KR20060127886A - Novel benzofuran derivatives can be used for the prevention and treatment of 5-HT6 receptor-related disorders - Google Patents

Abstract

The present invention relates to compounds of formula (I) wherein P, R ³ , W ₁ and W ₂ are as described herein, pharmaceutical compositions containing the compounds, methods for their preparation, and 5-HT ₆ relates to the use of a compound for the manufacture of a medicament for a receptor-related disorder.

Description

NOVEL BENZOFURAN DERIVATIVES, WHICH CAN BE USED IN PROPHYLAXIS OR TREATMENT OF 5-HT6 RECEPTOR-RELATED DISORDER}

The present invention relates to novel compounds, pharmaceutical compositions containing the compounds, methods for their preparation, and the use of the compounds for the preparation of medicaments for 5-HT ₆ receptor-related disorders.

Obesity is a condition characterized by an increase in body fat content resulting in excess body weight above the acceptable standard. Obesity is the most important nutritional disorder in the West and represents a major health problem in all industrialized countries. This disorder results in increased mortality due to the development of diseases such as cardiovascular disease, digestive system disease, respiratory disease, cancer and type 2 diabetes. The search for compounds that reduce weight has been conducted for decades. One series of studies has been the activation of the serotonergic system by direct activation of serotonin receptor subtypes or inhibition of serotonin reuptake. However, the exact receptor subtype profile required is unknown.

Serotonin (5-hydroxytrytamine or 5-HT), the major transporter of the peripheral and central nervous systems, regulates a wide range of physiological and pathological functions including anxiety, sleep control, aggression, food intake and depression. Many serotonin receptor subtypes have been identified and cloned. One of these, 5-HT ₆ receptor, was cloned by several groups in 1993 (Ruat, M. et al. (1993) Biochem. Biophys. Res. Commun. 193: 268-276; Sebben, M. et. al. (1994) NeuroReport 5: 2553-2557). This receptor positively couples to adenylyl cyclase to show affinity for antidepressants such as clozapine. Recently, the effects of 5-HT ₆ antagonists and 5-HT ₆ antisense oligonucleotides on reducing food intake in rats have been reported (Bentley, JC et al. (1999) Br J Pharmacol. Suppl. 126, P66; Bentley, JC et al. (1997) J. Psychopharmacol.Suppl.A64, 255; Woolley ML et al. (2001) Neuropharmacology 41: 210-219).

Compounds with improved affinity and selectivity for the 5-HT ₆ receptor are described, for example, in WO 00/34242 and Isaac, M. et al. (2000) 6-Bicyclopiperazinyl-1-arylsulphonylindoles and 6-Bicyclopiperidinyl-1-arylsulphonylindoles derivatives as novel, potent and selective 5-HT ₆ receptor antagonists. Bioorganic & Medicinal Chemistry Letters 10: 1719-1721 (2000), Bioorganic & Medicinal Chemistry Letters 13: 3355-3359 (2003), Expert Opinion Therapeutic Patents 12 (4) 513-527 (2002).

It has been surprisingly found that the compounds according to the invention exhibit affinity for the 5-HT ₆ receptor as antagonists in the nanomolar range. The compounds according to the invention and their pharmaceutically acceptable salts have 5-HT ₆ receptor antagonists, agonists and partial agonist activities, treat and prevent obesity and type 2 diabetes, reduce weight and weight gain, and anxiety Depression, panic attacks, memory disorders, cognitive impairment, epilepsy, sleep disorders, migraine, anorexia, bulimia, binge eating disorder, obsessive-compulsive disorder, psychosis, Alzheimer's disease, Parkinson's disease, Huntington's chorea and / or schizophrenia, It is thought to be of potential use for the treatment or prevention of central nervous system disorders such as panic attacks, attention deficit hyperactivity disorder (ADHD), withdrawal from drug abuse, neurodegenerative diseases characterized by neuronal cell failure, and pain. . Reduction in body weight and weight gain (eg, treating weight disorders) is particularly achieved by reducing food intake. The term "weight disorder" as used herein refers to a disorder caused by an imbalance between calorie intake and calorie consumption resulting in abnormal (eg, excessive) weight. Such weight disorders include obesity.

Disclosure of the Invention

One object of the present invention is in the form of a compound of formula (I), and pharmaceutically acceptable salts, hydrates, solvates, geometric isomers, tautomers, optical isomers, and drug precursors thereof:

[In the meal,

P is selected from substituents of the formulas (II) to (VII):

In the formula,

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

Wherein the dashed bonds indicate that P and R ³ may be attached to the A or B ring, respectively, at any carbon atom allowing substitution, provided that both P and R ³ are not attached to ring B at the same time;

R ¹ is selected from:

(a) C _1-6- alkyl,

(b) C _1-6 -alkoxy-C _1-6- alkyl,

(c) C _3-6 -alkenyl,

(d) hydroxy-Ci_ ₆ -alkyl,

(e) halo-Ci_ ₆ -alkyl,

(f) aryl,

(g) arylcarbonylmethyl,

(h) aryl-C _3-6 -alkenyl,

(i) aryl-C _1-6 -alkyl,

(j) C _3-7 -cycloalkyl,

(k) heteroaryl,

(l) 4-piperidinyl,

(m) N- substituted 4-piperidinyl (wherein the substituent is C _1-6 - alkyl and aryl -C _1-6 - selected from alkyl),

(o) heteroaryl-C _1-6 -alkyl,

Wherein any heteroaryl or aryl moiety, alone or as part of another group, may be substituted at one or more positions independently with a substituent selected from:

(a) hydrogen,

(b) halogen,

(c) C _1-6 -alkyl,

(d) hydroxy,

(e) C _1-6 -alkoxy,

(f) C _2-6 -alkenyl,

(g) C _2-3 -alkynyl,

(h) phenyl,

(i) phenoxy,

(j) benzyloxy,

(k) benzoyl,

(l) benzyl,

(m) -OCF ₃ ,

(n) -CN,

(o) hydroxy-C _1-6 -alkyl,

(p) C ₁ - ₆ - alkoxy -C _1-6 - alkyl,

(q) halo-Ci_ ₆ -alkyl,

(r) -NR ⁹ R ⁹ ,

(s) -NO ₂ ,

(t) -CONR ⁹ R ⁹ ,

(u) -NR ⁷ COR ¹⁰ ,

(v) -C (= 0) R ¹⁰ ,

(x) C _1-6 -alkoxycarbonyl,

(y) C _1-6 -alkylthio,

(z) -SCF ₃ ,

(aa) -CHF = CH ₂ ,

(ab) methylsulfonyl, or

(ac) -COOH

Provided that when the substituent on the aryl or heteroaryl moiety is selected from phenyl, phenoxy, benzyloxy, benzoyl and benzyl, the phenyl ring thereof is halogen, C _1-4 -alkyl, C _1-4 -alkylthio, C Optionally substituted with one or more of _1-4 -alkoxy, cyano, or trifluoromethyl);

R ² is selected from:

(a) hydrogen,

(b) C _1-6 -alkyl,

(c) C _1-6 -alkoxy-C _2-6 alkyl,

(d) hydroxy-C _2-6 -alkyl,

(e)-(CH ₂ ) _m -CH ₂ -F (wherein m is 2-4),

(f) 3,3,3-trifluoropropyl, or

(g) C _1-4 -alkylsulfonyl, wherein P is selected from substituents of the formula (V);

W ₁ and W ₂ are each independently selected from:

(a) hydrogen,

(b) halogen,

(c) C _1-6 -alkyl,

(d) hydroxy,

(e) C _1-6 -alkoxy,

(f) C _1-6 -alkylthio,

(g) C _2-6 -alkenyl,

(h) phenyl,

(i) phenoxy,

(j) benzyloxy,

(k) benzoyl,

(l) benzyl,

(m) -OCF ₃ ,

(n) -CN,

(o) hydroxy-C _1-6 -alkyl,

(p) C _1-6 -alkoxy-C _1-6 -alkyl,

(q) halo-Ci_ ₆ -alkyl,

(r) -CONR ⁹ R ⁹ ,

(s) -C (= O) R ¹⁰ ,

(t) C _1-6 -alkoxycarbonyl,

(u) -SCF ₃ , or

(v) -CHF = CH ₂

Provided that W ₁ and W ₂ are selected from phenyl, phenoxy, benzoyl, benzyloxy and benzyl, their phenyl rings are halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, or tri If may be optionally substituted with one or more of the fluoromethyl, and that the W ₁ and W _2-methoxy, is selected from methyl and halogen, at least one of W ₁ and W ₂ selected from hydrogen);

R ³ is H when P is a substituent of formula (II), wherein R ¹ is N-substituted 4-piperidinyl, or R ³ is a group selected from:

R ³ is also a group selected from:

Additionally it may be a group selected from:

-O- (C = NH) NR ¹¹ R ¹¹ , or

-(CH ₂ ) _n -O-NH (C = NH) -NR ¹¹ R ¹¹

here,

n = 0, 1, 2 or 3

r is each independently 0, 1 or 2,

o = 1, 2, or 3,

p is each independently 1 or 2,

s = 2 or 3,

t = 0 or 1,

t ₁ = 1 or 2,

t ₂ = 0 or 1,

f = 1, 2, 3 or 4, and

f ₁ = 1, 2 or 4;

(Where r is not 0 when t ₁ and p are 1 at the same time);

X is selected from O, NR ⁷ and S;

X ₁ is selected from NR ⁷ and S;

X ₂ is selected from O, NR ⁷ and S, provided that X ₂ is selected from NR ⁷ and S when t ₂ = 0;

X ₃ is selected from NR ⁷ and S, provided that when r = 1 X ₃ is selected from S;

X ₄ is selected from O, NR ⁷ and S, provided that when 4 is selected from 2, 3 and 4, X ₄ is selected from S and NR ⁷ ;

Q is selected from CH ₂ , SO ₂ and oxygen, provided that when Q is SO ₂ or oxygen, p is 1;

Z is selected from SO ₂ and oxygen;

When P is selected from substituents of the formulas (V) to (VII), R ³ is further selected from the following groups:

In the formula,

n = 0, 1, 2 or 3,

r = 0, 1 or 2,

o = 1, 2 or 3,

p = 1 or 2,

s = 2 or 3, and

f = 1, 2, 3 or 4;

R ⁴ is a group selected from:

(a) hydrogen,

(b) C _1-6 -alkyl,

(c) 2-cyanoethyl,

(d) hydroxy-C _2-6 -alkyl,

(e) C _3-6 -alkenyl,

(f) C _3-6 -alkynyl,

(g) C _3-7 -cycloalkyl,

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

(i) C _1-6 -alkoxy-C _2-6 -alkyl,

(j) -C (= NH) -NR ¹¹ R ¹¹ ,

(k) -C (= 0) -NR ¹¹ R ¹¹ ,

(l) -CH ₂ -CO-NR ¹¹ R ¹¹ , or

(m) 3,3,3-trifluoropropyl;

R ⁵ is selected from:

(a) hydrogen,

(b) C _1-4 -alkyl,

(c) hydroxy-Ci_ ₄ -alkyl,

(d) C _1-4 -alkoxymethyl,

(e) halo-Ci_ ₄ -alkyl,

(f) -NR ¹¹ R ¹¹ ,

(g) -CO-NR ¹¹ R ¹¹ ,

(h) hydroxy, provided that the hydroxy group is not attached to a carbon atom adjacent to the ring nitrogen atom, or

(i) fluorine, provided that the fluorine atom is not attached to a carbon atom adjacent to the ring nitrogen atom;

R ⁶ is selected from:

(a) hydrogen,

(b) C _1-4 -alkyl,

(c) hydroxy-Ci_ ₄ -alkyl,

(d) C _1-4 -alkoxy-C _1-4 -alkyl,

(e) hydroxy, provided that the hydroxy group is not attached to a carbon atom adjacent to the heterocyclic ring nitrogen atom and the heterocyclic ring is not substituted with oxo,

(f) fluorine, provided that the fluorine atom is not attached to a carbon atom adjacent to the ring nitrogen atom, or

(g) halo-Ci_ ₄ -alkyl;

Each R ⁷ is independently selected from:

(a) hydrogen, provided that R ⁷ is not hydrogen when present at the same time as r, wherein r is 1 or 2,

(b) C _1-4 -alkyl,

(c) hydroxy-C _2-4 -alkyl, or

(d) methoxy-C _2-4 -alkyl;

Each R ⁸ is independently selected from:

(a) hydrogen, or

(b) C _1-4 -alkyl, and

When both R ⁸ are selected from C _1-4 -alkyl at the same time, the C _1-4 -alkyl may be attached to the same or different carbon atoms, and if two groups are present at the same carbon atom, they are cyclopropane together May form a ring;

Each R ⁹ is independently selected from:

(a) hydrogen,

(b) C _1-6 -alkyl,

(c) C _3-7 -cycloalkyl, or

Wherein two R ⁹ groups together with the nitrogen to which they are attached form a heterocyclic ring; Provided that when the two R ⁹ groups form a piperazine ring, the nitrogen of the piperazine ring allowing substitution is optionally substituted with C _1-4 -alkyl, and the two R ⁹ groups further form a piperidine ring. When formed, any ring carbon atom in the piperidine may be optionally substituted with methyl;

R ¹⁰ is selected from:

(a) C _1-6 -alkyl,

(c) aryl, or

(d) heteroaryl,

Wherein heteroaryl or aryl may be substituted at one or more positions with a substituent selected from halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, trifluoromethyl;

Each R ¹¹ is independently selected from:

(a) hydrogen,

(b) methyl, or

(c) ethyl, provided that R ¹¹ is on the R ⁴ or R ²⁶ group selected from —CH ₂ —CO—NR ¹¹ R ¹¹ ;

R ¹² is selected from:

(a) hydrogen,

(b) C _1-6 -alkyl,

(c) aryl,

(d) aryl-C _1-6 -alkyl,

(e) C _3-7 -cycloalkyl,

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

(g) heteroaryl, or

(h) heteroaryl-C _1-6 -alkyl,

Wherein any heteroaryl or aryl moiety, alone or as part of another group, is optionally substituted at one or more positions independently with a substituent selected from:

(a) hydrogen,

(b) halogen,

(c) C _1-6 -alkyl,

(d) hydroxy,

(e) C _1-6 -alkoxy,

(f) C _2-6 -alkenyl,

(g) C _2-6 -alkynyl,

(h) phenyl,

(i) phenoxy,

(j) benzyloxy,

(k) benzoyl,

(l) benzyl,

(m) -OCF ₃ ,

(n) -CN,

(o) hydroxy-C _1-6 -alkyl,

(p) C _1-6 -alkoxy-C _1-6 -alkyl,

(q) halo-Ci_ ₆ -alkyl,

(r) -NR ⁹ R ⁹ ,

(s) -NO ₂ ,

(t) -CONR ⁹ R ⁹ ,

(u) -NR ⁷ COR ¹⁰ ,

(v) -C (= 0) R ¹⁰ ,

(x) C _1-6 -alkoxycarbonyl,

(y) C _1-6 -alkylthio,

(z) -SCF ₃ ,

(aa) -CHF = CH ₂ ,

(ab) methylsulfonyl, or

(ac) -COOH,

Provided that the substituent on the aryl or heteroaryl moiety is selected from phenyl, phenoxy, benzyloxy, benzoyl, and benzyl, wherein the phenyl ring is halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cya Optionally substituted with one or more of furnace, or trifluoromethyl);

R ¹³ is selected from:

(a) C _1-6 -alkyl,

(b) C _3-6 -cycloalkyl,

(c) aryl,

(d) heteroaryl,

(e) aryl-C _1-2 -alkyl, or

(f) heteroaryl-C _1-2 -alkyl,

Wherein any heteroaryl or aryl moiety may be substituted at one or more positions with a substituent selected from halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, trifluoromethyl, and acetyl );

R ¹⁴ is selected from:

(a) aryl,

(b) heteroaryl,

(c) aryl-C _1-3 -alkyl, or

(d) heteroaryl-C _1-3 -alkyl,

Wherein any heteroaryl or aryl moiety may be substituted at one or more positions with a substituent selected from halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, and trifluoromethyl;

R ¹⁵ is selected from:

(a) fluorine, or

(b) hydroxy;

R ¹⁶ is selected from:

(a) hydrogen (where r = 0),

(b) amino,

(c) dimethylamino,

(d) F, or

(e) OH;

R ¹⁷ is selected from:

(a) hydrogen,

(b) C _1-4 -alkyl,

(c) hydroxy, provided that the hydroxy group is not attached to a carbon atom adjacent to the ring nitrogen atom;

R ¹⁸ is selected from:

(a) hydrogen, or

(b) fluorine;

R ¹⁹ is selected from:

(a) hydrogen,

(b) methyl,

(c) trifluoromethyl, or

(d) C _1-2 -alkoxymethyl;

Provided that at least one of R ¹⁹ and R ¹¹ , when present simultaneously, is selected from non-hydrogen substituents, and R ¹⁹ is selected from trifluoromethyl or C _1-2 -alkoxymethyl, Each R ¹¹ is selected from hydrogen);

R ²⁰ is selected from:

(a) hydrogen,

(b) C _1-4 -alkyl,

(c) hydroxy-Ci_ ₄ -alkyl,

(d) C _1-4 -alkoxy-C _1-4 -alkyl, or

(e) fluoromethyl;

Provided that when t ₂ is 1, R ²⁰ is H;

R ²¹ and R ²² are each independently selected from:

(a) hydrogen, or

(b) methyl,

Provided that when present at the same time as R ¹¹ , at least two of R ¹¹ , R ²¹ and R ²² are selected from hydrogen;

R ²³ is selected from:

(a) hydroxy-Ci_ ₄ -alkyl,

(b) C _1-4 -alkoxymethyl,

(c) halo-Ci_ ₄ -alkyl, or

^{(d) -CO-NR 11 R} 11 ( only, R ⁴ is ^{-C (= NH) -NR 11 R} 11, -C (= O) -NR 11 R 11, and -CH ₂ -CO-NR ¹¹ R Not selected from ¹¹ );

R ²⁴ is selected from:

(a) hydroxymethyl,

(b) methoxymethyl, or

(c) fluoromethyl;

Each R ²⁵ is independently selected from:

(a) hydrogen,

(b) C _1-4 -alkyl,

(c) hydroxy-Ci_ ₄ -alkyl,

(d) C _1-4 -alkoxy-C _1-4 -alkyl, or

(e) fluoromethyl;

Provided that both R ²⁵ are simultaneously selected from C _1-4 -alkyl, wherein said C _1-4 -alkyl can be attached to the same or different carbon atoms, and that one R ²⁵ is hydroxy-C _{When selected from 1-4} -alkyl, C _1-4 -alkoxy-C _1-4 -alkyl, and fluoromethyl, another R ²⁵ represents hydrogen; And

R ²⁶ is selected from:

(a) 2-cyanoethyl,

(b) C _3-6 -alkenyl,

(c) C _3-6 -alkynyl,

(d) C _3-7 -cycloalkyl,

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

(f) -CH ₂ -CO-NR ¹¹ R ¹¹ , or

(g) 3,3,3-trifluoropropyl;

With the proviso that R ² and R ¹² in formula (III) are not simultaneously selected from hydrogen; And R ² and R ¹² may together form a heterocyclic ring selected from piperidine, pyrrolidine, morpholine, piperazine, thiomorpholine, provided that R ² and R ^{12 together} piperazine in the case of forming the ring, the piperazine nitrogen of the terminal (distal) C ₁ - ₄ may be optionally substituted with alkyl or aryl, wherein said aryl is a halogen, in one or more positions with one or more C ₁ - ₄ - alkyl, C ₁ - ₄ -May be substituted with a substituent selected from alkoxy, cyano, trifluoromethyl; R ² and R ¹² together form a heteroaromatic ring of formula (VIII):

In which v is 0, 1 or 2;

And provided that when R ¹⁵ is selected from hydroxy, R ¹⁸ is selected from hydrogen.

Preferred are compounds of formula (1b):

[In the meal,

P is selected from substituents of the formulas (II) to (VII):

In the formula,

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

Wherein the dashed bonds indicate that R ³ may be attached to A or B at any carbon atom allowing substitution;

R ¹ is selected from:

(a) C _1-6 -alkyl,

(b) C _1-6 -alkoxy-C _2-6 -alkyl,

(c) C _3-6 -alkenyl,

(d) hydroxy-C _2-6 -alkyl,

(e) halo-Ci_ ₆ -alkyl,

(f) aryl,

(g) arylcarbonylmethyl,

(h) aryl-C _3-6 -alkenyl,

(i) aryl-C _1-6 -alkyl,

(j) C _3-7 -cycloalkyl,

(k) heteroaryl,

(o) heteroaryl-C _1-6 -alkyl,

Wherein any heteroaryl or aryl moiety, alone or as part of another group, may be optionally substituted independently at one or more positions with a substituent selected from:

(b) halogen,

(c) C _1-6 -alkyl,

(d) hydroxy,

(e) C _1-6 -alkoxy,

(f) C _2-6 -alkenyl,

(g) C _2-3 -alkynyl,

(h) phenyl,

(i) phenoxy,

(j) benzyloxy,

(k) benzoyl,

(l) benzyl,

(m) -OCF ₃ ,

(n) -CN,

(o) hydroxy-C _1-6 -alkyl,

(p) C ₁ - ₆ - alkoxy -C _1-6 - alkyl,

(q) halo-Ci_ ₆ -alkyl,

(r) -NR ⁹ R ⁹ ,

(s) -NO ₂ ,

(t) -CONR ⁹ R ⁹ ,

(u) -NR ⁷ COR ¹⁰ ,

(v) -C (= 0) R ¹⁰ ,

(x) C _1-6 -alkoxycarbonyl,

(y) C _1-6 -alkylthio,

(z) -SCF ₃ ,

(aa) -CHF = CH ₂ ,

(ab) methylsulfonyl, or

(ac) -COOH,

Provided that the substituent on the aryl or heteroaryl moiety is selected from phenyl, phenoxy, benzyloxy, benzoyl and benzyl, wherein the phenyl ring is halogen, C _1-4 -alkyl, C _1-4 -alkylthio, C Optionally substituted with one or more of _1-4 -alkoxy, cyano, or trifluoromethyl);

R ² is selected from:

(a) hydrogen,

(b) C _1-6 -alkyl,

(c) C _1-6 -alkoxy-C _2-6 alkyl,

(d) hydroxy-C _2-6 alkyl,

(e)-(CH ₂ ) _m -CH ₂ -F, wherein m is 2 to 4, or

(g) C _1-4 -alkylsulfonyl, wherein P is selected from substituents of the formula (V);

W ₁ and W ₂ are each independently selected from:

(a) hydrogen,

(b) halogen,

(c) C _1-6 -alkyl,

(d) hydroxy,

(e) C _1-6 -alkoxy,

(f) C _1-6 -alkylthio,

(g) C _2-6 -alkenyl,

(m) -OCF ₃ ,

(n) -CN,

(o) hydroxy-C _1-6 -alkyl,

(p) C _1-6 -alkoxy-C _1-6 -alkyl,

(q) halo-Ci_ ₆ -alkyl,

(r) -CONR ⁹ R ⁹ ,

(s) -C (= O) R ¹⁰ ,

(t) C _1-6 -alkoxycarbonyl,

(u) -SCF ₃ , or

(v) -CHF = CH ₂ ,

(Where, W ₁ and W _2, if is not selected from hydroxy, methoxy, methyl and halogen, at least one of W ₁ and W ₂ is selected from hydrogen);

R ³ is selected from:

In the formula,

n = 0, 1, 2 or 3,

r = 0, 1 or 2,

o = 1, 2 or 3,

p = 1 or 2,

s = 2 or 3,

t = 0 or 1,

t ₂ = 0 or 1,

f = 1, 2, 3 or 4, and

f ₁ = 1, 2 or 4;

X ₁ is selected from NR ⁷ and S;

X ₂ is selected from O, NR ⁷ and S, provided that t ₂ = 0 and s = 2, X ₂ is selected from NR ⁷ and S;

X ₃ is selected from NR ⁷ and S, provided that when r = 1 X ₃ is selected from S;

X ₄ is selected from O, NR ⁷ and S, provided that when the f is selected from 2 and 3 X ₄ is selected from S and NR ⁷ and R ⁶ is simultaneously selected from hydrogen and C _1-4 alkyl;

When P is a group selected from substituents of formulas (V) to (VII), R ³ is further selected from the following groups:

In the formula,

r = 0, 1 or 2,

o = 1, 2 or 3,

p is each independently 1 or 2,

s = 2 or 3, and

f = 1, 2, 3 or 4;

R ⁴ is selected from:

(a) hydrogen,

(b) C _1-6 -alkyl,

(c) 2-cyanoethyl,

(d) hydroxy-C _2-6 -alkyl,

(e) C _3-6 -alkenyl,

(f) C _3-6 -alkynyl,

(g) C _3-7 -cycloalkyl,

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

(i) C _1-6 -alkoxy-C _2-6 -alkyl,

(l) -CH ₂ -CO-NR ¹¹ R ¹¹ , or

(m) 3,3,3-trifluoropropyl;

R ⁵ is selected from:

(a) hydrogen,

(b) C _1-4 -alkyl,

(c) hydroxy-Ci_ ₄ -alkyl,

(d) C _1-4 -alkoxymethyl,

(e) halo-Ci_ ₄ -alkyl,

(f) -NR ¹¹ R ¹¹ ,

(h) hydroxy, provided that the hydroxy group is not attached to a carbon atom adjacent to the ring nitrogen atom, or

(i) fluorine, provided that the fluorine atom is not attached to a carbon atom adjacent to the ring nitrogen atom;

R ⁶ is selected from:

(a) hydrogen,

(b) C _1-4 -alkyl,

(c) hydroxy-Ci_ ₄ -alkyl,

(d) C _1-4 - alkoxy -C ₁ - ₄ - alkyl,

(e) hydroxy, provided that the hydroxy group is not attached to a carbon atom adjacent to the heterocyclic ring nitrogen atom,

(f) fluorine, provided that the fluorine atom is not attached to a carbon atom adjacent to the ring nitrogen atom, or

(g) halo-Ci_ ₄ -alkyl;

Each R ⁷ is independently selected from:

(a) hydrogen (wherein R ⁷ is not hydrogen and r is 1 or 2 when present simultaneously with r),

(b) C _1-4 -alkyl,

(c) hydroxy-C _2-4 -alkyl, or

(d) methoxy-C _2-4 -alkyl;

Each R ⁸ is independently selected from:

(a) hydrogen, or

(b) C _1-4 -alkyl, provided that both R ⁸ are simultaneously selected from C _1-4 -alkyl, the C _1-4 -alkyl may be attached to the same or different carbon atoms, or two groups When present at the same carbon atom, they may together form a cyclopropane ring);

Each R ⁹ is independently selected from:

(a) hydrogen,

(b) C _1-6 -alkyl

(c) C _3-7 -cycloalkyl, or

Both R ⁹ groups together with the nitrogen to which they are attached form a heterocyclic ring; When both R ⁹ groups form a piperazine ring, the nitrogen of the piperazine ring allowing substitution may be optionally substituted with C _1-4 -alkyl; In addition, when two R ⁹ groups form a piperidine ring, any ring carbon atom in the piperidine ring may be optionally substituted with methyl;

R ¹⁰ is selected from:

(a) C _1-6 -alkyl,

(c) aryl, or

(d) heteroaryl,

Wherein heteroaryl or aryl may be optionally substituted at one or more positions with a substituent selected from halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, trifluoromethyl;

R ¹¹ are each independently selected from:

(a) hydrogen,

(b) methyl, or

(c) ethyl, with R ¹¹ being present on the group R ²⁶ or R ⁴ selected from -CH ₂ -CO-NR ¹¹ R ¹¹ ;

R ¹² is selected from:

(a) hydrogen,

(b) C _1-6 -alkyl,

(c) aryl,

(d) aryl-C _1-6 -alkyl,

(e) C _3-7 -cycloalkyl,

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

(g) heteroaryl, or

(h) heteroaryl-C _1-6 -alkyl,

Wherein any heteroaryl or aryl moiety, alone or as part of another group, may be optionally substituted independently at one or more positions with a substituent selected from:

(b) halogen,

(c) C _1-6 -alkyl,

(d) hydroxy,

(e) C _1-6 -alkoxy,

(f) C _2-6 -alkenyl,

(g) C _2-3 -alkynyl,

(h) phenyl,

(i) phenoxy,

(j) benzyloxy,

(k) benzoyl,

(l) benzyl,

(m) -OCF ₃ ,

(n) -CN,

(o) hydroxy-C _1-6 -alkyl,

(p) C _1-6 -alkoxy-C _1-6 -alkyl,

(q) halo-Ci_ ₆ -alkyl,

(r) -NR ⁹ R ⁹ ,

(s) -NO ₂ ,

(t) -CONR ⁹ R ⁹ ,

(u) -NR ⁷ COR ¹⁰ ,

(v) -C (= 0) R ¹⁰ ,

(x) C _1-6 -alkoxycarbonyl,

(y) C _1-6 -alkylthio,

(z) -SCF ₃ ,

(aa) -CHF = CH _2,

(ab) methylsulfonyl, or

(ac) -COOH,

Provided that when the substituent on the aryl or heteroaryl moiety is selected from phenyl, phenoxy, benzyloxy, benzoyl, and benzyl, its phenyl ring is halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cya Optionally substituted by one or more of: furnace, or trifluoromethyl);

R ¹³ is selected from:

(a) C _1-6 -alkyl,

(b) C _3-6 -cycloalkyl,

(c) aryl,

(d) heteroaryl,

(e) aryl-C _1-2 -alkyl, or

(f) heteroaryl-C _1-2 -alkyl,

Wherein any heteroaryl or aryl moiety may be optionally substituted at one or more positions with substituents selected from halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, trifluoromethyl, and acetyl Can be);

R ¹⁴ is selected from:

(a) aryl,

(b) heteroaryl,

(c) aryl-C _1-3 -alkyl, or

(d) heteroaryl-C _1-3 -alkyl,

Wherein any heteroaryl or aryl moiety may be substituted at one or more positions with substituents selected from halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, and trifluoromethyl) ;

R ²⁰ are each independently selected from:

(a) hydrogen,

(b) methyl,

Provided that when t ₂ is 1, R ²⁰ is H;

R ²¹ and R ²² are each independently selected from:

(a) hydrogen, or

(b) methyl,

Provided that when present at the same time as R ¹¹ , at least two of R ¹¹ , R ²¹ and R ²² are selected from hydrogen;

R ²³ is selected from:

(a) hydroxy-Ci_ ₄ -alkyl,

(b) C _1-4 -alkoxymethyl, or

(c) halo-C _1-4 -alkyl;

R ²⁵ are each independently selected from:

(a) hydrogen,

(b) C _1-4 -alkyl,

(c) hydroxy-Ci_ ₄ -alkyl,

(d) C _1-4 -alkoxy-C _1-4 -alkyl, or

(e) fluoromethyl,

(Provided that both R ²⁵ together are C _1-4 - if selected from alkyl, said C _1-4 - alkyl may be bonded to the same or different carbon atoms, and R ²⁵ is a _hydroxy-1- -C _{When selected from 4} -alkyl, C _1-4 -alkoxy-C _1-4 -alkyl, and fluoromethyl, another R ²⁵ represents hydrogen;

R ²⁶ is selected from:

(a) 2-cyanoethyl,

(b) C _3-6 -alkenyl,

(c) C _3-6 -alkynyl,

(d) C _3-7 -cycloalkyl,

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

(f) -CH ₂ -CO-NR ¹¹ R ¹¹ , or

(g) 3,3,3-trifluoropropyl;

With the proviso that R ² and R ¹² in formula (III) are not simultaneously selected from hydrogen; In addition, the R ² and R ¹² together may form a heterocyclic ring selected from piperidine, pyrrolidine, morpholine, piperazine thiomorpholine, and R ² and R ¹² together piperazine ring When forming, the terminal piperazine nitrogen may be optionally substituted with C _1-4 alkyl or aryl, wherein the aryl is halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano at one or more positions Optionally substituted with a substituent selected from trifluoromethyl; Or R ² and R ¹² together form a heteroaromatic ring of formula (VIII):

(Where v is 0 or 1).

In addition, preference is given to:

P is selected from substituents of the formulas (II) to (V):

Wherein x is 2, y is 0 and j is 1;

R ¹ is selected from:

(f) aryl,

(i) aryl-C _1-3 -alkyl,

(k) heteroaryl,

(o) heteroaryl-C _1-3 -alkyl,

Wherein any heteroaryl or aryl moiety, alone or as part of another group, may be optionally substituted at one or more positions independently with a substituent selected from:

(b) halogen,

(c) C _1-4 -alkyl,

(d) hydroxy,

(e) C _1-4 -alkoxy,

(m) -OCF ₃ ,

(n) -CN,

(o) hydroxy-C _1-4 -alkyl,

(p) C _1-2 -alkoxy-C _1-2 -alkyl,

(q) halo-Ci- ₃ -alkyl,

(r) -NR ⁹ R ⁹ ,

(t) -CONR ⁹ R ⁹ ,

(u) -NR ⁷ COR ¹⁰ ,

(v) -C (= 0) R ¹⁰ ,

(x) C _1-3 -alkoxycarbonyl,

(y) C _1-3 -alkylthio, or

(ab) methylsulfonyl,

R ² is selected from:

(a) hydrogen,

(b) C _1-4 -alkyl,

W ₁ and W ₂ are each independently selected from:

(a) hydrogen,

(b) halogen,

(c) C _1-4 -alkyl,

(d) hydroxy,

(e) C _1-4 -alkoxy,

(f) C _1-4 -alkylthio,

(m) -OCF ₃ ,

(n) -CN,

(o) hydroxy-C _1-2 -alkyl,

(p) C _1-2 -alkoxy-C _1-2 -alkyl,

(q) -CF ₃ ,

(r) -CONR ⁹ R ⁹ ,

(s) acetyl,

(t) C _1-4 -alkoxycarbonyl, or

Provided that when W ₁ and W ₂ are not selected from hydroxy, methoxy, methyl and halogen, at least one of W ₁ and W ₂ is selected from hydrogen;

R ³ is a group selected from:

In the formula,

n = 0, 1, 2 or 3

r is 0, 1 or 2,

o = 1, 2, or 3,

p is 1 or 2,

s = 2 or 3,

t = 0 or 1,

t ₂ = 0 or 1, and

f = 1, 2, 3 or 4;

X ₁ is selected from NR ⁷ and S;

X ₂ is selected from O, NR ⁷ and S, provided that t ₂ is selected from NR ⁷ and S when t = 0 and s = 2;

X ₃ is selected from NR ⁷ and S, provided that when r = 1 X ₃ is selected from S;

X ₄ is selected from O, NR ⁷ and S provided that when f is selected from 2 and 3 X ₄ is selected from S and NR ⁷ and R ⁶ is simultaneously selected from hydrogen and C _1-4 alkyl; or;

When P is a group selected from formula (V) wherein j = 1, R ³ is additionally selected from the following groups;

R ⁴ is selected from:

(a) hydrogen,

(b) C _1-4 -alkyl,

(d) hydroxy-C _2-4- alkyl,

(g) C _3-6 -cycloalkyl,

(h) C _3-6 -cycloalkyl-C _1-4 -alkyl,

(i) C _1-4 -alkoxy-C _2-4 -alkyl

(m) 3,3,3-trifluoropropyl;

R ⁵ is selected from:

(a) hydrogen,

(b) C _1-4 -alkyl,

(c) hydroxy-Ci_ ₄ -alkyl,

(d) C _1-4 -alkoxymethyl,

(e) halo-Ci_ ₄ -alkyl,

(f) -NR ¹¹ R ¹¹ ,

(g) hydroxy, provided that the hydroxy group is not bonded to a carbon atom adjacent to a ring nitrogen atom, or

(h) fluorine, provided that the fluorine atom is not bonded to a carbon atom adjacent to the ring nitrogen atom;

R ⁶ is selected from:

(a) hydrogen,

(b) C _1-4 -alkyl,

(c) hydroxy-Ci_ ₄ -alkyl,

(d) C _1-4 -alkoxy-C _1-4 -alkyl,

(e) hydroxy, provided that the hydroxy group is not bonded to a carbon atom adjacent to the heterocyclic ring nitrogen atom,

(f) fluorine, provided that the fluorine atom is not bonded to a carbon atom adjacent to the ring nitrogen atom, or

(g) halo-Ci_ ₄ -alkyl;

R ⁷ are each independently selected from:

(a) hydrogen, provided that when R ⁷ is present at the same time as r and said r is 1 or 2, R ⁷ is not hydrogen;

(b) C _1-4 -alkyl,

(c) hydroxy-C _2-4 -alkyl, or

(d) methoxy-C _2-4 -alkyl;

R ⁸ are each independently selected from:

(a) hydrogen, or

(b) C _1-4 - alkyl (provided that, the amount at the same time R ⁸ C _1-4 - if selected from alkyl, said C _1-4 - alkyl or may be bonded to the same or different carbon atoms, or the two groups When present at the same carbon atom, they may together form a cyclopropane ring);

Each R ⁹ is independently selected from:

(a) hydrogen,

(b) C _1-6 -alkyl, or

Both R ⁹ groups together with the nitrogen to which they are attached form a heterocyclic ring; Provided that when two R ⁹ groups form a piperazine ring, the nitrogen of the piperazine ring allowing substitution is optionally substituted with C _1-4 -alkyl;

R ¹⁰ is selected from:

(a) C _1-6 -alkyl,

(c) aryl, or

(d) heteroaryl,

Wherein heteroaryl or aryl may be substituted at one or more positions with substituents selected from halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, trifluoromethyl;

R ¹¹ are each independently selected from:

(a) hydrogen, or

(b) methyl,

(c) ethyl, with R ¹¹ being on the R ²⁶ group selected from -CH ₂ -CO-NR ¹¹ R ¹¹ ;

R ¹² is selected from:

(a) hydrogen,

(c) aryl,

(d) aryl-C 1-3 alkyl,

(g) heteroaryl, or

(h) heteroaryl-C 1-3 alkyl,

Wherein any heteroaryl or aryl moiety, alone or as part of another group, may be optionally substituted independently at one or more positions with a substituent selected from:

(b) halogen,

(c) C _1-4 -alkyl,

(d) hydroxy,

(e) C _1-4 -alkoxy,

(m) -OCF ₃ ,

(n) -CN,

(o) hydroxy-C _1-3 -alkyl,

(p) C _1-3 -alkoxy-C _1-3 -alkyl,

(q) halo-Ci_ ₄ -alkyl,

(r) -NR ⁹ R ⁹ ,

(t) -CONR ⁹ R ⁹ ,

(u) -NR ⁷ COR ¹⁰ ,

(v) -C (= 0) R ¹⁰ ,

(x) C _1-3 -alkylthio, or

(ab) methylsulfonyl;

R ¹³ is selected from:

(c) aryl,

(d) heteroaryl,

(e) Aryl-C _1-2 -alkyl, or

(f) heteroaryl-C _1-2 -alkyl,

Wherein any heteroaryl or aryl moiety may be optionally substituted at one or more positions with substituents selected from halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, trifluoromethyl and acetyl has exist);

R ¹⁴ is selected from:

(a) aryl,

(b) heteroaryl,

(c) aryl-C _1-3 -alkyl, or

(d) heteroaryl-C _1-3 -alkyl;

Wherein any heteroaryl or aryl moiety may be optionally substituted at one or more positions with substituents selected from halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, and trifluoromethyl );

R ²⁰ is selected from:

(a) hydrogen, or

(b) methyl,

Provided that when t ₂ is 1, R ²⁰ is H;

R ²¹ and R ²² are each independently selected from:

(a) hydrogen, or

(b) methyl,

Provided that when present at the same time as R ¹¹ , at least two of R ¹¹ , R ²¹ and R ²² are selected from hydrogen;

R ²³ is selected from:

(a) hydroxy-Ci_ ₄ -alkyl,

(b) C _1-4 -alkoxymethyl, or

(c) halo-C _1-4 -alkyl;

R ²⁵ is selected from:

(a) hydrogen,

(b) C _1-4 -alkyl,

(c) hydroxy-Ci_ ₄ -alkyl,

(d) C _1-4 -alkoxy-C _1-4 -alkyl, or

(e) fluoromethyl;

(Provided that when both R ²⁵ are simultaneously selected from C _1-4 -alkyl, the C _1-4 -alkyl may be bonded to the same or different carbon atom, and one R ²⁵ is hydroxy-C _{1- When selected from 4} -alkyl, C _1-4 -alkoxy-C _1-4 -alkyl, and fluoromethyl, other R ²⁵ represents hydrogen;

R ²⁶ is selected from:

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

(f) -CH ₂ -CO-NR ¹¹ R ¹¹ , or

(g) 3,3,3-trifluoropropyl;

With the proviso that R ² and R ¹² in formula (III) are not selected from hydrogen at the same time; In addition, the R ² and R ¹² may together form a heterocyclic ring selected from piperidine, pyrrolidine, morpholine, piperazine thiomorpholine, and R ² and R ¹² together form a piperazine ring When formed, the terminal piperazine nitrogen may be optionally substituted with C _1-4 alkyl or aryl, wherein the aryl is halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano at one or more positions Optionally substituted with a substituent selected from trifluoromethyl; Or R ² and R ¹² together form a heteroaromatic ring of formula (VIII):

(Where v is 0 or 1).

Preferred compound sets within the present invention are compounds of formula (XII):

(XII)

(XII)

(W ₁ , W ₂ , P and R ³ are as defined in formula (lb)).

More preferred compounds of formula (XII) are the following compounds:

P is selected from substituents of the formulas (II) to (IV);

x is 2 and y is 0;

R ¹ is selected from aryl and heteroaryl, wherein any heteroaryl or aryl moiety is independently selected from halogen, C _1-4 -alkyl, C _1-4 -alkoxy and trifluoromethyl at one or more positions Optionally substituted with a substituent;

R ² is selected from hydrogen;

W ₁ and W ₂ are hydrogen;

R ³ is a group selected from:

here,

p = 1 or 2,

R ⁴ is selected from:

(a) hydrogen, or

(b) C _1-4 -alkyl;

R ¹¹ are each independently selected from:

(a) hydrogen, or

(b) methyl,

(c) ethyl, provided that R ¹¹ is on the group R ²⁶ selected from -CH ₂ -CO-NR ¹¹ R ¹¹ ;

R ¹² and R ¹³ are each independently selected from aryl and heteroaryl,

Wherein any heteroaryl or aryl moiety is independently at one or more positions halogen, C _1-4 -alkyl, C _1-4 -alkoxy, and Optionally substituted with a substituent selected from CF ₃ ;

R ²⁵ is selected from:

(a) hydrogen, or

(b) C _1-4 -alkyl;

R ²⁶ is selected from:

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

(f) -CH ₂ -CO-NR ¹¹ R ¹¹ , or

(g) 3,3,3-trifluoropropyl.

In more preferred compounds of Formula (XII),

P is selected from substituents of the formulas (II)-(IV);

x is 2 and y is 0;

R ¹ , R ¹² and R ¹³ are each independently phenyl or 2-methoxy-5-methylphenyl, 2-methylphenyl, 4-methylphenyl, 4-fluorophenyl, 3,4-dimethoxyphenyl, 2-chlorophenyl, Substitutes selected from 2-trifluoromethylphenyl, 2,6-dichlorophenyl, 3-chloro-4-methylphenyl, 3-methylphenyl, 3,6-dichloro-2-methylphenyl, and 2-chloro-5-fluorophenyl Phenyl; Or heteroaryl or substituted heteroaryl selected from 2-thienyl, 5-chloro-2-thienyl, 5-chloro- and 1,3-dimethyl-1H-pyrazol-4-yl;

R ² is selected from hydrogen;

W ₁ and W ₂ are hydrogen;

R ³ is a group selected from:

R ⁴ are each independently selected from:

(a) hydrogen, or

(b) methyl,

R ¹¹ are each independently selected from:

(a) hydrogen, or

(b) methyl;

R ²⁵ are each independently selected from:

(a) hydrogen, or

(b) methyl.

Another preferred set of compounds of the invention is a compound of formula (XIII):

(XIII)

(XIII)

(W ₁ , W ₂ , P and R ³ are as defined in formula (lb)).

More preferred compounds of formula (XIII) are the following compounds:

P is selected from substituents of the formulas (II) to (IV);

x is 2 and y is 0;

R ¹ is selected from aryl and heteroaryl, wherein any heteroaryl or aryl moiety is independently selected at one or more positions from halogen, C _1-4 -alkyl, trifluoromethoxy, and C _1-4 -alkoxy Optionally substituted with a substituent;

R ² is selected from hydrogen;

W ₁ and W ₂ are hydrogen;

R ³ is a group selected from:

here,

R ⁴ are each independently selected from:

(a) hydrogen, or

(b) C _1-4 -alkyl;

R ²⁵ are each independently selected from:

(a) hydrogen, or

(b) C _1-4 - alkyl, with the proviso that both R ²⁵ is C _1-4 - When referring to an alkyl, wherein the C _1-4 - can be bonded to the alkyl are the same or different carbon atoms;

R ¹² and R ¹³ are each independently selected from aryl and heteroaryl, wherein any heteroaryl or aryl moiety is independently at one or more positions halogen, C _1-4 -alkyl, trifluoromethyl, and C _1- It may be optionally substituted with a substituent selected from ₄ -alkoxy.

In more preferred compounds of formula (XIII),

P is selected from substituents of formula (II);

R ¹ is selected from 2-methoxy-5-methylphenyl;

R ² is selected from hydrogen;

W ₁ and W ₂ are hydrogen;

R ³ is a group selected from:

R ⁴ are each independently selected from:

a) hydrogen, or

b) methyl;

R ²⁵ are each independently selected from:

a) hydrogen, or

b) methyl.

Preferred compounds are as follows:

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

N- (7-piperidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide,

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

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

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

N- (7-pyrrolidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide,

4-fluoro-N- (7-pyrrolidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride,

4-fluoro-N- (7-morpholin-4-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride,

N- (7-morpholin-4-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride,

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

2-methoxy-5-methyl- N- (7-pyridin-4-yl-1-benzofuran-5-yl) benzenesulfonamide,

N- (7-pyridin-3-yl-1-benzofuran-5-yl) benzenesulfonamide trifluoroacetate,

2-methoxy-5-methyl- N- (7-pyridin-3-yl-1-benzofuran-5-yl) benzenesulfonamide trifluoroacetate,

N- (7-pyrazin-2-yl-1-benzofuran-5-yl) benzenesulfonamide trifluoroacetate,

N- (7-pyrimidin-5-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride, and

N- [7- (1-Aza-bicyclo [2.2.2] oct-2-en-3-yl) -benzofuran-5-yl] -2-methoxy-5-methyl-benzenesulfonamide hydrochloride ,

2- [4- (5-{[(2-chlorophenyl) sulfonyl] amino} -1-benzofuran-7-yl) piperazin-1-yl] -N, N-diethylacetamide hydrochloride,

  N, N-diethyl-2- [4- (5-{[(2-methoxy-5-methylphenyl) sulfonyl] amino} -1-benzofuran-7-yl) piperazin-1-yl] acet Amide hydrochloride,

N- [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,

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

2-methoxy-5-methyl-N- {7-[(2-morpholin-4-ylethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride,

N- {7-[(2-morpholin-4-ylethyl) amino] -1-benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide hydrochloride,

2,6-dichloro-N- {7-[(2-morpholin-4-ylethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride,

N- (7-{[2 (dimethylamino) ethyl] amino} -1-benzofuran-5-yl) -2-methoxy-5-benzenesulfonamide hydrochloride,

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

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

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

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

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

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

N- {7-[(3-aminopyrrolidin-1-yl) methyl] -1-benzofuran-5-yl} -2-methoxy-5-methylbenzenesulfonamide hydrochloride,

N- [7 (6,6-dioxidohexahydrothieno [3,4-b] pyrazin-1 (2H) -yl) -1-benzofuran-5-yl] -2-methoxy-5- Methylbenzenesulfonamide hydrochloride,

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

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

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

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

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

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

N- {7-[(3-morpholin-4-ylpropyl) amino] -1-benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide hydrochloride,

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

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

N- [7-({[(2R) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -2-methoxy-5-methylbenzenesulfonamide hydro Chloride,

N- [7-({[(2R) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -2- (trifluoromethyl) benzenesulfonamide hydro Chloride,

N- [7-({[(2R) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -3-methylbenzenesulfonamide hydrochloride,

N- [7-({[(2R) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] thiophene-2-sulfonamide hydrochloride,

5-chloro-N- [7-({[(2R) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] thiophene-2-sulfonamide hydrochloride ,

5-chloro-N- [7-({[(2R) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -1,3-dimethyl-1H- Pyrazole-4-sulfonamide hydrochloride,

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

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

N- (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) -1H-pyrazole -4-sulfonamide hydrochloride,

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

N- {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 hydro Chloride,

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,

3,6-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-dimethyl-piperazin-1-yl) methyl] -N- (2- methylphenyl) -1-benzofuran-5-sulfonamido-de, trifluoroacetate,

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

7- (1,4-diazepane-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-{[(2R) -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-diazepane-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-[(1 S , 4 S ) -2,5-diazabicyclo [2.2.1] hept-2-ylmethyl] -N- (2-methoxy-5-methylphenyl) -1-benzofuran-5 Sulfonamides, trifluoroacetates,

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

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

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

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

2-chloro-N- [7- (1,4-diazepane-1-ylmethyl) -1-benzofuran-5-yl] benzenesulfonamide dihydrochloride,

N- [7- (1,4-diazepane-1-ylmethyl) -1-benzofuran-5-yl] -2-methylbenzenesulfonamide, dihydrochloride,

N- [7- (1,4-diazepane-1-ylmethyl) -1-benzofuran-5-yl] thiophen-2-sulfonamide dihydrochloride,

2-methoxy-5-methyl-N- {7-[(2-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide, dihydrochloride,

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

2,5-dichloro-N- {7-[(2-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} thiophene-3-sulfonamide dihydrochloride,

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

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

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

N - {7 - [(1 S, 4 S) -2,5- diazabicyclo [2.2.1] hept-2-ylmethyl] -1-benzofuran-5-yl} -2-methoxy -5 Methylbenzenesulfonamide, dihydrochloride,

N - {7 - [(1 S, 4 S) -2,5- diazabicyclo [2.2.1] hept-2-ylmethyl] -1-benzofuran-5-yl} -2- (trifluoromethyl Methyl) benzenesulfonamide, dihydrochloride,

N - {7 - [(1 S, 4 S) -2,5- diazabicyclo [2.2.1] hept-2-ylmethyl] -1-benzofuran-5-yl} -2-methyl-benzenesulfonamide , Dihydrochloride,

2-methoxy-5-methyl-N- {7-[(trans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide, bistrifluoro acetate,

2-methyl-N- {7-[(trans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide, bistrifluoroacetate,

2-chloro-N- {7-[(trans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} 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-diazepane, trifluoroacetate,

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

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

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-{[(3R) -pyrrolidin-3-ylamino] methyl} -1-benzofuran-5-sulfonamide, 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-7-yl] benzenesulfonamide, trifluoroacetate,

2-methoxy-5-methyl-N- {5-[(3-methylpiperazin-1-yl) methyl] -1-benzofuran-7-yl} benzenesulfonamide, bis (trifluoroacetate,

2-methoxy-5-methyl-N- [5- (piperidin-4-ylmethyl) -1-benzofuran-7-yl] benzenesulfonamide, trifluoroacetate.

Another object of the invention is a process for the preparation of the above-mentioned compounds, comprising the following steps:

(a) provision of dihalogenated 4-nitrophenol by halogenation of 4-nitrophenol,

(b) provision of halogenated nitrobenzofuran by ring closure of dihalogenated 4-nitrophenol with trimethylsilylacetylene,

(c) provision of an amine-substituted nitrobenzofuran by nucleophilic substitution with an amine of a halogenated nitrobenzofuran,

(d) provision of BOC-protected amine-substituted nitrobenzofuran by BOC-protection of amine-substituted benzofuran,

(e) provision of BOC-protected amine-substituted aminobenzofuran by reduction of BOC-protected amine-substituted nitrobenzofuran,

(f) tributylstannyl heterocycle, tributylstannyl heteroaryl compound, or heterocycle-substituted or heteroaryl-substituted nitrobenzofuran by coupling heteroaryl boric acid or heteroaryl boric acid ester with halogenated nitrobenzofuran offer,

(g) the provision of heterocycle-substituted or heteroaryl-substituted aminobenzofurans by reduction of heterocycle-substituted or aryl-substituted nitrobenzofurans,

(h) provision of heterocycle-substituted or heteroaryl-substituted arylsulfonylaminobenzofuran by arylsulfonylation of heterocycle-substituted or heteroaryl-substituted aminobenzofuran,

(i) provision of BOC-protected amine-substituted arylsulfonylaminobenzofuran by arylsulfonylation of BOC-protected amine-substituted aminobenzofuran,

(j) removal of BOC-protecting groups from BOC-protected amine-substituted arylsulfonylaminobenzofuran,

(k) provision of BOC-protected amine-substituted benzylaminobenzofuran by benzylation of BOC-protected amine-substituted aminobenzofuran,

(l) removal of BOC-protecting groups from BOC-protected amine-substituted benzylaminobenzofuran,

(m) provision of BOC-protected amine-substituted benzoylaminobenzofuran by benzoylation of BOC-protected amine-substituted aminobenzofuran,

(n) removal of BOC-protecting groups from BOC-protecting amine-substituted benzoylaminobenzofuran,

(o) provision of BOC-protected amine-substituted phenylaminocarbonylaminobenzofuran by reaction of BOC-protected amine-substituted aminobenzofuran with aryl isocyanate, and

(p) Removal of BOC-protecting groups from BOC-protected amine-substituted phenylaminocarbonylaminobenzofuran.

Additional synthetic steps to reach the compounds of the present invention are shown in Schemes 7-14.

A further object of the present invention is the abovementioned compounds for use in therapy to achieve weight loss and weight loss reduction, in particular for the treatment or prevention of 5-HT ₆ receptor related disorders.

Another object of the invention is an active ingredient in combination with a pharmaceutically acceptable diluent or carrier, in particular for use in the treatment or prevention of 5-HT ₆ receptor related disorders, in order to achieve weight loss and weight gain reduction. As pharmaceutical formulations containing the compounds as mentioned above.

Another subject of the invention is a method of treating a human or animal subject with a 5-HT ₆ receptor related disorder to achieve weight loss and weight gain reduction. The method may comprise a therapeutically effective amount of one or more compounds of any of the formulas herein, salts thereof, or compositions containing such compounds or salts, such as in a subject (eg, human or animal, dog, cat, Horses, cows).

The methods described herein may also include identifying a subject in need of treatment of a 5-HT ₆ receptor related disorder to achieve weight loss and weight gain reduction. The identification of the subject in need of such treatment may be at the discretion of the subject or health care professional and may be subjective (eg, opinion) or objective (eg, measurable by a test or diagnostic method).

Another object of the present invention is a method of treating or preventing 5-HT ₆ receptor related disorders for achieving weight loss and weight gain reduction, comprising administering to a subject in need thereof an effective amount of a compound mentioned above Way.

Another object of the present invention is a method of modulating (eg, inhibiting or promoting) 5-HT ₆ receptor activity, comprising administering an effective amount of the aforementioned compounds to a subject in need of such treatment.

Another object of the present invention is the use of the aforementioned compounds for the manufacture of a medicament for use in the prevention or treatment of 5-HT ₆ receptor related disorders for achieving weight loss and weight gain reduction.

The aforementioned compounds may be agonists, partial agonists or antagonists of the 5-HT ₆ receptor. Preferably the compound acts as a partial agonist or antagonist for the 5-HT ₆ receptor.

Another subject of the invention is an active ingredient in combination with a cosmetically acceptable diluent or carrier, in particular for use in the prevention or treatment of 5-HT ₆ receptor related disorders, to achieve weight loss and weight gain reduction. Cosmetic compositions containing the aforementioned compounds.

Examples of 5-HT ₆ receptor related disorders include obesity; Type II diabetes; Central nervous system disorders such as anxiety, depression, panic attacks, memory disorders, cognitive impairment, epilepsy, sleep disorders, migraine, anorexia, bullia, binge eating disorder, obsessive compulsive disorder, psychosis, Alzheimer's disease, Parkinson's disease, Huntington's chorea, schizophrenia , Attention deficit hyperactivity disorder (ADHD), withdrawal from drug abuse, neurodegenerative diseases characterized by neuronal growth insufficiency, and pain.

The compounds and compositions are useful for the treatment of diseases for achieving weight loss and weight gain reduction. The disease is obesity; Type II diabetes; Central nervous system disorders such as anxiety, depression, panic attacks, memory disorders, cognitive impairment, epilepsy, sleep disorders, migraine, anorexia, bullia, binge eating disorder, obsessive compulsive disorder, psychosis, Alzheimer's disease, Parkinson's disease, Huntington's chorea, schizophrenia , Attention deficit hyperactivity disorder (ADHD), withdrawal from drug abuse, neurodegenerative diseases and pain characterized by neuronal growth insufficiency. In one aspect, the invention relates to a method of treating or preventing a disease, comprising administering to a subject in need thereof an effective amount or composition as set forth herein.

Justice

The following definitions shall apply throughout the specification and the appended claims.

Unless stated or indicated otherwise, the term “C _1-6 -alkyl” refers to a linear or branched alkyl group having 1 to 6 carbon atoms. Examples of such C _1-6 -alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight and branched chain pentyl and hexyl. As part of the range "C _1-6 -alkyl", all subgroups thereof, 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 and the like are contemplated. "Halo -C _1-6 - alkyl" is a C _1-6 substituted by one or more halogen atoms; means an alkyl group; Examples of the halo-C _1-6 -alkyl include 2-fluoroethyl, fluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl. Likewise, “aryl-C _1-6 -alkyl” means a C _1-6 -alkyl group substituted with one or more aryl groups.

Unless stated or indicated otherwise, the term “hydroxy-C _1-6 -alkyl” means a linear or branched alkyl group having a hydrogen atom substituted with OH. Examples of such hydroxy-C _1-6 -alkyl include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl and 2-hydroxy-2-methylpropyl.

Unless stated or otherwise indicated, the term "C _1-6 -alkoxy" means a linear or branched alkoxy group having 1 to 6 carbon atoms. Examples of the C _1-6 -alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight and branched chains. Pentoxy and hexoxy. As part of the range "C _1-6 -alkoxy", all subgroups thereof, 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 and the like are contemplated.

Unless stated or otherwise indicated, the term C _1-6 -alkoxy-C _1-6 -alkyl refers to a linear or branched alkoxy group having 1 to 6 carbon atoms linked to an alkyl group having 1 to 6 carbon atoms. Examples of the C _1-6 -alkoxy-C _1-6 -alkyl include methoxymethyl, ethoxymethyl, iso-propoxymethyl, n-butoxymethyl, t-butoxymethyl and straight and branched chain pentoxy Methyl is included. As part of the range "C _1-6 -alkoxy-C _1-6 -alkyl", a subgroup thereof, 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 and the like are contemplated.

Unless stated or otherwise indicated, the term "C _2-6 -alkenyl" refers to a linear or branched alkenyl group having 2 to 6 carbon atoms. Examples of the C _2-6 -alkenyl include vinyl, allyl, 2,3-dimethylallyl, 1-butenyl, 1-pentenyl and 1-hexenyl. As part of the range "C _2-6 -alkenyl", a subgroup thereof, such as C _2-5 -alkenyl, C _2-4 -alkenyl, C _2-3 -alkenyl, C _3-6 -alkenyl, C _4-5 -alkenyl and the like are contemplated. Likewise, "aryl-C _2-6 -alkenyl" refers to a C _2-6 -alkenyl group substituted with one or more aryl groups. Examples of such aryl-C _2-6 -alkenyl include styryl and cinnamil.

를 의미한다. The term "oxo"

Means.

Unless stated or otherwise indicated, the term "C _2-6 -alkynyl" refers to a linear or branched alkynyl group having 2 to 6 carbon atoms. Examples of the C _2-6 -alkynyl include ethynyl, 1-propynyl, 1-butynyl and 1-hexynyl. As the range "C _2-6 -alkynyl", all subgroups thereof such as C _2-5 -alkynyl, C _2-4 -alkynyl, C _2-3 -alkynyl, C _3-6 -alkynyl, C _4-5 -alkynyl and the like are contemplated.

Unless stated or otherwise indicated, the term "C _3-7 -cycloalkyl" means a cyclic alkyl group having 3 to 7 carbon atoms. Examples of the cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl and cycloheptyl. As part of the range "C _3-7 -cycloalkyl", all subgroups thereof, such as C _3-6 -cycloalkyl, C _3-5 -cycloalkyl, C _3-4 -cycloalkyl, C _4-7 -cyclo Alkyl, C _4-6 -cycloalkyl, C _4-5 -cycloalkyl, C _5-7 -cycloalkyl, C _6-7 -cycloalkyl and the like.

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

Likewise, aryloxy means an aryl group bonded to an oxygen atom.

The term “heteroaryl” refers to a monocyclic or bicyclic aromatic ring system in which only one ring needs to be aromatic and the heteroaryl moiety can be linked to the rest of the molecule via a carbon or nitrogen atom in any ring and , Having 5 to 10 ring atoms (monocyclic or bicyclic), wherein at least one ring atom is other than carbon, such as nitrogen, sulfur, oxygen and selenium. Examples of the heteroaryl ring include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, chromamanyl, quinazolinyl , Indolyl, isoindolinyl, indolinyl, isoindolinyl, indazolyl, pyrazolyl, pyridazinyl, quinolinyl, isoquinolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 1 , 2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, benzodioxolyl, benzodioxyyl, benzothienyl, benzimidazolyl, benzothiazolyl, Benzothiadiazolyl, benzotriazolyl and 2,1,3-benzoxadiazolyl groups. When the bicyclic heteroaryl ring is substituted, it may be substituted in any ring.

Unless stated or otherwise indicated, the term “heterocyclic” is a non-aromatic (ie partial or non-aromatic) having from 4 to 10 ring atoms having one or more heteroatoms, such as O, N or S, and the remaining ring atoms being carbon. Fully saturated) monocyclic or bicyclic ring system. Examples of heterocyclic groups include piperidyl, tetrahydropyranyl, tetrahydrofuranyl, azefinyl, azetidinyl, pyrrolidinyl, morpholinyl, imidazolinyl, thiomorpholinyl, pyranyl , Dioxanyl, piperazinyl, octahydropuro [3,4 b ] pyrazinyl and 1-azabicyclo [2.2.2] oct-2-en-3-yl groups. If present, the sulfur atoms may be present in oxidized form (ie S═O or O═S═O). An example of when containing sulfur in oxidized form heterocyclic groups include octahydro-thieno [3,4 b] pyrazine-6,6-dioxide and 1,1-thio formyl morpholine oxide is included.

Unless otherwise stated or indicated, the term "halogen" means chlorine, fluorine, bromine or iodine.

The term -S (O) _x -in which x is 0, 1 or 2 has the meaning described by the formulas IX to XI:

The term "leaving group" means a group that is released from a molecule during a nucleophilic substitution reaction. Examples of leaving groups are iodide, bromide, chloride, methanesulfonate, hydroxy, methoxy, thiomethoxy, tosyl, or suitable protonated forms thereof (eg H ₂ O, MeOH), in particular Bromide and methanesulfonate.

"Arbitrary" or "optionally" means that an event or situation described subsequently may occur, but need not necessarily occur, and the above description includes both when the event or situation occurs and when it does not. .

"Pharmaceutically acceptable" means that it is useful in the manufacture of pharmaceutical formulations that are generally safe, nontoxic, biologically, or otherwise undesirable, and include those that are useful for veterinary as well as human pharmaceutical uses.

“Treatment” as described herein includes the prevention of a named disorder or condition or the alleviation or removal of a disorder once established.

"Effective amount" means the amount of a compound that provides a therapeutic effect on a treated subject. The therapeutic effect can be objective (ie, measurable with a given test or marker) or subjective (ie, a subject displays or feels an effect).

The term “drug precursor form” means a pharmacologically acceptable derivative, such as an ester or an amide, in which the derivative is transformed in vivo in the body to form the active drug. References are made to Goodman and Gilman's, The Pharmacological basis of Therapeutics, 8 ^th ed., Mc-Graw-Hill, Int. Ed. 1992, "Biotransformation of Drugs" p. 13-15 and in "The Organic Chemistry of Drug Design and Drug Action", Richard B. Silverman. Chapter 8, p 352. (Academic Press, Inc. 1992. ISBN 0-12-643730-0).

The following abbreviations are used:

BINAP means 2,2'-bis (diphenylphosphino) 1-1'-binafyl,

BOC means tert-butyloxycarbonyl,

CV stands for coefficient of variation,

DCM stands for dichloromethane,

DME means 1,2-dimethoxyethane,

DMSO means dimethyl sulfoxide,

EDTA means ethylenediamine tetraacetic acid,

EtOH means ethanol,

EtOAc means ethyl acetate,

EGTA means ethylenebis (oxyethylenenitrilo) tetraacetic acid,

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

HPLC stands for high performance liquid chromatography,

LSD means lysergic acid, diethylamide,

MeCN means acetonitrile,

SPA stands for Scintillation Proximity Assay,

t-BuOK means potassium tert-butoxide,

TEA means triethylamine,

TFA means trifluoroacetic acid,

THF means tetrahydrofuran,

Xantphos means 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene.

All possible isomeric forms for the compounds presented (pure enantiomers, diastereomers, tautomers, racemic mixtures and unequal mixtures of the two enantiomers) are within the scope of the present invention. The compounds may also occur in cis- or trans-, E- or Z- double bond isomeric forms. All isomeric forms are contemplated.

The compounds of formula (I) can be used as they are or as appropriate as their pharmaceutically acceptable salts (acid or base addition salts). The pharmaceutically acceptable addition salts mentioned above are meant to include the therapeutically active non-toxic acid and base addition salt forms that the compounds can form. Compounds with basic characteristics can be converted to their pharmaceutically acceptable acid addition salts by treating the base form with a suitable acid. Exemplary acids include inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid; And organic acids such as formic acid, acetic acid, propionic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid , Citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid and the like. Exemplary base addition salt forms are sodium, potassium, calcium salts and salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzatin, and salts with amino acids such as, for example, arginine and lysine. .

For example, sulfonamide derivatives of formula (I), wherein P is selected from substituents of formulas (II) and (III) wherein R ² is hydrogen, or the corresponding potassium, sodium or calcium salts thereof, or other It can be converted into a salt of an alkali metal or alkaline earth metal. As used herein, the term "addition salt" also includes solvates in which each compound and salt thereof can form such as, for example, hydrates, alcoholates, and the like.

For clinical use, the compounds of the present invention are formulated in pharmaceutical formulations for oral, rectal, parenteral or other dosage forms. Pharmaceutical formulations are generally prepared by mixing the active substance or a pharmaceutically acceptable salt thereof with conventional pharmaceutical excipients. Examples of excipients are water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide and the like. The formulation may also include other pharmaceutical actives and conventional additives such as stabilizers, wetting agents, emulsifiers, flavoring agents, buffers and the like. In general, the amount of active compound is from 0.1 to 95% by weight of the formulation, preferably from 0.2 to 20% by weight of the parenteral formulation, more preferably from 1 to 50% by weight in the formulation for oral administration.

The formulations may further be prepared by known methods such as granulation, compression, microencapsulation, spray coating and the like. The compositions can be prepared by conventional methods in the form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections. Liquid formulations can be prepared by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules may be coated in a conventional manner.

In a further aspect, the invention, including any of the methods set forth herein, relates to a method of preparing a compound of any of the formulas herein, including reacting one or more compounds of any of the formulas set forth herein. The compound of formula (I) may be prepared by conventional methods or by analogous methods.

The method described above can be performed to provide a compound of the present invention in the form of a free base or acid addition salt. Pharmaceutically acceptable acid addition salts can be obtained by dissolving free base in a suitable organic solvent and treating the solution with acid, according to conventional methods for preparing acid addition salts from base compounds. Examples of addition salt forming acids have been mentioned above.

The compounds of formula (I) may have one or more chiral carbon atoms, so they are optical isomers, for example as pure enantiomers or as a mixture of enantiomers (racemates), or of mixtures comprising diastereomers. In form. Separation of mixtures of optical isomers to obtain pure enantiomers is well known in the art and can be achieved, for example, by fractional crystallization of salts using optically active (chiral) acids or by chromatographic separation on a chiral column. .

Chemicals used in the synthetic routes set forth herein include, for example, solvents, reagents, catalysts and protecting and deprotecting reagents. The methods described above may also further comprise steps for adding or removing suitable protecting groups, before or after the steps specifically described herein, to ultimately enable the synthesis of the compounds. In addition, various synthetic steps may be performed in order of rotation or in order to provide the desired compound. Synthetic chemical conversion and group protection methods (protection and deprotection) useful for the synthesis of applicable compounds are known in the art, for example in R. Larock, Comprehensive Organic Transformations , VCH Publishers (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3 ^rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis , John Wiley and Sons (1994); And L. Paquette ed., Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons (1995) and their subsequent edits.

Starting materials required for the preparation of compounds of formula I are known or can be prepared analogously to the preparation of known compounds. Dosage levels and frequency of administration of a particular compound can affect the influence of the particular compound employed, metabolic stability and length of action of the compound, age, weight, general health, sex, regimen, mode and time of administration, excretion, drug combination, treatment of the patient. The severity of the condition and the patient under treatment can vary. Daily dosages range from, for example, from about 0.001 mg to about 100 mg per kg body weight when administered once or several times, eg, at a dose of about 0.01 mg to about 25 mg, respectively. In general, the dosage is given orally, but parenteral administration may also be selected.

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

The following specific examples are to be understood as illustrative only and in no way limit the remainder of the disclosure. Without further elucidation, one skilled in the art will be able to utilize the present invention to its fullest extent based on the description herein. All publications used herein are hereby incorporated by reference in their entirety.

Way

¹ H nuclear magnetic resonance (NMR) and ¹³ C NMR were recorded on Bruker Advance DPX 400, Bruker DRX-500, JEOL JNM-EX 270 or Varian MERCURY plus 400 MHz spectrometer. All spectra were recorded using residual solvent or tetramethylsilane (TMS) as internal standard. Ionspray mass spectrometer (MS) spectra were obtained on a Perkin-Elmer API 150EX mass spectrometer. Preparative HPLC / MS was performed on a Waters / Micromass Platform ZQ system equipped with System A: ACE 5 C8 column (19 × 50 mm) or System B: Xterra MS C18, 5 μm column (19 × 50 mm). The following HPLC equipment was also used: System C: Gilson / YMC AQ C18; 150 × 30 mm; System D: Gilson Finnigan / YMC ODS AQ 5 μm column (20 × 50 mm); System E: Gyncotech HPLC-UV “SYS-2”; Ace C8, 5 μm column (21 × 50 mm) and System F: Gyncotech HPLC-UV “SYS-2”; Ace C8, 5 μm column (30 × 150 mm). Eluents used in systems A, C to F: MeCN in milliQ-water with 0.1% TFA. Eluent used in System B: MilliQ water, MeCN and NH ₄ HCO ₃ (100 mM). Analytical HPLC is Agilent 1100, column: ACE 3 C8 (System A) or column: YMC ODS-AQ (System B) or column: Chromolith C18 (50 × 4.6 mm) (System C), eluent: MilliQ / 0.1% TFA And on MeCN. Preparative flash chromatography was performed on Merck silica gel 60 (230-400 mesh). Reactions performed under controlled microwave energy were performed with Personal Chemistry Smith Creator using 0.5-2 mL, 2-5 mL or 20 mL Smith Process Vials equipped with aluminum caps and diaphragms.

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

Detailed descriptions of the experiments are given for each specific synthesis example. Schemes 1-6 are merely illustrative of some of the ways in which the compounds of the present invention may be synthesized, and various modifications to these synthetic schemes may be made. Any primary or secondary amine nitrogen of R ³ , if present, optionally reacts with a nitrogen protecting group such as tert-butoxycarbonyl (t-BOC) or benzyl in a reaction targeting the compound of formula (I). Can be protected. N-deprotection is then carried out in a conventional manner as described in [Protective Groups in Organic Synthesis, John Wiley & Sons, 1991].

Scheme 1

[Wherein, R = H or SiMe ₃ ,

Hal = Cl, Br, or I,

R ³ is defined in formula (I)].

Scheme 2

[R = H or SiMe ₃ ,

Hal = Cl, Br, or I,

Het = heteroaryl group or heterocyclic group within the R ³ range defined for formula (I). Representative 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,

R ¹ is defined in formula (I)].

Scheme 3

[Hal = Cl, Br, or I,

R ³ and R ¹² are defined in formula (I)].

Scheme 4

[R = H or SiMe ₃ ,

R ³ and R ¹⁴ are defined in formula (I)].

Scheme 5

[R = H or SiMe ₃ ,

R ³ and R ¹⁴ are defined in formula (I)].

Scheme 6

[R = H or SiMe ₃ ,

R ³ and R ¹⁴ are defined in formula (I)].

Scheme 7

R ¹ is defined in formula (I) and Am is attached to the rest of the molecule by a nitrogen atom. Representative Am groups are described in FIG. 1.

1

Wherein each R ¹¹ is independently selected from hydrogen or methyl.

Scheme 8

R ¹² is defined in formula (I) and Am is attached to the rest of the molecule by a nitrogen atom. Representative Am groups are described in FIG. 1.

Scheme 9

R ¹² is defined in formula (I) and Am is attached to the rest of the molecule by a nitrogen atom. Representative Am groups are described in FIG. 1.

Scheme 10

[R ¹² defined in formula (I);

P is a suitable protecting group such as t-BOC and

z = 0, 1 or 2].

Scheme 11

[R ¹ as defined in formula (I);

Suitable protecting groups such as P t-BOC and

z = 0, 1 or 2].

Scheme 12

R ¹ is defined in formula (I) and Am is attached to the rest of the molecule by a nitrogen atom. Representative Am groups are described in FIG. 1.

Scheme 13

R ¹ is defined in formula (I) and Am is attached to the rest of the molecule by a nitrogen atom. Representative Am groups are described in FIG. 1.

Scheme 14

R ¹² is defined in formula (I) and Am is attached to the rest of the molecule by a nitrogen atom. Representative Am groups are described in FIG. 1.

Intermediate 1

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

7-iodo-5-nitro-1-benzofuran (300 mg, 1.0 mmol), xantose (60 mg, 0.1 mmol), Pd ₂ (dba) ₃ (23 mg, 25 mmol in xylene (10 mL) ), Sodium tert-butoxide (125 mg, 1.3 mmol) (Castro, CE; Stephens, RD J. Org. Chem . 1963, 28, 2163 and Doad, GJS; Barltrop, JA; Petty, CM; Owen , TC Tetrahedron Lett. 1989, 30, prepared according to the process of 1597-1598), N, N'-dimethylpropane-1,3-diamine (540 μl, 5 mmol). Mixture Stir at 120 ° C. for 2 hours, allow to cool, then filter through a Celite pad. The filtrate was concentrated in vacuo to afford the crude title compound. MS m / z 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) is dissolved in DCM (10 mL), DCM (5 mL ) Di-tert-butyl dicarbonate (327 mg, 1.5 mmol) was added at 0 ° C. The mixture was stirred at 0 ° C. for 15 minutes, then the ice bath was removed and the mixture was stirred for 2 hours at room temperature. Water was added, the organic material was extracted with chloroform (2 ×), and the combined organic layers were dried (MgSO ₄ ) and filtered. The volatiles were evaporated to give a yellow oil which was filtered over silica gel and eluted with EtOAc. The volatiles were evaporated and the crude material of tert-butyl methyl [3- (methyl {5-nitro-1-benzofuran-7-yl} amino)] propyl] carbamate dissolved in EtOH, EtOH (4 mL Raney nickel excess was added as a suspension in) followed by hydrazine hydrate (300 μL, 6 mmol). The reaction mixture was stirred at rt for 2 h and filtered through a pad of celite pretreated with water. The celite pad was washed with MeOH and the filtrate was concentrated in vacuo to afford the crude title compound (250 mg) which was used directly in the next step.

Intermediate 3

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

Benzenesulfonyl chloride (115 μl, 0.9 mmol) was added tert-butyl 3-[(5-amino-1-benzofuran-7-yl) (methyl) amino] propyl (methyl) carbamate in DCM (2 mL) Intermediate 2: 250 mg, 0.75 mmol) was added to the mixture, followed by pyridine (1 ml). The reaction mixture was stirred at rt for 4 h. The volatiles were evaporated in vacuo and the residue obtained was purified using RP-HPLC (Gilson / YMC AQ C18; 150x30 mm) and the title compound was obtained as beige oil (202 mg, 43% over 4 steps). Was done; HPLC 93%, R _T : 2.49 min (System A); 95%, R _T : 2.27 min (System B); ¹ H NMR (CDCl ₃ ) δ ppm 1.41 (s, 9H), 1.60-1.75 (m, 2H), 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), 7.33-7.58 (m, 4H), 7.71-7.79 (m, 2H); MS m / z 474 (M + H) ⁺ .

Example 1

N- (7- {methyl [3- (methylamino) propyl] amino} -1-benzofuran-5-yl) benzenesulfonamide hydrochloride

Tert-butyl methyl [3- (methyl {5-[(phenylsulfonyl) amino] -1-benzofuran-7-yl} amino) propyl] carbamate (Intermediate 3; 202 mg, 0.43 in DCM (2 mL)) mmol) was treated with TFA (2 mL) at 0 ° C. for 10 minutes and stirred at room temperature for an additional 30 minutes. After concentration in vacuo, the residue was re-dissolved in MeOH and treated with excess 1M HCl in diethyl ether. Removal of the solvent gave the title compound (173 mg, 98%) as a white solid; HPLC 100%, R _T : 1.65 min (System A); 100%, R _T : 0.630 min (System B); ¹ H NMR (Methanol- d 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); MS m / z 374 (M + H) ⁺ .

Intermediate 4

1- (5-nitro-1-benzofuran-7-yl) piperidine

Step 1. 2-Bromo-6-iodo-4-nitrophenol. A solution of 4-nitrophenol (130 g, 0.96 mol) in acetonitrile (500 mL) was cooled to 0 ° C. Chlorosulfonic acid (120 g, 1.03 mol) was added while maintaining the temperature below 5 ° C. The resulting mixture was stirred at 0-5 ° C. for 30 minutes. N-bromosuccinimide (181 g, 1.01 mol) was added to the mixture partially for 7 hours while maintaining the temperature below 8 ° C. The reaction was then quenched by adding a solution of NaHSO ₃ (250 g, 2.4 mol) in water (600 mL) while maintaining the temperature below 20 ° C. The aqueous phase was removed and the remaining organic phase was 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. The temperature was adjusted to 50 ° C. and ICl (152 g, 0.936 mol) was added while maintaining the temperature at 50 to 80 ° C. When the addition was complete, water (1000 mL) was added to precipitate the product. After cooling to 10 ° C., the product was isolated by filtration to yield 290 g (90%) of 2-bromo-6-iodo-4-nitrophenol. ¹ H NMR (270 MHz, CDCl ₃ ) δ ppm 6.53 (s, 1 H) 8.42 (d, J = 2.72 Hz, 1 H) 8.58 (d, J = 2.72 Hz, 1 H).

Step 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), CuI (2.22 g, 11.63 mmol) and Et ₃ N ( 117.70 g, 1163.12 mmol) was added. N ₂ atmosphere was established and (trimethylsilyl) acetylene (59.98 g, 610.64 mmol) was added slowly for 2 hours followed by PdCl ₂ (PPh ₃ ) ₂ (4.08 g, 5.82 mmol). The reaction mixture was stirred overnight until intermediate 2-bromo-4-nitro-6-[(trimethylsilyl) ethynyl] phenol was fully formed and then heated to 85 ° C. for 8 hours. The mixture was diluted with acetonitrile (1500 mL) and activated carbon (6 g) was added followed by water (600 mL). The resulting suspension was heated to 85 ° C. and carbon was removed by filtration. After distillation, the volume was adjusted to 1950 mL by the addition of water (1600 mL). The product was obtained as an oily precipitate that solidified on cooling. The liquid was poured off and the solid residue was dissolved in acetonitrile (500 mL). The volatiles were removed to yield 149.7 g (82%) of 7-bromo-5-nitro-2- (trimethylsilyl) -benzofuran. ¹ H NMR (270 MHz, CDCl ₃ ) δ ppm 0.39 (s, 9 H) 7.12 (s, 1 H) 8.38 (d, J = 2.23 Hz, 1 H) 8.42 (d, J = 2.23 Hz, 1 H) .

Step 3. 1- (5-Nitro-1-benzofuran-7-yl) piperidine. 7-bromo-5-nitro-2- (trimethylsilyl) benzofuran (1.57 g, 5 mmol; obtained in step 2), piperidine (0.47 g, 5.5. Mmol) in xylene (15 mL), A mixture of Pd (OAc) ₂ (56 mg, 0.25 mmol), BINAP (0.31 g, 0.5 mmol) and NaOtBu (0.96 g, 10 mmol) was stirred at 110 ° C. for 6 hours. The cooled mixture was filtered through celite and concentrated to afford an oil, which was placed in an SiO ₂ -colum and eluted with EtOAc / hexanes (25:75) to give 1- (5-nitro-1-benzofuran-7 -Yl) piperidine was obtained. Yield: 650 mg (53%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.62-1.70 (m, 2 H), 1.77-1.85 (m, 4 H), 3.36 (t, 4 H), 6.86 (d, 1 H), 7.64 ( d, 1 H), 7.73 (d, 1 H), 8.09 (d, 1 H); GC-MS (EI +) m / z 246 M ⁺ for C ₁₃ H ₁₄ N ₂ O ₃ .

Intermediate 5

4- (5-nitro-1-benzofuran-7-yl) morpholine

Prepared according to the procedure of Intermediate 4 (Step 3) starting from morpholine. Yield: 460 mg (37%); ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.40-3.45 (m, 4 H), 3.94-3.98 (m, 4 H), 6.90 (d, 1 H), 7.64 (d, 1 H), 7.74 ( d, 1 H), 8.15 (d, 1 H); C ₁₂ H ₁₂ N ₂ O ₄ GC-MS (EI +) m / z 248 (M) ^{+ for} .

Intermediate 6

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

Dissolve 1- (5-nitro-1-benzofuran-7-yl) piperidine (630 mg, 2.56 mmol; Intermediate 4) in EtOAc (50 mL), add PtO ₂ , and mix the mixture for 36 hours. Stir under H ₂ . Filtration through celite and concentration of the filtrate provided 7-piperidin-1-yl-1-benzofuran-5-amine. Yield: 540 mg (98%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.59-1.65 (m, 2 H), 1.71-1.83 (m, 4 H), 3.21-3.26 (m, 4 H), 3.55 (br s, 2 H) , 6.19 (d, 1 H), 6.45 (d, 1 H), 6.56 (d, 1 H), 7.51 (d, 1 H); C ₁₃ H ₁₆ N ₂ O GC-MS (EI +) m / z for 216 M ⁺ .

Intermediate 7

7-morpholin-4-yl-1-benzofuran-5-amine

Prepared according to the procedure of intermediate 6 starting from 4- (5-nitro-1-benzofuran-7-yl) morpholine (intermediate 5). Yield: 520 mg (98%); ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.28-3.32 (m, 4 H), 3.56 (br s, 2 H), 3.91-3.95 (m, 4 H), 6.17 (d, 1 H), 6.50 (d, 1 H), 6.58 (d, 1 H), 7.50 (d, 1 H); GC-MS (EI +) m / z 218 (M) ⁺ for C ₁₂ H ₁₄ N ₂ O ₂ .

Example 2

N- (7-piperidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide

Synthesis was performed following the procedure of intermediate 3 starting from 7-piperidin-1-yl-1-benzofuran-5-amine (intermediate 6). Yield: 70 mg (39%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.57-1.62 (m, 2 H), 1.70-1.78 (m, 4 H), 3.16 (t, 4 H), 6.39 (br s, 1 H), 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); MS (ESI +) for C ₁₉ H ₂₀ N ₂ O ₃ S m / z 357 (M + H) ⁺ ; HPLC 97% (System A).

Example 3

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

Synthesis was performed following the procedure of intermediate 3 starting from 7-piperidin-1-yl-1-benzofuran-5-amine (intermediate 6). Yield: 55 mg (29%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.56-1.65 (m, 2 H), 1.70-1.79 (m, 4 H), 3.19 (t, 4 H), 6.43 (d, 1 H), 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, CDCl ₃ ) 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; MS (ESI +) for C ₁₉ H ₂₀ N ₂ O ₃ S m / z 375 (M + H) ⁺ . HPLC 100% (System A).

Example 4

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

Synthesis was carried out according to the procedure of intermediate 3 starting from 7-piperidin-1-yl-1-benzofuran-5-amine (intermediate 6). Yield: 100 mg (48%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.52-1.57 (m, 2 H), 1.62-1.66 (m, 4 H), 3.09-3.15 (m, 4 H), 3.69 (s, 3 H), 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, 1 H), 9.80 (br s, 1 H); MS (ESI +) for C ₂₁ H ₂₄ N ₂ O ₅ S m / z 417 (M + H) ⁺ ; HPLC 100% (System A).

Intermediate 8

1- (5-nitro-1-benzofuran-7-yl) pyrrolidine

Synthesis was performed as described for intermediate 4 (step 3). Yield 26%. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.03-2.08 (m, 4 H), 3.66-3.72 (m, 4 H), 6.82 (d, 1 H), 7.23 (d, 1 H), 7.67 ( d, 1 H), 7.81 (d, 1 H); GC-MS (EI +) m / z 232 M ⁺ for C ₁₂ H ₁₂ N ₂ O ₃ .

Intermediate 9

7-pyrrolidin-1-yl-1-benzofuran-5-amine

Synthesis was performed as described for intermediate 6. Yield 48%. MS (ESI +) for C ₁₂ H ₁₄ N ₂ O m / z 203 (M + H) ⁺ .

Example 5

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

The title compound was prepared following the procedure of intermediate 3 starting from 7-pyrrolidin-1-yl-1-benzofuran-5-amine (intermediate 9). Yield: 70 mg (43%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.88-1.93 (m, 4 H), 3.38-3.43 (m, 4 H), 3.71 (s, 3 H), 3.75 (s, 3 H), 6.16 (d, 1 H), 6.60 (d, 1 H), 6.75 (d, 1 H), 7.01 (d, 1 H), 7.24-7.29 (m, 2 H), 7.80 (d, 1 H), 9.71 (s, 1 H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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; MS (ESI +) for C ₂₀ H ₂₂ N ₂ O ₅ S m / z 403 (M + H) ⁺ ; HPLC 98% (System A).

Example 6

N- (7-pyrrolidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide

The title compound was prepared following the procedure of intermediate 3 starting from 7-pyrrolidin-1-yl-1-benzofuran-5-amine (intermediate 9). Yield: 30 mg (22%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.86-1.93 (m, 4 H), 3.36-3.43 (m, 4 H), 6.13 (br s, 1 H), 6.59 (br s, 1 H ), 6.73 (d, 1 H), 7.45-7.60 (m, 3 H), 7.73 (d, 2 H), 7.79 (d, 1 H), 9.92 (s, 1 H); ^{13 C NMR (100 MHz, DMSO-} d 6) 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; MS (ESI +) for C ₁₈ H ₁₈ N ₂ O ₃ S m / z 343 (M + H) ⁺ ; HPLC 95% (System A).

Example 7

4-fluoro-N- (7-pyrrolidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride

The title compound was prepared following the procedure of intermediate 3 starting from 7-pyrrolidin-1-yl-1-benzofuran-5-amine (intermediate 9). Yield: 65 mg (41%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.87-1.94 (m, 4 H), 3.38-3.44 (m, 4 H), 6.13 (d, 1 H), 6.58 (d, 1 H), 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- d ₆ ) δ 24.73, 48.85, 100.97, 101.73, 106.99, 116.13, 116.36, 128.38, 129.71, 1129.80, 133.51, 134.59, 135.99, 140.77, 145.48, 162.88, 165.38; C ₁₈ H ₁₇ FN ₂ O ₃ S MS (ESI +) for m / z 361.0 (M + H) ⁺ ; HPLC 98%.

Example 8

4-fluoro-N- (7-morpholin-4-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride

The title compound was prepared following the procedure of intermediate 3 starting from intermediate 7. Yield: 100 mg (53%); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.08-3.14 (m, 4 H), 3.72-3.78 (m, 4 H), 6.47 (d, 1 H), 6.83 (d, 1 H), 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- d 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; C ₁₈ H ₁₇ FN ₂ O ₄ S MS (ESI +) for m / z 377.2 (M + H) ⁺ ; HPLC 100%.

Example 9

N- (7-morpholin-4-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride,

The title compound was prepared following the procedure of intermediate 3 starting from intermediate 7. Yield: 75 mg (42%); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.06-3.12 (m, 4 H), 3.71-3.78 (m, 4 H), 6.46 (d, 1 H), 6.82 (d, 1 H), 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- d ₆ ) 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; MS (ESI +) for C ₁₈ H ₁₈ N ₂ O ₄ S m / z 359.2 (M + H) ⁺ ; HPLC 97%.

Example 10

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

The title compound was prepared following the procedure of intermediate 3 starting from intermediate 7. Yield: 45 mg (21%); ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.23-3.28 (m, 4 H), 3.75 (s, 3 H), 3.89 (s, 3 H), 3.89-3.93 (m, 4 H), 6.53 ( br s, 1 H), 6.65 (d, 1 H), 6.76 (br s, 1 H), 6.82 (d, 1 H), 6.89 (br s, 1 H), 7.18 (d, 1 H), 7.35 (dd, 1 H), 7.57 (d, 1 H); MS (ESI +) for C ₂₀ H ₂₂ N ₂ 0 ₆ S m / z 419.0 (M + H) ⁺ ; HPLC 88%.

Intermediate 10

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

tert -Butyl 4- (5-nitro-1-benzofuran-7-yl) piperazin-1-carboxylate * (1 g, 2.9 mmol) was dissolved in THF / EtOH (1: 4). Excess Raney-Ni (slurry in ethanol) was added followed by hydrazine-hydrate (0.58 g, 11.5 mmol). The reaction mixture was stirred at rt overnight. Filtration and evaporation yielded 1.19 g of the title product, which was used for 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 WO 2002100822.

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

A stock solution of tert -butyl 4- (5-amino-1-benzofuran-7-yl) piperazin-1-carboxylate (0.12 g, 0.378 mmol; intermediate 10) in acetonitrile was charged with K ₂ CO ₃ (52 mg, 0.378 mmol), and to each benzyl bromide (0.378 mmol). The mixture was mixed for 3 hours at room temperature. The reaction process was controlled by LC-MS. Workup: Filtration and purification by preparative HPLC using acetonitrile-water gradient containing 0.1% trifluoroacetic acid. N -deprotection was carried out according to the procedure of Example 1 and treated with 2M HCl in ether to give the target hydrochloride salt.

Example 11

N- (3,5-dimethylbenzyl) -7-piperazin-1-yl-1-benzofuran-5-amine hydrochloride

Prepared by the general procedure A from 1- (bromomethyl) -3,5-dimethylbenzene (75 mg, 0.378 mmol). Yield: 8 mg (6%). HPLC 93%, R _T : 1.240 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 2.30 (s, 6 H) 3.47-3.64 (m, 8 H) 4.52 (s, 2 H) 6.86-6.95 (m, 2 H) 7.08-7.09 ( m, 3H) 7.32 (s, 1H) 7.93 (s, 1H). LC-MS 336 (M + H) ⁺ .

Example 12

N- (3,4-difluorobenzyl) -7-piperazin-1-yl-1-benzofuran-5-amine hydrochloride

Prepared by the general procedure A from 4- (bromomethyl) -1,2-difluorobenzene (78 mg, 0.378 mmol). Yield: 6 mg (5%). HPLC 97%, R _T : 1.499 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 3.46-3.63 (m, 8 H) 4.73 (s, 2 H) 6.86-6.94 (m, 2 H) 7.36 (s, 1 H) 7.49-7.64 ( m, 2H) 7.91-8.00 (m, 2H). LC-MS 344 (M + H) ⁺ .

Example 13

N- (3,5-dimethoxybenzyl) -7-piperazin-1-yl-1-benzofuran-5-amine hydrochloride

Prepared by the general procedure A from 1- (bromomethyl) -3,5-dimethoxybenzene (87 mg, 0.378 mmol). Yield: 8 mg (6%). HPLC 93%, R _T : 1.355 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 3.47-3.65 (m, 8 H) 3.76 (s, 6H) 4.56 (s, 2 H) 6.54 (s, 1H) 6.64 (s, 2H) 6.89 ( s, 1 H) 6.95 (s, 1 H) 7.35 (s, 1 H) 7.92 (s, 1 H). LC-MS 368 (M + H) ⁺ .

Example 14

N-benzyl-7-piperazin-1-yl-1-benzofuran-5-amine hydrochloride

A stock solution of tert -butyl 4- (5-amino-1-benzofuran-7-yl) piperazin-1-carboxylate (0.12 g, 0.378 mmol; intermediate 10) in acetonitrile was charged with K ₂ CO ₃ (52 mg, 0.378 mmol), and to benzyl bromide (65 mg, 0.378 mmol). The mixture was shaken for 3 hours at room temperature. The product was controlled by LC-MS and filtered and purified by preparative HPLC using an acetonitrile-water gradient containing 0.1% trifluoroacetic acid. N-deprotection and conversion to hydrochloride salts were performed by treatment with 2 M HCl in ether. Yield: 19 mg (16.4%). HPLC 92%, R _T : 1.240 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 3.56 (d, 8 H) 4.65 (s, 2 H) 6.94 (s, 2 H) 7.43 (s, 6 H) 7.92 (s, 1 H). LC-MS 308 (M + H) ⁺ .

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

Tert -butyl 4- (5-amino-1-benzofuran-7-yl) piperazine-1-carboxylate (0.12 g, 0.378 mmol; intermediate 10) and pyridine (274 μl, 3.40 in DCM (2 mL) stock solution) was added to each benzoyl chloride (0.454 mmol). The mixture was shaken for 2 hours at room temperature. The product was controlled by LC-MS and the solvent was removed. Purification of the product was carried out by preparative HPLC using an acetonitrile-water gradient containing 0.1% trifluoroacetic acid. The final product was obtained after conversion to the corresponding hydrochloride salt by N -deprotection and treatment of 2 M HCl in ether according to the procedure of Example 1.

Example 15

N- (7-piperazin-1-yl-1-benzofuran-5-yl) benzamide hydrochloride

Prepared by the general procedure B from tert -butyl 4- (5-amino-1-benzofuran-7-yl) piperazin-1-carboxylate (64 mg, 0.454 mmol; intermediate 10). Yield: 3 mg (3%). HPLC 94%, R _T : 1.534 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz Methanol- d ₄ ) δ ppm 3.46-3.61 (m, 8 H) 6.85 (d, J = 2.23 Hz, 1H) 7.28 (d, J = 1.24 Hz, 1H) 7.52-7.59 ( m, 4H) 7.78 (d, J = 1.98 Hz, 1H) 7.95 (d, J = 6.68 Hz, 2H). LC-MS 322 (M + H) ⁺ .

Example 16

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

Prepared by the general procedure B from 4-methoxybenzoyl chloride (77 mg, 0.454 mmol). Yield: 2 mg (1.5%). HPLC 99%, R _T : 1.568 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 3.44-3.61 (m, 8 H) 3.87 (s, 2H) 6.84 (d, J = 2.23 Hz, 1H) 7.04 (d, J = 8.91 Hz , 2 H) 7.27 (d, J = 1.48 Hz, 1 H) 7.52 (d, J = 1.73 Hz, 1 H) 7.77 (d, J = 1.98 Hz, 1 H) 7.93 (d, J = 8.91 Hz, 2 H). LC-MS 352 (M + H) ⁺ .

Example 17

2-bromo-5-methoxy-N- (7-piperazin-1-yl-1-benzofuran-5-yl) benzamide hydrochloride

Prepared by the general procedure B from 2-bromo-5-methoxybenzoyl chloride (113 mg, 0.454 mmol). Yield: 10 mg (6.2%). HPLC 85%, R _T : 1.685 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 3.46-3.48 (m, 4 H) 3.59-3.61 (m, 4 H) 3.84 (s, 3 H) 6.84 (d, J = 1.98 Hz, 1 H ) 6.97 (dd, J = 8.66, 2.72 Hz, 1 H) 7.10 (d, J = 2.97 Hz, 1 H) 7.23 (s, 1 H) 7.54-7.59 (m, 2H) 7.78 (d, J = 1.98 Hz, 1 H). LC-MS 430 (M + H) ⁺ .

Example 18

3-methyl-N- (7-piperazin-1-yl-1-benzofuran-5-yl) benzamide hydrochloride

Prepared by the general procedure B from 3-methylbenzoyl chloride (70 mg, 0.454 mmol). Yield: 14 mg (11.1%). HPLC 93%, R _T : 1.666 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 2.43 (s, 3 H) 3.46-3.62 (m, 8 H) 6.84 (d, J = 1.73 Hz, 1 H) 7.39 (d, J = 4.21 Hz , 2H) 7.76 (d, J = 10.14 Hz, 3H). LC-MS 336 (M + H) ⁺ .

Example 19

N- (7-piperazin-1-yl-1-benzofuran-5-yl) -3- (trifluoromethyl) benzamide hydrochloride

Prepared by the general procedure B from 3- (trifluoromethyl) benzoyl chloride (95 mg, 0.454 mmol). Yield: 12 mg (8.2%). HPLC 88%, R _T : 1.779 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 3.45-3.63 (m, 8 H) 6.86 (d, J = 2.23 Hz, 1H) 7.31 (d, J = 1.73 Hz, 1H) 7.58 (s , 1 H) 7.75-7.79 (m, 2H) 7.92 (s, 1H) 8.24 (m, 2H). LC-MS 390.1 (M + H) ⁺ .

Example 20

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

Prepared by the general procedure B from 2,4-dichlorobenzoyl chloride (95 mg, 0.454 mmol). Yield: 19 mg (12.9%). HPLC 93%, R _T : 1.803 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 3.47-3.62 (m, 8 H) 6.84 (d, J = 2.23 Hz, 1H) 7.21 (d, J = 2.23 Hz, 1H) 7.44-7.78 (m, 5 H). LC-MS 390 (M + H) ⁺ .

Example 21

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

Prepared by the general procedure B from 3,5-dimethoxybenzoyl chloride (91 mg, 0.454 mmol). Yield: 18.3 mg (12.7%). HPLC 91%, R _T : 1.666 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 2.76-7.82 (m, 8 H) 3.04 (s, 6 H) 5.87 (s, 1 H) 6.02 (d, J = 1.57 Hz, 1 H) 6.30 (d, J = 1.57 Hz, 2H) 6.41-6.49 (m, 1H) 6.78-6.79 (m, 1H) 6.98-6.69 (m, 1H). LC-MS 382 (M + H) ⁺ .

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

Stock solution and pyridine of tert -butyl 4- (5-amino-1-benzofuran-7-yl) piperazin-1-carboxylate (0.12 g, 0.378 mmol; intermediate 10) in acetonitrile (2 mL) 274 μl, 3.4 mmol) was added to each aryl isocyanate (0.416 mmol). The mixture was mixed overnight at room temperature. The reaction process was controlled by LC-MS. Work-up: Filtration and purification by preparative HPLC using acetonitrile-water gradient containing 0.1% trifluoroacetic acid. The final product was obtained after conversion to the hydrochloride salt by N -deprotection and treatment of 2 M HCl in ether according to the procedure of Example 1.

Example 22

N- (3,5-dimethoxyphenyl) -N '-(7-piperazin-1-yl-benzofuran-5-yl) urea hydrochloride.

Prepared by the general procedure C (method A) from 1-isocyanato-3,5-dimethoxybenzene (75 mg, 0.416 mmol). Yield: 11 mg (8%). HPLC 100%, R _T : 1.673 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 3.44-3.46 (m, 4 H) 3.56-3.57 (m, 4 H) 3.75 (s, 6 H) 6.78 (d, J = 1.98 Hz, 2 H ) 7.03 (s, 2H) 7.27 (d, J = 1.48 Hz, 1H) 7.72 (d, J = 1.98 Hz, 2H). LC-MS 397 (M + H) ⁺ .

Example 23

N- (2,4-dichlorophenyl) -N '-(7-piperazin-1-yl-benzofuran-5-yl) urea hydrochloride.

Prepared by the general procedure C (method A) from 2,4-dichloro-1-isocyanatobenzene (78 mg, 0.416 mmol). Yield: 9 mg (6%). HPLC 100%, R _T : 1.775 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 3.46-3.47 (m, 4H) 3.58-3.59 (m, 4H) 6.80 (d, J = 1.98 Hz, 1H) 7.06-7.07 (m, 1 H) 7.26 (d, J = 2.23 Hz, 1 H) 7.29 (d, J = 2.47 Hz, 1 H) 7.46 (d, J = 2.47 Hz, 1 H) 7.74 (d, J = 1.98 Hz, 1 H) 8.13 (d, J = 8.91 Hz, 1 H). LC-MS 405 (M + H) ⁺ .

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

A stock solution of tert -butyl 4- (5-amino-1-benzofuran-7-yl) piperazine-1-carboxylate (0.12 g, 0.378 mmol; intermediate 10) in acetonitrile was diluted with triethylamine (158 μL , 1.13 mmol), to each isocyanate (0.416 mmol). The mixture was mixed overnight at room temperature. The reaction process was controlled by LC-MS. Work-up: Filtration and purification by preparative HPLC using acetonitrile-water gradient containing 0.1% trifluoroacetic acid. The final product was obtained after conversion to the corresponding hydrochloride salt by N -deprotection and treatment of 2 M HCl in ether according to the procedure of Example 1.

Example 24

N- (2-methoxyphenyl) -N '-(7-piperazin-1-yl-1-benzofuran-5-yl) urea hydrochloride

Prepared by the above general procedure (method B) from 1-isocyanato-2-methoxybenzene (60 mg, 0.416 mmol). Yield: 33 mg (23.8%). HPLC 93%, R _T : 1.673 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 3.44-3.60 (m, 8 H) 3.92 (s, 3 H) 6.79-6.99 (m, 5 H) 7.12-7.21 (m, 1 H) 7.73 ( d, J = 2.23 Hz, 1 H) 8.05 (d, J = 7.67 Hz, 1 H). LC-MS 367.1 (M + H) ⁺ .

Example 25

N-phenyl-N '-(7-piperazin-1-yl-1-benzofuran-5-yl) urea hydrochloride

Prepared by the above general procedure (method B) from isocyanatobenzene (50 mg, 0.416 mmol). Yield: 31 mg (24.4%). HPLC 93%, R _T : 1.583 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 3.43-3.47 (m, 4H) 3.56-3.60 (m, 4H) 6.80 (d, J = 2.23 Hz, 1H) 7.09-7.21 (m, 2H) 7.22-7.31 (m, 3H) 7.43 (d, J = 8.41 Hz, 2H) 7.74 (d, J = 2.23 Hz, 1H). LC-MS 337 (M + H) ⁺ .

Example 26

N- (3-fluorophenyl) -N '-(7-piperazin-1-yl-benzofuran-5-yl) urea hydrochloride

Prepared by the above general procedure (method B) from 1-fluoro-3-isocyanatobenzene (57 mg, 0.416 mmol). Yield: 5 mg (3.7%). HPLC 93%, R _T : 1.700 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 3.46-3.47 (m, 4 H) 3.57-3.60 (m, 4 H) 6.77-6.81 (m, 2 H) 7.08-7.09 (m, 2 H) 7.22-7.28 (m, 2H) 7.42-7.47 (m, 1H) 7.74 (d, J = 1.98 Hz, 1H). LC-MS 355 (M + H) ⁺ .

Example 27

N- (7-piperazin-1-yl-1-benzofuran-5-yl-)-N '-[trifluoromethyl) phenyl] urea hydrochloride

Prepared by the above general procedure (method B) from 1-isocyanato-3- (trifluoromethyl) benzene (78 mg, 0.416 mmol). Yield: 27 mg (17.7%). HPLC 91%, R _T : 1.932 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 3.44-3.47 (m, 4H) 3.57-3.61 (m, 4H) 6.81 (d, J = 2.23 Hz, 1H) 7.12-7.30 (m, 3H) 7.51 (m, 2H) 7.74 (d, J = 2.23 Hz, 1H) 7.96 (s, 1H). LC-MS 405 (M + H) ⁺ .

Intermediate 11

4- (5-nitro-1-benzofuran-7-yl) pyridine

7-iodo-5-nitrobenzofuran (2.00 g, 0.00692 mol), 4-tributylstannylpyridine (2.80 g, 0.00761 mol), copper (I) iodide (132 mg, 0.692 mmol) and dichlorobis (Triphenylphosphine) palladium (II) (49 mg, 0.0692 mmol) was added to a 50 mL test tube, followed by DMF (20 mL). The mixture was heated at 100 ° C. overnight in StemBlock. After cooling to room temperature, aqueous sodium hydroxide (2 M; 4 mL) was added and the solution 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 ×) and the combined organic phases were evaporated. The residue was then triturated with ether and the precipitate was dried in vacuo overnight to yield a pale brown solid. Yield: 686 mg (41%); HLPC (System A) purity = 99%, m / z = 241 (M + H) +, 1 H NMR (270 MHz, DMSO- d 6) δ ppm 7.33 (d, J = 2.23 Hz, 1 H) 7.98 ( m, 2H) 8.38 (d, J = 2.23 Hz, 1H) 8.50 (d, J = 2.47 Hz, 1H) 8.75 (d, J = 2.23 Hz, 1H) 8.79 (m, 2H).

Intermediate 12

3- (5-nitro-1-benzofuran-7-yl) pyridine

The title compound was prepared following the procedure described for intermediate 11 using 3-tributylstannylpyridine. Yield: 145 mg (35%); HLPC (System A) Purity = 97%, m / z = 241 (M + H) ⁺ , ¹ H NMR (270 MHz, DMSO- d ₆ ) δ ppm 7.32 (d, J = 2.23 Hz, 1 H) 7.63 ( dd, J = 7.79, 4.82 Hz, 1H) 8.33 (m, 1H) 8.36 (d, J = 2.23 Hz, 1H) 8.44 (d, J = 2.47 Hz, 1H) 8.72 (m, 2H) 9.14 (d, J = 1.73 Hz, 1 H).

Intermediate 13

2- (5-nitro-1-benzofuran-7-yl) pyridine

The title compound was prepared following the procedure described for intermediate 11 using 2-tributylstannylpyridine. Yield: 282 mg (42%); HLPC (System A) Purity = 98%, m / z = 241 (M + H) ⁺ , ¹ H NMR (270 MHz, DMSO- d ₆ ) δ ppm 7.33 (d, J = 2.23 Hz, 1 H) 7.53 ( m, 1 H) 8.06 (m, 1 H) 8.41 (m, 2 H) 8.72 (d, J = 2.47 Hz, 1 H) 8.84 (m, 1 H) 8.99 (d, J = 2.47 Hz, 1 H) .

Intermediate 14

2- (5-nitro-1-benzofuran-7-yl) pyrazine

The title compound was prepared following the procedure described for intermediate 11 using 2-tributylstannylpyrazine. Yield: 238 mg (57%); HLPC (System A) Purity = 97%, m / z = 242 (M + H) ⁺ , ¹ H NMR (270 MHz, DMSO- d ₆ ) δ ppm 7.35 (d, J = 2.23 Hz, 1 H) 8.43 ( d, J = 2.23 Hz, 1 H) 8.78 (m, 2H) 8.92 (m, 2H) 9.58 (s, 1H).

Intermediate 15

2- (5-nitro-1-benzofuran-7-yl) pyrimidine

The title compound was prepared following the procedure described for intermediate 11 using 2-tributylstannylpyrimidine. Yield: 219 mg (52%); HLPC (System A) purity = 97%, m / z = 242 (M + H) +, 1 H NMR (270 MHz, DMSO- d 6) δ ppm 7.32 (d, J = 2.23 Hz, 1 H) 7.61 ( t, J = 4.95 Hz, 1 H) 8.40 (d, J = 2.23 Hz, 1 H) 8.81 (d, J = 2.47 Hz, 1 H) 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 addition of ethanol (20 mL), Raney-Nickel (slurry in ethanol; 2 mL) and hydrazine hydrate (4 mL) were added and the mixture was left to stir overnight at room temperature. The product was used directly in the subsequent reaction after filtration through celite and evaporation of the solvent.

Example 28

2-methoxy-5-methyl-N- (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 converted to 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 precipitates were combined and dried under vacuum. Yield: 56 mg (55%); HLPC (System A) purity = 98%, m / z = 395 (M + H) +, 1 H NMR (270 MHz, DMSO- d 6) d ppm 2.21 (s, 3 H) 3.87 (s, 3 H) 7.09 (m, 2H) 7.35 (dd, J = 8.54, 2.10 Hz, 1H) 7.56 (m, 2H) 8.14 (d, J = 2.23 Hz, 1H) 8.25 (d, J = 6.68 Hz, 2 H) 8.98 (d, J = 6.68 Hz, 2H) 10.13 (s, 1H).

Example 29

N- (7-pyridin-3-yl-1-benzofuran-5-yl) benzenesulfonamide trifluoroacetate

The title compound was prepared following the procedure described in Example 28 using 3- (5-amino-1-benzofuran-7-yl) pyridine * and purified by preparative HPLC. Yield: 63 mg (51%); HLPC (System A) Purity = 95%, m / z = 351 (M + H) ⁺ , ¹ H NMR (270 MHz, Methanol- d ₄ ) d ppm 6.90 (d, J = 2.23 Hz, 1H) 7.49 ( m, 5H) 7.74 (m, 2H) 7.89 (d, J = 2.23 Hz, 1H) 8.01 (m, 1H) 8.77 (m, 2H) 9.19 (d, J = 1.73 Hz, 1H) . Prepared following the procedure of Intermediate 16 using 3- (5-nitro-1-benzofuran-7-yl) pyridine (Intermediate 12).

Example 30

2-methoxy-5-methyl-N- (7-pyridin-3-yl-1-benzofuran-5-yl) benzenesulfonamide triple luoroacetate

The title compound was prepared following the procedure described in Example 28 using 3- (5-amino-1-benzofuran-7-yl) pyridine * and purified by preparative HPLC (System D). Yield: 67 mg (50%); HLPC (System A) Purity = 97%, m / z = 395 (M + H) ⁺ , ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 2.17 (s, 3 H) 3.95 (s, 3 H) 6.88 (d, J = 2.23 Hz, 1 H) 7.01 (d, J = 8.41 Hz, 1 H) 7.29 (m, 1 H) 7.48 (d, J = 2.23 Hz, 2 H) 7.54 (m, 1 H) 7.86 (d, J = 2.23 Hz, 1 H) 8.10 (m, 1 H) 8.84 (m, 2 H) 9.24 (d, J = 1.98 Hz, 1 H). Prepared following the procedure of Intermediate 16 using 3- (5-nitro-1-benzofuran-7-yl) pyridine (Intermediate 12).

Example 31

N- (7-pyrazin-2-yl-1-benzofuran-5-yl) benzenesulfonamide trifluoroacetate

The title compound was prepared following the procedure described in Example 28 using 2- (5-amino-1-benzofuran-7-yl) pyrazine * and purified by preparative HPLC (System D). Yield: 20 mg (17%), HLPC (System A) purity = 98%, m / z = 352 (M + H) ⁺ , ¹ H NMR (270 MHz, DMSO- d ₆ ) d ppm 7.07 (d, J = 2.23 Hz, 1 H) 7.53 (m, 3 H) 7.76 (m, 2 H) 7.91 (d, J = 1.98 Hz, 1 H) 8.14 (d, J = 2.23 Hz, 1 H) 8.67 (d, J = 2.47 Hz, 1 H) 8.82 (m, 1 H) 9.45 (d, J = 1.73 Hz, 1 H) 10.39 (s, 1 H). Prepared following the procedure of Intermediate 16 using 2- (5-nitro-1-benzofuran-7-yl) pyrazine (Intermediate 14).

Intermediate 17

5- (5-nitro-1-benzofuran-7-yl) pyrimidine

Pd (PPh ₃ ) ₄ (240 mg, 209 mmol) is added to 7-iodo-5-nitro-1-benzofuran (1.00 g, 3.45 mmol) in DME (11 mL) and the resulting mixture is stirred for 10 minutes. Stirred. The color changed from dark red to mustard yellow. Pyrimidine-5-boronic acid (0.24 g, 0.21 mmol) and 1 M Na ₂ CO ₃ (5 mL) were added and the reaction mixture was refluxed at 100 ° C. for 2.5 h. The mixture was concentrated under vacuum and the residue was dissolved in 1 M HCl (50 mL) and washed with diethyl ether (50 mL). The aqueous layer was made basic (pH 8) by addition of K ₂ CO ₃ and extracted with chloroform (3 ×). The combined organic layer was dried over K ₂ CO ₃ , filtered and concentrated to give 0.455 g (55%) of a yellow solid. HPLC 100%, R _T : 1.870 min (System A; 10-97% over 3 min). ¹ H NMR (270 MHz, CDCl ₃ ) d ppm 7.06 (d, J = 2.47 Hz, 1 H) 7.90 (d, J = 2.23 Hz, 1 H) 8.45 (d, J = 2.23 Hz, 1 H) 8.63 ( d, J = 2.23 Hz, 1 H) 9.28-9.31 (m, 3H). LC-MS 242 (M + H) ⁺ .

Intermediate 18

7-pyrimidin-5-yl-1-benzofuran-5-amine

Raney-nickel (slurry in ethanol; 2 mL) and hydrazine (0.378 g, 7.55 mmol) were added 5- (5-nitro-1-benzofuran-7-yl) pyrimidine in ethanol / THF (100 mL: 25 mL). (0.455 g, 1.87 mmol, intermediate 17). The mixture was stirred at rt for 3 h, filtered through celite and concentrated in vacuo to yield 0.317 g (80%) of the title compound as a yellow solid. HPLC 100%, R _T : 0.957 min (System A; 10-97% over 3 min). ¹ H NMR (270 MHz, Methanol- d ₄ ) d ppm 6.77 (d, J = 2.23 Hz, 1 H) 7.05 (q, J = 2.23 Hz, 2 H) 7.76 (d, J = 2.23 Hz, 1 H) 9.14 (s, 1 H) 9.26 (s, 2 H). LC-MS 212 (M + H) ⁺ .

Example 32

N- (7-pyrimidin-5-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride

Benzenesulfonyl chloride (0.093 g, 0.524 mmol) and pyridine (347 mL, 430 mmol) were added to 7-pyrimidin-5-yl-1-benzofuran-5-amine (0.100 g, 0.473 in dichloromethane (2 mL). mmol; intermediate 18). The mixture was stirred at rt for 1 h and the solvent was removed. The crude product was purified by preparative HPLC using an acetonitrile-water gradient containing 0.1% trifluoroacetic acid and then converted to the hydrochloride salt by treatment with 2 M HCL in diethyl ether. This yielded 0.071 g (43%) of the title compound as a yellow solid. HPLC 97%, R _T : 1.863 min (System A; 10-97% over 3 min). ¹ H NMR (500 MHz, DMSO- d ₆ ) d ppm 6.98 (d, J = 2.20 Hz, 1 H) 7.34 (d, J = 2.20 Hz, 1 H) 7.50-7.54 (m, 3H) 7.58-7.60 (m, 1H) 7.80-7.82 (m, 1H) 7.97 (d, J = 2.20 Hz, 1H) 9.10 (s, 2H) 9.20 (s, 1H) 9.87 (s, 1H). GC-MS 351 (M ⁺ ).

Example 33

N -[7- (1-Aza-bicyclo [2.2.2] oct-2-en-3-yl) -benzofuran-5-yl] -2-methoxy-5-methyl-benzenesulfonamide hydrochloride

3-tributylstannanyl-1-aza-bicyclo [2.2.2] oct-2-ene (2.14 g, 5.36 mmol; prepared according to Bioorg. Med. Chem. Lett. 1994 , 4, 2837-2840) Was added to a mixture of 7-iodo-5-nitro-benzofuran (0.52 g, 1.79 mmol), Pd (PPh ₃ ) ₄ (0.206 g, 0.17 mmol) in DMF (10 mL). The mixture was heated at 160 ° C. for 10 minutes in a sealed reaction vessel using controlled microwave energy. The reaction mixture was diluted with CHCl ₃ , then filtered through a pad of celite and concentrated under reduced pressure. The residue was purified using gradient elution, (CHCl ₃ CHCl ₃ + 10% MeOH + 0.4% NH ₃ ) and then repeated chromatography on silica with CHCl ₃ + 10% MeOH + 0.4% NH ₃ to give 399.5 mg of 3- (5-nitro-benzofuran-7-yl) -1-aza-bicyclo [2.2.2] oct-2-ene was obtained. The intermediate was dissolved in a solvent system of EtOH: THF (4: 1; 20 mL), Raney-Ni (˜1.0 mL in EtOH) was added followed by hydrazine monohydrate (6 equiv). The mixture was stirred vigorously for 3 hours and then filtered through celite pretreated with water. The filtrate was concentrated and then toluene was added and re-evaporated to give 340 mg of crude intermediate (7- (1-aza-bicyclo [2.2.2] oct-2-en-3-yl) -benzofuran -5-ylamine) was obtained. Most of this material (325 mg; 1.35 mmol) was dissolved in DCM (5 mL). Pyridine (1.05 mL) was added followed by 2-methoxy-5-methyl-benzenesulfonyl chloride (267 mg, 1.20 mmol). The resulting mixture was stirred at rt for 16 h and then concentrated under reduced pressure. The residue was purified by column chromatography on silica using gradient elution (CHCl ₃ CHCl ₃ + 10% MeOH + 0.4% NH ₃ ) to give 230 mg of free base of the title compound. The free base was dissolved in MeOH and 1 M HCl in ether was added to the solution. More ether was added and the precipitate was collected by filtration to give 182 mg of HCl-salt. The product was dissolved in CH ₃ CN: MeOH (2: 1) and then purified by preparative reverse phase HPLC. The pure HPLC fractions were pooled and then concentrated to give the TFA-salts of the final product. TFA-salt was converted to HCl-salts: yield N- [7- (1-aza-bicyclo [2.2.2] oct-2-en-3-yl) -benzofuran-5-yl] -2- 100 mg of methoxy-5-methyl-benzenesulfonamide hydrochloride; ¹ H NMR (270 MHz, DMSO- d 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 obscured by solvent signal, 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, 1 H), 9.98 (m, s, 1 H); SGC-MS (EI +) m / z 425 (M) ⁺ for C ₂₃ H ₂₄ N ₂ O ₄ .

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) piperazin-1-carboxylate (0.59 g, 1.87 mmol; intermediate 10) was dissolved in DCM. 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 rt overnight. Filtration through a silica plug gave 0.66 g (72%) of the title product. HPLC purity 92%, R _T = 2.56 min (System A; 10-97% MeCN over 3 min). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.48 (s, 9 H) 3.07-3.21 (m, 4 H) 3.51-3.65 (m, 4 H) 6.51 (d, J = 2.0 Hz, 1 H) 6.62 (d, J = 2.3 Hz, 1 H) 6.93 (d, J = 2.0 Hz, 1 H) 7.00 (s, 1 H) 7.18-7.31 (m, 2 H) 7.36-7.47 (m, 1 H) 7.47- 7.57 (m, 2H) 7.90 (dd, J = 7.9, 1.6 Hz, 1H). MS (ESI +) m / z 492.2 (M + H) ⁺ .

Intermediate 20

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

tert -butyl 4- (5-{[(2-chlorophenyl) sulfonyl] amino} -1-benzofuran-7-yl) piperazine-1-carboxylate (0.66 g, 1.34 mmol; intermediate 19) Dissolve in DCM (5 mL) and add TFA (30% solution of TFA in DCM; 5 mL) and stir the mixture for 30 minutes. The solvent was evaporated. The residue was dissolved in water, the pH was adjusted to pH 8 and extracted with EtOAc. The organic layer was dried and evaporated to afford 0.41 g (80%) of the title product which was used for the next step without further purification. HPLC purity 93%, R _T = 1.61 min (System A; 10-97% MeCN over 3 min).

Intermediate 21

1- (5-nitro-1-benzofuran-7-yl) piperazine

Removal of the Nt-BOC group in tert -butyl 4- (5-nitro-1-benzofuran-7-yl) piperazine-1-carboxylate * was carried out according to the procedure of intermediate 20, giving 2.3 g (80% ) Was obtained as a yellow solid. HPLC purity 94%, R _T = 1.37 min (System A; 10-97% MeCN over 3 min). * Already described in WO 2002100822.

Intermediate 22

N, N-diethyl-2- [4- (5-nitro-1-benzofuran-7-yl) piperazin-1-yl] acetamide

1- (5-nitro-1-benzofuran-7-yl) piperazine (0.4 g, 1.6 mmol; Intermediate 21) and 2-chloro- N in the presence of K ₂ CO ₃ (0.45 g, 3.2 mmol) in DMF , A mixture of N -diethylacetamide (0.48 g, 3.2 mmol) was heated at 225 ° C. for 5 minutes using controlled microwave energy. The solvent was evaporated and the residue was triturated with MeCN to give 0.31 g (54%) of the title compound as a yellow solid. HPLC purity 80%, R _T == 1.63 min (System A; 10-97% MeCN over 3 min). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.02 (t, J = 7.0 Hz, 3H) 1.14 (t, J = 7.0 Hz, 3H) 2.58-2.77 (m, 4H) 3.14-3.50 (m, 10H) 7.14 (d, J = 2.3 Hz, 1H) 7.53 (d, J = 2.3 Hz, 1H) 8.18 (dd, J = 12.5, 2.3 Hz, 2H).

Intermediate 23

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

Of the nitro group in N, N-diethyl-2- [4- (5-nitro-1-benzofuran-7-yl) piperazin-1-yl] acetamide (0.3 g, 0.83 mmol; intermediate 22) Reduction was carried out according to the procedure of intermediate 10. Yield: 0.19 g (70%). The material was used for the next step without further purification. MS (ESI +) m / z 331.2 (M + H) ⁺ .

Example 34

2- [4- (5-{[(2-chlorophenyl) sulfonyl] amino} -1-benzofuran-7-yl) piperazin-1-yl] -N, N-diethylacetamide hydrochloride

2- [4- (5-amino-1-benzofuran-7-yl) piperazin-1-yl] -N, N-diethylacetamide (0.095 g, 0.29 mmol; intermediate 23) was obtained from Intermediate 19 According to the procedure it was reacted with 2-chlorobenzenesulfonyl chloride. Yield: 0.06 g (41%) after purification by preparative HPLC (System E; 20-50% MeCN). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.08 (t, J = 6.9 Hz, 3H) 1.15 (t, J = 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, J = 1.0 Hz, 1H) 6.86 (d, J = 1.3 Hz, 1H) 6.93 (d, J = 1.5 Hz, 1 H) 7.47 (t, J = 7.0 Hz, 1 H) 7.60 (q, J = 7.7 Hz, 2 H) 7.91 (d, J = 1.3 Hz, 1 H) 8.01 (d, J = 7.8 Hz, 1 H) 10.08 (s, 1 H) 10.46 (s, 1 H). HPLC purity 92%, R _T = 1.85 min (System A; 10-97% MeCN over 3 min). MS (ESI +) m / z 505.2 (M + H) ⁺ .

Example 35

N, N-diethyl-2- [4- (5-{[(2-methoxy-5-methylphenyl) sulfonyl] amino} -1-benzofuran-7-yl) piperazin-1-yl] a Cetamide Hydrochloride

2- [4- (5-amino-1-benzofuran-7-yl) piperazin-1-yl] -N, N-diethylacetamide (0.095 g, 0.29 mmol; intermediate 23) was obtained from Intermediate 19 According to the procedure it was reacted with 2-methoxy-5-methylphenylsulfonyl chloride. Yield: 0.05 g (33%) after preparative HPLC (System F; 10-50% MeCN). HPLC purity 93%, R _T = 1.87 min (System A; more than 3 min 10-97% MeCN). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.08 (t, J = 7.0 Hz, 3H) 1.16 (t, J = 7.0 Hz, 3H) 2.20 (s, 3H) 3.08-3.45 (m , 7 H) 3.58-3.73 (m, 4 H) 3.87 (s, 3 H) 4.40 (s, 2 H) 6.61 (d, J = 1.8 Hz, 1 H) 6.85 (d, J = 2.0 Hz, 1 H ) 6.93 (d, J = 1.8 Hz, 1 H) 7.04 (d, J = 8.5 Hz, 1 H) 7.32 (dd, J = 8.8, 2.0 Hz, 1 H) 7.52 (d, J = 1.8 Hz, 1 H ) 7.89 (d, J = 2.3 Hz, 1 H) 9.75 (s, 1 H) 10.07 (s, 1 H) MS (ESI +) m / z 515.4 (M + H) ⁺ .

Intermediate 24

3- (7-bromo-1-benzofuran-2-yl) quinuclidin-3-ol

Step 1. 3-[(trimethylsilyl) ethynyl] quinucridin-3-ol.

A mixture of 3-quinuclidinone hydrochloride (24.12 g, 0.149 mol) and Na ₂ CO ₃ (27 g, 0.25 mol) in water (500 mL) was extracted with dichloromethane (500 mL). The organic layer was evaporated to dryness. The residue was dissolved in THF (200 g) and slowly added to a solution of TMS-Li-acetylide (1.1 equiv) in THF (200 g) at 0-5 ° C. When the addition was complete, a NaHCO ₃ solution in water (500 mL) was added. The organic layer was washed with more water (500 mL) and evaporated to dryness to give 20.89 g (63%) of the title compound as a white solid. ¹ H NMR (270 MHz, CDCl ₃ ) δ ppm 0.15 (s, 9 H) 1.27-1.46 (m, 1 H) 1.47-1.73 (m, 1 H) 1.80-2.14 (m, 3 H) 2.61-3.02 ( m, 5H) 3.17 (dd, J = 13.86, 1.73 Hz, 1H) 4.14 (br s, 1H).

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

2,6-dibromonitrophenol (3.0 g, 0.0119 mol), 3-[(trimethylsilyl) ethynyl] quinusidin-3-ol (2.66 g, 0.0119 mol; obtained in step 1), Cu ₂ O (1.70 g, 0.0119 mol) and pyridine (200 mL) were added to a round bottom flask. The resulting mixture was stirred under reflux overnight, filtered through celite and the solvent was evaporated. The residue was purified by chromatography on silica using ethyl acetate (250 mL) and methanol (500 mL) as eluent. The methanol fractions were evaporated to give 1.12 g (29%) of the title compound. HPLC purity = 90%, m / z = 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) to give formic acid (40 mL) was added to the flask. The resulting mixture was heated at reflux overnight. Concentration in vacuo gave 562 mg (99%) of the title product. HPLC purity = 90%, m / z = 305 (M + H) ⁺ .

Intermediate 26

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

Dissolve 3- (7-bromo-1-benzofuran-2-yl) -1-azabicyclo [2.2.2] oct-2-ene (300 mg, 0.986 mmol; Intermediate 25) in methanol (2 mL) I was. A solution of concentrated aqueous ammonia (25%; 10 mL) and CuCl ₂ (15 mg) was added and the resulting mixture was stirred at 120 ° C. for 48 hours. The mixture was passed through a silica plug using methanol / ammonia solution (9: 1) as eluent. Concentration in vacuo gave 236 mg of the crude title product. The material was used directly for subsequent experiments.

Example 36

N -[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 ml, 0.986 mmol) were dissolved in ethanol (5 mL). The mixture was shaken for 2 hours. Purification by preparative HPLC (20-90% acetonitrile / TFA-water gradient). Evaporation gave 47 mg of TFA salt, which was converted to HCl salt by stirring it in HCl / ether. Yield: 37 mg (18%), HPLC purity = 99%, m / z = 381 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 1.74-1.91 (m, 2H) 2.10-2.26 (m, 2 H) 3.15-3.29 (m, 2 H) 3.49-3.57 (m, 1 H) 3.64-3.78 (m, 2 H) 6.97-7.01 (m, 1 H) 7.13-7.28 (m , 3H) 7.38-7.57 (m, 4H) 7.70-7.76 (m, 2H).

Example 37

N -[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 following the same procedure as in Example 36. Yield: 56 mg (25%), HPLC Purity = 99%, m / z = 425 (M + H) ⁺ , ¹ H NMR (270 MHz, CDCl ₃ ) δ ppm 1.77-1.96 (m, 2H) 2.06- 2.20 (m, 2 H) 2.22 (s, 3 H) 3.14-3.32 (m, 2 H) 3.39-3.48 (m, 1 H) 3.55-3.71 (m, 2 H) 3.97 (s, 3 H) 6.89- 6.95 (m, 2H) 7.06-7.29 (m, 5H) 7.41 (dd, J = 7.92, 0.99 Hz, 1H).

Example 38

N- [7- (1-azabicyclo [2.2.2.] Oct-3-yloxy) -1-benzofuran-5-yl] benzenesulfonamide Hydrochloride

Step 1. 3-[(5-nitro-1-benzofuran-7-yl) oxy] quinuclidin.

7-iodo-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) , CuI (0.13 g, 0.69 mmol) and toluene (20 mL) were mixed together and heated at 140 ° C. overnight. The solvent was removed under vacuum and the crude product was purified by flash chromatography (eluent: hexane and chloroform: MeOH: triethylamine; 9: 0.9: 0.1) to give 3-[(5-nitro-1-benzofuran -7-yl) oxy] quinuclidin (3.46 mmol) was obtained.

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

3-[(5-nitro-1-benzofuran-7-yl) oxy] quinuclidin (1.38 g, 4.79 mmol; obtained in step 1) is dissolved in ethanol: THF (100 mL: 25 mL), Raney-nickel (slurry in ethanol; 6 mL) and hydrazine (891 mL, 0.18 mmol) were added. The mixture was stirred at rt for 3 h, then filtered through celite and the solvent removed under vacuum. Purification by crude product flash chromatography [eluent: DCM: methanol (6: 1) and chloroform: MeOH: triethylamine (9: 1: 0.1)] afforded 7- (1-aza bicyclo [2.2.2]. ] Oct-3-yloxy) -1-benzofuran-5-amine (500 mg; 40%) was obtained.

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

Benzenesulfonyl chloride (30 mL, 0.232 mmol) and pyridine (141 mL, 1.74 mmol) were added to 7- (1-azabicyclo [2.2.2] oct-3-yloxy) -1-benzo in DCM (2 mL). To furan-5-amine (0.50 g, 0.194 mmol; obtained in step 2). The mixture was shaken at room temperature for 2 hours and then the solvent was removed under vacuum. Purification of the product was carried out by preparative HPLC using an acetonitrile-water gradient containing 0.1% trifluoroacetic acid. The resulting TFA salt was converted to hydrochloride salt by treatment with 2 M HCl in ether. Yield: 11.0 mg (11.8%). HPLC 100%, R _T : 1.680 (System B; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 0.91 (t, J = 7.05 Hz, 1 H) 1.31 (m, 1 H) 1.89-2.36 (m, 5 H) 3.32-3.46 (m, 4 H ) 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). LC-MS 399 (M + H) ⁺ .

Example 39

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

The title compound was diluted with 7- (1-azabicyclo [2.2.2] oct-3-yloxy) -1-benzofuran-5-amine (obtained in Example 38, step 2) and 2-chlorobenzenesulfonyl chloride (0.49 g, 0.232 mmol) was prepared according to the procedure of Example 38, step 3. Yield: 55 mg (54%). HPLC 100%, R _T : 1.760 (System B; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 1.80-2.35 (m, 5 H) 2.18 (d, J = 7.42 Hz, 1 H) 2.25 (s, 1 H) 3.29-3.30 (m, 2 H ) 3.41 (t, J = 8.04 Hz, 2 H) 3.83 (dd, J = 13.61, 7.92 Hz, 1 H) 3.97 (s, 1 H) 6.73-6.76 (m, 2 H) 6.99-7.05 (m, 2 H) 7.33-7.36 (m, 1H) 7.50-7.54 (m, 1H) 7.70 (t, J = 2.60 Hz, 1H) 7.96 (d, J = 7.67 Hz, 1H). LC-MS 433 (M + H) ⁺ .

Example 40

N- [7- (1-azabicyclo [2.2.2.] Oct-3-yloxy) -1-benzofuran-5-yl] -2-methoxy-5-methylbenzenesulfonamide hydrochloride

The title compound was purified from 7- (1-azabicyclo [2.2.2] oct-3-yloxy) -1-benzofuran-5-amine (obtained in Example 38, step 2) and 2-methoxy-5- Prepared according to the procedure of Example 38, step 3 from methylbenzenesulfonyl chloride (0.51 g, 0.232 mmol). Yield: 80 mg (77%). HPLC 100%, R _T : 1.794 (System B; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 0.92 (d, J = 7.92 Hz, 1 H) 1.28-1.37 (m, 1 H) 1.99 (d, J = 11.13 Hz, 3H) 2.21 (s , 3H) 2.36 (s, 1H) 3.46-3.48 (m, 4H) 3.85 (d, J = 7.18 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, J = 8.41 Hz, 1H) 7.32 (d, J = 7.42 Hz, 1H) 7.49 (s, 1H) 7.70 (d, J = 1.48 Hz, 1 H). LC-MS 443 (M + H) ⁺ .

Intermediate 27

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

7-iodo-5-nitrobenzofuran (1.00 g, 3.46 mmol), 4- (2-aminoethyl) morpholine (0.54 g, 4.15 mmol), NaOt-Bu (0.47 g, 0.00484 mol), xanthose ( 0.20 g, 0.346 mmol) and Pd ₂ dba ₃ (80 mg, 0.0865 mol) were heated in xylene (20 mL) at 120 ° C. for 1.5 h. The reaction mixture was filtered through celite and the solvent was evaporated. The residue was passed through a silica plug using a 90: 9: 1 mixture of DCM / MeOH / NH ₃ (25% aqueous) after dichloromethane (DCM) as eluent. The product-containing fractions were concentrated to give 0.978 g (97%) of the title compound as a dark yellow oil. HPLC purity = 97%, m / z = 292 (M + H) ⁺ , ¹ H NMR (270 MHz, CDCl ₃ ) δ ppm 2.44-2.61 (m, 4 H) 2.75 (t, J = 5.81 Hz, 2 H ) 3.31-3.43 (m, 2 H) 3.69-3.82 (m, 4 H) 6.85 (d, J = 1.98 Hz, 1 H) 7.36 (d, J = 1.98 Hz, 1 H) 7.70 (d, J = 1.98 Hz, 1H) 7.90 (d, J = 2.23 Hz, 1H).

Intermediate 28

N ⁷ -(2-morpholin-4-ylethyl) -1-benzofuran-5,7-diamine

(2-Morpholin-4-ylethyl) (5-nitro-1-benzofuran-7-yl) amine (450 mg, 1.545 mmol; Intermediate 27) was dissolved in THF (5 mL). Ethanol (100 mL), Raney-nickel (cat.) And hydrazine hydrate (2 mL) were added and then the mixture was left to stir at room temperature for 2 hours. The product was filtered through celite and the solvent was evaporated and used directly in the subsequent reaction.

Intermediate 29

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

In a test tube, 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 CuI (130 mg, 0.692 mmol) were added. Toluene (15 mL) was added and the solution was heated in StemBlock for 72 hours. After filtration through celite, the crude material was purified by flash chromatography (EtOAc / DCM; 1: 1). Yield: 32%, HPLC purity = 90%, m / z = 293 (M + H) ⁺ .

Intermediate 30

[7- (2-morpholin-4-ylethoxy) -1-benzofuran-5-yl] amine

The title compound was prepared following the same procedure as Intermediate 28, starting from Intermediate 29. The product was used directly in a continuous reaction (Example 45).

Example 41

N -{7-[(2-morpholin-4-ylethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride

Triethylamine (62 μl in a solution of N ^7- (2-morpholin-4-ylethyl) -1-benzofuran-5,7-diamine (58 mg, 0.221 mmol; Intermediate 28) in dichloromethane (2 mL) , 0.442 mmol) and benzenesulfonyl chloride (39 mg, 0.221 mmol) were added. The mixture was stirred at rt for 1 h and evaporated. The residue was purified by preparative HPLC (System D), the pure fractions were evaporated and the resulting TFA salt was converted to HCl salt. Yield: 32%, HPLC purity = 100%, m / z = 402 (M + H) ⁺ , ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 3.43 (t, J = 6.06 Hz, 2H) 3.40 -3.61 (m, J = 6.06, 6.06 Hz, 4H) 3.68 (t, J = 6.06 Hz, 2H) 3.75-4.14 (m, 4H) 6.48-6.55 (m, 2H) 6.64 (d, J = 2.23 Hz, 1 H) 7.41-7.59 (m, 3H) 7.65-7.74 (m, 3H).

Example 42

2-methoxy-5-methyl- N -{7-[(2-morpholin-4-ylethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride

The title compound was prepared following the procedure in Example 41. Yield: 37%, HPLC purity = 100%, m / z = 446 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 2.18-2.24 (s, 3H) 3.35-3.60 ( m, 4 H) 3.43 (t, J = 5.94 Hz, 2 H) 3.67 (t, J = 5.94 Hz, 2 H) 3.74-4.07 (m, 4 H) 3.94-3.99 (m, 3 H) 6.51 (d , J = 1.98 Hz, 1 H) 6.63 (dd, J = 4.08, 2.10 Hz, 2 H) 7.03 (d, J = 8.41 Hz, 1 H) 7.32 (dd, J = 8.78, 2.60 Hz, 1 H) 7.49 (d, J = 2.23 Hz, 1 H) 7.64 (d, J = 2.23 Hz, 1 H).

Example 43

N -{7-[(2-morpholin-4-ylethyl) amino] -1-benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide hydrochloride

The title compound was prepared following the procedure in Example 41. Yield: 38%, HPLC purity = 100%, m / z = 470 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 3.15-3.63 (m, 4H) 3.43 (t, J = 5.94 Hz, 2H) 3.67 (t, J = 6.06 Hz, 2H) 3.72-4.14 (m, 4H) 6.49 (d, J = 1.73 Hz, 1H) 6.64 (dd, J = 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- N -{7-[(2-morpholin-4-ylethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride

The title compound was prepared following the procedure in Example 41. Yield: 19%, HPLC purity = 100%, m / z = 470 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 3.22-3.60 (m, 4H) 3.45 (t, J = 5.94 Hz, 2 H) 3.69 (t, J = 5.94 Hz, 2 H) 3.72-4.13 (m, 4 H) 6.58 (d, J = 1.98 Hz, 1 H) 6.67 (dd, J = 9.65, 1.98 Hz, 2H) 7.33-7.41 (m, 1H) 7.45-7.52 (m, 2H) 7.66 (d, J = 1.98 Hz, 1H).

Example 45

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

The title compound was prepared following the procedure of Example 41 starting from [7- (2-morpholin-4-ylethoxy) -1-benzofuran-5-yl] amine (intermediate 30). Yield: 32%, HPLC purity = 99%, m / z = 447 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 2.20 (s, 3H) 3.26-3.74 (m, 4 H) 3.66-3.72 (m, 2 H) 3.75-4.15 (m, 4 H) 3.96 (s, 3 H) 4.49-4.57 (m, 2 H) 6.73 (d, J = 2.23 Hz, 1 H) 6.85 (d, J = 1.98 Hz, 1 H) 6.96 (d, J = 1.98 Hz, 1 H) 6.99-7.04 (m, 1 H) 7.27-7.34 (m, 1 H) 7.51 (d, J = 2.23 Hz, 1 H) 7.70 (d, J = 2.23 Hz, 1 H).

Example 46

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

The title compound was prepared following the procedure of Example 41 starting from [7- (2-morpholin-4-ylethoxy) -1-benzofuran-5-yl] amine (intermediate 30). Yield: 28%, HPLC purity = 98%, m / z = 417 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d 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, J = 2.23 Hz, 1H) 6.82 (d, J = 1.98 Hz, 1 H) 6.89 (d, J = 1.98 Hz, 1 H) 7.27-7.40 (m, 2H) 7.46-7.57 (m, 2H) 7.73 (d, J = 2.23 Hz, 1H).

Example 47

3-chloro-4-methyl- N -[7- (2-morpholin-4-ylethoxy) -1-benzofuran-5-yl] benzenesulfonamide Hydrochloride

The title compound was prepared following the procedure of Example 41 starting from [7- (2-morpholin-4-ylethoxy) -1-benzofuran-5-yl] amine (intermediate 30). Yield: 11%, HPLC Purity = 99%, m / z = 451 (M + H) ⁺ , ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 2.36-2.39 (m, 3H) 3.31-3.71 ( m, 4 H) 3.68-3.74 (m, 2H) 3.75-4.22 (m, 4H) 4.54-4.61 (m, 2H) 6.77 (d, J = 1.98 Hz, 1H) 6.87 (q, J = 1.98 Hz, 2 H) 7.35-7.40 (m, 1 H) 7.48-7.54 (m, 1 H) 7.66 (d, J = 1.73 Hz, 1 H) 7.75 (d, J = 1.98 Hz, 1 H).

Intermediate 31

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

Xylene (75 mL) to 7-iodo-5-nitro-1-benzofuran (1.00 g, 3.46 mmol), N , N -dimethylethane-1,2-diamine (0.37 g, 4.15 mmol), Pd ₂ (dba) ₃ (0.08 g, 0.87 mmol), Xantphos (0.20 g, 0.35 mmol) and Cs ₂ CO ₃ (1.59 g, 4.84 mmol). The mixture was stirred at 120 ° C. overnight, filtered through celite and the solvent removed under vacuum. Purification by crude product flash chromatography [eluent: DCM: MeOH (6: 1) and DCM: MeOH: Et ₃ N (9: 1: 0.1)] gave 0.378 g (44%) of the title compound. HPLC 90%, R _T : 1.430 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 2.44 (d, J = 3.22 Hz, 6H) 2.81 (t, J = 6.56 Hz, 2H) 3.52 (t, J = 6.56 Hz, 2H) 6.97 (d, J = 2.23 Hz, 1 H) 7.40 (d, J = 2.23 Hz, 1 H) 7.89 (t, J = 1.98 Hz, 2 H). LC-MS 250 (M + H) ⁺ .

Example 48

N- (7-{[2 (dimethylamino) ethyl] amino} -1-benzofuran-5-yl) -2-methoxy-5-benzenesulfonamide

Step 1. N ⁷ -[2- (dimethylamino) ethyl] -1-benzofuran-5,7-diamine.

Raney-nickel (slurry in ethanol; 2 mL) and hydrazine (295 μL, 6.08 mmol) were added [2- (dimethylamino) ethyl] (5-nitro-) in a mixture of ethanol (100 mL) and THF (25 mL). To 1-benzofuran-7-yl) amine (0.378 g, 1.52 mmol; intermediate 31). The reaction mixture was stirred at rt for 2 h. Additional Raney-Nickel (slurry in ethanol; 2 mL) and hydrazine (295 μl, 6.08 mmol) were added and stirring continued overnight. The mixture was filtered through celite and the solvent was removed. The crude product was used for the next step without further purification.

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

2-methoxy-5-methylbenzenesulfonyl chloride (0.145 g, 0.657 mmol) and pyridine (398 μl, 4.93 mmol) were added with N ^7- [2- (dimethylamino) ethyl]-in DCM (1 mL). To 1-benzofuran-5,7-diamine (0.120 g, 0.547 mmol; that of Step 1). The mixture was shaken for 1 hour at room temperature, the solvent was removed in vacuo and the product was purified by preparative HPLC using an acetonitrile-water gradient containing 0.1% trifluoroacetic acid. The resulting TFA salt was treated with 2M HCl in ether to convert to a hydrochloride salt to give 13.3 mg (6%) of the title product. HPLC 99%, R _T : 1.692 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 2.21 (s, 3 H) 2.94 (s, 6 H) 3.40 (t, J = 5.69 Hz, 2 H) 3.60-3.64 (m, 2H) 3.97 (s, 3H) 6.52 (s, 1H) 6.64 (t, J = 2.10 Hz, 1H) 7.03 (d, J = 8.41 Hz, 1H) 7.32 (d, J = 6.19 Hz, 1H) 7.50 (d, J = 1.98 Hz, 1 H) 7.65 (d, J = 2.23 Hz, 2 H). LC-MS 404 (M + H) ⁺ .

Example 49

2-chloro-N- (7-{[2- (dimethylamino)}-1-benzofuran-5-yl) benzenesulfonamide hydrochloride

2-chlorobenzenesulfonyl chloride (0.139 g, 0.657 mmol) and pyridine (398 μl, 4.93 mmol) were diluted with N ^7- [2- (dimethylamino) ethyl] -1-benzofuran- in DCM (1 mL). To 5,7-diamine (0.120 g, 0.547 mmol; Example 48, step 1). The mixture was shaken for 1 hour at room temperature, the solvent was removed in vacuo and the product was purified by preparative HPLC using an acetonitrile-water gradient containing 0.1% trifluoroacetic acid. The resulting TFA salt was treated with 2M HCl in ether to convert to a hydrochloride salt to give 22.8 mg (10%) of the title product. HPLC 99%, R _T : 1.651 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 2.94 (s, 6 H) 3.40 (s, 2 H) 3.65 (d, J = 1.48 Hz, 2 H) 6.65 (d, J = 1.73 Hz, 1 H) 7.36 (t, J = 7.18 Hz, 2H) 7.50-7.56 (m, 3H) 7.66 (d, J = 1.73 Hz, 1H) 7.97 (d, J = 7.67 Hz, 1H). LC-MS 394 (M + H) ⁺ .

Intermediate 32

N- (5-nitro-1-benzofuran-7-yl) pyridin-4-yl-amine

7-iodo-5-nitro-1-benzofuran (1.00 g, 3.46 mmol) in xylene (200 mL), 4-aminopyridine (0.39 g, 4.15 mmol), xantphos (0.20 g, 0.36 m Mol), Pd ₂ (dba) ₃ (0.08 g, 0.09 mmol) and NaOtBu (0.47 g, 4.84 mmol) were heated at 120 ° C. overnight. The reaction mixture was filtered through celite and a yellow precipitate formed which was collected by filtration to give 0.52 g (60%) of the title product. HPLC 96%, R _T : 1.344 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 6.91-7.12 (m, 4H) 8.00 (d, J = 2.23 Hz, 1H) 8.15-8.24 (m, 2H) 8.37 (d, J = 2.23 Hz, 1 H). LC-MS 256 (M + H) ⁺ .

Intermediate 33

5-amino-1-benzofuran-7-yl) pyridin-4-yl-amine

Raney-nickel (slurry in ethanol; 2 mL) and hydrazine (404 μL, 8.33 mmol) were added N- (5-nitro-1-benzofuran-7-yl) in ethanol (40 mL) and THF (10 mL). To pyridin-4-yl-amine (0.52 g, 2.08 mmol; intermediate 32). The mixture was stirred at rt for 3 h, filtered through celite and the solvent removed in vacuo to yield 0.27 g (53%) of the title product. HPLC 96%, R _T : 0.964 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 6.69 (d, J = 2.23 Hz, 1 H) 6.72 (d, J = 2.23 Hz, 1 H) 6.77 (d, J = 1.98 Hz, 1 H) 6.83 (dd, J = 4.95, 1.48 Hz, 2H) 7.62 (d, J = 1.98 Hz, 1H) 8.08-8.10 (m, 2H). LC-MS 226 (M + H) ⁺ .

Example 50

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

Benzenesulfonyl chloride (65 μl, 0.48 mmol) and pyridine (289 μl, 3.58 mmol) were dissolved in (5-amino-1-benzofuran-7-yl) pyridin-4-yl-amine in DCM (2 mL). (90 mg, 0.40 mmol; Intermediate 33). 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 concentration gradient containing 0.1% trifluoroacetic acid. The resulting TFA salt was treated with 2 M HCl in ether to convert to a hydrochloride salt to give 78.7 mg (45%) of the title product. HPLC 100%, R _T : 1.560 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 6.91 (s, 1 H) 7.04 (d, J = 2.23 Hz, 2H) 7.36 (d, J = 1.98 Hz, 1H) 7.51-7.65 (m , 3H) 7.74-7.77 (m, 2H) 8.03 (d, J = 1.98 Hz, 1H) 8.32 (d, J = 6.93 Hz, 2H) 10.43 (s, 1H) 10.84 (s, 1H ). LC-MS 366 (M + H) ⁺ .

Example 51

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

2-chlorobenzenesulfonyl chloride (101 mg, 0.48 in the same manner as in N- [7- (pyridin-4-ylamino) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride (Example 50) mmol). This gave 60.3 mg (32%) of 2-chloro-N- [7- (pyridin-4-ylamino) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride. HPLC 100%, R _T : 1.639 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 6.92 (s, 1 H) 7.03 (d, J = 2.23 Hz, 1 H) 7.09 (d, J = 1.98 Hz, 1 H) 7.36 (d, J = 2.23 Hz, 1 H) 7.48-7.53 (m, 1 H) 7.60-7.68 (m, 2 H) 8.02-8.06 (m, 2 H) 8.33 (d, J = 7.18 Hz, 2 H) 10.74 (s, 1 H) 10.86 (s, 1 H). LC-MS 400 (M + H) ⁺ .

Example 52

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

2-methoxy-5-methylbenzenesulfonyl chloride in the same manner as in N- [7- (pyridin-4-ylamino) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride (Example 50) (105 mg, 0.48 mmol). This gave 50.9 mg (26%) of 2-methoxy-5-methyl-N- [7- (pyridin-4-ylamino) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride. HPLC 100%, R _T : 1.692 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 2.21 (s, 3 H) 3.86 (s, 3 H) 6.91 (s, 1 H) 7.02-7.09 (m, 3 H) 7.33-7.38 (m, 2 H) 7.55 (d, J = 1.73 Hz, 1 H) 8.00 (d, J = 1.98 Hz, 1 H) 8.32 (d, J = 6.93 Hz, 2 H) 10.04 (s, 1 H) 10.78 (s, 1 H). LC-MS 410 (M + H) ⁺ .

Example 53

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

Step 1. 7-Bromo-2-trimethylsilanyl-benzofuran-5-ylamine.

7-bromo-5-nitro-2-trimethylsilylbenzofuran (5.0 g, 15.9 mmol; Intermediate 4, step 2) over 2.5 bar with PtO ₂ (363 mg, 1.6 mmol) in EtOAc (100 mL) Was reduced overnight at H ₂ . The resulting mixture was filtered through wet celite to give 4.5 g (quantitative) of 7-bromo-2-trimethylsilanyl-benzofuran-5-ylamine.

Step 2. N- (7-Bromo-2-trimethylsilanyl-benzofuran-5-yl) -2-methoxy-5-methyl-benzenesulfonamide.

Using pyridine (3.2 mL, 40 mmol) as the base, the amine from step 1 (4.5 g, 15.9 mmol) was added 2-methoxy-5-methylphenylsulfonyl chloride (3.5 g) in dichloromethane (200 mL). , 15.9 mmol) and 2.5 hours at ambient temperature. The resulting mixture was washed with water, dried and concentrated to 7.4 g (100%) of N- (7-bromo-2-trimethylsilanyl-benzofuran-5-yl) -2-methoxy-5-methyl- Benzenesulfonamide was obtained as a dark orange solid.

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

Bromide (168 mg, 0.36 mmol), ( tert -butoxycarbonyl) piperazine (134 mg, 0.72 mmol), Mo (CO) from step 2 under microwave heating adjusted to 150 ° C./15 min. ₆ (48 mg, 0.18 mmol), trans-di (acetateto) bis [o- (di-o-tolylphosphino) benzyl] dipalladium (II) (Herrmann's catalyst, 36 mg, 0.04 mmol) Heck carbonylation was performed by mixing aqueous K ₂ CO ₃ (4 M; 300 μl, 1.3 mmol) and diglyme (1 mL). This results in (4- [5- (2-methoxy-5-methyl-benzenesulfonylamino) -2-trimethylsilanyl-benzofuran-7-carbonyl] -piperazin-1-car, the product of which TMS remains. Acid tert-butyl ester) was obtained about 50% and the product without TMS, ie about 7% of the title product. Both products were separated neatly by preparative HPLC (Gilson; using a gradient of 30-70% MeCN). TMS product yield: 53 mg (24%) yellow oil. HPLC 100% R _T = 2.06 (System C; 2-95% MeCN over 2 minutes). The TMS group was removed by stirring in t-BuN ⁺ F ⁻ (0.5 mL, 1 M in THF) in THF (3 mL) at ambient temperature for 1 h 20 min. Purification using preparative HPLC (concentration gradient of 30-70% MeCN) gave the additional material of the title product as a yellow oil.

Step 4. 2-methoxy-5-methyl-N- [7- (piperazin-1-ylcarbonyl) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride. Of 4- [5- (2-methoxy-5-methyl-benzenesulfonylamino) -benzofuran-7-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester (step 3) in ethyl acetate HCl / ether was added to the solution to deprotect the Nt-BOC group of the substrate and stirred overnight at ambient temperature. The solution was concentrated to give the title product 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 over 2 min). ¹ H NMR (400 Mz, Methanol- d ₄ ) δ ppm 2.17 (s, 3H), 3.19 (m, 2H), 3.34 (m, 2H), 3.49 (m, 2H), 3.91 (s, 3H), 4.01 (m, 2H), 6.80 (d, J = 2.2 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 7.28 (dd, J = 8.6, 2.0 Hz, 1H), 7.45 (d, J = 2.2 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H). ¹³ C NMR (400 Mz, MeOH- d 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. 166.24 (C = O). MS (ESI) for C ₂₁ H ₂₃ N ₃ O ₅ S m / z 430 (M + H).

Example 54

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

4- [5- (2-methoxy-5-methyl-benzenesulfonylamino) -2-trimethylsilanyl-benzofuran-7-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester in THF LiAlH ₄ (22 mg, 0.56 mmol) was added to a solution of (94 mg, 0.16 mmol; obtained in Example 53, step 3) and stirred at 80 ° C. overnight (only 50% t-BOC- after 3 hours). And conversion to TMS-deprotected bisamine product). The solution was neutralized by addition of aqueous 1 M HCl and extracted with ethyl acetate, but little product in the organic phase. Thus, the resulting aqueous phase was made acidic and then concentrated. Purification by preparative HPLC (Gilson; gradient of 20-50% MeCN) gave 14 mg of pure product as TFA salt. Aqueous 6 M HCl was used to convert to HCl salt. Concentration gave the final product as a white solid. Yield: 15 mg. HPLC 100% R _T = 2.51 min (System A; 30-80% MeCN over 3 min), 0.94 min (System C; 2-95% MeCN over 2 min). ¹ H NMR (400 Mz, MeOH- d ₄ ) δ ppm 2.14 (s, 3H), 2.98 (s, 3H), 3.66 (br m, 9H), 4.69 (s, 2H), 6.80 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 2.2 Hz, 1H), 7.14 (dd, J = 8.3, 2.2 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 2.2 Hz, 1H). MS (ESI) for C ₂₁ H ₂₅ N ₃ O ₄ S m / z 416 (M + H).

Example 55

N- {7-[(3-aminopyrrolidin-1-yl) methyl] -1-benzofuran-5-yl} -2-methoxy-5-methylbenzenesulfonamide hydrochloride

{1- [5- (2-methoxy-5-methyl-benzenesulfonylamino) -2-trimethylsilanyl-benzofuran-7-carbonyl] -pyrrolidin-3-yl} -carbamic acid in THF LiAlH ₄ (22 mg, 0.56 mmol) was added to a solution of tert-butyl ester ^* (84 mg, 0.14 mmol) and the resulting mixture was stirred at 80 ° C. for 4 hours. Ethyl acetate was added and the mixture was washed with 1 M aqueous HCl followed by water, dried and concentrated to afford 37 mg of mono boc-protected diamine. (According to HPLC, a 34% reduction in the furan ring). Purification by preparative HPLC (Gilson; gradient of 40-80% MeCN) gave pure boc-protected diamine. N-deprotection was carried out neatly in 6 M aqueous HCl overnight (at 25 ° C. overnight using HCl / ether to give 25% product and some by-products) before the product was obtained as a yellow solid. Yield: 16 mg. HPLC 92% R _T = 1.30 min (System A; 30-80% MeCN over 3 min), 1.03 min (System C; 2-95% MeCN over 2 min). The peak in the proton NMR spectrum was wide due to the morphological flexibility of the pyrrolidine ring. ¹ H NMR (400 Mz, Methanol- d ₄ ) δ ppm 1.44 (br s, 1H), 2.17 (s, 3H), 2.38 (br s, 1H), 3.37-3.83 (br 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). MS (ESI) for C ₂₁ H ₂₅ N ₃ O ₄ S m / z 416 (M + H). ^* Example 53 following the procedure of (Step 3) pyrrolidin-3-yl-carbamic acid tert- butyl ester prepared from.

Intermediate 34

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

Cis- 3,4-dichlorotetrahydrothiophene 1,1-dioxide (5.0 g, 26.0 mmol) in dioxane (40 mL) to ethane-1,2-diamine in dioxane (25 mL) (10.4 g , 173.0 mmol) was added dropwise at 0 ° C. The mixture was heated at 100 ° C. for 3 hours, then cooled to room temperature and stirring continued overnight. The two layers were separated and the bottom layer containing ethylene diamine and amine salt was washed twice with dioxane. The dioxane layers were combined and the solvent removed in vacuo. The crude product was recrystallized from toluene to give 2.7 g (59%) of the title compound as white crystals. HPLC 98%, R _T : 0.292 (System B; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 2.67-2.76 (m, 2 H) 2.86-2.96 (m, 2 H) 3.13-3.20 (m, 2 H) 3.33-3.44 (m, 2 H) 3.63-3.70 (m, 2H). LC-MS 177 (M + H) ⁺ . ^* Already described in US Pat. No. 3,882,122.

Intermediate 35

1- (5-nitro-1-benzofuran-7-yl) octahydrothieno [3,4-b] pyrazine 6,6-dioxide

Xylene (150 mL) 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), Pd ₂ (dba) ₃ (0.08 g, 0.87 mmol), xantphos (0.20 g, 0.35 mmol) and Cs ₂ CO ₃ (1.59 g, 4.84 mmol) . The resulting mixture was stirred at 120 ° C. overnight, filtered through celite and the solvent removed in vacuo. The crude product was purified by flash chromatography [eluent: DCM and DCM: MeOH (1: 1)] and then recrystallized from MeOH to give 0.354 g (8%) of the title product. HPLC 90%, R _T : 1.390 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, CDCl ₃ ) δ ppm 2.85 (dd, J = 12.62, 7.42 Hz, 1H) 3.16-3.49 (m, 6H) 3.71 (t, J = 11.63 Hz, 1H) 4.02-4.05 (m, 1 H) 5.17-5.25 (m, 1 H) 6.93 (d, J = 2.23 Hz, 1 H) 7.62 (t, J = 2.72 Hz, 1 H) 7.77 (d, J = 1.98 Hz, 1 H ) 8.19 (d, J = 1.98 Hz, 1 H). LC-MS 338 (M + H) ⁺ .

Intermediate 36

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

Raney-nickel (slurry in ethanol; 2 mL) and hydrazine (204 mL, 4.20 mmol) were dissolved in 1- (5-nitro-1-benzofuran-7- in a mixture of THF (20 mL) and EtOH (80 mL). To 1) octahydrothieno [3,4-b] pyrazine 6,6-dioxide (0.354 g, 1.05 mmol; intermediate 35). The resulting mixture was stirred at rt overnight, after which further Raney-nickel (slurry in ethanol; 2 mL) and hydrazine (204 mL, 4.20 mmol) were added and stirring continued overnight. The mixture was filtered through celite and the solvent removed in vacuo to give 0.338 g (quantitative). HPLC 90%, R _T : 0.782 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 2.79 (dd, J = 12.49, 7.30 Hz, 1 H) 2.90-3.25 (m, 4H) 3.43-3.64 (m, 3H) 3.91-3.94 ( m, 1 H) 5.01-5.07 (m, 1 H) 6.33 (d, J = 1.98 Hz, 1 H) 6.61 (dd, J = 12.99, 2.10 Hz, 2 H) 7.62 (d, J = 1.98 Hz, 1 H). LC-MS 308 (M + H) ⁺ .

Example 56

N- [7 (6,6-dioxidohexahydrothieno [3,4-b] pyrazin-1 (2H) -yl) -1-benzofuran-5-yl] -2-methoxy-5- Methylbenzenesulfonamide hydrochloride

2-methoxy-5-methylbenzenesulfonyl chloride (0.094 g, 0.428 mmol) and pyridine (259 μl, 3.21 mmol) were added to 7- (6,6-dioxidohexahydrothier in DCM (1 mL). To [3,4-b] pyrazine-1 (2H) -yl-1-benzofuran-5-amine (0.110 g, 0.357 mmol; intermediate 36) The mixture was shaken at room temperature for 1 hour, The solvent was removed in vacuo and the residue was purified by preparative HPLC using an acetonitrile-water gradient containing 0.1% trifluoroacetic acid The resulting TFA salt was treated with 2 M HCl in ether to give a hydrochloride salt. Conversion resulted in 20.0 mg (11%) of the title product HPLC 98%, R _T : 1.483 (System A; 10-97% MeCN over 3 min) ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 3.08-3.12 (m, 2H) 3.37-3.79 (m, 6H) 3.96 (s, 3H) 4.55 (d, J = 3.96 Hz, 1H) 6.77 (d, J = 2.23 Hz, 1H) 6.84 (d, J = 1.98 Hz, 1 H) 7.03 (d, J = 8.41 Hz, 1 H) 7.12 (d, J = 1.98 Hz, 1 H) 7.31 (dd, J = 8.78, 1.86 Hz, 1 H) 7.51 (d, J = 1.73 Hz, 1 H) 7.74 (d, J = 2.23 Hz, 1 H) LC-MS 492 (M + H) ⁺ .

Example 57

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

Benzenesulfonyl chloride (0.076 g, 0.428 mmol) and pyridine (259 mL, 3.21 mmol) were added to 7- (6,6-dioxidohexahydrothieno [3,4-b] in DCM (1 mL). To pyrazin-1 (2H) -yl-1-benzofuran-5-amine (0.110 g, 0.357 mmol; intermediate 36) The mixture was shaken for 1 hour at room temperature, the solvent removed in vacuo, and 0.1 The residue was purified by preparative HPLC using acetonitrile-water gradient containing% trifluoroacetic acid The resulting TFA salt was converted to hydrochloride salt by treatment with 2 M HCl in ether to 27.0 mg (17%) HPLC 99%, R _T : 1.556 (System A; 10-97% MeCN over 3 minutes) ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 3.17 (d, J = 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, J = 1.98 Hz, 1 H) 7.42-7.54 (m, 3H) 7.69-7.77 (m, 3H) LC-MS 448 (M + H) ⁺ .

Example 58

N -{7-[(2-pyrrolidin-1-ylethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride

To test tubes containing benzenesulfonyl chloride (42 mg, 0.235 mmol) in N ^7- (2-pyrrolidin-1-ylethyl) -1-benzofuran-5,7-diamine in dichloromethane (3 mL) ^* (48 mg, 0.195 mmol) solution was added. After addition of triethylamine (55 μl, 0.391 mmol), the mixture was shaken for 1 hour and then concentrated. The residue was purified by preparative HPLC. The resulting TFA-salts were treated with HCl / ether and evaporated to afford the title compound. Yield: 5%, HPLC purity = 99%, m / z = 386 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 1.95-2.26 (m, 4H) 3.03-3.24 ( m, 2 H) 3.38-3.47 (m, 2 H) 3.58-3.65 (m, 2 H) 3.64-3.77 (m, 2 H) 6.45-6.48 (m, 1 H) 6.55-6.57 (m, 1 H) 6.65 (d, J = 2.23 Hz, 1 H) 7.40-7.59 (m, 3H) 7.67 (d, J = 2.23 Hz, 1 H) 7.68-7.73 (m, 2H). ^* Prepared in two steps starting from 2-pyrrolidin-1-yl-ethylamine: i) Pd-catalyzed amination of 7-iodo-5-nitro-benzofuran according to the procedure of intermediate 31 (5 -Nitro-benzofuran-7-yl)-(2-pyrrolidin-1-yl-ethyl) -amine and ii) according to the procedure of Example 48 (step 1) (5-nitro-benzofuran-7 Nitro group of -yl)-(2-pyrrolidin-1-yl-ethyl) -amine to reduce N ^7- (2-pyrrolidin-1-ylethyl) -1-benzofuran-5,7-diamine Get.

Example 59

2-methoxy-5-methyl- N -{7-[(2-pyrrolidin-1-ylethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride

The title compound was prepared following the procedure described in Example 58. Yield: 18%, HPLC Purity = 98%, m / z = 430 (M + H) ⁺ , ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 1.81-1.92 (m, 2H) 1.96-2.08 ( m, 2 H) 2.18-2.22 (m, 3 H) 3.00-3.12 (m, 2 H) 3.31-3.37 (m, 2 H) 3.39-3.45 (m, 2 H) 3.55-3.63 (m, 2 H) 3.87-3.90 (m, 3H) 6.34-6.37 (m, 1H) 6.59-6.63 (m, 1H) 6.77 (d, J = 2.20 Hz, 1H) 7.03-7.07 (m, 1H) 7.32 ( m, 1 H) 7.48-7.50 (m, 1 H) 7.83 (d, J = 1.88 Hz, 1 H).

Example 60

N -{7-[(2-pyrrolidin-1-ylethyl) amino] -1-benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide hydrochloride

The title compound was prepared following the procedure described in Example 58. Yield: 31%, HPLC purity = 99%, m / z = 454 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d 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, J = 1.98 Hz, 1H) 6.63 (d, J = 1.98 Hz, 1 H) 6.66 (d, J = 2.23 Hz, 1 H) 7.60-7.76 (m, 3 H) 7.88-7.95 (m, 1 H) 7.99-8.05 (m, 1 H).

Example 61

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

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

Example 62

2-methoxy-5-methyl- N -{7-[(3-morpholin-4-ylpropyl) amino] -1-benzofuran-5-yl} benzensulfonamide hydrochloride

The title compound was prepared following the procedure described in Example 58 using N ^7- (3-morpholin-4-yl-propyl) -benzofuran-5,7-diamine. ^* Yield: 5%, HPLC Purity = 98%, m / z = 460 (M + H) ⁺ , ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 1.99-2.15 (m, 2H) 2.18-2.27 (m, 3H) 3.17-3.40 (m, 6H) 3.61-4.05 (m, 6H) 3.94-3.98 (m, 3H) 6.46 (d, J = 1.73 Hz, 1H) 6.53-6.57 (m , 1 H) 6.61 (d, J = 2.23 Hz, 1 H) 6.99-7.06 (m, 1 H) 7.27-7.34 (m, 1 H) 7.47-7.52 (m, 1 H) 7.60 (d, J = 2.23) Hz, 1 H). ^* Prepared in two steps starting from 3-morpholin-4-yl-propylamine: i) Pd-catalyzed amination of 7-iodo-5-nitro-benzofuran according to the procedure of intermediate 31 (3- Obtain morpholin-4-yl-propyl)-(5-nitro-benzofuran-7-yl) -amine and ii) follow the procedure of Example 48 (step 1) to (3-morpholin-4-yl-propyl Reduction of the nitro group of)-(5-nitro-benzofuran-7-yl) -amine to afford N ^7- (3-morpholin-4-yl-propyl) -benzofuran-5,7-diamine.

Example 63

N -{7-[(3-morpholin-4-ylpropyl) amino] -1-benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide hydrochloride

The title compound was prepared following the procedure described in Example 58 using N ^7- (3-morpholin-4-yl-propyl) -benzofuran-5,7-diamine. Yield: 13%, HPLC purity = 99%, m / z = 484 (M + H) ⁺ , ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 1.99-2.15 (m, 2H) 3.03-3.38 ( m, 6H) 3.38-3.57 (m, 2H) 3.62-3.85 (m, 2H) 3.89-4.14 (m, 2H) 6.44 (d, J = 1.98 Hz, 1H) 6.53 (d, J = 1.98 Hz, 1 H) 6.62 (d, J = 2.23 Hz, 1 H) 7.60-7.75 (m, 3H) 7.89-7.94 (m, 1H) 7.99-8.05 (m, 1H).

Example 64

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

The title compound was prepared following the procedure described in Example 58 using N ^7- (3-morpholin-4-yl-propyl) -benzofuran-5,7-diamine. Yield: 15%, HPLC purity = 99%, m / z = 464 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 2.04-2.18 (m, 2H) 2.35-2.40 ( m, 3 H) 3.06-3.24 (m, 2 H) 3.27-3.41 (m, 4 H) 3.44-3.57 (m, 2 H) 3.65-3.81 (m, 2 H) 3.98-4.13 (m, 2 H) 6.43-6.49 (m, 2H) 6.63 (d, J = 1.98 Hz, 1 H) 7.34-7.40 (m, 1 H) 7.47-7.52 (m, 1 H) 7.65 (d, J = 1.98 Hz, 1 H ) 7.66 (d, J = 1.98 Hz, 1 H).

Intermediate 37

{[(2 R ) -1-ethylpyrrolidin-2-yl] methyl} (5-nitro-1-benzofuran-7-yl) amine

Using (R) -2-aminomethyl-1-ethylpyrrolidine, the title compound was prepared following the procedure described in Intermediate 27. Yield: 100%, HPLC purity = 90%, m / z = 290 (M + H) ⁺ .

Intermediate 38

N ⁷ -{[(2 R ) -1-ethylpyrrolidin-2-yl] methyl} -1-benzofuran-5,7-diamine

{[( 2R ) -1-ethylpyrrolidin-2-yl] methyl} (5-nitro-1-benzofuran-7-yl) amine (Intermediate 37), following the procedure described in Intermediate 28 The title compound was prepared. The product obtained was used directly for the next reaction.

Example 65

N -[7-({[(2 R ) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride

The title compound was prepared according to the procedure of Example 41 using N ⁷ -{[( 2R ) -1-ethylpyrrolidin-2-yl] methyl} -1-benzofuran-5,7-diamine. . Yield: 7 mg (8%), HPLC purity = 95%, m / z = 400 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 1.29 (t, J = 7.30 Hz, 3 H) 1.83-2.39 (m, 4 H) 3.05-3.28 (m, 2 H) 3.37-3.54 (m, 1 H) 3.54-3.61 (m, J = 6.06, 3.34 Hz, 2 H) 3.63-3.77 ( m, 2 H) 6.47 (d, J = 1.73 Hz, 1 H) 6.57 (d, J = 1.98 Hz, 1 H) 6.65 (d, J = 2.23 Hz, 1 H) 7.39-7.59 (m, 3 H) 7.65-7.73 (m, 3H).

Example 66

N- [7-({[( 2R ) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -2 -methoxy -5-methylbenzenesulfonamide Hydrochloride

The title compound was prepared according to the procedure of Example 41 using N ⁷ -{[( 2R ) -1-ethylpyrrolidin-2-yl] methyl} -1-benzofuran-5,7-diamine. . Yield: 16 mg (17%), HPLC purity = 97%, m / z = 444 (M + H) ⁺ , ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 1.27 (t, J = 7.18 Hz, 3 H) 1.85-2.20 (m, 2 H) 2.19-2.23 (s, 3 H) 2.24-2.42 (m, 1 H) 3.01-3.28 (m, 3 H) 3.38-3.53 (m, 1 H) 3.54- 3.60 (m, 2H) 3.63-3.81 (m, 2H) 3.94-3.98 (s, 3H) 6.53 (d, J = 1.73 Hz, 1H) 6.64 (dd, J = 3.84, 1.86 Hz, 2H ) 7.00-7.06 (m, 1 H) 7.28-7.35 (m, 1 H) 7.45-7.51 (m, 1 H) 7.64 (d, J = 1.98 Hz, 1 H).

Example 67

N -[7-({[(2 R ) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -2- (trifluoromethyl) benzenesulfonamide hydrochloride

The title compound was prepared according to the procedure of Example 41 using N ⁷ -{[( 2R ) -1-ethylpyrrolidin-2-yl] methyl} -1-benzofuran-5,7-diamine. . Yield: 21 mg (21%), HPLC purity = 99%, m / z = 468 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 1.29 (t, J = 7.30 Hz, 3 H) 1.82-2.39 (m, 4 H) 3.05-3.28 (m, 2 H) 3.40-3.53 (m, 1 H) 3.53-3.61 (m, 2 H) 3.63-3.78 (m, 2 H) 6.50 ( d, J = 1.98 Hz, 1 H) 6.66 (dd, J = 5.57, 2.10 Hz, 2 H) 7.58-7.77 (m, 3 H) 7.88-7.95 (m, 1 H) 7.97-8.05 (m, 1 H ).

Example 68

N -[7-({[(2 R ) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -3-methylbenzenesulfonamide hydrochloride

The title compound was prepared according to the procedure of Example 41 using N ⁷ -{[( 2R ) -1-ethylpyrrolidin-2-yl] methyl} -1-benzofuran-5,7-diamine. . Yield: 15 mg (16%), HPLC purity = 96%, m / z = 414 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 1.29 (t, J = 7.30 Hz, 3 H) 1.81-2.38 (m, 4 H) 2.30-2.34 (s, 3 H) 3.02-3.27 (m, 2 H) 3.39-3.54 (m, 1 H) 3.54-3.61 (m, 2 H) 3.64- 3.79 (m, 2 H) 6.47 (d, J = 1.98 Hz, 1 H) 6.57 (d, J = 1.73 Hz, 1 H) 6.66 (d, J = 2.23 Hz, 1 H) 7.26-7.41 (m, 2 H) 7.44-7.55 (m, 2H) 7.67 (d, J = 1.98 Hz, 3H).

Example 69

N -[7-({[(2 R ) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] thiophene-2-sulfonamide hydrochloride

The title compound was prepared according to the procedure of Example 41 using N ⁷ -{[( 2R ) -1-ethylpyrrolidin-2-yl] methyl} -1-benzofuran-5,7-diamine. . Yield: 17 mg (19%), HPLC purity = 99%, m / z = 406 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 1.30 (t, J = 7.30 Hz, 3 H) 1.82-2.42 (m, 4 H) 3.02-3.28 (m, 2 H) 3.39-3.57 (m, 1 H) 3.57-3.64 (m, 2 H) 3.64-3.82 (m, 2 H) 6.49- 6.54 (m, J = 1.98 Hz, 1 H) 6.64 (d, J = 1.98 Hz, 1 H) 6.69 (d, J = 1.98 Hz, 1 H) 7.04 (dd, J = 4.95, 3.71 Hz, 1 H) 7.43 (dd, J = 3.71, 1.24 Hz, 1 H) 7.63-7.72 (m, 2H).

Example 70

5-chloro- N- [7-({[( 2R ) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] thiophene -2-sulfonamide hydro Chloride

The title compound was prepared according to the procedure of Example 41 using N ⁷ -{[( 2R ) -1-ethylpyrrolidin-2-yl] methyl} -1-benzofuran-5,7-diamine. . Yield: 5 mg (5%), HPLC purity = 99%, m / z = 440 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 1.32 (t, J = 7.30 Hz, 3 H) 1.84-2.42 (m, 4 H) 3.06-3.28 (m, 2 H) 3.44-3.58 (m, 1 H) 3.59-3.65 (m, 2 H) 3.65-3.82 (m, 2 H) 6.52 ( d, J = 1.73 Hz, 1 H) 6.68 (d, J = 1.98 Hz, 1 H) 6.73 (d, J = 2.23 Hz, 1 H) 6.95-6.99 (m, 1 H) 7.22-7.26 (m, 1 H) 7.72 (d, J = 2.23 Hz, 1 H).

Example 71

5-chloro- N -[7-({[(2 R ) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -1,3-dimethyl-1H-pyrazole-4-sulfonamide hydrochloride

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

Example 72

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

The title compound was prepared following the procedure described in Example 58 using N ^7- [3- (2-methyl-piperidin-1-yl) -propyl] -benzofuran-5,7-diamine. Yield: 9%, HPLC purity = 97%, m / z = 428 (M + H) ⁺ , ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 1.29 (d, J = 6.43 Hz, 0.3 H, Rotational isomer) 1.32 (d, J = 6.43 Hz, 3 H) 1.45-2.17 (m, 8 H) 2.91-3.07 (m, 1 H) 3.13-3.27 (m, 3 H) 3.35 (t, J = 6.43 Hz , 2H) 3.39-3.56 (m, 1H) 6.43-6.49 (m, 2H) 6.61 (d, J = 2.23 Hz, 1H) 7.40-7.58 (m, 3H) 7.63 (d, J = 1.98 Hz, 1 H) 7.68-7.74 (m, 2H). * 3- (2-Methyl-piperidin-1-yl)-Prepared in two steps starting from propylamine: i) 7-iodo-5-nitro-benzofuran was converted to Pd- according to the procedure of intermediate 31; Catalyzed Amination to Prepare [3- (2-Methyl-piperidin-1-yl) -propyl]-(5-nitro-benzofuran-7-yl) -amine, and ii) Example 48 (Step 1 N ^7- [3- (2-methyl-piperi) by reducing the nitro group of (3-morpholin-4-yl-propyl)-(5-nitro-benzofuran-7-yl) -amine according to the procedure of Din-1-yl) -propyl] -benzofuran-5,7-diamine.

Example 73

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

The title compound was prepared following the procedure described in Example 58 using N ^7- [3- (2-methyl-piperidin-1-yl) -propyl] -benzofuran-5,7-diamine. Yield: 7%, HPLC purity = 98%, m / z = 472 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 1.29 (d, J = 6.43 Hz, 0.3 H, rotation Isomer) 1.31 (d, J = 6.43 Hz, 3 H) 1.48-2.16 (m, 8 H) 2.18-2.22 (m, 3 H) 2.88-3.05 (m, 1 H) 3.11-3.27 (m, 3 H) 3.31-3.39 (m, 2 H) 3.38-3.55 (m, 1 H) 3.94-3.98 (m, 3 H) 6.46-6.49 (m, 1 H) 6.58 (d, J = 1.98 Hz, 1 H) 6.61 ( d, J = 1.98 Hz, 1 H) 6.99-7.05 (m, 1 H) 7.27-7.34 (m, 1 H) 7.48-7.52 (m, 1 H) 7.60 (d, J = 1.98 Hz, 1 H).

Example 74

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

The title compound was prepared following the procedure described in Example 58 using N ^7- [3- (2-methyl-piperidin-1-yl) -propyl] -benzofuran-5,7-diamine. Yield: 1%, HPLC purity = 97%, m / z = 496 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 1.29 (d, J = 6.43 Hz, 0.3 H, rotation Isomer) 1.33 (d, J = 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, 1 H) 6.46-6.49 (m, 1 H) 6.53 (d, J = 1.98 Hz, 1 H) 6.63 (d, J = 2.23 Hz, 1 H) 7.60-7.76 (m, 3 H ) 7.88-7.94 (m, 1H) 7.99-8.06 (m, 1H).

Example 75

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

The title compound was prepared following the procedure described in Example 58 using N ^7- [3- (2-methyl-piperidin-1-yl) -propyl] -benzofuran-5,7-diamine. Yield: 10%, HPLC Purity = 97%, m / z = 480 (M + H) ⁺ , ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 1.30 (d, J = 6.43 Hz, 0.4 H, rotation Isomer) 1.35 (d, J = 6.43 Hz, 3 H) 1.50-2.16 (m, 8 H) 2.17-2.21 (m, 3 H) 2.93-3.08 (m, 1 H) 3.15-3.27 (m, 3 H) 3.38 (t, J = 6.43 Hz, 2 H) 3.41-3.58 (m, 1 H) 3.70-3.73 (m, 3 H) 6.46-6.49 (m, 1 H) 6.56 (d, J = 1.73 Hz, 1 H ) 6.66 (d, J = 1.98 Hz, 1 H) 7.66 (d, J = 1.98 Hz, 1 H).

Intermediate 39

5- (5-Nitro-benzofuran-7-yl) -pyridin-2-ylamine

7-iodo-5-nitrobenzofuran (289 mg, 1.0 mmol), pinacolborane (192 mg, 1.5 mmol) and PdCl ₂ (dppf) .DCM were added to the test tube with dioxane (4 mL). . Triethylamine (304 mg, 3.0 mmol) was carefully added to the solution and the mixture was heated in StemBlock overnight at 70 ° C. to give 5-nitro-7- (4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl) -1-benzofuran was formed in place. Then 2-amino-5-iodopyridine (220 mg, 1.0 mmol) and aqueous barium hydroxide (1 mL; 2 M) were added. The resulting mixture was stirred overnight at 70 ° C., then filtered through celite and evaporated. The residue was extracted with chloroform / water and evaporated to afford the title product. Yield: 82%, HPLC Purity = 82%, m / z = 256 (M + H) ⁺ .

Intermediate 40

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

The title compound was prepared from 5- (5-nitro-benzofuran-7-yl) -pyridin-2-ylamine (intermediate 39) following the procedure of intermediate 28. The product was used directly in the subsequent reaction.

Example 76

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

5- (5-amino-1-benzofuran-7-yl) pyridin-2-amine, following the procedure of Example 41 except that flash chromatography (eluent: 30% EtOAc in hexanes) was used in the purification step. The title compound was prepared from (Intermediate 40). Yield: 7%, HPLC purity = 93%, m / z = 410 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 2.20 (s, 3H) 3.96 (s, 3H ) 6.84 (d, J = 2.23 Hz, 1 H) 6.99-7.05 (m, J = 8.41 Hz, 1 H) 7.10-7.17 (m, J = 9.90 Hz, 1 H) 7.27-7.36 (m, 3 H) 7.51-7.55 (m, 1H) 7.82 (d, J = 2.23 Hz, 1H) 8.27-8.34 (m, 2H).

Intermediate 41

2-methoxy-5-methyl-N- (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 * following the procedure of intermediate 20 (1.5 g, 2.99 mmol) was reacted and the product was used in the next step without further purification. Yield: 1.2 g (100%). HPLC purity 99%, R _T = 1.60 min (System A; 10-97% MeCN over 3 min). Prepared from tert -butyl 4- (5-amino-1-benzofuran-7-yl) piperazine-1-carboxylate (Intermediate 10) according to the procedure of Intermediate 19.

Example 77

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

Cyclopropanecarbaldehyde (0.087 g, 1.25 mmol) was added 2-methoxy-5-methyl-N- (7-piperazin-1-yl-1-benzofuran-5-yl) benzenesulfonamide (0.1 in methanol). g, 0.25 mmol; intermediate 41). 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 from the reaction mixture was collected by filtration to give the free base (0.063 g; 55%) of the title compound. The free base was dissolved in MeOH and treated with HCl / ether 1 M to afford the title compound. Yield: 0.029 g (43%). HPLC 100%, R _T = 1.82 min (System A; 10-97% MeCN over 3 min). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.37-0.48 (m, 2 H) 0.59-0.72 (m, 2 H) 1.09-1.22 (m, 1 H) 2.20 (s, 3 H) 3.03 ( dd, J = 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, J = 1.8 Hz, 1H) 6.85 (d, J = 2.0 Hz, 1 H) 6.95 (d, J = 1.8 Hz, 1 H) 7.03 (d, J = 8.5 Hz, 1 H) 7.32 (dd, J = 8.4, 2.1 Hz, 1 H) 7.51 (d, J = 2.0 Hz, 1 H) 7.89 (d, J = 2.3 Hz, 1 H) 9.74 (s, 1 H). C ₂₄ H ₂₉ N ₃ O ₄ S MS (ESI +) for m / z 456.2 (M + H) ⁺ .

Example 78

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

2-methoxy-5-methyl-N- (7-piperazin-1-yl-1-benzofuran-5-yl) benzenesulfonamide (0.1 g, 0.25 mmol; intermediate 41) according to the procedure of example 77 And 3,3,3-trifluoropropanal to prepare the title compound. The precipitate from the reaction mixture was collected by filtration to give the free base (0.075 g; 60%) of the title compound. The free base was dissolved in MeOH and treated with HCl / ether 1 M to afford the title compound. Yield: 0.078 g (96%). HPLC 98%, R _T = 1.84 min (System A; 10-97% MeCN over 3 min). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.20 (s, 3 H) 2.93-3.10 (m, 2 H) 3.15 (s, 2 H) 3.16-3.30 (m, 4 H) 3.36-3.50 ( m, 2H) 3.60-3.77 (m, 3H) 3.87 (s, 3H) 6.58 (d, J = 1.8 Hz, 1H) 6.85 (d, J = 2.3 Hz, 1H) 6.95 (d, J = 1.8 Hz, 1H) 7.03 (d, J = 8.5 Hz, 1H) 7.25 (s, 2H) 7.31 (dd, J = 8.5, 2.3 Hz, 1H) 7.38 (s, 2H) 7.51 (s , 3H) 7.89 (d, J = 2.3 Hz, 1H) 9.74 (s, 1H). MS (ESI +) for C ₂₃ H ₂₆ F ₃ N ₃ O ₄ S m / z 498.2 (M + H) ⁺ .

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 rt for 2 h, and the mixture was stirred overnight. After this, additional Br ₂ (40.85 g, 255.6 mmol) was added and the mixture was stirred overnight. The two phases formed upon standing were separated and the base layer was distilled to give 3,3-dibromo-1,1,1-trifluoroacetone as a yellow oil (10.37 g, 8.6%). ¹ H NMR (270 MHz, CDCl ₃ ) δ ppm 6.23 (s, 1 H). * Rec. Trav. Chim. Pays-Bas 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). NaOAc (12.61 g, 153.72 mmol) was added and the resulting mixture was stirred at 100 ° C. overnight. The mixture was extracted with EtOAc (50 mL) and the solvent was evaporated from the organic phase. The residue was redissolved in EtOAc (20 mL) and filtered to give 3,3,3-trifluoro-2-oxopropanal (1.35 g, 24%). * Rec. Trav. Chim. Pays-Bas 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) was cooled to 0 ° C. and N-benzylethane- in DMF (10 mL) A 1,2-diamine (0.37 g, 2.72 mmol) solution was added. After stirring at room temperature overnight, the mixture was concentrated in vacuo. The residue was redissolved in THF (5 mL), then citric acid buffer (5.3 mL; 0.4 M) and then NaBH ₃ CN (0.31 g, 4.9 mmol) were added. The resulting mixture was stirred at rt overnight. The mixture was made basic (pH 8) with aqueous NaOH (8 mL; 1 M) and the aqueous layer was extracted twice with DCM (15 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified for LC-MS preparation to give 1-benzyl-3- (trifluoromethyl) piperazine (66 mg, 12%). HPLC 94%, RT = 1.25 min (System A; 10-97% MeCN over 3 min). ¹ H NMR (270 MHz, CDCl ₃ ) δ ppm 2.77 (s, 2 H) 3.17-3.31 (m, 1 H) 3.32-3.64 (m, 3 H) 3.83-4.02 (m, 1 H) 4.13-4.31 ( m, 2H) 6.68 (s, 1H) 7.30-7.55 (m, 5H). MS (ESI +) m / z 245. * Rec. Trav. Chim. Pays-Bas 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). Pd (5% on carbon, 0.074 g) was added and hydrogenation was performed overnight at 3 bar and 70 ° C. The reaction mixture was filtered through celite and the pad was rinsed with water (5 mL). The solvent was removed in vacuo and toluene (20 mL) was added to the residue and then re-concentrated in vacuo to remove the residue. The desired product was sublimed on an evaporator and 0.15 g (32%) was collected as white powder. ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 2.67-2.87 (m, 3H) 2.91-3.05 (m, 2H) 3.12-3.21 (m, 1H). MS (ESI +) m / z 155. * Rec. Trav. Chim. Pays-Bas 1995, 114, 97-102.

Intermediate 46

1- (5-nitro-1-benzofuran-7-yl) -3- (trifluoromethyl) piperazine

To 7-iodo-5-nitro-1-benzofuran (231.4 mg, 0.08 mmol) was added: xantforce (92.6 mg, 0.16 mmol), Pd ₂ dba ₃ (36.6 mg, 0.04 mmol), sodium tert -Butoxide (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 100 ° C. for 3 days. Filtration with Celite and purification by flash chromatography using EtOAc: heptane (1: 1) as eluent gave 1- (5-nitro-1-benzofuran-7-yl) -3- (trifluoromethyl) piperazine. (112 mg, 44% yield) was obtained. HPLC 90%, RT = 1.648 min (System A; 10-97% MeCN over 3 min), MS (ESI +) m / z 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) in THF (6 mL) and EtOH (25 mL) Dissolved. Raney nickel (slurry in ethanol; 1 mL) and H ₂ NNH ₂ (61.4 mg, 1.23 mmol) were added and the mixture was stirred at rt overnight. Filtration with Celite and concentration gave 7- [3- (trifluoromethyl) piperazin-1-yl] -1-benzofuran-5-amine (55 mg, 63%). This material was used in the next reaction step without further purification.

Example 79

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

7- [3- (trifluoromethyl) piperazin-1-yl] -1-benzofuran-5-amine (59 mg, 0.19 mmol; intermediate 47) in DCM (2 mL), pyridine (155 mL, 1.93 mmol) and 6-methoxy-m-toluene-sulfonyl chloride (42.6 mg, 0.19 mmol) were stirred overnight at room temperature. Volatile materials were removed under vacuum. The residue was redissolved in MeOH (1.5 mL) and the solution was filtered. MeOH (100 mL), HCl in ether (500 mL) and ether (500 mL) were added followed by removal of the solvents in vacuo to 2-methoxy-5-methyl-N- {7- [3- (trifluoro Rhomethyl) piperazin-1-yl] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride was obtained as a brown oil (44.1 mg, 47%). HPLC 100%, RT = 1.861 min (System A; 10-97% MeCN over 3 min). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 2.23 (s, 3 H) 2.28 (s, 1 H) 2.98-3.24 (m, 1 H) 3.46-3.71 (m, 2 H) 3.85 (s, 1 H) 3.96 (s, 3 H) 4.09-4.19 (m, 1 H) 4.56-4.70 (m, 1 H) 6.75 (d, J = 1.98 Hz, 2 H) 6.98 (d, J = 1.73 Hz, 1 H) 7.02 (s, 1 H) 7.05 (s, 1 H) 7.33 (dd, J = 8.04, 2.60 Hz, 1 H) 7.52 (d, J = 1.73 Hz, 1 H) 7.73 (d, J = 2.23 Hz , 1 H) 8.10-8.19 (m, 1 H) 8.64-8.74 (m, 1 H) 8.90 (d, J = 5.20 Hz, 1 H). MS (ESI +) m / z 470 (M + H) ⁺ .

Intermediate 48

tert -Butyl [1- (5-nitro-1-benzofuran-7-yl) piperidin-4-yl] carbamate

7-iodo-5-nitro-1-benzofuran (2.78 g, 9.61 mmol), tert -butyl piperidin-4-ylcarbamate (2.31 g, 12.0 mmol), Pd ₂ (dba) ₃ (0.22 g, 0.24 mmol), xantforce (0.56 g, 0.96 mmol) and sodium tert -butoxide (1.29 g, 13.0 mmol) were added xylene (200 mL). The mixture was heated at 120 ° C. for 16 h with stirring. The reaction mixture was allowed to come to room temperature, filtered through a pad of celite and concentrated in vacuo. The crude product was purified by flash chromatography using DCM as eluent to afford 1.03 g (84%) of the title product. HPLC 94%, R _T : 2.770 (System B; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 1.45 (s, 9 H) 1.62-1.72 (m, 2 H) 1.75-2.03 (m, 2 H) 2.94-3.02 (m, 2 H) 3.55- 3.57 (m, 1 H) 3.88-3.93 (m, 2 H) 7.01 (d, J = 2.23 Hz, 1 H) 7.64 (d, J = 2.23 Hz, 1 H) 7.93 (d, J = 2.23 Hz, 1 H) 8.13 (d, J = 2.23 Hz, 1 H). LC-MS 362 (M + H) ⁺ .

Intermediate 49

tert -Butyl [1- (5-amino-1-benzofuran-7-yl) piperidin-4-yl] carbamate

Hydrazine (1.038 mL, 28 mmol) and Raney-Nickel (slurry in ethanol; 10 mL) were dissolved in tert -butyl [1- (5-nitro-1-benzofuran) in a mixture of THF (50 mL) and ethanol (150 mL). -7-yl) piperidin-4-yl] carbamate (1.03 g, 2.85 mmol; intermediate 48). The mixture was stirred at rt for 16 h, filtered through a pad of celite and concentrated in vacuo to afford 1.02 g (quantity) of the title product. HPLC 95%, R _T : 1.746 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (270 MHz, Methanol- d ₄ ) δ ppm 1.45 (s, 9 H) 1.65-1.69 (m, 2 H) 1.72-1.96 (m, 2 H) 2.76-2.85 (m, 2 H) 3.50- 3.54 (m, 1 H) 3.76 (d, J = 12.62 Hz, 2 H) 6.33 (d, J = 1.98 Hz, 1 H) 6.54 (d, J = 1.98 Hz, 1 H) 6.60 (d, J = 2.23 Hz, 1H) 7.59 (d, J = 1.98 Hz, 1H). LC-MS 332 (M + H) ⁺ .

Example 80

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

2- (trifluoromethyl) benzenesulfonyl chloride (89.0 mg, 0.36 mmol) and pyridine (219 mL) were added tert -butyl [1- (5-amino-1-benzofuran-7-) in DCM (1 mL). Yl) piperidin-4-yl] carbamate (100.0 mg, 0.30 mmol; intermediate 49). After the mixture was shaken at room temperature for 1 hour, the solvent was removed in vacuo and the residue was purified by preparative HPLC using an acetonitrile-water gradient containing 0.1% trifluoroacetic acid. Treatment with 2 M HCl in ether performed N-deprotection and conversion to hydrochloride salts. This gave 76.1 mg (57%) of the title product. HPLC 100%, R _T : 1.834 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 1.70-1.72 (m, 2 H) 2.00-2.02 (m, 2 H) 2.78 (t, J = 11.30 Hz, 2 H) 3.21 (s, 1 H ) 3.71 (d, J = 12.56 Hz, 2 H) 6.60 (d, J = 1.88 Hz, 1 H) 6.83 (d, J = 2.20 Hz, 1 H) 6.85-6.91 (m, J = 1.88 Hz, 1 H ) 7.80-7.81 (m, 2H) 7.88-7.89 (m, 1H) 7.96-7.98 (m, 1H) 8.08-8.10 (m, 4H) 10.40 (s, 1H). LC-MS 440 (M + H) ⁺ .

Example 81

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

Benzenesulfonyl chloride (64.0 mg, 0.36 mmol) and pyridine (219 mL) were added tert -butyl [1- (5-amino-1-benzofuran-7-yl) piperidine-4- in DCM (1 mL). To]] carbamate (100.0 mg, 0.30 mmol; intermediate 49). The mixture was shaken at rt for 1 h, the solvent was removed in vacuo and the residue was purified by preparative HPLC using an acetonitrile-water gradient containing 0.1% trifluoroacetic acid. Treatment with 2 M HCl in ether performed N-deprotection and conversion to hydrochloride salts. This gave 31.3 mg (28%) of the title product. HPLC 100%, R _T : 1.612 (System A; 10-97% MeCN over 3 minutes). ^{1 H NMR (500 MHz, DMSO-} d 6) δ ppm 1.69 - 1.70 (m, 2 H) 2.00 - 2.01 (m, 2 H) 2.76 (t, J = 11.30 Hz, 2 H) 3.18 - 3.26 (m, 1 H) 6.54 (d, J = 1.88 Hz, 1 H) 6.82 (d, J = 2.20 Hz, 1 H) 6.86 (d, J = 1.88 Hz, 1 H) 7.52 (t, J = 7.54 Hz, 2 H ) 7.57-7.68 (m, 1H) 7.71-7.72 (m, 2H) 7.88 (d, J = 2.20 Hz, 1H) 8.14 (s, 3H) 10.03 (s, 1H). LC-MS 372 (M + H) ⁺ .

Example 82

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

2-Chlorobenzenesulfonyl chloride (76.0 mg, 0.36 mmol) and pyridine (219 mL) were converted to tert -butyl [1- (5-amino-1-benzofuran-7-yl) piperidine in DCM (1 mL). -4-yl] carbamate (100.0 mg, 0.30 mmol; intermediate 49). The mixture was shaken for 1 hour at room temperature, the solvent was removed in vacuo and the residue was purified by preparative HPLC using an acetonitrile-water gradient containing 0.1% trifluoroacetic acid. Treatment with 2 M HCl in ether performed N-deprotection and conversion to hydrochloride salts. This gave 60.6 mg (50%) of the title product. HPLC 100%, R _T : 1.702 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 1.69-1.72 (m, 2 H) 2.01-2.02 (m, 2 H) 2.76 (t, J = 11.62 Hz, 2 H) 3.21 (s, 1 H ) 3.68 (d, J = 12.56 Hz, 2 H) 6.58 (s, 1 H) 6.82 (d, J = 2.20 Hz, 1 H) 6.88 (s, 1 H) 7.47 (t, J = 7.54 Hz, 1 H ) 7.62-7.63 (m, 2H) 7.87 (d, J = 1.88 Hz, 1H) 7.99 (d, J = 7.54 Hz, 1H) 8.23 (s, 3H) 10.33 (s, 1H). LC-MS 406 (M + H) ⁺ .

Example 83

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

2-methoxy-5-methylbenzenesulfonyl chloride (80.0 mg, 0.36 mmol) and pyridine (219 mL) were converted to tert -butyl [1- (5-amino-1-benzofuran-7- in DCM (1 mL). Yl) piperidin-4-yl] carbamate (100.0 mg, 0.30 mmol; intermediate 49). The mixture was shaken for 1 hour at room temperature, the solvent was removed in vacuo and the residue was purified by preparative HPLC using an acetonitrile-water gradient containing 0.1% trifluoroacetic acid. Treatment with 2 M HCl in ether performed N-deprotection and conversion to hydrochloride salts. This gave 59.0 mg (47%) of the title product. HPLC 100%, R _T : 1.731 (System A; 10-97% MeCN over 3 minutes). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 1.70-1.76 (m, 2H) 2.05 (d, J = 10.05 Hz, 2H) 2.20 (s, 3H) 2.76 (t, J = 11.46 Hz , 2H) 3.19-3.21 (m, 1H) 3.65 (d, J = 12.56 Hz, 2H) 3.87 (s, 3H) 6.58 (d, J = 1.88 Hz, 1H) 6.81 (d, J = 2.20 Hz, 1 H) 6.89 (d, J = 1.88 Hz, 1 H) 7.04 (d, J = 8.48 Hz, 1 H) 7.32 (dd, J = 8.48, 2.20 Hz, 1 H) 7.51 (d, J = 2.20 Hz, 1 H) 7.86 (d, J = 1.88 Hz, 1 H) 8.35 (d, J = 3.45 Hz, 3 H) 9.65 (s, 1 H). LC-MS 416 (M + H) ⁺ .

Intermediate 50

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

And

Intermediate 51

tert -Butyl Trance -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-hydroxypiperidine-1-carboxylate * (3.8 g, 17.3 mmol; cis / trans Mixture of isomers), 1,10-phenanthroline (0.50 g, 2.8 mmol), CuI (0.26 g, 1.4 mmol) and Cs ₂ CO ₃ (4.5 g, 13.8 mmol) were added toluene (20 Ml). The reaction mixture was filtered through celite and evaporated. The resulting diastereomers were separated by flash chromatography using heptane / EtOAc [(4: 1) → (2: 1)] to yield 255 mg of the cis -isomer and 919 mg of the trans- Isomers were obtained.

Cis -isomer (intermediate 50): yield: 10%, HPLC purity = 70%, m / z = 381 (M + H) ⁺ .

Trans -isomer (intermediate 51): yield: 35%, HPLC purity = 94%, m / z = 381 (M + H) ⁺ .

* Manufactured according to the procedure described in WO2001085728.

Intermediate 52

tert -Butyl cis-4-[(5-amino-1-benzofuran-7-yl) oxy] -3-fluoropiperidine-1-carboxylate

Tert -butyl cis-3-fluoro-4-[(5-nitro-1-benzofuran-7-yl) oxy] piperidine-1- cart dissolved in THF (10 mL) and ethanol (40 mL) To a solution of carboxylate (200 mg, 0.526 mmol; intermediate 50) was added Raney-nickel (as a slurry in ethanol) and hydrazine hydrate (0.2 mL). The mixture was stirred at rt for 30 min, then filtered through celite and evaporated. The residue was redissolved in toluene and evaporated again. This material was used directly in subsequent experiments.

Intermediate 53

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

The title compound was prepared from intermediate 51 following the procedure of intermediate 52 and used directly in the subsequent experiments.

Example 84

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

Tert -butyl cis-4-[(5-amino-1-benzofuran-7-yl) oxy] -3-fluoropiperidine-1-carboxylate (92 mg, 0.263) in dichloromethane (3 mL) To a solution of mmol; intermediate 52) 6-methoxy- m -toluenesulfonyl chloride (70 mg, 0.315 mmol) and triethylamine (73 mL, 0.525 mmol) were added. The mixture was shaken at room temperature for 1 hour and then evaporated. Purification by preparative HPLC (gradient 50-85% MeCN in TFA / water). The residue was dissolved in methanol (0.5 mL) and HCl / ether (2 mL). After stirring the solution for 2 hours, the solvent was evaporated to afford the title compound. Yield: 25 mg (20%), HPLC purity = 95%, m / z = 435 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 1.90-2.37 (m, 2H) 2.16-2.26 (m, 3 H) 3.14-3.46 (m, 2 H) 3.48-3.74 (m, 2 H) 3.92-3.98 (m, 3 H) 4.73-4.88 (m, 1 H) 4.89-5.12 (m , 1 H) 6.72 (d, J = 2.23 Hz, 0.2 H, rotational isomer) 6.75 (d, J = 1.98 Hz, 1 H) 6.80 (d, J = 1.98 Hz, 0.2 H, rotational isomer) 6.87 (d, J = 1.98 Hz, 1 H) 6.95 (d, J = 1.98 Hz, 0.2 H, rotamers) 6.98-7.05 (m, 2 H) 7.27-7.35 (m, 1 H) 7.50-7.53 (m, 1 H) 7.72 (d, J = 2.23 Hz, 1 H).

Example 85

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

tert-butyl trans-4 - [(5-amino-1-benzofuran-7-yl) oxy] -3-fluoro-piperidine-1-carboxylate (Intermediate 53) and 6-methoxy-m- The title compound was prepared following the same procedure as in Example 84 starting from toluenesulfonyl chloride. Yield: 8 mg (5%), HPLC purity = 92%, m / z = 435 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 2.12-2.30 (m, 2H) 2.21 (s, 3 H) 3.14-3.34 (m, 2 H) 3.37-3.53 (m, 1 H) 3.63-3.79 (m, 1 H) 3.95 (s, 3 H) 4.72-4.83 (m, 1 H) 4.95-5.20 (m, 1 H) 6.73 (d, J = 2.23 Hz, 1 H) 6.84 (d, J = 1.73 Hz, 1 H) 6.99 (d, J = 1.98 Hz, 1 H) 7.00-7.05 (m , 1 H) 7.28-7.35 (m, 1 H) 7.50 (d, J = 1.98 Hz, 1 H) 7.70 (d, J = 1.98 Hz, 1 H).

Example 86

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

The title compound was prepared following the procedure described in Example 84 using 2- (trifluoromethyl) benzenesulfonyl chloride. Yield: 27 mg (21%), HPLC purity = 100%, m / z = 459 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 1.94-2.37 (m, 2H ) 3.14-3.49 (m, 3 H) 3.53-3.70 (m, 1 H) 4.78-5.16 (m, 2 H) 6.74 (d, J = 2.23 Hz, 0.3 H, rotational isomers) 6.77 (d, J = 2.23 Hz, 1 H) 6.79 (d, J = 1.98 Hz, 0.3 H, rotational isomers) 6.87 (d, J = 1.98 Hz, 1 H) 6.95 (d, J = 1.98 Hz, 0.3 H, rotational isomers) 7.02 (d , J = 1.98 Hz, 1 H) 7.61-7.74 (m, 3 H) 7.75 (d, J = 2.23 Hz, 1 H) 7.88-7.95 (m, 1 H) 7.98-8.06 (m, 1 H).

Example 87

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

tert -butyl trans- 4-[(5-amino-1-benzofuran-7-yl) oxy] -3-fluoropiperidine-1-carboxylate (intermediate 53) and 2- (trifluoromethyl The title compound was prepared following the procedure described in Example 84 starting from benzenesulfonyl chloride. Yield: 49 mg (25%), HPLC purity = 100%, m / z = 459 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 2.13-2.31 (m, 2H) 3.15-3.56 (m, 3 H) 3.64-3.79 (m, 1 H) 4.77-4.97 (m, 1 H) 5.00-5.24 (m, 1 H) 6.75 (d, J = 1.98 Hz, 1 H) 6.81- 6.84 (m, 1H) 6.99 (d, J = 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

tert -butyl trans-4-[(5-amino-1-benzofuran-7-yl) oxy] -3-fluoropiperidine-1-carboxylate (intermediate 53) and 2-chlorobenzenesulfonyl chloride The title compound was prepared following the procedure described in Example 84 starting from. Yield: 40 mg (22%), HPLC purity = 100%, m / z = 425 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 2.09-2.35 (m, 2H) 3.10-3.57 (m, 3 H) 3.62-3.79 (m, 1 H) 4.73-4.96 (m, 1 H) 4.97-5.23 (m, 1 H) 6.74 (d, J = 2.23 Hz, 1 H) 6.85 ( d, J = 1.98 Hz, 1 H) 7.05 (d, J = 1.73 Hz, 1 H) 7.31-7.40 (m, 1 H) 7.45-7.58 (m, 2 H) 7.71 (d, J = 2.23 Hz, 1 H) 7.96 (dd, J = 7.79, 1.61 Hz, 1 H).

Example 89

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

tert -butyl trans- 4-[(5-amino-1-benzofuran-7-yl) oxy] -3-fluoropiperidine-1-carboxylate (intermediate 53) and 3-methylbenzenesulfonyl chloride The title compound was prepared following the procedure described in Example 84 starting from. Yield: 47 mg (27%), HPLC purity = 100%, m / z = 405 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 2.12-2.34 (m, 2H) 2.28-2.34 (m, 3 H) 3.15-3.57 (m, 3 H) 3.64-3.78 (m, 1 H) 4.73-4.97 (m, 1 H) 4.98-5.21 (m, 1 H) 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

tert -butyl trans- 4-[(5-amino-1-benzofuran-7-yl) oxy] -3-fluoropiperidine-1-carboxylate (intermediate 53) and 3,6-dichloro-2 The title compound was prepared following the procedure described in Example 84 starting from -methylbenzenesulfonyl chloride. Yield: 39 mg (19%), HPLC purity = 98%, m / z = 473 (M + H) ⁺ , ¹ H NMR (270 MHz, methanol- d ₄ ) δ ppm 2.11-2.34 (m, 2H) 2.47-2.54 (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, J = 1.98 Hz, 1 H) 6.83 (d, J = 1.73 Hz, 1 H) 7.06 (d, J = 1.98 Hz, 1 H) 7.26 (d, J = 1.98 Hz, 1 H) 7.50 (d, J = 1.98 Hz, 1H) 7.74 (d, J = 2.23 Hz, 1H).

Example 91

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

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

Intermediate 54

2,3-dihydro-benzofuran-5-sulfonyl chloride

Chlorosulfonic acid (43.4 g, 0.366 mol) in DCM (10 mL) was added to a 2,3-dihydrobenzofuran (20 g, 0.166 mol) cold solution (5 ° C.) in DCM (200 mL). After addition, the reaction was allowed to stand overnight at room temperature while stirring. The reaction mixture was quenched with water (150 mL) whose temperature was maintained below 10 ° C. The organic phase was separated and washed with an aqueous solution of NaHCO ₃ (13,9 g dissolved in 150 mL of water). Organic solvents were evaporated to afford 3.3 g (23%) of the title compound. ¹ H NMR 270 MHz (CDCl ₃ ) δ ppm 3.32 (t, J = 8.91 Hz, 2H) 4.75 (t, J = 8.91 Hz, 2H) 6.90 (d, J = 9.15 Hz, 1H) 7.78-7.90 (m, 2 H)

Intermediate 55

7-iodo-2,3-dihydro-benzofuran-5-sulfonyl chloride

A solution of ICl (7.7 g, 47 mmol) in DCM (100 mL) at reflux under nitrogen atmosphere was added 2,3-dihydro-benzofuran-5-sulfonyl chloride (5 g, 23 mmol) in DCM (100 mL); Dropwise to a solution of intermediate 54). The reaction was heated at reflux overnight. The reaction mixture was cooled to room temperature and acetonitrile (50 mL) was added. The resulting mixture is washed with a saturated solution of NaHCO ₃ , After separation of the organic phase, volatiles were removed in vacuo to yield 8 g of brown oil, which was used in the next step without further purification. ¹ H NMR 270 MHz (CDCl ₃ ) δ ppm 3.45 (t, J = 8.91 Hz, 2H) 4.82 (t, J = 8.91 Hz, 2H) 7.79 (d, J = 1.48 Hz, 1H) 8.16 (d , J = 1.98 Hz, 1 H).

Intermediate 56

7-iodo-benzofuran-5-sulfonyl chloride

AIBN (270 mg, 1.3 mmol) and NBS (2.5 g, 14 mmol) at 70 ° C. were dissolved in 7-iodo-2,3-dihydro-benzofuran-5-sulfonyl chloride (4.4 in chlorobenzene (30 mL). g, 13 mmol; intermediate 55). The reaction was stopped by heating 1 hour after the addition. 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 to give 4 g (90%) of the title compound as yellow crystals. ¹ H NMR 270 MHz (CDCl ₃ ) δ ppm 7.07 (d, J = 2.23 Hz, 1H) 7.90 (d, J = 2.23 Hz, 1H) 8.29-8.37 (m, 1H).

Intermediate 57

7-iodo-N- (2-methoxy-5-methylphenyl) -1-benzofuran-5-sulfonamide

5-methyl-2-methoxyaniline (4.25 g, 31 mmol) in a solution of 7-iodo-1-benzofuran-5-sulfonyl chloride (10.75 g, 31 mmol; intermediate 56) in dichloromethane (200 mL) ) And pyridine (7.4 mL, 93 mmol) were added and stirred at ambient temperature overnight. The dark red solution was washed with water, separated, dried and filtered through a plug of silica to remove most of the red impurities and finally concentrated. Yield: 13.51 g (99%) red solid. HPLC 90% R _T = 2.58 min (System A; 30-80% MeCN over 3 min), 1.75 min (System C; 2-95% MeCN over 2 min). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.23 (m, 3 H) 3.52 (s, 3 H) 6.54 (d, J = 8.30 Hz, 1 H) 6.79 (dd, J = 8.42, 1.59 Hz, 1 H) 6.86 (d, J = 2.20 Hz, 1 H) 6.96 (s, 1 H) 7.31 (d, J = 1.71 Hz, 1 H) 7.71 (d, J = 2.20 Hz, 1 H) 7.95 (d, J = 1.71 Hz, 1 H) 8.04 (d, J = 1.71 Hz, 1 H). MS (ESI) for C ₁₆ H ₁₄ INO ₄ S m / z 444 (M + H).

Example 92

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

Step 1. 7- (3-Methyl-piperazin-1-carbonyl) -benzofuran-5-sulfonic acid (2-methoxy-5-methyl-phenyl) -amide.

K ₂ CO ₃ in diglyme (3 mL) in 7-iodo-N- (2-methoxy-5-methylphenyl) -1-benzofuran-5-sulfonamide (100 mg, 0.23 mmol; intermediate 57) 112 mg, 0.81 mmol), 2-methylpiperazine (45 mg, 0.46 mmol), Hermann catalyst (25 mg, 0.02 mmol) and Mo (CO) ₆ (30 mg, 0.12 mmol) are added and StemBlock at 120 ° C. Warmed at. 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 (Gilson; gradient of 30-70% MeCN), made basic with NaOH, washed with water and then the title amide product. Yield: 36 mg (36%). HPLC 88% R _T = 1.09 (System C; 2-95% MeCN over 2 minutes). MS (ESI) for C ₂₂ H ₂₅ N ₃ O ₅ S m / z 444 (M + H).

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

To 7- (3-methyl-piperazine-1-carbonyl) -benzofuran-5-sulfonic acid (2-methoxy-5-methyl-phenyl) -amide (30 mg, 0.07 mmol; Step 1) obtained. LiAlH ₄ (9.0 mg, 0.24 mmol) in dry THF (4 mL) was added and the mixture was warmed to reflux. After 1 hour, HPLC analysis showed 15% product and residual impurities. The mixture was added to 2 M HCl, concentrated and purified by preparative HPLC (Gilson; gradient of 30-70% MeCN). Pure fractions were removed, HCl / ether was added and concentrated to afford the title compound as a colorless solid. Yield: 1.3 mg (5%). HPLC 90% R _T = 1.17 min (System A; 30-80% MeCN over 3 min), 1.13 min (System C; 2-95% MeCN over 2 min). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.29 (d, J = 7.0 Hz, 2 H) 2.21 (s, 3 H) 2.72 (m, 1 H) 2.86 (m, 1 H) 3.38 (s , 4H) 3.43-3.64 (m, 4H) 4.30 (d, J = 6.59 Hz, 2H) 6.62 (d, J = 8.30 Hz, 1H) 6.81-6.88 (m, 1H) 6.99 (d, J = 2.44 Hz, 1 H) 7.25 (d, J = 1.95 Hz, 1 H) 7.76 (br s, 1 H) 7.94 (d, J = 2.20 Hz, 1 H) 8.08 (d, J = 1.71 Hz, 1 H). MS (ESI) for C ₂₂ H ₂₇ N ₃ O ₄ S m / z 430 (M + H).

Intermediate 58

7-Iodo- N -(2-methylphenyl) -1-benzofuran-5-sulfonamide

7-iodo-1-benzofuran-5-sulfonyl chloride (10 g, 29.2 mmol; intermediate 56) and 2-methyl aniline (3.43 mL, 32.1 mmol) are dissolved in dichloromethane (150 mL) and pyridine ( 3.53 mL, 43.8 mmol) was added. The solution was stirred overnight, washed with 1 M HCl (2 × 100 mL), dried over sodium sulphate and evaporated to afford the crude product which was recrystallized from methanol. Yield: 5.32 g (44%) of beige solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.05 (s, 3 H) 6.36 (s, 1 H) 6.95 (d, J = 2.3 Hz, 1 H) 7.11-7.19 (m, 3H) 7.28 (d , J = 7.5 Hz, 1 H) 7.81 (d, J = 2.3 Hz, 1 H) 7.99 (d, J = 1.8 Hz, 1 H) 8.08 (d, J = 1.8 Hz, 1 H).

Intermediate 59

N -(2-methylphenyl) -7-vinyl-1-benzofuran-5-sulfonamide

7-iodo- N- (2-methylphenyl) -1-benzofuran-5-sulfonamide (0.41 g, 1 mmol; intermediate 58), tributylvinyltin (0.32 mL, 1.1 mmol), bis (triphenylforce Pin) palladium diacetate (10 mg) and acetonitrile (3 mL) were heated to 180 ° C. under microwave radiation for 5 minutes. The mixture was cooled down, filtered and evaporated. The resulting oil was washed with hexane (2 × 50 mL), dissolved in diethyl ether (50 mL), filtered and evaporated to afford the crude product which was crystallized from ethanol: water (3: 1). Yield 0.19 g (61%) of a grayish white solid. ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm 1.93 (s, 3 H) 5.57 (dd, J = 11.3, 1.0 Hz, 1 H) 6.12 (dd, J = 17.8, 1.0 Hz, 1 H) 6.84 7.07 (m, 6H) 7.62 (d, J = 1.8 Hz, 1 H) 7.84 (d, J = 1.8 Hz, 1 H) 8.14 (d, J = 2.3 Hz, 1 H) 9.43 (s, 1 H ).

Intermediate 60

7-formyl N -(2-methylphenyl) -1-benzofuran-5-sulfonamide

N- (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). Dissolved. Osmium tetroxide (84 mg, 0.33 mmol) and then a solution of sodium periodate (2.82 g, 13.2 mmol) in water (10 mL) were added with stirring. After stirring for 90 minutes, 1 M HCl (40 mL) and then water (200 mL) were added. The precipitated product was recovered by filtration, washed with water and dried in vacuo. Yield: 0.95 g (91%) of a grayish white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.05 (s, 3 H) 6.38 (s, 1 H) 6.95 (d, J = 2.3 Hz, 1 H) 7.11 (dd, J = 5.1, 1.1 Hz, 2 H) 7.13-7.19 (m, 2H) 7.91 (d, J = 2.3 Hz, 1H) 8.25 (dd, J = 15.8, 1.8 Hz, 2H) 10.42 (s, 1H).

Example 93

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

7-formyl- N- (2-methylphenyl) -1-benzofuran-5-sulfonamide (20 mg, 0.06 mmol; Intermediate 60), N- ( tert -butoxycarbonyl) piperazine (13 mg, 0.07 mmol), acetic acid (36 mL, 0.63 mmol), sodium triacetoxyborohydride (27 mg, 0.13 mmol) were combined with dry THF (3 mL) and heated to 130 ° C. under microwave radiation for 5 minutes. The solution was cooled down, filtered and evaporated. The residue was dissolved in methanol (3 mL) and treated with concentrated hydrochloric acid (0.3 mL). This solution was heated to 100 ° C. under microwave radiation for 5 minutes. The solvent was evaporated to give the crude product, which was prep Gilgil system with preparative HPLC (ACE 5 C8 column (30 × 150 mm), flow rate: 35 mL / min, eluent: 15-40 in 0.1% TFA in MilliQ water Gradient of% MeCN). Yield: 16 mg (50%). Analytical HPLC was performed on Agilent 1100, column: ACE 3 C8 (System A) or column: YMC-Pack (System B), eluent: MilliQ / 0.1% TFA and MeCN. HPLC 99% R _T = 1.48 (System A; 10-97% MeCN over 3 minutes) 99% R _T = 1.31 (System B; 10-90% MeCN over 3 minutes). MS (ESI +) for C ₂ oH ₂₃ N ₃ 0 ₃ S m / z 386 (M + 1). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.89 (s, 3 H) 2.65-2.72 (m, 4 H) 3.10-3.17 (m, 4 H) 3.95 (s, 2 H) 6.92 (d, J = 2.3 Hz, 1H) 6.96-6.99 (m, 2H) 6.99-7.02 (m, J = 3.2, 1.8, 1.8 Hz, 2H) 7.51 (d, J = 1.8 Hz, 1H) 7.87 (d , J = 2.3 Hz, 1 H) 7.96 (d, J = 1.8 Hz, 1 H).

Example 94

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

Using 7-formyl- N- (2-methylphenyl) -1-benzofuran-5-sulfonamide (40 mg, 0.12 mmol; intermediate 60) and 3,5-dimethylpiperazine (16 mg, 0.14 mmol) The title compound was prepared following the procedure described in Example 93, [Note: without HCl deprotection step]. Yield: 21.5 mg (40%). HPLC 97% R _T = 1.57 (System A; 10-97% MeCN over 3 minutes) 99% R _T = 1.39 (System B; 10-90% MeCN over 3 minutes). MS (ESI +) for C ₂₂ H ₂₇ N ₃ O ₃ S m / z 414 (M + l). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.19 (d, J = 6.8 Hz, 6 H) 1.91 (s, 3H) 2.11 (dd, J = 12.7, 11.4 Hz, 2H) 2.96 (dd , J = 12.9, 2.4 Hz, 2 H) 3.27 (ddd, J = 11.1, 6.7, 3.3 Hz, 2 H) 3.91 (s, 2 H) 6.90 (d, J = 2.3 Hz, 1 H) 6.95-7.03 ( m, 4H) 7.57 (d, J = 1.5 Hz, 1 H) 7.86 (d, J = 2.3 Hz, 1 H) 7.91 (d, J = 1.8 Hz, 1 H).

Example 95

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

Practiced using 7-formyl- N- (2-methylphenyl) -1-benzofuran-5-sulfonamide (40 mg, 0.12 mmol; intermediate 60) and 2-methylpiperazine (14 mg, 0.14 mmol) The title compound was prepared following the procedure described in Example 93. [Note: no HCl deprotection step]. Yield: 31.6 mg (59%). HPLC 99% R _T = 1.50 (System A; 10-97% MeCN over 3 minutes) 99% R _T = 1.33 (System B; 10-90% MeCN over 3 minutes). MS (ESI +) for C ₂₁ H ₂₅ N ₃ O ₃ S m / z 400 (M + l). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.20 (d, J = 6.8 Hz, 3H) 1.90 (s, 3H) 2.33 (dd, J = 12.7, 10.7 Hz, 1H) 2.47 (td , J = 12.4, 3.1 Hz, 1 H) 2.87-2.94 (m, J = 12.8 Hz, 1 H) 3.00-3.09 (m, 2 H) 3.26-3.34 (m, J = 10.0, 6.8, 6.8, 3.0 Hz , 2H) 3.94-4.04 (m, 2H) 6.92 (d, J = 2.3 Hz, 1H) 6.97 (dt, J = 5.0, 2.2 Hz, 2H) 7.01 (td, J = 3.6, 2.0 Hz, 2 H) 7.55 (d, J = 1.8 Hz, 1 H) 7.87 (d, J = 2.0 Hz, 1 H) 7.95 (d, J = 1.8 Hz, 1 H).

Example 96

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

7-formyl- N- (2-methylphenyl) -1-benzofuran-5-sulfonamide (40 mg, 0.12 mmol; intermediate 60) and N- ( tert -butoxycarbonyl) homopiperazine (28 mg, 0.14 mmol) to give the title compound, following the procedure described in Example 93. Yield: 21.0 mg (31%). HPLC 99% R _T = 1.34 (System A; 10-97% MeCN over 3 minutes) 99% R _T = 1.18 (System B; 10-90% MeCN over 3 minutes). MS (ESI +) for C ₂₁ H ₂₅ N ₃ O ₃ S m / z 400 (M + l). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.94 (s, 3 H) 2.10-2.17 (m, 2 H) 3.28-3.35 (m, 4 H) 3.49-3.59 (m, 4 H) 4.60 ( s, 2H) 6.92-7.04 (m, 5H) 7.72 (d, J = 1.8 Hz, 1H) 7.94 (d, J = 2.3 Hz, 1H) 8.09 (d, J = 1.8 Hz, 1H) .

Example 97

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

7-formyl- N- (2-methylphenyl) -1-benzofuran-5-sulfonamide (80 mg, 0.24 mmol; intermediate 60) and trans-2,5-dimethylpiperazine (58 mg, 0.48 mmol) Using to prepare the title compound according to the method described in Example 93 [Note: no HCl deprotection step]. Yield: 32.2 mg (30%). HPLC 99% R _T = 1.58 (System A; 10-97% MeCN over 3 minutes) 99% R _T = 1.40 (System B; 10-90% MeCN over 3 minutes). MS (ESI +) for C ₂₂ H ₂₇ N ₃ O ₃ S m / z 414 (M + l). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.12 (d, J = 6.5 Hz, 3H) 1.22 (d, J = 5.8 Hz, 3H) 1.91 (s, 3H) 2.23 (dd, J = 13.1, 11.3 Hz, 1 H) 2.75-2.86 (m, 3 H) 3.14-3.21 (m, 1 H) 3.27 (dd, J = 12.2, 2.4 Hz, 1 H) 3.72 (d, J = 14.3 Hz, 1 H) 4.37 (d, J = 14.3 Hz, 1 H) 6.91 (d, J = 2.3 Hz, 1 H) 6.97-7.03 (m, 4 H) 7.58 (d, J = 1.8 Hz, 1 H) 7.86 ( d, J = 2.3 Hz, 1 H) 7.91 (d, J = 1.8 Hz, 1 H).

Example 98

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

7-formyl- N- (2-methylphenyl) -1-benzofuran-5-sulfonamide (40 mg, 0.12 mmol; intermediate 60) and ( 3R ) -3-methyl-1-tritylpiperazine (48 mg, 0.14 mmol) to give the title compound, according to the method described in Example 93. Yield: 22.8 mg (35%). HPLC 96% R _T = 1.49 (System A; 10-97% MeCN over 3 minutes) 96% R _T = 1.31 (System B; 10-90% MeCN over 3 minutes). MS (ESI +) for C ₂₁ H ₂₅ N ₃ O ₃ S m / z 400 (M + l). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.32 (d, J = 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, 2 H) 3.24-3.27 (m, 1 H) 3.33 (dt, J = 11.9, 1.8 Hz, 1 H) 3.91 (d, J = 14.1 Hz, 1 H) 4.50 (d, J = 14.1 Hz, 1 H) 6.94 (d, J = 2.3 Hz, 1 H) 6.96-6.99 (m, 2 H) 7.01 (dd, J = 4.0, 2.8 Hz, 2 H) 7.56 (d, J = 1.8 Hz , 1 H) 7.88 (d, J = 2.0 Hz, 1 H) 7.99 (d, J = 1.8 Hz, 1 H).

Intermediate 61

N- (2-methoxy-5-methylphenyl) -7-vinyl-1-benzofuran-5-sulfonamide

N- (2-methoxy-5-methylphenyl) -7-iodo-1-benzofuran-5-sulfonamide (443 mg, 1.0 mmol; Intermediate 57), tributyl (vinyl) in acetonitrile (3 mL) Each of five batches of a mixture of tin (350 mg, 1.1 mmol) and bis (triphenylphosphine) palladium diacetate (15 mg, 0.02 mmol) was heated to 180 ° C. in a Smith Creator microwave oven for 5 minutes. The combined reaction mixture was filtered and concentrated to give 2.0 g of crystalline crude, which was passed through a SiO ₂ column using EtOAc / hexane (gradient 5:95-> 25:75) as eluent, to 1.3 g ( 75%) of a greyish white crystal product was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.26 (s, 3 H), 3.53 (s, 3 H), 5.56 (dd, 1 H), 6.16 (dd, 1 H), 6.57 (d, 1 H) , 6.79-6.98 (m, 4H), 7.38 (d, 1H), 7.71-7.74 (m, 2H), 7.94 (d, 1H); MS (ESI +) for C ₁₈ H ₁₇ NO ₄ S m / z 344 (M + H) ⁺ .

Intermediate 62

7-formyl N -(2-methoxy-5-methylphenyl) -1-benzofuran-5-sulfonamide

Osmium tetroxide (84 mg, 0.33 mmol) was dissolved in N- (2-methoxy-5-methylphenyl) -7-vinyl-1-benzofuran-5-sulfonamide (1.25 g, 3.3 in dioxane (30 mL). mmol; intermediate 61) and lutidine (0.71 g, 6.6 mmol). A solution of sodium periodate (2.82 g, 13.2 mmol) in water (10 mL) was added under stirring. After 90 minutes, aqueous HCl (2 M; 40 mL) was added to give a clear solution. Water (200 mL) was added to give a precipitate, which was recovered by filtration. This material was washed with water and dried to give 1.12 g (88%) of the title product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.27 (s, 3 H), 3.55 (s, 3 H), 6.57 (d, 1 H), 6.80-6.85 (m, 1 H), 6.92 (d, 1 H), 7.02 (br s, 1 H), 7.38 (d, 1 H), 7.85 (d, 1 H), 8.22 (d, 1 H), 8.28 (d, 1 H), 10.38 (s, 1 H ).

Example 99

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

7-formyl- N- (2-methoxy-5-methylphenyl) -1-benzofuran-5-sulfonamide in 1,2-dichloroethane (3 mL) (100 mg, 0,29 mmol; Intermediate 62) A mixture of, 2-methylpiperazine (32 mg, 0,32 mmol) and sodium triacetoxyborohydride (245 mg, 1,16 mmol) was stirred overnight. 100 mg of crude was filtered and concentrated and purified by preparative HPLC to give 30 mg (19%) of the title product after concentration. ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 1.27 (d, 3 H), 2.24 (s, 3 H), 2.33-2.40 (m, 1 H), 2.46-2.55 (m, 1 H), 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 , 1 H), 6.87 (dd, 1 H), 6.97 (d, 1 H), 7.28 (d, 1 H), 7.66 (d, 1 H), 7.91 (d, 1 H), 8.04 (d, 1 H); MS (ESI +) for C ₂₂ H ₂₇ N ₃ O ₄ S m / z 430 (M + H) ⁺ ; HPLC 99%, R _T = 1.66 (System A; 10-97% MeCN over 3 minutes), 99% R _T = 1.46 (System B; 10-97% MeCN over 3 minutes).

Example 100

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

The title compound was prepared according to the procedure of Example 99. Yield: 55 mg (69%). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 2.16-2.23 (m, 2 H), 2.23 (s, 3 H), 3.35-3.42 (m, 4 H), 3.39 (s, 3 H), 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, 1 H), 7.98 (d, 1 H), 8.18 (d, 1 H); MS (ESI +) for C ₂₂ H ₂₇ N ₃ O ₄ S m / z 430 (M + H) ⁺ ; HPLC 99%, R _T = 1.50 (System A; 10-97% MeCN over 3 minutes), 99% R _T = 1.33 (System B; 10-97% MeCN over 3 minutes).

Example 101

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

The title compound was prepared according to the procedure of Example 99. Yield: 26 mg (34%). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 2.24 (s, 3 H), 2.91-2.96 (m, 4 H), 3.26-3.32 (m, 4 H), 3.38 (s, 3 H), 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 , 1 H), 8.08 (d, 1 H); C ₂₁ H ₂₅ N ₃ O ₄ S MS (ESI +) for mz 416 (M + H) ⁺ ; HPLC 99%, R _T = 1.58 (System A; 10-97% MeCN over 3 minutes), 99% R _T = 1.39 (System B; 10-97% MeCN over 3 minutes).

Example 102

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

The title compound was prepared according to the procedure of Example 99. Yield: 39 mg (48%). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 1.26 (d, 6 H), 2.20-2.28 (m, 2 H), 2.23 (s, 3 H), 3.03-3.08 (m, 2 H), 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, 1 H), 7.69 (d, 1 H), 7.90 (d, 1 H), 8.02 (d, 1 H); MS (ESI +) for C ₂₃ H ₂₉ N ₃ O ₄ S m / z 444 (M + H) ⁺ ; HPLC 99%, R _T = 1.70 (System A; 10-97% MeCN over 3 minutes), 99% R _T = 1.50 (System B; 10-97% MeCN over 3 minutes).

Example 103

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

The title compound was prepared according to the procedure of Example 99. Yield: 11 mg (13%). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 1.17 (d, 3 H), 1.26 (d, 3 H), 2.16-2.24 (m, 1 H), 2.24 (s, 3 H), 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, 1 H), 4.36 (d, 1 H), 6.66 (d, 1 H), 6.87 (dd, 1 H), 6.97 (d, 1 H), 7.29 (d, 1 H), 7.67 (d, 1 H) , 7.91 (d, 1 H), 8.02 (d, 1 H); MS (ESI +) for C ₂₃ H ₂₉ N ₃ O ₄ S m / z 444 (M + H) ⁺ ; HPLC 99%, R _T = 1.70 (System A; 10-97% MeCN over 3 minutes), 99% R _T = 1.49 (System B; 10-97% MeCN over 3 minutes).

Example 104

7-[(1 S ,4 S ) -2,5-diazabicyclo [2.2.1] hept-2-ylmethyl] -N- (2-methoxy-5-methylphenyl) -1-benzofuran-5-sulfonamide, trifluoroacetate

The title compound was prepared according to the procedure of Example 99. Yield: 46 mg (73%). ¹ H NMR (400 MHz, CD ₃ OD) δ 2.20 (d, 1 H), 2.23 (s, 3 H), 2.54 (d, 1 H), 3.38 (s, 3 H), 3.44-3.50 (m, 2 H), 3.56 (dd, 1 H), 3.78 (dd, 1 H), 4.28 (br s, 1 H), 4.54 (br s, 1 H), 4.61 (d, 1 H), 4.71 (d, 1 H), 6.64 (d, 1 H), 6.88 (dd, 1 H), 7.04 (d, 1 H), 7.28 (d, 1 H), 7.83 (d, 1 H), 7.97 (d, 1 H ), 8.16 (d, 1 H); MS (ESI +) for C ₂₂ H ₂₅ N ₃ O ₄ S m / z 428 (M + H) ⁺ ; HPLC 99%, R _T = 1.50 (System A; 10-97% MeCN over 3 minutes), 99% R _T = 1.32 (System B; 10-97% MeCN over 3 minutes).

Example 105

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

The title compound was prepared according to the procedure of Example 99. Yield: 31 mg (49%). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ 1.35 (d, 3 H), 2.24 (s, 3 H), 2.56-2.65 (m, 1 H), 2.87-3.11 (overlapped m, 4 H), 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, 1 H), 6.98 (d, 1 H), 7.29 (d, 1 H), 7.66 (d, 1 H), 7.92 (d, 1 H), 8.07 (d, 1 H); MS (ESI +) for C ₂₂ H ₂₇ N ₃ O ₄ S m / z 430 (M + H) ⁺ ; HPLC 99%, R _T = 1.58 (System A; 10-97% MeCN over 3 minutes), 99% R _T = 1.40 (System B; 10-97% MeCN over 3 minutes).

Intermediate 63

7-methyl-5-nitro-1-benzofuran

7-iodo-5-nitro-benzofuran (6.5 g, 22.1 mmol), Pd (OAc) ₂ (1 g, 3.9 mmol), P (o-tolyl) ₃ (5.5 g, 18.2 mmol), Me ₄ Sn (8.05 g, 42 mmol) and Et ₃ N (3.16 mL, 20.4 mmol) are dissolved in DMF (40 mL), partitioned into 13 tubes, and each controlled at 100 ° C. for 10 minutes using controlled microwave energy. Heated. The reaction mixture is combined, filtered and the solvent is evaporated. The crude material was purified by flash chromatography-purified using an (iso-hexane of 10% EtOAc in isohexane gradient used). Yield: 2.82 g (70%) of 7-methyl-5-nitro-1-benzofuran. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.51-2.64 (m, 3H) 6.90 (d, J = 2.3 Hz, 1H) 7.77 (d, J = 2.3 Hz, 1H) 8.04 (d, J = 1.3 Hz, 1 H) 8.37 (d, J = 2.3 Hz, 1 H); HPLC 96% Rt = 2.31 min (System A; 10-97% in 3 min, ACE column). MS (ESI +) for C ₉ H ₇ NO ₃ m / z 178 (M + H) ⁺ .

Intermediate 64

7- (bromomethyl) -5-nitro-benzofuran

7-methyl-5-nitro-1-benzofuran (2.1 g, 12 mmol; intermediate 63) was dissolved in CCl ₄ and heated to 80 ° C. Benzoyl peroxide (0.43 g, 1,6 mmol) was added followed by a small amount of NBS (2.1 g, 12 mmol). The reaction mixture was heated at reflux overnight with stirring. Additional benzoyl peroxide (0.08 mmol) and NBS (0.2 mmol) were added and the reaction mixture was stirred for additional overnight. After this time the mixture was filtered and concentrated. The crude was redissolved in DCM and washed with water. The organic solvent was dried (MgSO ₄ ) and evaporated. The residue was purified using preparative HPLC of 45-70% MeCN gradient. This gave 0.7 g (22%) of 7- (bromomethyl) -5-nitro-benzofuran as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.78 (s, 2 H) 6.96 (d, J = 2.3 Hz, 1 H) 7.84 (d, J = 2.3 Hz, 1 H) 8.28 (d, J = 2.3 Hz, 1H) 8.49 (d, J = 2.3 Hz, 1H). HPLC Rt = 1.9 min (System A; 30-80% MeCN over 3 min, ACE column).

Example 106

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

Step 1:  tert -Butyl 4-[(5-nitro-1-benzofuran-7-yl) methyl] piperazin-1-carboxylate

7- (bromomethyl) -5-nitro-1-benzofuran (145 mg, pure 70 mol%, 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 dry MeCN (5 mL) and heated to 80 ° C. with StemBlock for 2 hours with stirring. The solvent was evaporated under reduced pressure and the residue was partitioned between water and DCM (x2). The organic layer was combined, dried (Na ₂ SO ₄ ) and purified using flashtube (10% MeOH in DCM). This resulted in the title product (123 mg, 78%) as a pale yellow solid. HPLC 98%, R _T = 1.70 min (System A; 10-97% MeCN over 3 minutes), 99%, R _T = 1.55 min (System B; 10-97% MeCN over 3 minutes). MS (ESI +) for C ₁₈ H ₂₃ N ₃ O ₅ m / z 362 (M + H) ⁺ .

Step 2: 4- (5-Amino-benzofuran-7-ylmethyl) -piperazine-1-carboxylic acid tert -Butyl ester

Raney nickel (slurry in ethanol) and hydrazine hydrate (66 μL, 1.36 mmol) were converted to tert-butyl 4-[(5-nitro-1-benzofuran-7-yl in ethanol: THF (4: 1; 10 mL). ) Methyl] piperazin-1-carboxylate (123 mg, 0.34 mmol; obtained in step 1). The mixture was stirred for 1 hour at room temperature. Unreacted starting material was still present and additional Raney nickel and hydrazine hydrate (33 μL, 0.68 mmol) were added with continuous stirring for 1 hour. The mixture was filtered through a pad of celite, which was rinsed several times with ethanol. The solvent was evaporated to yield 119 mg (quant) of the title amine as a green sticky oil which was used directly in the next step.

Step 3: 2-chloro-N- [7- (piperazin-1-ylmethyl) -1-benzofuran-5-yl] benzenesulfonamide dihydrochloride

Dry pyridine (20 μL, 0.24 mmol) and 2-chlorobenzenesulfonyl chloride (25 μL, 0.18 mmol) were added 4- (5-amino-benzofuran- in a mixture of dry DCM: THF (2: 1; 3 mL). To a solution of 7-ylmethyl) -piperazine-1-carboxylic acid tert -butyl ester (40 mg, 0,12 mmol; obtained in step 2) was added. The resulting mixture was stirred for 3 hours, after which the volatiles were evaporated. The product was purified using flashtube (15% MeOH in DCM). The residue was dissolved in TFA: water (9: 1; 2 mL) and the mixture was stirred at rt for 30 min to complete removal of Nt-BOC groups. The reaction mixture was made basic by addition of saturated aqueous Na ₂ CO ₃ (pH 8-9) and extracted with DCM (x 2). The organic layer was combined, dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by preparative HPLC (System A; 10-40% MeCN). Pure fractions were combined and concentrated. The obtained TFA salt was dissolved in MeOH and 1 M HCl in ether was added and then concentrated to give the title compound as a pale yellow solid (10 mg, 18%). HPLC 100%, R _T = 1.38 min (System A; 10-97% MeCN over 3 minutes), 100%, R _T = 1.23 min (System B; 10-97% MeCN over 3 minutes). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 2.86-2.92 (m, 4 H) 3.25-3.28 (m, 4 H) 4.04-4.08 (m, 2H) 6.73 (d, J = 2.26 Hz, 1 H) 7.15 (d, J = 2.01 Hz, 1 H) 7.26-7.31 (m, 1 H) 7.32 (d, J = 2.26 Hz, 1 H) 7.42-7.47 (m, 1 H) 7.47-7.52 (m , 1 H) 7.70 (d, J = 2.26 Hz, 1 H) 7.90 (dd, J = 8.03, 1.51 Hz, 1 H). MS (ESI +) for C ₁₉ H ₂₀ ClN ₃ O ₃ S m / z 406 (M + H).

Example 107

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

4- (5-Amino-benzofuran-7-ylmethyl) -piperazine-1-carboxylic acid tert -butyl ester (40 mg, 0,12 mmol; obtained in Example 106, step 2) and 2-methyl Starting with benzenesulfonyl chloride (26 μL, 0.18 mmol), the title compound was prepared following the procedure of Example 106, step 3. The crude product was purified by preparative HPLC (System B; 10-40% MeCN). The title compound (10 mg, 19%) was obtained as a colorless solid. HPLC 99%, R _T = 1.41 min (System A; 10-97% MeCN over 3 minutes), 99%, R _T = 1.26 min (System B; 10-97% MeCN over 3 minutes). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 2.66 (s, 3 H) 3.50-3.65 (m, 8 H) 4.67 (s, 2 H) 6.86 (d, J = 2.01 Hz, 1 H) 7.22 7.29 (m, 1H) 7.30-7.37 (m, 2H) 7.40-7.48 (m, 2H) 7.81-7.90 (m, 2H). MS (ESI +) for C ₂ oH ₂₃ N ₃ 0 ₃ S m / z 386 (M + H) ⁺ .

Example 108

N- [7- (piperazin-1-ylmethyl) -1-benzofuran-5-yl] thiophen-2-sulfonamide, dihydro chloride

4- (5-Amino-benzofuran-7-ylmethyl) -piperazine-1-carboxylic acid tert -butyl ester (40 mg, 0,12 mmol; obtained in Example 106, step 2) and 2-ti Starting with offfensulfonyl chloride (33 mg, 0.18 mmol), the title compound was prepared following the procedure of Example 106, step 3. Additional 2-thiophenesulfonyl chloride (10 mg, 0.05 mmol) was added for 1 hour with continuous stirring. The crude product was purified by preparative HPLC (System B; 10-40% MeCN). The title compound (3 mg, 6%) was obtained as a colorless solid. HPLC 95%, R _T = 1.25 min (System A; 10-97% MeCN over 3 minutes), 95%, R _T = 1.11 min (System B; 10-97% MeCN over 3 minutes). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 3.43-3.49 (m, 4 H) 3.50-3.57 (m, 4 H) 4.59 (s, 2 H) 6.90 (d, J = 2.26 Hz, 1 H ) 7.05 (dd, J = 5.02, 3.76 Hz, 1H) 7.35 (d, J = 2.26 Hz, 1H) 7.45-7.50 (m, 2H) 7.70 (dd, J = 5.02, 1.51 Hz, 1H) 7.88 (d, J = 2.26 Hz, 1 H). MS (ESI +) for C ₁₇ H ₁₉ N ₃ O ₃ S ₂ m / z 378 (M + H) ⁺ .

Example 109

2-chloro-N- [7- (1,4-diazepane-1-ylmethyl) -1-benzofuran-5-yl] benzenesulfonamide dihydrochloride

Step 1: tert -Butyl 4-[(5-nitro-1-benzofuran-7-yl) methyl] -1,4-diazepane-1-carboxylate

The title product was prepared, starting from 1-boc-homopiperazine (103 μL, 0.53 mmol), obtained as a pale yellow solid, according to the procedure of Example 106, step 1. Yield: 109 mg (66%). HPLC 98%, R _T = 1.73 min (System A; 10-97% MeCN over 3 minutes), 100%, R _T = 1.57 min (System B; 10-97% MeCN over 3 minutes). MS (ESI +) for C ₁₉ H ₂₅ N ₃ O ₅ m / z 376 (M + H) ⁺ .

Step 2: 4- (5-Amino-benzofuran-7-ylmethyl) -1,4-diazepane-1-carboxylic acid tert-butyl ester

Example 106, steps starting from tert -butyl 4-[(5-nitro-1-benzofuran-7-yl) methyl] -1,4-diazepane-1-carboxylate (obtained in step 1) The title compound was prepared following the procedure in 2.

Step 3: 2-Chloro-N- [7- (1,4-diazepane-1-ylmethyl) -1-benzofuran-5-yl] benzenesulfonamide dihydrochloride

4- (5-amino-benzofuran-7-ylmethyl) -1,4-diazepane-1-carboxylic acid tert-butyl ester (36 mg, 0.10 mmol; obtained in step 2) and 2-chlorobenzenesulfur The title compound was prepared following the procedure of Example 106, step 3 starting from phonyl chloride (21 μL, 0.16 mmol). The crude was purified by preparative HPLC (System B; 10-40% MeCN). The title compound (16 mg, 33%) was obtained as a colorless solid. HPLC 95%, R _T = 1.31 min (System A; 10-97% MeCN over 3 minutes), 96%, R _T = 1.17 min (System B; 10-97% MeCN over 3 minutes). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 2.25-2.37 (m, 2H) 3.41-3.48 (m, 2H) 3.48-3.59 (m, J = 4.52 Hz, 2H) 3.69-3.75 ( m, J = 3.51 Hz, 2H) 3.74-3.83 (m, 2H) 4.70 (s, 2H) 6.86 (d, J = 2.26 Hz, 1H) 7.36-7.41 (m, 1H) 7.42 (d , J = 2.01 Hz, 1 H) 7.51-7.59 (m, 3H) 7.85 (d, J = 2.01 Hz, 1H) 8.00-8.04 (m, J = 7.91, 1.13 Hz, 1H). MS (ESI +) for C ₂₀ H ₂₂ ClN ₃ O ₃ S m / z 420 (M + H) ⁺ .

Example 110

N- [7- (1,4-diazepane-1-ylmethyl) -1-benzofuran-5-yl] -2- methylbenzene sulfonamide, dihydrochloride

4- (5-amino-benzofuran-7-ylmethyl) -1,4-diazepane-1-carboxylic acid tert-butyl ester (36 mg, 0.10 mmol; obtained in Example 109, step 2) and 2 The title compound was prepared following the procedure of Example 106, step 3 starting from -methylbenzenesulfonyl chloride (23 μL, 0.16 mmol). The title compound (13 mg, 28%) was obtained as a colorless solid. HPLC 99%, R _T = 1.35 min (System A; 10-97% MeCN over 3 minutes), 100%, R _T = 1.22 min (System B; 10-97% MeCN over 3 minutes). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 2.26-2.32 (m, 2 H) 2.66 (s, 3 H) 3.40-3.60 (m, 4 H) 3.69-3.83 (m, 4 H) 4.69 ( s, 2 H) 6.86 (d, J = 2.26 Hz, 1 H) 7.23-7.29 (m, 1 H) 7.32-7.38 (m, 2 H) 7.41-7.46 (m, 1 H) 7.47 (d, J = 2.26 Hz, 1 H) 7.84-7.90 (m, 2H). MS (ESI +) for C ₂₁ H ₂₅ N ₃ O ₃ S m / z 400 (M + H) ⁺ .

Example 111

N- [7- (1,4-diazepane-1-ylmethyl) -1-benzofuran-5-yl] thiophen-2-sulfonamide dihydrochloride

The title compound is obtained in 4- (5-amino-benzofuran-7-ylmethyl) -1,4-diazepane-1-carboxylic acid tert-butyl ester (36 mg, 0.10 mmol; Example 109, step 2 ) And 2-thiophenesulfonyl chloride (29 mg, 0.16 mmol) according to the procedure of Example 106, step 3. Additional 2-thiophenesulfonyl chloride (10 mg, 0.06 mmol) was added with continued stirring for 1 hour. The title compound (10 mg, 22%) was obtained as a colorless solid. HPLC 100%, R _T = 1.20 min (System A; 10-97% MeCN 3 min), 100%, R _T = 1.06 min (System B; 10-97% MeCN 3 min). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 2.20-2.29 (m, 2 H) 3.34-3.41 (m, 2 H) 3.41-3.55 (m, 2 H) 3.63-3.69 (m, 2 H) 3.69-3.77 (m, 2H) 4.66 (s, 2H) 6.84 (d, J = 2.26 Hz, 1H) 6.98 (dd, J = 5.02, 3.76 Hz, 1H) 7.32 (d, J = 2.01 Hz , 1 H) 7.42 (dd, J = 3.76, 1.25 Hz, 1 H) 7.47 (d, J = 2.26 Hz, 1 H) 7.63 (dd, J = 5.02, 1.25 Hz, 1 H) 7.82 (d, J = 2.26 Hz, 1 H). C ₁₈ H ₂₁ N ₃ O ₃ S ₂ MS (ESI +) for m / z 392 (M + H) ^+.

Example 112

2-methoxy-5-methyl-N- {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

Tert-butyl 3-methylpiperazin-1-carboxylate (94 mg, 0.47 mmol), 7- (bromomethyl) -5-nitro-1-benzofuran (120 mg, 70 in dry MeCN (5 mL) A mixture of mol%, 0.39 mmol; intermediate 64) and K ₂ CO ₃ (162 mg, 1.17 mmol) was heated at 80 ° C. while stirring with StemBlock for 1 hour 45 minutes. The solvent was evaporated under reduced pressure and the residue fractionated between water and DCM (x2). The organic layer was combined, dried (Na ₂ SO ₄ ) and purified using flashtube (10% MeOH in DCM). This resulted in the title product (115 mg, 78%) as sticky pale yellow oil. HPLC 99%, R _T = 2.47 min (System A; 5-60% MeCN 3 min), 99%, R _T = 2.27 min (System B; 5-60% MeCN 3 min). C ₁₉ H ₂₅ N ₃ O ₅ MS (ESI +) for m / z 376 (M + H) ^+.

Step 2:  tert -Butyl 4-[(5-amino-1-benzofuran-7-yl) methyl] -3-methylpiperazin-1-carboxylate

Raney nickel (slurry in ethanol) and hydrazine hydrate (97 μl, 2.0 mmol) were converted to tert-butyl 3-methyl-4-[(5-nitro-1-benzofuran in ethanol: THF (4: 1; 5 mL). -7-yl) methyl] piperazin-1-carboxylate (115 mg, 0.31 mmol; obtained in step 1). The resulting mixture was stirred at rt for 1.5 h and then filtered through celite. The celite pad was rinsed several times with ethanol. Evaporation of the solvent gave the crude product (136 mg) as a pale green solid. The material was used in the next step without further purification. HPLC 98%, R _T = 1.77 min (System A; 5-60% MeCN 3 min), 100%, R _T = 1.50 min (System B; 5-60% MeCN 3 min). C ₁₉ H ₂₇ N ₃ O ₃ For MS (ESI +) m / z 346 (M + H) ^+.

Step 3: 2-methoxy-5-methyl-N- {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) were dissolved in tert-butyl 4-[(5- in DCM: THF (2: 1; 3 mL)). Amino-1-benzofuran-7-yl) methyl] -3-methylpiperazin-1-carboxylate (45 mg crude material, 0.10 mmol; obtained in step 2) was added to the solution. The reaction mixture was stirred at rt for 2 h and the solvent was evaporated under reduced pressure and then purified by flashtube (15% MeOH in DCM). The residue was dissolved in TFA: water (9: 1; 4.5 mL) and the mixture was stirred at rt for 1 h to remove Nt-BOC groups. The reaction mixture was diluted with DCM (10 mL) and saturated aqueous Na ₂ CO ₃ was added to reach pH 8-9 (˜15 mL). The phases were separated using a "phase separation" filter and the organic phase was concentrated. The crude product was purified by preparative HPLC (System B; 10-40% MeCN). The pure fractions were combined and concentrated to give the product as free base, which was dissolved in MeOH and 1 M HCl in ether (200 μl, 0.2 mmol) was added. Evaporation of the solvent gave the title compound (19 mg, 38%) as a greyish white solid. HPLC 99%, R _T = 1.46 min (System A; 10-97% MeCN 3 min), 100%, R _T = 1.29 min (System B; 10-97% MeCN 3 min). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.72 (d, J = 6.53 Hz, 3 H) 2.20 (s, 3 H) 3.39-3.62 (m, 5 H) 3.67-3.74 (m, 1 H ) 3.87-3.96 (m, 1 H) 3.98 (s, 3 H) 4.60 (d, J = 13.55 Hz, 1 H) 4.93 (d, J = 13.80 Hz, 1 H) 6.87 (d, J = 2.26 Hz, 1 H) 7.04 (d, J = 8.53 Hz, 1 H) 7.28-7.37 (m, 2 H) 7.52 (d, J = 2.26 Hz, 1 H) 7.54 (d, J = 2.01 Hz, 1 H) 7.85 ( d, J = 2.01 Hz, 1 H). MS (ESI +) for C ₂₂ H ₂₇ N ₃ O ₄ S m / z 430 (M + H) ^+.

Example 113

2-methyl-N- {7-[(2-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide dihydrochloride

The title product was converted to tert-butyl 4-[(5-amino-1-benzofuran-7-yl) methyl] -3-methylpiperazin-1-carboxylate (45 mg crude, 0.10 mmol; Example 112, Prepared according to the procedure of Example 112, step 3 starting from o-toluenesulfonyl chloride (22 μl, 0.15 mmol). The title compound (17 mg, 35%) was obtained as a greyish white solid. HPLC 99%, R _T = 1.42 min (System A; 10-97% MeCN 3 min), 100%, R _T = 1.26 min (System B; 10-97% MeCN 3 min). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.69-1.74 (m, 3 H) 2.67 (s, 3 H) 3.37-3.62 (m, 5 H) 3.67-3.75 (m, 1 H) 3.84- 3.95 (m, 1 H) 4.57-4.65 (m, 1 H) 4.90-4.97 (m, J = 13.55 Hz, 1 H) 6.86 (d, J = 2.26 Hz, 1 H) 7.23-7.29 (m, J = 7.65, 7.65 Hz, 1 H) 7.31 (d, J = 2.01 Hz, 1 H) 7.32-7.36 (m, 1 H) 7.40-7.46 (m, 1 H) 7.50 (d, J = 2.01 Hz, 1 H) 7.85-7.90 (m, 2H). MS (ESI +) for C ₂₁ H ₂₅ N ₃ O ₃ S m / z 400 (M + H) ^+.

Example 114

2,5-dichloro-N- {7-[(2-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} thiophene-3-sulfonamide dihydrochloride

The title product was converted to tert-butyl 4-[(5-amino-1-benzofuran-7-yl) methyl] -3-methylpiperazin-1-carboxylate (45 mg crude, 0.10 mmol; Example 112, Prepared according to the procedure of Example 112, step 3 starting from 2) and 2,5-dichlorothiophene-3-sulfonyl chloride (38 mg, 0.15 mmol). The title compound (23 mg, 43%) was obtained as a greyish white solid. HPLC 98%, R _T = 1.61 min (System A; 10-97% MeCN 3 min), 100%, R _T = 1.43 min (System B; 10-100% MeCN 3 min). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.53 (d, J = 6.27 Hz, 3H) 2.87-3.02 (m, 1H) 3.14-3.27 (m, 2H) 3.39-3.47 (m, 1 H) 3.47-3.54 (m, 1 H) 4.12-4.24 (m, 1 H) 4.62-4.71 (m, 1 H) 6.89 (d, J = 2.26 Hz, 1 H) 7.13 (s, 1 H) 7.30 7.32 (m, J = 1.76 Hz, 1 H) 7.45 (d, J = 2.26 Hz, 1 H) 7.85 (d, J = 2.26 Hz, 1 H). * Two hydrogens are not visible in the spectrum. Perhaps "hide" behind the H ₂ O- and MeOH signals. C ₁₈ H ₁₉ Cl ₂ N ₃ O ₃ S ₂ MS (ESI +) for m / z 460 (M + H) ^+.

Example 115

2-methoxy-5-methyl-N- {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 is carried out 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) Prepared according to the procedure of Example 112, step 1. The crude product was purified using flash chromatography (eluent: 1% NEt _{3 in} DCM, 4% MeOH,). The title compound (102 mg, 87%) was obtained as a sticky pale yellow oil. HPLC 99%, R _T = 1.60 min (System A; 5-60% MeCN 3 min), 100%, R _T = 1.40 min (System B; 5-60% MeCN 3 min). C ₁₄ H ₁₇ N ₃ O ₃ MS (ESI +) for m / z 276 (M + H) ^+.

Step 2: tert -Butyl 2-methyl-4-[(5-nitro-1-benzofuran-7-yl) methyl] piperazin-1-carboxylate

Di-tert-butyl dicarbonate (89 mg, 0.41 mmol) was dried at 0 ° C. under N ₂ using a syringe with NEt ₃ (77 μl, 0.77 mmol) and 3-methyl-1-[(2) in DCM (2 mL). 5-nitro-1-benzofuran-7-yl) methyl] piperazine (102 mg, 0.37 mmol; obtained in step 1). The resulting mixture was allowed to reach room temperature and stirred for 1.5 hours. The reaction mixture was diluted with DCM and saturated aqueous Na ₂ CO ₃ was added. The organic layer was dried (Na ₂ SO ₄ ) and concentrated and purified by flash chromatography (eluent: 1.5% MeOH in DCM). This resulted in the title compound (124 mg, 89%) as a white foam. HPLC 90%, R _T = 2.53 min (System A; 5-60% MeCN 3 min), 90%, R _T = 2.35 min (System B; 5-60% MeCN 3 min). C ₁₉ H ₂₅ N ₃ O ₅ For MS (ESI +) m / z 376 (M + H) ^+.

Step 3: tert -Butyl 4-[(5-amino-1-benzofuran-7-yl) methyl] -2-methylpiperazin-1-carboxylate

The title compound was obtained from tert-butyl 2-methyl-4-[(5-nitro-1-benzofuran-7-yl) methyl] piperazin-1-carboxylate (124 mg, 0.33 mmol; obtained in step 2). Prepared according to the procedure of Example 112, step 2 using. Crude title compound (124 mg) was obtained as a pale green solid. The material was used for the next step without further purification. HPLC 100%, R _T = 1.82 min (System A; 5-60% MeCN 3 min), 100%, R _T = 1.57 min (System B; 5-60% MeCN 3 min). C ₁₉ H ₂₇ N ₃ O ₃ MS (ESI +) for m / z 346 (M + H) ^+.

Step 4: 2-methoxy-5-methyl-N- {7-[(3-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide, dihydrochloride

tert-butyl 4-[(5-amino-1-benzofuran-7-yl) methyl] -2-methylpiperazin-1-carboxylate (41 mg crude starting material, 0.11 mmol; obtained in step 3) Was dissolved in dry DCM: 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 rt for 2 h and the solvent was evaporated under reduced pressure and then purified by flashtube (11% MeOH in DCM). The residue was dissolved in TFA: water (9: 1; 4.5 mL) and the mixture was stirred at rt for 1 h to remove Nt-BOC groups. The reaction mixture was diluted with DCM (10 mL) and saturated aqueous Na ₂ CO ₃ was added to reach pH 8-9 (˜15 mL). The phases were separated using a "phase separation" filter and the organic phase was concentrated. The crude product was purified by preparative HPLC (System B; 10-40% MeCN). The pure fractions were combined and concentrated to give the product as free base, which was dissolved in MeOH and 1 M HCl in ether (200 μl, 0.2 mmol) was added. Evaporation of the solvent gave the title compound (16 mg, 29%) as a greyish white solid. HPLC 99%, R _T = 1.48 min (System A; 10-97% MeCN 3 min), 100%, R _T = 1.30 min (System B; 10-97% MeCN 3 min). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.38-1.45 (m, J = 6.53 Hz, 3 H) 2.20 (s, 3 H) 3.34-3.42 (m, J = 13.30 Hz, 1 H) 3.46 -3.78 (m, 5H) 3.79-3.91 (m, 1H) 3.98 (s, 3H) 4.71 (s, 2H) 6.87 (d, J = 2.26 Hz, 1H) 7.04 (d, J = 8.53 Hz, 1 H) 7.29-7.34 (m, J = 8.78, 2.01 Hz, 1 H) 7.37 (d, J = 2.26 Hz, 1 H) 7.51-7.53 (m, J = 2.01 Hz, 1 H) 7.54 (d , J = 2.26 Hz, 1H) 7.85 (d, J = 2.01 Hz, 1H). C ₂₂ H ₂₇ N ₃ O ₄ S MS (ESI +) for m / z 430 (M + H) ^+.

Example 116

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

The title compound was converted to tert-butyl 4-[(5-amino-1-benzofuran-7-yl) methyl] -2-methylpiperazin-1-carboxylate (41 mg crude starting material, 0.11 mmol; Example 115 Prepared in step 3) and 2- (trifluoromethyl) benzenesulfonyl chloride (25 μl, 0.17 mmol) according to the procedure of Example 115, step 4. The title compound (24 mg, 44%) was obtained as a greyish white solid. HPLC 98%, R _T = 1.56 min (System A; 10-97% MeCN 3 min), 97%, R _T = 1.37 min (System B; 10-97% MeCN 3 min). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.41 (d, J = 6.53 Hz, 3H) 3.36-3.44 (m, J = 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, J = 2.26 Hz, 1H) 7.41 (d, J = 2.01 Hz, 1H) 7.53 (d, J = 2.26 Hz, 1 H) 7.68-7.76 (m, 2H) 7.88 (d, J = 2.01 Hz, 1 H) 7.90-7.95 (m, J = 6.90, 2.13 Hz, 1 H) 8.09-8.13 (m, 1 H). C ₂₁ H ₂₂ F ₃ N ₃ O ₃ S MS (ESI +) for m / z 454 (M + H) ^+.

Example 117

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

The title compound was converted to tert-butyl 4-[(5-amino-1-benzofuran-7-yl) methyl] -2-methylpiperazin-1-carboxylate (41 mg crude starting material, 0.11 mmol; Example 115 Prepared in step 3) and 2-chlorobenzenesulfonyl chloride (22 μl, 0.17 mmol) according to the procedure of Example 115, step 4. The title compound (21 mg, 39%) was obtained as a greyish white solid. HPLC 100%, R _T = 1.42 min (System A; 10-97% MeCN 3 min), 100%, R _T = 1.26 min (System B; 10-97% MeCN 3 min). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.41 (d, J = 6.53 Hz, 3 H) 3.32-3.37 (m, 1H) 3.45-3.59 (m, 2H) 3.63-3.76 (m, 3 H) 3.78-3.89 (m, 1 H) 4.70 (s, 2 H) 6.86 (d, J = 2.26 Hz, 1 H) 7.36-7.41 (m, 1 H) 7.42 (d, J = 2.01 Hz, 1 H) 7.49-7.54 (m, 1H) 7.54-7.58 (m, 2H) 7.86 (d, J = 2.01 Hz, 1H) 8.02 (dd, J = 7.91, 1.63 Hz, 1H). MS (ESI +) for C ₂₀ H ₂₂ ClN ₃ O ₃ S m / z 420 (M + H) ^+.

Example 118

N -{7-[(1 S ,4 S ) -2,5-diazabicyclo [2.2.1] hept-2-ylmethyl] -1-benzofuran-5-yl} -2-methoxy-5-methylbenzenesulfonamide, dihydrochloride

Step 1: tert -Butyl (1 S ,4 S ) -5-[(5-nitro-1-benzofuran-7-yl) methyl] -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate

The title compound was diluted with 7- (bromomethyl) -5-nitro-1-benzofuran (120 mg, 70 mol%, 0.39 mmol; intermediate 64) and tert-butyl (1S, 4S)-(-)-2,5 Prepared according to the procedure of Example 112, step 1 starting from diazabicyclo- (2.2.1) heptan-2-carboxylate (93 mg, 0.47 mmol). The title compound (115 mg, 79%) was obtained as a sticky pale yellow oil. HPLC 99%, R _T = 2.34 min (System A; 5-60% MeCN 3 min), 99%, R _T = 2.15 min (System B; 5-60% MeCN 3 min). C ₁₉ H ₂₃ N ₃ O ₅ MS (ESI +) for m / z 374 (M + H) ^+.

Step 2: tert -Butyl (1 S ,4 S ) -5-[(5-amino-1-benzofuran-7-yl) methyl] -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate

The title compound is titled tert -butyl (1 S , 4 S ) -5-[(5-nitro-1-benzofuran-7-yl) methyl] -2,5-diazabicyclo [2.2.1] heptan-2- Prepared according to the procedure of Example 112, step 2 using carboxylate (116 mg, 0.31 mmol; obtained in step 1). The title compound (133 mg) was obtained as a pale green solid. The material was used for the next step without further purification. HPLC 99%, R _T = 1.69 min (System A; 5-60% MeCN 3 min), 100%, R _T = 1.45 min (System B; 5-60% MeCN 3 min). C ₁₉ H ₂₅ N ₃ O ₃ For MS (ESI +) m / z 344 (M + H) ^+.

Step 3: N -{7-[(1 S ,4 S ) -2,5-diazabicyclo [2.2.1] hept-2-ylmethyl] -1-benzofuran-5-yl} -2-methoxy-5-methylbenzenesulfonamide, dihydrochloride

The title compound is titled tert -butyl (1 S , 4 S ) -5-[(5-amino-1-benzofuran-7-yl) methyl] -2,5-diazabicyclo [2.2.1] heptan-2- The procedure of Example 112, step 3 starting from carboxylate (44 mg crude starting material, 0.10 mmol; obtained in step 2) and 6-methoxy-m-toluenesulfonyl chloride (34 mg, 0.15 mmol) Prepared according to The title compound (11 mg, 20%) was obtained as a greyish white solid. HPLC 100%, R _T = 1.39 min (System A; 10-97% MeCN 3 min), 100%, R _T = 1.24 min (System B; 10-97% MeCN 3 min). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 2.20 (s, 3 H) 2.28-2.34 (m, J = 12.80 Hz, 1 H) 2.61-2.70 (m, 1 H) 3.52-3.58 (m, J = 13.80, 2.76 Hz, 1 H) 3.64-3.72 (m, J = 13.30, 2.51 Hz, 1 H) 3.85-3.93 (m, 1 H) 3.98 (s, 3 H) 4.48 (s, 1 H) 4.65 (s, 1 H) 4.70-4.76 (m, 1 H) 4.77-4.82 (m, 2 H) 6.87 (d, J = 2.01 Hz, 1 H) 7.04 (d, J = 8.53 Hz, 1 H) 7.30- 7.34 (m, J = 8.53, 2.26 Hz, 1 H) 7.41 (d, J = 2.26 Hz, 1 H) 7.50 (d, J = 2.01 Hz, 1 H) 7.51-7.53 (m, J = 2.26 Hz, 1 H) 7.85 (d, J = 2.26 Hz, 1 H). C ₂₂ H ₂₅ N ₃ O ₄ S For MS (ESI +) m / z 428 (M + H) ^+.

Example 119

N -{7-[(1 S ,4 S ) -2,5-diazabicyclo [2.2.1] hept-2-ylmethyl] -1-benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide, dihydrochloride

The title compound is titled tert -butyl (1 S , 4 S ) -5-[(5-amino-1-benzofuran-7-yl) methyl] -2,5-diazabicyclo [2.2.1] heptan-2- Example 112, starting from carboxylate (44 mg crude starting material, 0.10 mmol; Example 118, obtained in step 2) and 2- (trifluoromethyl) benzenesulfonyl chloride (24 μl, 0.15 mmol) Prepared according to the procedure of step 3. The title compound (18 mg, 34%) was obtained as a greyish white solid. HPLC 99%, R _T = 1.46 min (System A; 10-97% MeCN 3 min), 100%, R _T = 1.29 min (System B; 10-97% MeCN 3 min). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 2.31-2.37 (m, J = 13.05 Hz, 1 H) 2.65-2.78 (m, J = 6.27 Hz, 1 H) 3.53-3.60 (m, J = 13.43, 2.89 Hz, 1 H) 3.67-3.76 (m, 1 H) 3.88-3.96 (m, J = 12.80 Hz, 1 H) 4.51 (s, 1 H) 4.66 (s, 1 H) 4.72-4.79 (m , 1 H) 4.84 (d, 2 H) 6.88 (d, J = 2.01 Hz, 1 H) 7.46 (d, J = 2.01 Hz, 1 H) 7.51 (d, J = 2.01 Hz, 1 H) 7.68-7.75 (m, 2H) 7.88 (d, J = 2.26 Hz, 1H) 7.89-7.94 (m, 1H) 8.09-8.13 (m, 1H). C ₂₁ H ₂₀ F ₃ N ₃ O ₃ S MS (ESI +) for m / z 452 (M + H) ^+.

Example 120

N -{7-[(1 S ,4 S ) -2,5-diazabicyclo [2.2.1] hept-2-ylmethyl] -1-benzofuran-5-yl} -2-methylbenzenesulfonamide, dihydrochloride

The title compound is titled tert -butyl (1 S , 4 S ) -5-[(5-amino-1-benzofuran-7-yl) methyl] -2,5-diazabicyclo [2.2.1] heptan-2- Starting from carboxylate (44 mg crude starting material, 0.10 mmol; Example 118, step 2) and o-toluenesulfonyl chloride (22 μl, 0.15 mmol) according to the procedure of Example 112, step 3 Manufactured. The title compound (15 mg, 31%) was obtained as a greyish white solid. HPLC 98%, R _T = 1.37 min (System A; 10-97% MeCN 3 min), 97%, R _T = 1.21 min (System B; 10-97% MeCN 3 min). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 2.28-2.34 (m, 1 H) 2.66 (s, 3 H) 2.67-2.72 (m, 1 H) 3.52-3.59 (m, J = 13.68, 2.64 Hz, 1 H) 3.63-3.76 (m, 1 H) 3.85-3.93 (m, J = 12.80 Hz, 1 H) 4.45-4.51 (m, 1 H) 4.65 (s, 1 H) 4.69-4.78 (m, 1 H) 4.78-4.83 (m, 2 H) 6.86 (d, J = 2.26 Hz, 1 H) 7.23-7.29 (m, 1 H) 7.31-7.36 (m, J = 7.53 Hz, 1 H) 7.37-7.46 (m, 2H) 7.48 (d, J = 2.26 Hz, 1H) 7.84-7.88 (m, 2H). C ₂₁ H ₂₃ N ₃ O ₃ S For MS (ESI +) m / z 398 (M + H) ^+.

Example 121

2-methoxy-5-methyl-N- {7-[(trans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide, bis (trifluor Low acetate)

Step 1: trans-2,5-dimethyl-1-[(5-nitro-1-benzofuran-7-yl) methyl] piperazine

The title compound was obtained from Example 112, 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). Prepared according to the procedure of step 1. This resulted in the title product (0.11 g, 60%) as a pale yellow solid. HPLC 98% R _T = 1.26 min (System A; 10-97% MeCN 3 min). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.93 (d, J = 6.3 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 1.48 (br s, 1H) 1.79 (dd, J = 11.0 , 10.3 Hz, 1 H) 2.29-2.41 (m, 1 H) 2.63-2.75 (m, 2 H) 2.80-2.89 (m, 1 H) 2.93 (dd, J = 12.0, 3.3 Hz, 1 H) 3.61 ( d, J = 14.6 Hz, 1 H) 4.28 (d, J = 14.3 Hz, 1 H) 6.91 (d, J = 2.3 Hz, 1 H) 7.76 (d, J = 2.3 Hz, 1 H) 8.29 (d, J = 2.3 Hz, 1 H) 8.41 (d, J = 2.3 Hz, 1 H). MS (ESI +) m / z 290.1 (M + H) ^+.

Step 2: tert -Butyl trans-2,5-dimethyl-4-[(5-nitro-1-benzofuran-7-yl) methyl] piperazin-1-carboxylate

Trans-2,5-dimethyl-1-[(5-nitro-1-benzofuran-7-yl) methyl] piperazin (0.11 g, 0.4 mmol; obtained in step 1) was dissolved in MeOH. Boc-Anhydride (0.114 g, 0.5 mmol) was added and the reaction stirred overnight at ambient temperature. The solvent was evaporated and the residue dissolved in DCM and washed with citric acid. The organic layer was dried (MgSO ₄ ) and evaporated to give 0.135 g (91%) of the title product. HPLC 96% Rt = 1.79 min (System A; 10-97% MeCN 3 min). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.07 (d, J = 6.5 Hz, 3 H) 1.27 (d, J = 6.8 Hz, 3 H) 1.46 (s, 9 H) 2.18-2.27 (m, 1 H) 2.82 (dd, J = 11.5, 4.3 Hz, 1 H) 2.98-3.06 (m, 1 H) 3.37 (dd, J = 13.1, 3.5 Hz, 1 H) 3.65-3.75 (d, J = 13.1 Hz, 1 H) 3.83-3.95 (m, 2 H) 4.16-4.27 (m, 1 H) 6.91 (d, J = 2.3 Hz, 1 H) 7.76 (d, J = 2.3 Hz, 1 H) 8.25-8.55 (m , 2 H). MS (ESI +) m / z 390.2 (M + H) ^+.

Step 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] piperazin-1-carboxylate (0.14 g, 0.35 mmol; obtained in step 2 ) Was dissolved in THF / EtOH (4: 1; 5 mL). Excess Raney-Ni (slurry in EtOH) was added followed by hydrazine hydrate (0.07 g, 1.39 mmol). The reaction mixture was stirred at ambient temperature overnight. After filtration and evaporation of the solvent, crude oil (0.11 g, 87%) was obtained which was used in the next step without further purification. HPLC 86% R _T = 1.15 min (System B; 10-97% MeCN 3 min). MS (ESI +) m / z 360.2 (M + H) ^+.

Step 4:  tert -Butyl trans-4-[(5-{[(2-methoxy-5-methylphenyl) sulfonyl] amino} -1-benzofuran-7-yl) methyl] -2,5-dimethylpiperazine-1- Carboxylate

tert-butyl trans-4-[(5-amino-1-benzofuran-7-yl) methyl] -2,5-dimethylpiperazin-1-carboxylate (0.037 g, 0.1 mmol; obtained in step 3 ) Was dissolved in DCM and 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 HCl and the organic layer was dried (MgSO ₄ ) and evaporated. The crude product was purified using flashtube (10% MeOH in DCM) to afford the title compound (0.026 g, 48%). HPLC 93% R _T = 2.01 min (System A; 10-97% MeCN 3 min), 93% R _T = 1.85 min (System B; 10-97% MeCN 3 min). MS (ESI +) m / z 544.2 (M + H) ^+.

Step 5: 2-methoxy-5-methyl-N- {7-[(trans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide, bis (Trifluoroacetate)

TFA: tert -butyl trans-4-[(5-{[(2-methoxy-5-methylphenyl) sulfonyl] amino} -1-benzofuran-7-yl) methyl] -in water (9: 1) A solution of 2,5-dimethylpiperazin-1-carboxylate (0.026 g, 0.047 mmol; obtained in step 4) was stirred at ambient temperature for 1 hour. Solvents were evaporated and the residue was purified by preparative HPLC (System A; 20-40% MeCN). The pure fractions were combined and concentrated to give the title compound as a colorless TFA-salt (0.020 mg, 63%). HPLC 100%, R _T = 1.52 min (System A; 10-97% MeCN 3 min), 100%, R _T = 1.25 min (System B; 10-97% MeCN 3 min). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.24 (d, J = 6.53 Hz, 3 H) 1.48 (d, J = 6.27 Hz, 3 H) 2.20 (s, 3 H) 2.61 (dd, J = 13.30, 11.54 Hz, 1 H) 3.05-3.23 (m, 3 H) 3.39-3.47 (m, 1 H) 3.50 (dd, J = 12.92, 2.64 Hz, 1 H) 3.97 (s, 3 H) 4.07 ( d, J = 13.80 Hz, 1 H) 4.60 (d, J = 13.80 Hz, 1 H) 6.80 (d, J = 2.26 Hz, 1 H) 7.03 (d, J = 8.53 Hz, 1 H) 7.24 (d, J = 2.01 Hz, 1 H) 7.29-7.33 (m, J = 8.78, 2.01 Hz, 1 H) 7.35 (d, J = 2.01 Hz, 1 H) 7.48-7.51 (m, J = 1.51 Hz, 1 H) 7.76 (d, J = 2.01 Hz, 1 H). MS (ESI +) for C ₂₃ H ₂₉ N ₃ O ₄ S m / z 444 (M + H) ^+.

Example 122

2-methyl-N- {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-7-yl) methyl] piperazin-1-carboxylate

The title product is obtained in tert -butyl trans-4-[(5-amino-1-benzofuran-7-yl) methyl] -2,5-dimethylpiperazin-1-carboxylate (Example 121, step 3) ) And 2-methylbenzenesulfonyl chloride (0.039 g, 0.2 mmol) according to the procedure of Example 121, step 4. Yield: 0.022 g (43%). HPLC 95% R _T = 1.99 min (System A; 10-97% MeCN 3 min), 93% R _T = 1.85 min (System B; 10-97% MeCN 3 min). MS (ESI +) m / z 514.2 (M + H) ^+.

Step 2: 2-Methyl-N- {7-[(trans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide, bis (trifluoroacetate )

The title compound is titled tert -butyl trans-2,5-dimethyl-4-[(5-{[(2-methylphenyl) sulfonyl] amino} -1-benzofuran-7-yl) methyl] piperazin-1-car Prepared according to the procedure of Example 121, step 5 starting from the carboxylate (0.022 g, 0.043 mmol; obtained in step 1). Yield: 0.017 g (62%). HPLC 100%, R _T = 1.49 min (System A; 10-97% MeCN 3 min), 100%, R _T = 1.22 min (System B; 10-97% MeCN 3 min). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.20-1.27 (m, 3 H) 1.43-1.51 (m, 3 H) 2.51-2.65 (m, 1 H) 2.63 (s, 3 H) 3.02- 3.25 (m, 3 H) 3.38-3.45 (m, 1 H) 3.45-3.53 (m, 1 H) 4.00-4.11 (m, 1 H) 4.53-4.64 (m, 1 H) 6.79 (d, J = 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, J = 8.03, 1.25 Hz, 1H). MS (ESI +) for C ₂₂ H ₂₇ N ₃ 0 ₃ S m / z 414 (M + H) ^+.

Example 123

2-chloro-N- {7-[(trans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide, bis (trifluoroacetate)

Step 1:  tert -Butyl trans-4-[(5-{[(2-chlorophenyl) sulfonyl] amino} -1-benzofuran-7-yl) methyl] -2,5-dimethylpiperazine-1-carboxylate

The title product is obtained in tert -butyl trans-4-[(5-amino-1-benzofuran-7-yl) methyl] -2,5-dimethylpiperazin-1-carboxylate (Example 121, step 3) ) And 2-chlorobenzensulfonyl chloride (0.043 g, 0.2 mmol) according to the procedure of Example 121, step 4. Yield: 0.017 g (26%). HPLC 94% R _T = 2.01 min (System A; 10-97% MeCN 3 min), 98% R _T = 1.85 min (System B; 10-97% MeCN 3 min). MS (ESI +) m / z 534.2 (M + H) ^+.

Step 2: 2-chloro-N- {7-[(trans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide, bis (trifluoroacetate )

The title compound is titled tert -butyl trans-4-[(5-{[(2-chlorophenyl) sulfonyl] amino} -1-benzofuran-7-yl) methyl] -2,5-dimethylpiperazin-1- Prepared according to the procedure of Example 121, step 5 starting from carboxylate (0.017 g, 0.032 mmol; obtained in step 1). Yield: 0.016 g (76%). HPLC 99%, R _T = 1.47 min (System A; 10-97% MeCN 3 min), 100%, R _T = 1.20 min (System B; 10-97% MeCN 3 min). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.23 (d, J = 6.53 Hz, 3H) 1.43 (d, J = 5.77 Hz, 3H) 2.48 (dd, J = 13.18, 11.42 Hz, 1 H) 3.00-3.06 (m, 2H) 3.10 (dd, J = 13.30, 3.26 Hz, 1H) 3.34-3.42 (m, 1H) 3.42-3.47 (m, 1H) 3.96 (d, J = 14.05 Hz, 1 H) 4.51 (d, J = 14.05 Hz, 1 H) 6.79 (d, J = 2.01 Hz, 1 H) 7.24 (d, J = 2.01 Hz, 1 H) 7.33-7.39 (m, 2 H) 7.47-7.53 (m, 1 H) 7.53-7.57 (m, 1 H) 7.76 (d, J = 2.26 Hz, 1 H) 7.94-7.99 (m, J = 7.78, 1.51 Hz, 1 H). MS (ESI +) for C ₂₁ H ₂₄ ClN ₃ O ₃ S m / z 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 added slowly. 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 afford the title compound as a pale brown solid. Yield: 8.6 g (99%). HPLC purity 93%, R _T = 1.72 min (System A; 10-97% MeCN 3 min); 96%, R _T = 1.67 min (System B; 10-97% MeCN 3 min). MS (ESI +) for C ₁₀ H ₁₀ O ₃ m / z 179 (M + H) ^+.

Intermediate 66

Methyl 5-[(2-methoxy-5-methylphenyl) sulfonyl] -2,3-dihydro-1-benzofuran-7-carboxylate

2-methoxy-5-methylbenzenesulfonic acid (1.13 g, 5.6 mmol) and phosphorous pentoxide in methyl 2,3-dihydro-1-benzofuran-7-carboxylate (1 g, 5.6 mmol; intermediate 65) Methanesulfonic acid solution (1:10; 13.5 mL) was added. The mixture was stirred at rt for 48 h. Additional 2-methoxy-5-methylbenzenesulfonic acid (0.56 g, 2.8 mmol) was added and the reaction mixture was stirred at 50 ° C for 15 h. The mixture was poured onto water / ice and the formed precipitate was filtered off, dissolved in DCM and evaporated. The crude product was purified using flash chromatography (eluent: isohexane: EtOAc 1: 1) to afford the title compound. Yield: 1.07 g (53%). MS (ESI +) for C ₁₈ H ₁₈ O ₆ S m / z 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 added to chlorobenzene (6 mL). N-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 h. The mixture was washed with saturated aqueous NaHCO ₃ and the organic layer was concentrated. Yield: 405 mg (46%) after purification with preparative HPLC (System F; 40-60% MeCN). MS (ESI +) for C ₁₈ H ₁₆ O ₆ S m / z 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) is dissolved in dry THF (3 mL) and THF 1 M lithium aluminum hydride in (0.3 mL) was added slowly. The mixture was stirred at rt overnight. After this time, water (0.15 mL) was added and stirring continued for 10 minutes, followed by 2M aqueous NaOH (0.15 mL) and water (0.45 mL). The precipitate formed was filtered off and the solvent was evaporated. The crude product was used for next step without further purification. MS (ESI +) for C ₁₇ H ₁₆ O ₅ S m / z 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 dry DCM (2 mL) and DMF (0.9 mL, 1.1 mmol) was added (high 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 rt for 17 h. did. The mixture was washed with 2 M NaOH (2 ×) and the organic layer was concentrated to give crude product. The material was used for the next step without further purification. MS (ESI +) for C ₁₇ H ₁₅ ClO ₄ S m / z 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 Nt-Boc -Piperazine (28 mg, 0.1 mmol) and sodium bicarbonate (13 mg, 0.1 mmol) were added. The mixture was heated at 80 ° C. in StemBlock overnight. The mixture was extracted with chloroform (x2) and the chloroform-layer was evaporated. Purification by preparative HPLC / MS (System A; 10-40% MeCN). The Nt-BOC derivative of the title compound obtained was dissolved in DCM (1 mL) and TFA (1 mL) was added. After stirring at room temperature overnight, the solvent was evaporated to afford the title compound. Yield: 11 mg (27%) after preparative HPLC / MS (System A; 10-40% MeCN). HPLC purity 98%, R _T = 1.50 min (System A; 10-97% MeCN 3 min); 99%, R _T = 1.30 min (System B; 10-90% MeCN 3 min). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.35 (s, 3 H) 3.26-3.46 (m, 8 H) 3.70 (s, 3 H) 4.34 (s, 2 H) 6.78 (d, J = 8.53 Hz , 1 H) 6.90 (d, J = 2.01 Hz, 1 H) 7.32 (dd, J = 8.41, 1.63 Hz, 1 H) 7.75 (d, J = 1.25 Hz, 1 H) 7.89-7.98 (m, 2 H ) 8.30 (d, J = 1.25 Hz, 1 H). MS (ESI +) for C ₂₁ H ₂₄ N ₂ O ₄ S m / z 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 of 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). Prepared. Yield: 882 mg (49%). MS (ESI +) for C ₁₆ H ₁₄ O ₅ S m / z 319 (M + H) ⁺ .

Step 2: Methyl 5- (phenylsulfonyl) -1-benzofuran-7-carboxylate

The title compound according to the procedure of Intermediate 67 starting from methyl 5- (phenylsulfonyl) -2,3-dihydro-1-benzofuran-7-carboxylate (198 mg, 0.6 mmol; obtained in step 1) Was prepared. Yield: 80 mg (41%) (after purification with preparative HPLC (System F; 40-70% MeCN)). MS (ESI +) for C ₁₆ H ₁₄ O ₅ S m / z 317 (M + H) ⁺ .

Step 3: [5- (phenylsulfonyl) -1-benzofuran-7-yl] methanol

Starting with methyl 5- (phenylsulfonyl) -1-benzofuran-7-carboxylate (80 mg, 0.25 mmol; obtained in step 2) the title compound was obtained following the procedure of intermediate 68. Crude material was used directly in the subsequent reaction. MS (ESI +) for C ₁₅ H ₁₂ O ₄ S m / z 289 (M + H) ⁺ .

Step 4: 7- (chloromethyl) -5- (phenylsulfonyl) -1-benzofuran

The title compound was prepared following the procedure of Intermediate 69 starting from [5- (phenylsulfonyl) -1-benzofuran-7-yl] methanol (73 mg, 0.3 mmol; obtained in step 3). The crude material was used directly in the subsequent reaction. C ₁₅ H ₁₁ ClO ₃ S MS (ESI +) for m / z 307 (M + H) ⁺ .

Step 5: 1-{[5- (phenylsulfonyl) -1-benzofuran-7-yl] methyl} piperazine, trifluoro acetate

Nt-BOC-piperazine (24 mg, 0.13 mmol) and sodium bicarbonate (11 mg, 0.13 mmol) were dissolved in 7- (chloromethyl) -5- (phenylsulfonyl) -1-benzofuran (2 mL) in ethanol (2 mL). 26 mg, 0.08 mmol; obtained in step 4). The mixture was stirred overnight at 80 ° C. in a STEM-block and the solvent was evaporated. The Nt-BOC derivative of the title compound obtained was dissolved in DCM (1 mL) and TFA (1 mL) was added. The mixture was stirred at rt for 2 h and then the solvent was evaporated to give the title compound. Yield: 6.1 mg (12%) (after purification with preparative HPLC / MS (System A; 10-40% MeCN)). HPLC purity 99%, R _T = 1.39 min (System A; 10-97% MeCN, 3 min); 96%, R _T = 1.16 min (System B; 10-90% MeCN, 3 min). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.10-3.17 (m, 4 H) 3.34-3.39 (m, 4 H) 4.20 (s, 2 H) 6.87-6.92 (m, 1 H) 7.46-7.58 ( m, 3H) 7.75 (d, J = 2.26 Hz, 1H) 7.92-7.97 (m, 3H) 8.26 (d, J = 1.76 Hz, 1H). MS (ESI +) for C ₁₉ H ₂₀ N ₂ O ₃ S m / z 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

Follow the procedure of 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). The title compound was prepared. Yield: 405 mg (22%). MS (ESI +) for C ₁₇ H ₁₆ O ₅ S m / z 333 (M + H) ⁺ .

Step 2: Methyl 5-[(4-methylphenyl) sulfonyl] -1-benzofuran-7-carboxylate

Procedure of intermediate 67 starting from methyl 5-[(4-methylphenyl) sulfonyl] -2,3-dihydro-1-benzofuran-7-carboxylate (117 mg, 0.4 mmol; obtained in step 1) According to the title compound. Yield: 62 mg (53%) (after purification with preparative HPLC (System F; 40-60% MeCN)). MS (ESI +) for C ₁₇ H ₁₆ O ₅ S m / z 331 (M + H) ⁺ .

Step 3: {5-[(4-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methanol

The title compound was prepared according to the procedure of intermediate 68 from methyl 5-[(4-methylphenyl) sulfonyl] -1-benzofuran-7-carboxylate (62 mg, 0.19 mmol; obtained in step 2). MS (ESI +) m / z 303 (M + H) ⁺ for C ₁₆ H ₁₄ O ₄ S.

Step 4: 7- (chloromethyl) -5-[(4-methylphenyl) sulfonyl] -1-benzofuran

The title compound was prepared according to the procedure of Intermediate 69 from {5-[(4-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methanol (57 mg, 0.2 mmol; obtained in step 3). MS (ESI +) for C ₁₆ H ₁₃ ClO ₃ S m / z 321 (M + H) ⁺ .

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

The title compound was prepared according to the procedure of Example 125, step 5 from 7- (chloromethyl) -5-[(4-methylphenyl) sulfonyl] -1-benzofuran (20 mg, 0.06 mmol; obtained in step 4). Prepared. Yield: 5.8 mg (15%) (after purification with preparative HPLC / MS (System A; 5-20% MeCN)). HPLC purity 99%, R _T = 1.52 min (System A; 10-97% MeCN, 3 min); 99%, R _T = 1.28 min (System B; 10-90% MeCN, 3 min). ¹ H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.37 (s, 3 H) 3.33-3.37 (m, 4 H) 3.44-3.50 (m, 4 H) 4.37 (s, 2 H) 6.90 (d, J = 2.26 Hz, 1 H) 7.28 (d, J = 8.03 Hz, 2 H) 7.75 (d, J = 2.26 Hz, 1 H) 7.81 (d, J = 8.28 Hz, 2 H) 7.97 (d, J = 1.51 Hz, 1H) 8.26 (d, J = 1.76 Hz, 1H). MS (ESI +) for C ₂ oH ₂₂ N ₂ 0 ₃ S m / z 371 (M + H) ⁺ .

Example 127

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

7- (chloromethyl) -5-[(2-methoxy-5-methylphenyl) sulfonyl] -1-benzofuran (66 mg, 0.19 mmol; Intermediate 69) is dissolved in ethanol (2 mL) and 1- boc-homopiperazine (57 mg, 0.28 mmol) and sodium bicarbonate (24 mg, 0.28 mmol) were added. The mixture was heated at 80 ° C. in StemBlock overnight. The mixture was extracted with chloroform (x2) and the chloroform layer was evaporated. The Nt-BOC derivative of the title compound obtained was dissolved in DCM (1 mL) and TFA (1 mL) was added. After stirring for 2 hours at room temperature, the solvent was removed to provide the title compound. Yield: 39 mg (32%) (after purification with preparative HPLC / MS (System A; 10-40% MeCN)). HPLC purity 99%, R _T = 1.41 min (System A; 10-97% MeCN, 3 min); 99%, R _T = 1.19 min (System B; 10-90% MeCN, 3 min). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.16 (bs, 2 H) 2.24 (s, 3 H) 3.30 (bs, 2 H) 3.39 (bs, 2 H) 3.54 (bs, 2 H) 3.57-3.67 (m, 5H) 4.50 (s, 2H) 6.69 (d, J = 8.78 Hz, 1H) 6.81 (d, J = 1.76 Hz, 1H) 7.23 (d, J = 8.53 Hz, 1H) 7.66 (s, 1 H) 7.81 (s, 1 H) 7.94 (s, 1 H) 8.22 (s, 1 H). MS (ESI +) for C ₂₂ H ₂₆ N ₂ O ₄ S m / z 415 (M + H) ⁺ .

Example 128

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

Prepared by the procedure of Example 127 according to the procedure of Example 127 starting from 7- (chloromethyl) -5- (phenylsulfonyl) -1-benzofuran (37 mg, 0.12 mmol; obtained in Example 125, step 4) It was. Yield: 9.4 mg (13%) (after purification with preparative HPLC / MS (System A; 10-40% MeCN)). HPLC purity 99%, R _T = 1.29 min (System A; 10-97% MeCN, 3 min); 99%, R _T = 1.16 min (System B; 10-90% MeCN, 3 min). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.28-2.35 (m, 2 H) 3.42-3.52 (m, 4 H) 3.65-3.77 (m, 4 H) 4.60 (s, 2 H) 6.93 (d, J = 2.26 Hz, 1 H) 7.46-7.53 (m, 2 H) 7.53-7.59 (m, 1 H) 7.77 (d, J = 2.26 Hz, 1 H) 7.92-7.97 (m, 2 H) 8.09 (d , J = 1.76 Hz, 1 H) 8.32 (d, J = 1.76 Hz, 1 H). MS (ESI +) for C ₂ oH ₂₂ N ₂ 0 ₃ S m / z 371 (M + H) ⁺ .

Example 129

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

Following the procedure of Example 127 starting from 7- (chloromethyl) -5-[(4-methylphenyl) sulfonyl] -1-benzofuran (32 mg, 0.10 mmol; obtained in Example 126, step 4) The title compound was prepared. Yield: 8.1 mg (13%) (after purification with preparative HPLC / MS (System A; 10-40% MeCN)). HPLC purity 99%, R _T = 1.42 min (System A; 10-97% MeCN, 3 min); 99%, R _T = 2.94 min (System B; 10-90% MeCN, 3 min). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.31 (bs, 2 H) 2.37 (s, 3 H) 3.41-3.54 (m, 4 H) 3.66-3.79 (m, 4 H) 4.61 (s, 2 H ) 6.91 (d, J = 2.26 Hz, 1 H) 7.26-7.31 (m, 2 H) 7.75 (d, J = 2.26 Hz, 1 H) 7.81 (d, J = 8.28 Hz, 2 H) 8.07 (d, J = 1.51 Hz, 1 H) 8.29 (d, J = 1.76 Hz, 1 H). MS (ESI +) for C ₂₁ H ₂₄ N ₂ O ₃ S 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) is dissolved in ethanol (2 mL) and tert- Butyl 3-methylpiperazin-1-carboxylate (41 mg, 0.21 mmol) and sodium bicarbonate (22 mg, 0.26 mmol) were added. The resulting mixture was heated at 80 ° C. in StemBlock overnight. The mixture was extracted with chloroform (x2) and the chloroform layer was concentrated. The Nt-BOC derivative of the title compound obtained was dissolved in DCM (1 mL) and TFA (1 mL) was added. The mixture was stirred at rt for 2 h and then the solvent was evaporated. Yield: 33 mg (36%) (after purification with preparative HPLC / MS (System A; 10-40% MeCN)). HPLC purity 99%, R _T = 1.55 min (System A; 10-97% MeCN, 3 min); 99%, R _T = 1.37 min (System B; 10-97% MeCN, 3 min). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.65 (d, J = 6.27 Hz, 3 H) 2.34 (s, 3 H) 3.35-3.61 (m, 6 H) 3.68 (s, 3 H) 3.90-3.99 (m, 1 H) 4.46 (d, J = 13.55 Hz, 1 H) 4.82 (d, J = 13.55 Hz, 1 H) 6.77 (d, J = 8.53 Hz, 1 H) 6.92 (d, J = 2.26 Hz , 1 H) 7.32 (dd, J = 8.53, 1.76 Hz, 1 H) 7.75 (d, J = 2.26 Hz, 1 H) 7.87 (d, J = 2.01 Hz, 1 H) 7.97 (d, J = 1.25 Hz , 1 H) 8.34 (d, J = 1.51 Hz, 1 H). MS (ESI +) for C ₂₂ H ₂₆ N ₂ O ₄ S 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) is dissolved in ethanol (2 mL) and 2- Methylpiperazine (21 mg, 0.21 mmol) and sodium bicarbonate (22 mg, 0.26 mmol) were added. The mixture was heated at 80 ° C. in StemBlock overnight. The mixture was extracted with chloroform (x2) and the chloroform layer was evaporated. The Nt-BOC derivative of the title compound obtained was dissolved in DCM (1 mL) and TFA (1 mL) was added. The mixture was stirred at rt for 2 h and then the solvent was evaporated. Yield: 28 mg (31%) (after purification with preparative HPLC / MS (System A; 10-40% MeCN)). HPLC purity 99%, R _T = 1.57 min (System A; 10-97% MeCN, 3 min); 99%, R _T = 1.35 min (System B; 10-97% MeCN, 3 min). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.80-0.90 (m, 2H) 1.30 (d, J = 6.27 Hz, 3H) 2.35 (s, 3H) 3.14 (t, J = 12.05 Hz, 1 H) 3.27-3.45 (m, 4 H) 3.70 (s, 3 H) 4.40 (s, 2 H) 6.78 (d, J = 8.53 Hz, 1 H) 6.91 (d, J = 2.26 Hz, 1 H) 7.32 (dd, J = 8.41, 1.88 Hz, 1H) 7.76 (d, J = 2.01 Hz, 1H) 7.88-7.99 (m, 2H) 8.32 (d, J = 1.51 Hz, 1H). MS (ESI +) for C ₂₂ H ₂₆ N ₂ O ₄ S m / z 414 (M + H) ⁺ .

Intermediate 70

(5-bromo-1-benzofuran-7-yl) amine

Step 1: ethyl 5-bromo-7-nitro-1-benzofuran-3-carboxylate

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) The mixture was heated to reflux for 4 hours. The mixture was cooled, filtered and evaporated to afford crude product which was recrystallized from ethanol. Yield: 6.6 g (58%) of a pale yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.29 (t, J = 7.0 Hz, 3H) 4.35 (q, J = 7.1 Hz, 2H) 7.83 (s, 1H) 8.39 (d, J = 2.0 Hz, 1 H) 8.43 (d, J = 2.0 Hz, 1 H).

Step 2: 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). 2 M NaOH (20 mL) was added and the mixture was heated to reflux for 2 hours. Ethanol was removed by evaporation, the remaining solution was acidified with concentrated HCl (4 mL), diluted with water, the product was collected by filtration, washed with water and dried in a vacuum oven. Yield: 4.65 g (93%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.43 (s, 1 H) 8.26 (d, J = 1.8 Hz, 1 H) 8.34 (d, J = 2.0 Hz, 1 H).

Step 3: 5-Bromo-7-nitro-1-benzofuran

5-Bromo-7-nitro-1-benzofuran-3-carboxylic acid (4.65 g, 16 mmol; obtained in step 2) is suspended in quinoline (25 mL), 0.1 g CuO is added, and The mixture was heated at 190 ° C for 30 minutes. The warmed reaction mixture was diluted with hot toluene (100 mL), filtered and the filter cake washed with hot toluene (400 mL total). The combined toluene extracts were washed with 1 M HCl (2 × 100 mL) and brine, evaporated, the solid product was washed with hexanes, collected by filtration and dried. Yield: 1.9 g (48%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.13 (d, J = 2.3 Hz, 1H) 8.20 (d, J = 2.0 Hz, 1H) 8.28 (d, J = 2.3 Hz, 1H) 8.32 (d, J = 2.0 Hz, 1 H).

Step 4: (5-bromo-1-benzofuran-7-yl) amine

5-bromo-7-nitro-1-benzofuran (1.9 g, 7.9 mmol; obtained in step 3), iron powder (2.3 g) methanol (20 mL), 1,4-dioxane (20 mL) and A mixture of ammonium chloride (2.3 g, dissolved in 10 mL of water) was refluxed overnight. The warmed mixture was filtered through wet celite, further washed with hot methanol, and the solvent was evaporated. The crude product was dissolved in hot ethanol / water (100 mL), then water was added to cause the product to begin to precipitate. The product was collected by filtration, washed with water and dried in a vacuum oven. Yield: 1.1 g (65%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 5.63 (s, 2 H) 6.68 (d, J = 2.0 Hz, 1 H) 6.81 (d, J = 2.3 Hz, 1 H) 6.96 (d, J = 2.0 Hz, 1 H) 7.92 (d, J = 2.3 Hz, 1 H).

Example 132

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

Step 1: N- (5-bromo-1-benzofuran-7-yl) -2-methoxy-5-methylbenzenesulfonamide

(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 in dry DCM (20 mL) a mixture of m -toluenesulfonyl chloride (0,78 g, 3.5 mmol) was stirred at rt for 2.5 h. Additional 6-methoxy- m -toluenesulfonyl chloride (0,26 g, 1.2 mmol) was added with continuous stirring overnight. The reaction mixture was diluted with DCM and extracted with water. The organic layer was concentrated. The product was precipitated from a mixture of DCM / isohexane / MeOH (80:20:20) and collected by filtration to give 580 mg (61%) of the title compound as a light brown solid. HPLC 94%, R _T = 2.32 min (System A; 30-80% MeCN, 3 min). MS (ESI +) m / z 396 (monoisotop. Mass + H) for C ₁₆ H ₁₄ BrNO ₄ S ⁺ .

Step 2: 2-methoxy-5-methyl-N- [5- (piperazin-1-ylmethyl) -1-benzofuran-7-yl] benzenesulfonamide, bis (trifluoroacetate)

Under argon, Pd (PPh ₃ ) ₂ OAc ₂ (189 mg, 0.25 mmol) and vinyltributyltin (295 μl, 1.01 mmol) were added N- (5-bromo-1-benzofuran-7-yl) in dry toluene. To 2-methoxy-5-methylbenzenesulfonamide (200 mg, 0.51 mmol; obtained in step 1). 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 was decanted off and the residue was dried under reduced pressure. Alkene intermediates were dissolved in dioxane (6 mL) and lutidine (120 μl, 1.0 mmol). Osmium tetroxide (26 mg, 0.10 mmol) was added and a color change from light brown to dark brown / black was observed. Sodium periodate (432 mg, 2.02 mmol) in water (1.5 mL, warmed to dissolve) was added with stirring. After 1 minute, a light brown precipitate formed. The mixture was stirred for 2 hours and partitioned between 2 M aqueous HCl and DCM. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated to give crude aldehyde as a black solid. Half of the material was suspended in dry THF (4 mL), Nt-BOC-piperazine (50 mg, 0.27 mmol), acetic acid (140 μl, 2.5 mmol) and sodium triacetoxyborohydride (104 mg, 0.49 mmol) was added. The reaction mixture was examined for 300 seconds at 130 ° C. using microwaves. The mixture was filtered, dissolved in MeOH (2 mL) and concentrated HCl (0.5 mL) and irradiated with microwave at 100 ° C. for 300 seconds. The solvent was evaporated and the residue was dissolved in MeOH and purified by preparative HPLC (System A; 19-40% MeCN). Pure fractions were combined and concentrated to give the title compound (31 mg, 20%) as a brown gum. HPLC 100%, R _T = 1.35 min (System A; 10-97% MeCN, 3 min), 99%, R _T = 1.15 min (System B; 10-97% MeCN, 3 min). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 2.22 (s, 3 H) 3.30-3.36 (m, 4 H) 3.43-3.50 (m, 4 H) 3.81 (s, 3 H) 4.29 (s, 2 H) 6.82 (d, J = 2.26 Hz, 1 H) 6.95 (d, J = 8.53 Hz, 1 H) 7.28-7.33 (m, J = 8.53, 2.26 Hz, 1 H) 7.43 (d, J = 1.51 Hz, 1 H) 7.48 (d, J = 1.51 Hz, 1 H) 7.56-7.59 (m, J = 2.26 Hz, 1 H) 7.77 (d, J = 2.26 Hz, 1 H). C ₂₁ H ₂₅ N ₃ O ₄ S MS (ESI +) for m / z 416 (M + H) ⁺ .

Example 133

2-methoxy-5-methyl-N- {5-[(3-methylpiperazin-1-yl) methyl] -1-benzofuran-7-yl} benzenesulfonamide, bis (trifluoroacetate)

Using the 2-methylpiperazine (27 mg, 0.27 mmol) the title compound was prepared following the procedure of Example 132, step 2. The title compound (18 mg, 11%) was obtained as a brown gum. HPLC 97%, R _T = 1.38 min (System A; 10-97% MeCN, 3 min), 98%, R _T = 1.18 min (System B; 10-97% MeCN, 3 min). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.33 (d, J = 6.53 Hz, 3H) 2.22 (s, 3H) 2.82 (dd, J = 13.18, 11.42 Hz, 1H) 2.94-3.04 (m, 1 H) 3.31-3.44 (m, 2 H) 3.51-3.59 (m, 2 H) 3.79-3.87 (m, 1 H) 3.81 (s, 3 H) 4.18 (s, 2 H) 6.81 (d , J = 2.01 Hz, 1 H) 6.95 (d, J = 8.53 Hz, 1 H) 7.27-7.32 (m, J = 8.53, 2.26 Hz, 1 H) 7.41 (d, J = 1.76 Hz, 1 H) 7.45 (d, J = 1.76 Hz, 1 H) 7.55-7.58 (m, J = 1.51 Hz, 1 H) 7.75 (d, J = 2.26 Hz, 1 H). MS (ESI +) for C ₂₂ H ₂₇ N ₃ O ₄ S m / z 430 (M + H) ⁺ .

Example 134

N- (2-methylphenyl) -7-{[(3 R ) -Pyrrolidin-3-ylamino] methyl} -1-benzofuran-5-sulfonamide, trifluoroacetate

7-formyl- N- (2-methylphenyl) -1-benzofuran-5-sulfonamide (80 mg, 0.24 mmol; Intermediate 60) and (R)-(+)-3-aminopyrrolidine (50 mg , 0.6 mmol), according to the procedure of Example 93, to prepare the title compound [Note: no HCl deprotection step]. Yield: 17.8 mg (28%). HPLC 97% R _T = 1.39 (System A; 10-97% MeCN, 3 minutes) 98% R _T = 1.22 (System B; 10-90% MeCN, 3 minutes). MS (ESI +) for C ₂ oH ₂₃ N ₃ 0 ₃ S m / z 386 (M + 1). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.94 (s, 3 H) 2.02-2.12 (m, 1 H) 2.44-2.54 (m, 1 H) 3.24-3.31 (m, 1 H) 3.40- 3.52 (m, 2H) 3.72 (dd, J = 12.8, 8.3 Hz, 1H) 4.04 (tt, J = 8.3, 5.5 Hz, 1H) 4.68 (d, J = 2.5 Hz, 2H) 6.92-7.03 (m, 5H) 7.73 (d, J = 1.5 Hz, 1 H) 7.94 (d, J = 2.3 Hz, 1 H) 8.08 (d, J = 1.8 Hz, 1 H).

Example 135

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

9-vorabicyclo [3.3.1] -nonane (9-BBN; 0.5 M in THF, 2.2 mL, 2.2 mmol) was dried under nitrogen atmosphere at 0 ° C. in 1- (4-methylidenepi in dry THF (2 mL). To a solution of ferridino) ethan-1-one (Maybridge Chemical Company, 140 mg, 1 mmol). After stirring for 1 hour at 0 ° C., the solution was allowed to warm to room temperature for 3 hours. Next, microwave reaction tube was placed in 7-iodo- N- (2-methylphenyl) -1-benzofuran-5-sulfonamide (40 mg, 0.1 mmol; intermediate 58), Hermanmann's catalyst (5 mg). , Dry THF (3 mL), 4 M aqueous NaOH (0.1 mL), and 1- [4- (9-borabicyclo [3.3.1] non-9-ylmethyl) -piperidine produced in situ Was charged with the above solution of -1-yl] -ethanone (0.75 mL, 0.17 mmol). The mixture was heated to 140 ° C. for 5 minutes by microwave irradiation. The reaction mixture and three similar mixtures were combined, filtered and evaporated. The residue was dissolved in DCM (20 mL) and extracted with 1 M HCl. After evaporation of the solvent, the crude acetylated derivative of the title product was purified by preparative HPLC-MS (System A 30-60% MeCN 0.1% TFA). The purified material was dissolved in methanol (3 mL), concentrated aqueous HCl (1 mL) was added and N-deprotected by heating to 120 ° C. for 1 hour by microwave irradiation. The final product was purified by preparative HPLC-MS (System A 30-60% MeCN 0.1% TFA) to give 5.9 mg (3%) of the title compound. HPLC 95% R _T = 1.75 (System A; 10-97% MeCN, 3 minutes) 95% R _T = 1.58 (System B; 10-90% MeCN, 3 minutes). MS (ESI +) for C ₂₁ H ₂₄ N ₂ O ₃ S m / z 385 (M + l). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.26-1.38 (m, 2H) 1.60-1.71 (m, J = 14.1 Hz, 2H) 1.87 (s, 2H) 1.89-1.97 (m, 2 H) 2.76-2.85 (m, 4 H) 3.11-3.19 (m, 1 H) 3.26-3.30 (m, 2 H) 6.88 (d, J = 2.3 Hz, 1 H) 6.96-7.03 (m, 4 H ) 7.27 (d, J = 1.5 Hz, 1 H) 7.83 (d, J = 2.3 Hz, 1 H) 7.86 (d, J = 1.8 Hz, 1 H).

Intermediate 71

tert -butyl 4-methylenepiperidine-1-carboxylate *

To a solution of methyl triphenylphosphonium bromide (2.69 g, 7.5 mmol) in THF (20 mL) at −78 ° C. was slowly added n-butyllithium (1.8 M; 4.2 mL, 7.5 mmol) in hexane. The mixture was stirred for 1 hour. Thereafter, a solution of tert -butyl 4-oxopiperidine-1-carboxylate (1 g, 5.0 mmol) in THF (10 mL) was added dropwise to the mixture. The resulting mixture was stirred at rt overnight. The reaction mixture was quenched with water and extracted with isohexane (x3). The combined isohexane layer was evaporated and filtered through a silica plug. The crude product was purified by flash chromatography using DCM as eluent to afford 0.58 g (59%) of the title compound. HPLC purity 91%, R _T = 2.47 min (System A; 10-97% MeCN, 3 min); 86%, R _T = 2.43 min (System B; 10-97% MeCN, 3 min). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.46 (s, 9 H) 2.12-2.22 (m, 4 H) 3.35-3.46 (m, 4 H) 4.73 (s, 2 H). MS (ESI +) for C ₁₁ H ₁₉ NO ₂ m / z 142 (MC ₄ H ₈ ) ⁺ .

* Already in J. Med. Chem. 2002, 45, 3143-3160.

Intermediate 72

tert -Butyl 3-methylenepyrrolidine-1-carboxylate *

from tert -butyl 3-oxopyrrolidine-1-carboxylate (0.8 g, 4.3 mmol), triphenylphosphonium bromide (2.31 g, 6.5 mmol) and n- BuLi (1.8 M; 2.4 mL, 6.5 mmol) Starting and following the procedure of intermediate 71 the title compound was prepared. Yield: 0.23 g (29%) (after purification by flash chromatography using DCM as eluent). HPLC purity 99%, R _T = 2.28 min (System A; 10-97% MeCN, 3 min); 99%, R _T = 2.21 min (System B; 10-97% MeCN, 3 min). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.23-1.40 (m, 9 H) 2.42 (t, J = 6.78 Hz, 2H) 3.31 (t, J = 7.40 Hz, 2H) 3.71-3.85 (m , 2H) 4.74-4.91 (m, 2H). MS (ESI +) for C ₁₀ H ₁₇ NO ₂ m / z 128 (MC ₄ H ₈ ) ⁺ .

* Already reported in Tetrahedron 1997, 53, 539-556.

Intermediate 73

tert -Butyl 3-methylenepiperidine-1-carboxylate

from tert -butyl 3-oxopiperidine-1-carboxylate (1 g, 5.0 mmol), triphenylphosphonium bromide (2.69 g, 7.5 mmol) and n-BuLi (1.8 M; 4.2 mL, 7.5 mmol) Starting and following the procedure of intermediate 71 the title compound was prepared. Yield: 0.28 g (28%) (after purification by flash chromatography using 10% isohexane in DCM as eluent). HPLC purity 95%, R _T = 2.43 min (System A; 10-97% MeCN, 3 min); 90%, R _T = 2.38 min (System B; 10-97% MeCN, 3 min). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.41-1.48 (m, 9 H) 1.56-1.65 (m, 2 H) 2.20-2.30 (m, 2 H) 3.38-3.47 (m, 2 H) 3.86 ( s, 2H) 4.74 (s, 1H) 4.80 (s, 1H). MS (ESI +) for C ₁₁ H ₁₉ NO ₂ m / z 142 (MC ₄ H ₈ ) ⁺ .

* Already reported in Tetrahedron 2002, 58, 7165-7175.

Example 136

N- (2-methylphenyl) -7- (pyrrolidin-3-ylmethyl) -1-benzofuran-5-sulfonamide, trifluoroacetate

9 BBN (0.5 M in THF; 1.5 mL, 0.75 mmol) was dried under nitrogen atmosphere at 0 ° C. and tert -butyl 3-methylenepyrrolidine-1-carboxylate (110 mg, 0.6 mmol) in dry THF (1 mL); To a solution of intermediate 72). After stirring for 1 hour at 0 ° C., the solution was allowed to warm to room temperature for 3 hours. Microwave reaction tubes were transferred to 7-iodo- N- (2-methylphenyl) -1-benzofuran-5-sulfonamide (90 mg, 0.2 mmol; intermediate 58), Hermann catalyst (10 mg), dry THF (2.5 mL) , 4 M aqueous NaOH (0.2 mL), and 3- (9-borabicyclo [3.3.1] non-9-ylmethyl) -pyrrolidine-1-carboxylic acid tert-butyl ester produced in situ (1.1 mL, 0.3 mmol) was charged with half of the solution. The mixture was heated by microwave irradiation at 140 ° C. for 5 minutes. This reaction mixture and similar mixture were combined, filtered and evaporated. The residue was dissolved in methanol (3 mL), concentrated HCl (0.5 mL) was added and the mixture was heated by microwave irradiation at 100 ° C. for 5 min to effect deprotection of the Nt-BOC group. Purification by preparative HPLC (System F 20-45% MeCN 0.1% TFA) gave 31 mg (13%) of the title compound. HPLC 98% R _T = 1.69 (System A; 10-97% MeCN, 3 minutes) 98% R _T = 1.53 (System B; 10-90% MeCN, 3 minutes). MS (ESI +) for C ₂ oH ₂₂ N ₂ 0 ₃ S m / z 371 (M + 1). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.57 (dq, J = 13.3, 8.8 Hz, 1 H) 1.87 (s, 3 H) 1.88-1.95 (m, 1 H) 2.58-2.70 (m, 1 H) 2.81 (dd, J = 11.4, 8.9 Hz, 1 H) 2.96 (ddd, J = 18.1, 14.0, 7.5 Hz, 2 H) 3.10-3.21 (m, 2H) 3.30 (ddd, J = 11.9, 8.2, 4.3 Hz, 1 H) 6.89 (d, J = 2.3 Hz, 1 H) 6.97-7.02 (m, 4 H) 7.32 (d, J = 1.8 Hz, 1 H) 7.85 (d, J = 2.0 Hz, 1 H) 7.87 (d, J = 1.8 Hz, 1 H).

Example 137

N- (2-methylphenyl) -7- (piperidin-3-ylmethyl) -1-benzofuran-5-sulfonamide, trifluoroacetate

tert -butyl 3-methylenepiperidine-1-carboxylate (120 mg, 0.6 mmol; intermediate 73) and 7-iodo- N- (2-methylphenyl) -1-benzofuran-5-sulfonamide (180 mg, 0.4 mmol; intermediate 58), to give the title compound following the procedure of Example 136. Yield: 40 mg (21%). HPLC 99% R _T = 1.74 (System A; 10-97% MeCN, 3 minutes) 100% R _T = 1.58 (System B; 10-90% MeCN, 3 minutes). MS (ESI +) for C ₂₁ H ₂₄ N ₂ O ₃ S m / z 385 (M + l). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.60-1.72 (m, 3 H) 1.85-1.95 (m, 2 H) 1.99 (s, 3 H) 2.15-2.26 (m, J = 11.3, 7.6 , 7.6, 3.8, 3.8 Hz, 1 H) 2.73 (t, J = 12.3 Hz, 1 H) 2.86-2.97 (m, 3 H) 3.24 (dd, J = 12.5, 3.5 Hz, 1 H) 3.34-3.37 ( m, 1H) 6.98 (d, J = 2.3 Hz, 1H) 7.05-7.09 (m, 2H) 7.09-7.12 (m, 2H) 7.41 (d, J = 1.8 Hz, 1H) 7.94 (d , J = 2.3 Hz, 1 H) 7.96 (d, J = 1.8 Hz, 1 H).

Intermediate 74

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) were added to 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 stirred at 100 ° C for 16 h. . The reaction mixture was filtered through celite and the volatiles were evaporated. The residue was dissolved in a mixture of methanol (10 mL) and DCM (90 mL). The mixture was filtered through a silica plug and the solvent was evaporated to give 2.22 g (99%) of the title compound as a brown oil. HPLC purity 70%, R _T = 1.26 min (System A; 10-97% MeCN, 3 min). MS (ESI +) for C ₈ H ₆ INO m / z 260 (M + H) ⁺ .

Intermediate 75

N- (7-iodo-1-benzofuran-5-yl) -2-methoxy-5-methylbenzenesulfonamide

Pyridine (1.43 mL) to a mixture of 7-iodo-1-benzofuran-5-amine (2.22 g, 8.6 mmol; intermediate 74) in dry DCM / THF (5: 1; 50 mL, partially dissolved starting material) , 17.1 mmol) and 6-methoxy- m -toluenesulfonyl chloride (2.64 g, 12.8 mmol) were added. The resulting mixture was stirred at ambient temperature overnight for 21 hours. The solvent was evaporated under reduced pressure and the crude product was purified using flash chromatography (eluent: 20% isohexane in DCM). Pure fractions were combined and concentrated to give the product (1.62 g, 42%) as a light brown, fluffy solid. HPLC 81%, R _T = 2.26 min (System A; 30-80% MeCN, 3 min), 86%, R _T = 2.27 min (System B; 10-97% MeCN, 3 min). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.22 (s, 3 H) 4.04 (s, 3 H) 6.77 (d, J = 2.01 Hz, 1 H) 6.92 (d, J = 8.28 Hz, 1 H) 7.25-7.29 (m, 1 H) 7.32 (d, J = 2.01 Hz, 1 H) 7.36 (d, J = 2.01 Hz, 1 H) 7.53-7.55 (m, J = 2.26 Hz, 1 H) 7.62 (d , J = 2.26 Hz, 1 H). C ₁₆ H ₁₄ INO ₄ For MS (ESI +) m / z 444 (M + H) ⁺ .

Example 138

2-methoxy-5-methyl-N- [7- (piperidin-4-ylmethyl) -1-benzofuran-5-yl] benzenesulfonamide, trifluoroacetate

tert -butyl 4-methylenepiperidine-1-carboxylate (120 mg, 0.6 mmol; Intermediate 71) and N- (7-iodo-1-benzofuran-5-yl) -2-methoxy-5 The title compound was prepared following the procedure of Example 136 starting from -methylbenzenesulfonamide (180 mg, 0.42 mmol; intermediate 75). Yield: 69 mg (33%). HPLC 96% R _T = 1.75 (System A; 10-97% MeCN, 3 minutes) 99% R _T = 1.58 (System B; 10-90% MeCN, 3 minutes). MS (ESI +) for C ₂₂ H ₂₆ N ₂ O ₄ S m / z 415 (M + l). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.22-1.34 (m, 2H) 1.61 (d, J = 13.6 Hz, 2H) 1.80-1.91 (m, J = 11.3, 7.6, 7.6, 3.6 , 3.6 Hz, 1 H) 2.10 (s, 3 H) 2.69 (d, J = 7.3 Hz, 2 H) 2.78 (td, J = 12.9, 2.6 Hz, 2 H) 3.24 (d, J = 2.0 Hz, 2 H) 3.87 (s, 3H) 6.62 (d, J = 2.3 Hz, 1H) 6.79 (d, J = 2.0 Hz, 1H) 6.93 (d, J = 8.5 Hz, 1H) 7.10 (d, J = 2.0 Hz, 1 H) 7.21 (dd, 1 H) 7.38 (d, J = 2.0 Hz, 1 H) 7.58 (d, J = 2.3 Hz, 1 H).

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, 40 mmol) and NaOH (1.76 g, 44 mmol) in water is heated overnight while stirring It was refluxed. The mixture was cooled and extracted with diethyl ether (2x100 mL) and the extract was washed with aqueous NaOH, brine, dried (MgSO ₄ ) and concentrated to give the product as pale yellow oil. Yield: 10.0 g (70%). ¹ H NMR (400 MHz, CDCl ₃ ) d 3.73 (t, 2 H), 4.31 (t, 2 H), 6.88 (t, 1 H), 7.50 (d, 2 H).

* Already in Tetrahedron Lett. 1998, 39, 2219-2222.

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 ethanol / dry ice bath Cooled for 30 minutes at. N-BuLi (2 mL of 1.5 M solution) in hexanes was added dropwise over 15 minutes. The reaction mixture was stirred for an additional 30 minutes at -78 ° C, then the bath was slowly warmed to 0 ° C. The mixture was poured onto water and extracted with diethyl ether (2x100 mL). The combined extracts were dried and concentrated to yield a light brown oil (0.5 g) containing the product contaminated with approximately 25% 2,3-dihydrobenzofuran. The material was used as such for further synthesis, but could be purified by flash chromatography [eluent: hexanes-> EtOAc / hexanes (5:95)] if necessary. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.30 (t, 2 H), 4.65 (t, 2 H), 6.71 (t, 1 H), 7.11 (dd, 1 H), 7.25 (dd, 1 H) .

* Already in Tetrahedron Lett. 1998, 39, 2219-2222.

Intermediate 78

7-bromo-5-[(4-methylphenyl) sulfonyl] -2,3-dihydro-1-benzofuran

7-bromo-1,2-dihydrobenzofuran (64 mg, 0.3 mmol; intermediate 77) and paratoluenesulfonic acid monohydrate (62 mg, 0.3 mmol) were mixed, followed by 1:10 of methanesulfonic acid and phosphorus pentoxide. A mixture (by weight) (1 mL) was added. The resulting mixture was stirred overnight at room temperature and then poured into ice / water. The obtained crystalline material was filtered and dried to give 120 mg of the title product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.40 (s, 3 H), 3.33 (t, 2 H), 4.73 (t, 2 H), 7.29 (d, 2 H), 7.65 (d, 1 H) , 7.79 (d, 2H), 7.89 (d, 1H); GC-MS (EI +) m / z 354 (M + H) ⁺ for C ₁₅ H ₁₃ BrSO ₃ .

Intermediate 79

7-bromo-5-[(4-methylphenyl) sulfonyl] -1-benzofuran

7-bromo-5-[(4-methylphenyl) sulfonyl] -2,3-dihydro-1-benzofuran (353 mg, 1 mmol; intermediate 78), NBS (178 mg, 1 mmol) and di A mixture of benzoylperoxide (24 mg, 0.1 mmol) in carbon tetrachloride (20 mL) was heated to 80 ° C for 2 h. TEA (2 mL) was added and the mixture was heated for an additional 2 hours. Flash chromatography using EtOAc / hexanes 10: 90 → 25: 75 as eluent gave the title product as a white crystalline material. Yield: 130 mg (37%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.39 (s, 3 H), 6.93 (d, 1 H), 7.30 (d, 2 H), 7.78 (d, 1 H), 7.84 (d, 2 H) , 8.02 (d, 1 H), 8.19 (d, 1 H).

Example 139

3-({5-[(4-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) pyrrolidine, trifluoroacetate

tert-butyl 3-methylenepiperidine-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), according to the procedure of Example 136, to prepare the title compound. Yield: 3 mg (3%). HPLC 97% R _T = 1.79 (System A; 10-97% MeCN for 3 minutes) 97% R _T = 1.61 (System B; 10-90% MeCN for 3 minutes). MS (ESI +) for C ₂₁ H ₂₃ NO ₃ S m / z 356 (M + l).

Example 140

2-methoxy-5-methyl-N- [5- (piperidin-4-ylmethyl) -1-benzofuran-7-yl] benzenesulfonamide, trifluoroacetate

tert-butyl 4-methylenepiperidine-1-carboxylate (120 mg, 0.6 mmol; Intermediate 71) and N- (5-bromo-1-benzofuran-7-yl) -2-methoxy-5 The title compound was prepared according to the procedure of Example 136 starting from -methylbenzenesulfonamide (150 mg, 0.42 mmol; Example 132, obtained in Step 1). Yield: 27 mg (12%). HPLC 97% R _T = 1.68 (System A; 10-97% MeCN for 3 minutes) 97% R _T = 1.52 (System B; 10-90% MeCN for 3 minutes). MS (ESI +) for C ₂₂ H ₂₆ N ₂ 0 ₄ S m / z 415 (M + 1). ¹ H NMR (400 MHz, Methanol- d ₄ ) δ ppm 1.22-1.33 (m, 2 H) 1.62-1.73 (m, 3 H) 2.13 (s, 3 H) 2.51 (d, J = 7.0 Hz, 2 H ) 2.80 (td, J = 12.7, 2.4 Hz, 2 H) 3.24-3.28 (m, 2 H) 3.77 (s, 3 H) 6.63 (d, J = 2.0 Hz, 1 H) 6.87 (d, J = 8.5 Hz, 1 H) 6.98 (d, J = 1.5 Hz, 1 H) 7.05 (d, J = 1.5 Hz, 1 H) 7.21 (dd, J = 8.2, 1.9 Hz, 1 H) 7.46 (d, J = 2.3 Hz, 1H) 7.59 (d, J = 2.3 Hz, 1H).

Biological test

The ability of the compounds according to the invention to bind to human 5-HT ₆ receptors and to be pharmaceutically useful can be measured using in vivo and in vitro assays known in the art.

(a) 5-HT ₆  Binding analysis

Binding affinity experiments for the 5-HT ₆ receptor are described in Boess F. G et al. Neuropharmacology 36 (4/5) 713-720, 1997, transfected with human 5-HT ₆ receptor using [ ³ H] -LSD as the labeling ligand, according to the general method as described. It was performed on HEK293 cells.

material

Cell culture

HEK-293 cell lines transfected with human 5-HT ₆ receptor were treated with 5% dialysis calf serum (Gibco BRL 10106-169), 0.5 mM sodium pyruvate and 400 μg / mL Geneticin (G-418) (Gibco BRL 10131 Cultured in Dulbeccos Modified Eagles Medium. Cells were passaged twice a week at 1:10.

chemical substance

Radioligand [ ³ H] LSD 60-240 Ci / mmol obtained from Amersham Pharmacia Biotech (Buckinghamshire, England) was placed in ethanol and stored at -20 ° C. Compounds were dissolved in 100% DMSO and diluted with binding buffer.

process

Compounds were diluted in Costar 96 well V-type bottom polypropylene plates (Corning Inc. Costar, NY, USA). Samples were incubated on Packard Optiplate (Packard Instruments B. V., Groningen, The Netherlands). The total amount of radioligand added was measured in Packard 24-well Barex plates (Packard Instruments B. V., Groningen, The Netherlands) in the presence of Microscint ™ 20 scintillation liquid (Packard Bioscience, Meriden, CT, USA).

Buffer

Binding buffer consists of 20 mM HEPES, 150 mM NaCl, 10 mM MgCl ₂ , and 1 mM, EDTA, pH 7.4.

Way

Membrane manufacturing

Cells were grown to approximately 90% coverage of a 24.5 x 24.5 mm petri dish. The medium was aspirated, rinsed with ice cold PBS, and cells were scraped off using 25 mL Tris buffer (50 mM Tris-HCl, 1 mM EDTA, 1 mM EGTA, pH 7.4) and a window scraper. Cells were then disrupted with a Polytron homogenizer and residual particulate material was removed by low speed centrifugation at 1000 × g for 5 minutes. Finally, the membrane was collected by high speed centrifugation (20OOx g), suspended in binding buffer, and aliquots frozen at -70 ° C.

Radioligand Bond

The frozen cell membranes were thawed and immediately re-homogenized with a Polytron homogenizer and then coupled to SPA malt aggregate beads (Amersham Life Sciences, Cardiff, England) for 30 minutes with continued shaking of the tube. After coupling, the beads were centrifuged at 1000 g for 10 minutes and then suspended in 20 mL of binding buffer per 96-well plate. The binding reaction was then initiated by adding radioligand and test compound to the bead-membrane suspension. After incubation at room temperature, the assay plates were scintillated.

Except for preparing membranes from HEK293 cells expressing human 5-HT ₆ receptors instead of HeLa cells, the original SPA method was followed (Dinh DM, Zaworski PG, Gill GS, Schlachter SK, Lawson CF, Smith MW. Validation of human 5-HT ₆ receptors expressed in HeLa cell membranes: saturation binding studies, pharmacological profiles of standard CNS agents and SPA development (The Upjohn Company Technical Report 7295-95-064 1995; 27 December)). Specific binding of [ ³ H] -LSD was saturable, while non-specific binding increased linearly with the concentration of radioligand added. [ ³ H] -LSD bound to the 5-HT ₆ receptor with high affinity. K _d values were estimated to be 2.6 ± 0.2 nM based on four separate experiments.

5-HT (236 nM) > 메티세르지드 (482 nM) > 메술레르진 (1970 nM) 이었다. The total binding of 3 nM of [ ³ H] -LSD, the radioligand concentration used in the competition experiments, is usually 6000 dpm, of which the specific binding is greater than 70%. 5-HT, when tested on two different membrane preparations, resulted in a concentration dependent inhibition of [ ³ H] -LSD binding with an overall mean K _i value of 236 nM. Analytical variability between the three experiments showed a CV of 10% at an average K _i value of 173 nM (SD 30) and a Hill coefficient of 0.94 (SD 0.09). The variation in the analysis was 3% (n = 4). All unlabeled ligands replaced the specific binding of [ ³ H] -LSD, although of different potency, in a concentration dependent manner. The rank order of the affinity for the 5-HT ₆ receptor of the reference compound is methiotepine (K _i 2 nM)> myanserine (190 nM)

5-HT (236 nM)> methiserzide (482 nM)> mesulergine (1970 nM).

Protein measurement

Protein concentration was measured by BioRad Protein Assay (Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.Anal. Biochem. 1976; 72: 248-54). Bovine serum albumin was used as standard.

Scintillation coefficient

Radioactivity was measured on a Packard TopCount ™ scintillation counter (Packard Instruments, Meriden, CT, USA) with a counting efficiency of approximately 20%. Counting efficiency was measured in a separate set of experiments.

Saturation Experiment

Radioligands of more than 6 concentrations (0.1-20 nM of [ ³ H] -LSD) were used in a double saturation experiment. Specific binding was calculated as the difference between total and non-specific binding, which was determined as binding of the radioligand in the presence of 5 μM lyslide. B _max and dissociation constant K _d were obtained from non-linear regression using Equation 1 below. L _u is the unbound concentration of radioligand and y is the bound amount.

(방정식 1)

(Equation 1)

Competition experiment

Total and non-specific binding of radioligands were defined in 8 replicates each. Samples containing test compounds were run in duplicate at 11 concentrations. Incubation was performed for 3 hours at room temperature. The concentration of the test compound that inhibited the IC ₅₀ value, ie 50% of the specific binding of the radioligand, was determined by nonlinear regression analysis, and the K _i value was calculated using Equation 2 below [Cheng YC Biochem. Pharmacol. 22, 3099-3108, 1973].

(방정식 2)

(Equation 2)

L = concentration of radioligand

K _d = affinity of radioligand

(b) 5-HT ₆  Intrinsic activity analysis

Antagonist for the 5-HT ₆ receptor were characterized by measuring the inhibition of 5-HT-induced cAMP increase in the HEK 293 cells expressing the human 5-HT ₆ receptor (Boess et al (1997) Neuropharmacology 36:. 713 -720). Briefly, HEK293 / 5-HT ₆ cells were seeded in a polylysine coated 96-well plate at a concentration of 25,000 / well, containing 5% dialysis calf serum for 48 hours at 37 ° C. in a 5% CO ₂ incubator. Grown in one DMEM (Dulbecco's Modified Eagle Medium) (no phenol-red). The medium was then aspirated and replaced with 0.1 mL assay medium (Hanks Balance Salt Solution with 20 mM HEPES, 1.5 mM isobutylmethylxanthine and 1 mg / mL bovine serum albumin). After addition of 50 μl of test substance dissolved in assay medium, cells were incubated at 37 ° C. for 10 minutes in a 5% CO ₂ incubator. The medium was aspirated again and the cAMP content was measured using a radio cAMP kit (Amersham Pharmacia Biotech, BIOTRAK RPA559). The efficacy of the antagonists was determined using the formula fK _i = IC ₅₀ / (1+ [5HT] / EC ₅₀ ), resulting in 50% inhibition of 5-HT induced cAMP increase ([5-HT] = 8-fold EC). ₅₀₎ it was determined by measuring.

Compounds according to the invention have selective affinity for the 5-HT ₆ receptor with IC _{50, corr} and K _i values of 0.5 nM to 5 μM _, or% inhibition of [ ³ H] -LSD ≥ 20% at 50 nM And antagonists, agonists or partial agonists at 5-HT ₆ . The compound showed good selectivity for 5-HT _1a , 5-HT _1b , 5-HT _2a , 5-HT _2b , 5-HT _2c .

(c) in vivo analysis of reduced food intake

For an overview of serotonin and food intake, see Blundell, J. E. and Halford, J. C. G. (1998) Serotonin and Appetite Regulation. Implications for the Pharmacological Treatment of Obesity. CNS Drugs 9: 473-495.

Obese (ob / ob) mice were chosen as the main animal model for screening because these mutant mice show high signal-to-noise ratios by consuming large amounts of food. To further validate and compare efficacy data, the effect of the compound on food consumption was also studied in wild-type (C57BL / 6J) mice. The amount of food consumed for 15 hours of compound injection was recorded.

All studies used 8 to 9 week old male mice (obesity type C57BL / 6JBom-Lep ^ob and lean wild type C57BL / 6JBom; Bomholtsgaard, Denmark) with mean weights of 50 g (obesity) and 25 g (lean). Animals were placed alone in cages at 23 ± 1 ° C., 40-60% humidity and had free access to water and standard laboratory meals. The 12 / 12-hour light / dark cycle was set to turn off at 5 pm. Animals were conditioned for at least 1 week before the start of the study.

Test compounds were dissolved in a solvent appropriate for each particular compound, such as cyclodextrin, cyclodextrin / methane sulfonic acid, polyethylene glycol / methane sulfonic acid, saline. Fresh solutions were prepared for each study. Doses of 30, 50 and 100 mg kg ^-1 day ^-1 were used. The purity of the test compound is of analytical grade.

Animals were weighed at the beginning of the study and randomized based on body weight. An Alzet osmotic minipump (Model 2001D; injection rate 8 μl / hour) was used and essentially the Alzet Technical Information Handbook (Alza Scientific Products, 1997; Theeuwes, F. and Yam, SI Ann. Biomed. Eng. 4 (4) 343-353, 1976). Continuous subcutaneous infusion lasting 24 hours was used. The minipump was charged with different concentrations of test compound or vehicle alone solution dissolved in the vehicle and maintained in a vehicle preheated to 37 ° C. (approximately 1 hour). Minipumps were implanted subcutaneously in the neck / dorsal under short acting anesthesia (metophan / enflurane). This surgical procedure lasted approximately 5 minutes.

The weight of the food pellets was measured at 5 pm and 8 pm for 2 days before (baseline) and 1 day after osmotic minipump implantation. Weighing was performed on a Mettler Toledo PR 5002 balance with a computer. Accidental spillage was corrected. At the end of the study animals were killed by cervical dislocation and aortic blood was sampled for later analysis of plasma drug concentrations.

Plasma sample protein was precipitated with methanol and centrifuged to transfer the supernatant to an HPLC vial and then introduced into a liquid chromatography / mass spectrometry system. The mass spectrometer was fitted with an electrospray cation method and multiple reaction monitoring. The concentration of the unknown sample was calculated using linear regression analysis of the standard forced to leave the origin.

Food consumption for 15 hours was measured for 3 consecutive days and a percentage of baseline value was derived for each animal from the days before and after treatment. The values are expressed as mean ± SD and ± SEM from 8 mice per dose group. Statistical assessments were performed with a Kruskal-Wallis one-way ANOVA using the base value%. When statistical significance was reached at the level of p <0.05, the Mann-Whitney U-test was performed for statistical comparison between the control and treatment groups.

The compounds according to the invention showed an effect (ie, reduced food intake) in the range of 5 to 200 mg / kg / d.

Table 4. In vitro functional data (fK _i ) at h-5-HT receptor . Data was expressed as fK _i = IC ₅₀ / (1+ [5HT] / EC ₅₀ ). The efficacy of the antagonists was determined using the formula fK _i = IC ₅₀ / (1+ [5HT] / EC ₅₀ ), resulting in 50% inhibition of 5-HT induced cAMP increase ([5-HT] = 8-fold EC). ₅₀₎ it was determined by measuring.

Example fK _i (nM) One 87 12 87 28 66 32 54 33 20

를 사용하여 계산하였다. Table 5. In vitro competitive binding data (K _i ) at h-5-HT receptor . IC ₅₀ values, ie the concentrations of test compounds that inhibit 50% of the specific binding of radioligand ([ ³ H] -LSD), were obtained by nonlinear regression analysis and K _i values

Calculated using.

Example K _i (nM) 92 5.56 36 20 67 13 84 7.5 85 7 86 7 87 5.3 89 14 91 56 54 17.4

Claims (27)

Compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, geometric isomers, tautomers, optical isomers, and drug precursor forms thereof:

[here, P is selected from substituents of the formulas (II) to (VII)

here, x, y and j are each independently selected from 0, 1 and 2; Wherein the dashed bond indicates that P and R ³ may be attached to the A or B ring, respectively, at any carbon atom allowing substitution, provided that both P and R ³ are not attached to ring B at the same time; R ¹ is selected from: (a) C _1-6- alkyl, (b) C _1-6 -alkoxy-C _1-6- alkyl, (c) C _3-6 -alkenyl, (d) hydroxy-Ci_ ₆ -alkyl, (e) halo-Ci_ ₆ -alkyl, (f) aryl, (g) arylcarbonylmethyl, (h) aryl-C _3-6 -alkenyl, (i) aryl-C _1-6 -alkyl, (j) C _3-7 -cycloalkyl, (k) heteroaryl, (l) 4-piperidinyl, (m) N- substituted 4-piperidinyl (wherein the substituent is C _1-6 - alkyl and aryl -C _1-6 - selected from alkyl), (o) heteroaryl-C _1-6 -alkyl, Wherein any heteroaryl or aryl moiety, alone or as part of another group, may be substituted at one or more positions independently with a substituent selected from: (a) hydrogen, (b) halogen, (c) C _1-6 -alkyl, (d) hydroxy, (e) C _1-6 -alkoxy, (f) C _2-6 -alkenyl, (g) C _2-3 -alkynyl, (h) phenyl, (i) phenoxy, (j) benzyloxy, (k) benzoyl, (l) benzyl, (m) -OCF ₃ , (n) -CN, (o) hydroxy-C _1-6 -alkyl, (p) C _1-6 -alkoxy-C _1-6 -alkyl, (q) halo-Ci_ ₆ -alkyl, (r) -NR ⁹ R ⁹ , (s) -NO ₂ , (t) -CONR ⁹ R ⁹ , (u) -NR ⁷ COR ¹⁰ , (v) -C (= 0) R ¹⁰ , (x) C _1-6 -alkoxycarbonyl, (y) C _1-6 -alkylthio, (z) -SCF ₃ , (aa) -CHF = CH ₂ , (ab) methylsulfonyl, or (ac) -COOH Provided that when the substituent on the aryl or heteroaryl moiety is selected from phenyl, phenoxy, benzyloxy, benzoyl and benzyl, the phenyl ring thereof is halogen, C _1-4 -alkyl, C _1-4 -alkylthio, C Optionally substituted with one or more of _1-4 -alkoxy, cyano, or trifluoromethyl); R ² is selected from: (a) hydrogen, (b) C _1-6 -alkyl, (c) C _1-6 -alkoxy-C _2-6 alkyl, (d) hydroxy-C _2-6 -alkyl, (e)-(CH ₂ ) _m -CH ₂ -F (wherein m is 2-4), (f) 3,3,3-trifluoropropyl, or (g) C _1-4 -alkylsulfonyl, wherein P is selected from substituents of the formula (V); W ₁ and W ₂ are each independently selected from: (a) hydrogen, (b) halogen, (c) C _1-6 -alkyl, (d) hydroxy, (e) C _1-6 -alkoxy, (f) C _1-6 -alkylthio, (g) C _2-6 -alkenyl, (h) phenyl, (i) phenoxy, (j) benzyloxy, (k) benzoyl, (l) benzyl, (m) -OCF ₃ , (n) -CN, (o) hydroxy-C _1-6 -alkyl, (p) C _1-6 -alkoxy-C _1-6 -alkyl, (q) halo-Ci_ ₆ -alkyl, (r) -CONR ⁹ R ⁹ , (s) -C (= O) R ¹⁰ , (t) C _1-6 -alkoxycarbonyl, (u) -SCF ₃ , or (v) -CHF = CH ₂ Provided that W ₁ and W ₂ are selected from phenyl, phenoxy, benzoyl, benzyloxy and benzyl, their phenyl rings are halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, or tri If may be optionally substituted with one or more of the fluoromethyl, and that the W ₁ and W _2-methoxy, is selected from methyl and halogen, at least one of W ₁ and W ₂ selected from hydrogen); R ³ is H when P is a substituent of formula (II), wherein R ¹ is N-substituted 4-piperidinyl, or R ³ is a group selected from:

R ³ is also a group selected from:

Additionally it may be a group selected from: -O- (C = NH) NR ¹¹ R ¹¹ , or -(CH ₂ ) _n -O-NH (C = NH) -NR ¹¹ R ¹¹ here, n = 0, 1, 2 or 3 r is each independently 0, 1 or 2, o = 1, 2, or 3, p is each independently 1 or 2, s = 2 or 3, t = 0 or 1, t ₁ = 1 or 2, t ₂ = 0 or 1, f = 1, 2, 3 or 4, and f ₁ = 1, 2 or 4; (Where r is not 0 when t ₁ and p are 1 at the same time); X is selected from O, NR ⁷ and S; X ₁ is selected from NR ⁷ and S; X ₂ is selected from O, NR ⁷ and S, provided that X ₂ is selected from NR ⁷ and S when t ₂ = 0; X ₃ is selected from NR ⁷ and S, provided that when r = 1 X ₃ is selected from S; X ₄ is selected from O, NR ⁷ and S, provided that when 4 is selected from 2, 3 and 4, X ₄ is selected from S and NR ⁷ ; Q is selected from CH ₂ , SO ₂ and oxygen, provided that when Q is SO ₂ or oxygen, p is 1; Z is selected from SO ₂ and oxygen; When P is selected from substituents of the formulas (V) to (VII), R ³ is further selected from the following groups:

In the formula, n = 0, 1, 2 or 3, r = 0, 1 or 2, o = 1, 2 or 3, p = 1 or 2, s = 2 or 3, and f = 1, 2, 3 or 4; R ⁴ is a group selected from: (a) hydrogen, (b) C _1-6 -alkyl, (c) 2-cyanoethyl, (d) hydroxy-C _2-6 -alkyl, (e) C _3-6 -alkenyl, (f) C _3-6 -alkynyl, (g) C _3-7 -cycloalkyl, (h) C _3-7 -cycloalkyl-C _1-4 -alkyl, (i) C _1-6 -alkoxy-C _2-6 -alkyl, (j) -C (= NH) -NR ¹¹ R ¹¹ , (k) -C (= 0) -NR ¹¹ R ¹¹ , (l) -CH ₂ -CO-NR ¹¹ R ¹¹ , or (m) 3,3,3-trifluoropropyl; R ⁵ is selected from: (a) hydrogen, (b) C _1-4 -alkyl, (c) hydroxy-Ci_ ₄ -alkyl, (d) C ₁ - ₄ - alkoxy-methyl, (e) halo-Ci_ ₄ -alkyl, (f) -NR ¹¹ R ¹¹ , (g) -CO-NR ¹¹ R ¹¹ , (h) hydroxy, provided that the hydroxy group is not attached to a carbon atom adjacent to the ring nitrogen atom, or (i) fluorine, provided that the fluorine atom is not attached to a carbon atom adjacent to the ring nitrogen atom; R ⁶ is selected from: (a) hydrogen, (b) C _1-4 -alkyl, (c) hydroxy-Ci_ ₄ -alkyl, (d) C _1-4 -alkoxy-C _1-4 -alkyl, (e) hydroxy, provided that the hydroxy group is not attached to a carbon atom adjacent to the heterocyclic ring nitrogen atom and the heterocyclic ring is not substituted with oxo, (f) fluorine, provided that the fluorine atom is not attached to a carbon atom adjacent to the ring nitrogen atom, or (g) halo-Ci_ ₄ -alkyl; Each R ⁷ is independently selected from: (a) hydrogen, provided that R ⁷ is not hydrogen when present at the same time as r, wherein r is 1 or 2, (b) C _1-4 -alkyl, (c) hydroxy-C _2-4 -alkyl, or (d) methoxy-C _2-4 -alkyl; Each R ⁸ is independently selected from: (a) hydrogen, or (b) C _1-4 -alkyl, and When both R ⁸ are selected from C _1-4 -alkyl at the same time, the C _1-4 -alkyl may be attached to the same or different carbon atoms, and if two groups are present at the same carbon atom, they are cyclopropane together May form a ring; Each R ⁹ is independently selected from: (a) hydrogen, (b) C _1-6 -alkyl, (c) C _3-7 -cycloalkyl, or; Wherein two R ⁹ groups together with the nitrogen to which they are attached form a heterocyclic ring; Provided that when the two R ⁹ groups form a piperazine ring, the nitrogen of the piperazine ring allowing substitution is optionally substituted with C _1-4 -alkyl, and the two R ⁹ groups further form a piperidine ring. When formed, any ring carbon atom in the piperidine may be optionally substituted with methyl; R ¹⁰ is selected from: (a) C _1-6 -alkyl, (c) aryl, or (d) heteroaryl, Wherein heteroaryl or aryl may be substituted at one or more positions with a substituent selected from halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, trifluoromethyl; Each R ¹¹ is independently selected from: (a) hydrogen, (b) methyl, or (c) ethyl, provided that R ¹¹ is on the R ⁴ or R ²⁶ group selected from —CH ₂ —CO—NR ¹¹ R ¹¹ ; R ¹² is selected from: (a) hydrogen, (b) C _1-6 -alkyl, (c) aryl, (d) aryl-C _1-6 -alkyl, (e) C _3-7 -cycloalkyl, (f) C _3-7 -cycloalkyl-C _1-4 -alkyl, (g) heteroaryl, or (h) heteroaryl-C _1-6 -alkyl, Wherein any heteroaryl or aryl moiety, alone or as part of another group, is optionally substituted at one or more positions independently with a substituent selected from: (a) hydrogen, (b) halogen, (c) C _1-6 -alkyl, (d) hydroxy, (e) C _1-6 -alkoxy, (f) C _2-6 -alkenyl, (g) C _2-6 -alkynyl, (h) phenyl, (i) phenoxy, (j) benzyloxy, (k) benzoyl, (l) benzyl, (m) -OCF ₃ , (n) -CN, (o) hydroxy-C _1-6 -alkyl, (p) C _1-6 -alkoxy-C _1-6 -alkyl, (q) halo-Ci_ ₆ -alkyl, (r) -NR ⁹ R ⁹ , (s) -NO ₂ , (t) -CONR ⁹ R ⁹ , (u) -NR ⁷ COR ¹⁰ , (v) -C (= 0) R ¹⁰ , (x) C _1-6 -alkoxycarbonyl, (y) C _1-6 -alkylthio, (z) -SCF ₃ , (aa) -CHF = CH ₂ , (ab) methylsulfonyl, or (ac) -COOH, Provided that the substituent on the aryl or heteroaryl moiety is selected from phenyl, phenoxy, benzyloxy, benzoyl, and benzyl, wherein the phenyl ring is halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cya Optionally substituted with one or more of furnace, or trifluoromethyl); R ¹³ is selected from: (a) C _1-6 -alkyl, (b) C _3-6 -cycloalkyl, (c) aryl, (d) heteroaryl, (e) aryl-C _1-2 -alkyl, or (f) heteroaryl-C _1-2 -alkyl, Wherein any heteroaryl or aryl moiety may be substituted at one or more positions with a substituent selected from halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, trifluoromethyl, and acetyl ); R ¹⁴ is selected from: (a) aryl, (b) heteroaryl, (c) aryl-C _1-3 -alkyl, or (d) heteroaryl-C _1-3 -alkyl, Wherein any heteroaryl or aryl moiety may be substituted at one or more positions with a substituent selected from halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, and trifluoromethyl; R ¹⁵ is selected from: (a) fluorine, or (b) hydroxy; R ¹⁶ is selected from: (a) hydrogen (where r = 0), (b) amino, (c) dimethylamino, (d) F, or (e) OH; R ¹⁷ is selected from: (a) hydrogen, (b) C _1-4 -alkyl, (c) hydroxy, provided that the hydroxy group is not attached to a carbon atom adjacent to the ring nitrogen atom; R ¹⁸ is selected from: (a) hydrogen, or (b) fluorine; R ¹⁹ is selected from: (a) hydrogen, (b) methyl, (c) trifluoromethyl, or (d) C _1-2 -alkoxymethyl; Provided that at least one of R ¹⁹ and R ¹¹ , when present simultaneously, is selected from non-hydrogen substituents, and R ¹⁹ is selected from trifluoromethyl or C _1-2 -alkoxymethyl, Each R ¹¹ is selected from hydrogen); R ²⁰ is selected from: (a) hydrogen, (b) C _1-4 -alkyl, (c) hydroxy-Ci_ ₄ -alkyl, (d) C _1-4 -alkoxy-C _1-4 -alkyl, or (e) fluoromethyl; Provided that when t ₂ is 1, R ²⁰ is H; R ²¹ and R ²² are each independently selected from: (a) hydrogen, or (b) methyl, Provided that when present at the same time as R ¹¹ , at least two of R ¹¹ , R ²¹ and R ²² are selected from hydrogen; R ²³ is selected from: (a) hydroxy-Ci_ ₄ -alkyl, (b) C _1-4 -alkoxymethyl, (c) halo-Ci_ ₄ -alkyl, or ^{(d) -CO-NR 11 R} 11 ( only, R ⁴ is ^{-C (= NH) -NR 11 R} 11, -C (= O) -NR 11 R 11, and -CH ₂ -CO-NR ¹¹ R Not selected from ¹¹ ); R ²⁴ is selected from: (a) hydroxymethyl, (b) methoxymethyl, or (c) fluoromethyl; Each R ²⁵ is independently selected from: (a) hydrogen, (b) C _1-4 -alkyl, (c) hydroxy-Ci_ ₄ -alkyl, (d) C _1-4 -alkoxy-C _1-4 -alkyl, or (e) fluoromethyl; Provided that both R ²⁵ are simultaneously selected from C _1-4 -alkyl, wherein said C _1-4 -alkyl can be attached to the same or different carbon atoms, and that one R ²⁵ is hydroxy-C _{When selected from 1-4} -alkyl, C _1-4 -alkoxy-C _1-4 -alkyl, and fluoromethyl, another R ²⁵ represents hydrogen; And R ²⁶ is selected from: (a) 2-cyanoethyl, (b) C _3-6 -alkenyl, (c) C _3-6 -alkynyl, (d) C _3-7 -cycloalkyl, (e) C _3-7 -cycloalkyl-C _1-4 -alkyl, (f) -CH ₂ -CO-NR ¹¹ R ¹¹ , or (g) 3,3,3-trifluoropropyl; With the proviso that R ² and R ¹² in formula (III) are not simultaneously selected from hydrogen; And R ² and R ¹² may together form a heterocyclic ring selected from piperidine, pyrrolidine, morpholine, piperazine, thiomorpholine, provided that R ² and R ^{12 together} When forming a azine ring, the distal piperazine nitrogen may be optionally substituted with C _1-4 alkyl or aryl, wherein the aryl is in one or more positions halogen, C _1-4 -alkyl, C _1- Or may be substituted with a substituent selected from ₄ -alkoxy, cyano, trifluoromethyl; R ² and R ¹² together form a heteroaromatic ring of formula (VIII):

In which v is 0, 1 or 2; And provided that when R ¹⁵ is selected from hydroxy, R ¹⁸ is selected from hydrogen. A compound of formula (1b) according to claim 1:

[here, P is selected from substituents of the formulas (II) to (VII):

here, x, y and j are each independently selected from 0, 1 and 2; Wherein the dashed bonds indicate that R ³ may be attached to A or B at any carbon atom allowing substitution; R ¹ is selected from: (a) C _1-6 -alkyl, (b) C _1-6 -alkoxy-C _2-6 -alkyl, (c) C _3-6 -alkenyl, (d) hydroxy-C _2-6 -alkyl, (e) halo-Ci_ ₆ -alkyl, (f) aryl, (g) arylcarbonylmethyl, (h) aryl-C _3-6 -alkenyl, (i) aryl-C _1-6 -alkyl, (j) C _3-7 -cycloalkyl, (k) heteroaryl, (o) heteroaryl-C _1-6 -alkyl, Wherein any heteroaryl or aryl moiety, alone or as part of another group, may be optionally substituted independently at one or more positions with a substituent selected from: (b) halogen, (c) C _1-6 -alkyl, (d) hydroxy, (e) C _1-6 -alkoxy, (f) C _2-6 -alkenyl, (g) C _2-3 -alkynyl, (h) phenyl, (i) phenoxy, (j) benzyloxy, (k) benzoyl, (l) benzyl, (m) -OCF ₃ , (n) -CN, (o) hydroxy-C _1-6 -alkyl, (p) C _1-6 -alkoxy-C _1-6 -alkyl, (q) halo-Ci_ ₆ -alkyl, (r) -NR ⁹ R ⁹ , (s) -NO ₂ , (t) -CONR ⁹ R ⁹ , (u) -NR ⁷ COR ¹⁰ , (v) -C (= 0) R ¹⁰ , (x) C _1-6 -alkoxycarbonyl, (y) C _1-6 -alkylthio, (z) -SCF ₃ , (aa) -CHF = CH ₂ , (ab) methylsulfonyl, or (ac) -COOH, Provided that the substituent on the aryl or heteroaryl moiety is selected from phenyl, phenoxy, benzyloxy, benzoyl and benzyl, wherein the phenyl ring is halogen, C _1-4 -alkyl, C _1-4 -alkylthio, C Optionally substituted with one or more of _1-4 -alkoxy, cyano, or trifluoromethyl); R ² is selected from: (a) hydrogen, (b) C _1-6 -alkyl, (c) C _1-6 -alkoxy-C _2-6 alkyl, (d) hydroxy-C _2-6 alkyl, (e)-(CH ₂ ) _m -CH ₂ -F, wherein m is 2 to 4, or (g) C _1-4 -alkylsulfonyl, wherein P is selected from substituents of the formula (V); W ₁ and W ₂ are each independently selected from: (a) hydrogen, (b) halogen, (c) C _1-6 -alkyl, (d) hydroxy, (e) C _1-6 -alkoxy, (f) C _1-6 -alkylthio, (g) C _2-6 -alkenyl, (m) -OCF ₃ , (n) -CN, (o) hydroxy-C _1-6 -alkyl, (p) C _1-6 -alkoxy-C _1-6 -alkyl, (q) halo-Ci_ ₆ -alkyl, (r) -CONR ⁹ R ⁹ , (s) -C (= O) R ¹⁰ , (t) C _1-6 -alkoxycarbonyl, (u) -SCF ₃ , or (v) -CHF = CH ₂ , (Where, W ₁ and W _2, if is not selected from hydroxy, methoxy, methyl and halogen, at least one of W ₁ and W ₂ is selected from hydrogen); R ³ is selected from:

here, n = 0, 1, 2 or 3, r = 0, 1 or 2, o = 1, 2 or 3, p = 1 or 2, s = 2 or 3, t = 0 or 1, t ₂ = 0 or 1, f = 1, 2, 3 or 4, and f ₁ = 1, 2 or 4; X ₁ is selected from NR ⁷ and S; X ₂ is selected from O, NR ⁷ and S, provided that t ₂ = 0 and s = 2, X ₂ is selected from NR ⁷ and S; X ₃ is selected from NR ⁷ and S, provided that when r = 1 X ₃ is selected from S; X ₄ is selected from O, NR ⁷ and S, provided that when the f is selected from 2 and 3 X ₄ is selected from S and NR ⁷ and R ⁶ is simultaneously selected from hydrogen and C _1-4 alkyl; When P is a group selected from substituents of formulas (V) to (VII), R ³ is further selected from the following groups:

here, r = 0, 1 or 2, o = 1, 2 or 3, p is each independently 1 or 2, s = 2 or 3, and f = 1, 2, 3 or 4; R ⁴ is selected from: (a) hydrogen, (b) C _1-6 -alkyl, (c) 2-cyanoethyl, (d) hydroxy-C _2-6 -alkyl, (e) C _3-6 -alkenyl, (f) C _3-6 -alkynyl, (g) C _3-7 -cycloalkyl, (h) C _3-7 -cycloalkyl-C _1-4 -alkyl, (i) C _1-6 -alkoxy-C _2-6 -alkyl, (l) -CH ₂ -CO-NR ¹¹ R ¹¹ , or (m) 3,3,3-trifluoropropyl; R ⁵ is selected from: (a) hydrogen, (b) C _1-4 -alkyl, (c) hydroxy-Ci_ ₄ -alkyl, (d) C _1-4 -alkoxymethyl, (e) halo-Ci_ ₄ -alkyl, (f) -NR ¹¹ R ¹¹ , (h) hydroxy, provided that the hydroxy group is not attached to a carbon atom adjacent to the ring nitrogen atom, or (i) fluorine, provided that the fluorine atom is not attached to a carbon atom adjacent to the ring nitrogen atom; R ⁶ is selected from: (a) hydrogen, (b) C _1-4 -alkyl, (c) hydroxy-Ci_ ₄ -alkyl, (d) C _1-4 - alkoxy -C ₁ - ₄ - alkyl, (e) hydroxy, provided that the hydroxy group is not attached to a carbon atom adjacent to the heterocyclic ring nitrogen atom, (f) fluorine, provided that the fluorine atom is not attached to a carbon atom adjacent to the ring nitrogen atom, or (g) halo-Ci_ ₄ -alkyl; Each R ⁷ is independently selected from: (a) hydrogen (wherein R ⁷ is not hydrogen and r is 1 or 2 when present simultaneously with r), (b) C _1-4 -alkyl, (c) hydroxy-C _2-4 -alkyl, or (d) methoxy-C _2-4 -alkyl; Each R ⁸ is independently selected from: (a) hydrogen, or (b) C _1-4 -alkyl, provided that both R ⁸ are simultaneously selected from C _1-4 -alkyl, the C _1-4 -alkyl may be attached to the same or different carbon atoms, or two groups When present at the same carbon atom, they may together form a cyclopropane ring); Each R ⁹ is independently selected from: (a) hydrogen, (b) C _1-6 -alkyl (c) C _3-7 -cycloalkyl, or Both R ⁹ groups together with the nitrogen to which they are attached form a heterocyclic ring; When both R ⁹ groups form a piperazine ring, the nitrogen of the piperazine ring allowing substitution may be optionally substituted with C _1-4 -alkyl; In addition, when two R ⁹ groups form a piperidine ring, any ring carbon atom in the piperidine ring may be optionally substituted with methyl; R ¹⁰ is selected from: (a) C _1-6 -alkyl, (c) aryl, or (d) heteroaryl, Wherein heteroaryl or aryl may be optionally substituted at one or more positions with a substituent selected from halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, trifluoromethyl; R ¹¹ are each independently selected from: (a) hydrogen, (b) methyl, or (c) ethyl, with R ¹¹ being present on the group R ²⁶ or R ⁴ selected from -CH ₂ -CO-NR ¹¹ R ¹¹ ; R ¹² is selected from: (a) hydrogen, (b) C _1-6 -alkyl, (c) aryl, (d) aryl-C _1-6 -alkyl, (e) C _3-7 -cycloalkyl, (f) C _3-7 -cycloalkyl-C _1-4 -alkyl, (g) heteroaryl, or (h) heteroaryl-C _1-6 -alkyl, Wherein any heteroaryl or aryl moiety, alone or as part of another group, may be optionally substituted independently at one or more positions with a substituent selected from: (b) halogen, (c) C _1-6 -alkyl, (d) hydroxy, (e) C _1-6 -alkoxy, (f) C _2-6 -alkenyl, (g) C _2-3 -alkynyl, (h) phenyl, (i) phenoxy, (j) benzyloxy, (k) benzoyl, (l) benzyl, (m) -OCF ₃ , (n) -CN, (o) hydroxy-C _1-6 -alkyl, (p) C _1-6 -alkoxy-C _1-6 -alkyl, (q) halo-Ci_ ₆ -alkyl, (r) -NR ⁹ R ⁹ , (s) -NO ₂ , (t) -CONR ⁹ R ⁹ , (u) -NR ⁷ COR ¹⁰ , (v) -C (= 0) R ¹⁰ , (x) C _1-6 -alkoxycarbonyl, (y) C _1-6 -alkylthio, (z) -SCF ₃ , (aa) -CHF = CH _2, (ab) methylsulfonyl, or (ac) -COOH, Provided that when the substituent on the aryl or heteroaryl moiety is selected from phenyl, phenoxy, benzyloxy, benzoyl, and benzyl, its phenyl ring is halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cya Optionally substituted by one or more of: furnace, or trifluoromethyl); R ¹³ is selected from: (a) C _1-6 -alkyl, (b) C _3-6 -cycloalkyl, (c) aryl, (d) heteroaryl, (e) aryl-C _1-2 -alkyl, or (f) heteroaryl-C _1-2 -alkyl, Wherein any heteroaryl or aryl moiety may be optionally substituted at one or more positions with substituents selected from halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, trifluoromethyl, and acetyl Can be); R ¹⁴ is selected from: (a) aryl, (b) heteroaryl, (c) aryl-C _1-3 -alkyl, or (d) heteroaryl-C _1-3 -alkyl, (Wherein any heteroaryl or aryl moieties, halogen, C _1-4 at one or more positions with one or more - may be substituted by alkoxy, cyano, and substituents selected from trifluoromethyl -alkyl, C _1-4 ); R ²⁰ are each independently selected from: (a) hydrogen, (b) methyl, Provided that when t ₂ is 1, R ²⁰ is hydrogen; R ²¹ and R ²² are each independently selected from: (a) hydrogen, or (b) methyl, Provided that when present at the same time as R ¹¹ , at least two of R ¹¹ , R ²¹ and R ²² are selected from hydrogen; R ²³ is selected from: (a) hydroxy-Ci_ ₄ -alkyl, (b) C _1-4 -alkoxymethyl, or (c) halo-C _1-4 -alkyl; R ²⁵ are each independently selected from: (a) hydrogen, (b) C _1-4 -alkyl, (c) hydroxy-Ci_ ₄ -alkyl, (d) C _1-4 -alkoxy-C _1-4 -alkyl, or (e) fluoromethyl, (Provided that both R ²⁵ together are C _1-4 - if selected from alkyl, said C _1-4 - alkyl may be bonded to the same or different carbon atoms, and R ²⁵ is a _hydroxy-1- -C _{When selected from 4} -alkyl, C _1-4 -alkoxy-C _1-4 -alkyl, and fluoromethyl, another R ²⁵ represents hydrogen; R ²⁶ is selected from: (a) 2-cyanoethyl, (b) C _3-6 -alkenyl, (c) C _3-6 -alkynyl, (d) C _3-7 -cycloalkyl, (e) C _3-7 -cycloalkyl-C _1-4 -alkyl, (f) -CH ₂ -CO-NR ¹¹ R ¹¹ , or (g) 3,3,3-trifluoropropyl; With the proviso that R ² and R ¹² in formula (III) are not simultaneously selected from hydrogen; In addition, the R ² and R ¹² together may form a heterocyclic ring selected from piperidine, pyrrolidine, morpholine, piperazine thiomorpholine, and R ² and R ¹² together piperazine ring When forming, the terminal piperazine nitrogen may be optionally substituted with C _1-4 alkyl or aryl, wherein the aryl is halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano at one or more positions Optionally substituted with a substituent selected from trifluoromethyl; Or R ² and R ¹² together form a heteroaromatic ring of formula (VIII):

(VIII) (Where v is 0 or 1). A compound according to claim 1 or 2, wherein [here, P is selected from substituents of formula (II)-(V):

Wherein x is 2, y is 0 and j is 1; R ¹ is selected from: (f) aryl, (i) aryl-C _1-3 -alkyl, (k) heteroaryl, (o) heteroaryl-C _1-3 -alkyl, Wherein any heteroaryl or aryl moiety, alone or as part of another group, may be optionally substituted at one or more positions independently with a substituent selected from: (b) halogen, (c) C _1-4 -alkyl, (d) hydroxy, (e) C _1-4 -alkoxy, (m) -OCF ₃ , (n) -CN, (o) hydroxy-C _1-4 -alkyl, (p) C _1-2 -alkoxy-C _1-2 -alkyl, (q) halo-Ci- ₃ -alkyl, (r) -NR ⁹ R ⁹ , (t) -CONR ⁹ R ⁹ , (u) -NR ⁷ COR ¹⁰ , (v) -C (= 0) R ¹⁰ , (x) C _1-3 -alkoxycarbonyl, (y) C _1-3 -alkylthio, or (ab) methylsulfonyl, R ² is selected from: (a) hydrogen, (b) C _1-4 -alkyl, W ₁ and W ₂ are each independently selected from: (a) hydrogen, (b) halogen, (c) C _1-4 -alkyl, (d) hydroxy, (e) C _1-4 -alkoxy, (f) C _1-4 -alkylthio, (m) -OCF ₃ , (n) -CN, (o) hydroxy-C _1-2 -alkyl, (p) C _1-2 -alkoxy-C _1-2 -alkyl, (q) -CF ₃ , (r) -CONR ⁹ R ⁹ , (s) acetyl, (t) C _1-4 -alkoxycarbonyl, or Provided that when W ₁ and W ₂ are not selected from methoxy, methyl and halogen, at least one of W ₁ and W ₂ is selected from hydrogen; R ³ is a group selected from:

here, n = 0, 1, 2 or 3 r is 0, 1 or 2, o = 1, 2, or 3, p is 1 or 2, s = 2 or 3, t = 0 or 1, t ₂ = 0 or 1, and f = 1, 2, 3 or 4; X ₁ is selected from NR ⁷ and S; X ₂ is selected from O, NR ⁷ and S, provided that t ₂ is selected from NR ⁷ and S when t = 0 and s = 2; X ₃ is selected from NR ⁷ and S, provided that when r = 1 X ₃ is selected from S; X ₄ is selected from O, NR ⁷ and S provided that when f is selected from 2 and 3 X ₄ is selected from S and NR ⁷ and R ⁶ is simultaneously selected from hydrogen and C _1-4 alkyl; or; When P is a group selected from formula (V) wherein j = 1, R ³ is additionally selected from the following groups;

R ⁴ is selected from: (a) hydrogen, (b) C _1-4 -alkyl, (d) hydroxy-C _2-4- alkyl, (g) C _3-6 -cycloalkyl, (h) C _3-6 -cycloalkyl-C _1-4 -alkyl, (i) C _1-4 -alkoxy-C _2-4 -alkyl (m) 3,3,3-trifluoropropyl; R ⁵ is selected from: (a) hydrogen, (b) C _1-4 -alkyl, (c) hydroxy-Ci_ ₄ -alkyl, (d) C _1-4 -alkoxymethyl, (e) halo-Ci_ ₄ -alkyl, (f) -NR ¹¹ R ¹¹ , (g) hydroxy, provided that the hydroxy group is not bonded to a carbon atom adjacent to a ring nitrogen atom, or (h) fluorine, provided that the fluorine atom is not bonded to a carbon atom adjacent to the ring nitrogen atom; R ⁶ is selected from: (a) hydrogen, (b) C _1-4 -alkyl, (c) hydroxy-Ci_ ₄ -alkyl, (d) C _1-4 -alkoxy-C _1-4 -alkyl, (e) hydroxy, provided that the hydroxy group is not bonded to a carbon atom adjacent to the heterocyclic ring nitrogen atom, (f) fluorine, provided that the fluorine atom is not bonded to a carbon atom adjacent to the ring nitrogen atom, or (g) halo-Ci_ ₄ -alkyl; R ⁷ are each independently selected from: (a) hydrogen, provided that when R ⁷ is present at the same time as r and said r is 1 or 2, R ⁷ is not hydrogen; (b) C _1-4 -alkyl, (c) hydroxy-C _2-4 -alkyl, or (d) methoxy-C _2-4 -alkyl; R ⁸ are each independently selected from: (a) hydrogen, or (b) C _1-4 - alkyl (provided that, the amount at the same time R ⁸ C _1-4 - if selected from alkyl, said C _1-4 - alkyl or may be bonded to the same or different carbon atoms, or the two groups When present at the same carbon atom, they may together form a cyclopropane ring); Each R ⁹ is independently selected from: (a) hydrogen, (b) C _1-6 -alkyl, or Both R ⁹ groups together with the nitrogen to which they are attached form a heterocyclic ring; Provided that when two R ⁹ groups form a piperazine ring, the nitrogen of the piperazine ring allowing substitution is optionally substituted with C _1-4 -alkyl; R ¹⁰ is selected from: (a) C _1-6 -alkyl, (c) aryl, or (d) heteroaryl, Wherein heteroaryl or aryl may be substituted at one or more positions with substituents selected from halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, trifluoromethyl; R ¹¹ are each independently selected from: (a) hydrogen, or (b) methyl, (c) ethyl, with R ¹¹ being on the R ²⁶ group selected from -CH ₂ -CO-NR ¹¹ R ¹¹ ; R ¹² is selected from: (a) hydrogen, (c) aryl, (d) aryl-C _1-3 -alkyl, (g) heteroaryl, or (h) heteroaryl-C _1-3 -alkyl, Wherein any heteroaryl or aryl moiety, alone or as part of another group, may be optionally substituted at one or more positions independently with a substituent selected from: (b) halogen, (c) C _1-4 -alkyl, (d) hydroxy, (e) C _1-4 -alkoxy, (m) -OCF ₃ , (n) -CN, (o) hydroxy-C _1-3 -alkyl, (p) C _1-3 -alkoxy-C _1-3 -alkyl, (q) halo-Ci_ ₄ -alkyl, (r) -NR ⁹ R ⁹ , (t) -CONR ⁹ R ⁹ , (u) -NR ⁷ COR ¹⁰ , (v) -C (= 0) R ¹⁰ , (x) C _1-3 -alkylthio, or (ab) methylsulfonyl; R ¹³ is selected from: (c) aryl, (d) heteroaryl, (e) Aryl-C _1-2 -alkyl, or (f) heteroaryl-C _1-2 -alkyl, Wherein any heteroaryl or aryl moiety may be optionally substituted at one or more positions with substituents selected from halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, trifluoromethyl and acetyl has exist); R ¹⁴ is selected from: (a) aryl, (b) heteroaryl, (c) aryl-C _1-3 -alkyl, or (d) heteroaryl-C _1-3 -alkyl; Wherein any heteroaryl or aryl moiety may be optionally substituted at one or more positions with substituents selected from halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, and trifluoromethyl ); R ²¹ and R ²² are each independently selected from: (a) hydrogen, or (b) methyl, Provided that when present at the same time as R ¹¹ , at least two of R ¹¹ , R ²¹ and R ²² are selected from hydrogen; R ²³ is selected from: (a) hydroxy-Ci_ ₄ -alkyl, (b) C _1-4 -alkoxymethyl, or (c) halo-C _1-4 -alkyl; R ²⁵ is selected from: (a) hydrogen, (b) C _1-4 -alkyl, (c) hydroxy-Ci_ ₄ -alkyl, (d) C _1-4 -alkoxy-C _1-4 -alkyl, or (e) fluoromethyl; (Provided that when both R ²⁵ are simultaneously selected from C _1-4 -alkyl, the C _1-4 -alkyl may be bonded to the same or different carbon atom, and one R ²⁵ is hydroxy-C _{1 -4} -alkyl, C _1-4 -alkoxy-C _1-4 -alkyl, and fluoromethyl, other R ²⁵ represents hydrogen; R ²⁶ is selected from: (e) C _3-7 -cycloalkyl-C _1-4 -alkyl, (f) -CH ₂ -CO-NR ¹¹ R ¹¹ , or (g) 3,3,3-trifluoropropyl; Provided that R ² and R ¹² of formula (III) are not selected from hydrogen at the same time; and wherein R ² and R ¹² together are selected from piperidine, pyrrolidine, morpholine, piperazine thiomorpholine Heterocyclic ring, and when R ² and R ¹² together form a piperazine ring, the terminal piperazine nitrogen may be optionally substituted with C _1-4 alkyl or aryl, wherein the aryl is one In the above position may be optionally substituted with a substituent selected from halogen, C _1-4 -alkyl, C _1-4 -alkoxy, cyano, trifluoromethyl; or R ² and R ¹² together may be selected from formula (VIII) To form a heteroaromatic ring:

(VIII) Where v is 0 or 1). The compound according to any one of claims 1 to 3, having the formula (XII).

(XII) A compound according to claim 4 wherein: [P is selected from substituents of the formulas (II) to (IV):

; x is 2 and y is 0; R ¹ is selected from aryl and heteroaryl, wherein any heteroaryl or aryl moiety is independently selected from halogen, C _1-4 -alkyl, C _1-4 -alkoxy and trifluoromethyl at one or more positions Optionally substituted with a substituent; R ² is selected from hydrogen; W ₁ and W ₂ are hydrogen; R ³ is a group selected from:

(In the meal, p = 1 or 2); R ⁴ is selected from: (a) hydrogen, or (b) C _1-4 -alkyl; R ¹¹ are each independently selected from: (a) hydrogen, or (b) methyl, (c) ethyl, provided that R ¹¹ is on the R ²⁶ group selected from -CH ₂ -CO-NR ¹¹ R ¹¹ ; R ¹² and R ¹³ are each independently selected from aryl and heteroaryl, Wherein any heteroaryl or aryl moiety is independently at one or more positions halogen, C _1-4 -alkyl, C _1-4 -alkoxy, and Optionally substituted with a substituent selected from CF ₃ ; R ²⁵ is selected from: (a) hydrogen, or (b) C _1-4 -alkyl; R ²⁶ is selected from: (e) C _3-7 -cycloalkyl-C _1-4 -alkyl, (f) -CH ₂ -CO-NR ¹¹ R ¹¹ , or (g) 3,3,3-trifluoropropyl]. 6. A compound according to claim 5, wherein R ¹ , R ¹² and R ¹³ are each independently phenyl or 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-fluor Substituted phenyl selected from rophenyl; Or heteroaryl or substituted heteroaryl selected from 2-thienyl, 5-chloro-2-thienyl, 5-chloro- and 1,3-dimethyl-1H-pyrazol-4-yl; R ² is selected from hydrogen. A compound according to claim 5 or 6, wherein [R ³ is a group selected from:

R ⁴ are each independently selected from: (a) hydrogen, or (b) methyl, R ¹¹ are each independently selected from: (a) hydrogen, or (b) methyl; R ²⁵ are each independently selected from: (a) hydrogen, or (b) methyl]. The compound of claim 5, wherein R ⁴ is selected from: (a) hydrogen, (b) methyl, or (c) ethyl. The compound of claim 5, wherein R ⁴ or R ¹¹ is selected from hydrogen. The compound according to any one of claims 1 to 3, having the formula (XIII).

(XIII) The compound of claim 10, wherein: [P is selected from substituents of the formulas (II) to (IV):

; x is 2 and y is 0; R ¹ is selected from aryl and heteroaryl, wherein any heteroaryl or aryl moiety is independently selected at one or more positions from halogen, C _1-4 -alkyl, trifluoromethoxy, and C _1-4 -alkoxy Optionally substituted with a substituent; R ² is selected from hydrogen; W ₁ and W ₂ are hydrogen; R ³ is a group selected from:

here, R ⁴ are each independently selected from: (a) hydrogen, or (b) C _1-4 -alkyl; R ²⁵ are each independently selected from: (a) hydrogen, or (b) C _1-4 - alkyl (where both R ²⁵ is C _1-4 - When referring to an alkyl, wherein the C _1-4 - can be bonded to the alkyl are the same or different carbon atoms); R ¹² and R ¹³ are each independently selected from aryl and heteroaryl, wherein any heteroaryl or aryl moiety is independently at one or more positions halogen, C _1-4 -alkyl, trifluoromethyl, and C _1- Optionally substituted with a substituent selected from ₄ -alkoxy]. The compound of claim 11, wherein [P is selected from substituents of the formula (II):

R ¹ is selected from 2-methoxy-5-methylphenyl; R ² is selected from hydrogen; W ₁ and W ₂ are hydrogen; R ³ is a group selected from:

; R ⁴ are each independently selected from: a) hydrogen, or b) methyl; R ²⁵ are each independently selected from: a) hydrogen, or b) methyl]. The compound according to any one of claims 1 to 12, selected from: N- (7- {methyl [3- (methylamino) propyl] amino} -1-benzofuran-5-yl) benzenesulfonamide hydrochloride, N- (7-piperidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide, 4-fluoro-N- (7-piperidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide, 3,4-dimethoxy-N- (7-piperidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride, 3,4-dimethoxy-N- (7-pyrrolidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide, N- (7-pyrrolidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide, 4-fluoro-N- (7-pyrrolidin-1-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride, 4-fluoro-N- (7-morpholin-4-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride, N- (7-morpholin-4-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride, 3,4-dimethoxy-N- (7-morpholin-4-yl-1-benzofuran-5-yl) benzenesulfonamide, 2-methoxy-5-methyl- N- (7-pyridin-4-yl-1-benzofuran-5-yl) benzenesulfonamide, N- (7-pyridin-3-yl-1-benzofuran-5-yl) benzenesulfonamide trifluoroacetate, 2-methoxy-5-methyl- N- (7-pyridin-3-yl-1-benzofuran-5-yl) benzenesulfonamide trifluoroacetate, N- (7-pyrazin-2-yl-1-benzofuran-5-yl) benzenesulfonamide trifluoroacetate, N- (7-pyrimidin-5-yl-1-benzofuran-5-yl) benzenesulfonamide hydrochloride, and N- [7- (1-Aza-bicyclo [2.2.2] oct-2-en-3-yl) -benzofuran-5-yl] -2-methoxy-5-methyl-benzenesulfonamide hydrochloride , 2- [4- (5-{[(2-chlorophenyl) sulfonyl] amino} -1-benzofuran-7-yl) piperazin-1-yl] -N, N-diethylacetamide hydrochloride,   N, N-diethyl-2- [4- (5-{[(2-methoxy-5-methylphenyl) sulfonyl] amino} -1-benzofuran-7-yl) piperazin-1-yl] acet Amide hydrochloride, N- [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, N- {7-[(2-morpholin-4-ylethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride, 2-methoxy-5-methyl-N- {7-[(2-morpholin-4-ylethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride, N- {7-[(2-morpholin-4-ylethyl) amino] -1-benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide hydrochloride, 2,6-dichloro-N- {7-[(2-morpholin-4-ylethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride, N- (7-{[2 (dimethylamino) ethyl] amino} -1-benzofuran-5-yl) -2-methoxy-5-benzenesulfonamide hydrochloride, 2-chloro-N (7-{[2- (dimethylamino)}-1-benzofuran-5-yl) benzenesulfonamide hydrochloride, N- [7- (pyridin-4-ylamino) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride, 2-chloro-N- [7- (pyridin-4-ylamino) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride, 2-methoxy-5-methyl-N- [7- (pyridin-4-ylamino) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride, 2-methoxy-5-methyl-N- [7- (piperazin-1-ylcarbonyl) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride, 2-methoxy-5-methyl-N- [7- (piperazin-1-ylmethyl) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride, N- {7-[(3-aminopyrrolidin-1-yl) methyl] -1-benzofuran-5-yl} -2-methoxy-5-methylbenzenesulfonamide hydrochloride, N- [7 (6,6-dioxidohexahydrothieno [3,4-b] pyrazin-1 (2H) -yl) -1-benzofuran-5-yl] -2-methoxy-5- Methylbenzenesulfonamide hydrochloride, N- [7 (6,6-dioxidohexahydrothieno [3,4-b] pyrazin-1 (2H) -yl) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride, N- {7-[(2-pyrrolidin-1-ylethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride, 2-methoxy-5-methyl-N- {7-[(2-pyrrolidin-1-ylethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride, N- {7-[(2-pyrrolidin-1-ylethyl) amino] -1-benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide hydrochloride, 3-chloro-4-methyl-N- {7-[(2-pyrrolidin-1-ylethyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride, 2-methoxy-5-methyl-N- {7-[(3-morpholin-4-ylpropyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride, N- {7-[(3-morpholin-4-ylpropyl) amino] -1-benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide hydrochloride, 3-chloro-4-methyl-N- {7-[(3-morpholin-4-ylpropyl) amino] -1-benzofuran-5-yl} benzenesulfonamide hydrochloride, N- [7-({[(2R) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] benzenesulfonamide hydrochloride, N- [7-({[(2R) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -2-methoxy-5-methylbenzenesulfonamide hydro Chloride, N- [7-({[(2R) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -2- (trifluoromethyl) benzenesulfonamide hydro Chloride, N- [7-({[(2R) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -3-methylbenzenesulfonamide hydrochloride, N- [7-({[(2R) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] thiophene-2-sulfonamide hydrochloride, 5-chloro-N- [7-({[(2R) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] thiophene-2-sulfonamide hydrochloride , 5-chloro-N- [7-({[(2R) -1-ethylpyrrolidin-2-yl] methyl} amino) -1-benzofuran-5-yl] -1,3-dimethyl-1H- Pyrazole-4-sulfonamide hydrochloride, N- (7-{[3- (2-methylpiperidin-1-yl) propyl] amino} -1-benzofuran-5-yl) benzenesulfonamide hydrochloride, 2-methoxy-5-methyl-N- (7-{[3- (2-methylpiperidin-1-yl) propyl] amino} -1-benzofuran-5-yl) benzenesulfonamide hydrochloride, N- (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) -1H-pyrazole -4-sulfonamide hydrochloride, N- [7- (6-aminopyridin-3-yl) -1-benzofuran-5-yl] -2-methoxy-5-methylbenzenesulfonamide, N- {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 hydro Chloride, 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, 3,6-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-dimethyl-piperazin-1-yl) methyl] -N- (2- methylphenyl) -1-benzofuran-5-sulfonamido-de, trifluoroacetate, N- (2-methylphenyl) -7-[(3-methylpiperazin-1-yl) methyl] -1-benzofuran-5-sulfonamide, trifluoroacetate, 7- (1,4-diazepane-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-{[(2R) -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-diazepane-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-[(1 S , 4 S ) -2,5-diazabicyclo [2.2.1] hept-2-ylmethyl] -N- (2-methoxy-5-methylphenyl) -1-benzofuran-5 Sulfonamides, trifluoroacetates, N- (2-methoxy-5-methylphenyl) -7-[(2-methylpiperazin-1-yl) methyl] -1-benzofuran-5-sulfonamide, trifluoroacetate, 2-chloro-N- [7- (piperazin-1-ylmethyl) -1-benzofuran-5-yl] benzenesulfonamide dihydrochloride, 2-methyl-N- [7- (piperazin-1-ylmethyl) -1-benzofuran-5-yl] benzenesulfonamide, dihydrochloride, N- [7- (piperazin-1-ylmethyl) -1-benzofuran-5-yl] thiophen-2-sulfonamide, dihydrochloride, 2-chloro-N- [7- (1,4-diazepane-1-ylmethyl) -1-benzofuran-5-yl] benzenesulfonamide dihydrochloride, N- [7- (1,4-diazepane-1-ylmethyl) -1-benzofuran-5-yl] -2-methylbenzenesulfonamide, dihydrochloride, N- [7- (1,4-diazepane-1-ylmethyl) -1-benzofuran-5-yl] thiophen-2-sulfonamide dihydrochloride, 2-methoxy-5-methyl-N- {7-[(2-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide, dihydrochloride, 2-methyl-N- {7-[(2-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide dihydrochloride, 2,5-dichloro-N- {7-[(2-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} thiophene-3-sulfonamide dihydrochloride, 2-methoxy-5-methyl-N- {7-[(3-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide, dihydrochloride, N- {7-[(3-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} -2- (trifluoromethyl) benzenesulfonamide, dihydrochloride, 2-chloro-N- {7-[(3-methylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide, dihydrochloride, N - {7 - [(1 S, 4 S) -2,5- diazabicyclo [2.2.1] hept-2-ylmethyl] -1-benzofuran-5-yl} -2-methoxy -5 Methylbenzenesulfonamide, dihydrochloride, N - {7 - [(1 S, 4 S) -2,5- diazabicyclo [2.2.1] hept-2-ylmethyl] -1-benzofuran-5-yl} -2- (trifluoromethyl Methyl) benzenesulfonamide, dihydrochloride, N - {7 - [(1 S, 4 S) -2,5- diazabicyclo [2.2.1] hept-2-ylmethyl] -1-benzofuran-5-yl} -2-methyl-benzenesulfonamide , Dihydrochloride, 2-methoxy-5-methyl-N- {7-[(trans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide, bistrifluoro acetate, 2-methyl-N- {7-[(trans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} benzenesulfonamide, bistrifluoroacetate, 2-chloro-N- {7-[(trans-2,5-dimethylpiperazin-1-yl) methyl] -1-benzofuran-5-yl} 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-diazepane, trifluoroacetate, 1-{[5- (phenylsulfonyl) -1-benzofuran-7-yl] methyl} -1,4-diazepane, trifluoroacetate, 1-({5-[(4-methylphenyl) sulfonyl] -1-benzofuran-7-yl} methyl) -1,4-diazepane, trifluoroacetate, 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-{[(3R) -pyrrolidin-3-ylamino] methyl} -1-benzofuran-5-sulfonamide, 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-7-yl] benzenesulfonamide, trifluoroacetate, 2-methoxy-5-methyl-N- {5-[(3-methylpiperazin-1-yl) methyl] -1-benzofuran-7-yl} benzenesulfonamide, bis (trifluoroacetate, 2-methoxy-5-methyl-N- [5- (piperidin-4-ylmethyl) -1-benzofuran-7-yl] benzenesulfonamide, trifluoroacetate. 14. A compound according to any one of claims 1 to 13 for use in therapy. 14. A compound according to any one of claims 1 to 13 for use in the treatment or prevention of 5-HT ₆ receptor-related disorders in order to achieve a reduction in body weight and weight gain. 16. The method of claim 15, wherein the disorder is obesity; Type 2 diabetes; Anxiety, depression, panic attacks, memory disorders, cognitive disorders, epilepsy, sleep disorders, migraine, anorexia, bulimia, binge eating disorder, obsessive compulsive disorder, psychosis, Alzheimer's disease, Parkinson's disease, Huntington's chorea, mental Compounds selected from central nervous system disorders such as schizophrenia, attention deficit hyperactivity disorder (ADHD), withdrawal from drug abuse, neurodegenerative diseases characterized by neuronal cell failure, and pain. A pharmaceutical formulation containing a compound according to any one of claims 1 to 13 as an active ingredient, together with a pharmaceutically acceptable diluent or carrier. 18. The pharmaceutical formulation of claim 17 for use in the prevention or treatment of 5-HT ₆ receptor-related disorders to achieve a reduction in body weight and weight gain. 19. The method of claim 17 or 18, wherein the disorder is obesity; Type 2 diabetes; Anxiety, depression, panic attacks, memory disorders, cognitive impairment, epilepsy, sleep disorders, migraine, anorexia, bullia, binge eating disorder, obsessive compulsive disorder, psychosis, Alzheimer's disease, Parkinson's disease, Huntington's chorea, schizophrenia, attention deficit hyperactivity Pharmaceutical formulations selected from disorders, neurodegenerative diseases characterized by withdrawal from drug abuse, neurodegenerative diseases characterized by neuronal growth insufficiency, and pain. In the prevention or treatment of a 5-HT ₆ receptor-related disorder, a decrease in body weight and weight gain, comprising administering an effective amount of a compound according to any one of claims 1 to 13 to a subject in need of such treatment How to achieve it. 21. The method of claim 20, wherein the disorder is obesity; Type 2 diabetes; Anxiety, depression, panic attacks, memory disorders, cognitive impairment, epilepsy, sleep disorders, migraine, anorexia, bullia, binge eating disorder, obsessive compulsive disorder, psychosis, Alzheimer's disease, Parkinson's disease, Huntington's chorea, schizophrenia, hyperactivity deficit A central nervous system disorder such as behavioral disorders, withdrawal from drug abuse, neurodegenerative disorders characterized by neuronal growth insufficiency, and pain. A method comprising administering an effective amount of a compound according to any one of claims 1 to 13 to a subject in need of such treatment for modulating 5-HT ₆ receptor activity. Use of a compound according to any one of claims 1 to 13 for the manufacture of a medicament for use in the prevention or treatment of 5-HT ₆ receptor-related disorders for achieving a reduction in body weight and weight gain. The method of claim 21, wherein the disorder is obesity; Type 2 diabetes; Anxiety, depression, panic attacks, memory disorders, cognitive impairment, epilepsy, sleep disorders, migraine, anorexia, bullia, binge eating disorder, obsessive compulsive disorder, psychosis, Alzheimer's disease, Parkinson's disease, Huntington's chorea, schizophrenia, attention deficit hyperactivity Uses are selected from central nervous system disorders such as disorders, withdrawal from drug abuse, neurodegenerative diseases characterized by neuronal growth insufficiency, and pain. Cosmetic composition containing a compound according to any one of claims 1 to 13 as an active ingredient, together with a cosmetically acceptable diluent or carrier. The cosmetic composition of claim 25 for use in the treatment or prevention of 5-HT ₆ receptor-related disorders for achieving a reduction in weight and weight gain. 27. The method of claim 26, wherein the disorder is obesity; Type 2 diabetes; Anxiety, depression, panic attacks, memory disorders, cognitive impairment, epilepsy, sleep disorders, migraine, anorexia, bullia, binge eating disorder, obsessive compulsive disorder, psychosis, Alzheimer's disease, Parkinson's disease, Huntington's chorea, schizophrenia, attention deficit hyperactivity Cosmetic compositions selected from disorders of the central nervous system, such as disorders, withdrawal from drug abuse, neurodegenerative diseases characterized by neuronal cell failure.