example 121, step 3) and 2-methylbenzenesulfonyl chloride (0.039 g, 0.2 mmol). Yield: 0.022 g (43%). HPLC: 95%, _W = 1.99 min (System A, 10-97% Mesa for 3 min); 93% B _t = 1.85 min (System B, 10-97% Mesa for 3 min). M8 (E81 +), t / ζ: 514.2 (M + H) ⁺ .

Step 2. 2-Methyl-Y- {7 - [(trans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide bis (trifluoroacetate).

The title product was obtained according to the procedure for Example 121, step 5, starting from tert-butyl-trans-2,5-dimethyl-4 - [(5 - {[(2-methylphenyl) sulfonyl] amino} -1-benzofuran-7-yl ) -methyl] piperazine-1-carboxylate (0.022 g, 0.043 mmol; obtained in step 1). Yield: 0.017 g (62%). HPLC: 100%, _Vt =

1.49 min (System A, 10-97% Mesa for 3 min), 100% B _t = 1.22 min (System B, 10-97% Mesa for 3 min). 'H NMR (400 MHz, methanol-b ₄ ) δ ppm 1.20-1.27 (m, 3H), 1.43-1.51 (m, 3H), 2.51-2.65 (m, 1H), 2.63 (s, 3H), 3, 02-3.25 (m, 3H), 3.38-3.45 (m, 1H), 3.45-3.53 (m, 1H), 4.00-4.11 (m, 1H), 4.53-4.64 (m, 1H), 6.79 (d, 1 = 2.26 Hz, 1H), 7.15-7.35 (m, 4H), 7.40-7.46 ( m, 1H), 7.75-7.80 (m, 1H), 7.82-7.87 (m, 1 = 8.03, 1.25 Hz, 1H). M8 (E81 +) for С22Н27Ы ₃ О ₃ 8, t / ζ: 414 (М + Н) ⁺ .

Example 123. 2-Chloro-Y- {7 - [(trans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide bis (trifluoroacetate).

Step 1. Tert-Butyl-Trais-4 - [(5 - {[(2-chlorophenyl) sulfonyl] amino} -1-benzofuran-7-yl) methyl] -2,5dimethylpiperazine-1-carboxylate.

The title product was obtained according to the procedure for Example 121, step 4, starting from tert-butyl trans-4 - [(5-amino -1-benzofuran-7-yl) methyl] -2,5-dimethylpiperazin-1-carboxylate (obtained in Example 121, step 3) and 2-chlorobenzenesulfonyl chloride (0.043 g, 0.2 mmol). Yield: 0.017 g (26%). HPLC: 94%, _W = 2.01 min (System A, 10-97% Mesa for 3 min); 98% B _t = 1.85 min (System B, 10-97% Mesa for 3 min). M8 (E81 +), t / ζ: 534.2 (M + H) ⁺ .

Stage 2. 2-Chloro-Y- {7 - [(trais-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofurai-5-yl} benzenesulfonamide bis (trifluoroacetate).

The title compound was prepared according to the procedure for Example 121, step 5, starting from tert-butyl-trans-4 - [(5 - {[(2-chlorophenyl) sulfonyl] amino} -1-benzofurai-7-yl) methyl] - 2,5-dimethylpiperazine-1-carboxylate (0.017 g, 0.032 mmol; obtained in step 1). Yield: 0.016 g (76%). HPLC: 99%, _W = 1.47 min (System A, 10-97% Mesa for 3 min), 100% B _t = 1.20 min (System B, 10-97% Mesa for 3 min ) 'H NMR (400 MHz, methanol-b ₄ ) δ ppm 1.23 (d, 1 = 6.53 Hz, 3H), 1.43 (d, 1 = 5.77 Hz, 3H), 2.48 (dd, 1 = 13.18, 11.42 Hz, 1H ), 3.00-3.06 (m, 2H), 3.10 (dd, 1 = 13.30, 3.26 Hz, 1H), 3.34-3.42 (m, 1H),

- 77 010298

3.42-3.47 (m, 1Η), 3.96 (d, 1 = 14.05 Hz, 1Η), 4.51 (d, 1 = 14.05 Hz, 1Η), 6.79 (d , 1 = 2.01 Hz, 1Η), 7.24 (d, 1 = 2.01 Hz, 1Η), 7.33-7.39 (m, 2Η), 7.47-7.53 (m, 1Η), 7.53-7.57 (m, 1Η), 7.76 (d, 1 = 2.26 Hz, 1Η), 7.94-7.99 (m, 1 = 7.78,

1.51 Hz, 1Η). M8 (Ε8Σ +) for ^ ιΗ ₂₄ ΟΝ ₃ Ο ₃ 8, t / ζ: 434 (M + H) ⁺ .

Intermediate 65.

Methyl 2,3-dihydro-1-benzofuran-7-carboxylate.

2,3-Dihydrobenzofuran-7-carboxylic acid (8 g, 48.7 mmol) was dissolved in methanol (39.6 ml, 975 mmol) and concentrated sulfuric acid (2.6 ml, 48.7 mmol) was slowly added. The mixture was refluxed at 80 ° C. for 17 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed with brine. The organic layer was evaporated to give the title compound as a beige solid. Yield: 8.6 g (99%). HPLC: purity 93%, K _t = 1.72 min (system A; 10-97% MeCN for 3 min), 96%, K _t = 1.67 min (system B; 10-97% MeCN for 3 min). M8 (Ε8Σ +) for ί _'71 Η ₇₎ Ο _3, v / ζ: 179 (M + H) ^+.

Intermediate 66.

Methyl 5 - [(2-methoxy-5-methylphenyl) sulfonyl] -2,3-dihydro-1-benzofuran-7-carboxylate.

To methyl 2,3-dihydro-1-benzofuran-7-carboxylate (1 g, 5.6 mmol; intermediate 65) was added 2-methoxy-5-methylbenzenesulfonic acid (1.13 g, 5.6 mmol) and a solution of phosphorus pentoxide and methanesulfonic acid (1:10; 13.5 ml). The mixture was stirred at room temperature for 48 hours. An additional amount of 2-methoxy-5-methylbenzenesulfonic acid (0.56 g, 2.8 mmol) was added and the reaction mixture was stirred at 50 ° C. for 15 hours. The mixture was poured into the mixture. ice water and the precipitate formed is filtered off, dissolved in dichloromethane and evaporated. The crude product was purified using flash chromatography (eluent: isohexane: ethyl acetate = 1: 1) to obtain the title compound. Yield: 1.07 g (53%). M8 (Ε8Σ +) for Χ ₈ Η _{! 8} Ο ₆ 8, t / ζ: 363 (M + H) ⁺ .

Intermediate 67.

Methyl 5 - [(2-methoxy-5-methylphenyl) sulfonyl] -1-benzofuran-7-carboxylate.

Methyl 5 - [(2-methoxy-5-methylphenyl) sulfonyl] -2,3-dihydro-1-benzofuran-7-carboxylate (879 mg, 2.4 mmol; intermediate 66) was dissolved in chlorobenzene (6 ml) . Ν-Bromosuccinimide (432 mg, 2.4 mmol) and benzoyl peroxide (58 mg, 0.24 mmol) were added and the mixture was stirred at 100 ° C for 17 hours. The mixture was washed with a saturated aqueous NaΗCΟ ₃ solution and the organic layer was concentrated. Yield: 405 mg (46%), after purification by preparative HPLC (system E; 40-60% MeC #). M8 (Ε8Σ +) for χ ₈ Η ₁₆ Ο ₆ δ, t / ζ: 361 (M + H) ⁺ .

Intermediate 68. {5 - [(2-Methoxy-5-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methanol.

Methyl 5 - [(2-methoxy-5-methylphenyl) sulfonyl] -1-benzofuran-7-carboxylate (400 mg, 1.1 mmol; intermediate 67) was dissolved in anhydrous THF (3 ml) and 1 M was slowly added. a solution of lithium aluminum hydride in THF (0.3 ml). The mixture was stirred at room temperature overnight. After this time, water (0.15 ml) was added and stirring was continued for 10 minutes, then a 2M aqueous solution of αΝ (0.15 ml) and water (0.45 ml) were added. The precipitate formed is filtered off and the solvent is evaporated. The crude product is used in the next step without further purification. M8 +) for ΟπΗκΑδ, t / ζ: 333 (M + H) ⁺ .

Intermediate 69.

7- (Chloromethyl) -5- [(2-methoxy-5-methylphenyl) sulfonyl] -1-benzofuran.

Oxalyl chloride (0.1 ml, 1.1 mmol) was dissolved in anhydrous dichloromethane (2 ml) and DMF (0.9 ml, 1.1 mmol) was added (a very exothermic reaction). {5 - [(2-Methoxy-5-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methanol (370 mg, 1.1 mmol; intermediate 68) was added and the resulting mixture was stirred at room temperature for 17 hours The mixture was washed with a 2 M solution of ΝαΟΗ (2 times) and the organic layer was concentrated to give a crude product. This substance is used in the next step without further purification. M8 (Ε8Σ +) for Χ ₇ Ηι ₅ ΟΟ ₄ δ, t / ζ: 351 (M + H) ⁺ .

Example 124. 1 - ({5 - [(2-Methoxy-5-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) piperazine trifluoroacetate.

7- (Chloromethyl) -5 - [(2-methoxy-5-methylphenyl) sulfonyl] -1-benzofuran (35 mg, 0.1 mmol; intermediate 69) was dissolved in ethanol (2 ml) and Ν-tert- BOC-piperazine (28 mg, 0.1 mmol) and sodium bicarbonate (13 mg, 0.1 mmol). The mixture is heated overnight at a temperature of 80 ° C in 81etB1osk. The mixture was extracted with chloroform (2 times) and the chloroform layers were evaporated. Purification was carried out by preparative HPLC with mass spectrometry (system A; 10-40% MesCs. The resulting Ν-tert-BOC derivative of the title compound was dissolved in dichloromethane (1 ml) and TFA (1 ml) was added. After stirring for overnight at room temperature, the solvent was evaporated to give the title compound Yield: 11 mg (27%), after purification by preparative HPLC with mass spectrometry (system A; 10-40% MeC #). HPLC: 98% purity, K _t = 1.50 min (system a, 10-97% MeCN over 3 min), 99%, r _t = 1.30 min (system B, 10-90% MeCN in flow 3 min). '11 NMR (400 MHz, SES1 ₃₎ δ ppm 2.35 (s, 3Η), 3,26-3,46 (m, 8Η), 3,70 (c, 3Η), 4.34 (s, 2Η), 6.78 (d, 1 = 8.53 Hz, 1Η), 6.90 (d, 1 = 2.01 Hz, 1Η), 7.32 (dd, 1 = 8 41, 1.63 Hz, 1Η), 7.75 (d, 1 = 1.25 Hz, 1Η), 7.89-7.98 (m,

- 78 010298

2H), 8.30 (d, 1 = 1.25 Hz, 1H). M8 +) for C ₂ 1H ₂₄ X ₂ O ₄ 8, t / ζ: 401 (M + H) ⁺ .

Example 125. 1 - {[5- (Phenylsulfonyl) -1-benzofuran-7-yl] methyl} piperazine trifluoroacetate.

Step 1. Methyl 5- (phenylsulfonyl) -2,3-dihydro-1-benzofuran-7-carboxylate.

The title compound was prepared according to the procedure for preparing intermediate 66, starting from methyl 2,3-dihydro-1-benzofuran-7-carboxylate (1 g, 5.6 mmol; intermediate 65) and benzenesulfonic acid (0.89 g 5.6 mmol). Yield: 882 mg (49%). M8 (E8H) for C16H14O58, t / ζ: 319 (M + H) ⁺ .

Stage 2. Methyl 5- (phenylsulfonyl) -1-benzofuran-7-carboxylate.

The title compound was prepared according to the procedure for preparing intermediate 67, starting from methyl 5- (phenylsulfonyl) -2,3-dihydro-1-benzofuran-7-carboxylate (198 mg, 0.6 mmol; obtained in step 1). Yield: 80 mg (41%), after purification by preparative HPLC (system P; 4070% MeCX). M8 (E8H) for C16H14O58, t / ζ: 317 (M + H) ⁺ .

Step 3. [5- (Phenylsulfonyl) -1-benzofuran-7-yl] methanol.

The title compound was prepared according to the procedure for preparing intermediate 68, starting from methyl 5- (phenylsulfonyl) -1-benzofuran-7-carboxylate (80 mg, 0.25 mmol; obtained in step 2). The crude substance is directly used in the subsequent reaction. M8 (E8I +) for C1 ₅ H1 ₂ O ₄ 8, t / ζ: 289 (M + H) ⁺ .

Step 4. 7- (Chloromethyl) -5- (phenylsulfonyl) -1-benzofuran.

The title compound was prepared according to the procedure for preparing intermediate 69, starting from [5- (phenylsulfonyl) -1-benzofuran-7-yl] methanol (73 mg, 0.3 mmol; obtained in step 3). The crude substance is directly used in the subsequent reaction. M8 (E8H) for С15НцС1О ₃ 8, t / ζ: 307 (M + H) ⁺ .

Step 5. 1- {[5- (Phenylsulfonyl) -1-benzofuran-7-yl] methyl} piperazine trifluoroacetate.

X-tert-BOC-piperazine (24 mg, 0.13 mmol) and sodium bicarbonate (11 mg, 0.13 mmol) are added to a solution of 7- (chloromethyl) -5- (phenylsulfonyl) -1-benzofuran (26 mg, 0.08 mmol; obtained in step 4) in ethanol (2 ml). The mixture was stirred at 80 ° C in 81 eB1osk overnight and the solvent was evaporated. The resulting X-tert-BOC derivative of the title compound was dissolved in dichloromethane (1 ml) and TFA (1 ml) was added. The mixture was then stirred at room temperature for 2 hours, the solvent was evaporated, yielding the title compound. Yield: 6.1 mg (12%), after purification by preparative HPLC with mass spectrometry (system A; 10-40% MeCX). HPLC: 99% purity, K _T = 1.39 min (system A; 10-97% MeCX for 3 min), 96%, K _T = 1.16 min (system B; 10-90% MeCX for 3 min). ^! H NMR (400 MHz, COC1 ₃ ) δ ppm 3.10-3.17 (m, 4H), 3.34-3.39 (m, 4H), 4.20 (s, 2H), 6.87-6.92 (m, 1H), 7, 46-7.58 (m, 3H), 7.75 (d, 1 = 2.26 Hz, 1H), 7.92-7.97 (m, 3H), 8.26 (d, 1 = 1, 76 Hz, 1H). M8 (E8I +) for C1 ₉ H ₂₀ X ₂ O ₃ 8, t / ζ: 357 (M + H) ⁺ .

Example 126. 1 - ({5 - [(4-Methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) piperazine trifluoroacetate. Step 1. Methyl 5 - [(4-methylphenyl) sulfonyl] -2,3-dihydro-1-benzofuran-7-carboxylate.

The title compound was prepared according to the procedure for preparing intermediate 66, starting from methyl 2,3-dihydro-1-benzofuran-7-carboxylate (1 g, 5.6 mmol; intermediate 65) and 4-methylbenzenesulfonic acid (0, 97 g, 5.6 mmol). Yield: 405 mg (22%). M8 (E8H) for C ₁₇ H ₁₆ O ₅ 8, t / ζ: 333 (M + H) ⁺ .

Stage 2. Methyl 5 - [(4-methylphenyl) sulfonyl] -1-benzofuran-7-carboxylate.

The title compound was prepared according to the procedure for preparing intermediate 67, starting from methyl 5 - [(4-methylphenyl) sulfonyl] -2,3-dihydro-1-benzofuran-7-carboxylate (117 mg, 0.4 mmol; obtained at stage 1). Yield: 62 mg (53%), after purification by preparative HPLC (system P; 40-60% MeCX). M8 +) for C1 ₇ H ₁₆ O ₅ 8, t / ζ: 331 (M + H) ⁺ .

Step 3. {5 - [(4-Methylphenyl) sulfonyl] -1-benzofuran-7-yl} methanol.

The title compound was prepared according to the procedure for preparing intermediate 68, starting from methyl 5 - [(4-methylphenyl) sulfonyl] -1-benzofuran-7-carboxylate (62 mg, 0.19 mmol; obtained in Step 2). M8 (E8I +) for C1 ₆ H1 ₄ O ₄ 8, t / ζ: 303 (M + H) ⁺ .

Step 4. 7- (Chloromethyl) -5 - [(4-methylphenyl) sulfonyl] -1-benzofuran.

The title compound was prepared according to the procedure for preparing intermediate 69, starting from {5 - [(4-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methanol (57 mg, 0.2 mmol; obtained in step 3). М8 (Е8I +) for С1 ₆ Н ₁₃ С1О ₃ 8, t / ζ: 321 (М + Н) ⁺ .

Step 5.1: 1 - ({5 - [(4-Methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) piperazine trifluoroacetate.

The title compound was prepared according to the procedure for Example 125, Step 5, starting from 7 (chloromethyl) -5 - [(4-methylphenyl) sulfonyl] -1-benzofuran (20 mg, 0.06 mmol; obtained in Step 4). Yield: 5.8 mg (15%), after purification by preparative HPLC with mass spectrometry (system A; 5-20% MeCX). HPLC: 99% purity, K _T = 1.52 min (system A; 10-97% MeCX for 3 min), 99%, K _T = 1.28 min (system B; 10-90% MeCX for 3 min). ¹ H NMR (400 MHz, SLOROFORM-Ό) δ ppm 2.37 (s, 3H), 3.33-3.37 (m, 4H), 3.44-3.50 (m, 4H), 4.37 (s, 2H), 6.90 (d, 1 = 2.26 Hz, 1H), 7.28 (d, 1 = 8.03 Hz, 2H), 7.75 (d, 1 = 2.26 Hz, 1H), 7.81 (d, 1 = 8.28 Hz, 2H), 7.97 (d, 1 = 1.51 Hz, 1H), 8.26 (d, 1 = 1.76 Hz, 1H). M8 +) for

- 79 010298

Κο ^ Ν ^, t / ζ: 371 (M + H) ⁺ .

Example 127. 1 - ({5 - [(2-Methoxy-5-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) -1,4-diazepantrifluoroacetate.

7- (Chloromethyl) -5 - [(2-methoxy-5-methylphenyl) sulfonyl] -1-benzofuran (66 mg, 0.19 mmol; intermediate 69) was dissolved in ethanol (2 ml) and 1-BOC- was added homopiperazine (57 mg, 0.28 mmol) and sodium bicarbonate (24 mg, 0.28 mmol). The mixture is heated at a temperature of 80 ° C in 81etB1osk overnight. The mixture was extracted with chloroform (2 times) and the chloroform layers were evaporated. The resulting Ν-tert-BOC derivative of the title compound was dissolved in dichloromethane (1 ml) and TFA (1 ml) was added. After stirring at room temperature for 2 hours, the solvent was evaporated, yielding the title compound. Yield: 39 mg (32%), after purification by preparative HPLC with mass spectrometry (System A, 10-40% MeSSch HPLC:. 99% purity, R _t = 1.41 min (System A, 10-97% MeCN for 3 min), 99%, K _t = 1.19 min (system B; 10-90% MeCN for 3 min). '11 NMR (400 MHz, C1) C1 _; ) δ ppm 2.16 (brs, 2H), 2.24 (s, 3H), 3.30 (br, 2H), 3.39 (br, 2H), 3.54 (br, 2H), 3.57-3 67 (m, 5H), 4.50 (s, 2 N), 6.69 (d, 1 = 8.78 Hz, 1H), 6.81 (d, 1 = 1.76 Hz, 1H), 7.23 (d, 1 = 8.53 Hz, 1H), 7.66 (s, 1H), 7.81 (s, 1H), 7.94 (s, 1H), 8.22 (s, 1H) ) M8 (Ε8Ι +) for СЩ ^ О ^, т / ζ: 415 (М + Н) ⁺ .

Example 128. 1 - {[5- (Phenylsulfonyl) -1-benzofuran-7-yl] methyl} -1,4-diazepantrifluoroacetate.

The title compound was prepared according to the procedure for EXAMPLE 127, starting from 7 (chloromethyl) -5- (phenylsulfonyl) -1-benzofuran (37 mg, 0.12 mmol; obtained in Example 125, step 4). Yield: 9.4 mg (13%), after purification by preparative HPLC with mass spectrometry (system A; 1040% MeSSch HPLC:. 99% purity, R _t = 1.29 min (System A, 10-97% MeCN for 3 min), 99%, K _t = 1.16 min (system B; 10-90% MeCN for 3 min). '11 NMR (400 MHz, C1) C1 _; ) δ ppm 2.28-2.35 (m, 2H), 3.42-3.52 (m, 4H), 3.65-3.77 (m, 4H), 4.60 (s, 2H), 6, 93 (d, 1 = 2.26 Hz, 1H), 7.46-7.53 (m, 2H), 7.53-7.59 (m, 1H), 7.77 (d, 1 = 2, 26 Hz, 1H), 7.92-7.97 (m, 2H), 8.09 (d, 1 = 1.76 Hz, 1H), 8.32 (d, 1 = 1, 76 Hz, 1H) . M8 (Ε8Ι +) for C2οН22N2Ο ₃ 8, t / ζ: 371 (M + H) ⁺ .

Example 129. 1 - ({5 - [(4-Methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) -1,4-diazepantrifluoroacetate.

The title compound was prepared according to the procedure for EXAMPLE 127, starting from 7 (chloromethyl) -5 - [(4-methylphenyl) sulfonyl] -1-benzofuran (32 mg, 0.10 mmol; obtained in Example 126, step 4). Yield: 8.1 mg (13%), after purification by preparative HPLC with mass spectrometry (System A, 10-40% MeSSch HPLC:. 99% purity, R _t = 1.42 min (System A, 10-97 % MeCN over 3 min), 99%, r _t = 2.94 min (system B, 10-90% MeCN over 3 min) '11 NMR (400 MHz, S1MK) δ ppm 2.31. (broth, 2H), 2.37 (s, 3H), 3.41-3.54 (m, 4H), 3.66-3.79 (m, 4H), 4.61 (s, 2H), 6.91 (d, 1 = -2.26 Hz, 1H), 7.26-7.31 (m, 2H), 7.75 (d, 1 = 2.26 Hz, 1H), 7.81 ( d, 1 = 8.28 Hz, 2H), 8.07 (d, 1 = 1, 51 Hz, 1H), 8.29 (d, 1 = 1, 76 Hz, 1H). M8 (Ε8Ι +) for СДН. ^ OeZ, m / z: 385 (M + H) ⁺ .

Example 130. 1 - ({5 - [(2-Methoxy-5-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) -2-methylpiperazine trifluoroacetate.

7- (Chloromethyl) -5 - [(2-methoxy-5-methylphenyl) sulfonyl] -1-benzofuran (60 mg, 0.17 mmol; intermediate 69) was dissolved in ethanol (2 ml) and tert-butyl- 3-methylpiperazine-1 carboxylate (41 mg, 0.21 mmol) and sodium bicarbonate (22 mg, 0.26 mmol). The resulting mixture was heated at 80 ° C in 81 eB1osk overnight. The mixture was extracted with chloroform (2 times) and the chloroform layers were concentrated. The resulting Ν-tert-BOC derivative of the title compound was dissolved in dichloromethane (1 ml) and TFA (1 ml) was added. Then the mixture was stirred at room temperature for 2 hours, the solvent was evaporated. Yield: 33 mg (36%), after purification by preparative HPLC with mass spectrometry (system A; 10-40% Mesch. HPLC: purity 99%, K _t = 1.55 min (system A; 10-97% MeCN for 3 min), 99%, K _t = 1.37 min (system B; 10-97% MeCN for 3 min). '11 NMR (400 MHz, C1X'E) δ ppm 1.65 (d, 1 = 6.27 Hz, 3H), 2.34 (s, 3H), 3.35-3.61 (m, 6H), 3.68 (s, 3H), 3.90-3, 99 (m, 1H), 4.46 (d, 1 = 13.55 Hz, 1H), 4.82 (d, 1 = 13.55 Hz, 1H), 6.77 (d, 1 = 8.53 Hz, 1H), 6.92 (d, 1 = 2.26 Hz, 1H), 7.32 (dd, 1 = 8.53, 1.76 Hz, 1H), 7.75 (d, 1 = 2 , 26 Hz, 1H), 7.87 (d, 1 = 2.01 Hz, 1H), 7.97 (d, 1 = 1.25 Hz, 1H), 8.34 (d, 1 = 1, 51 Hz, 1H). M8 (Ε8Ι +) for MF ^ O ^, m / z: 414 (M + H) ⁺ .

Example 131. 1 - ({5 - [(2-Methoxy-5-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) -3-methylpiperazine trifluoroacetate.

7- (Chloromethyl) -5 - [(2-methoxy-5-methylphenyl) sulfonyl] -1-benzofuran (60 mg, 0.17 mmol; intermediate 69) was dissolved in ethanol (2 ml) and 2-methylpiperazine ( 21 mg, 0.21 mmol) and sodium bicarbonate (22 mg, 0.26 mmol). The mixture is heated at a temperature of 80 ° C in 81etB1osk overnight. The mixture was extracted with chloroform (2 times) and the chloroform layers were evaporated. The resulting трет-tert-BOC derivative of the title compound was dissolved in dichloromethane (1 ml) and TFA (1 ml) was added. Then the mixture was stirred at room temperature for 2 hours, the solvent was evaporated. Yield: 28 mg (31%), after purification by preparative HPLC with mass spectrometry (system A; 10-40% Mesch. HPLC: purity 99%, K _t = 1.57 min (system A; 10-97% MeCN for 3 min), 99%, K _t = 1.35 min (system B; 10-97% MeCN for 3 min). 'N NMR (400 MHz, SESc) δ ppm 0.800.90 (m , 2H), 1.30 (d, 1 = 6.27 Hz, 3H), 2.35 (s, 3H), 3.14 (t, 1 = 12.05 Hz, 1H), 3.27-3 45 (m, 4H), 3.70 (s, 3H),

- 80 010298

4.40 (s, 2H), 6.78 (d, 1 = 8.53 Hz, 1H), 6.91 (d, 1 = 2.26 Hz, 1H), 7.32 (dd, 1 = 8 41, 1.88 Hz, 1H), 7.76 (d, 1 = 2.01 Hz, 1H), 7.88-7.99 (m, 2H), 8.32 (d, 1 = 1, 51 Hz, 1H). M8 (Ε8Ι +) for С ₂₂ Н _{2 &} О ₂ О ₄ 8, t / ζ: 414 (М + Н) ⁺ .

Product 70. (5-Bromo-1-benzofuran-7-yl) amine.

Stage 1. Ethyl 5-bromo-7-nitro-1-benzofuran-3-carboxylate.

A mixture of 5-bromo-2-hydroxy-3-nitrobenzaldehyde (8.9 g, 36.2 mmol), diethyl bromomalonate (6.3 ml, 37.3 mmol) and potassium carbonate (4.6 g) in butanone (50 ml ) refluxed for 4 hours. The mixture was cooled, filtered and evaporated to give a crude product, which was recrystallized from ethanol. Yield: 6.6 g (58%) of a pale yellow solid. 'H NMR (400 MHz, DMSO-b ₆ ) δ ppm 1.29 (t, 1 = 7.0 Hz, 3H), 4.35 (q, 1 = 7.1 Hz, 2H), 7.83 (s, 1H), 8.39 (d, 1 = 2.0 Hz, 1H), 8.43 (d, 1 = 2.0 Hz, 1H).

Stage 2.5. 5-Bromo-7-nitro-1-benzofuran-3-carboxylic acid.

Ethyl 5-bromo-7-nitro-1-benzofuran-3-carboxylate (5.5 g, 17.5 mmol; obtained in step 1) was suspended in ethanol (20 ml). A 2 M solution No. OH (20 ml) was added and the mixture was refluxed for 2 hours. Ethanol was removed by evaporation and the remaining solution was acidified with concentrated HCl (4 ml), diluted with water and the product was collected by filtration, washed with water and dried in vacuum drying cabinet. Yield: 4.65 g (93%). ¹ H NMR (400 MHz, DMSO-b ₆ ) δ ppm 7.43 (s, 1H), 8.26 (d, 1 = 1.8 Hz, 1H), 8.34 (d, 1 = 2.0Hz, 1H).

Stage 3. 5-Bromo-7-nitro-1-benzofuran.

5-Bromo-7-nitro-1-benzofuran-3-carboxylic acid (4.65 g, 16 mmol; obtained in stage 2) is suspended in quinoline (25 ml), 0.1 g of CuO is added and the mixture is heated at 190 ° C for 30 minutes The hot reaction mixture was diluted with hot toluene (100 ml), filtered and the filter cake washed with hot toluene (a total of 400 ml). The combined toluene extracts were washed with 1 M HC1 (2 times 100 ml) and brine, evaporated and the solid was washed with hexane, collected by filtration and dried. Yield: 1.9 g (48%). ¹ H NMR (400 MHz, DMSO-b ₆ ) δ ppm 7.13 (d, 1 = 2.3 Hz, 1H), 8.20 (d, 1 = 2.0 Hz, 1H), 8.28 (d, 1 = 2.3 Hz, 1H), 8, 32 (d, 1 = 2.0 Hz, 1H).

Stage 4. (5-Bromo-1-benzofuran-7-yl) amine.

A mixture of 5-bromo-7-nitro-1-benzofuran (1.9 g, 7.9 mmol) was obtained in step 3), iron powder (2.3 g), methanol (20 ml), 1,4-dioxane (20 ml) and ammonium chloride (2.3 g, dissolved in 10 ml of water) are refluxed overnight. The hot mixture is filtered through wet celite, which is then washed with hot methanol and the solvents are evaporated. The crude product is dissolved in a hot ethanol / water mixture (100 ml) and then water is added so that the product begins to crystallize. The product is collected by filtration, washed with water and dried in a vacuum oven. Yield: 1.1 g (65%). ¹ H NMR (400 MHz, DMSO-b ₆ ) δ ppm 5.63 (s, 2H), 6.68 (d, 1 = 2.0 Hz, 1H), 6.81 (d, 1 = 2.3 Hz, 1H), 6.96 (d, 1 = 2 , 0 Hz, 1H), 7.92 (d, 1 = 2.3 Hz, 1H).

Example 132. 2-Methoxy-5-methyl- [5- (piperazin-1-methyl) -1-benzofuran-7-yl] benzenesulfonamide bis (trifluoroacetate).

Stage 1. N- (5-Bromo-1-benzofuran-7-yl) -2-methoxy-5-methylbenzene-sulfonamide.

A mixture of (5-bromo-1-benzofuran-7-yl) amine (500 mg, 2.4 mmol; intermediate 70, step 4), pyridine (0.38 ml, 4.7 mmol) and 6-methoxy- m-toluenesulfonyl chloride (0.78 g, 3.5 mmol) in anhydrous dichloromethane (20 ml) was stirred at room temperature for 2.5 hours. An additional amount of 6-methoxy-m-toluenesulfonyl chloride (0.26 g, 1, 2 mmol) with continuous stirring overnight. The reaction mixture was diluted with dichloromethane and extracted with water. The organic layer is concentrated. The product was precipitated using a dichloromethane / isohexane / methanol mixture (80:20:20) and collected by filtration to obtain the title compound in an amount of 580 mg (61% yield) as a light brown solid. HPLC: 94%, R _t = 2.32 min (System A, 30-80% MeCN over 3 min). M8 (Ε8Ι +) for С ^ Н ^ В ^ О ^, т / ζ: 396 (monoisotopic mass + Н) ⁺ .

Step 2. 2-Methoxy-5-methyl-Y- [5 - (piperazin-1-ylmethyl) -1-benzofuran-7-yl] benzenesulfonamidbis (trifluoroacetate).

Pb (PPI ₃ ) ₂ OAc ₂ (189 mg, 0.25 mmol) and vinyl tributyltin (295 μl, 1.01 mmol) are added to Ν- (5 bromo-1-benzofuran-7-yl) -2-methoxy-5- methylbenzenesulfonamide (200 mg, 0.51 mmol; obtained in step 1) in anhydrous toluene in an argon atmosphere. The mixture was stirred at 110 ° C. over the weekend (62 hours). The reaction mixture was filtered and concentrated. The crude mixture was stirred with isohexane for 10 minutes. Isohexane is removed by decantation and the residue is dried under reduced pressure. The intermediate alkene is dissolved in dioxane (6 ml) and lutidine (120 μl, 1.0 mmol). Osmium tetroxide (26 mg, 0.10 mmol) is added and a color change from light brown to dark brown / black is observed. With stirring, sodium periodate (432 mg, 2.02 mmol) in water (1.5 ml, heated to dissolve) is added. After 1 min, a light brown precipitate formed. The mixture was stirred for 2 hours and partitioned between 2 M aqueous HC1 and dichloromethane. The organic layer was dried (№ ₂ 8o _4), filtered and concentrated to give the crude aldehyde as a black solid. Half of the material was suspended in anhydrous THF (4 ml) and Ν-tert-BOC-81 010298 piperazine (50 mg, 0.27 mmol), acetic acid (14 0 μl, 2.5 mmol) and sodium triacetoxyborohydride (104 mg, 0.49 mmol). The reaction mixture is irradiated using microwaves for 300 s at a temperature of 130 ° C. The mixture is filtered, dissolved in methanol (2 ml) and concentrated HCl (0.5 ml) and irradiated using microwaves for 300 s at a temperature of 100 ° C. The solvent was evaporated, the residue was dissolved in methanol and purified by preparative HPLC (system A; 19-40% MeCI). Pure fractions were combined and concentrated to give the title compound (31 mg, 20% yield) as a brown gum. HPLC: 100%, K _t = 1.35 min (system A; 10-97% MeCI for 3 min), 99%, K _t = 1.15 min (system B; 10-97% MeCI for 3 min ) ¹ H NMR (400 MHz, methanol-a ₄ ) δ ppm 2.22 (s, 3H), 3.30-3.36 (m, 4H), 3.43-3.50 (m, 4H), 3.81 (s, 3H), 4.29 (s, 2H), 6.82 (d, 1 = 2.26 Hz, 1H), 6.95 (d, 1 = 8.53 Hz, 1H), 7.28-7.33 (m, 1 = 8.53 , 2.26 Hz, 1H), 7.43 (d, 1 = 1.51 Hz, 1H), 7.48 (d, 1 = 1.51 Hz, 1H), 7.567.59 (m, 1 = 2 , 26 Hz, 1H); 7.77 (d, 1 = 2.26 Hz, 1H). M8 +) for С ₂ 1Н ₂₅ AND ₃ О ₄ 8, t / ζ: 416 (М + Н) ⁺ .

Example 133. 2-Methoxy-5-Methyl-I- {5 - [(3-methylpiperazin-1-yl) methyl] -1-benzofuran-7-yl} benzenesulfonamide bis (trifluoroacetate).

The title compound was prepared according to the procedure for Example 132, Step 2, using 2 methylpiperazine (27 mg, 0.27 mmol). The title compound (18 g, 11% yield) was obtained as a brown gummy substance. HPLC: 97%, K _t = 1.38 min (system A; 10-97% MeCI for 3 min), 99%, K _t = 1.18 min (system B; 10-97% MeCI for 3 min ) ¹ H NMR (400 MHz, methanol-a ₄ ) δ ppm 1.33 (d, 1 = 6.53 Hz, 3H), 2.22 (s, 3H), 2.82 (dd, 1 = 13.18, 11.42 Hz, 1H), 2.94-3 04 (m, 1H), 3.313.44 (m, 2H), 3.51-3.59 (m, 2H), 3.79-3.87 (m, 1H), 3.81 (s, 3H) ), 4.18 (s, 2H), 6.81 (d, 1 = 2.01 Hz, 1H), 6.95 (d, 1 = 8.53 Hz, 1H), 7.27-7.32 (m, 1 = 8.53, 2.26 Hz, 1H), 7.41 (d, 1 = 1.76 Hz, 1H), 7.45 (d, 1 = 1.76 Hz, 1H), 7 55-7.58 (m, 1 = 1.51 Hz, 1H); 7.75 (d, 1 = 2.26 Hz, 1H). M8 (E8H) for C ₂₂ H ₂₇ And ₃ O ₄ 8, t / ζ: 430 (M + H) ⁺ .

Example 134. I- (2-Methylphenyl) -7 - {[(3K) -hyrrolidin-3-ylamino] methyl} -1-benzofuran-5-sulfonamide trifluoroacetate.

The title compound was prepared according to the procedure for Example 93, starting from 7-formyl-I (2-methylphenyl) -1-benzofuran-5-sulfonamide (80 mg, 0.24 mmol; intermediate 60) and (K) (+) -3-aminopyrrolidine (50 mg, 0.6 mmol). [Note: without the stage of deprotection using HC1]. Yield: 17.8 mg (28%). HPLC: 97%, K _t = 1.39 min (system A; 10-97% MeCI for 3 min), 98%, K _t = 1.22 min (system B; 10-90% MeCI for 3 min ) M8 (Ε8I +) for С ₂₀ Н ₂₃ AND ₃ О ₃ 8, t / ζ: 386 (М + Н) ⁺ . ¹ H NMR (400 MHz, methanol-a ₄ ) δ ppm 1.94 (s, 3H), 2.02-2.12 (m, 1H), 2.44-2.54 (m, 1H), 3.24-3.31 (m, 1H), 3, 40-

3.52 (m, 2H), 3.72 (dd, 1 = 12.8, 8.3 Hz, 1H), 4.04 (t, 1 = 8.3, 5.5 Hz, 1H), 4 68 (d, 1 = 2.5 Hz, 2H), 6.92-7.03 (m, 5H), 7.73 (d, 1 = 1.5 Hz, 1H), 7.94 (d, 1 = 2.3 Hz, 1H), 8.08 (d, 1 = 1.8 Hz, 1H).

Example 135. I- (2-Methylphenyl) -7- (piperidin-4-ylmethyl) -1-benzofuran-5-sulfonamide trifluoroacetate.

9-Borabicyclo [3.3.1] nonane (9-VVI; 0.5 M in THF, 2.2 ml, 2.2 mmol) is added to a solution of 1- (4 methylidene piperidino) ethan-1-one (Maubpade Sketua 1 Sotrapu , 140 mg, 1 mmol) in anhydrous THF (2 ml) in a nitrogen atmosphere at a temperature of 0 ° C. After stirring for 1 h at 0 ° C, the solution was allowed to warm to room temperature for 3 h. Then, 7-iodo-I- (2-methylphenyl) -1-benzofuran-5sulfonamide ( 40 mg, 0.1 mmol; intermediate 58), Hermann's catalyst (5 mg), anhydrous THF (3 ml), 4 M aqueous solution of IAOH (0.1 ml) and the above solution generated ίη δίΐιι 1- [4 (9 -borabicyclo [3.3.1] non-9-ylmethyl) piperidin-1-yl] ethanone (0.75 ml, 0.17 mmol). The mixture is heated by irradiation with microwaves at a temperature of 140 ° C for 5 minutes. This reaction mixture and three similar mixtures were combined, filtered and evaporated. The residue was dissolved in dichloromethane (20 ml) and washed with 1 M HC1. After evaporation of the solvent, the crude acetylated derivative of the title product was purified by preparative HPLC with mass spectrometry (system A; 30-60% MeCI, 0.1% TFA). The I-protection is removed from the purified substance by dissolving in methanol (3 ml), adding a concentrated aqueous HC1 solution (1 ml) and heating by irradiation with microwaves at a temperature of 120 ° C for 1 h. The final product is purified by preparative HPLC with mass spectrometry (system A; 30-60% MeCl, 0.1% TFA), to give 5.9 mg (3% yield) of the title compound. HPLC: 95%, K _t = 1.75 min (system A; 10-97% MeCI for 3 min), 95%, K _t = 1.58 min (system B; 10-90% MeCI for 3 min ) M8 (Ε8I +) for С ₂ 1Н ₂₄ AND ₂ О ₃ 8, t / ζ: 385 (М + 1). ^! H NMR (400 MHz, methanol-a ₄ ) δ ppm 1.26-1.38 (m, 2H), 1.60-1.71 (m, 1 = 14.1 Hz, 2H), 1.87 (s, 2H), 1.89-1.97 ( m, 2H), 2.76-2.85 (m, 4H), 3.11-3.19 (m, 1H), 3.26-3.30 (m, 2H), 6.88 (d, 1 = 2.3 Hz, 1H), 6.96-7.03 (m, 4H), 7.27 (d, 1 = 1.5 Hz, 1H), 7.83 (d, 1 = 2.3 Hz, 1H), 7.86 (d, 1 = 1.8 Hz, 1H).

Intermediate 71. tert-Butyl-4-methylene piperidine-1-carboxylate *.

To a solution of methyltriphenylphosphonium bromide (2.69 g, 7.5 mmol) in THF (20 ml) at -78 ° C, n-butyllithium (1.8 M; 4.2 ml, 7.5 mmol) in hexane was slowly added. The mixture was stirred for 1 hour. After this time, a solution of tert-butyl 4-oxopiperidin-1 carboxylate (1 g, 5.0 mmol) in THF (10 ml) was added dropwise to the mixture. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with isohexane (3 times). United

82 010298 isohexane layers are evaporated and filtered through a silica layer. The crude product was purified using flash chromatography with dichloromethane as eluent to give 0.58 g (59% yield) of the title compound. HPLC: purity 91%, K _t = 2.47 min (system A; 10-97% MeCN for 3 min), 86%, K _t = 2.43 min (system B; 10-97% MeCN for 3 min). ¹ H NMR (400 MHz, SES1 ₃ ) δ ppm 1.46 (s, 9H), 2.12-2.22 (m, 4H), 3.35-3.46 (m, 4H), 4.73 (s, 2H). M8 (Ε8Ι +) for С _П Н ₁₉ Ю ₂ , t / ζ: 142 (М-С4Н8) ⁺ .

* Previously described in 1. Meb. Siet., 45, 3143-3160 (2002).

Intermediate 72.

tert-Butyl-3-methylene pyrrolidine-1-carboxylate *.

The title compound was prepared according to the procedure for the preparation of intermediate 71, starting from tert-butyl-3-oxopyrrolidine-1-carboxylate (0.8 g, 4.3 mmol), triphenylphosphonium bromide (2.31 g, 6.5 mmol) and n-butyllithium (1.8 M; 2.4 ml, 6.5 mmol). Yield: 0.23 g (29%), after purification by flash chromatography using dichloromethane as an eluent. HPLC: 99% purity, K _t = 2.28 min (system A; 10-97% MeCN for 3 min), 99%, K _t = 2.21 min (system B; 10-97% MeCN for 3 min). Ή NMR (400 MHz, SOSR) δ ppm 1.23-1.40 (m, 9H), 2.42 (t, 1 = 6.78 Hz, 2H), 3.31 (t, 1 = 7.40 Hz, 2H), 3.71-3 85 (m, 2H); 4.74-4.91 (m, 2H). M8 (Ε8Ι +) for 0 11 ^ 0-. t / ζ: 128 (M-C ₄ H ₈ ) ⁺ .

* Previously described in tehaye6gop, 53, 539-556 (1997).

Intermediate 73.

tert-butyl-3-methylene-piperidine-1-carboxylate *

The title compound was prepared according to the procedure for the preparation of intermediate 71, starting from tert-butyl-3-oxopiperidin-1-carboxylate (1 g, 5.0 mmol), triphenylphosphonium bromide (2.69 g, 7.5 mmol) and n -butyl lithium (1.8 M; 4.2 ml, 7.5 mmol). Yield: 0.28 g (28%), after purification by flash chromatography with 10% isohexane in dichloromethane as eluent. HPLC: 95% purity, K _t = 2.43 min (system A; 10-97% MeCN for 3 min), 90%, K _t = 2.38 min (system B; 10-97% MeCN for 3 min). Ή NMR (400 MHz, SOSR) δ ppm 1.41-1.48 (m, 9H), 1.56-1.65 (m, 2H), 2.20-2.30 (m, 2H), 3.38-3.47 (m, 2H) ), 3.86 (s, 2H), 4.74 (s, 1H), 4.80 (s, 1H). M8 (Ε8Ι +) for С _П Н ₁₉ Ю ₂ , t / ζ: 142 (МС4Н8) ⁺ .

* Previously described in tegaye6gop, 58, 7165-7175 (2002).

Example 136. No. (2-Methylphenyl) -7- (pyrrolidin-3-ylmethyl) -1-benzofuran-5-sulfonamide trifluoroacetate.

9-ΒΒΝ (0.5 M in THF; 1.5 ml, 0.75 mmol) is added to a solution of tert-butyl 3-methylene pyrrolidine-1 carboxylate (110 mg, 0.6 mmol; intermediate 72) in anhydrous THF ( 1 ml) in an atmosphere of nitrogen at a temperature of 0 ° C. After stirring for 1 h at 0 ° C, the solution was allowed to warm to room temperature for 3 h. 7-iodo-I- (2-methylphenyl) -1-benzofuran-5-sulfonamide was loaded into a test tube for the reaction under microwave irradiation (90 mg, 0.2 mmol; intermediate 58), Hermann catalyst (10 mg), anhydrous THF (2.5 ml), 4 M aqueous solution No. 1OH (0.2 ml) and half of the above solution generated ίη δίΐιι t of 3- (9-borabicyclo [3.3.1] non-9-ylmethyl) pyrrolidine-1-carboxylic acid butyl ester (1.1 ml, 0.3 mmol). The mixture is heated by irradiation with microwaves at a temperature of 140 ° C for 5 minutes. This reaction mixture and the like are combined, filtered and evaporated. The residue was dissolved in methanol (3 ml), concentrated HC1 (0.5 ml) was added, and the mixture was heated under microwave irradiation at a temperature of 100 ° C for 5 min to remove the трет-tert-BOC group. By purification by preparative HPLC (system P; 20-45% MeCNO, 0.1% TFA), 31 mg (13% yield) of the title compound are obtained. HPLC: 98%, K _t = 1.69 min (system A; 10-97% MeCN for 3 min), 98%, K _t = 1.53 min (system B; 10-90% MeCN for 3 min ) M8 (Ε8Ι +) for C.N-UOl t / ζ: 371 (M + 1). ^! H NMR (400 MHz, methanol-6 ₄ ) δ ppm 1.57 (dec., 1 = 13.3, 8.8 Hz, 1H), 1.87 (s, 3H), 1.88-1.95 (m, 1H), 2.58-2.70 (m, 1H), 2.81 (dd, 1 = 11, 4, 8.9 Hz, 1H), 2.96 (ddd, 1 = 18.1, 14.0, 7.5 Hz, 2H), 3.10-3.21 (m, 2H), 3.30 (ddd, 1 = 11.9, 8.2, 4.3 Hz, 1H), 6.89 (d, 1 = 2.3 Hz, 1H), 6.97-7.02 (m, 4H), 7.32 (d, 1 = 1.8 Hz, 1H), 7.85 (d, 1 = 2.0 Hz, 1H), 7, 87 (d, 1 = 1.8 Hz, 1H).

Example 137. No. (2-Methylphenyl) -7- (piperidin-3-ylmethyl) -1-benzofuran-5-sulfonamide trifluoroacetate.

The title compound was prepared according to the procedure for Example 136, starting from tert-butyl 3-methylene piperidin-1-carboxylate (120 mg, 0.6 mmol; intermediate 73) and 7-iodo-I- (2 methylphenyl) -1-benzofuran-5 -sulfonamide (180 mg, 0.4 mmol; intermediate 58). Yield: 40 mg (21%). HPLC: 99%, K _t = 1.74 min (system A; 10-97% MeCN for 3 min), 100%, K _t = 1.58 min (system B; 10-90% MeCN for 3 min )

M8 (Ε8Ι +) for С ₂ 1Н ₂₄ ^ О ₃ 8, m / ζ: 385 (M + 1). ^! H NMR (400 MHz, methanol-6 ₄ ) δ ppm 1.60-1.72 (m, 3H), 1.85-1.95 (m, 2H), 1.99 (s, 3H), 2.15-2.26 (m, 1 = 11.3 , 7.6, 7.6, 3.8, 3.8 Hz, 1H), 2.73 (t, 1 = 12.3 Hz, 1H), 2.86-2.97 (m, 3H), 3.24 (dd, 1 = 12.5, 3.5 Hz, 1H), 3.34-3.37 (m, 1H), 6.98 (d, 1 = 2.3 Hz, 1H), 7 05-7.09 (m, 2H), 7.09-7.12 (m, 2H), 7.41 (d, 1 = 1.8 Hz, 1H), 7.94 (d, 1 = 2 , 3 Hz, 1H), 7.96 (d, 1 = 1.8Hz, 1H).

Intermediate 74.

- 83 010298

7-iodo-1-benzofuran-5-amine.

7-Iodo-5-nitro-1-benzofuran (2.5 g, 8.6 mmol) and iron (2.51 g, 45.0 mmol) are introduced into a round bottom flask. Methanol (25 ml), 1,4-dioxane (25 ml) and ammonium chloride (2.5 g, 46.7 mmol) dissolved in water (50 ml) were added and the mixture was heated at 100 ° C for 16 h. The reaction mixture is filtered through celite and the volatile components are removed by evaporation. The residue was dissolved in a mixture of methanol (10 ml) and dichloromethane (90 ml). The mixture was filtered through a pad of silica and the solvent was evaporated, yielding 2.22 g (99%) of the title compound as a brown oil. HPLC: purity: 70%, R _t = 1.26 min (System A, 10-97% Mesa for 3 min). M8 (E81 +) for С ₈ Н ₆ 1ЫО, t / ζ: 260 (М + Н) ⁺ .

Intermediate 75.

Y- (7-Iodo-1-benzofuran-5-yl) -2-methoxy-5-methylbenzenesulfonamide.

To a mixture of 7-iodo-1-benzofuran-5-amine (2.22 g, 8.6 mmol; intermediate 74) in an anhydrous dichloromethane / THF mixture (5: 1; 50 ml; the starting material was partially dissolved), pyridine ( 1.43 ml, 17.1 mmol) and 6-methoxy-m-toluenesulfonyl chloride (2.64 g, 12.8 mmol). The resulting mixture was stirred at room temperature for 21 hours. The solvent was evaporated under reduced pressure and the crude product was purified using flash chromatography (eluent: 20% isohexane in dichloromethane). Pure fractions were combined and concentrated to give the product (1.62 g, 42% yield) as a light brown fluffy solid. HPLC: 81%, K _t = 2.26 min (system A; 30-80% МеСЫ for 3 min), 86%, K _t = 2.27 min (system B; 10-97% МеСЫ for 3 min )

Ή NMR (400 MHz, СОС1 _; ) δ ppm 2.22 (s, 3H), 4.04 (s, 3H), 6.77 (d, 1 = 2.01 Hz, 1H), 6.92 (d, 1 = 8.28 Hz, 1H), 7.25-7.29 (m, 1H), 7.32 (d, 1 = 2.01 Hz, 1H), 7.36 (d, 1 = 2.01 Hz, 1H), 7.53-7 55 (m, 1 = 2.26 Hz, 1H); 7.62 (d, 1 = 2.26 Hz, 1H). M8 (E81 +) for C1bH1 ₄ lO ₄ , t / z: 444 (M + H) ⁺ .

Example 138. 2-Methoxy-5-methyl-Y- [7- (piperidin-4-ylmethyl) -1-benzofuran-5-yl] benzenesulfonamiditrifluoroacetate.

The title compound was prepared according to the procedure for Example 136, starting from tert-butyl 4-methylene piperidin-1-carboxylate (120 mg, 0.6 mmol; intermediate 71) and Y- (7-iodo-1-benzofuran-5-yl) -2 -methoxy-5-methylbenzenesulfonamide (180 mg, 0.42 mmol; intermediate 75). Yield: 69 mg (33%). HPLC: 96%, R _t = 1.75 min (System A, 10-97% Mesa for 3 min), 99%, R _t = 1.58 min (System B, 10-90% Mesa for 3 min ) M8 (E81 +) for C ₂₂ H ₂₆ N ₂ O ₄ 8, t / ζ: 415 (M + 1). ¹ H NMR (400 MHz, methanol-6 ₄ ) δ ppm 1.22-1.34 (m, 2H), 1.61 (d, 1 = 13.6 Hz, 2H), 1.80-1.91 (m, 1 = 11.3, 7.6, 7 6, 3.6, 3.6 Hz, 1H), 2.10 (s, 3H), 2.69 (d, 1 = 7.3 Hz, 2H), 2.78 (16, 1 = 12, 9, 2.6 Hz, 2H), 3.24 (d, 1 = 2.0 Hz, 2H), 3.87 (s, 3H), 6.62 (d, 1 = 2.3 Hz, 1H) 6.79 (d, 1 = 2.0 Hz, 1H), 6.93 (d, 1 = 8.5 Hz, 1H), 7.10 (d, 1 = 2.0 Hz, 1H), 7 21 (dd, 1H), 7.38 (d, 1 = 2.0 Hz, 1H), 7.58 (d, 1 = 2.3 Hz, 1H).

Intermediate 76.

2- (2,6-Dibromophenoxy) ethyl bromide *.

A mixture of 2,6-dibromophenol (10.2 g, 40 mmol), 1,2-dibromoethane (7.6 g, 4 0 mmol) and NaOH (1.76 g, 44 mmol) in water is refluxed overnight with stirring. The mixture was cooled, extracted with diethyl ether (2 times, 100 ml each), the extract was washed with an aqueous NaOH solution, brine, dried (MD8O ₄ ) and concentrated to give the product as a pale yellow oil. Yield: 10.0 g (70%). Ή NMR (400 MHz, GOST) δ 3.73 (t, 2H), 4.31 (t, 2H), 6.88 (t, 1H), 7.50 (d, 2H).

* Previously described in tegabe6gop Le11., 39, 2219-2222 (1998).

Intermediate 77.

7-Bromo-2,3-dihydrobenzofuran *.

A solution of 2- (2,6-dibromophenoxy) ethyl bromide (1.08 g, 3 mmol; intermediate 76) in a mixture of THF (12 ml) and hexane (3 ml) was cooled in a bath with ethanol / dry ice for 30 minutes . A solution of n-butyllithium in hexane (2 ml of a 1.5 M solution) was added dropwise over 15 minutes. The reaction mixture was stirred at -78 ° C for the next 30 minutes, after which the bath was allowed to slowly warm to 0 ° C. The mixture was poured into water and extracted with diethyl ether (2 times 100 ml). The combined extract was dried and concentrated to give a pale brown oil (0.5 g) containing a product contaminated with approximately 25% 2,3-dihydrobenzofuran. This substance is used as it is for further synthesis, but, if necessary, it can be purified by flash chromatography [eluent: hexane, ethyl acetate / hexane (5:95)]. ¹ H NMR (400 MHz, SES1 ₃ ) δ 3.30 (t, 2H), 4.65 (t, 2H), 6.71 (t, 1H), 7.11 (dd, 1H), 7.25 (dd, 1H).

* Previously described in tegabe6gop Le11., 39, 2219-2222 (1998).

Intermediate 78.

7-Bromo-5 - [(4-methylphenyl) sulfonyl] -2,3-dihydrobenzofuran.

7-Bromo-1,2-dihydrobenzofuran (64 mg, 0.3 mmol; intermediate 77) and ptoluenesulfonic acid monohydrate (62 mg, 0.3 mmol) are mixed and then the mixture is added in a ratio of 1:10 (by weight) methanesulfonic acid and phosphorus pentoxide (1 ml). The resulting mixture was stirred overnight at room temperature and then poured into ice water. The resulting crystalline material was filtered off and dried, yielding 120 mg of the title compound. ¹ H NMR (400 MHz, SIS1 ₃ ) δ 2.40 (s, 3H), 3.33 (t, 2H), 4.73 (t, 2H), 7.29 (d, 2H), 7.65 (d, 1H), 7.79 (d, 2H), 7.89 (d, 1H); M8 (E1 +) with gas chromatography for C1 ₅ H ₁₃ Br8O ₃ , t / ζ: 354 (M + H) ⁺ .

Intermediate 79.

7-Bromo-5 - [(4-methylphenyl) sulfonyl] -1-benzofuran.

A mixture of 7-bromo-5 - [(4-methylphenyl) sulfonyl] -2,3-dihydro-1-benzofuran (353 mg, 1 mmol; intermediate 78), NB8 (178 mg, 1 mmol) and dibenzoyl peroxide (24 mg, 0.1 mmol) in carbon tetrachloride (20 ml) is heated at 80 ° C for 2 hours. TEA (2 ml) is added and the mixture is heated for the next 2 hours. Flash chromatography using ethyl acetate / hexane in a ratio of 10:90 25:75 as the eluent, the title product is obtained in the form of a white crystalline substance. Yield: 130 mg (37%).

¹ H NMR (400 MHz, SIS) δ 2.39 (s, 3H), 6.93 (d, 1H), 7.30 (d, 2H), 7.78 (d, 1H), 7.84 ( d, 2H), 8.02 (d, 1H), 8.19 (d, 1H).

Example 139. 3 - ({5 - [(4-Methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) pyrrolidine trifluoroacetate.

The title compound was prepared according to the procedure for Example 136, starting from tert-butyl-

3-methylpiperidin-1-carboxylate (60 mg, 0.3 mmol; intermediate 73) and 7-bromo-5 - [(4 methylphenyl) sulfonyl] -1-benzofuran (70 mg, 0.21 mmol; intermediate 79) . Yield: 3 mg (3%). HPLC: 97%, I _t = 1.79 min (system A; 10-97% MECA for 3 min), 97%, I _t = 1.61 min (system B; 10-90% MECA for 3 min ) M8 (E81 +) for С ₂ 1Н ₂₃ НО ₃ 8, t / ζ: 356 (М + 1).

Example 140. 2-Methoxy-5-methyl-Y- [5- (piperidin-4-ylmethyl) -1-benzofuran-7-yl] benzenesulfonamide trifluoroacetate.

The title compound was prepared according to the procedure for Example 136, starting from tert-butyl-

4- methylene piperidin-1-carboxylate (120 mg, 0.6 mmol; intermediate 71) and Y- (5-bromo-1-benzofuran-7-yl) -2-methoxy-5-methylbenzenesulfonamide (150 mg, 0.42 mmol ; obtained in example 132, step 1). Yield: 27 mg (12%). HPLC: 97%, I _t = 1.68 min (system A; 10-97% MECA for 3 min), 97%, I _t = 1.52 min (system B; 10-90% MECA for 3 min ) M8 (E81 +) for C ₂₂ H ₂₆ N ₂ O ₄ 8, t / ζ: 415 (M + 1). ^! H NMR (400 MHz, methanol-b ₄ ) δ ppm 1.22-1.33 (m, 2H), 1.62-1.73 (m, 3H), 2.13 (s, 3H), 2.51 (d, 1 = 7.0 Hz, 2H) 2.80 (1b, 1 = 12.7, 2.4 Hz, 2H), 3.24-3.28 (m, 2H), 3.77 (s, 3H), 6.63 (d, 1 = 2.0 Hz, 1H), 6.87 (d, 1 = 8.5 Hz, 1H), 6.98 (d, 1 = 1.5 Hz, 1H), 7.05 (d, 1 = 1 5 Hz, 1H), 7.21 (dd, 1 = 8.2, 1.9 Hz, 1H), 7.46 (d, 1 = 2.3 Hz, 1H), 7.59 (d, 1 = 2.3 Hz, 1H).

Biological research

The ability of a compound of the invention to bind to the human 5-HT ₆ receptor and suitability for use in the pharmaceutical industry can be determined using tests of w uguo and w U11go, known in the art.

(a) 5-HT ₆ Binding Test

The binding affinity experiment for the 5-HT ₆ receptor was performed in the case of HEK293 cells transfected with the human 5-HT ₆ receptor using | ³ H | -L8O as a labeled ligand according to the general method, as described by Voe§8 Eb. et al., Yeigoryagtasodu, 36 (4/5), 713-720 (1997).

Cell Culture Materials

The HEK293 cell line transfected with the human 5-HT ₆ receptor was cultured in Eagle's Dulbecco modified medium containing 5% dialyzed fetal bovine serum (b1bco BJB 10106-169), 0.5 mM sodium pyruvate and 400 μg / ml geneticin ( 6-418) (b1bco bb 10131-019).

Cells were passaged 1:10 twice a week.

Chemicals

The radioligand [ ³ H] L8O 60-240 Ci / mmol, manufactured by AtepDat Ryagtaa Wu1es11 (Wiskdyatkyge, England), was stored in ethanol and stored at a temperature of -20 ° C. Compounds were dissolved in 100% DMSO and diluted with binding buffer.

Methodology

Compounds were diluted in 96-well polypropylene plates with a U-shaped bottom of Soyag (Sogspd 1ps. Soyag, ΚΥ, USA). Samples were incubated in Raskagb OrDr1a1e (Raskagb 1p81gitep18 V.U., boschdep, Netherlands). The total amount of radioligand added was measured on Wage 24-well plates.

Buffer

The binding buffer consisted of 20 mM HEPES, 150 mM NaCl, 10 mM MDCl ₂ and 1 mM EDTA, pH 7.4.

- 85 010298

Membrane Preparation Methods

Cells were cultured to approximately 90% confluence on 24.5 mm x 24.5 mm culture plates. The medium was removed and, after washing with ice-cold phosphate-buffered saline (PB8), the cells were scraped off using 25 ml of Tris buffer (50 mM Tris-HC1, 1 mM EDTA, 1 mm ECTA, pH 7.4 and a window scraper. Cells then destroyed with the help of a Po1u1gop homogenizer and the remaining partial material was removed by low-speed centrifugation with an acceleration of 1000 d for 5 minutes Finally, the membranes were collected by high-speed centrifugation (20,000 d), suspended in binding buffer and frozen in aliquots at temperatures -70 ° C.

Radio Ligand Binding

Frozen cell membranes were thawed, immediately re-homogenized using a Po1u1gop homogenizer, and bound to spheres coated with wheat germ agglutinin for 8PA (Integrate KI’e 8c1epsek, Sagy1kk, England) for 30 min with continuous shaking of the tubes. After binding, the spheres were centrifuged for 10 min with an acceleration of 1000 d and then suspended in 20 ml of binding buffer on a 96-well plate. The binding reaction was then initiated by adding a radioligand and test compounds to the membrane suspension on spheres. After incubation at room temperature, assay plates were analyzed for radioactivity using a scintillation counter.

The original 8PA method was followed, except that the membranes were obtained from HEK293 cells expressing the human 5-HT ₆ receptor, instead of HeLa (Τ) cells, OMV, Qat ^ kk R.S., SS8 S8, 8y1as1e8 .K., Kakhkh'kop S.E., 8th M.A. '^ ayyNoy ok yitai 5-HT ₆ geser! erg eckerkke t nea se11 tätgapek: kaigiuyu tiitd zhShez, ryagtasood1sa1 ryokyyek ok to! apyagy ΟΝ8 adep! kai 8Peerierei1 7295-95-064, December 27, 1995). The specific binding of [ ³ H] -E8O was "saturable", while the non-specific binding increased linearly with the concentration of the added radioligand. [ ³ H] -E8O binds with high affinity to 5-HT ₆ receptors. The value of K _th was estimated at 2.6 ± 0.2 nM, based on four separate experiments.

Complete binding to 3 nM [ ³ H] -E8O, the concentration of radioligand used in competition experiments, was typically 6,000 yt (decays per minute), and specific binding was more than 75%. 5-HT caused concentration-dependent inhibition of [ ³ H] -E8O binding with a total average K value of 236 nM when testing was performed using two different membrane preparations.

The variability between the tests during the three experiments showed CV (coefficient of variation) of 10% with average values of K] = 173 nM (tolerance 30) and the Hill coefficient 0.94 (tolerance 0.09). The “inside” test variability was 3% (n = 4). All unlabeled ligands were replaced by specific [ ³ H] -E8O binding in a concentration-dependent manner, although with different efficiencies. The order of affinity for the 5-HT ₆ receptor of standard compounds was: methiotepine (K] = 2nm)> mianserin (190 nM) = 5-HT (236 nM)> metisergide (482 nM)> mesulergin (1970 nM )

Protein Definition

Protein concentrations were determined with the help of VuKai Protein Akkau (Vgaykogy M.M. A garay apy kepy когχ-rye koge 1st tsiapiayop ok tyugodgat diapyek oktogo ryu1i1ίζίιιμt rytpuyt, okay. 72, 248-254 (1976)). Bovine serum albumin was used as a standard.

Scintillation counter

Radioactivity was determined in a Raskag TorSoip ™ ™ scintillation counter (Raskag! Pclitep! K, Mepyep, ST, USA) with a counting efficiency of approximately 20%. Counting efficiency was determined in separate series of experiments.

Saturation experiments

In saturation experiments, at least 6 concentrations were used in duplicate of the radioligand (0.1-20 nM [ ³ H] -E8O). Specific binding was calculated as the difference between total binding and non-specific binding, which was defined as radioligand binding in the presence of 5 μM lysuride. B _max and the dissociation constant, K _d, were determined by nonlinear regression analysis using equation 1. _n is unrelated to the radioligand concentration and y is the amount bound.

Vshah 'k k + K _a (equation 1)

Competition experiments

Total and nonspecific radioligand binding was determined on eight replicates for each case. Samples containing the test compound were used in duplicate at 11 concentrations. Incubations were carried out at room temperature for 3 hours. Value! C5 ₀ , that is,

- 86 010298 the concentration of the test compound, which inhibits 50% of the specific binding of the radioligand, was determined using non-linear regression analysis and the value of K; calculated using equation 2 [Syepd, US, Vusyet. Ryagtaso., 22, 3099-3108 (1973)].

TS

TO; = --- γ- (equation 2)

A Κ _ά

G = concentration of radioligand;

Κ _ά = affinity of the radioligand (b) Test for inherent 5-HT ₆ activity.

Antagonists of the 5-HT ₆ receptor were characterized by measuring the inhibition of 5-HT caused by an increase in cAMP (cyclic adenosine monophosphate) in HEK293 cells expressing the human 5-HT ₆ receptor (see Boe88 et al., Cheigoryagtaso-1odu, 36, 713, 713- 720 (1997)). Briefly, HEK293 / 5-HT ₆ cells were seeded in polylysine-coated 96-well plates at a density of 25,000 per well and cultured in EMEM (Dulbecco's modified Eagle's medium) (without phenol red) containing 5% dialyzed fetal calf serum in 48 hours at a temperature of 37 ° C in an incubator containing 5% CO ₂ atmosphere. The medium was then removed and replaced with 0.1 ml of test medium (Hanks balanced salt solution containing 20 mM HEPES, 1.5 mM isobutyl methylxanthine and 1 mg / ml bovine serum albumin). After adding test substances, 50 μl dissolved in the test medium, the cells were incubated for 10 min at 37 ° C in an incubator containing 5% CO ₂ atmosphere. The medium was then removed and the content of cAMP was determined using a kit with radioactive cAMP (Ategate Ryagtas1a 1B'u1esI, Vyutkak KRA 559). The effectiveness of the antagonists was quantified by measuring the concentration that causes 50% inhibition of 5-HT (at [5-HT] = 8-fold EC ₅₀ ), induced by an increase in cAMP, using the formula: ίΚ _; = 1C ₅₀ / (1 + [5-HT] / EC ₅₀ ).

The compounds of the invention have selective affinity for 5-HT ₆ receptors with K values _; and 1C ₅₀ , _corr . from 0.5 nM to 5 μM or show a% inhibition of [3H] -B8O> 20% at 50 nM and are 5-HT ₆ antagonists, agonists or partial agonists. The compounds exhibit good selectivity for 5-HT _1a, 5-HT _1b, 5-HT _2a, 5-HT _2b and 5-HT _2c.

(c) Test ίη νίν Тест to reduce food intake.

For a review of serotonin and food intake, see B1ipbe11 TE. Na1Gogb B.S.O. 8th1shp apb ArreShe Kediayop. 1tr11sayop8 Gogh Le Riagtasood1ca1 tgea ^ eL oG Oe8yu, SC8 Ogid8, 9, 473-495 (1998).

An obese (ob / ob) mouse was selected as the main animal model for screening, as this mutant mouse consumes large amounts of food, resulting in a high signal of noise level. To further substantiate and compare efficacy data, the effect of the compounds on food intake was also studied in wild-type mice (C57BB / 61). The amount of food consumed was recorded within 15 hours after administration of the compounds.

In all studies used male mice (obese S57VT / 6Tot ^LEP-ob and lean S57V / 61ot wildtype; Votyo1ΐ8daa ^ b, Oeptagk) aged 8-9 weeks with an average body weight of 50 g (obese) and 25 g (lean ) Animals were placed individually in cages at a temperature of 23 + 1 ° C, 40-60% humidity and they had free access to water and standard laboratory food. A 12/12-hour light / dark cycle was set to turn off the light at 5 pm. Animals were conditioned for at least one week before the start of the study.

Test compounds were dissolved in solvents suitable for each particular compound, such as cyclodextrin, cyclodextrin / methanesulfonic acid, polyethylene glycol / methanesulfonic acid, physiological saline. Fresh solutions were prepared for each study. Doses of 30, 50 and 100 mg / kg / day were used. Test compounds have analytical purity.

Animals were weighed at the start of the study and randomized by body weight. AHe1 osmotic mini-pumps (model 2001Ό; infusion rate of 8 μl / h) were used and loaded essentially as recommended in the AEe Technical Information Guide! (ANA 8c1epNys Rgo6is18, 1997; TIeslte G. and Wat 8.Ι., App. B ^ oteb. Epd. 4 (4), 343-353 (1976)). A continuous subcutaneous infusion of 24 hours was used. The mini-pumps were filled either with various concentrations of the test compounds dissolved in the excipient or with a solution of the excipient only and kept in the excipient preheated to a temperature of 37 ° C (for approximately 1 hour). Mini-pumps were implanted subcutaneously in the neck / back area under short-term anesthesia (methofan / enflurane). This surgical procedure lasts approximately 5 minutes.

The mass of feed pellets was measured at 5 p.m. and 8 p.m. for two days before (baseline) and 1 day after implantation of osmotic mini-pumps. Weighing was carried out using a computer-related balance MeLeg to1s6o RK 5002. Random losses were corrected. At the end of the study, the animals were killed by displacement of the cervical vertebrae and from

- 87 010298 took blood from the body for subsequent analysis of the concentration of the drug in the plasma.

Proteins in the plasma sample were precipitated with methanol, centrifuged and the supernatant transferred to HPLC tubes and injected into the liquid chromatography / mass spectrometry system. A mass spectrometer is intended for electron-beam ionization with the formation of positive ions and for monitoring multiple reactions. Linear regression analysis of standards, accelerated at the beginning, was used to calculate concentrations of unknown samples.

Food consumption over 15 hours was measured for three consecutive days and a percentage of the basal level was obtained for each animal, based on the day before and after treatment. Values were expressed as mean ± tolerance and ± standard deviation when using eight animals per dosing group. Statistical evaluation was carried out according to Kgi8ka1- ^ a1118, ANVA, using basal values in percent. If the statistical value reached a level of p <0.05, a Mapp-S1ch1peu C-test was carried out for statistical comparison between the control and the treated groups.

The compounds of the invention have an effect (i.e., reduced food intake) in the range of 5-200 mg / kg / day.

Table 4. Data ίη νίΐτο on functionality in relation to the 5-HT receptor (£ CD

Data were expressed as 1K, = HS ₅₀ / (1+ [5-ΗΓ] / EC ₅₀ ). Antagonist efficacy was quantified by measuring the concentration that causes inhibition of 50% 5-HT (at [5-HT] = 8 times the EC ₅₀ ) induced by an increase in cAMP using the formula 1K, = HS ^ H ^ -HT ^ EC ^).

Table 4

Table 5. ίη νίΐτο competition binding data for the human 5-HT receptor (K!).

The value of GS ₅₀ , that is, the concentration of the test compound, which inhibits 50% of the specific binding of the radioligand ([ ³ Η] -Ε8Ώ), was determined using nonlinear regression analysis and the value of K! calculated using the equation

Claims (7)

CLAIM 1. The compound of formula (I) P where P is selected from the substituents of the formulas (Π) - (νΠ) - 88 010298 where x, y and_ |, each independently, are selected from 0, 1 and 2; where the dashed lines indicate that P and B ³ , respectively, can be attached either to A or to the B-ring at any carbon atom that can be substituted, provided that P and B ³ are both not simultaneously attached to ring B; B ^{1 is} selected from the group consisting of: (a) _C1-6 alkyl, (b) _C1-6 alkoxy _C1-6 alkyl, (c) C6-6 alkenyl, (b) hydroxy _C1-6 alkyl, (e) halogen C1 _-6- alkyl, (D) aryl, (e) arylcarbonylmethyl, (1) aryl-C3-6-alkenyl, (ΐ) aryl-C1 _-6- alkyl, (Ϊ) C3 _-7- cycloalkyl, (k) heteroaryl , (l) 4-piperidinyl, (t) L-substituted 4-piperidiyl, where the substituents are selected from _C1-6 alkyl and aryl _C1-6 alkyl, (o) heteroaryl _C1-6 alkyl, where any heteroaryl or an aryl residue, one or as part of another group, may be independently substituted at one or more positions with a substituent selected from the group consisting of: (a) hydrogen, (b) halogen, (c) _C1-6 alkyl, (b) hydroxy, (e) _C1-6 alkoxy, (D) C2-6 alkenyl, (e) C2-3 alkynyl , (1) phenyl, (ΐ) phenoxy, (Ϊ) benzyloxy, (k) benzoyl, (l) benzyl, (t) -OCP3, (η) -СЫ, (o) hydroxy-C1 _-6- alkyl, ( p) C1 _-6 alkoxy C1 _-6 alkyl, (c) halo-C1 _-6 -alkyl, (g) -YV ^{9 9} (8) -YO _2, (ΐ) -SOYV ^{9 9} (i) -BY ⁷ COB ¹⁰ , (ν) -C (= O) B ¹⁰ , (x) C1 _-6- alkoxycarbonyl, (y) C1 _-6 -alkylthio, (ζ) -8СР3, (aa) -СНР = CH ₂ , (ab) methylsulfonyl or (ac) -COOH, - 89 010298 with the proviso that when the substituent of the above aryl or heteroaryl residue selected from the group consisting of phenyl, phenoxy, benzyloxy, benzoyl and benzyl, it, on the phenyl ring may be optionally substituted by one or more halogen atoms, C 1 _- 4 alkyl, C 1 -C _- 4-alkylthio, C _1-4 alkoxy, cyano or trifluoromethyl; K ^{2 is} selected from the group consisting of: (a) hydrogen, (b) C1 _-6 alkyl, (c) C1 _-6 alkoxy-C2 _-6 alkyl, (b) hydroxy-C2 _-6 alkyl, (e) - (ΠΗ ₂ ) _ω ^ Η2-Ε, where m is 2-4, (ί) 3,3,3-trifluoropropyl, or (d) C 1 _- 4 alkylsulfonyl, with the proviso that R is selected from substituents of formula (V); and W ₂ , each independently, is selected from the group consisting of: (a) hydrogen, (b) halogen, (c) _C1-6 alkyl, (b) hydroxy, (e) _C1-6 alkoxy, (ί) _C1-6 alkylthio, (e) C2-6 alkenyl , (I) phenyl, (1) phenoxy, (]) benzyloxy, (k) benzoyl, (l) benzyl, (t) -ΟΟ ^, (p) -SK, (o) hydroxy-C1 _-6- alkyl, (p) C1 _-6- alkoxy-C1 _{- 6} -alkyl, (d) halo-C1 _-6 -alkyl, (g) ^ ΟΝβΥ ^9, (h) -C ((F ^10, (ΐ) C1 _-6 -alkoxycarbonyl, (i) ₃ or -8SR (ν ) -COTH ^, provided that when W _{2 is} selected from the group consisting of phenyl, phenoxy, benzoyl, benzyloxy and benzyl, their phenyl rings may optionally be substituted with one or more halogen atoms, C1 _- 4-alkyl, C1 _- 4-alkoxy, cyano or trifluoromethyl; and provided that when and W ₂ are not selected from the group consisting of methoxy, methyl, and halogen, for Men it least one of and is hydrogen; K ³ means Η when P means a substituent of formula (II), where K ¹ means Ν-substituted 4 piperidinyl, or K ³ means a group selected from G G - 90 010298 K ³ may also be a group selected from additionally, a group selected from —O— (C = NΗ) NK ¹¹ K ¹¹ or - (CH ₂ ) _p —O — NO (C = KN) —NK ¹¹ K ¹¹ ; where n = 0, 1, 2 or 3, g, each independently, means 0, 1 or 2, o = 1, 2 or 3, p, each independently, means 1 or 2, s = 2 or 3, 1 = 0 or 1, ΐι = 1 or 2, 1 ₂ = 0 or 1, ί = 1, 2, 3 or 4 and £ 1 = 1, 2 or 4, provided that when r and p simultaneously mean 1, r does not mean 0; X is selected from O, Ν £ ⁷ and 8; X 'is selected from ΝΙΑ and 8; X _{2 is} selected from O, ΝΒ ⁷ and 8, provided that X _{2 is} selected from ΝΙΑ and 8 when 1 ₂ = 0; X _{3 is} selected from ΝΙΑ and 8, provided that X ₃ is 8 when r = 1; - 91 010298 X _{4 is} selected from O, ΝΕ ⁷ and 8, provided that X _{4 is} selected from ΝΙΤ and 8 when ί is selected from 2, 3 and 4; O is selected from CH ₂ , 8 O ₂ and oxygen, provided that when O is 8 O ₂ or oxygen, p is 1; Ζ choose from 8O ₂ and oxygen; when P is a group selected from substituents of the formulas (ν) - (νΠ), K ³ is additionally selected from the following groups: where n = 0, 1, 2 or 3, r = 0, 1 or 2, o = 1, 2 or 3, p = 1 or 2, 8 = 2 or 3 and ί = 1, 2, 3 or 4; where K ^{4 is} selected from the group consisting of: (a) hydrogen, (b) _C1-6 alkyl, (c) 2-cyanoethyl, (ά) hydroxy- _C2-6 alkyl, (e) C3-6 alkenyl, (ί) C3-6 alkynyl , (d) C3-7 cycloalkyl, (1) C3-7 cycloalkyl-C1-4 alkyl, (ΐ) C1 _-6 alkoxy-C _2-6 alkyl, 0) -C - (= NН) -N-К ¹¹ К ¹¹ , (k) -С- ^ О ^ -К ¹¹ ^ ¹ , (l) -СН2-СО-№К ^П К ^П or (t) 3 , 3,3-trifluoropropyl; K ^{5 is} selected from the group consisting of: (a) hydrogen, (b) C1 _-4 alkyl, (c) hydroxy-C1 _-4 -alkyl, (ά) C1 _-4 -alkoksimetila, (f) halo-C1 _-4 -alkyl, (ί) -№ ^P K ^P , (d) -CO-YK ^P K ^P , (1) a hydroxyl group, provided that the above hydroxyl group is not attached to a carbon atom adjacent to the ring nitrogen atom, or (ΐ) fluorine, provided that the above fluorine atom is not attached to a carbon atom adjacent to the nitrogen atom of the ring; K ^{6 is} selected from the group consisting of: (a) hydrogen, (b) C1 _-4 alkyl, (c) hydroxy-C1 _-4 alkyl, (ά) C1 _-4 alkoxy-C1 _-4 alkyl, (e) hydroxyl group, provided that the above hydroxyl group is not attached to the carbon atom adjacent to the nitrogen atom of the heterocycle; and also provided that the above heterocycle is not substituted by an oxo group; (ί) fluorine, provided that the above fluorine atom is not attached to a carbon atom adjacent to the nitrogen atom of the ring; or (d) halo-C1 _-4 -alkyl; - 92 010298 K ⁷ , each independently, is selected from the group consisting of: (a) hydrogen, provided that K ⁷ does not mean hydrogen when g is simultaneously present and the above g means 1 or 2, (b) C1 _-4 alkyl, (c) hydroxy-C2-4 alkyl, or (b) methoxy-C _2-4 alkyl; To ⁸ , each independently, is selected from: (a) hydrogen or (b) C1 _-4 alkyl, and when both simultaneously K ⁸ are C1 _-4 -alkyl, C1 _-4 -alkyl as defined above may be attached to the same or different carbon atoms, or when two groups are at the same carbon atom, they can together form a cyclopropane ring; To ⁹ , each independently, is selected from: (a) hydrogen, (b) _C1-6 alkyl, (c) C3-7 cycloalkyl or, where two K ⁹ groups together with the nitrogen atom to which they are attached form a heterocycle; and with the proviso that when two K ⁹ groups form a piperazine ring, the nitrogen atom of the above piperazine ring which may be substituted, is substituted with C1 _-4 alkyl; and provided that when two K ⁹ groups form a piperidine ring, any carbon atom in the above piperidine ring may optionally be substituted with methyl; K ¹⁰ choose from: (a) C1-6 alkyl, (c) aryl, or (b) heteroaryl, where heteroaryl or aryl can be substituted at one or more positions with substituents selected from a halogen atom, C _{! -4} alkyl, C _4-4 - alkoxy, cyano, trifluoromethyl; To ¹¹ , each independently, is selected from: (a) hydrogen, (b) methyl, or (c) ethyl, provided that K ¹¹ is in the K ⁴ or K ²⁶ group meaning —CH ₂ —C0 — S — K ¹¹ K ¹¹ ; K ^{12 is} selected from the group consisting of: (a) hydrogen, (b) _C1-6 alkyl, (c) aryl, (b) aryl _C1-6 alkyl, (f) C3-7 cycloalkyl, (£) C _3-7 cycloalkyl C1 _-4- alkyl, (d) heteroaryl or (11) heteroaryl-C1 _-6- alkyl, where any heteroaryl or aryl residue, one or as part of another group, is optionally independently substituted at one or more positions with substituents selected from the group, consisting of: (a) hydrogen, (b) halogen, (c) C1-6 alkyl, (b) hydroxy, (e) C1-6 alkoxy, (£) C2-6 alkenyl, (e) C _2-6 - alkynyl, (1) phenyl, (ί) phenoxy, (ί) benzyloxy, (k) benzoyl, (l) benzyl, (t) -0С? 3, (η) -ΌΝ, (o) hydroxy-C1 _-6 - alkyl, (p) C1 _-6- alkoxy-C1 _-6- alkyl, (c. |) halogen-C1 _-6- alkyl, (g) -JCC ⁹ , (h) -02, - 93 010298 (ΐ) -SOKHK'K. (i) -NA ⁷ SOK ¹⁰ , (ν) -С (= О) К ¹⁰ , (x) С1 _-6- alkoxycarbonyl, (y) С1 _-6- alkylthio, (ζ) -8С? 3, (aa) —CHP = CH ₂ , (ab) methylsulfonyl or (ac) —COOH, provided that. when a substituent of the above aryl or heteroaryl residue is selected from the group consisting of phenyl, phenoxy, benzyloxy, benzoyl and benzyl, its phenyl ring may optionally be substituted with one or more halogen atoms, C1-4 alkyl, C1-4 alkoxy, cyano or trifluoromethyl; K ^{13 is} selected from the group consisting of: (a) C1 _-6 alkyl, (b) C3-6 cycloalkyl, (c) aryl, (b) heteroaryl, (e) aryl-C1 _-2 -alkyl or (£) heteroaryl-C 1 _-2 alkyl, where any heteroaryl or aryl residue may be substituted in one or more positions by substituents selected from a halogen atom, C1-4 alkyl, C1-4 alkoxy, cyano, trifluoromethyl and acetyl; K ^{14 is} selected from the group consisting of: (a) aryl, (b) heteroaryl, (c) aryl-C1 _-3 alkyl, or (b) heteroaryl-C1 _-3 alkyl, wherein any aryl or heteroaryl residue may be substituted at one or more positions with substituents selected from a halogen atom, a C1 _-4 alkyl, C1 _-4 alkoxy, cyano and trifluoromethyl; K ¹⁵ choose from: (a) fluorine; or (b) hydroxy; K ^{16 is} selected from the group consisting of: (a) hydrogen, provided that r = 0, (b) amino, (c) dimethylamino, (b) P or (e) OH; K ¹⁷ choose from: (a) hydrogen, (b) C1 _-4 alkyl, (c) hydroxyl group, provided that the above hydroxyl group is not attached to the carbon atom adjacent to the nitrogen atom of the ring; K ^{18 is} selected from: (a) hydrogen or (b) fluorine; K ^{19 is} selected from the group consisting of: (a) hydrogen, (b) methyl, (c) trifluoromethyl, or (b) C1 _-2 alkoxymethyl; and provided that at least one of K ¹⁹ and K ¹¹ , when they are both present simultaneously, does not mean hydrogen; and also provided that when K ^{19 is} selected from trifluoromethyl or C1 _-2 alkoxymethyl, each K ¹¹ is hydrogen; K ^{20 is} selected from the group consisting of: (a) hydrogen, (b) C1 _-4 alkyl, (c) hydroxy-C1 _-4 -alkyl, (b) C1 _-4 alkoxy-C1 _-4 -alkyl or (e) fluoromethyl; provided that when ΐ2 means 1, K ²⁰ means H; - 94 010298 K ²¹ and K ²² , each independently, are selected from: (a) hydrogen or (b) methyl, 11 11 21 22 provided that when at the same time as K are present, at least two of K, K and K oz start hydrogen; K ^{23 is} selected from the group consisting of: (a) hydroxy-C _1-4 alkyl, (b) C _1-4 alkoxymethyl, (c) halo-C1-4 alkyl, or (b) -CO-HC. ¹¹ ^ ¹ , provided that K ^{4 is} not selected from -C - (= XH) -X-K ^P K ^P , -C - (= O) -X-K ^P K. ¹¹ and -CH ₂ CO-X -K ¹¹ To ¹¹ ; K ²⁴ choose from: (a) hydroxymethyl, (b) methoxymethyl or (c) fluoromethyl; To ²⁵ , each independently, is selected from the group consisting of: (a) hydrogen, (b) C1-4 alkyl, (c) hydroxy-C1-4 alkyl, (b) C1-4 alkoxy-C1-4 alkyl or (e) fluoromethyl; with the proviso that when both K ^{25 are} simultaneously C 1-4 alkyl, the aforementioned C 1-4 alkyls may be attached to the same or different carbon atoms; and also provided that when one K ^{25 is} selected from hydroxy-C _1-4 alkyl, C _1-4 alkoxy-C _1-4 alkyl and fluoromethyl, the other K ²⁵ is hydrogen; and K ^{26 is} selected from the group consisting of: (a) 2-cyanoethyl, (b) C3-6 alkenyl, (c) C3-6 alkynyl, (b) C3-7 cycloalkyl, (e) C3-7 cycloalkyl C1-4 alkyl, ( D) -CH ₂ -CO-HC ¹¹ K ¹¹ or (d) 3,3,3-trifluoropropyl; provided that K ² and K ¹² in the formula (III) do not simultaneously mean hydrogen; and provided that the above K ² and K ¹² together can form a heterocycle selected from piperidine, pyrrolidine, morpholine, piperazine, thiomorpholine, and provided that when K ² and K ¹² together form a piperazine ring, the peripheral nitrogen atom in piperazine may optionally be substituted with C1-4 alkyl or aryl, and wherein the above aryl is substituted in one or more positions with substituents selected from a halogen atom, C _1-4 alkyl, C _1-4 alkoxy, cyano, trifluoromethyl; or K ² and K ¹² together form a heteroaromatic ring of formula (VIII) wherein ν is 0, 1 or 2; and also provided that when K ¹⁵ is hydroxy, K ¹⁸ is hydrogen; and its pharmaceutically acceptable salts, hydrates, solvates, geometric isomers, tautomers where P is selected from the substituents of the formulas (P) - (UP) - 95 010298 T’o G * ¹³ \ ^{8 (0} x ^ - ² A A (P) (W) (Iv) (V) k \ A> r ^p or (VI) AK ⁷ (VII) where x, y and _ |, each independently, are selected from 0, 1 and 2; where the dashed lines indicate that K ³ can be attached to either the A or B ring at any carbon atom that can be substituted; K ^{1 is} selected from the group consisting of: (a) C1 _-6 alkyl, (b) C 1 _-6 alkoxy-C _2-6 alkyl, (c) _C3-6 alkenyl, (6) hydroxy-C2-6 alkyl, (e) halo -C1 _-6- alkyl, (ί) aryl, (e) arylcarbonylmethyl, (b) aryl-C _3-6 -alkenyl, (ί) aryl-C1 _-6- alkyl, (Ϊ) C _3-7 -cycloalkyl, (k) heteroaryl, (o) heteroaryl- _C1-6 alkyl, wherein any heteroaryl or aryl residue, one or as part of another group, may optionally be independently substituted at one or more positions with a substituent selected from the group consisting of: (b) halogen, (c) _C1-6 alkyl, (6) hydroxy, (e) _C1-6 alkoxy, (ί) C2-6 alkenyl, (e) C _2-3 alkynyl, (b) phenyl, (ί) phenoxy, (Ϊ) benzyloxy, (k) benzoyl, (l) benzyl, (t) -OSR3, (n) -SY, (o) hydroxy-C1 _-6 -alkyl, (p) C1 _{- 6-} alkoxy-C1 _-6- alkyl, (ς) halogen-C1 _-6- alkyl, (g) -YK ⁹ K ⁹ , (8) -YO2, (1) -SYNK ⁹ K ⁹ , (and) -YK ⁷ SOK ¹⁰ , (ν) -С (= О) К ¹⁰ , (х) С1 _-6- alkoxycarbonyl, (у) С1 _-6- alkylthio, (ζ) -8СР3, (aa) -СНР = СН2, (ab ) methylsulfonyl or (ac) -COOH, provided that when the substituent of the above aryl or heteroaryl residue is selected from the group consisting of phenyl, phenoxy, benzyloxy, benzoyl and benzyl, its phenyl ring may be optionally substituted by one or more halogen, C1 _-4 alkyl, C1 _-4 -alkylthio, C _1. 4-alkoxy, cyano or trifluoromethyl; - 96 010298 K ^{2 is} selected from the group consisting of: (a) hydrogen, (b) C _1- b-alkyl, (c) C _1- b-alkoxy-C _2- b-alkyl, (ά) hydroxy-C _2- b-alkyl, (e) - (CH ₂ ) _t -CH ₂ -P, where t is 2-4, or (d) C _1-4 -alkylsulfonyl, provided that P is selected from the substituents of formula (ν); and ^ 2 each independently selected from the group consisting of: (a) hydrogen, (b) halogen, (c) C _1- b-alkyl, (a) hydroxy, (e) C _1- b-alkoxy, (ί) C _1- b-alkylthio, (e) C2- 6-alkenyl, (t) -OSRE, (p) -SI, (o) hydroxy-C _1-6 -alkyl, (p) C _1-6- alkoxy-C _1-6 -alkyl, (c |) halogen -C _1-6 -alkyl, (g) -COIC ⁹ K ⁹ , (h) -C (= O) K ¹⁰ , (ΐ) С _1- b-alkoxycarbonyl, (i) -8СР ₃ or (ν) - CHP = CH2, provided that when and ^ _{2 is} not selected from the group consisting of hydroxy, methoxy, methyl and a halogen atom, at least one of ^ ₁ and ^ ₂ means hydrogen; K ³ is a group selected from: - 97 010298 where n = 0, 1, 2 or 3, r = 0, 1 or 2, o = 1, 2 or 3, p = 1 or 2, s = 2 or 3, 1 = 0 or 1, ΐ ₂ = 0 or 1, £ = 1, 2, 3 or 4 and £ 1 = 1, 2 or 4; X 'is selected from ΝΕ ⁷ and 8; X _{2 is} selected from O, ΝΕ ⁷ and 8, provided that when ΐ ₂ = 0 and 8 = 2, then X _{2 is} selected from ΝΕ ⁷ and 8; X _{3 is} selected from ΝΕ ⁷ and 8, provided that X ₃ means 8 when r = 1; X _{4 is} selected from O, ΝΕ ⁷ and 8, provided that X4 is selected from ΝΕ ⁷ and 8 when £ is selected from 2 and 3, and K ^{6 is} simultaneously selected from hydrogen and C4-alkyl; when P means a group selected from substituents of the formulas (ν) - (νΠ), and K ³ , in addition, is selected from the following groups: where r = 0, 1 or 2, o = 1, 2 or 3, p, each independently, means 1 or 2, 8 = 2 or 3 and £ = 1, 2, 3 or 4; K ^{4 is} selected from the group consisting of: (a) hydrogen, (b) C1 _-6 alkyl, (c) 2-cyanoethyl, (b) hydroxy-C _2-6 -alkyl, (e) C _3-6 alkenyl, (£) S3-6- alkynyl, (d) C3-7 cycloalkyl, (e) C _3-7 cycloalkyl-C1 _-4 -alkyl, (ΐ) C1 _-6 -alkoxy-C _2-6 -alkyl, (1) -SΗ ₂ - CO-N-K ¹¹ K ¹¹ or (t) 3,3,3-trifluoropropyl; K ^{5 is} selected from the group consisting of: (a) hydrogen, (b) C1 _-4 alkyl, (c) hydroxy-C1 _-4 -alkyl, (b) C1 _-4 -alkoksimetila, (f) halo-C1 _-4 -alkyl, (ί) -YAK ¹¹ K ¹¹ , (E) hydroxyl group, provided that the above hydroxyl group is not attached to the carbon atom adjacent to the ring nitrogen atom, or (ΐ) fluorine, provided that the above fluorine atom is not attached to the carbon atom adjacent to ring nitrogen atom; K ^{6 is} selected from the group consisting of: (a) hydrogen, (b) C1 _-4 alkyl, (c) hydroxy-C1 _-4 -alkyl, (b) C1 _-4 alkoxy-C1 _-4 -alkyl, (e) a hydroxyl group, with the proviso that the above hydroxyl group is not attached - 98 010298 to the carbon atom adjacent to the nitrogen atom of the heterocycle; (£) fluorine, provided that the above fluorine atom is not attached to a carbon atom adjacent to the nitrogen atom of the ring; or (e) halogen-C1-4alkyl; K ⁷ , each independently, is selected from the group consisting of: (a) hydrogen, provided that K ⁷ does not mean hydrogen when g is simultaneously present and the above g means 1 or 2, (b) C1 _-4 alkyl, (c) hydroxy-C2-4 alkyl, or (s) methoxy C2-4 alkyl; To ⁸ , each independently, is selected from: (a) hydrogen or (b) C1 _-4 -alkyl, with the proviso that when simultaneously two K ⁸ are C1 _-4 -alkyl, C1 _-4 -alkyl as defined above may be attached to the same or different carbon atoms, or when two groups are on the same carbon atom, they can together form a cyclopropane ring; To ⁹ , each independently, is selected from: (a) hydrogen, (b) C1 _-6 alkyl, (c) C3-7 tskloalkila or ⁹ wherein the two groups K together with the nitrogen atom to which they are attached, form a heterocycle; and provided that when the two K ⁹ groups form a piperazine ring, the nitrogen atom of the above piperazine ring, which may be substituted, may optionally be substituted with C1-4 alkyl; and provided that when two K ⁹ groups form a piperidine ring, any carbon atom in the above piperidine ring may optionally be substituted with methyl; K ¹⁰ choose from: (a) C1-6 alkyl, (c) aryl or (s) heteroaryl, where heteroaryl or aryl may optionally be substituted at one or more positions with substituents selected from a halogen atom, C1-4 alkyl, C1-4 alkoxy cyano trifluoromethyl; To ¹¹ , each independently, is selected from: (a) hydrogen, (b) methyl, or (c) ethyl, with the proviso that K ¹¹ is in the K ⁴ or K ²⁶ group meaning —SCH — CO — H — KZ'K ¹¹ ; K ^{12 is} selected from the group consisting of: (a) hydrogen, (b) C1 _-6 alkyl, (c) aryl, (d) aryl-C1 _-6 -alkyl, (e) C3-7 cycloalkyl, (£) Cs _-7 cycloalkyl-C1 _{- 4-} alkyl, (e) heteroaryl or (I) heteroaryl- _C1-6 alkyl, where any heteroaryl or aryl residue, one or as part of another group, may optionally be independently substituted at one or more positions with substituents selected from the group, consisting of: (b) halogen, (c) C1-6 alkyl, (i) hydroxy, (e) C1-6 alkoxy, (£) C2-6 alkenyl, (e) C2-3 alkynyl, (I) phenyl , (ί) phenoxy, (ί) benzyloxy, (k) benzoyl, (l) benzyl, (t) -ОСО ₃ , (η) -ΟΝ, (o) hydroxy-С1 _-6- alkyl, (p) С1 _{- 6-} alkoxy-C _2-6 -alkyl, - 99 010298 (s. |) Halogen-C1 _-6- alkyl, (g) -hick, (8) -ΝΟ ₂ , (ΐ) -coic ⁹ to ⁹ , (i) -IR ⁷ SOK ¹⁰ , (ν) -С (= О) К ¹⁰ , (x) С1 _-6- alkoxycarbonyl, (y) С1 _-6- alkylthio, (ζ) -§С? 3, (aa) <ΗΤ = ΟΗ ₂ , (ab) methylsulfonyl or (ac) -COO11, provided that when a substituent of the above aryl or heteroaryl residue is selected from the group consisting of phenyl, phenoxy, benzyloxy, benzoyl and benzyl, its phenyl ring may optionally be substituted with one or more halogen atoms, C _{1- 4-} alkyl, C _1-4 -alkoxy, cyano or trifluoromethyl; K ^{13 is} selected from the group consisting of: (a) C1 _-6 alkyl, (b) C3-6 cycloalkyl, (c) aryl, (b) heteroaryl, (e) aryl-C1 _-2 -alkyl or (£) heteroaryl-C 1 _-2 alkyl, wherein any aryl or heteroaryl residue may be optionally substituted in one or more positions with substituents selected from halogen, C1 _-4 alkyl, C1 _-4 alkoxy, cyano, trifluoromethyl, and acetyl; K ^{14 is} selected from the group consisting of: (a) aryl, (b) heteroaryl, (c) aryl-C1 _-3 alkyl, or (b) heteroaryl-C1 _-3 alkyl, wherein any aryl or heteroaryl residue may be substituted at one or more positions with substituents selected from a halogen atom, a C1 _-4 alkyl, C1 _-4 alkoxy, cyano and trifluoromethyl; To ²⁰ , each independently, is selected from: (a) hydrogen or (b) methyl, provided that when ΐ ₂ = 1, K ²⁰ means Η; K ²¹ and K ²² , each independently, are selected from: (a) hydrogen or (b) methyl, 11 11 21 22 provided that when present simultaneously with K, at least two of K, K and K are hydrogen; K ^{23 is} selected from the group consisting of: (a) hydroxy-C1 _-4 -alkyl, (b) C1-4 alkoxymethyl or (c) halo-C1 _-4 -alkyl; To ²⁵ , each independently, is selected from the group consisting of: (a) hydrogen, (b) C1 _-4 alkyl, (c) hydroxy-C1 _-4 -alkyl, (b) C1 _-4 alkoxy-C1 _-4 -alkyl or (e) fluoromethyl; with the proviso that when simultaneously both K ^{25 are} C 1-4 alkyl, the aforementioned C 1-4 alkyls may be attached to the same or different carbon atoms; and also provided that one K ^{25 is} selected from hydroxy-C 1-4 alkyl, C _1-4 alkoxy-C _1-4 alkyl, and fluoromethyl, the other K ²⁵ is hydrogen; K ^{26 is} selected from the group consisting of: (a) 2-cyanoethyl, (b) C3-6 alkenyl, (c) C3-6 alkynyl, (b) C3-7 cycloalkyl, (e) C _3-7 cycloalkyl-C1 _-4 -alkyl, - 100 010298 (£) -CΗ ₂ -CO-NK ¹¹ K ¹¹ or (e) 3,3,3-trifluoropropyl; and provided that K ² and K ¹² in the formula (III) do not simultaneously mean hydrogen; and provided that the above K ² and K ¹² together can form a heterocycle selected from piperidine, pyrrolidine, morpholine, piperazine, thiomorpholine, and provided that when K ² and K ¹² together form a piperazine ring, the peripheral nitrogen atom in piperazine may optionally be substituted with C _1-4 alkyl or aryl, and wherein the above aryl may be optionally substituted at one or more positions with substituents selected from a halogen atom, C _1-6 alkyl, C ₁ alkoxy, cyano, trifluoromethyl; or K ² and K ¹² together form a heteroaromatic ring of formula (VIII) where ν is 0 or 1. 3. The compound according to claim 1 or 2, where P is selected from the substituents of formulas (P) - (Y) ίο η Ν-Κ L OU ^to \ > or> (P) (W) (Iv) (V) where x means 2, y means 0 and _ | means 1; K ^{1 is} selected from the group consisting of: (£) aryl, (1) S1_ _{aryl-3-alkyl,} (k) heteroaryl, (o) heteroaryl-S1_ ₃ alkyl, wherein any aryl or heteroaryl residue, alone or as part of another group may be optionally substituted independently in one or more positions with a substituent selected from the group consisting of: (b) halogen, (c) S1_ ₄ alkyl, (b) hydroxy, (e) S1_ ₄ -alkoxy, (t) -OSR _3, (η) -SCH (o) hydroxy-C1. _4- alkyl, (p) С _1- 2-alkoxy-С _1-2 -alkyl, (ς) halogen-С1_ ₃ -alkyl, (g)-^ ⁹ ^ (l) -СОККИ ⁹ , (и) - \ 1 \ CO | _3, (ν) -C (= O) To ¹⁰ (x) S1_ ₃ -alkoxycarbonyl, (y) S1_ ₃ -alkylthio or (ab) methylsulfonyl; K ² choose from: (a) hydrogen, (b) S1_ ₄ alkyl; and ^ ₂ each independently selected from the group consisting of: (a) hydrogen, (b) halogen, (c) Cu, alkyl, (b) hydroxy, (e) S1_ ₄ -alkoxy, (£) S1_ ₄ -alkylthio, (t) -OSR3, (η) ΛΝ, ( o) hydroxy-C1. ₂ -alkyl, (p) C1. ₂ -alkoxy S1_ ₂ alkyl, (I) -SR3, - 101 010298 (g) ΧΟΝ ^ ^9, (h) acetyl, (ΐ) C1 _-4 -alkoxycarbonyl, or with the proviso that, when ^ _'1 and \\' ₂ are not selected from the group consisting of methoxy, methyl, and a halogen atom, at least one of ^ ' ₁ and \ Y ₂ means hydrogen; K ³ is a group selected from: where n = 0, 1, 2 or 3, r means 0, 1 or 2, o = 1, 2 or 3, p means 1 or 2, s = 2 or 3, ΐ = 0 or 1, ΐ2 = 0 or 1 and ί = 1, 2, 3 or 4; X! selected from ΝΗ ⁷ and 8; X _{2 is} selected from O, ΝΗ ⁷ and 8, provided that X _{2 is} selected from ΝΗ ⁷ and 8 when ΐ = 0 and 8 = 2; X _{3 is} selected from ΝΗ ⁷ and 8, provided that X ₃ means 8 when r = 1; X is selected from O, ΝΗ ⁷ and 8, provided that X4 is selected from ΝΗ ⁷ and 8 when ί is selected from 2 and 3, and K ^{6 is} simultaneously selected from hydrogen and C1-4 alkyl; or when P means a group selected from substituents of the formula (V), where] = 1 and K ³ also means the following group: T ^ ΝΓ K ⁷ K ^{4 is} selected from the group consisting of: (a) hydrogen, (b) C1-4 alkyl, (b) hydroxy-C2-4 alkyl, - 102 010298 (d) C3-6 cycloalkyl, (1) a C _3-6 -cycloalkyl-C1 _-4 -alkyl, (ί) C1 _-4 alkoxy-C _2-4 -alkyl, or (t) 3,3 3-trifluoropropyl; In ⁵ choose from the group consisting of: (a) hydrogen, (b) C1 _-4 alkyl, (c) hydroxy-C1 _-4 -alkyl, (b) C1 _-4 -alkoksimetila, (f) halo-C1 _-4 -alkyl, (D) -YV ¹¹ B ¹¹ , (e) a hydroxyl group, provided that the above hydroxyl group is not attached to the carbon atom adjacent to the ring nitrogen atom, or (1) fluorine, provided that the above fluorine atom is not attached to the carbon atom adjacent to ring nitrogen atom; In ⁶ choose from the group consisting of: (a) hydrogen, (b) C1 _-4 alkyl, (c) hydroxy-C1 _-4 -alkyl, (b) C1 _-4 alkoxy-C1 _-4 -alkyl, (e) a hydroxyl group, with the proviso that the above hydroxyl group is not attached to the carbon atom adjacent to the nitrogen atom of the heterocycle; (D) fluorine, provided that the above fluorine atom is not attached to a carbon atom adjacent to the nitrogen atom of the ring; or (d) halo-C1 _-4 -alkyl; In ⁷ , each independently, is selected from the group consisting of: (a) hydrogen, with the proviso that B ⁷ is not hydrogen when simultaneously present above and g r is 1 or 2, (b) C1 _-4 alkyl, (c) hydroxy-C2-4 alkyl, or (b) methoxy C2-4 alkyl; At ⁸ , each independently, is selected from: (a) hydrogen or (b) C1 _-4 alkyl, and provided that when both simultaneously at ⁸ are C1 _-4 -alkyl, C1 _-4 -alkyl as defined above may be attached to the same or different carbon atoms , or, when two groups are on the same carbon atom, they can together form a cyclopropane ring; At ⁹ , each independently, is selected from: (a) hydrogen, (b) _C1-6 alkyl, or where two ^B9 groups together with the nitrogen atom to which they are attached form a heterocycle; and provided that when two B ⁹ groups form a piperazine ring, the nitrogen atom of the above piperazine ring, which may be substituted, is optionally substituted with C1-4 alkyl; At ¹⁰ choose from: (a) C1 _-6 alkyl, (c) aryl, or (b) heteroaryl, wherein aryl or heteroaryl may be optionally substituted in one or more positions with substituents selected from halogen, C _1-4 -alkyl, C _1-4 alkoxy, cyano, trifluoromethyl; At ¹¹ , each independently, is selected from: (a) hydrogen, (b) methyl or (c) ethyl, provided that B ¹¹ is in group B ²⁶ meaning —CH ₂ —CO — S — B ¹¹ B ¹¹ ; ^{12 is} selected from the group consisting of: (a) hydrogen, (c) aryl, (b) aryl-C1 _-3 -alkyl, (d) heteroaryl, or (1) heteroaryl-C1 _-3 alkyl, wherein any aryl or heteroaryl residue, alone or as part of another group may optionally be independently substituted at one or more positions with substituents selected from the group consisting of: - 103 010298 (b) halogen, (c) C1 _-4 alkyl, (ά) hydroxy, (e) C 1 _-4 alkoxy, (t) -OSE3 (n) -0Ν, (o) hydroxy-C 1 _{- 3} -alkyl, (p) С1 _-3- alkoxy-С1 _-3- alkyl, (с. |) Halogen-С1 _-4- alkyl, (g) -ΝΗ ^ ⁹ , (ΐ) -CONK ⁹ K ⁹ , ( i) -ΝΠ JUICE. (ν) -C (= O) K ¹⁰ , (x) C _1-3 -alkylthio or (aB) methylsulfonyl; K ^{13 is} selected from the group consisting of: (c) aryl, (ά) heteroaryl, (e) aryl-C1 _-2 alkyl or (ί) heteroaryl-C1 _-2- alkyl, wherein any heteroaryl or aryl residue may be optionally substituted at one or more positions with substituents selected from halogen, C1 _-4 alkyl, C1 _-4 alkoxy, cyano, trifluoromethyl, and acetyl; K ^{14 is} selected from the group consisting of: (a) aryl, (b) heteroaryl, (c) aryl-C1 _-3 alkyl or (ά) heteroaryl-C1 _-3 alkyl, wherein any aryl or heteroaryl residue may be optionally substituted in one or more positions with substituents selected from a halogen atom, C1-4 alkyl, C1-4 alkoxy, cyano and trifluoromethyl; K ²¹ and K ²² , each independently, are selected from: (a) hydrogen or (b) methyl, 11 11 21 22 provided that when present simultaneously with K, at least two of K, K and K are hydrogen; K ²³ choose from: (a) hydroxy-C1 _-4 -alkyl, (b) C1-4 alkoxymethyl or (c) halo-C1 _-4 -alkyl; K ^{25 is} selected from the group consisting of: (a) hydrogen, (b) C1 _-4 alkyl, (c) hydroxy-C1 _-4 -alkyl, (ά) C1 _-4 alkoxy-C1 _-4 -alkyl or (e) fluoromethyl; with the proviso that when both K ^{25 are} simultaneously C 1-4 alkyl, the above C 1-4 alkyls may be attached to the same or different carbon atoms; and also provided that when one K ^{25 is} selected from hydroxy-C! -4-alkyl, C _{! -4-} alkoxy-C _{! -4-} alkyl and fluoromethyl, the other K ²⁵ is hydrogen; K ^{26 is} selected from the group consisting of: (e) C _3-7 -cycloalkyl-C1 _-4 -alkyl, (ί) -СЩ-СО-КГК. ¹¹ ^ ¹ or (d) 3,3,3-trifluoropropyl; provided that K ² and K ¹² in the formula (III) do not simultaneously mean hydrogen; and also provided that the above K ² and K ¹² together can form a heterocycle selected from piperidine, pyrrolidine, morpholine, piperazine, thiomorpholine, and provided that when K ² and K ¹² together form a piperazine ring, the peripheral nitrogen atom in piperazinyl can be optionally substituted with C1 _-4 alkyl or aryl, and wherein said aryl being optionally substituted at one or more positions with substituents selected from halogen, C1 _-4 alkyl, C1 _-4 alkoxy, cyano, trifluoromethyl; or K ² and K ¹² together form a heteroaromatic ring of formula (VIII): - 104 010298 where ν means 0 or 1. 4. The compound according to any one of claims 1 to 3, which has the General formula (XII) 5. The compound according to claim 4, where P is selected from the substituents of the formulas (Π ^ -Ον) E ° ₂ ? ^with about 2 M SG> ' 3 (0), (P) (W) (Iv) x is 2 and y is 0; K ¹ is selected from aryl and heteroaryl, wherein any aryl or heteroaryl residue may be optionally substituted independently at one or more positions with substituents selected from halogen, S1_ ₄ -alkyl, S1_ ₄ -alkoxy and trifluoromethyl; K ² means hydrogen; and mean hydrogen; K ³ means a group selected from: where p = 1 or 2, K ⁴ choose from: (a) hydrogen or (b) S1_ ₄ alkyl; - 105 010298 To ¹¹ , each independently, is selected from: (a) hydrogen; (b) methyl; (c) ethyl, provided that K ¹¹ is in the K ²⁶ group meaning —CH ₂ —C0 — No. — K ¹¹ K ¹¹ ; K ¹² and K ¹³ each independently selected from aryl and heteroaryl; wherein any aryl or heteroaryl residue may be optionally substituted independently at one or more positions with a substituent selected from halogen, C1 _-4 -alkyl, C1 _-4 -alkoxy and CF3; K ²⁵ choose from: (a) hydrogen or (b) C1-4 alkyl; K ^{26 is} selected from the group consisting of: (e) C _3-7 cycloalkyl-C _2-4 alkyl, (£) -CH ₂ -c0 ^QC-n at ¹¹ or (d) 3,3,3-trifluoropropyl. 6. The compound according to claim 5, where K ¹ , K ¹² and K ¹³ are each independently selected from phenyl or substituted phenyl selected from the group consisting of 2-methoxy-5-methylphenyl, 2-methylphenyl, 4-methylphenyl, 4-fluorophenyl, 3,4-dimethoxyphenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2,6-dichlorophenyl, 3-chloro-4-methylphenyl, 3-methylphenyl, 3,6-dichloro-2-methylphenyl and 2-chloro-5- fluorophenyl; or selected from heteroaryl or substituted heteroaryl selected from 2-thienyl, 5-chloro-2-thienyl, 5-chloro and 1,3dimethyl-1H-pyrazol-4-yl; and K ² means hydrogen. 7. The compound according to any one of paragraphs.5-6, where K ³ represents a group selected from where K ⁴ each independently selected from: (a) hydrogen or (b) methyl; To ¹¹ , each independently, is selected from: (a) hydrogen or (b) methyl; To ²⁵ , each independently, is selected from: (a) hydrogen; or (b) methyl. 8. The compound according to claim 5, where K ^{4 are} independently selected from: (a) hydrogen; (b) methyl; or (c) ethyl. 9. The compound according to any one of claims 5 to 8, where K ⁴ or K ¹¹ means hydrogen. 10. The compound according to any one of claims 1 to 3, which has the General formula (X) ^g (X) 11. The compound of claim 10, where P is selected from the substituents of the formulas (ΙΙ) - (ΐν) - 106 010298 (Π) (W) (IV) where x means 2 and y means 0; I ¹ is selected from aryl and heteroaryl, wherein any aryl or heteroaryl residue may be optionally substituted independently at one or more positions with a substituent selected from halogen, C1 _-4 alkyl, trifluoromethoxy and Cp ₄ -alkoxy; I ² means hydrogen; and W ₂ mean hydrogen; I ³ means a group selected from where I ⁴ , each independently, selected from: (a) hydrogen or (b) C1 _-4 alkyl; I am ²⁵ , each independently, choose from: (a) hydrogen or (b) C1 _-4 -alkyl, with the proviso that when both I ²⁵ are C1 _-4 -alkyl, C _1-4 alkyls as defined above may be attached to the same or different carbon atoms; I ¹² and I ¹³ , each independently, are selected from aryl and heteroaryl, where any heteroaryl or aryl residue may optionally be independently substituted at one or more positions with a substituent selected from a halogen atom, Cp ₄ alkyl, trifluoromethyl and Cp ₄ alkoxy. 12. The compound according to claim 11, where P is selected from a substituent of formula (II) I ¹ means 2-methoxy-5-methylphenyl; I ² means hydrogen; and W ₂ mean hydrogen; I ³ means a group selected from I ⁴ , each independently, choose from: (a) hydrogen or (b) methyl; I am ²⁵ , each independently, choose from: (a) hydrogen; or (b) methyl. 13. The compound according to any one of claims 1 to 12, which is selected from Y- (7- {methyl [3- (methylamino) propyl] amino} -1-benzofuran-5-yl) benzenesulfonamide hydrochloride, Y- (7-piperidine- 1-yl-1-benzofuran-5-yl) benzenesulfonamide, 4-fluoro-Y- (7-piperidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide, 3.4- dimethoxy-Y- (7-piperidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride, 3.4- dimethoxy-Y- (7-pyrrolidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide, Y- (7-pyrrolidin-1-yl-1-benzofuran-5-yl) benzene sulfonamide, 4-fluoro-Y- (7-pyrrolidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride, 4-fluoro- Y- (7-morpholin-4-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride, Y- (7-morpholin-4-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride, - 107 010298 3,4-dimethoxy-X- (7-morpholin-4-yl-1-benzofuran-5-yl) benzenesulfonamide, 2-methoxy-5-methyl-X- (7-pyridin-4-yl-1-benzofuran-5-yl) benzenesulfonamide, X- (7-pyridin-3-yl-1-benzofuran-5-yl) benzenesulfonamide trifluoroacetate, 2-methoxy-5-methyl-X- (7-pyridin-3-yl-1-benzofuran-5-yl) benzenesulfonamide trifluoroacetate, X- (7-pyrazin-2-yl-1-benzofuran-5-yl) benzenesulfonamide trifluoroacetate, X- (7-pyrimidin-5-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride and X- [7- (1-azabicyclo [2.2.2] oct-2-en-3-yl) benzofuran-5-yl] -2-methoxy-5-methylbenzenesulfonamide hydrochloride, 2- [4- (5 - {[(2-chlorophenyl) sulfonyl] amino} -1-benzofuran-7-yl) piperazin-1-yl] -X, diethylacetamide hydrochloride, X, X-diethyl-2- [4- (5- {[(2-methoxy-5-methylphenyl) sulfonyl] amino} -1-benzofuran-7-yl) piperazin-1yl] acetamide hydrochloride, X- [7- (1-azabicyclo [2.2.2] oct-3-yloxy) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride, X- [7- (1-azabicyclo [2.2.2] oct-3-yloxy) -1-benzofuran-5-yl] -2-chlorobenzenesulfonamide hydrochloride, X- [7- (1-azabicyclo [2.2.2] oct-3-yloxy) -1-benzofuran-5-yl] -2-methoxy-5benzenesulfonamide hydrochloride, X- {7 - [(2-morpholin-4-yl-ethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride, 2-methoxy-5-methyl-X- {7 - [(2-morpholin-4-yl-ethyl) amino] -1-benzofuran-5yl} benzenesulfonamide hydrochloride, X- {7 - [(2-morpholin-4-yl-ethyl) amino] -1-benzofuran-5-yl} -2 (trifluoromethyl) benzenesulfonamide hydrochloride, 2,6-dichloro-X- {7 - [(2-morpholin-4-yl-ethyl) amino] -1-benzofuran-5yl} benzenesulfonamide hydrochloride, X- (7 - {[2- (dimethylamino) ethyl] amino} -1-benzofuran-5-yl) -2-methoxy-5benzenesulfonamide hydrochloride, 2-chloro-X- (7- {2- (dimethylamino)} - 1-benzofuran-5-yl) benzenesulfonamide hydrochloride, X- [7- (pyridin-4-ylamino) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride, 2-chloro-X- [7- (pyridin-4-ylamino) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride, 2-methoxy-5-methyl-X- [7- (pyridin-4-ylamino) -1- benzofuran-5yl] benzenesulfonamide hydrochloride, 2-methoxy-5-methyl-X- [7- (piperazin-1-ylcarbonyl) -1-benzofuran-5yl] benzenesulfonamide hydrochloride, 2-methoxy-5-methyl-X- [7- (piperazin-1-ylmethyl) -1-benzofuran-5yl] benzenesulfonamide hydrochloride, X- {7 - [(3-aminopyrrolidin-1-yl) methyl] -1-benzofuran-5-yl} -2-methoxy-5methylbenzenesulfonamide hydrochloride, X- [7- (6,6-dioxohexahydrothieno [3,4-b] pyrazin-1- (2H) -yl) -1-benzofuran-5-yl] -2-methoxy-5methylbenzenesulfonamide hydrochloride, X- [7- (6,6-dioxohexahydrothieno [3,4-b] pyrazin-1- (2H) -yl) -1-benzofuran-5yl] benzenesulfonamide hydrochloride, X- {7 - [(2-pyrrolidin-1-ethyl-ethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride, 2- methoxy-5-methyl-X- {7 - [(2-pyrrolidin-1-ethyl) amino] - 1-benzofuran-5 yl} benzenesulfonamide hydrochloride, X- {7 - [(2-pyrrolidin-1-ethylethyl) amino] -1-benzofuran-5-yl} -2 (trifluoromethyl) benzenesulfonamide hydrochloride, 3- chloro- 4-methyl-X- {7 - [(2-pyrrolidin-1-ethylethyl) amino] -1-benzofuran-5yl} benzenesulfonamide hydrochloride, 2- methoxy-5-methyl-X- {7 - [(3-morpholin-4-ylpropyl) amino] -1-benzofuran-5yl} benzenesulfonamide hydrochloride, X- {7 - [(3-morpholin-4-ylpropyl) amino] -1-benzofuran-5-yl} -2 (trifluoromethyl) benzenesulfonamide hydrochloride, 3- chloro-4-methyl-X- {7 - [(3-morpholin-4-ylpropyl) amino] -1-benzofuran-5yl} benzenesulfonamide hydrochloride, X- [7 - ({[(2K) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5yl] benzenesulfonamide hydrochloride, X- [7 - ({[(2K) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -2-methoxy-5methylbenzenesulfonamide hydrochloride, X- [7 - ({[(2K) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -2 (trifluoromethyl) benzenesulfonamide hydrochloride, X- [7 - ({[(2K) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -3methylbenzenesulfonamide hydrochloride, - 108 010298 No. [7 - ({[((2K) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] thiophen-2sulfonamide hydrochloride, 3-chloro-I- [7 - ({[((2K) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] thiophen-2sulfonamide hydrochloride, 5-chloro-I- [7 - ({[((2K) -1-ethylpyrrolidin-2-yl] methyl} amino} -1-benzofuran-5-yl] -1,3-dimethyl-1Npyrazol-4-sulfonamide hydrochloride, Ν- (7- {[3 - (2-methylpiperidin-1-yl) propyl] amino} -1-benzofuran-5yl) benzenesulfonamide hydrochloride, 2-methoxy-5-methyl-Y- (7 - {[3- (2-methylpiperidin-1-yl) propyl] amino} -1-benzofuran-5yl) benzenesulfonamide hydrochloride, Ν- (7- {[3 - (2-methylpiperidin-1-yl) propyl] amino} -1-benzofuran-5-yl) -2 (trifluoromethyl) benzenesulfonamide hydrochloride, 5-chloro-1,3-dimethyl-I- (7 - {[3- (2-methylpiperidin-1-yl) propyl] amino} -1-benzofuran-5-yl) -1Npyrazol-4-sulfonamide hydrochloride, No. [ 7- ( 6-aminopyridin-3-yl) -1-benzofuran-5-yl] -2-methoxy-5-methylbenzenesulfonamide, Ν- {7- [4- (cyclopropylmethyl) piperazin-1-yl] -1-benzofuran-5-yl} -2-methoxy-5 methylbenzenesulfonamide hydrochloride, 2-methoxy-5-methyl-H- {7- [4- (3,3,3-trifluoropropyl) piperazin-1-yl] -1-benzofuran-5yl} benzenesulfonamide hydrochloride, 2-methoxy-5-methyl-I- {7 - [3 - (trifluoromethyl) piperazin-1-yl] -1-benzofuran-5 yl} benzenesulfonamide hydrochloride, Ν- [7- (aminopiperidin-1-yl) -1-benzofuran-5-yl] -2 (trifluoromethyl) benzenesulfonamide hydrochloride, No. [7- (aminopiperidin-1-yl) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride, No. [7- (aminopiperidin-1-yl) -1-benzofuran-5-yl] -2-chlorobenzenesulfonamide hydrochloride, Ν- [7- (aminopiperidin-1-yl) -1-benzofuran-5-yl] -2-methoxy -5 methylbenzenesulfonamide hydrochloride, No. (7 - {[cis-3-fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl) -2-methoxy-5methylbenzenesulfonamide hydrochloride, No. (7 - {[trans-3-fluoropiperidine- 4-yl] oxy} -1-benzofuran-5-yl) -2-methoxy-5methylbenzenesulfonamide hydrochloride, No. (7 - {[cis-3-fluorop peridin-4-yl] oxy} -1-benzofuran-5-yl) -2 (trifluoromethyl) benzenesulfonamide hydrochloride, No. (7 - {[trans-3-fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl ) -2 (trifluoromethyl) benzenesulfonamide hydrochloride, 2-chloro-I- (7 - {[trans-3-fluoropiperidin-4-yl] oxy} -1-benzofuran-5yl) benzenesulfonamide hydrochloride, No. (7 - {[trans-3-fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl) -3 methylbenzenesulfonamide hydrochloride, 3,6-dichloro-Y- (7 - {[trans-3-fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl) -2 methylbenzenesulfonamide hydrochloride, 2-chloro-5-fluoro-L- (7 - {[trans-3-fluoropiperidin-4-yl] oxy} -1-benzofuran-5yl) benzenesulfonamide hydrochloride, No. (2-methoxy-5-methylphenyl) -7- [ (3-methylpiperazin-1-yl) methyl] -1-benzofuran-5sulfonamide hydrochloride, No. (2-methylphenyl) -7- (piperazin-1-ylmethyl) -1-benzofuran-5-sulfonamide trifluoroacetate, 7 - [(3,5 -dimethylpiperazin-1-yl) methyl] -Y- (2-methylphenyl) -1-benzofuran-5-sulfonamide trifluoroacetate, No. (2-methylphenyl) -7 - [(3-methylpiperazin-1-yl) methyl] - 1-benzofuran- 5-sulfonamide trifluoroacetate, 7- (1,4-diazepan-1-ylmethyl) -I- (2-methylphenyl) -1-benzofuran-5-sulfonamide trifluoroacetate, 7 - {(trans-2,5-dimethylpiperazin-1-yl) methyl} -H- (2-methylphenyl) -1-benzofuran-5sulfonamide trifluoroacetate, No. (2-methylphenyl) -7 - {[(2K) -2- methylpiperazin-1-yl] methyl} -1-benzofuran-5sulfonamide trifluoroacetate, No. (2-methoxy-5-methylphenyl) -7 - [(3-methylpiperazin-1-yl) methyl] -1-benzofuran-5sulfonamide trifluoroacetate, 7- (1,4-diazepan-1-ylmethyl) -H- (2-methoxy-5-methylphenyl) -1-benzofuran-5sulfonamide trifluoroacetate, No. (2-methoxy-5-methylphenyl) -7- (piperazin-1- ilmethyl) -1-benzofuran-5sulfonamide trifluoroacetate, 7 - {(cis-3,5-dimethylpiperazin-1-yl) methyl} -Y- (2-methoxy-5-methylphenyl) -1-benzofuran-5-sulfonamide trifluoroacetate, - 109 010298 7 - {[trans-2,5-dimethylpiperazin-1-yl] methyl} -N- (2-methoxy-5-methylphenyl) -1-benzofuran-5sulfonamide trifluoroacetate, 7 - [(18.48) -2,5-diazabicyclo [2.2.1] hept-2-ylmethyl] -N- (2-methoxy-5-methylphenyl) -1-benzofuran-5sulfonamide trifluoroacetate, N- (2-methoxy-5-methylphenyl) -7 - [(2-methylpiperazin-1-yl) methyl] -1-benzofuran-5sulfonamide trifluoroacetate, 2-chloro-H- [7- (piperazin-1-methylmethyl) -1-benzofuran-5-yl] benzenesulfonamide dihydrochloride, 2-methyl-N- [7- (piperazin-1-ylmethyl) -1-benzofuran-5- il] benzenesulfonamide dihydrochloride, Ν- [7- (piperazin-1-ylmethyl) -1-benzofuran-5-yl] thiophen-2-sulfonamide dihydrochloride, 2-chloro-H- [7- (1,4-diazepan-1-methylmethyl) -1- benzofuran-5-yl] benzenesulfonamide dihydrochloride, N- [7- (1,4-diazepan-1-ylmethyl) -1-benzofuran-5-yl] -2-methylbenzenesulfonamide dihydrochloride, Ν- [7- (1,4-diazepan-1-ylmethyl) -1-benzofuran-5-yl] thiophen-2-sulfonamide dihydrochloride, 2-methoxy-5-methyl-H- {7 - [(2-methylpiperazin-1-yl) methyl] -1-benzofuran-5 yl} benzenesulfonamide dihydrochloride, 2-methyl-H- {7 - [(2-methylpiperazin-1-yl) methyl] -1-benzofuran-5yl} benzenesulfonamide dihydrochloride, 2,5-dichloro-N- {7 - [(2-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} thiophen-3 sulfonamide dihydrochloride, 2-methoxy-5-methyl-H- {7 - [(3-methylpiperazin-1-yl) methyl] -1-benzofuran-5 yl} benzenesulfonamide dihydrochloride, Ν- {7 - [(3-methylpiperazin-1-yl) methyl] - 1-benzofuran-5-yl} -2 (trifluoromethyl) benzenesulfonamide dihydrochloride, 2-chloro-Y- {7 - [(3-methylpiperazin-1-yl) methyl] -1-benzofuran-5yl} benzenesulfonamide dihydrochloride, N- {7 - [(18.48) -2,5-diazabicyclo [2.2.1] hept-2-ylmethyl] -1-benzofuran-5-yl} -2-methoxy-5methylbenzenesulfonamide dihydrochloride, N- {7 - [(I8,48) -2,5-diazabicyclo [2.2.1] hept-2-ylmethyl] -1-benzofuran-5-yl} -2 (trifluoromethyl) benzenesulfonamide dihydrochloride, N- {7 - [(18.48) -2,5-diazabicyclo [2.2.1] hept-2-ylmethyl] -1-benzofuran-5-yl} -2 methylbenzenesulfonamide dihydrochloride, 2-methoxy-5-methyl-N- {7 - [(trans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5yl} benzenesulfonamide bistrifluoroacetate, 2-methyl-N- {7 - [(Ίrans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5yl} benzenesulfonamide bistrifluoroacetate, 2-chloro-N- {7 - [(trans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5yl} benzenesulfonamide bistrifluoroacetate, 1 - ({5 - [(2-methoxy-5-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) piperazine trifluoroacetate, 1- {[5- (phenylsulfonyl) -1-benzofuran-7-yl] methyl} piperazine trifluoroacetate, 1 - ({5 - [(4-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) piperazine trifluoroacetate, 1 - ({5 - [(2-methoxy-5-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) -1,4 diazepantrifluoroacetate, 1- {[5- (phenylsulfonyl) -1-benzofuran-7-yl] methyl} -1,4-diazepantrifluoroacetate, 1 - ({5 - [(4-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) -1,4-diazepantrifluoroacetate, 1 - ({5 - [(2-methoxy-5-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) -2 methylpiperazine trifluoroacetate, 1 - ({5 - [(2-methoxy-5-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) -3 methylpiperazine trifluoroacetate, N- (2-methylphenyl) -7 - {[((3Κ) -pyrrolidin-3-ylamino] methyl} -1-benzofuran-5sulfonamide trifluoroacetate, N- (2-methylphenyl) -7- (piperidin-4-ylmethyl) -1-benzofuran-5-sulfonamide trifluoroacetate, N- (2-methylphenyl) -7- (pyrrolidin-3-ylmethyl) -1-benzofuran-5-sulfonamide trifluoroacetate, N- (2-methylphenyl) -7- (piperidin-3-ylmethyl) -1-benzofuran-5-sulfonamide trifluoroacetate, 2- methoxy-5-methyl-N- [7- (piperidin-4-ylmethyl) -1-benzofuran-5-yl] benzenesulfonamide trifluoroacetate, 3 - ({5 - [(4-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) pyrrolidine trifluoroacetate, 2-methoxy-5-methyl-N- [5- (piperidin-4-ylmethyl) -1- benzofuran-7yl] benzenesulfonamide trifluoroacetate, 2-methoxy-5-methyl-H- {5 - [(3-methylpiperazin-1-yl) methyl] -1-benzofuran-7 yl} benzenesulfonamide bistrifluoroacetate, 2-methoxy-5-methyl-N- [5- (piperidin-4-ylmethyl) -1-benzofuran-7yl] benzenesulfonamide trifluoroacetate. 14. The use of a compound according to any one of claims 1 to 13 for the treatment or prevention of disorders associated with - 110 010298 taken with a 5-HT6 receptor to achieve weight loss and weight gain. 15. The application of clause 14, where the violation is chosen from obesity; type II diabetes; disorders of the central nervous system, such as fear, depression, panic attacks, memory impairment, cognitive impairment, epilepsy, sleep disturbances, migraine, anorexia, bulimia, eating disorders after a plentiful table, obsessive-compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease , Huntington’s chorea, schizophrenia, attention deficit hyperactive disorder, drug discontinuation, neurodegenerative diseases characterized by a slowdown in neuronal growth, and pain. 16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 as an active ingredient in combination with a pharmaceutically acceptable diluent or carrier. 17. The pharmaceutical composition according to clause 16 for use in the prophylaxis or treatment of disorders associated with the 5-HT ₆ receptor, to achieve weight loss and weight gain. 18. The pharmaceutical composition according to clause 16 or 17, where the violation is selected from obesity; type II diabetes; disorders of the central nervous system, such as fear, depression, panic attacks, memory impairment, cognitive impairment, epilepsy, sleep disturbances, migraine, anorexia, bulimia, eating disorders after a plentiful table, obsessive-compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease , Huntington’s chorea, schizophrenia, attention deficit hyperactive disorder, drug discontinuation, neurodegenerative diseases characterized by a slowdown in neuronal growth, and pain. 19. A method of preventing or treating a disorder associated with a 5-HT6 receptor to achieve weight loss and weight gain, comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 13. 20. The method according to claim 19, where the violation is chosen from obesity; type II diabetes; disorders of the central nervous system, such as fear, depression, panic attacks, memory impairment, cognitive impairment, epilepsy, sleep disturbances, migraine, anorexia, bulimia, eating disorders after a plentiful table, obsessive-compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease , Huntington’s chorea, schizophrenia, attention deficit hyperactive disorder, drug discontinuation, neurodegenerative diseases characterized by a slowdown in neural growth, and pain. 21. A method of modulating the activity of a 5-HT ₆ receptor, comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 13. 22. The use of a compound according to any one of claims 1 to 13 for the manufacture of a medicament for use in the prophylaxis or treatment of a disorder associated with a 5-HT ₆ receptor, in order to achieve a reduction in body weight and weight gain. 23. The use of a compound according to claim 22, wherein the disorder is selected from obesity; type II diabetes; disorders of the central nervous system, such as fear, depression, panic attacks, memory impairment, cognitive impairment, epilepsy, sleep disturbances, migraine, anorexia, bulimia, eating disorders after a plentiful table, obsessive-compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease , Huntington’s chorea, schizophrenia, attention deficit hyperactive disorder, drug discontinuation, neurodegenerative diseases characterized by a slowdown in neural growth, and pain. 24. A cosmetic composition comprising a compound according to any one of claims 1 to 13 as an active ingredient in combination with a cosmetically acceptable diluent or carrier. 25. The cosmetic composition according to paragraph 24 for use in the prophylaxis or treatment of disorders associated with the 5-HT6 receptor, to achieve weight loss and weight gain. 26. The cosmetic composition according A.25, where the violation is chosen from obesity; type II diabetes; disorders of the central nervous system, such as fear, depression, panic attacks, memory impairment, cognitive impairment, epilepsy, sleep disturbances, migraine, anorexia, bulimia, eating disorders after a plentiful table, obsessive-compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease , Huntington’s chorea, schizophrenia, attention deficit hyperactive disorder, drug discontinuation, neurodegenerative diseases characterized by a slowdown in neural growth, and pain.