EA011581B1 - Heterocyclic compounds useful for the treatment of obesity and cns disorders - Google Patents

Abstract

The present invention relates to compounds of the general formula (I),wherein D is a five-membered heterocyclic or heteroaryl ring, P is sulfone or sulfonamide; and A, B, W, X, Y and Rare as defined in the description; to pharmaceutical compositions comprising these compounds, and to the use of the compounds for the prophylaxis and treatment of medical conditions relating to obesity, type II diabetes, and/or CNS disorders.

Description

This invention relates to substituted sulfonic and sulfonamide derivatives, to pharmaceutical compositions comprising these compounds, and to the use of these compounds for the prevention and treatment of medical conditions associated with obesity, type 2 diabetes mellitus and / or central nervous system (CNS) disorders, for achieve weight loss and increase body weight, as well as for cosmetic use.

BACKGROUND OF THE INVENTION

Obesity is a condition that is characterized by an increase in fat in the body, which leads to excess body weight compared to generally accepted standards. In the West, obesity is the most important digestive disorder, and it is a serious public health problem in all industrialized countries. This disorder leads to increased mortality due to an increase in cases of diseases such as cardiovascular disease, digestive pathology, respiratory disease, cancer and type 2 diabetes. The search for compounds that reduce body weight has been carried out for many decades. One of the directions of the search was the activation of serotonergic systems either by targeted activation of serotonin receptor subtypes, or by inhibition of reuptake of serotonin. However, the exact exact profile of receptor subtypes is not known.

Serotonin (5-hydroxytryptamine or 5-HT), a key transmitter of the peripheral and central nervous system, modulates a wide range of physiological and pathological functions, including anxiety, sleep regulation, aggression, food intake and depression. Many subtypes of serotonin receptors have been identified and cloned. One of them, the 5-HT ₆ receptor, was cloned by several groups in 1993 (Kia1, M. e1 a1. (1993) Vusyet. Vyuruk. Kek. Sottip. 193: 268-276; 8ebb, M. e1 a1. ( 1994) HeigoKerop 5: 2553-2557). This receptor is positively associated with adenylyl cyclase and exhibits an affinity for antidepressants such as clozapine. Earlier in the literature, the effects of a 5-HT6 antagonist and 5-HT6 antisensory oligonucleotides on the reduction of food intake by rats were described (Wepbeu, 1.C. e1 a1. (1999) Vg. 1. Ryagtas. 8irr. 126, P66; Wepbeu, EC. e1 a1. (1997) 1. P8usborbagtaso1. 8irr1. A64, 255; Uoo11eu M.E. e1 a1. (2001) No. igorbagtasoodu).

Compounds with increased affinity and selectivity for the 5-HT ₆ receptor were identified, for example, in XVO 00/34242 and in the publication 1kaas, M. e1 a1. (2000) 6-V1sus1or1regah1pu1-1aguki1Gopubpb1e8 apb 6-V1sus1or1repbshu1-1-agu18i1Gopu1tbo1e8 bepuabuyke ak poue1, p1eS apb ke1esbue 5NT ₆ geser1og ap1ad. Vyuudashs & Meb1ssa1 Szet181gu Lebeg 10: 1719-1721 (2000).

Description of the Related Art

In the publication EMeb.Sbet. 1970, 13 (4), 592-598 describe P- (4 {[2- (diethylamino) ethyl] amino} -1naphthyl) amides; M- {5,6,7,8-tetrahydro-4 - [(3-piperidinopropyl) amino] -1-naphthyl} amides and derivatives of structurally similar amides and ureas as schistosomicides.

Νθ 99/42465 describes sulfonamide derivatives that bind to the 5-HT ₆ receptor and can be used to treat CNS disorders such as anxiety, depression, epilepsy, obsessive-compulsive disorders, cognitive disorders, AENE, anorexia and bulimia, schizophrenia drug abuse.

Νθ 01/32646 A1 describes compounds that bind to the 5-HT ₆ receptor and are used to treat CNS disorders, and also, along with other uses, can be used to treat appetite disorders.

Νθ 99/37623 A2 describes compounds that bind to the 5-HT ₆ receptor and are used to treat CNS disorders, and also, along with other uses, can be used to treat appetite disorders.

Νθ 99/42465 A3 describes compounds that bind to the 5-HT ₆ receptor and are used to treat CNS disorders, and also, along with other uses, can be used to treat appetite disorders.

EP 0815861 A1 describes compounds that bind to the 5-HT ₆ receptor and are used to treat CNS disorders.

Νθ 99/02502 A2 describes compounds that bind to the 5-HT ₆ receptor and are used to treat CNS disorders, and also, along with other uses, can be used to treat appetite disorders.

Νθ 98/27 081 A1 describes compounds that bind to the 5-HT ₆ receptor and are used to treat CNS disorders, and, along with other uses, can be used to treat

- 1 011581 appetite disorders.

EP 0701819 discloses compounds that bind to 5-HT receptor and _u are used for the treatment of CNS disorders and obesity.

In US patent No. 6191141 and \ UO 01/12629 described compounds that bind to the 5-HT ₆ receptor and are used to treat disorders of the central nervous system.

Description of the invention

It has been unexpectedly found that the compounds of formula (I) show affinity for the 5-HT ₆ receptor as antagonists in the range of low nanomole values. The compounds of this invention and their pharmaceutically acceptable salts possess antagonist, agonist, and partial agonist activity on 5-HT ₆ receptors and are believed to be useful in the treatment or prevention of obesity and type 2 diabetes, to achieve weight loss and weight gain body, as well as for the treatment or prevention of disorders of the central nervous system, such as anxiety, depression, panic attacks, memory disorders, cognitive disorders, sleep disorders, migraine, anorexia, bulimia, disorders related to alcoholism and smoking, obsessive-compulsive disorders, psychosis, Alzheimer's disease, Parkinson's disease, Huntington's disease and / or schizophrenia, attention deficit (aye medicines. Weight loss and weight gain (for example, treatment of disorders associated with abnormal body weight) is achieved, along with other means, reducing food intake. As used herein, the term “abnormal body mass disorders” refers to disorders caused by an imbalance between energy absorption and energy expenditure, resulting in abnormal (eg, excess) body mass. Such weight loss disorders include obesity.

Definitions

Unless otherwise stated or indicated, the term “C ₁ . ₆ alkyl "(or" C _2-6 alkenyl ") refers to a straight or branched chain hydrocarbon group containing from 1 to 6 carbon atoms (or from 2 to 6 carbon atoms). Examples of said lower alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, as well as straight and branched chain pentyl and hexyl. Alkenyl groups contain in the chain one or more double carbon-carbon bonds.

Unless otherwise stated or indicated, the term “ _C1-6 alkoxy” refers to a straight or branched chain alkoxy group containing from 1 to 6 carbon atoms. Examples of said lower alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, as well as straight and branched chain pentoxy and hexoxy.

Unless otherwise stated or indicated, the term “ _C1-6 alkoxyalkyl” refers to a straight or branched chain alkoxyalkyl group containing from 1 to 6 carbon atoms. Examples of said lower alkoxyalkyl group include methoxymethyl, ethoxymethyl, isopropoxymethyl, n-butoxymethyl, tert-butoxyethyl, as well as straight and branched chain pentoxymethyl.

The term “C _2-6 alkenyl” as used herein refers to straight or branched chain alkenyl groups containing from 2 to 6 carbon atoms. Typical examples of such groups include vinyl, allyl, 2,3-dimethylallyl, 1-butenyl, 1-pentenyl and 1-hexenyl groups.

The term “C _2-6 alkynyl” as used herein refers to straight and branched chain alkynyl groups containing from 2 to 6 carbon atoms. Typical examples of such groups include ethynyl, 1-propynyl, 1-butynyl, 1-pentinyl and 1-hexynyl groups.

Unless otherwise stated or indicated, the term “halogen” will mean fluoro, chloro, bromo or iodo.

The term “alkyl halide” refers to an alkyl group substituted with one or more halogen groups (eg, E, C1, Br, I).

The term “C _3-7 cycloalkyl” refers to a cyclic alkyl group containing a C ₃ to C ₇ ring, which may be saturated or partially unsaturated. Examples of said cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, methylcyclohexyl, cyclohexenyl, cyclohexadienyl and cycloheptyl.

The term “C _{5-1 0} cycloalkenyl” refers to a cyclic alkenyl group containing a ring of C ₅ to C ₁₀ . Examples of said cycloalkenyl include 1-cyclopentyl, 2-cyclopentenyl, 1-cyclohexenyl, 1-cycloheptenyl, 1-cyclooctenyl, 1-cyclononenyl and 1-cyclodecenyl.

The term “heterocycle” refers to a hydrocarbon ring system containing from 4 to 8 ring atoms, of which at least one may be a heteroatom (eg, 8, N or O) as part of a ring. The term includes saturated, unsaturated, aromatic and non-aromatic heterocycles. Suitable heterocyclic groups include thienyl, furyl, pyridyl, pyrrolidinyl, imidazolyl, pyrazolyl, piperidyl, azepinyl, morpholinyl, pyranyl, dioxanyl, pyridazinyl, pyrimidinyl and piperazinyl.

Unless otherwise stated or indicated, the term “aryl” refers to hydrocarbon

- 2 011581 a ring system containing at least one aromatic ring. Examples of aryl groups include phenyl, cinnamyl, pentalenyl, indenyl, 1-naphthyl, 2-naphthyl, antryl and phenanthryl.

The term “heteroaryl” refers to a hydrocarbon ring system containing at least one aromatic ring that contains at least one heteroatom, such as O, N, or 8. Examples of heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl and indolyl.

The compounds of formula (I)

or a pharmaceutically acceptable salt thereof, wherein the Ό ring is a five-membered heterocyclic or heteroaryl ring, said ring comprising one or two atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms, provided that when Ό contains an oxygen atom, Ό represents heteroaryl;

each independently represents —Ν—, - (CH) - or —C—, provided that at least one group is —Ν—;

P represents a group of formula (a), (b) or (c)

, or>

(a) (b) (c) where x = 0, 1 or 2, and y = 0;

and P and K ³ can be attached to any carbon atom that is substitutable, or when P is (c), then P can also be attached to any nitrogen atom in ring Ό that is substitutable;

K ¹ is (e) arylcarbonylmethyl, (e) C _3-7 cycloalkyl-C _1-6 alkyl, wherein the cyclic ring is optionally partially unsaturated, or (i) an Ar group;

where Ar is (a) phenyl, (b) 1-naphthyl, (c) 2-naphthyl, (b) aryl-C _1-6 alkyl, (e) cinnamyl, (1) 5-7 membered, optionally aromatic a partially saturated or fully saturated mono- or bicyclic heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms, (e) a bicyclic ring system comprising at least one heterocyclic ring, as defined in paragraph (1) and the group Ag, where the group Ag is substituted in one or more positions by groups (a) H, X or Υ or (b A 5-7 membered, optionally aromatic, partially saturated or fully saturated heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur atoms;

K ² represents (a) H or (b) C _1-6 alkyl, or K ¹ and K ^{2 are} connected to form —CH ₂ CH ₂ OCH ₂ CH ₂ - or

where ν is 0-2,

X and Υ independently represent (a) H, (b) halogen,

- 3 011581 (s) C _1-6 alkyl, (ά) CEs, (1) C _1-6 alkoxy, (ί) phenoxy, (t) -CU, (o) straight or branched C _1-6 alkyl halides, ( g) -YK ⁴ TO ⁵

K ⁴ and K ⁵ independently represent (b) C _1-6 alkyl;

K ³ is a group selected from any of the following groups:

where K ³ is optionally substituted on each carbon atom, which allows the substitution of K ,, groups, where Kd independently represents H or (C _1-2 ) alkyl, and where two Kd groups can be on the same carbon atom at the same time, where

s. | = 1 or 2, t = 1 or 2 and

K ⁶ independently represents (a) H, (b) linear or branched C _1-6 alkyl.

The pyrrole ring, when attached to ring A, has the following numbering of positions:

where P ₁ -P ₃ show the position on the pyrrole ring.

Preferably when

K ¹ represents an Ar group;

Ar is (a) phenyl, (b) 1-naphthyl, (c) 2-naphthyl or (1) 5-7 membered optionally aromatic partially saturated or fully saturated heterocyclic ring containing from 1 to 4 heteroatoms selected from atoms oxygen, nitrogen and sulfur, where the Ar group is substituted in one or more positions by the groups (a) H, (b) halogen, (c) C _1-6 alkyl, (ά) -Сез, (1) C _1-6 alkoxy , (p) phenyloxy,

K ² represents (a) H or (b) C _1-6 alkyl;

X and Υ are H;

K ^{3 is} selected from any of the following groups:

where K ³ may be substituted on each carbon atom, which allows substitution of K _d groups, where Kd independently represents H or C _1-6 alkyl, and where two groups of Kd can be on the same carbon atom at the same time, where

s. | = 1 or 2, t = 1 or 2, and

- 4 011581

I ⁶ independently represents (a) H, (b) C _1-6 alkyl (preferably C _1-3 alkyl), in particular methyl.

Preferably, I ⁶ is H or methyl. Preferably, Ό is pyrrolyl, thienyl or furanyl.

Preferably, P is

where I ¹ , x and y have the meanings defined for formula I. Preferably also, P represents

where I ¹ and I ² have the meanings defined for formula I. Preferably, I ² represents N.

Another object of this invention is a compound of General formula (IV)

where P represents a group of formula (c), I ¹ , x, y, X and Υ have the meanings defined in claim 1, and I ³ has the meanings defined in clause 2, and where Ό represents a five-membered heteroaryl ring, wherein said ring includes one or two atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms; and when the heteroaryl ring includes one or two nitrogen atoms, the H ⁶ group is attached to any nitrogen atom that allows substitution.

Preferably, Ό represents thiophene, and P is attached to the ring Ό, forming any of the following structures:

Preferably, Ό is pyrrole, and P is attached to the nitrogen atom in the ring Ό, forming any of the following structures:

Preferably also, Ό is furan, and P is attached to the ring Ό, forming any of the following structures:

Another object of the present invention is a compound of General formula (VI)

where P represents a group of formula (a) or (b), the values of which are defined in claim 1, preferably, where I ² represents H, I ³ , X and Υ have the meanings defined for formula I.

Another object of this invention is a compound of General formula (VII)

X (UP) where P is a group of formula (a) or (b), the values of which are defined for formula (I), preferably, where I ² represents H, I ³ , X and Υ have the meanings defined for formula I.

Another object of this invention is a compound of General formula (VIII)

x (CS) where P represents a group of formula (a) or (b), the meanings of which are defined in claim 1, preferably where I ² represents H, I ³ , X and Υ have the meanings defined for formula I. Another object of the present invention is a compound of General formula (IX)

where I ⁷ in the formula (IX) represents:

(a) H, (b) C _1-6 alkyl, (c) benzyl, (ά) -CH ₂ -CH ₂ -OH or (e) -CH2-CH2-O-CH3 and where P represents a group of the formula ( a) or (b), the values of which are defined for formula I, preferably, where I ² represents H, X, Υ and I ³ have the meanings defined I ³ , X and Υ have the meanings defined for formula I.

Another object of this invention is a compound of General formula (X)

where P represents a group of formula (a) or (b), the values of which I ³ , X and Υ have the meanings defined for formula I, preferably, where I ² represents H, X, Υ and I ³ have the meanings, I ³ , X and Υ have the meanings defined for formula I.

Preferred compounds of formula (IV) are 4- (1,4-diazepan-1-yl) -2- (phenylsulfonyl) thieno [3,2-c] pyridine hydrochloride;

4- (1,4-diazepan-1-yl) -2 - [(3,4-dichlorophenyl) sulfonyl] thieno [3,2-c] pyridine hydrochloride;

4- (1,4-diazepan-1-yl) -2- (4-tert-butylphenylsulfonyl) thieno [3,2-c] pyridine hydrochloride; 4- (1,4-diazepan-1-yl) -2- (4-tert-butylphenylsulfonyl) thieno [3,2-c] pyridine hydrochloride; 4- (1,4-diazepan-1-yl) -2- (3,4-dimethylphenylsulfonyl) thieno [3,2-c] pyridine hydrochloride; 2 - [(4-bromophenyl) sulfonyl] -4- (1,4-diazepan-1-yl) thieno [3,2-c] pyridine hydrochloride; 2- (phenylsulfonyl) -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride;

2- (3-methoxybenzenesulfonyl) -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride;

2- (4-methoxybenzenesulfonyl) -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride;

4-piperazin-1-yl-2 hydrochloride - {[4- (trifluoromethyl) phenyl] sulfonyl} thieno [3,2-c] pyridine; 2 - [(2-tert-butylphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride; 2 - [(3,4-dichlorophenyl) sulfonyl] -4-piperazin-1 -ylthieno [3,2-c] pyridin-2-sulfonamide hydrochloride; 2 - [(4-tert-butylphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride;

2- (1-naphthylsulfonyl) -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride;

2 - [(3-fluorophenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonamide hydrochloride; 2- (mesitylsulfonyl) -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride;

2 - [(2-methoxyphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride;

2 - [(2,4-Dimethoxyphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride;

2 - [(2,4-Dimethylphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride;

2 - [(2,5-dimethylphenyl) sulfonyl] -4-piperazin-1 -ylthieno [3,2-c] pyridine hydrochloride; 2 - [(2-ethylphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride;

4- (piperazinyl) -2- (3-methoxybenzylsulfonyl) thienopyridine hydrochloride;

2- (benzylsulfonyl) -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride;

4-piperazin-1-yl-2 hydrochloride - {[4- (trifluoromethyl) benzyl] sulfonyl} thieno [3,2-c] pyridine; 2 - [(3-bromobenzyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride;

2 - [(2,3-difluorobenzyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride; 2 - [(4-bromobenzyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride;

2 - {[2,5-bis (trifluoromethyl) benzyl] sulfonyl} -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride; 2 - [(4-methylbenzyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride;

2 - {[5-chloro-2- (trifluoromethyl) benzyl] sulfonyl} -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride; 2 - [(3,5-dimethoxybenzyl) sulfonyl] -4-piperazin-1 -ylthieno [3,2-c] pyridine hydrochloride; 2 - [(2-naphthylmethyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride;

4-piperazin-1-yl-2- {[4- (1,2,3-thiadiazol-4-yl) benzyl] sulfonyl} thieno [3,2-c] pyridine hydrochloride; 1 - (4-pyrrolidin-1-yl-phenyl) -2 - [(4-piperazin-1-ylthieno [3,2-c] pyridin-2-yl) sulfonyl] ethanone hydrochloride; and 1 - [4- (diethylamino) phenyl] -2 - [(4-piperazin-1-ylthieno [3,2-c] pyridin-2-yl) sulfonyl] ethanone hydrochloride.

Preferred compounds of formula (IV) are

- 6 011581 1- (4-methylphenylsulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; 1- (3-Chloro-2-methylphenylsulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; l- (3,4-dimethoxyphenylsulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; 4- (4-piperazin-1-yl-pyrrolo [3,2-c] pyridin-1-sulfonyl) benzonitrile hydrochloride;

l- (4,5-Dichlorothiophen-2-sulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; 1- (2-chloro-4-fluorophenylsulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; 1-phenylmethanesulfonyl-4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride;

1- (5-chlorothiophen-2-sulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; l- (4-Butylbenzenesulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride;

1- (4-Phenoxybenzenesulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride;

1- (phenylsulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride;

1 - [(4-chlorophenyl) sulfonyl] -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; 1 - [(4-methoxyphenyl) sulfonyl] -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; 1 - [(2-methoxy-5-methylphenyl) sulfonyl] -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; and 4-piperazin-1-yl-1 hydrochloride - {[2- (trifluoromethyl) phenyl] sulfonyl} -1H-pyrrolo [3,2-c] pyridine. Preferred compounds of formula (VI) are Y- (4-methylphenyl) -4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridin-2-sulfonamide hydrochloride;

p-tolylamide hydrochloride 2-bromo-4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridin-3-sulfonic acid;

4- (4-methylpiperazin-1-yl) -n-phenylthieno [3,2-c] pyridin-2-sulfonamide hydrochloride;

4-piperazin-1-ylthieno [3,2-c] pyridin-2sulfonic acid hydrochloride of (3-fluoro-5-trifluoromethylphenyl) amide;

4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid hydrochloride of (4-chlorophenyl) amide;

4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid hydrochloride of (4-isopropylphenyl) amide;

4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid p-tolylamide hydrochloride;

4- (4-methylpiperazin-1-yl) -Y- (2-cyclohex-1-en-1-ethyl) thieno [3,2-c] pyridin-2-sulfonamide hydrochloride;

2- (4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridin-2-ylsulfonyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride;

4- (4-methylpiperazin-1-yl) -Y- (2-thien-2-yl-ethyl) thieno [3,2-c] pyridin-2-sulfonamide hydrochloride;

4- (4-methylpiperazin-1-yl) -Y- [1 - (1-naphthyl) ethyl] thieno [3,2-c] pyridin-2-sulfone amide hydrochloride;

4- (4-methylpiperazin-1-yl) -Y- (4-hexylphenyl) thieno [3,2-c] pyridin-2-sulfonamide hydrochloride;

N- (3-chlorobenzyl) -4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridin-2-sulfonamide;

4- (4-methylpiperazin-1-yl) -L- [1- (4-fluorophenyl) ethyl] thieno [3,2-c] pyridin-2-sulfone- hydrochloride

amide; hydrochloride N- (2,3-difluorobenzyl) -4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridin-2-sulfone-

amide;

4- (4-methylpiperazin-1-yl) -L- (4-chloro-2,5-dimethoxyphenyl) thieno [3,2-c] pyridin-2sulfonamide hydrochloride;

2-bromo-4- (4-methylpiperazin-1-yl) -L- (2-cyclohex-1-en-1-ethyl-ethyl) thieno [3,2-c] pyridin-3-sulfonamide hydrochloride;

2-bromo-4- (4-methylpiperazin-1-yl) -L - [(1§) -1 - (2-naphthyl) ethyl] thieno [3,2-c] pyridin-3sulfonamide hydrochloride;

2-bromo-4- (4-methylpiperazin-1-yl) -L- [1- (4-fluorophenyl) ethyl] thieno [3,2-c] pyridin-3sulfonamide hydrochloride;

2-bromo-4- (4-methylpiperazin-1-yl) -L- (2,4,5-trimethoxyphenyl) thieno [3,2-c] pyridin-3-sulfonamide; hydrochloride No. (3,4-dichlorophenyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonamide; No. (2,4-difluorophenyl) -4-piperazin-1-thieno [3,2-c] pyridin-2-sulfonamide hydrochloride; 4-piperazin-1-yl-L- [3- (trifluoromethyl) phenyl] thieno [3,2-c] pyridin-2-sulfonamide hydrochloride; N- (3-ethylphenyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonamide hydrochloride; No. (3,4-dimethoxyphenyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonamide hydrochloride; No. (4-bromo-2-methylphenyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonamide hydrochloride; 2- (4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride;

4-piperazin-1-ylthieno [3,2-s] pyridin-2-sulfonic acid hydrochloride of (2-thiophen-2-yl-ethyl) amide;

4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid amide hydrochloride of (4-chloro-2,5-dimethoxyphenyl) amide;

4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid phenethylamide hydrochloride;

4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid hydrochloride (2,6-diethylphenyl) amide

- 7 011581 you;

(3-Phenylpropyl) amide hydrochloride of 4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid; 4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid amide hydrochloride (3,3-diphenylpropyl) amide;

[2- (5-Methoxy-1H-indol-3-yl) ethyl] amide of 4-piperazin-1-ylthieno [3,2-c] pyridin-2sulfonic acid hydrochloride;

4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid 4-trifluoromethylbenzylamide hydrochloride;

4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid benzyl ethylamide hydrochloride; Y- (3-ethylphenyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-3-sulfonamide hydrochloride; Y- (4-isopropylphenyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-3-sulfonamide hydrochloride; Y- (4-methylphenyl) -4- (pyrrolidin-3-yloxy) thieno [3,2-c] pyridin-2-sulfonamide hydrochloride; Y- (4-methylphenyl) -4- (piperidin-4-yloxy) thieno [3,2-c] pyridin-2-sulfonamide hydrochloride; Y- (2,3-difluorobenzyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonamide hydrochloride; N- (3-Chlorobenzyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonamide hydrochloride; 4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid phenylamide hydrochloride;

4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid hydrochloride of (4-tert-butylphenyl) amide;

4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridin-2-sulfonic acid phenylamide hydrochloride; (3-chlorophenyl) amide hydrochloride of 4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridin-2-sulfonic acid;

phenylamide hydrochloride 2-bromo-4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridin-3-sulfonic acid;

(4-methylphenyl) amide hydrochloride of 4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridin-3-sulfonic acid; and Ν-phenyl -? - piperazin-1 -ylthieno [2,3-c] pyridin-2-sulfonamide hydrochloride. Preferred compounds of formula (VII) are No. (4-methylphenyl) -4-piperazin-1-ylfuro [3,2-c] pyridin-2-sulfonamide hydrochloride; No. phenyl-4-piperazin-1-ylfuro hydrochloride [3,2-c] pyridin-2-sulfonamide; and Ν-phenyl -? - piperazin-1-ylfuro [2,3-c] pyridin-2-sulfonamide hydrochloride. A preferred compound of formula (VIII) is 4-piperazin-1-ylthiazolo [4,5-c] pyridin-2-sulfonic acid phenylamide hydrochloride. Preferred compounds of formula (IX) are No. (4-methylphenyl) -4-piperazin-1-yl-1H-pyrrolo [3, 2-c] pyridin-2-sulfonamide hydrochloride; No. phenyl-4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridin-2-sulfonamide hydrochloride; and Ν-phenyl -? - piperazin-1-yl-1H-pyrrolo [2,3-c] pyridin-2-sulfonamide hydrochloride.

Another object of the present invention is a method for producing compounds described above, where

P represents

where the specified method includes the following stages: obtaining a halogen-substituted pyridine condensed with a heteroaromatic 5-membered ring, restoration of an aromatic nitro group; aromatic nucleophilic substitution with thiol via an intermediate diazo compound; oxidation of the thiol derivative to sulfone; introduction of a halogen atom through electrophilic aromatic substitution; aromatic nucleophilic substitution of halogen with diamine.

Another object of the present invention is a method for producing compounds described above, where

P represents

where the specified method includes the following stages: obtaining pyridine condensed with a heteroaromatic 5-membered ring; the introduction of a carboxyl fragment; converting the carboxyl fragment to an amino group through Curtius rearrangement; the interaction of the amino group with sulfonyl chloride.

Another object of the present invention is a method for producing a compound described above, where

P represents

- 8 011581

where the specified method includes the following stages: obtaining pyridine condensed with a heteroaromatic 5-membered ring; the introduction of the sulfonyl chloride fragment by nucleophilic addition; reacting the sulfonyl chloride moiety with aniline to produce a sulfonamide; aromatic nucleophilic substitution of chlorine with diamine.

All possible diastereomeric forms (pure enantiomers, tautomers, racemic mixtures and mixtures containing unequal amounts of two enantiomers) are included in the scope of this invention. Such compounds may also exist in the form of cis or trans, E or Ζ isomeric forms with respect to the double bond. All isomeric forms are intended.

The compounds of formulas (Ι) - (ΧΙΙ) can be used on their own or, when appropriate, in the form of their pharmacologically acceptable salts (acid or base addition salts).

The pharmacologically acceptable addition salts as mentioned above are intended to include therapeutically active non-toxic acid or base addition salt forms which the compounds are capable of forming. Compounds that possess basic properties can be converted into pharmaceutically acceptable acid addition salts by treating the base form with a suitable acid. Typical examples of acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid; and organic acids such as acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid , malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid, and the like. Typical examples of the base addition salt forms are sodium, potassium, calcium, and salts with pharmaceutically acceptable amines, such as, for example, ammonia, alkylamines, benzathiine, and amino acids, such as, for example, arginine and lysine. The term “addition salt” as used herein includes solvates that can form compounds and their salts, such as, for example, hydrates, alcoholates, and the like.

For clinical use, the compounds of this invention are formulated in pharmaceutical formulations for oral, rectal, parenteral or other route of administration. Pharmaceutical formulations are usually prepared by mixing the active compound or a pharmaceutically acceptable salt thereof with well-known pharmaceutical excipients. In addition, the preparations can also be prepared by known methods, such as granulation, compression, microencapsulation, spray coating, etc. The preparations can be obtained by conventional methods in the form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injectable preparations containing a certain dose of the active ingredient. Liquid preparations may be prepared by dissolving or suspending the active compound in water or other suitable carriers.

Tablets and granules may contain a suitable coating.

Another object of the present invention is a compound described above for use in therapy.

Another object of the present invention is a compound described above for use in the treatment or prevention of disorders associated with the 5-HT ₆ receptor, such as obesity, type II diabetes mellitus and / or central nervous system disorders, to achieve weight loss and increase body weight.

Another object of the present invention is a compound described above for use in the treatment or prevention of disorders of the central nervous system.

Another object of the present invention is a compound described above for use in the treatment or prevention of type сахар diabetes.

Another object of the present invention is a compound described above, for use in the treatment or prevention of obesity, to achieve a decrease in body weight and increase body weight.

Another object of this invention is a pharmaceutical preparation comprising the compound described above as an active ingredient in combination with a pharmaceutically acceptable diluent or carrier.

Another object of the present invention is a pharmaceutical preparation comprising a compound described above as an active ingredient for use in the treatment or prevention of a 5-HT ₆ receptor-related disorder, such as obesity, type II diabetes mellitus and / or central nervous system disorder , to achieve weight loss and weight gain.

Another object of the present invention is a compound as described above, as an active ingredient for use in the treatment or prophylaxis of central nervous system disorders.

Another object of the present invention is a pharmaceutical preparation comprising a compound described above as an active ingredient for use in the treatment or prevention of type II diabetes mellitus.

Another object of the present invention is a pharmaceutical preparation comprising the compound described above as an active ingredient for use in the treatment or prevention of obesity, in order to achieve a decrease or increase in body weight.

Another object of the present invention is a method of treating or preventing a disorder associated with a 5-HT ₆ receptor, such as obesity, type II diabetes mellitus and / or a central nervous system disorder, in order to achieve a decrease in body weight and an increase in body weight, which includes administering to a subject (e.g., a mammal, human, horse, dog or cat) in need of such treatment, an effective amount of one or more compounds represented by any of the formulas described above, their salt forms or compositions, to which include compounds or their salt forms.

Another object of the present invention is a method of treating or preventing central nervous system disorders, which comprises administering to a subject in need of such treatment an effective amount of one or more of the compounds represented by any of the formulas described above, their salt forms or compositions, which include compounds or their salt forms.

Another object of this invention is a method of treating or preventing type II diabetes mellitus, which comprises administering to a subject in need of such treatment an effective amount of one or more of the compounds represented by any of the formulas described above, their salt forms or compositions, which include compounds or their salt forms.

Another object of the present invention is a method for the treatment or prevention of obesity, which includes the introduction to a subject in need of such treatment, an effective amount of one or more compounds represented by any of the formulas described above, their salt forms or compositions, which include compounds or their salt forms .

Another object of the present invention is a method of modulating the activity of 5-HT ₆ receptor, comprising administering to a subject in need thereof an effective amount of one or more compounds represented by any of the formulas described above, their salt forms or compositions, which include compounds or their salt forms.

Another object of this invention is the use of one or more compounds represented by any of the formulas described above, their salt forms or compositions, which include compounds or their salt forms, for the manufacture of a medicament for use in the treatment or prevention of a disorder associated with 5- HT ₆ receptor, such as obesity, type II diabetes mellitus and / or central nervous system disorder, to reduce body weight and increase body weight.

Another object of this invention is the use of one or more compounds represented by any of the formulas described above, their salt forms or compositions, which include compounds or their salt forms, for the manufacture of a medicament for use in the treatment or prevention of disorders of the central nervous system.

Another object of the present invention is the use of one or more compounds represented by any of the formulas described above, their salt forms or compositions, which include compounds or their salt forms, for the manufacture of a medicament for use in the treatment or prevention of type II diabetes mellitus.

Another object of the present invention is the use of one or more compounds represented by any of the formulas described above, their salt forms or compositions, which include these compounds or their salt forms, for the manufacture of a medicament for use in the treatment or prevention of obesity, in order to achieve a reduction body weight and weight gain.

The methods described herein also include the step of identifying a subject in need of treatment for obesity, type II diabetes mellitus or a central nervous system disorder, or in need of weight loss and weight gain.

The invention also relates to the cosmetic use of one or more compounds represented by any of the formulas described above, in order to reduce weight, and also in the form of cosmetic compositions containing these compounds.

In addition, the invention relates to a non-therapeutic method for improving the appearance of a mammalian body, including a human, which comprises orally administering to said mammal one or more compounds represented by any of the formulas described above.

The term “effective amount” refers to an amount of a compound that guarantees a therapeutic effect on a subject undergoing treatment. The therapeutic effect can be evaluated objectively (that is, it can be measured using some test or marker) or subject

- 10 011581 objectively (that is, the subject speaks of a testimony or a sense of action).

For clinical use, the compounds of this invention are included in pharmaceutical formulations for oral, rectal, parenteral or other route of administration. Typically, the amount of active compounds is in the range from 0.1 to 95% by weight of the drug, preferably in the range of 0.2-20% by weight in preparations for parenteral use, and preferably in the range from 1 to 50% by weight in preparations for oral administration introduction.

The usual daily dose of the active compound varies widely and will depend on various factors, such as, for example, the individual need of each patient and the route of administration. Typically, dosages for oral and parenteral administration will range from 5 to 1000 mg per day of active compound, preferably from 50 to 150 mg per day.

Production methods

In an additional aspect, the present invention relates to a method for producing compounds of any of the formulas described herein, which comprises reacting any one or more compounds of the formulas described in the description, including any methods described in this invention. Compounds represented by the above formulas can be prepared by standard methods or similar methods, for example, methods similar to those presented below.

Chemical compounds used in the above methods may include, for example, solvents, reagents, catalysts, reagents for introducing or removing a protecting group.

The methods described above may also further include steps carried out before or after the steps described, to add or remove suitable protecting groups and to ultimately synthesize the compounds represented by any of the above formulas, their salt forms or compositions, which include compounds or their salt forms. In addition, the various stages of the synthesis can be carried out in a different sequence or in a different order to obtain the target compounds. Methods for changing the sequence of chemical synthesis and the use of protective groups (introduction and deprotection) that can be used to synthesize compounds that can be used later are known in the art and include, for example, the methods described in the publications: J. Lagosck, Sotrgeyepzgue Ogdash Tgapziogtabopz, VСΗ РиЬ11зёгз (1989); Τ / Ψ. Ogeepe apb R.O.M. HUiK Prgoesiue Ogoirz ίη Ogdashs 8n1yes1z, 2 ' ¹ Eb., 1o1t \ UPeu apb 8opz (1991); B. E1ezeg apb M. E1ezeg, E1ezeg apb Ezhezeg'z Yaadeiz yog Ogdashs 8n1yez1z, 1o1t \ Ubeu apb 8opz (1994); apb b. Raskschepe, eb., Epsus osobrei yaiedep1z yog Ogdashs 8yp1yyz1z, 1o1t \ UPeu apb 8opz (1995) and subsequent editions of this publication.

The specific examples presented below should be considered only as illustrative and not limiting the scope of this invention. Without further clarification, it is believed that a qualified specialist in the art based on this description will be able to apply this invention with the greatest completeness. All publications cited herein are incorporated by reference in their entireties.

Ways

The 'H-NMR and ¹³ C-NMR spectra were recorded on a Vgikeg Lbuapse PPX 400 spectrometer at 400.1 and 100.6 MHz, respectively. All spectra were recorded using residual solvent or tetramethylsilane (TMS) as an internal standard. IR spectra were recorded on a Regksh-E1teg 8res1git 1000 ET4Ya spectrophotometer. The spectra of ion-spray mass spectrometry (MS) were obtained on a Rekt-E1teg Α PI 150EX mass spectrometer. Accurate mass determinations were carried out using a dual sensor Mkgotazs LST. Preparative HPLC / MS was carried out using a ^ a1egz / M1sgotazz P1a1yogt системы system equipped with system A (column ACE 5 C8 (19x50 mm) eluents: М1ШЦ water, МеСИ and Μί11ίΟ water / МеСИ / О, 1% TFA) and system B (column X1egga M8 C 18.05 μm (19x50 mm), eluents: M1ShTs water, MeCI and IN ₄ NSO ₃ (100 mM)). HPLC analysis was performed on an Adbep apparatus! 1100 [ACE 3 C8 column (system A) or ΥMS-Rask column (system B), eluents: М1ШЦ / 0.1% TFUK and МеСИ]. Elemental analysis was performed on a Va ^^ o E1 apparatus. Preparative flash chromatography was performed on Megk 60 silica gel (230-400 mesh).

Table 4

Example K ² The EU to' 41 Ν- (4-methylphenyl) hydrochloride - 4- (4-methylpiperazin-1- il) thieno [3,2-c] pyridin-2sulfonamide xxx '1 N n about Υ SI

- 11 011581

42 2-bromo-4- (4-methylpiperazin-1yl) thieno [3,2-c] pyridin-3sulfonic acid hydrochloride of p-tolylamide ......... Vg 1 n 0 sn 43 4- (4methylpiperain-1-yl) -phenylthieno [3,2-c] pyridin-2sulfonamide hydrochloride N n Ψ sn 44 (P-fluoro-5-trifluoromethyl-phenyl) -amide 4-piperazin-1-ylthieno [3,2с] pyridin-2-sulfonic acid hydrochloride H ⁱⁿ ^ ' ^h ^ *' with ₽, n n f 45 Hydrochloride (4- 4-piperazin1-ylthieno [3,2-c] pyrilin-2sulfonic acid chlorophenyl) amide n n F 46 4 piperazin-1-ylthieno (3,2s] pyridin-2-sulfonic acid amide hydrochloride (4isopropylphenyl) amide n n f 47 4piperazin-1-ylthieno [3,2c] pyridin-2-sulfonic acid p-tolylamide hydrochloride n n f 48 4- (4- methylpiperazin-1-yl) -Ν- (2cyclohex-1-en-1ylethyl) thieno [3,2-c] pyridin-2sulfonamide hydrochloride n n f 49 Hydrochloride 2- (4- (4methylpiperazin-1- il) thieno [3,2-c] pyridin-2ylsulfonyl) -1,2,3,4tetrahydroisoquinoline Ο,., Ο ^h OO n f

- 12 011581

fifty 4- (4 Methylpiperazin-1-yl) -Ν ~ (2thien-2-yl-ethyl) thieno [3,2c] pyridin-2-sulfonamide hydrochloride n N -.4 51 4- (4 Methylpiperazin-1-yl) -N- [1- (1naphthyl) ethyl] thieno [3,2s] pyridin-2-sulfonamide hydrochloride n .-4 52 4- (4methylpiperazin-1-yl) -Ν- (4hexylphenyl) thieno [3.2s] pyridin-2-sulfonamide hydrochloride one * n -.4 53 Ν- (3-Chlorobenzyl) -4- (4methylpiperazin-1- il) thieno [3,2-c] pyridin-2sulfonamide n F 54 4 - (4 Methylpiperazin-1-yl) -Ν- [1- (4 fluorophenyl) ethyl] thieno [3,2с] pyridin-2-sulfonamide hydrochloride n nine 55 Ν- (2,3difluorobenzyl) -4- (4methylpiperazin-1yl) thieno [3,2-c] pyridin-2sulfonamide hydrochloride Χφ n F 56 4- (4- methylpiperazin-1-yl) -Ν- (4chloro-2,5-dimethoxyphenyl) thieno [3,2с] pyridin-2-sulfonamide hydrochloride n ¹ I F 57 2-bromo-4- (4methylpiperazin-1-yl) -Ν- (2cyclohex-1-en-1- hydrochloride ilethyl) thieno [3,2-c] pyridin-3sulfonamide Vg and F

- 13 011581

58 2- [2-Bromo-4- (4 methylpiperazin-1 yl) benzo [b] thiophen-3sulfonyl] -1,2,3,4 tetrahydroisoquinoline Vg f 59 2-bromo hydrochloride ~ 4- (4methyliperazin-1-yl) -N- [1- (4fluorophenyl) ethyl] thieno [3,2с] pyridin-3-sulfonamide Vg ° Άο, f 60 2-bromo-4- (4methylpiperazin-1-yl) -Ν- (4chloro) hydrochloride - (2,5- dimeto xiphenyl) thieno [3,2- c] pyridin-3-sulfonamide Vg Η ί f 61 N- (3,4-Dichlorophenyl) -4-piperazin-1ylthieno [3,2-c] pyridin-2sulfonamide hydrochloride νΰ ⁰¹ ή n 0 62 Hydrochloride N- (2,4-difluorophenyl) -4-piperazin-1ylthieno [3,2-c] pyridin-2sulfonamide Η P n f 63 4-piperazin-1-yl hydrochloride N- [3- (trifluoromethyl) phenyl] thieno [3,2-c] pyridin-2-sulfonamide n and 0 64 Ν- (3-Ethylphenyl) hydrochloride - 4-piperazin-1-ylthieno [3,2- c] pyridin-2-sulfonamide n ¹ n f 65 Hydrochloride N- (3,4-dimethoxyphenyl) -4-piperazin1-ylthieno [3,2-c] pyridin-2sulfonamide o o- Р, P * ¹ 0 * n f 66 Y- (4-bromo-2-methylphenyl) -4-piperazin-1ylthieno [3,2-c] pyridin-2sulfonamide hydrochloride | n f

- 14 011581

67 (2- (4-piperazin-1ylthieno [3,2-s] pyridin-2sulfonyl hydrochloride) -1,2,3,4tetrahydroisoquinoline 0 .---. ° n X — 7 ' -------------------------------------------------- -------------------------------------------------- -------------------------------------------------- -------------------------------------------------- -------------------------------------------------- -------------------------one 68 4-piperazin-1ylthieno [3,2-c] pyridin-2sulfonic acid hydrochloride of (2-thiophen-2-ethyl) amide n and 0 69 (4-Chloro-2,5-dimethoxy-phenyl) -amide of 4-piperazin-1-ylthieno (3.2s] pyridin-2-sulfonic acid hydrochloride And * n F 70 4piperazin-1-ylthieno [3.2s] pyridin-2-sulfonic acid phenethylamide hydrochloride BUT n 0 71 4 piperazin-1-ylthieno [3,2s] pyridin-2-sulfonic acid hydrochloride (2,6diethylphenyl) amide 4? n 0 72 4piperazin-1-ylthieno [3,2s] pyridin-2-sulfonic acid amide hydrochloride (3phenylpropyl) n n f 73 (Piperazin-1-ylthieno [3.2s] pyridin-2-sulfonic acid amide hydrochloride of (3,3 diphenylpropyl) amide -. "'N-Uu-C1 Ό n 0 74 [2- (5-Methoxy-1-indindol-3-yl) ethyl] amide of 4 piperazin-1-ylthieno [3,2с] pyridin-2-sulfonic acid hydrochloride νθώ n f

- 15 011581

75 4pilerazin-1-ylthieno [3,2s] pyridin-2-sulfonic acid hydrochloride 4 trifluoromethylbenzylamide kh? n 0 76 4-piperazin-1-ylthieno [3,2c] pyridin-2-sulfonic acid benzyl ethylamide hydrochloride σν n 0 77 Ν- (3-Ethylphenyl) hydrochloride - 4-piperazin-1-ylthieno [3,2- c] pyridin-3-sulfonamide V " FROM' 0 78 Ν- (4isopropylphenyl) -4-piperazine- hydrochloride 1-ylthieno [3,2-c] pyridin-3sulfonamide _ABOUT 0 79 Ν- (4-methylphenyl) hydrochloride - 4- (pyrrolidin-3- yloxy) thieno [3,2-c) pyridin-2sulfonamide P1 n Oh * 'ύ 80 Ν- (4-methylphenyl) hydrochloride - 4- (piperidin-4- yloxy) thieno [3,2-c] pyridin-2sulfonamide and n b 81 N- (2,3-difluorobenzyl) -4-piperazin-1ylthieno [3,2-c] pyridium-2sulfonamide hydrochloride (I and T1N-ZO _g - n 0 82 Hydrochloride Ν- (3-chlorobenzyl) - 4-piperazin-1-ylthieno [3,2- c] pyridin-2-sulfonamide W ^ MH-ZOG * n 0

Scheme 5 ~ - * - + br - ^^ yN, but

- 16 011581

Explanations for Scheme 5: ί) Malonic acid, pyridine, piperidine, heating; ίί) ethyl chloroformate, acetone, ΝαΝ ₃ . -10 ° C; ίίί) diphenyl ether, 220 ° C; ίν) POC1 ₃ , heating; ν) gaseous §O ₂ , n-VI, N-chlorosuccinimide, CH ₂ Cl ₂ ; νί) Β ¹ -ΝΗ2, pyridine; νίί) HB ³ , K2CO ₃ , DMSO, heating.

Intermediate 47. (2E) -3- (5-Bromthien-2-yl) acrylic acid.

Malonic acid (44.40 g, 426.7 mmol) is added to a mixture of 5-bromothiophen-2-carbaldehyde (50 g, 261.7 mmol), piperidine (2.84 ml) and pyridine (150 ml). The mixture was refluxed for 1 h at 80 ° C and then at 100 ° C overnight. Volatile solvents are evaporated, the residue is dissolved in water and acidified with hydrochloric acid (pH 2). The crude product is crystallized in ethanol. Yield: 55.24 g (90.5%). ^! H-NMR (270 MHz, CH ₃ OH-b ₄ ) δ ppm 6.14 (d, 1 = 15.83 Hz, 1H), 7.11-7.16 (m, 2H), 7.68 (d, 1 = 16.36 Hz, 1H); MS 233.1 (M-H) ⁺ ; purity (HPLC) 94%.

Intermediate 48. (2E) -3- (5-Bromthien-2-yl) acryloyl azide.

To a solution of (2E) -3- (5-bromothien-2-yl) acrylic acid (1.04 g, 4.46 mmol) in chloroform (20 ml) was added thionyl chloride (1.04 ml), the mixture was refluxed for 2 hours at 75 ° C and used in the next step. The resulting solution was added dropwise with stirring to a suspension of sodium azide (0.58 g, 8.93 mmol), dioxane (3 ml) and water (3 ml) while cooling in an ice bath. After 10 minutes, the precipitate formed is filtered off and washed with water. The residue was dissolved in dichloromethane, dried with MgSO ₄ , filtered and the solvent was removed, yielding 0.96 g (83.4%) of the product. ¹ H-NMR (270 MHz, CH ₃ OH-b ₄ ) δ ppm 6.20 (d, 1 = 15.57 Hz, 1H), 7.15-7.25 (m, 2H), 7.80 (d, 1 = 15.57 Hz, 1H); MS 258.1 (M-H) ⁺ ; purity (HPLC) 65%.

Intermediate 49. 2-Bromthieno [3,2-c] pyridin-4 (5H) -one.

A solution of (2E) -3- (5-bromothien-2-yl) acryloyl azide (18.00 g, 69.7 mmol) in dichloromethane (100 ml) was added dropwise to diphenyl ether (90 ml) at 150 ° C. The temperature was raised to 220 ° C and the mixture was kept at this temperature for 1 hour. The mixture was cooled to room temperature and added to ether. The resulting solid precipitate was collected by filtration.

Yield: 13.58 g (84.6%). Я-NMR (270 MHz, DMSO-b ₆ ) δ 6.82 (d, 1 = 7.13 Hz, 1Н), 7.27 (d, 1 = 6.86 Hz, 1Н), 7.54 (s , 1H); 11.55 (s, 1H); MS 230.1 (M-H) ⁺ ; purity (HPLC) 92%.

Intermediate 50. 2-Bromo-4-chlorothieno [3,2-c] pyridine.

Phosphorus oxychloride (4.08 g, 26.6 mmol) was added dropwise to 2-bromothieno [3,2-c] pyridin-4 (5H) one (2.04 g, 8.87 mmol) at 0 ° C. The mixture is heated to 135 ° C and maintained at this temperature for 2.5 hours, then carefully poured into a mixture of water and ice. The resulting precipitate was collected by filtration and dried, yielding 1.78 g (80.7%) of the title product. ¹ H-NMR (270 MHz CH ₃ OH-b ₄ ) δ ppm 7.67 (d, 1H), 7.88 (dddd, 1 = 6.33 Hz, 2H), 8.19 (d, 1 = 5.54 Hz, 1H); MS 248.0 (M-H) ⁺ ; purity (HPLC) 100%.

Intermediate 51 and 52. 4-Chloro-thieno [3,2-s] pyridin-2-sulfonyl chloride and 2-bromo-4-chlorothieno [3,2-c] pyridin-3-sulfonyl chloride.

n-Butyllithium (1.5 ml, 2.4 mmol) was added to 2-bromo-4-chlorothieno [3,2-c] pyridine (0.5 g, 2 mmol) dissolved in dry THF (15 ml) at -78 ° C in a nitrogen atmosphere. The mixture is stirred for 40 minutes. The solution obtained above is added to dry ether saturated with §O ₂ (gas.) At -78 ° C. The mixture was warmed to room temperature and ether was added. The precipitate was removed by filtration. The two title products were obtained and used in the next step without further purification as follows: Ν-chlorosuccinimide (2.07 g, 10.3 mmol) was added to [(4-chlorothieno [3,2-c] pyridin2- il) sulfonyl] lithium and [(2-bromo-4-chlorothieno [3,2-c] pyridin-3-yl) sulfonyl] lithium in dichloromethane (150 ml) at 0 ° C. The mixture is heated to 60 ° C and maintained at this temperature for 2 hours, extracted with water (3x50 ml). The organic phase was separated, dried with MgSO ₄ , filtered and volatile solvents were removed by distillation in vacuo. Raw products are used in the next step without further purification.

Intermediate 53 and 54. 4-chloro-2-thieno [3,2-c] pyridin-2-sulfonic acid p-tolylamide and 2-bromo-4-chlorothieno [3,2-c] pyridin-3 p-tolylamide -sulfonic acid.

p-Toluidine (30 mg, 2.87 mmol) was added to the solution of 4-chlorothieno [3,2-c] pyridin-2-sulfonyl chloride and 2-bromo-4-chlorothieno [3,2-c] pyridin-3-sulfonyl chloride (0.07 g, 0.26 mmol) in dichloromethane and pyridine (0.19 ml). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the crude mixture was used in the next step without further purification.

Examples 41 and 42. 4- (4-Methylpiperazin-1-yl) thieno [3,2-c] pyridin-2-sulfonic acid p-tolylamide hydrochloride and 2-bromo-4- (4-methylpiperazine- p-tolylamide hydrochloride 1-yl) thieno [3,2-c] pyridin-3sulfonic acid.

A mixture of 4-chloro-2-thieno [3,2-c] pyridin-2-sulfonic acid p-tolylamide and 2-bromo-p-tolylamide

4-chlorothieno [3,2-c] pyridin-3-sulfonic acid (70 mg, 0.21 mmol) in DMSO (2 ml), 1-methylpiperazine (0.344 ml, 3.1 mmol) and K ₂ CO ₃ ( 28.5 mg, 0.21 mmol) is heated to 100 ° C and maintained at this temperature overnight. The reaction mixture was dissolved in water and extracted with ethyl acetate (3x10 ml). The organic layers were combined and the solvent was removed. Products purified by HPLC to give 1.9 mg

- 17 011581 4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridin-2-sulfonic acid p-tolylamide. The free base is converted to the hydrochloride salt by treatment with HCl in ether: ¹ H-NMR (270 MHz, methanol-b4) δ ppm 2.26 (s, 3H), 2.98 (s, 3H), 3.40-3.55 (m, 8H), 7.02-7.10 (m, 6H), 7.55 (d, 1 = 5.81 Hz, 1H), 7.69 (s, 1H), 8.13 (d, 1 = 5.81 Hz, 1H); LC-MS 403 (M + H) ⁺ ; purity (LC-MS) 92%; and 3.8 mg of 2-bromo-4- (4methylpiperazin-1-yl) thieno [3,2-c] pyridin-3-sulfonic acid p-tolylamide. The free base is converted to the hydrochloride salt by treatment with HCl in ether: 'H-NMR (270 MHz, methanol-b4) δ ppm 2.21 (s, 1H), 3.00 (d, 3H), 3.50-3.77 (m, 8H), 7.00-7.10 (m, 6H), 7.63 (d, 1 = 5.81 Hz, 1H), 8.19 (d, 1 = 5.81 Hz, 1H); LC-MS 481 (M + H) ⁺ ; purity (LC-MS) 98%.

The interaction of sulfonyl chloride with amines (method H).

To a solution of amine (1.3 eq.) And pyridine (8 eq.) In DCM, sulfonyl chloride (1 eq.) Was added and the reaction mixture was stirred overnight. After adding Tpkashche ™ (~ 2 equiv.), The mixture was gently shaken for an additional 3 hours. The suspension was filtered through a small pad of silica using DCM and ethyl acetate. The solvent was evaporated, the residue was dissolved in DCM and washed with 1M aqueous HC1 (2 times). The combined organic phases were dried (MgSO ₄ ), filtered and the solvent was removed to give the sulfonamide. Upon receipt of products of insufficient purity, they are purified by flash chromatography on silica gel. The products are used in the next stage (method B).

Linking with aromatic amines (method I).

To the reaction mixtures obtained in Method H dissolved in DMSO (2 ml), amines (15 eq.) And K ₂ CO 3 (1 eq.) Are added. The reaction mixtures were stirred at 100 ° C. for 24 hours and then concentrated. The products are purified by LC-MS. Solvents were removed in vacuo using 8ReebUas and purified by preparative LC / MS. Products that are not sufficiently pure (purity <90%) are purified by preparative chromatography using acetonitrile-water gradients containing 0.1% trifluoroacetic acid. After HPLC analysis, fractions with a purity> 90% are collected and concentrated. The deprotection of the amino group in piperazine is first carried out by dissolving the compound in methanol and adding small portions of 1M HCl / ether. The reaction mixtures were analyzed by TLC. The solvents are concentrated in vacuo using 8 reebuac.

Removal of the BOC protecting group (method b).

The sulfonic or sulfonamide derivative (obtained by methods H and I) is dissolved in a small amount of a 1: 1 MeOH / DCM mixture and treated with an excess of 1M HC1 in diethyl ether. Stirring at room temperature overnight leads to the formation of a precipitate, which is collected by filtration, to obtain products in the form of their hydrochlorides.

Example 43. 4- (4-Methylpiperazin-1-yl) -Y-phenylthieno [3,2-c] pyridin-2-sulfonamide hydrochloride.

The synthesis is carried out essentially in accordance with methods H-b. Yield: 8.1 mg (33.8%). 'H-NMR (270 MHz, CH ₃ OH-b ₄ ) δ ppm 8.13 (d, 1 = 5.81 Hz, 1H), 7.67 (s, 1H), 7.54 (d, 1 = 5.81 Hz, 1H), 7.55-7.53 (m 5H); 2.97 (s, 3H) (4H is covered by a solvent signal); LC-MS 389 (M-H) ⁺ ; purity (HPLC) 100%.

Example 44. 4-Piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid amide hydrochloride (3-fluoro-5-trifluoromethylphenyl) amide.

4- [2- (3-Fluoro-5-trifluoromethylphenylsulfamoyl) thieno [3,2-c] pyridin-4-yl] piperazine-1-carboxylic acid tert-butyl ester (0.235 mmol, 1 equiv.) is used as thienopyridine in the way H-b. Yield: 25.7 mg. HPLC: 1 ^ = 3.395 (system: from 5% to 50% ASU for 3 min, C8), purity: 100%, LC / MS: 1B = 1.375 (system: 30 to 60% ASU for 1.5 min, NuregSh ΒΌ8), purity: 99%. MS: 461 (M + 1). Ή-NMR (270 MHz CH ₃ OH-b ₄ ) δ ppm 3.47 (m, 4H), 3.53 (s, 1H), 3.87 (m, 4H), 7.21 (m, 1H), 7.29 (m, 1H), 7.33 (s , 1H); 7.66 (d, 1 = 6.33 Hz, 1H).

Example 45. Hydrochloride of (4-chlorophenyl) amide 4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid.

4-chlorothieno [3,2-c] pyridin-2-sulfonic acid (3-fluoro-5-trifluoromethylphenyl) amide (0.208 mmol, 1 equiv.) Was used as thienopyridine in the method H-b. Yield: 7.2 mg. HPLC: C = 3.039 (system: from 5% to 50% ASU for 3 min, C8), purity: 100%, LC / MS: 1 ^ = 0.905 (system: 30% to 60% ASU for 1, 5 min, NuregSh ΒΌ8), purity: 97%. MS: 409 (M + 1). Ή-NMR (270 MHz, CH ₃ OH-b ₄ ) δ ppm 3.50 (m, 4H), 3.91 (m, 4H), 7.25 (m, 4H), 7.71 (dd, 1 = 6.33, 0.53 Hz, 1H), 7.96 (d, 1 = 0.79 Hz, 1H), 8.04 (d, 1 = 6.33 Hz, 1H).

Example 46. Hydrochloride of (4-isopropylphenyl) amide 4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid.

The 4-chlorothieno [3,2-c] pyridin-2-sulfonic acid (4-isopropylphenyl) amide (0.201 mmol, 1 equiv.) Is used as thienopyridine in the H-b method. Yield: 6.9 mg. HPLC: 1 | <= 3.255 (System: 5% to 50% ASU for 3 min, C8), purity: 95%, LC / MS: 1 ^ = 1.255 (system: 30 to 60% ASU for 1 5 min, NuregSh ΒΌ8), purity: 98%, MS: 417 (M + 1). ^! H-NMR (270 MHz, CH ₃ OH-b ₄ ) δ ppm 1.18 (d, 1 = 6.86 Hz, 6H), 2.83 (m, 2H), 3.52 (m, 4H), 4.00 (m, 4H), 7.14 (m, 3H ), 7.75 (d, 1 = 6.60 Hz, 1H), 8.02 (m, 1H).

Example 47. 4-Piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid p-tolylamide hydrochloride.

- 18 011581

To a solution of 4-chlorothieno [3,2-c] pyridin-2-sulfonyl chloride (0.640 g, 2.39 mmol) in DCM (20 ml) was added pyridine (1.9 ml, 23.9 mmol) and then p-tolylamine (0.307 g, 2.86 mmol).

The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated, redissolved in DMSO (10 ml) and piperazine-1-carboxylic acid tert-butyl ether (1.34 g, 7.17 mmol) and K ₂ CO _{3 were} added. (0.989 g, 7.17 mmol). The mixture was stirred at 100 ° C. for 16 hours and then concentrated. The crude reaction mixture was dissolved in E1OLs (100 ml) and washed with brine (2x50 ml). The organic phase is dried (Na ₂ 8 O ₄ ) and concentrated. The crude intermediate is purified by column chromatography on silica using a mixture of EULS / n-pentane (1: 1) as eluent. The intermediate was dissolved in EULS / MOH and diethyl ether saturated with HCl (gas) was added. The mixture was stirred at room temperature for 16 hours. The precipitate was collected by filtration and washed with diethyl ether / n-pentane, to give 0.475 g of a crude product. Purification by preparative reverse phase HPLC affords 0.133 g of pure product: ¹ H-NMR (DMSO-a ₆ , 25 ° C, 270.17 MHz) δ 10.61 (br s, 1H), 9.23 (br .s, 2H), 8.13 (d, 1 = 5.80 Hz, 1H), 7.91 (s, 1H), 7.67 (d, 1 = 5.80 Hz, 1H), 7.09 -7.07 (m, 4H), 3.68-3.59 (m, 4H), 3.33-3.22 (m, 4H), 2.20 (s, 3H) t / ζ (Е8Н) 399 (M + H).

Example 48. 4- (4-Methylpiperazin-1-yl) -Y- (2-cyclohex-1-en-1-yl-ethyl) thieno [3,2-c] pyridin-2-sulfonamide hydrochloride.

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 25.6 mg. 'H-NMR (270 MHz, DMSO-th ₆ ) δ ppm 10.49-10.48 (m, 1H), 8.23-7.95 (m, 3H), 7.72-7.71 (m, 1H), 5.34-5.33 (m, 1H) ), 4.14-4.11 (m, 2H), 3.53-3.51 (m, 2H), 3.29-3.25 (m, 2H), 2.98-2.97 (m , 2H), 2.85 (s, 3H), 2.04-1.81 (m, 4H), 1.57-1.15 (m, 8H); LC-MS 420.17 (M-H) ⁺ ; purity (LC-MS) 97%.

Example 49. 2- (4- (4-Methylpiperazin-1-yl) thieno [3,2-c] pyridin-2-ylsulfonyl) hydrochloride -

1,2,3,4-tetrahydroisoquinoline.

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 15.5 mg. 'H-NMR (270 MHz, DMSO-a ₆ ) δ ppm 10.49-10.48 (m, 1H), 8.17-8.15 (m, 1H), 7.86-7.85 (m, 1H), 7.70-7.65 (m, 2H ), 7.28-7.12 (m, 3H), 3.97-3.94 (m, 2H), 3.87-3.85 (m, 2H), 3.25-3.18 (m , 2H), 2.84 (s, 3H), 1.67-1.65 (m, 2H), 3.51-3.34 (6H is closed by the solvent signal); LC-MS 428.13 (M-H) ⁺ ; purity (LC-MS) 99%.

Example 50. Hydrochloride of 4- (4-methylpiperazin-1-yl) -Y- (2-thien-2-yl-ethyl) thieno [3,2-c] pyridin-2sulfonamide.

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 29.5 mg. ¹ H-NMR (270 MHz, DMSO-a ₆ ) δ ppm 10.28-10.27 (m, 1H), 8.34-8.33 (m, 1H), 8.19-8.17 (m, 1H), 8.01-8.00 (m, 1H) ), 7.71-7.69 (m, 1H), 7.31-7.30 (m, 1H), 6.91-6.87 (m, 1H), 4.13-4.10 (m , 2H), 3.53-3.51 (m, 2H), 3.29-3.25 (m, 2H), 3.17-3.16 (m, 2H), 2.99-2.95 (m, 4H); 2.86 (s, 3H); LC-MS 422.09 (M-H) ⁺ ; purity (LC-MS) 99%.

Example 51. Hydrochloride of 4- (4-methylpiperazin-1-yl) -Y- [1- (1-naphthyl) ethyl] thieno [3,2-c] pyridin-2sulfonamide.

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 20.1 mg. ¹ H-NMR (270 MHz, DMSO-a ₆ ) δ ppm 10.28-10.27 (m, 1H), 8.85-8.84 (m, 1H), 8.02-8.01 (m, 1H), 7.67-7.60 (m, 4H) ), 7.53-7.50 (m, 2H), 7.39-7.36 (m, 2H), 4.72-4.70 (m, 1H), 3.87-3.84 (m , 1H), 3.72-3.70 (m, 1H), 3.23-3.13 (m, 4H), 2.84 (s, 3H), 1.42-1.40 (m, 3H) ); LC-MS 466.15 (M-H) ⁺ ; purity (LC-MS) 99%.

Example 52. 4- (4-Methylpiperazin-1-yl) -Y- (4-hexylphenyl) thieno [3,2-c] pyridin-2sulfonamide hydrochloride.

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 8.0 mg. ¹ H-NMR (270 MHz, DMSO-a ₆ ) δ ppm 10.39-10.38 (m, 1H), 8.16-8.15 (m, 1H), 7.90-7.89 (m, 1H), 7.66-7.65 (m, 1H ), 7.09-7.08 (m, 4H), 4.00-3.98 (m, 2H), 3.51-3.48 (m, 2H), 3.26-3.22 (m , 2H), 2.85 (s, 3H), 2.49-2.45 (m, 2H), 1.48-1.46 (m, 2H), 1.24-1.22 (m, 8H) ), 0.82-0.81 (m, 3H); LC-MS 472.20 (M-H) ⁺ ; purity (LC-MS) 98%.

Example 53. Hydrochloride Y- (3-chlorobenzyl) -4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridin-2sulfonamide.

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 30.7 mg. ¹ H-NMR (270 MHz, DMSO-a ₆ ) δ ppm 10.25-10.24 (m, 1H), 8.78-8.77 (m, 1H), 8.18-8.17 (m, 1H), 7.91-7.90 (m, 1H) ), 7.68-7.67 (m, 1H), 7.26-7.19 (m, 3H), 4.21-4.20 (m, 2H), 4.08-4.05 (m , 2H), 3.54-3.51 (m, 2H), 3.28-3.23 (m, 2H), 2.87 (s, 3H), 2.84-2.60 (2H is closed by a signal solvent); LC-MS 436.08 (M-H) ⁺ ; purity (LC-MS) 94%.

Example 54. 4- (4-Methylpiperazin-1-yl) -Y- [1- (4-fluorophenyl) ethyl] thieno [3,2-c] pyridin2-sulfonamide hydrochloride.

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 32.9 mg. ¹ H-NMR (270 MHz, DMSO-to ₆₎ δ ppm: 10.16-10.15 (m, 1H), 8.75-8.73 (m, 1H), 7.63-7.62 (m, 2H), 7.25-7.24 (m, 2H) ), 6.91-6.88 (m, 2H), 4.58-4.55 (m, 1H), 4.02-3.95 (m, 2H), 3.55-3.53 (m , 2H), 3.25-3.21 (m, 2H), 2.68 (s, 3H), 1.31-1.30 (m, 3H), 2.70-2.64 (2H is closed by a signal solvent); LC-MS 434.12 (M-H) ⁺ ; purity (LCMS) 92%.

Example 55. Hydrochloride Y- (2,3-difluorobenzyl) -4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridin-2sulfonamide.

- 19 011581

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 26.7 mg. ¹ H-NMR (270 MHz, DMSO-b ₆ ) δ 10.36-10.35 (m, 1H), 8.82-8.81 (m, 1H), 7.96-7.95 (m, 1H), 7.69-7.68 (m, 1H), 7.27-7.10 (m, 2H), 4.26-4.25 (m, 2H), 4.11-4.08 ( m, 2H), 3.54-3.52 (m, 2H), 3.28-3-24 (m, 2H), 2.68 (s, 3H), 2.86-2.60 (2H closed solvent signal); LC-MS 438.10 (M-H) ⁺ ; purity (LC-MS) 93%.

Example 56. 4- (4-Methylpiperazin-1-yl) -Y- (4-chloro-2,5-dimethoxyphenyl) thieno [3,2-c] pyridin-2-sulfonamide hydrochloride.

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 14.6 mg. 'H-NMR (270 MHz, DMSO-be) δ ppm 10.27-10.26 (m, 1H), 10.14-10.13 (m, 1H), 8.18-8.17 (m, 1H), 7.83-7.82 (m, 1H ), 7.69-7.68 (m, 1H), 7.09-7.07 (m, 2H), 4.00 (s, 2H), 3.76-3.75 (m, 2H), 3.51-3.48 (m, 2H); 3.24-3.22 (m, 2H); 2.85 (s, 3H); LC-MS 482.08 (M-H) ⁺ ; purity (LC-MS) 95%.

Example 57. 2-Bromo-4- (4-methylpiperazin-1-yl) -Y- (2-cyclohex-1-en-1-yl-ethyl) thieno [3,2-c] pyridin-3-sulfonamide hydrochloride.

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 4.6 mg. ¹ H-NMR (270 MHz, DMSO-b ₆ ) δ ppm 10.30-10.29 (m, 1H), 8.31-8.27 (m, 2H), 7.89-7.88 (m, 1H), 5.27-5.26 (m, 1H ), 3.68-3.52 (m, 4H), 3.05-3.04 (m, 2H), 2.88-2.87 (m, 3H), 2.04-2.03 (m , 2H), 2.77-1.81 (m, 2H), 1.54-1.15 (m, 10H); LC-MS 498.08 (M-H) ⁺ ; purity (LC-MS) 93%.

Example 58. 2- [2-Bromo-4- (4-methylpiperazin-1-yl) benzo [b] thiophen-3-sulfonyl] hydrochloride -

1,2,3,4-tetrahydroisoquinoline.

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 3.7 mg. ^! H-NMR (270 MHz, DMSO-b ₆ ) δ ppm 10.30-10.29 (m, 1H), 9.24-9.22 (m, 1H), 8.09-8.08 (m, 1H), 7.67-7.35 (m, 7H) ), 4.69-4.66 (m, 1H), 2.86-2.85 (m, 3H), 1.50-1.48 (m, 3H), 3.23-2.51 (8H closed by solvent signal); LC-MS 544.06 (M-H) ⁺ ; purity (LC-MS) 92%.

Example 59. 2-Bromo-4- (4-methylpiperazin-1-yl) -Y- [1- (4-fluorophenyl) eth-2-yl] thieno [3,2c] pyridin-3-sulfonamide hydrochloride.

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 4.3 mg. ¹ H-NMR (270 MHz, DMSO-b ₆ ) δ ppm 10.35-10.34 (m, 1H), 9.16-9.14 (m, 1H), 8.23-8.22 (m, 1H), 7.80-7.79 (m, 1H) ), 7.26-7.25 (m, 1H), 4.55-4.52 (m, 1H), 3.54-3.52 (m, 2H), 2.88-2.87 (m , 3H), 1.38-1.36 (m, 3H), 3.17-2.83 (6H closed with a solvent signal); LC-MS 512.04 (M-H) ⁺ ; purity (LC-MS) 93%.

Example 60. 2-Bromo-4- (4-methylpiperazin-1-yl) -Y- (4-chloro) - (2,5-dimethoxyphenyl) thieno [3,2-c] pyridin-3-sulfonamide hydrochloride.

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 0.7 mg, LC-MS 561.91 (M-H) ⁺ ; purity (LC-MS) 95%.

Example 61. Hydrochloride Y- (3,4-dichlorophenyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonamide.

3,4-Dichloroaniline (0.49 mmol) dissolved in acetonitrile (1 ml) and pyridine (0.440 ml, 4.03 mmol) was added to a solution of 4-chlorothieno [3,2-c] pyridin-2-sulfonyl chloride ( 0.445 mmol) in acetonitrile (1 ml). The reaction mixture was shaken for 1 h, monitoring the progress of the reaction by HPLC, then the solvent was removed. The crude product is used in the next step without further purification. To the reaction mixture obtained in the previous step, dissolved in DMSO (1 ml), piperazine (15 equivalents) and K ₂ CO ₃ (1 equivalent) were added. The reaction mixture was stirred at 100 ° C. for 24 hours, then concentrated. The product was purified by LC-MS to give 5.8 mg (2.6%) of the title product. Ή-NMR (270 MHz, CH ₃ OH-b ₄ ) δ ppm 8.07-8.05 (m, 2H), 7.73 (d, 1 = 6.60 Hz, 1H), 7.46-7.41 (m, 2H), 7.16 (dd, 1 = 8.71, 2.38 Hz, 1H), 3.94-3.90 (m, 4H), 3.92 (m, 4H), 3.53-3.50 (m, 4H); LC-MS 443 (M-H) ⁺ ; purity (HPLC) 95%.

Example 62. Y- (2,4-difluorophenyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonamide hydrochloride.

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 4.3 mg (2.1%). ¹ NNMR (270 MHz, CH ₃ OH-b ₄ ) δ ppm 8.22 (s, 1H), 8.07-8.01 (m, 2H), 7.79-7.72 (m, 1H), 7.55-7.47 (m, 1H), 7.046, 94 (m, 2H), 4.00-3.96 (m, 4H), 3.53-3.43 (m, 4H), 2.66 (s, 1H); LC-MS 411 (M-H) ⁺ ; purity (HPLC) 98%.

Example 63. 4-piperazin-1-yl-L- [3- (trifluoromethyl) phenyl] thieno [3,2-c] pyridin-2sulfonamide hydrochloride.

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 2.6 mg (1.2%). ¹ NNMR (270 MHz, CH ₃ OH-b ₄ ) δ ppm 8.05 (d, 1 = 6.60 Hz, 2H), 7.80-7.60 (m, 3H), 7.50-7.47 (m, 2H), 3.94-3.90 ( m, 4H); 3.56-3.49 (m, 4H); LC-MS 443 (M-H) ⁺ ; purity (HPLC) 99%.

Example 64. Hydrochloride Y- (3-ethylphenyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonamide.

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 1.4 mg (0.7%). ¹ NNMR (270 MHz, CH ₃ OH-b ₄ ) δ ppm 8.35 (s, 1H), 7.58-6.92 (m, 7H), 3.54-3.44 (m, 2H), 3.01-2.95 (m, 4H), 2, 66 (s, 1H), 2.18-2.01 (m, 3H); LC-MS 403 (M-H) ⁺ ; purity (HPLC) 100%.

Example 65. Hydrochloride Y- (3,4-dimethoxyphenyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonamide.

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 7.7 mg (3.6%). ¹ N

- 20 011581

NMR (270 MHz, CH ₃ OH-b ₄ ) δ 8.04 (d, 1 = 6.60 Hz, 1H), 7.77-7.75 (m, 2H), 6.85-6.83 ( m, 2H), 6.68-6.83 (m, 1H), 3.87-3.85 (m, 4H), 3.77-3.75 (m, 6H), 3.49-3, 45 (m, 4H); 2.65 (s, 1H); LC-MS 435 (M-H) ⁺ ; purity (HPLC) 98%.

Example 66. Hydrochloride Y- (4-bromo-2-methylphenyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonamide.

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 12.2 mg (5.3%). ¹ NNMR (270 MHz, CH ₃ OH-b ₄ ) δ ppm 8.07 (d, 1 = 6.33 Hz, 1H), 7.86-7.79 (m, 2H), 7.40 (d, 1 = 1.58 Hz, 1H), 7.307.29 (m , 1H), 7.08 (d, 1 = 8.71 Hz, 1H), 3.96-3.92 (m, 4H), 3.53-3.51 (4H), 2.66 (s, 1H), 2.11 (s, 3H); LC-MS 467 (M-H) ⁺ ; purity (HPLC) 90%.

Example 67. 2- (4-Piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride.

The synthesis is carried out essentially in accordance with the procedure of method Hb from tert-butyl ether 4- [2- (3,4-dihydro-1H-isoquinoline-2-sulfonyl) thieno [3,2-c] pyridin-4 -yl] piperazine-1-carboxylic acid (0.235 mmol, 1 equiv.). Yield: 4.0 mg. LC / MS: 1 _K = 0.801 (system: from 30% to 60% ASA for 1.5 min, NuregkP VB8), purity: 92%. MS: 415 (M + 1). Ή-NMR (270 MHz, DMSO-b ₆ ) δ ppm 2.87 (t, 1 = 5.81 Hz, 2H), 3.30 (s, 4H), 4.43 (s, 2H), 7.15 (m, 4H), 7.70 (d, 1 = 5.54 Hz, 1H), 8.12 (s, 1H), 8.18 (d, 1 = 5.54 Hz, 1H) 6 aliphatic protons are closed by the peak of water in the spectrum and therefore cannot be analyzed.

Example 68. Hydrochloride of (2-thiophen-2-yl-ethyl) amide of 4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid.

The synthesis is carried out essentially in accordance with the method of method Hb from tert-butyl ether 4- [2- (2-thiophen-2-yl-ethyl-sulfamoyl) thieno [3,2-c] pyridin-4-yl] piperazin-1 -carboxylic acid (0.235 mmol, 1 equiv.). Yield: 8.7 mg. LC / MS: 1 _K = 0.430 (system: 30 to 60% ASA for 1.5 min, NuregkI WB8), purity: 93%. MS: 409 (M + 1). ^! H-NMR (270 MHz, DMSO-b ₆ ) δ ppm 2.25 (s, 1H), 2.75 (s, 1H), 2.96 (t, 1 = 6, 99 Hz, 1H), 3.16 (q, 1 = 6.51 Hz, 1H), 3.31 (s, 4H), 3.70 (s, 4H), 6.90 (m, 1H), 7.32 (t, 1 = 5.54 Hz, 1H), 7.70 (d, 1 = 5.81 Hz, 1H), 8.04 (d, 1 = 1.85 Hz, 1H), 8.18 (d, 1 = 5.54 Hz, 1H), 8.36 (m, 1H), 9.05 (s, 1H).

Example 69. Hydrochloride of (4-chloro-2,5-dimethoxyphenyl) amide of 4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonic acid.

The synthesis is carried out essentially in accordance with the method of method Hb from tert-butyl ether 4- [2- (4-chloro-2,5-dimethoxyphenylsulfamoyl) thieno [3,2-c] pyridin-4-yl] piperazine -1-carboxylic acid (0.112 mmol, 1 equiv.), Which is used as thienopyridine in method C. Yield: 14.7 mg. LC / MS: 1 _K = 0.610 (system: 30% to 60% ASA for 1.5 minutes, UMS), purity: 92%. MS: 469 (M + 1). ^! NYAMR (270 MHz, DMSO-b ₆₎ δ ppm: 3.17 (s, 1H), 3.27 (s, 4H), 3.38 (s, 3H), 3.58 (d, 1 = 4.22 Hz, 4H), 3.77 (s, 3H) ), 7.08 (s, 1H), 7.69 (d, 1 = 5.81 Hz, 1H), 7.81 (s, 1H), 8.16 (d, 1 = 5.81 Hz, 1H ), 9.07 (s, 1H), 10.17 (s, 1H).

Example 70. 4-Piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid phenethylamide hydrochloride.

The synthesis is carried out essentially in accordance with the procedure of method Hb from 4- (2-phenethylsulfamoylthieno [3,2-c] pyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (0.112 mmol, 1 equiv .). Yield: 3.8 mg. LC / MS: 1 _K = 0.410 (system: 30 to 60% ASA for 1.5 min, UMS), purity: 91%. MS: 403 (M + 1). Ή-NMR (270 MHz, CH ₃ OH-b ₄ ) δ ppm 1.44 (d, 1 = 7.13 Hz, 2H), 3.51 (d, 1 = 4.75 Hz, 4H), 3.54 (s, 2H), 3.94 (m, 4H), 7.05 (m, 4H), 7.16 (m, 1H), 7.62 (s, 1H), 7.72 (d, 1 = 6.60 Hz, 1H), 8.00 (d, 1 = 6.60 Hz, 1H).

Example 71. Hydrochloride of (2,6-diethylphenyl) amide 4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid.

The synthesis is carried out essentially in accordance with the procedure of method Hb from 4- [2- (2,6-diethylphenylsulfamoyl) thieno [3,2-c] pyridin-4-yl] piperazine-1-carboxylic tert-butyl ester acid (0.112 mmol, 1 equiv.). Yield: 9.0 mg. LC / MS: 1 _K = 0.830 (system: 30% to 60% ASA for 1.5 minutes, UMS), purity: 92%. MS: 431 (M + 1). Ή-NMR (270 MHz, DMSO-b ₆ ) δ ppm 0.96 (t, 1 = 7.52 Hz, 6H), 2.25 (m, 1H), 2.43 (s, 2H), 2.75 (t, 1 = 1.72 Hz, 1H), 3.26 (s, 4H), 3.62 (s, 4H), 7.09 (s, 1H), 7.12 (s, 1H), 7.23 (m, 1H), 7.73 (d , 1 = 5.81 Hz, 1H), 7.77 (s, 1H), 8.19 (d, 1 = 5.81 Hz, 1H), 9.04 (s, 1H), 9.95 (s, 1H).

Example 72. The hydrochloride of (3-phenylpropyl) amide 4-piperazin-1-ylthieno [3,2-c] pyridin-2sulfonic acid.

The synthesis is carried out essentially in accordance with the procedure of method Hb from 4- [2- (3-phenylpropylsulfamoyl) thieno [3,2-c] pyridin-4-yl] piperazine-1-carboxylic acid tert-butyl ester ( 0.112 mmol, 1 equiv.). Yield: 13.0 mg. LC / MS: 1 _K = 0.726 (system: 30% to 60% ASA for 1.5 minutes, UMS), purity: 91%. MS: 417 (M + 1). Ή-NMR (270 MHz, CH ₃ OH-b ₄ ) δ ppm 1.82 (m, 2H), 2.63 (m, 2H), 3.04 (t, 1 = 6.86 Hz, 2H), 3.55 (s, 4H), 4.09 (s, 4H) ), 7.16 (m, 4H), 7.82 (d, 1 = 6.60 Hz, 1H), 8.05 (d, 1 = 6.33 Hz, 1H), 8.14 (s, 1H )

Example 73. Hydrochloride of (3,3-diphenylpropyl) amide of 4-piperazin-1-ylthieno [3,2-c] pyridin-2sulfonic acid.

The synthesis is carried out essentially in accordance with the procedure of method Hb from 4- [2- (3,3-diphenylpropylsulfamoyl) thieno [3,2-c] pyridin-4-yl] piperazine-1-carboxylic tert-butyl ester acids (0.112

- 21 011581 mmol, 1 equiv.). Yield: 14.4 mg. LC / MS: 1 _I = 1.109 (system: 30% to 60% ASA for 1.5 minutes, UMS), purity: 93%. MS: 493 (M + 1). Ή-NMR (270 MHz, DMSO-4 ₆ ) δ ppm 2.20 (m, 2H), 2.80 (m, 2H), 3.29 (s, 4H), 3.67 (d, 1 = 5.01 Hz, 4H), 4.01 (m, 1H ), 7.14 (m, 8H), 7.71 (d, 1 = 5.81 Hz, 1H), 7.95 (s, 1H), 8.18 (d, 1 = 5.81 Hz, 1H ), 8.27 (m, 2H), 9.13 (s, 2H).

Example 74. Hydrochloride of [2- (5-methoxy-1H-indol-3-yl) ethyl] amide of 4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid.

The synthesis is carried out essentially in accordance with the method of method Hb from tert-butyl ether 4 {2- [2- (5-methoxy-1H-indol-3-yl) ethylsulfamoyl] thieno [3,2-c] pyridin-4 -yl} piperazine-1-carboxylic acid (0.112 mmol, 1 equiv.). Yield: 6.1 mg. LC / MS: 1 _H = 0.364 (system: 30% to 60% ASA for 1.5 minutes, ΥΜΟ, purity: 91%. MS: 472 (M + 1). Ή-NMR (270 MHz, CH ₃ OH-th ₄ ) δ ppm 2.85 (t, 1 = 6.20 Hz, 2H), 3.48 (t, 1 = 6.20 Hz, 2H), 3.55 (m, 4H) 3.80 (s, 3H), 4.02 (m, 4H), 6.44 (dd, 1 = 8.71, 2.37 Hz, 1H), 6.80 (m, 2H), 6, 97 (s, 1H), 7.64 (s, 1H), 7.67 (s, 1H), 7.97 (d, 1 = 6.60 Hz, 1H).

Example 75. 4-Piperazin-1-ylthieno [3,2-c] pyridin-2sulfonic acid 4-trifluoromethylbenzylamide hydrochloride.

The synthesis is carried out essentially in accordance with the procedure of method Hb from 4- [2- (4-trifluoromethylbenzylsulfamoyl) thieno [3,2-c] pyridin-4-yl] piperazine-1-carboxylic acid tert-butyl ester ( 0.112 mmol, 1 equiv.), Which is used as thienopyridine in method C. Yield: 1.9 mg. LC / MS: 1 _H = 0.771 (system: 30 to 60% ASA for 1.5 minutes, ΥΜ0), purity: 91%. MS: 457 (M + 1). Ή-NMR (270 MHz, CH ₃ OH-th ₄ ) δ ppm 3.54 (m, 4H), 3.98 (m, 4H), 4.36 (s, 2H), 7.49 (m, 4H), 7.74 (d, 1 = 6.86 Hz, 1H ), 8.02 (s, 1H), 8.07 (d, 1 = 6.60 Hz, 1H).

Example 76. 4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonic acid benzyl ethylamide hydrochloride.

The synthesis is carried out essentially in accordance with the method of method Hb from tert-butyl ether 4 [2- (benzylethylsulfamoyl) thieno [3,2-c] pyridin-4-yl] piperazine-1-carboxylic acid (0.112 mmol, 1 equiv .). Yield: 6.4 mg. LC / MS: 1 _H = 0.930 (system: 30% to 60% ASA for 1.5 minutes, ΥΜ0 '). purity: 95%. MS: 417 (M + 1). Ή-NMR (270 MHz, CH ₃ OH-th ₄ ) δ ppm 1.03 (t, 1 = 7.13 Hz, 3H), 3.37 (m, 2H), 3.57 (s, 2H), 3.75 (m, 2H), 4.11 (s, 2H) ), 4.50 (s, 2H), 5.80 (s, 1H), 7.32 (m, 5H), 7.84 (d, 1 = 6.60 Hz, 1H), 8.07 (d , 1 = 6.60 Hz, 1H); 8.14 (s, 1H).

The intermediate product 55. tert-Butyl-4- (3 - {[((3-ethylphenyl) amino] sulfonyl} thieno [3,2-c] pyridin-4-yl) piperazine-1-carboxylate.

The title compound (82.7 mg, 76%) was obtained as an off-white solid from tert-butyl-4- [3- (chlorosulfonyl) thieno [3,2-c] pyridin-4-yl] piperazine- 1-carboxylate (90.0 mg, 0.215 mmol) and 3-ethylaniline (33.9 mg, 0.28 mmol). Я-NMR (400 MHz, SES1 ₃ ) δ 1.03 (t, 1 = 1.5 Hz, 3H), 1.48 (s, 9H), 2.47 (q, 1 = 7.7 Hz, 2H ), 3.00-3.53 (m, 6H), 4.02-4.44 (m, 2H), 6.66 (d, 1 = 8.0 Hz, 1H), 6.75 (s, 1H), 6.66 (d, 1 = 8.0 Hz, 1H), 7.02 (t, 1 = 7.8 Hz, 1H), 7.67 (d, 1 = 5.5 Hz, 1H) 8.24 (s, 1H), 8.39 (d, 1 = 5.5 Hz, 1H), 9.80 (s, 1H). MS (Ε8Σ +) t / ζ 503.2 (M + H) ⁺ , HPLC 97%, I _t : 3.93 min. (5-99% MECA for 3 minutes).

Example 77. Hydrochloride Y- (3-ethylphenyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-3-sulfonamide.

Prepared from tert-butyl 4- (3 - {[((3-ethylphenyl) amino] sulfonyl} thieno [3,2-c] pyridin-4-yl) piperazine-1-carboxylate (81.1 mg, 0.161 mmol) 19 mg (98%) of the product are obtained in the form of a white solid (38.0 mg, 54%). Ή-NMR (400 MHz, CH ₃ OH-th ₄ ) δ 1.09 (t, 1 = 7.5 Hz, 3H), 2.51 (q, 1 = 7.5 Hz, 2H), 3.59 (br s, 8H), 6.89-6.92 (m, 3H), 7.12-7.14 (m, 1H), 8.06 (d, 1 = 6.0 Hz, 1H), 8.36 (d, 1 = 6.0 Hz, 1H); 8.49 (s, 1H). MS (Ε8Σ +) t / ζ 403.2 (M + H) ⁺ . HPLC 95%, I, _t : 3.02 min. (5-99% MECA for 3 minutes).

Intermediate 56. tert-Butyl-4- (3-bromothieno [3,2-c] pyridin-4-yl) piperazine-1 carboxylate.

A mixture of 3-bromo-4-chlorothieno [3,2-c] pyridine (729 mg, 2.93 mmol,), tert-butylpiperazine-1-carboxylate (1.64 g, 8.80 mmol) and K ₂ CO ₃ (811 mg, 5.87 mmol) in DMSO (45 ml) was stirred for 5 days at 100 ° C. After addition of H ₂ O and ethyl acetate, the layers were separated. The aqueous phase was extracted twice with ethyl acetate, the combined organic phases were washed with water and brine, and dried (MgO ₄ ). After filtering and removing the solvent, the residue was purified by flash chromatography on silica gel (pentane / ethyl acetate 8: 2) to give the product as a white powder (398 mg, 34%). HPLC 99%. I _t : 3.27 min. (5-99% MECA for 3 minutes). Ή-NMR (400 MHz, CH ₃ OH- ₄ ) δ 1.48 (s, 9H), 3.21 (br s, 4H), 3.71 (s br, 4H), 7.61 ( d, 1 = 6.1 Hz, 1H), 7.72 (s, 1H), 8.08 (d, Σ = 5.6 Hz, 1H). MS (Ε8Σ +) t / ζ 398.2 (M + H) ⁺ .

Intermediate 57. {4- (4 - [(tert-Butoxycarbonyl) piperazin-1-yl] thieno [3,2-c] pyridin-3yl) sulfonyl} lithium.

To a suspension of tert-butyl-4- (3-bromothieno [3,2-c] pyridin-4-yl) piperazine-1-carboxylate (4.055 g, 10.18 mmol) in diethyl ether (30 ml) at -78 ° C in an atmosphere of L ₂ , a 1.6 M solution of n-CuL in hexane (9.5 ml, 15.2 mmol) was added dropwise. The mixture was stirred for 1 h, then a saturated solution of 8O ₂ in THF (25 ml) was pipetted into the mixture at -78 ° C. Overnight, the reaction mixture was allowed to slowly warm to room temperature. Then, the solvent was evaporated, the residue was washed several times with diethyl ether and dried in vacuo to obtain 4.094 g of solid non

- 22 011581 all white matter containing 66% of the title compound and 34% (n-butylsulfonyl) lithium as a by-product. The resulting mixture was used in the next step without further purification. Я-NMR (400 MHz, CH ₃ OH-a ₄ ) δ 1.48 (s, 9H), 3.22 (br s, 4H), 3.72 (s br., 4H),?, 60 ( d, 1 = 5.5 Hz, 1H), 8.06 (d, 1 = 5.5 Hz, 1H), 8.14 (s, 1H). MS (E8H ·) t / ζ 384.0 (M + H) ⁺ . HPLC I: 2.62 min (599% ΜβΟΝ for 3 min).

Intermediate 58. tert-Butyl-4- [3- (chlorosulfonyl) thieno [3,2-c] pyridin-4-yl] piperazine-1-carboxylate.

To a suspension of ({4- [4- (tert-butoxycarbonyl) piperazin-1-yl] thieno [3,2-c] pyridin-3-yl} sulfonyl) lithium (2.751 g,?, 06 mmol (3.126 g crude mixture product)) in DCM (40 ml) at 0 ° C, Ν chlorosuccinimide (1.338 g, 10.0 mmol) was added. After 20 minutes, the temperature was raised to room temperature and the reaction mixture was stirred for an additional 2.5 hours. The resulting product solution was washed with water and the aqueous phase was extracted with DCM. The combined organic extracts were washed with brine and dried over MgSO ₄ . After filtering and evaporating the solvent, the residue was washed several times with pentane to give the product as an off-white solid (2.024 g, 69%). Ή-NMR (400 MHz, CH ₃ OH-a ₄ ) δ 1.4? (s, 9H), 3.11 (br s, 4H), 3.2-4.3 (s br., 4H), 7.68 (d, 1 = 5.5 Hz, 1H), 8, 45 (d, 1 = 5.5 Hz, 1H), 8.60 (s, 1H). MS (E8H ·) t / ζ 418.2 (M + H) ⁺ ; HPLC 92%, I: 3.76 min (5-99% ΜβΟΝ over 3 min).

Intermediate 59. tert-Butyl-4- (3 - {[((4-isopropylphenyl) amino] sulfonyl} thieno [3,2-c] pyridin-4-yl) piperazine-1-carboxylate.

The title compound (58.3 mg, 52%) was obtained as an off-white solid from tert-butyl-4- [3- (chlorosulfonyl) thieno [3,2-c] pyridin-4-yl] piperazin- 1-carboxylate (90.0 mg, 0.215 mmol) and 4-isopropylaniline (37.9 mg, 0.28 mmol). Ή-NMR (400 MHz, SES1 ₃ ) δ 1.12 (d, 1 = 7.0 Hz, 6H), 1.47 (s, 9H), 2.76 (sept, 1 = 6.9 Hz, 2H ), 3.01-3.53 (m, 6H), 4.04-4.41 (m, 2H), 6.79 (d, 1 = 8.5 Hz, 2H), 6.66 (d, 1 = 8.5 Hz, 2H), 7.69 (d, 1 = 5.5 Hz, 1H), 8.23 (s, 1H), 8.40 (d, 1 = 5.5 Hz, 1H) 9.90 (s, 1H). MS (E8H ·) t / ζ 517.2 (M + H) ⁺ ; HPLC 97%, I: 4.01 min (5-99% GeCN for 3 min).

Example 78. No. (4-Isopropylphenyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-3-sulfonamide hydrochloride.

The expected product is obtained from tert-butyl-4- (3 - {[((4-isopropylphenyl) amino] sulfonyl} thieno [3,2-c] pyridin-4-yl) piperazine-1-carboxylate (60.0 mg, 0.116 mmol), which results in 19 mg (98%) of the product in the form of a solid off-white solid (25.8 mg, 49%) according to method H-b. ¹ H-NMR (400 MHz, CH3OH-a4) δ 1.16 (d, 1 = 7.0 Hz, 6H), 2.81 (sept, 1 = 6.8 Hz, 1H), 3.59 (s broad., 8H), 7.00 (d, 1 = 8.0 Hz, 2H), 7.10 (d, 1 = 8.0 Hz, 2H), 8.07 (s, broad, 1H), 8 37 (s br., 1H); 8.50 (s, 1H). MS (E8H ·) t / ζ 417.2 (M + H) ⁺ ; HPLC 94%, Hg: 3.14 min (5-99% Μ βΟΝ over 3 min).

Example 79. Hydrochloride No. (4-methylphenyl) -4- (pyrrolidin-3-yloxy) thieno [3,2-c] pyridin-2-sulfonamide.

4-Chloro-No. (4-methylphenyl) thieno [3,2-c] pyridin-2-sulfonamide (60.0 mg, 0.17 mmol) in dry DMF (1 ml) and No. 1H (5.1 mg, 0.21 mmol) was added to pyrrolidin-3-ol (18.5 mg, 0.21 mmol) in a nitrogen atmosphere. The mixture was kept in a microwave oven at 200 ° C for 5 minutes. The product was purified by preparative HPLC.

Yield: 29.9 mg (43.4%). Я-NMR (270 MHz, CH ₃ OH-a ₄ ) δ ppm 8.09 (s, 1H), 7.71 (d, 1 = 6.93 Hz, 1H), 7.46 (d, 1 = 6, 93Hz, 1H), 7.47-7.44 (m, 4H), 4.67 (d, 1 = 3.22 Hz, 1H), 3.97 (s, 2H), 2.26 (s, 3H). LC-MS 390 (MH) ⁺ ; purity (HPLC) 99%.

Example 80. Hydrochloride No. (4-methylphenyl) -4- (piperidin-4-yloxy) thieno [3,2-c] pyridin-2-sulfonamide.

The synthesis is carried out essentially in accordance with the procedure for the preparation of Ν- (4methylphenyl) -4- (pyrrolidin-3-yloxy) thieno [3,2-c] pyridin-2-sulfonamide hydrochloride. Yield: 16.2 mg (22.7%). Ή NMR (270 MHz, CH ₃ OH-a ₄ ) δ ppm 7.81-7.78 (m, 2H), 7.62 (d, 1 = 6.93 Hz, 1H), 7.13-7.04 (m, 4H), 4.05-3.94 ( m, 1H), 3.90-3.88 (m, 2H), 3.63-3.58 (m, 2H), 2.27 (s, 3H), 2.06-2.03 (m, 2H), 2.01-1.71 (m, 2H); LC-MS 404 (MH) ⁺ ; purity (HPLC) 99%.

Example 81. Hydrochloride No. (2,3-difluorobenzyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonamide.

Yield: 74.4 mg (39.2%). Я-NMR (270 MHz, CH ₃ OH-a ₄ ) δ ppm 8.10-8.03 (m, 2H), 7.81 (d, 1 = 6.68 Hz, 1H), 7.16-7.05 (m, 3H), 4.37 (s, 2H) 4.11-4.07 (m, 4H); 3.59-3.53 (m, 4H); LC-MS 425 (M-H) ⁺ ; purity (HPLC) 90%.

Example 82. No. (3-Chlorobenzyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonamide hydrochloride.

Yield: 74.4 mg (44.7%). Я-NMR (270 MHz, CH ₃ OH-a ₄ ) δ ppm 8.04-8.01 7.85 (d, 1 = 6.93 Hz, 1H), 7.227.15 (m, 4H), 4.30 (s, 2H), 4.14-4.10 (m 4H); 3.60-3.54 (m, 4H); LC-MS 423 (M-H) ⁺ ; purity (HPLC) 90%.

- 23 011581

Table 5

Example The EU Th ⁴ 83 4 - (1,4-Diazepan-1-yl) -2 (phenylsulfonyl) thieno [3,2-c] pyridine hydrochloride (At ABOUT 84 Hydrochloride 4 - (1,4-diazepan-1-yl) -2- [(3,4-dichlorophenyl) sulfonyl] thieno [3,2- c] pyridine ABOUT 85 4- (1,4-diazepan-1-yl) -2- (1- hydrochloride naphthylsulfonyl) thieno [3,2-c] pyridine $ ABOUT СО СО 4- (1,4-Diazepan-1-yl) -2- [4-tert-butylphenylsulfonyl) thieno [3,2s] pyridine hydrochloride ABOUT

87 4- (1,4-diazela n-1-yl) -2 - hydrochloride - [3, 4-dimethylphenylsulfonyl) thieno [3,2- c] pyridine BUT 0 88 2 - ((4-Bromophenyl) sulfonyl] hydrochloride] - 4- (1,4-diazepan-1-yl) thieno [3, 2- c] pyridine 0 89 2- (phenylsulfonyl) -4piperain-1-ylthieno [3,2-c] pyridine hydrochloride σ 0 90 Hydrochloride 2- (3- me toxibeneolsulfonyl) -4-piperazine-1- ylthieno [3,2-c] pyridine 0 91 2- (4methoxybenzenesulfonyl) -4-piperazin-1ylthieno [3,2-c] pyridine hydrochloride -0-0 = - 0 92 4-piperazin-1-yl-2 hydrochloride - {[4 trifluoromethyl) phenyl] sulfonyl} thieno [3,2c] pyridine 0 93 Hydrochloride 2 - ([2-tert- butylphenyl) sulfonyl] -4-piperazin-1- ylthieno [3,2-c] pyridine 0 94 2 - ((3,4-Dichlorophenyl) sulfonyl] '-4-pylerazin-1ylthieno [3,2-c] pyridin-2-sulfonamide hydrochloride 0, ^ - C1 0 95 Hydrochloride 2 - [(4-tert- butylphenyl) sulfonyl] -4-piperazin-1- ylthieno [3,2-c] pyridine 1 ^4-7 96 2- (1-Naphthylsulfonyl) -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride 0 97 2 - [(3-Fluorophenyl) sulfonyl] hydrochloride] - 4-piperazin-1-ylthieno [3,2-c] pyridin-2sulfonamide sous R 0 98 2- (mesitylsulfonyl) -4 piperazin-1-ylthieno [3,2-c] pyridine hydrochloride BUT- 0 99 Hydrochloride 2 - [(2- methoxyphenyl) sulfonyl] -4-piperazin-1ylthieno [3,2-c] pyridine ά _? 0

- 24 011581

one hundred Hydrochloride 2 - [{2,4- dime to si phenyl) sulfonyl] -4-piperazine- 1-ylthieno [3,2-c] pyridine Φ 101 Hydrochloride 2 - ((2,4- dimethylphenyl) sulfonyl] -4-piperazin-1- ylthieno [3,2-c] pyridine XX 0 102 Hydrochloride 2 - ((2,5- dimethylphenyl} sulfonyl] -4-piperazin-1- ylthieno [3,2-c] pyridine XX 0 103 2 - [(2-Ethylphenyl) sulfonyl] hydrochloride] - 4-piperazin-1-ylthieno [3,2-c] pyridine αζ 0 104 4- (piperazinyl) -2- (3methoxybenzylsulfonyl) thienopyridine hydrochloride ^ό α> 0 105 2- (Benzylsulfonyl) -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride CX φ 106 4-piperazin-1-yl-2 hydrochloride - {[4- (trifluoromethyl) benzyl] sulfonyl] thieno- [3,2-s] pyridine φ 107 Hydrochloride 2— [(3 - bromobenzyl} sulfonyl] -4-piperazin-1- ylthieno [3,2-c] pyridine φ 108 Hydrochloride 2 - ((2,3- difluorobenzyl) sulfonyl] -4-piperazine-1- ylthieno [3,2-c] pyridine Ρ φ 109 Hydrochloride 2 - [(4- bromobenzyl) sulfonyl] -4-piperazine-1- ylthieno [3,2-c] pyridine ΑΧ φ 110 Hydrochloride 2 - {(2,5- bis (trifluoromethyl) benzyl] sulfonyl) -4- piperazin-1-ylthieno [3,2-c] pyridine ^0Ρ 'ΌΧ φ 111 Hydrochloride 2 - ((4- methylbenzyl) sulfonyl] -4-piperazin-1- ylthieno [3,2-c] pyridine χχ ^ φ 112 Hydrochloride 2 - {[5-chloro-2- {trifluoromethyl) benzyl] sulfonyl} -4- piperazin-1-ylthieno (3,2-c] pyridine φ

- 25 011581

I 113 Hydrochloride 2-G (3.5— dimethoxybenzyl) sulfonyl) -4-liperazin- 1-ylthieno [3,2-c] pyridine 0 0 114 Hydrochloride 2— [(2 - naphthylmethyl) sulfonyl] -4-piperazine-1- ylthieno [3,2-c] pyridine F 115 4-piperazin-1-yl-2 hydrochloride - {[4- (1,2, 3-thiadiazole-5- il) benzyl] sulfonyl] thieno [3.2— c] pyridine ‘H-8 0 116 1- (4-Pyrrolidin-1-yl-phenyl) - hydrochloride - 2 - [(4-piperazin-1-ylthieno [3,2- c] pyridin-2-yl) sulfonyl] propanone 0 117 1- [4- (Diethylamino) phenyl] -2- hydrochloride [(4-piperazin-1-ylthieno [3,2-c] pyridin- 2-yl) sulfonyl] propanone 0 118 1- (4-Bromophenyl) -2 - [(4-piperazin-1ylthymo [3,2-c] pyridin-2- il) sulfonyl] propanone 0 119 1- (3-Methoxyphenyl) -2 - [(4-piperazin-1ylthieno [3,2-c] pyridin-2- il) sulfonyl] propanone l 0 120 1-Phenyl-2- [(4-piperaein-1-ylthieno [3,2- c] pyridin-2-yl) sulfonyl] propanone 0

Scheme 6

Explanations for Scheme 6: ί) amines containing a protective BOC group (B ⁴ ), K2CO3, DMSO; ίί) thiophenols (B ^! -8H), Cu2 (1) O, DMF; ίίί) No. OAc, oxon, water; ίν) a.TFUK, b.НС1, methanol.

Intermediate 60. tert-Butyl-4- (2-bromothieno [3,2-c] pyridin-4-yl) piperazine-1-carboxylate.

2-Bromo-4-chlorothieno [3,2-c] pyridine (5.0 g, 20.24 mmol) and K ₂ CO ₃ (13.97 g, 101.2 mmol) are stirred in DMSO (20 ml) s subsequent addition of tert-butyl piperazine-1-carboxylate (4.14 g, 22.26 mmol). The reaction mixture was stirred at 100 ° C for 6 days. The reaction mixture was filtered to remove carbonate and water (50 ml) and ethyl acetate were added. The phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases were dried (MgSO ₄ ) and the solvent was evaporated. The crude product was purified by flash chromatography using ethyl acetate / hexane (2/8) as the eluent to give 2 g of the expected product, yield 25%, purity 99%. ¹ H-NMR (270 MHz, ί.ΌΟ ₃ ) δ 1.48 (s, 9H), 1.52-1.63 (m, 1H), 3.42-3.47 (m, 4H), 3 , 61-3.64 (m, 4H), 7.22 (dd, 1 = 5.4, 1Hz, 1H), 7.35 (d, 1 = 1Hz, 1H), 8.04 (d, 1 = 5.4Hz, 1H). 111 // = 398.91 (M + H), bromide sample.

Intermediate 61. tert-Butyl-4- (2-bromothieno [3,2-c] pyridin-4-yl) -1,4-diazepan-1 carboxylate.

According to the procedure described above, starting from 2-bromo-4-chlorothieno [3,2-c] pyridine (7.5 g, 30.45 mmol), K ₂ CO ₃ (6.7 g, 33.5 mmol ) and tert-butyl 1,4-diazepane-1-carboxylate (21.0 g, 152.2 mmol) in DMSO (30 ml) using flash chromatography to give 3.04 g of the title compound (yield) 25%). HPLC purity 92%; Я-NMR (270 MHz, SIS) δ 1.38 (s, 4.5H), 1.43 (s, 4.5H), 1.96-2.11 (m, 2H), 3.36-3 41 (m, 1H), 3.46-3.51 (m, 1H), 3.65-3.87 (m, 6H), 7.02-7.04 (m, 1H), 7.40 -7.42 (m, 1H), 7.94 (d, 1 = 5.4 Hz, 1H), ™ / ζ = 411.97 (M + H).

Linking with thiophenols (method M).

Intermediate 62. tert-Butyl- (4- (2-phenylthio) thieno [3,2-c] pyridin-4-yl) -1,4-diazepan-1 carboxylate.

tert-Butyl-4- (2-bromothieno [3,2-c] pyridin-4-yl) -1,4-diazepan-1-carboxylate (0.31 g, 0.752 mmol),

- 26 011581 powdered KOH (0.084 g, 1.5 mmol) and Cu ₂ (CO (0.1 g, 0.75 mmol) are mixed with DMF (1 ml) and a solution of benzenediol (0.016 g, 1.5 mmol) is added in DMF (1 ml) The reaction mixture is heated to 120 ° C and maintained at this temperature for 15 hours

The reaction mixture was poured onto a loose layer of silica and eluted with chloroform to give a crude product. The crude product was purified by flash chromatography using ethyl acetate / hexane (2/8) as the eluent to give 0.21 g of the expected product, yield 64%, purity 90%. ¹ H-NMR (270 MHz, CPC1 ₃ ) δ 1.37 (s, 4.5H), 1.43 (s, 4.5H), 1.97-2.10 (m, 2H), 3.36 -3.43 (m, 1H), 3.46-3.53 (m, 1H), 3.64-3.73 (m, 2H), 3.78-3.96 (m, 4H), 7 05 (d, 1 = 5.4 Hz, 1H), 7.22-7.32 (m, 5H), 7.59-7.63 (m, 1H), 7.97 (d, 1 = 5 4 Hz, 1H). t / ζ = 442.15 (M + H).

Oxidation of thio derivatives (method Ν).

Intermediate 63. tert-Butyl- (4- (2-phenylsulfonyl) thieno [3,2-c] pyridin-4-yl) -1,4-diazepan-1-carboxylate.

Into a solution of tert-butyl- (4- (2-phenylthio) thieno [3,2-c] pyridin-4-yl) -1,4-diazepan-1-carboxylate (0.21 g, 0.48 mmol) and IAOAc (0.5 g) in ethanol (10 ml) (pH ~ 5) was added oxone (0.64 g, 1.04 mmol) and the resulting mixture was dissolved in water (1 ml). The reaction mixture was stirred at room temperature for 16 hours. Oxone (0.32 g) in water (1 ml) was added. A complete 8M conversion is obtained after 8 hours. Water (50 ml) and chloroform (30 ml) are added. The phases are separated and the aqueous phase is extracted with chloroform. The combined organic phases were dried over (MgSO ₄ ) and the solvent was evaporated to give a crude product, which was purified by reverse phase chromatography (10 ^ 90) to obtain 0.191 g of the expected product as a yellow oil (86% yield, 98% purity). 'H-NMR (270 MHz, CPC1 ₃ ) δ 1.28 (s, 4.5H), 1.38 (s, 4.5H), 1.99-2.03 (m, 2H), 3.31 -3.40 (m, 1H), 3.42-3.47 (m, 1H), 3.63-3.69 (m, 2H), 3.85-3.98 (m, 4H), 7 02 (d, 1 = 5.4Hz, 1H), 7.48-7.61 (m, 3H), 7.76-8.01 (m, 3H), 8.06-8.08 (m, 1H). t / ζ = 474.01 (M + H).

Removal of the tert-butyl carboxylate protecting group (method O).

Example 83. 4- (1,4-Diazepan-1-yl) -2- (phenylsulfonyl) thieno [3,2-c] pyridine hydrochloride. tert-Butyl- (4- (2-phenylsulfonyl) thieno [3,2-c] pyridin-4-yl) -1,4-diazepan-1-carboxylate (0.165 g, 0.348 mmol) was dissolved in DCM (2 ml) and TFA (1 ml) was added to the resulting solution. The reaction mixture was stirred for 2 hours. The solvent was evaporated. Methanol and HCl in ether (x 3) were added to the residue, yielding 0.118 g of the target HCl salt (yield 85%, purity 98%). 'H-NMR (270 MHz, CHOH-b ₄ ) δ 2.45-2.52 (m, 2H), 3.45-3.52 (m, 2H), 3.70-3.79 (m, 2H), 4.18-4.22 (m, 2H), 4.30-4.40 (m, 2H), 7.62-7.76 (m, 5H), 7.91 (d, 1 = 5.4Hz, 1H), 8.11 (dd, 1 = 5.4, 1Hz, 1H), 8.41 (d, 1 = 1Hz, 1H), t ^ = 374.09 (M + H-HC1) .

Intermediate 64. tert-Butyl-4 - ([2- (4-tert-butylphenyl) thio] thieno [3,2-c] pyridin-4-yl) 1,4-diazepan-1-carboxylate.

The product was obtained according to the procedure of Method M. Purification by flash chromatography using ethyl acetate / hexane (2/8) as the eluent afforded 0.035 g (99% purity) of the title compound. ¹ H-NMR (270 MHz, CPC1 ₃ ) δ 1.28 (s, 9H), 1.38 (s, 4.5H), 1.43 (s, 4.5H), 1.98-2.03 (m, 2H), 3.35-3.41 (m, 1H), 3.46-3.52 (m, 1H), 3.62-3.72 (m, 2H), 3.77-3 93 (4H), 7.04 (d, 1 = 5.4 Hz, 1H), 7.27-7.34 (m, 4H), 7.54-7.56 (m, 1H), 7, 95 (d, 1 = 5.4 Hz, 1H). m ^ = 498.0 (M + H).

Intermediate 65. tert-Butyl-4 - ([2- (4-tert-butylphenyl) sulfonyl] thieno [3,2-c] pyridin4-yl) -1,4-diazepan-1-carboxylate.

According to Method B, from tert-butyl-4 - ([2- (4-tert-butylphenyl) thio] thieno [3,2-c] pyridin-4yl) -1,4-diazepan-1-carboxylate (0.035 g , 0.070 mmol), oxone (0.17 g, 0.28 mmol), IaOAc (0.5 g) in UNN (2 ml followed by reverse phase chromatography (40 ^ 70)), 6 mg of product are obtained. Yield 17%, purity 98%). ^! H-NMR (270 MHz, CPC1 ₃ ) δ 1.32 (s, 9H), 1.35 (s, 9H), 2.05-2.15 (m, 2H), 3.45-3.62 ( m, 2H), 3.75-4.13 (m, 6H), 7.20-7.27 (m, 5H), 7.58 (d, 1 = 10.8 Hz, 1H), 7.93 (d, 1 = 10.8 Hz, 1H). m ^ = 530.0 (M + H).

Intermediate 66. tert-Butyl-4 - ([2- (3,4-dimethylphenyl) thio] thieno [3,2-c] pyridin-4-yl) 1,4-diazepan-1-carboxylate.

The title compound was prepared according to method M. Purification by flash chromatography using ethyl acetate / hexane (2/8) as the eluent afforded 0.022 g (95% purity) of the product. ^! H-NMR (270 MHz, CPC1 ₃ ) δ 1.38 (s, 4.5H), 1.43 (s, 4.5H), 1.96-2.04 (m, 2H), 2.21 ( s, 3H), 2.22 (s, 3H), 3.37-3.45 (m, 2H), 3.47-3.50 (m, 2H), 3.77-3.95 (m, 4H), 7.01-7.12 (m, 3H), 7.16 (s, 1H), 7.53 (dd, 1 = 5.4, 1 Hz, 1H), 7.94 (d, 1 = 5.4 Hz, 1H). m ^ = 470.3 (M + H).

Intermediate 67. tert-Butyl-4 - ([2- (3,4-dimethylphenyl) sulfonyl] thieno [3,2-c] pyridin4-yl) -1,4-diazepan-1-carboxylate.

According to Method B, starting from tert-butyl-4 - ([2- (3,4-dimethylphenyl) thio] thieno [3,2-c] pyridin-4-yl) -1,4-diazepan-1- carboxylate (0.022 g, 0.047 mmol), oxone (0.11 g, 0.19 mmol) and IAOAc (0.5 g) in a UNN (2 ml), followed by reverse phase chromatography (40 ^ 70), 9 mg product (yield 38%, purity 92%). ^! H-NMR (270 MHz, CPC1 ₃ ) δ 1.35 (s, 9H), 2.08-2.20 (m, 2H), 2.33 (s, 6H), 3,523.59 (m, 2H) 3.83-3.88 (m, 2H), 4.08-4.18 (m, 4H), 7.21-7.28 (m, 2H), 7.31-7.35 (m, 1H), 7.73-7.75 (m, 2H), 8.02 (d, 1 = 5.4 Hz, 1H). t / ζ = 502.21 (M + H).

Intermediate 68. tert-Butyl-4 - ([2- (1-naphthyl) thio] thieno [3,2-c] pyridin-4-yl) -1,4 diazepan-1-carboxylate.

- 27 011581

The title compound was prepared according to method M. Purification by flash chromatography using ethyl acetate / hexane (2/8) as the eluent gave 0.055 g of a product with a purity (HPLC) of 99%. Я-NMR (270 MHz, СОС1 ₃ ) δ 1.37 (s, 4.5H), 1.43 (s, 4.5H), 1.89-2.20 (m, 2H), 3.30- 3.40 (m, 1H), 3.43-3.50 (m, 1H), 3.60, 3.90 (m, 6H), 6.99 (d, 1 = 5.4 Hz, 1H) 7.39 (dd, 1 = 8.1, 1 Hz, 1H), 7.50-7.61 (m, 5H), 7.79-7.88 (m, 2H), 7.92 (d , 1 = 5.4 Hz, 1H); 8.40-8.44 (m, 1H). 111 // 498.26 (M + H).

Intermediate 69. tert-Butyl- (4- [2- (1-naphthyl) sulfonyl] thieno [3,2-c] pyridin-4-yl) -1,4 diazepan-1-carboxylate.

According to Method B, starting from tert-butyl- (4- [2- (1-naphthyl) thio] thieno [3,2-c] pyridin-4yl) -1,4-diazepan-1-carboxylate (0.055 g 0.112 mmol), oxone (0.27 g, 0.448 mmol) and NaOAc (0.5 g) in E1OH (2 ml), followed by reverse phase chromatography (40 ^ 70), 15 mg of product are obtained. Yield 26%, purity 93%. Я-NMR (270 MHz, СОС1 ₃ ) δ 1.34 (s, 9Н), 2.06-2.10 (m, 2Н), 3.48-3.62 (m, 2Н), 3.78- 3.86 (m, 2H), 3.95-4.16 (m, 4H), 7.19-7.31 (m, 2H), 7.60-7.75 (m, 3H), 7, 92-7.99 (m, 2H), 8.18 (m, 1 = 8.1 Hz, 1H), 8.50-8.53 (m, 1H), 8.77-8.80 (m, 1H). ™ / ζ = 524.22 (M + H).

Example 84. 4- (1,4-Diazepan-1-yl) -2 - [(3,4-dichlorophenyl) sulfonyl] thieno [3,2-c] pyridine hydrochloride.

tert-Butyl-4- {2 - [(3,4-dichlorophenyl) sulfonyl] thieno [3,2-c] pyridin-4-yl} -1,4-diazepan-1 carboxylate is obtained from 3,4-dichlorothiophenol (60 mg, 15%) as a beige solid in accordance with the general methods A and B described above. Я-NMR (270 MHz, SES1 ₃ ) δ 8.27-8.14 (m, 1H), 8.11-8.04 (m, 2H), 7.87-7.80 (m, 1H), 7.67-7.62 (m, 1H), 7.26-7.20 (m, 1H), 4.18-3.98 (m, 4H), 3.87-3.74 (m, 2H) ), 3.61-3.44 (m, 2H), 2.20-2.00 (m, 2H), 1.33 (s, 9H); MS t / ζ 542 (M + 1). The title compound (50 mg, 95%) was obtained as a beige solid in accordance with General Procedure C described above. Ή-NMR (270 MHz, CH ₃ OH-b ₄ ) δ 8.48 (s, 1H), 8.30 (d, 1 = 1.85 Hz, 1H), 8.05 (dd, 1 = 8, 58, 1.98 Hz, 1H), 7.92 (d, 1 = 6.86 Hz, 1H), 7.83 (d, 1 = 8.44 Hz, 1H), 7.69 (d, 1 = 6.86 Hz, 1H), 4.41-4.34 (m, 2H), 4.24-4.16 (m, 2H), 3.76-3.69 (m, 2H), 3.51 -3.43 (m, 2H); 2.52-2.42 (m, 2H); MS t / ζ 442 (M + 1).

Example 85. 4- (1,4-Diazepan-1-yl) -2- (1-naphthylsulfonyl) thieno [3,2-c] pyridine hydrochloride.

The title compound was prepared from tert-butyl [4- [2- (1-naphthyl) sulfonyl] thieno [3,2s] pyridin-4-yl] -1,4-diazepan-1-carboxylate (15 mg, 0.029 mmol) in accordance with method O, yielding 12 mg of the target product (yield 90%, purity 95%). ¹ H-NMR (270 MHz, CH ₃ OH-b ₄ ) δ 2.40-2.50 (m, 2H), 3.45-3.55 (m, 2H), 3.65-3.75 ( m, 2H), 4.06-4.26 (m, 2H), 4.27-4.46 (m, 2H), 7.58-7.80 (m, 4H), 7.83-7, 86 (m, 1H), 8.06 (d, 1 = 8.1 Hz, 1H), 8.20 (d, 1 = 8.1 Hz, 1H), 8.48 (s, 1H), 8, 53-8.56 (m, 1H); 8.83-8.86 (m, 1). m ^ = 424.06 (M + H-HC1).

Example 86. 4- (1,4-Diazepan-1-yl) -2 - ([4-tert-butylphenylsulfonyl) thieno [3,2-c] pyridine hydrochloride.

The title compound was prepared from tert-butyl- (4- [2- (4-tert-butylphenyl) sulfonyl] thieno [3,2-c] pyridin-4-yl) -1,4-diazepan-1-carboxylate ( 6 mg, 11.3 mmol) in accordance with method O, yielding 4 mg of the desired product (yield 76%, purity 88%). Ή NMR (270 MHz, CH ₃ OH-b ₄ ) δ 1.33 (s, 9H), 2.41-2.47 (m, 2H), 3.41-3.49 (m, 2H), 3 65-3.78 (m, 2H), 4.15-4.25 (m, 2H), 4.29-4.40 (m, 2H), 7.65-7.70 (m, 3H) 7.90 (d, 1 = 5.4 Hz, 1H), 8.00-8.04 (m, 2H), 8.37 (s, 1H). m ^ = 430.06 (M + H-).

Example 87. 4- (1,4-Diazepan-1-yl) -2- [3,4-dimethylphenylsulfonyl)] thieno [3,2-c] pyridine hydrochloride.

The title compound was prepared from tert-butyl- (4- [2- (3,4-dimethylphenyl) sulfonyl] thieno [3,2-c] pyridin-4-yl) -1,4-diazepan-1-carboxylate ( 6 mg, 0.012 mmol) in accordance with method O, yielding 6 mg of the desired product (yield 88%, purity 89%). Я-NMR (270 MHz, CH ₃ OH-b ₄ ) δ 2.34 (s, 6H), 2.45-2.55 (m, 2H), 3.42-3.51 (m, 2H), 3.67-3.76 (m, 2H), 4.10-4.20 (m, 2H), 3.58-3.70 (m, 2H), 7.39-7.41 (m, 1H) ), 7.64-7.67 (m, 1H), 7.79-7.84 (m, 2H), 7.89-7.91 (m, 1H), 8.36 (s, 1H). m ^ = 402.07 (M + H-HC1).

Example 88. 2 - [(4-Bromophenyl) sulfonyl] -4- (1,4-diazepan-1-yl) thieno [3,2-c] pyridine hydrochloride.

Trifluoroacetic acid (1 ml) is slowly added to the solution of tert-butyl-4- {2 - [(4-bromophenyl) thio] thieno [3,2-c] pyridin-4-yl} -1,4-diazepan-1- carboxylate (26 mg, 0.047 mmol) in CH ₂ Cl ₂ at 0 ° C. The reaction mixture was allowed to warm to room temperature, stirred for 40 minutes and then concentrated in vacuo. The residue was dissolved twice in MeOH and concentrated in vacuo. The residue was redissolved in MeOH and an excess of 1M HCl in diethyl ether (4 ml) was slowly added to the resulting solution. Removal of the solvents in vacuo afforded the title compound (21 mg, 91%) as a yellow solid. Ή-NMR (270 MHz, CH ₃ OH-b ₄ ) δ 8.41 (s, 1H), 8.06-7.99 (m, 2H), 7.92 (d, 1 = 6.86 Hz, 1H), 7.87-7.80 (m, 2H), 7.66 (d, 1 = 6.86 Hz, 1H), 4.38-4.31 (m, 2H), 4.22-4 14 (m, 2H), 3.74-3.67 (m, 2H), 3.50-3.42 (m, 2H), 2.51-2.39 (m, 2H); MS t / ζ 452 (M + 1).

Example 89. 2- (Phenylsulfonyl) -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride.

To a stirred solution of tert-butyl-4- [2- (phenylthio) thieno [3,2-c] pyridin-4-yl] piperazine-1 carboxylate (350 mg, 0.819 mmol) in ethanol is added a solution of oxone in water. The composition of the reaction mixture is controlled by LCMS. When all of the starting material has been consumed, two peaks in the chromatogram indicate the presence of the product and L-oxide. After purification by preparative HPLC, the resulting Boc product

- 28 011581 treated with HC1 in ether. The solution was centrifuged and the supernatant removed. Ether is added, then centrifuged and decanted (repeated three times) to remove excess HC1. The remaining ether is finally removed by evaporation using ZrssbUas. Yield 18%, purity (HPLC) = 98%, t / ζ 360.0 (M + H). Ή-NMR (270 MHz, CH ₃ OH-b ₄ ) δ ppm 3.56 (m, 4H), 4.08 (m, 4H), 7.68 (m, 4H), 7.77 (dd, 1 = 6.60, 0.79 Hz, 1H), 8.04 (d, 1 = 6.33 Hz, 1H), 8.12 (m, 2H), 8.39 (d, 1 = 0.79 Hz, 1H).

Example 90. 2- (3-Methoxybenzenesulfonyl) -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride.

4- [2- (3-Methoxyphenylsulfanyl) thieno [3,2-c] pyridin-4-yl] piperazine-1 carboxylic acid tert-butyl ester (120 mg, 50%) is obtained from 3-methoxythiophenol (130 μl, 1 mmol ) and tert-butyl-4 (2-bromothieno [3,2-c] pyridin-4-yl) piperazine-1-carboxylate (215 mg, 0.52 mmol) in accordance with the methodology of General Method M described above. Я-NMR (270 MHz, SES1 ₃ ) δ 1.48 (s, 9H), 3.42-3.51 (m, 4H), 3.58-3.67 (m, 4H), 3.74 ( s, 3H), 6.76 (dd, 1 = 8.18, 2.38 Hz, 1H), 6.84-6.92 (m, 2H), 7.16-7.23 (m, 2H) 7.51 (s, 1H); 8.04 (d, 1 = 5.81 Hz, 1H); MS t / ζ 458 (M + 1). Thus, the title compound was prepared from 4- [2- (3-methoxyphenylsulfanyl) thieno [3,2-c] pyridin-4-yl] piperazine-1 carboxylic acid tert-butyl ester (7 mg, 7%) after trituration in diethyl ether in the form of a beige solid in accordance with the General methods B and C described above. Ή-NMR (27 0 MHz, CO ₃ OE) δ 8.31 (s, 1H), 8.09 (d, 1 = 6.33Hz, 1H), 7.71-7.62 (m, 2H), 7.59-7.50 (m, 2H), 7.30-7.23 (m, 1H), 3.98-3.92 (m, 4H), 3.87 (s, 3H), 3, 54-3.48 (m, 4H); MS t / ζ 390 (M + 1).

Example 91. 2- (4-Methoxybenzenesulfonyl) -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride.

4- [2- (4-Methoxyphenylsulfanyl) thieno [3,2-c] pyridin-4-yl] piperazine-1 carboxylic acid tert-butyl ester (100 mg, 42%) was obtained from 4-methoxythiophenol (130 μl, 1 mmol ) and tert-butyl-4 (2-bromothieno [3,2-c] pyridin-4-yl) piperazine-1-carboxylate (215 mg, 0.52 mmol) in accordance with General Method M described above. Ή-NMR (270 MHz, SES1 ₃ ) δ 1.48 (s, 9H), 3.40-3.47 (m, 4H), 3.58-3.65 (m, 4H), 3.79 ( s, 3H), 6.83-6.89 (m, 2H), 7.15 (d, 1 = 5.54 Hz, 1H), 7.35 (s, 1H), 7.38-7.43 (m, 2H), 7.99 (d, 1 = 5.81 Hz, 1H); MS t / ζ 458 (M + 1).

4- [2- (4-Methoxyphenylsulfanyl) thieno [3,2-c] pyridin-4-yl] piperazine-1 carboxylic acid tert-butyl ester (25 mg, 23%) was obtained as a clear liquid in accordance with General Procedure B described above. Я-NMR (270 MHz, СОС1 _; ) δ 1.48 (s, 9Н), 3.67-3.91 (m, 11Н), 7.01 (d, 1 = 8.97 Hz, 2Н), 7 27-7.37 (m, 1H), 7.93 (d, 1 = 8.97 Hz, 2H), 8.01-8.19 (m, 2H); MS t / ζ 490 (M + 1). Thus, the title compound was prepared according to Procedure C; Ή-NMR (CO ₃ OE) δ 8.25 (s, 1H), 8.09-7.89 (m, 3H), 7.69 (d, 1 = 6.33 Hz, 1H), 7.17 -7.10 (m, 2H), 4.00-3.93 (m, 4H), 3.87 (s, 3H), 3.55-3.48 (m, 4H); MS t / ζ 390 (M + 1).

Example 92. 4-piperazin-1-yl-2 - {[4- (trifluoromethyl) phenyl] sulfonyl} thieno [3,2-c] pyridine hydrochloride.

2 - {[4- (Trifluoromethyl) phenyl] thio} -4-piperazin-1-ylthieno [3,2-c] pyridine (0.42 mmol) was dissolved in TFA (1.5 ml) at 0 ° C, stirred over 15 minutes and add H ₂ O ₂ (100 μl). The mixture was stirred at room temperature overnight, add No. 1OH (2M), extracted with ethyl acetate (3x), washed with brine, dried over No. 1 ₃ 8O ₄ . The solvent was removed and the residue was purified by preparative HPLC to give 154.7 mg (86.2%) of the product. Ή-NMR (270 MHz, DMSO-b ₆ ) δ ppm 9.79 (s, 1H), 8.56 (s, 1H), 8.35 (d, 1 = 8.44Hz, 2H), 8.12-8.05 (m, 3H), 7.79 ( d, 1 = 6.33Hz, 1H), 3.98-3.96 (m, 4H), 3.32-3.31 (m, 4H); LC-MS 428 (M-H) ⁺ ; purity (HPLC) 95%.

Example 93. The hydrochloride of 2 - [[2-tert-butylphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine.

The title compound was prepared according to the MO method. Yield: 10.6 mg (6.3%) of 2 - [(2-tert-butylphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride. ¹ H-NMR (270 MHz, DMSO-b ₆ ) δ ppm 9.57 (s, 1H), 8.42 (s, 1H), 8.26-8.22 (m, 1H), 8.06-8.04 (m, 1H), 7.68-7, 55 (m, 4H), 3.87-3.86 (m, 4H), 3.34-3.33 (m, 4H), 1.51-1.43 (m, 9H); LC-MS 400 (M-H) ⁺ ; purity (HPLC) 90%.

Example 94. The hydrochloride of 2 - [(3,4-dichlorophenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridin-2sulfonamide.

The title compound was prepared according to the M-O method. Yield: 47.9 mg (22.9%). Ή-NMR (270 MHz, DMSO-b ₆ ) δ ppm 9.36 (s, 1H), 8.51 (s, 1H), 8.38 (d, 1 = 2.11 Hz, 1H), 8.06-7.94 (m, 3H), 7.70 -7.68 (m, 1H), 3.81-3.77 (m, 4H), 3.31-3.29 (m, 4H); LC-MS 427 (M-H) ⁺ ; purity (HPLC) 95%.

Example 95. Hydrochloride of 2 - [(4-tert-butylphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine.

A solution of oxone (0.52 g, 0.84 mmol) in water (4 ml) is converted into a buffer solution with a pH of ~ 6 by adding sodium oxide acetate and 2 - [(4-tert-butylphenyl) thio] -4- is added to the solution piperazin-1-ylthieno [3,2-c] pyridine (0.42 mmol) in ethanol (30 ml). The mixture was stirred at room temperature for 2 hours and an additional amount of oxone (0.52 g, 0.84 mmol) was added. The reaction mixture was stirred overnight. Water was added to the mixture, extracted with dichloromethane (2x20 ml) and the solvent was removed. The residue was purified by preparative HPLC. Yield: 41.9 mg (22.0%). Ή-NMR (500 MHz, CH ₃ OH-b ₄ ) δ ppm 8.38 (s, 1H), 8.05-8.01 (m, 3H), 7.80 (d, 1 = 6.59 Hz, 1H), 7.71-7.69 (m, 2H) 4.15-4.13 (m, 4H); 3.59-3.57 (4H); 1.37-1.33 (m, 9H); LC-MS 416 (M-H) ⁺ ; purity (HPLC) 95%.

- 29 011581

Example 96. 2- (1-Naphthylsulfonyl) -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride.

The title compound was prepared according to the MO method. Yield: 3.4 mg (0.2%). Ή-NMR (270 MHz, DMSO-b ₆ ) δ ppm 9.34 (s, 1H), 8.82 (s, 1H), 8.44 (s, 1H), 8.26-8.06 (m, 5H), 7.797.65 (m, 3H), 3 79-3.78 (m, 4H); 3.32-3.30 (m, 4H); LC-MS 410 (M-H) ⁺ , purity (HPLC) 95%.

Example 97. Hydrochloride of 2 - [(3-fluorophenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridin-2sulfonamide.

2-Bromo-4-chlorothieno [3,2-c] pyridine (190 mg, 0.50 mmol) in DMF (1 ml) was added to a mixture of 3 fluorobenzenethiol (9.5 mg, 1.0 mmol), KOH (56 mg 0.2 mmol) and Cu ₂ O (71 mg, 0.5 mmol) in DMF (1 ml). The reaction mixture is heated to 120 ° C and maintained at this temperature overnight. The mixture was filtered through a pad of silica and the solvent was removed. The residue was dissolved in TFA (1.5 ml) at 0 ° C and the solution was stirred for 15 minutes, H ₂ O ₂ (100 μl) was added and the mixture was stirred at room temperature overnight. 2M NaOH was added, the solution was extracted with ethyl acetate, washed with brine and the solvent was removed. The residue was purified by preparative HPLC. Yield: 30.1 mg (16.1%). Ή-NMR (270 MHz, DMSO-b ₆ ) δ ppm 9.34 (s, 1H), 8.45 (s, 1H), 8.16 (d, 1 = 5.69 Hz, 1H), 7.97-7.93 (m, 2H), 7.76 -7.62 (m, 3H), 3.30 (s, 4H) (4H is closed with a solvent signal); LCMS 378 (M-H) ⁺ ; purity (HPLC) 99%.

Example 98. 2- (Mesitylsulfonyl) -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride.

The title compound was prepared according to the MO method. Yield: 32.0 mg (16.1%). Ή-NMR (270 MHz, DMSO-b ₆ ) δ ppm 9.32 (s, 1H), 8.20-8.14 (m, 2H), 7.66 (d, 1 = 5.69 Hz, 1H), 7.14 (s, 2H), 3.29 (s, 4H), 2.65 (s, 6H), 2.28 (s, 3H) (4H is closed by the solvent signal); LC-MS 402 (M-H) ⁺ ; purity (HPLC) 95%.

Example 99. Hydrochloride of 2 - [(2-methoxyphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine.

The title compound was prepared according to the MO method. Yield: 14.7 mg (7.6%). Ή-NMR (270 MHz, DMSO-be) δ ppm 9.33 (s, 1H), 8.24 (s, 1H), 8.15 (d, 1 = 5.94 Hz, 1H), 8.00 (dd, 1 = 7.92, 1.48 Hz , 1H), 7.77-7.68 (m, 2H), 7.28-7.18 (m, 2H), 3.30 (s, 4H) (7H is closed by the solvent signal); LC-MS 390 (M-H) ⁺ ; purity (HPLC) 99%.

Example 100. The hydrochloride of 2 - [(2,4-dimethoxyphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine.

The title compound was prepared according to the MO method. Yield: 42.7 mg (20.5%). Ή-NMR (270 MHz, DMSO-b ₆ ,) δ ppm 9.39 (s, 1H), 8.37 (s, 1H), 8.13 (d, 1 = 5.69 Hz, 1H), 7.68-7.66 (m, 2H), 7.54 (d, 1 = 2.23 Hz, 1H), 7.19 (d, 1 = 8.66 Hz, 1H), 3.29 (s, 4H) (10H is closed by the solvent signal); LC-MS 420 (M-H) ⁺ ; purity (HPLC) 98%.

Example 101. 2 - [(2,4-Dimethylphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride.

The title compound was prepared according to the MO method. Yield: 17.8 mg (9.3%). Ή-NMR (270 MHz, DMSO-b ₆ ) δ ppm 9.32 (s, 1H), 8.27 (s, 1H), 8.15 (d, 1 = 5.94 Hz, 1H), 8.00 (d, 1 = 8.17 Hz, 1H), 7.67 (d, 1 = 5.94 Hz, 1H), 7.35-7.26 (m, 2H), 3.29 (s, 4H), 2.34 (s, 3H) (7H is closed by a signal solvent); LC-MS 388 (M-H) ⁺ ; purity (HPLC) 98%.

Example 102. The hydrochloride of 2 - [(2,5-dimethylphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine.

The title compound was prepared according to the MO method. Yield: 16.9 mg (8.8%). Ή-NMR (270 MHz, DMSO-b ₆ ) δ ppm 9.17 (s, 1H), 8.29 (s, 1H), 8.18-18.15 (m, 1H), 7.94 (s, 1H), 7.66 (d, 1 = 5, 69 Hz, 1H), 7.47 (d, 1 = 7.67 Hz, 1H), 7.32 (d, 1 = 8.16 Hz, 1H), 3.29 (s, 2H), 2.42 (s, 3H) (7H closed with a solvent signal); LC-MS 388 (M-H) ⁺ ; purity (HPLC) 99%.

Example 103. Hydrochloride of 2 - [(2-ethylphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine.

The title compound was prepared according to the MO method. Yield: 22.6 mg (11.2%). Ή-NMR (270 MHz, DMSO-b ₆ ) δ ppm 9.19 (s, 1H), 8.32 (s, 1H), 8.17 (d, 1 = 5.69 Hz, 1H), 8.08 (d, 1 = 7.92 Hz, 1H), 7.73-7.66 (m, 2H), 7.52 (t, 1 = 7.67 Hz, 2H), 3.29 (s, 4H), 3.00 (q, 1 = 7.34 Hz , 2H), 1.10 (m, 3H) (4H is closed with a solvent signal); LC-MS 388 (M-H) ⁺ ; purity (HPLC) 100%.

Scheme 7

Explanations for Scheme 7: ί) n-VI, diethyl ether, ίί) § О ₂ (gas.); ίίί) benzyl bromide (s), DMF, heating; ίν) diamine (s), K ₂ CO ₃ , DMF, heating; ν) HC1, diethyl ether.

Intermediate 70. Lithium 4-Chlortieno [3,2-c] pyridin-2-sulfinate.

2-Bromo-4-chlorothieno [3,2-c] pyridine (5.00 g, 20.1 mmol) was suspended in dry ether (100 ml) and the mixture was cooled to -78 ° C in an atmosphere of L ₂ . N-SiO (1.6 M in hexane, 15 ml) was added to the mixture, and the reaction mixture was stirred at -78 ° C for 2 hours. §O ₂ (gas) was bubbled through the reaction mixture for 1 hour. After bubbling stopped the mixture is stirred for an hour at

- 30 011581

-78 ° C and then the mixture was allowed to warm to room temperature. The precipitate formed is filtered and washed with ether to give lithium sulfonate salt (3.59 g, 74%), which is used in the next step without further purification. ¹ H-NMR (270 MHz, DMSO-to ₆₎ δ ppm: 7.26 (s, 1H), 7.99 (d, 1 = 5.54 Hz, 1H), 8.14 (d, 1 = 5.54 Hz, 1H). MS (M-S + 1) 234.

Benzylation of sulfinate salts (method P).

To a suspension of lithium 4-chlorothieno [3,2-c] pyridin-2-sulfinate (100 mg, 0.42 mmol) in dry DMF (2 ml), benzyl bromide (0.83 mmol, 2 equiv.) Was added and the mixture was stirred in for 16 hours at 110 ° C. LCMS analysis shows the target product and the absence of residues of the starting material. The mixture is treated with polystyrene-thiophenol (200 mg) and stirred for 16 hours. The suspension is filtered, washed with additional DMF (2 ml). The resulting product is used without further purification.

Nucleophilic substitution of chlorine (Method O).

Potassium carbonate (172 mg, 1.25 mmol) and tert-butyl piperazine-1-carboxylate (155 mg, 0.84 mmol) are added to crude solutions of benzyl sulfone in DMF (4 ml). The resulting mixture was heated and incubated for 16 hours at 110 ° C. LCMS shows the presence of the target compound and the absence of the starting material. The reaction mixtures were filtered and then the solvent was removed under reduced pressure. Pure target compounds are obtained using preparative HPLC.

Removal of the protective BOC group (method I).

Piperazine derivatives containing BOC protecting groups are dissolved in HCl / diethyl ether (1 ml, 1.0 M) at room temperature and stirred for 16 hours. Removing the solvent under reduced pressure gives crude hydrochloride salts. After trituration with acetonitrile, the desired compound is obtained in the form of a white solid.

Intermediate 71. tert-Butyl-4- [2- (benzylsulfonyl) thieno [3,2-c] pyridin-4-yl] piperazine-1-carboxylate.

Lithium 4-Chlortieno [3,2-c] pyridin-2-sulfinate (0.44 mmol) is treated with benzyl bromide (0.59 mmol) in accordance with method P described above and further reacted with tert-butyl piperazine-1- carboxylate as described in method O. Yield: 0.009 g (7% after two stages). ^! H-NMR (300 MHz, SECD) δ 8.14 (d, 1 = 5.5 Hz, 1H), 7.27-7.40 (m, 5H), 7.15-7.21 (m, 2H ), 4.45 (s, 2H), 3.503.56 (m, 4H), 3.40-3.45 (m, 4H), 1.49 (s, 9H); MS (Е8Н ·) for С23Н27Ы3О482 t / ζ 474 (M + H) ⁺ . HPLC 77%. Jt: 3.93 min (ACE3 C8 50x4 mm, 5-50% acetonitrile for 3 min).

Intermediate 72. tert-Butyl-4- (2 - {[4- (trifluoromethyl) benzyl] sulfonyl} thieno [3,2-c] pyridin-4-yl) piperazine-1-carboxylate.

Lithium 4-Chlortieno [3,2-c] pyridin-2-sulfinate (0.44 mmol) is treated with 4- (trifluoromethyl) benzyl bromide (0.59 mmol) in accordance with method P described above, and then further reacted with tert-butylpiperazine-1-carboxylate in accordance with the method of OB. Yield: 0.02 g (16% for two stages). The solid is beige. ¹ H-NMR (300 MHz, SECD) δ 8.16 (d, 1 = 6 Hz, 1H), 7.53-7.61 (d, 1 = 9 Hz, 2H), 7.49 (s, 1H ), 7.26-7.36 (m, 4H), 4.51 (s, 2H), 3.49-3.60 (m, 4H), 3.36-3.49 (m, 4H), 1.49 (s, 9H); MS (Е8Н) for С24Н26Б3Ы3О482 t / ζ 542 (M + H) ⁺ ; HPLC 71%, Jat: 4.07 min (ACE3 C8 50x4 mm, 5-50% acetonitrile for 3 min).

Intermediate 73. tert-Butyl-4- {2 - [(3-bromobenzyl) sulfonyl] thieno [3,2-c] pyridin-4yl} piperazine-1-carboxylate.

Lithium 4-Chlortieno [3,2-c] pyridin-2-sulfinate (0.44 mmol) is treated with 3-bromobenzyl bromide (0.59 mmol) in accordance with method P described above and reacted with tert-butyl piperazine-1-carboxylate in accordance with method 0. Yield: 0.023 g (10% for two steps). The solid is beige. ¹ H-NMR (300 MHz, SECD) δ 8.16 (d, 1 = 6 Hz, 1H), 7.50-7.55 (m, 2H), 7.32-7.40 (m, 2H) 7.10-7.24 (m, 3H), 4.44 (s, 2H), 3.61-3.73 (m, 8H), 1.50 (s, 9H); MS (Е8Н) for С23Н26БгЫ3О482 t / ζ 554 (M + H) ⁺ ; HPLC 77%, Jat: 4.07 min (ACE3 C8 50x4.6 mm, 5-50% acetonitrile for 3 min).

Intermediate 74. tert-Butyl-4- (2 - {[3- (trifluoromethyl) benzyl] sulfonyl} thieno [3,2-c] pyridin-4-yl) piperazine-1-carboxylate.

Lithium 4-Chlortieno [3,2-c] pyridin-2-sulfinate (0.44 mmol) is treated with 3- (trifluoromethyl) benzyl bromide (0.59 mmol) in accordance with method P described above, and then reacted with tert -butylpiperazine-1-carboxylate in accordance with method O. Yield: 0.023 g (10% for two stages). The solid is beige. ¹ H-NMR (300 MHz, OECD) δ 8.14 (d, 1 = 6 Hz, 1H), 7.85-7.91 (m, 1H), 7.61-7.72 (m, 2H) 7.50-7.60 (m, 1H), 7.12-7.31 (m, 2H), 4.74 (s, 2H), 3.52-3.71 (m, 8H), 1 50 (s, 9H); MS (Е8Н) for С24Н26Б3Ы3О482 t / ζ 542 (M + H) ⁺ ; HPLC 85%, Jat: 2.13 min (UMS O1) 8 AO, 33x3 mm, 10-90% acetonitrile for 3 min).

Intermediate 75. tert-Butyl-4- (2 - {[2,5-bis (trifluoromethyl) benzyl] sulfonyl} thieno [3,2c] pyridin-4-yl) piperazin-1-carboxylate.

Lithium 4-Chlortieno [3,2-c] pyridin-2-sulfinate (0.44 mmol) is treated with 2,5-bis (trifluoromethyl) benzyl bromide (0.59 mmol) in accordance with method P described above, and then subjected

- 31 011581 interaction with tert-butylpiperazine-1-carboxylate in accordance with method O. Yield: 0.01 g (4% for two stages). The solid is beige. ¹ H-NMR (300 MHz, SES13) δ 8.16 (d, 1 = 5.8 Hz, 1H), 8.00 (s, 1H), 7.74-7.85 (m, 3H), 4 76 (s, 2H), 3.56-3.64 (m, 4H), 3.47-3.56 (m, 4H), 1.49 (s, 9H); MS (Ε8Ι +) for С25Н25Б6М3О482 t / ζ 610 (M + H) ⁺ ; HPLC 73%, CT: 2.36 min (UMS O1) 8 Ar, 33x3 mm, 10-90% acetonitrile for 3 min).

Intermediate 76. Tert-Butyl-4- {2 - [(4-methylbenzyl) sulfonyl] thieno [3,2-c] pyridin-4yl} piperazine-1-carboxylate.

Lithium 4-Chlortieno [3,2-c] pyridin-2-sulfinate (0.44 mmol) is treated with 4-methylbenzyl bromide (0.59 mmol) in accordance with method P described above, and then reacted with tert-butylpiperazine- 1-carboxylate in accordance with method O. Yield: 0.005 g (3% for two stages). The solid is beige. 'H-NMR (300 MHz, SES1 ₃ ) δ 8.15 (d, 1 = 6 Hz 1H), 7.40 (s, 1H), 7.00-7.16 (m, 4H), 4.42 (s, 2H), 3.46-3.60 (m, 4H), 3.37-3.46 (m, 4H), 2.34 (s, 3H), 1.49 (s, 9H); MS (Ε8Ι +) for C ₂₄ H ₂₉ N ₃ O ₄ 8 ₂ t / ζ 488 (M + H) ⁺ ; HPLC 69%, K _t : 2.06 min (UMS ΘΌ8 Ar, 33x3 mm, 10-90% acetonitrile for 3 min).

Intermediate 77. tert-Butyl-4- (2 - {[5-chloro-2- (trifluoromethyl) benzyl] sulfonyl} thieno [3,2-c] pyridin-4-yl) piperazine-1-carboxylate.

Lithium 4-Chlortieno [3,2-c] pyridin-2-sulfinate (0.44 mmol) is treated with 5-chloro-2- (trifluoromethyl) benzyl bromide (0.59 mmol) in accordance with method P described above, and then react with tert-butylpiperazine-1-carboxylate in accordance with method p. Yield: 0.019 g (7.5% for two stages). The solid is beige. ¹ H-NMR (300 MHz, SES13) δ 8.12-8.14 (m, 1H), 7.80-7.88 (m, 2H), 7.47-7.66 (m, 2H), 4.71 (s, 2H), 3.74-3.83 (m, 4H), 3.63-3.72 (m, 4H), 1.49 (s, 9H); MS (Ε8Ι +) for С24Н25С1Б3Ы3О482 t / ζ 576 (M + H) ⁺ . HPLC 74%, CT: 2.30 min (UMS ΘΌ8 Ar, 33x3 mm, 1090% acetonitrile for 3 min).

Intermediate 78. tert-Butyl-4- {2 - [(3,4-difluorobenzyl) sulfonyl] thieno [3,2-c] pyridin4-yl} piperazine-1-carboxylate.

Lithium 4-Chlortieno [3,2-c] pyridin-2-sulfinate (0.44 mmol) is treated with 3,4-bis (trifluoromethyl) benzyl bromide (0.59 mmol) in accordance with method P described above, and then subjected interaction with tert-butylpiperazine-1-carboxylate in accordance with method p. Yield: 0.014 g (6% for two stages). The solid is beige. ¹ H-NMR (300 MHz, SES13) δ 8.17-8.21 (m, 1H), 7.71 (s, 1H), 7.07-7.39 (m, 4H), 4.59 ( s, 2H), 3.55-3.68 (m, 8H), 1.49 (s, 9H); MS (Ε8Ι +) for С23Н25Б2М3О482 t / ζ 510 (M + H) ⁺ . HPLC 64%, CT: 2.02 min (UMS OE8 Ar, 33x3 mm, 10-90% acetonitrile for 3 min).

Intermediate 79. tert-Butyl-4- {2 - [(3,5-dimethoxybenzyl) sulfonyl] thieno [3,2-c] pyridin-4-yl} piperazin-1-carboxylate.

Lithium 4-Chlortieno [3,2-c] pyridin-2-sulfinate (0.44 mmol) is treated with 3,5-dimethoxybenzyl bromide (0.59 mmol) in accordance with method P described above, and then reacted with tert- butylpiperazine-1-carboxylate in accordance with method p. Yield: 0.02 g (10% for two stages). The solid is beige. ¹ H-NMR (300 MHz, SES1 ₃ ) δ 8.14-8.18 (m, 1H), 7.55 (s, 1H), 6.40-6.45 (m, 1H), 6.26 -6.34 (m, 2H), 4.39 (s, 2H), 3.54-3.72 (m, 14H), 1.50 (s, 9H); MS (Ε8Ι +) for С ₂₅ Н ₃₁ НЫ ₃ О ₆ 8 ₂ t / ζ 534 (М + Н) ⁺ . HPLC 69%, CT 1.99 min (UMS O1) 8 Ar, 33x3 mm, 10-90% acetonitrile for 3 min).

Example 104. 4- (piperazinyl) -2- (3-methoxybenzylsulfonyl) thienopyridine. A mixture (1: 1) of lithium 4-chlorothienopyridine-2-sulfinate (0.176 g, 0.734 mmol) and 2-methoxybenzyl bromide (0.295 g, 1.47 mmol) in DMF (5 ml) is heated to 100 ° C and maintained at this temperature for 2 h. BOC-piperazine (546 mg, 2.94 mmol) was added to the mixture and the reaction mixture was heated at 110 ° C for 1.5 h. The solvent was removed and the crude product was purified by preparative HPLC to obtain 17.4 mg 4- ( 4-tert-butyloxycarbonylpiperazinyl) -2- (3-methoxybenzylsulfonyl) thienopyridine. The product containing the BOC protecting group is dissolved in 2 ml of MeOH and 4 ml of HCl / ether are added to the mixture to obtain 21.9 mg of 4- (piperazinyl) -2- (3-methoxybenzylsulfonyl) thienopyridine. ¹ H-NMR (CO ₃ OO / P ₃ O 1: 1) δ 6.42-6.38 (m, 1H), 7.51-7.48 (m, 1H), 7.39-7.35 (m, 1H), 6.92-6.85 (m, 1H), 6.64-6.59 (m, 1H), 6.48-6.39 (m, 2H), 3.643.58 (m , 4H), 3.19-3.13 (m, 4H), 2.96 (s, 3H), 2.92 (s, 2H); MS (Ε8Ι) 404 (M + H) ⁺ ; purity (HPLC, UMS column) 94%.

Intermediate 80. tert-Butyl-4- [2- (benzylsulfonyl) thieno [3,2-c] pyridin-4-yl] piperazine-1-carboxylate.

Lithium 4-Chlortieno [3,2-c] pyridin-2-sulfinate (0.44 mmol) is treated with benzyl bromide (0.59 mmol) in accordance with method P described above and then reacted with tert-butyl piperazine-1-carboxylate in accordance with the method of r. Yield: 0.00 g of product (7% for two stages). The solid is beige. ¹ H-NMR (300 MHz, SES13) δ 8.14 (d, 6 = 5.5, Hz 1H), 7.27-7.40 (m, 5H), 7.15-7.21 (m, 2H) 4.45 (s, 2H); 3.50-3.56 (m, 4H); 3.40-3.45 (m, 4H); 1.49 (s, 9H); MS (Ε8Ι +) for С23Н27Ы3О482 t / ζ 474 (M + H) ⁺ . HPLC 77%, CT 3.93 min (ACE3 C8 50x4 mm, 5-50% acetonitrile for 3 min).

- 32 011581

Example 105. 2- (Benzylsulfonyl) -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride. tert-Butyl-4- [2- (benzylsulfonyl) thieno [3,2-c] pyridin-4-yl] piperazine-1-carboxylate (0.01 g, 0.02 mmol) was treated according to method B, yielding target product in the form of a white solid. Yield: 0.009 g (100%). Я-NMR (300 MHz, DMSO-b ₆ ) δ 8.98 (s, 1H), 8.13-8.20 (d, 1 = 8 Hz, 1H), 8.00 (s, 1H), 7 64-7.71 (m, 1H), 7.18-7.35 (m, 5H), 4.93 (s, 2H), 3.60-3.70 (m, 4H), 3.22 3.34 (m, 4H); MS (Ε8Σ +) for С1 ₈ Н ₁₉ Н ₃ О ₂ 8 ₂ , С1 Н t / ζ 374 (М + Н) ⁺ . HPLC 90%, _W 2.91 m (C8 ASE3 50x4 mm, 5-50% acetonitrile for 3 min).

Intermediate 81. tert-Butyl-4- (2 - {[4- (trifluoromethyl) benzyl] sulfonyl} thieno [3,2-c] pyridin-4-yl) piperazine-1-carboxylate.

Lithium 4-Chlortieno [3,2-c] pyridin-2-sulfinate (0.44 mmol) is treated with 4- (trifluoromethyl) benzyl bromide (0.59 mmol) in accordance with method P described above, and then reacted with tert -butylpiperazine-1-carboxylate in accordance with method p. Yield: 0.02 g (16% for two stages). The solid is beige. ¹ H-NMR (300 MHz, SES13) δ 8.16 (d, 1 = 6 Hz, 1H), 7.537.61 (d, 1 = 9 Hz 2H), 7.49 (s, 1H), 7.26 -7.36 (m, 4H), 4.51 (s, 2H), 3.49-3.60 (m, 4H), 3.36-3.49 (m, 4H), 1.49 (s 9H); MS (Ε8Σ +) for С24Н26Е3Ы3О482 t / ζ 542 (M + H) ⁺ . HPLC 71%, W 4.07 min (ACE3 C8 50x4 mm, 5-50% acetonitrile for 3 min).

Example 106. 4-piperazin-1-yl-2 - [[4- (trifluoromethyl) benzyl] sulfonyl} thieno [3,2-c] pyridine hydrochloride.

tert-Butyl-4- (2 - {[4- (trifluoromethyl) benzyl] sulfonyl} thieno [3,2-c] pyridin-4-yl) piperazine-1 carboxylate (0.02 g, 0.03 mmol) is treated in accordance with method B, obtaining the desired product as a white solid. Yield: 0.014 g (100%). The solid is white. ¹ H-NMR (300 MHz, DMSO-b ₆ ) δ 9.25 (s, 1H), 8.12-8.22 (m, 2H), 7.66-7.77 (m, 4H), 7 41-7.52 (m, 2H); 5.12 (s, 2H); 3.22-3.35 (m, 4H); MS (Ε8Σ +) for С1 ₉ Н ₁₈ Е ₃ Н ₃ О ₂ 8 ₂ , С1 Н t / ζ 442 (М + Н) ⁺ . HPLC 90%, BT 3.53 min. (ACE3 C8 50x4.6 mm, 5-50% acetonitrile for 3 minutes).

Intermediate 82. tert-Butyl-4- {2 - [(3-bromobenzyl) sulfonyl] thieno [3,2-c] pyridin-4yl} piperazine-1-carboxylate.

Lithium 4-Chlortieno [3,2-c] pyridin-2-sulfinate (0.44 mmol) is treated with 3-bromobenzyl bromide (0.59 mmol) in accordance with method P described above, and then reacted with tert-butylpiperazine- 1-carboxylate in accordance with method p. Yield: 0.023 g (10% for two stages). The solid is beige. ¹ H-NMR (300 MHz, SES13) δ 8.16 (d, Σ = 6 Hz, 1H), 7.50-7.55 (m, 2H), 7.32-7.40 (m, 2H) 7.10-7.24 (m, 3H), 4.44 (s, 2H), 3.61-3.73 (m, 8H), 1.50 (s, 9H); MS (Е8Н) for С23Н26ВгЫ3О482 t / ζ 554 (M + H) ⁺ . HPLC 77%, W 4.07 (ACE3 C8 50x4.6 mm, 5-50% acetonitrile for 3 minutes).

Example 107. Hydrochloride of 2 - [(3-bromobenzyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine. tert-Butyl-4- {2 - [(3-bromobenzyl) sulfonyl] thieno [3,2-c] pyridin-4-yl} piperazine-1-carboxylate (0.023 g, 0.04 mmol) is treated according to the method B, obtaining the target product in the form of a white solid. Yield: 0.013 g (67%). The solid is white. ¹ H-NMR (300 MHz, DMSO6) δ 9.19 (s, 1H), 8.18 (d, Σ = 6 Hz, 1H), 8.05 (s, 1H), 7.70 (d, Σ = 6 Hz, 1H), 7.53-7.58 (m, 1H), 7.43-7.45 (m, 1H), 7.19-7.32 (m, 2H), 4.98 ( s, 2H); 3.24-3.35 (m, 4H); MS (Ε8Σ +) for С18Н18ВгЫ3О282. C1 H t / ζ 452 (M + H) ⁺ . HPLC 90%, W 3.30 min (ACE3 C8 50x4.6 mm, 5-50% acetonitrile for 3 min).

Intermediate 83. tert-Butyl-4- {2 - [(3,4-difluorobenzyl) sulfonyl] thieno [3,2-c] pyridin4-yl} piperazine-1-carboxylate.

Lithium 4-Chlortieno [3,2-c] pyridin-2-sulfinate (0.44 mmol) is treated with 3,4-bis (trifluoromethyl) benzyl bromide (0.59 mmol) in accordance with method P described above, and then subjected interaction with tert-butylpiperazine-1-carboxylate in accordance with method p. Yield: 0.014 g (6% for two stages). The solid is beige. ¹ H-NMR (300 MHz, SES13) δ 8.17-8.21 (m, 1H), 7.71 (s, 1H), 7.07-7.39 (m, 4H), 4.59 ( s, 2H), 3.55-3.68 (m, 8H), 1.49 (s, 9H); MS (Е8Н) for С23Н25Е2Ы3О482 t / ζ 510 (M + H) ⁺ . HPLC 64%, W 2.02 min (UMS OE8 Ar, 33x3 mm, 10-90% acetonitrile for 3 min).

Example 108. Hydrochloride of 2 - [(2,3-difluorobenzyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine.

The BOC protecting group is removed from tert-butyl 4- {2 - [(3,4-difluorobenzyl) sulfonyl] thieno [3,2-c] pyridin-4-yl} piperazine-1-carboxylate according to method B. Yield: 0.068 g (100%). The solid is white. Ή-NMR (300 MHz, DMSO-b ₆ ) 5 9.34 (s, 1H), 8.22 (s, 1H), 8.18 (d, 1 = 5.5 Hz, 1H), 7.70 (d, 1 = 5.5 Hz, 1H), 7.26-7.35 (m, 1H), 7.15-7.22 (m, 1H), 7.05-7.14 (m, 1H ), 5.08 (s, 2H), 3.34-3.42 (m, 4H), 3.25-3.34 (m, 4H); MS (Е8Н) for С ₁₈ Н ₁₇ Е ₂ Н ₃ О ₂ 8 ₂ , С1 Н t / ζ 410 (М + Н) ⁺ . HPLC 90%, _W 1.07 min (YMC OE8 Ar, 33x3 mm, 20-50% acetonitrile for 1.5 min).

Example 109. Hydrochloride of 2 - [(4-bromobenzyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine.

Lithium 4-Chlortieno [3,2-c] pyridin-2-sulfinate (0.42 mmol) is treated with 4-bromobenzyl bromide (0.59 mmol) in accordance with method P described above and then reacted with tert-butyl piperazine- 1-carboxylate in accordance with method p. The BOC protecting group is removed in

- 33 011581 in accordance with method K. Yield: 0.024 g (12% for three stages). The solid is white. ¹ NNMR (300 MHz, DMSO-a6) δ 8.99 (s, 1H), 8.18 (d, 1 = 5.5 Hz, 1H), 8.02 (s, 1H), 7.69 (d , 1 = 5.5 Hz, 1H), 7.53 (d, 1 = 8.5 Hz, 2H), 7.17 (d, 1 = 8.5 Hz, 2H), 4.95 (s, 2H ), 3.62-3.68 (m, 4H); 3.27-3.32 (m, 4H); MS (Ε8Ι +) for С18Н18ВгЫ3О2§2, С1 Н t / ζ 454 (М + Н) ⁺ . HPLC 90%. CT 1.24 min (° C О1) 8 AC, 33x3 mm, 20-50% acetonitrile for 1.5 min).

Intermediate 84. tert-Butyl 4- (2 - {[2,5-bis (trifluoromethyl) benzyl] sulfonyl} thieno [3,2c] pyridin-4-yl) piperazine-1-carboxylate.

Lithium 4-Chlortieno [3,2-c] pyridin-2-sulfinate (0.44 mmol) is treated with 2,5-bis (trifluoromethyl) benzyl bromide (0.59 mmol) in accordance with method P described above, and then subjected interaction with tert-butylpiperazine-1-carboxylate in accordance with method O. Yield: 0.01 g (% for two stages). The solid is beige. ¹ H-NMR (300 MHz, SES13) δ 8.16 (d, 1 = 5.8 Hz 1H), 8.00 (s, 1H), 7.74-7.85 (m, 3H), 4, 76 (s, 2H), 3.56-3.64 (m, 4H), 3.47-3.56 (m, 4H), 1.49 (s, 9H); MS (Ε8Ι +) for С25Н25Е6Ы3О482 t / ζ 610 (M + H) ⁺ . HPLC 73%, CT 2.36 min. (Υ \ 1Γ ΘΌ8 AC, 33x3 mm, 10-90% acetonitrile for 3 min).

Example 110. Hydrochloride 2 - {[2,5-bis (trifluoromethyl) benzyl] sulfonyl} -4-piperazin-1-ylthieno [3,2-c] pyridine.

The BOC protecting group is removed from tert-butyl 4- (2 - {[2,5- (trifluoromethyl) benzyl] sulfonyl} thieno [3,2-c] pyridin-4-yl) piperazine-1-carboxylate in accordance with Method K. Yield: 0.024 g (100%). The solid is white. ¹ H-NMR (300 MHz, DMSO-b6) δ 9.30 (s, 1H), 8.25 (s, 1H), 8.19 (d, 1 = 5.5 Hz, 1H), 8.00 -8.07 (m, 2H), 7.85 (s, 1H), 7.69 (d, 1 = 5.5 Hz, 1H), 5.22 (s, 2H), 3.24-3, 33 (m, 4H); MS (Ε8Ι +) for С20Н17Е6Ы3О282. C1 H t / ζ 510 (M + H) ⁺ . HPLC 90%, CT 1.08 min (ΥMS ΘΌ8 AC, 33x3 mm, 30-60% acetonitrile for 1.5 min).

Intermediate 85. tert-Butyl-4- {2 - [(4-methylbenzyl) sulfonyl] thieno [3,2-c] pyridin-4yl} piperazine-1-carboxylate.

Lithium 4-Chlortieno [3,2-c] pyridin-2-sulfinate (0.44 mmol) is treated with 4-methylbenzyl bromide (0.59 mmol) in accordance with method P described above, and then reacted with tert-butylpiperazine- 1-carboxylate in accordance with method O. Yield: 0.005 g (3% for two stages). The solid is beige. 'H-NMR (300 MHz, SES1 ₃ ) δ 8.15 (d, 1 = 6 Hz, 1H), 7.40 (s, 1H), 7.00-7.16 (m, 4H), 4, 42 (s, 2H), 3.46-3.60 (m, 4H), 3.37-3.46 (m, 4H), 2.34 (s, 3H), 1.49 (s, 9H) ; MS (Ε8Ι +) for С ₂₄ Н ₂₉ Н ₃ О ₄ 8 ₂ t / ζ 488 (М + Н) ⁺ . HPLC 69%, R _t 2.06 min. (ΥMS ΘΌ8 AC, 33x3 mm, 10-90% acetonitrile, 3 min).

Example 111. 2 - [(4-Methylbenzyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride.

The BOC protecting group is removed from tert-butyl 4- {2 - [(4-methylbenzyl) sulfonyl] thieno [3,2-c] pyridin-4-yl} piperazine-1-carboxylate according to method K. Yield: 0.05 g (75%). The solid is white. Я-NMR (300 MHz, DMSO- ₆ ) δ 9.18 (s, 1H), 8.17 (d, 1 = 5.5 Hz, 1H), 8.01 (s, 1H), 7.67 (d, 1 = 5.5 Hz, 1H), 7.38 (s, 1H), 7.19 (s, 1H), 7.11 (s, 1H), 7.00 (s, 1H), 4 86 (s, 2H); MS (Ε8Ι +) for C1 ₉ H ₂₁ S ₃ O ₂ 8 ₂ . C1 H t / ζ 388 (M + H) ⁺ . HPLC 90%, K _t 1.65 min. (ACE3 C8 50x3.0 mm, 10-97% acetonitrile for 3 min).

Intermediate 86. tert-Butyl-4- (2 - {[5-chloro-2- (trifluoromethyl) benzyl] sulfonyl} thieno [3,2-c] pyridin-4-yl) piperazine-1-carboxylate.

Lithium 4-Chlortieno [3,2-c] pyridin-2-sulfinate (0.44 mmol) is treated with 5-chloro-2- (trifluoromethyl) benzyl bromide (0.59 mmol) in accordance with method P described above, and then reacted with tert-butyl piperazine-1-carboxylate in accordance with method O. Yield: 0.019 g (7.5% for two steps). The solid is beige. ¹ H-NMR (300 MHz, SES13) δ 8.12-8.14 (m, 1H), 7.80-7.88 (m, 2H), 7.47-7.66 (m, 2H), 4.71 (s, 2H), 3.74-3.83 (m, 4H), 3.63-3.72 (m, 4H), 1.49 (s, 9H); MS (Ε8Ι +) for С24Н25С1Е3Ы3О482 t / ζ 576 (M + H) ⁺ . HPLC 74%, CT 2.30 min. (ΥMS O1) 8 AC, 33x3 mm, 10-90% acetonitrile for 3 min).

Example 112. The hydrochloride of 2 - {[5-chloro-2- (trifluoromethyl) benzyl] sulfonyl} -4-piperazin-1-ylthieno [3,2-c] pyridine.

The BOC protecting group is removed from tert-butyl 4- (2 - {[5-chloro-2- (trifluoromethyl) benzyl] sulfonyl} thieno [3,2-c] pyridin-4-yl) piperazine-1-carboxylate in according to method K.

Yield: 0.012 g (92%). The solid is white. ¹ H-NMR (300 MHz, DMSO-b6) δ 9.05 (s, 1H), 8.18-8.23 (m, 2H), 7.78-7.83 (m, 1H), 7, 72-7.76 (m, 1H), 7.69 (d, 1 = 5.5 Hz, 1H), 7.62-7.65 (m, 1H), 5.07 (s, 2H), 3 65-3.72 (m, 4H); 7.25-7.34 (m, 4H); MS (Ε8Ι +) for С19Н17С1Е3Ы3О282. C1 H t / ζ 476 (M + H) ⁺ . HPLC 90%, CT 1.65 min. (ACE3 C8 50x3.0 mm, 10-97% acetonitrile for 3 min).

Intermediate 87. tert-Butyl-4- {2 - [(3,5-dimethoxybenzyl) sulfonyl] thieno [3,2-c] pyridin-4-yl} piperazine-1-carboxylate.

Lithium 4-Chlortieno [3,2-c] pyridin-2-sulfinate (0.44 mmol) is treated with 3,5-dimethoxybenzyl bromide (0.59 mmol) in accordance with method P described above, and then reacted with tert- butylpiperazine-1-carboxylate in accordance with method O. Yield: 0.02 g (10% for two stages). The solid is beige. ¹ H-NMR (300 MHz, SES1 ₃ ) δ 8.14-8.18 (m, 1H), 7.55 (s,

- 34 011581

1H), 6.40-6.45 (m, 1H), 6.26-6.34 (m, 2H), 4.39 (s, 2H), 3.54-3.72 (m, 14H) 1.50 (s, 8H); MS (Е8Н) for С ₂₅ Нз1Ы ₃ О ₆ 8 ₂ t / ζ 534 (М + Н) ⁺ . HPLC 69%, I _, 1.99 min. (TMS O1) 8 Ar, 33x3 mm, 10-90% acetonitrile for 3 min).

Example 113. The hydrochloride of 2 - [(3,5-dimethoxybenzyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine.

The BOC protecting group is removed from tert-butyl 4- {2 - [(3,5-dimethoxybenzyl) sulfonyl] thieno [3,2c] pyridin-4-yl} piperazine-1-carboxylate according to method I. Yield: 0.01 g (62%). The solid is white. Я-NMR (300 MHz, DMSO-4 ₆ ) δ 9.09 (s, 1H), 8.18 (d, 1 = 6.7 Hz, 1H), 8.02 (s, 1H), 7.69 (d, 1 = 6.1 Hz, 1H), 6.45-6.48 (m, 1H), 6.35-6.38 (m, 2H), 4.84 (s, 2H), 3, 61-3.67 (m, 4H), 3.58 (s, 6H), 3.243.33 (m, 4H). MS (E8H) for C ₂₀ H ₂₂ N ₃ O ₄ 8 ₂ t / ζ 434 (M + H) ⁺ . HPLC 90%, I _, 1.60 min. (ACE3 C8 50x3.0 mm, 10-97% acetonitrile for 3 min).

Example 114. 2 - [(2-Naphthylmethyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride.

2- (Bromomethyl) naphthalene was used in accordance with the method of RH, receiving 12.4 mg of the target product. Ή-NMR (270 MHz, CH ₃ OH-b ₄ ) δ ppm (CH ₃ OH signal closes 4H) 3.70-3.79 (m, 4H), 4.95 (s, 2H), 7.36-7.58 (m, 3H), 7.70-7.91 (m, 6H), 8.02 (d, 1 = 6.60 Hz, 1H). MS (M + 1) 424.

Example 115. 4-piperazin-1-yl-2 - [[4- (1,2,3-thiadiazol-4-yl) benzyl] sulfonyl} thieno [3,2-c] pyridine hydrochloride.

4- [4- (Bromomethyl) phenyl] -1,2,3-thiadiazole is used in accordance with the method of P-I, getting 4.8 mg of the target product. Ή-NMR (270 MHz, CH ₃ OH-th ₄ ) δ ppm 3.41-3.50 (m, 4H), 3.54 (s, 2H), 3.89-3.98 (m, 4H), 7.45 (d, 1 = 8.44 Hz, 2H) 7.75 (d, 1 = 6.33 Hz, 1H); 7.96-8.13 (m, 4H); 9.31 (s, 1H). MS (M + 1) 458.

Example 116. Hydrochloride of 1- (4-pyrrolidin-1-ylphenyl) -2 - [(4-piperazin-1-ylthieno [3,2-c] pyridin2-yl) sulfonyl] ethanone.

2-Bromo-1- (4-pyrrolidin-1-ylphenyl) ethanone was used in accordance with the method of RH, receiving 19.6 mg of the target product. Ή-NMR (270 MHz, CH ₃ OH-th ₄ ) δ ppm 2.02-2.12 (m, 4H), 2.69 (s, 1H), 3.37 (t, 1 = 6.73 Hz, 4H), 3.54 (s, 1H), 3.56 3.64 (m, 4H), 4.12-4.22 (m, 4H), 6.55 (d, 1 = 8.97 Hz, 2H), 7.78-7.90 (m, 3H) ), 8.03 (d, 1 = 6.86 Hz, 1H), 8.41 (s, 1H). MS (M + 1) 471.

Example 117. Hydrochloride of 1- [4- (diethylamino) phenyl] -2 - [(4-piperazin-1-ylthieno [3,2-c] pyridin-2yl) sulfonyl] ethanone.

2-Bromo-1- [4- (diethylamino) phenyl] ethanone was used in accordance with the method of P-Y, receiving 9.0 mg of the target product. Ή-NMR (500 MHz, CH ₃ OH-b ₄ ) δ ppm 1.16 (t, 1 = 1.06 Hz, 6H), 3.49-3.66 (m, 10H), 4.14-4.27 (m, 4H), 7.13 (br s, 2H), 7.85 (d, 1 = 6.59 Hz, 1H), 7.98 (d, 1 = 8.48 Hz, 2H), 8.03 (d, 1 = 6.59 Hz, 1H) 8.47 (s, 1H). MS (M + 1) 473.

Example 118. 1- (4-Bromophenyl) -2 - [(4-piperazin-1-ylthieno [3,2-c] pyridin-2-yl) sulfonyl] ethanone.

2-Bromo-1- (4-bromophenyl) ethanone was used in accordance with method A to obtain 3.4 mg of the expected product. Ή-NMR (270 MHz, CH ₃ OH-th ₄ ) δ ppm 3.55 (s, 2H), 3.56-3.67 (m, 4H), 4.08-4.26 (m, 4H), 7.68 (d, 1 = 8.44 Hz, 2H) 7.79-7.98 (m, 3H), 8.06 (d, 1 = 6.60 Hz, 1H), 8.45 (s, 1H). (M + 1) 481.

Example 119. 1- (3-Methoxyphenyl) -2 - [(4-piperazin-1-ylthieno [3,2-c] pyridin-2-yl) sulfonyl] ethanone.

2-Bromo-1- (3-methoxyphenyl) ethanone was used in accordance with method A to obtain 1.0 mg of the expected product. Ή-NMR (270 MHz, CH ₃ OH-th ₄ ) δ ppm 3.54 (s, 2H), 3.55-6.62 (m, 1 = 10.03 Hz, 4H), 3.82 (s, 3H), 4.06-4.18 (m, 4H) 7.20 (dd, 1 = 8.05, 2.24 Hz, 1H), 7.34-7.49 (m, 2H), 7.57 (d, 1 = 7.39 Hz, 1H), 7.84 (d, 1 = 6.60 Hz, 1H), 8.06 (d, 1 = 6.60 Hz, 1H), 8.41 (s, 1H). MS (M + 1) 432.

Example 120. 1-Phenyl-2 - [(4-piperazin-1-ylthieno [3,2-c] pyridin-2-yl) sulfonyl] ethanone.

2-Bromo-1-phenylethanone was used in accordance with method A to obtain 1.2 mg of the expected product. Ή-NMR (270 MHz, CH ₃ OH-th ₄ ) δ ppm 3.55 (s, 2H), 3.57-3.66 (m, 4H), 4.10-4.24 (m, 4H), 7.46-4.57 (m, 2H), 7, 66 (t, 1 = 1.39 Hz, 1H), 7.86 (d, 1 = 6.60 Hz, 1H), 8.02 (dd, 1 = 14.12, 6.99 Hz, 3H), 8.46 (s, 1H). MS (M + 1) 402.

- 35 011581

Table 6

Example K ¹ to ⁴ 121 4-piperazin-1 ~ yl-1- hydrochloride (toluene-4-sulfonyl) -1H- pyrrolo [3,2-c] pyridine Hu 0 122 1- (3-Chloro-2-methylbenzenesulfonyl) -4-piperazin1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride δς 0 123 1- (3,4dimethoxybenzenesulfonyl) -4piperazin-1-yl-1H-pyrrolo (3.2s] pyridine hydrochloride ABOUT \ 0 124 4- (4-piperazin-1ylpyrrolo [3,2-c] pyridin-1sulfonyl) benzonitrile hydrochloride 0 125 1- (4,5-Dichlorothiophen-2sulfonyl) -4-piperazin-1-yl-1Hpyrrolo [3.2-c} pyridine hydrochloride cg 0 126 1- (2-chloro-4ftorbenzolsulfonil) -4-liperazin-1-yl-1H-pirr0Lo [3 _{g of} 2-c] pyridine E 0 127 1-phenylmethanesulfonyl hydrochloride 4-piperazin-1-yl-1H-pyrrolo [3,2- c] pyridine 6 0 128 1- (5-Chlorothiophen-2sulfonyl) -4-piperazin-1-yl-1Hpyrrolo [3.2-c] pyridine hydrochloride 0

129 Hydrochloride 1- (4- butylbenzenesulfonyl} -4-piperazine- 1-yl-1H-lirrolo [3,2-c] pyridine f 130 1- (4phenoxybeneolsulfonyl) -4piperazin-1-yl-1H-pyrrolo [3.2s] pyridine hydrochloride 0 Pb ° 0 131 Hydrochloride I- (phenylsulfonyl) -4- piperazin-1-yl-1H-pyrrolo [3,2- c] pyridine 0 0 132 Hydrochloride 1 - [(4- chlorophenyl) sulfonyl] -4-piperazin-1- IL-1H-pyrrolo [3,2-c] pyridine f C1 0 133 1 - [(4 Methoxyphenyl) sulfonyl] -4 piperazin-2-yl-1H-pyrrolo [3.2s] pyridine hydrochloride f /ABOUT 0 134 Hydrochloride 1 - [(2-methoxy-5methylphenyl) sulfonyl] -4-piperaein- 1-yl-ΊΗ-pyrrolo [3,2-c] pyridine xU 0 135 4-piperazin-1-yl-1 hydrochloride - ([2 trifluoromethyl) phenyl1 sulfonyl} -1Npyrrolo [3,2-c] pyridine SU ^R 0

Scheme 8

- 36 011581

K4

Explanations for Scheme 8: 1) Ethyl chloroformate, ΤΕΑ, acetone, ΝαΝ ₃ ; ίί) Βυ ₃ Ν, DXM and diphenylether; w) POC1 ₃ , ΝαΟΗ; ίν) amines containing a protective BOC group (K ⁴ ), K ₂ CO ₃ , DMSO; ν) ΝΗ ₂ (gas.), Να, ΝΗ ₄ Ο. THF; νί) sulfonyl chloride (K ¹ ), ΝαΗ, THF; νίί) HC1 / diethyl ether, methanol.

Intermediate 88. (2E) -3- (1- (Benzyl-1H-pyrrol-2-yl)) acryloyl azide.

To a mixture of 1-benzyl-1H-pyrrole-2-carbaldehyde (28.4 g, 0.125 mol) and TFA (13.5 ml, 0.187 mol) in acetone (300 ml) was added dropwise ethyl chloroformate (17.9 ml, 0 , 87 mol). The reaction mixture was stirred for 1.5 hours, then Ν; · ιΝ ₃ (13 g, 0.200 mol) in H ₂ O (100 ml) was added. After 2 hours, the reaction mixture was diluted with water and left overnight. Acetone was removed and the product was collected by filtration to obtain 21.4 g of a light brown solid. The compound is used in the next step.

The intermediate product 89.

1-Benzyl-1,5-dihydropyrrolo [3,2-c] pyridin-4-one is obtained in accordance with the publication procedure of S. Bisgosts; Ε. Vyapch 1-M, L1yuk1e; 1. MschreIeg; Teyayebgop, Wo1. 32, pp 773-780, (1976).

To a stirred solution of n-tributylamine (30 ml) in diphenyl ether (150 ml) heated to 195 ° C, a solution of acyl azide in DCM (150 ml) was slowly added over 30 minutes. The reaction mixture was stirred at 195 ° C for 1 h and then cooled to room temperature. Pentane (1.0 L) and ether (1.0 L) were added to the reaction mixture, and the precipitate was collected by filtration. The crude solid was triturated with ether to give 6.89 g (81%) of pure product. Purity (HPLC)>95%; MS (Ε8Ι) t / ζ 225 (t + H); Ή-NMR (DMSO-b ₆ , 25 ° C, 270.16) δ 10.84 (br s, 1H), 7.43-7.14 (m, 6H), 7.00 (d, 1 = 1.12 Hz, 1H), 6.57-6.49 (m, 2H), 5.83 (s, 2H).

Intermediate 90.

1-Benzyl-4-chloro-1H-indole.

POC1 ₃ (3.11 ml, 33.4 mmol) is added to 1-benzyl-1,5-dihydro-4H-pyrrolo [3,2-c] pyridin-4-one (3.75 g, 16.7 mmol ) and the reaction mixture was stirred at 120 ° C. for 2 hours. No. 1OH (1M) was added and the mixture was extracted three times with DCM. The organic layers were dried (MgSO ₄ ), filtered and the solvent removed. Purification by flash chromatography (DCM / heptane / MeOH 4: 15: 1) affords 1.17 g (29%) of the product, which is used in the next step.

Intermediate 91. tert-Butyl-4- (1-benzyl-1H-pyrrolo [3,2-c] pyridin-4-yl) piperazine-1 carboxylate.

A mixture of 1-benzyl-4-chloro-1H-indole (1.17 g, 4.82 mmol), K2CO3 (2.0 g, mmol) and BOC-piperazine (1.79 g, 9.64 mmol) in DMSO (75 ml) was stirred at 120 ° C. for 48 hours. Additional BOC-piperazine (4 equiv.) Was added and the reaction mixture was stirred for an additional 48 hours. The reaction mixture was diluted with ethyl acetate (200 ml) and the mixture was washed several times with water. Flash chromatography (DCM / MeOH / heptane 4: 1: 15) affords 0.51 g of the starting material and 0.38 g of the product. Ή-NMR (SB ₃ OB) δ 7.87-7.85 (m, 1H), 7.25-7.24 (m, 3H), 7.04-6.98 (m, 3H), 6, 73-6.71 (m, 1H), 6.53-6.52 (m, 1H), 5.19 (s, 2H), 3.63-3.59 (m, 8H), 1.47 ( s, 9H); MS (Ε8Ι) 393 (M + H) ⁺ ; purity (HPLC, ACE column) 95%.

Intermediate 92. tert-Butyl-4- (1H-pyrrolo [3,2-c] pyridin-4-yl) piperazine-1-carboxylate.

tert-Butyl 4- (1-benzyl-1H-pyrrolo [3,2-c] pyridin-4-yl) piperazine-1-carboxylate (383 mg, 0.488 mmol) was dissolved in THF (6 ml) and liquid ammonia ( 10 ml) in a 30 ml reactor. Να (67 mg, 2.93 mmol) was added in several portions, and the reaction mixture turned violet. After 30 min, ΝΗ ₄ Ο (sat.) Was added and the reaction mixture was left to spontaneously warm to room temperature. THF is removed and the residue is extracted with DCM. Recrystallization (DCM / heptane) affords 112 mg of the product as a white solid. ¹ H-NMR (SB ₃ OB) δ 8.66 (s, 1H), 7.89 (d, 1H, 1 = 5.80 Hz), 7.13-7.11 (m, 1H), 6, 89-6.86 (m, 1H), 6.57-6.56 (m, 1H), 3.673.60 (m, 8H), 1.48 (s, 9H); MS (Ε8Ι) 303 (M + H) ⁺ ; purity (HPLC, ACE column) 95%.

Sulfonylation Method 8: tert-butyl-4- (1H-pyrrolo [3,2-c] pyridin-4-yl) piperazin-1

- 37 011581 carboxylate (total 1.391 mmol, 1 equiv.) Is dissolved in THF (14 ml) and transferred to 10 ml vials equipped with threaded caps. A suspension of IAH (0.1488 mmol, 1.5 equiv.) In THF (15 ml) was carefully transferred into vials containing a solution of tert-butyl-4- (1H-pyrrolo [3,2-c] pyridin-4-yl) piperazine-1 carboxylate, and stirred for about 15 minutes. Various sulfonyl chlorides were dissolved in THF (2 ml) and each solution was added dropwise to the reaction mixture. The reactions were quenched with MeOH (100 μl), P8-trisamine (3 equiv.) Was added to each vial and the vials were shaken for 2 hours. The mixture was filtered and the filtrates were concentrated in vacuo. Products that are not sufficiently pure (purity <90%) are purified by preparative chromatography using acetonitrile-water gradients containing 0.1% trifluoroacetic acid. After HPLC analysis, fractions with a purity> 90% are collected and concentrated.

Method T for removing the BOC protecting group: the compound containing the BOC protecting group was dissolved in MeOH (2 ml) and a mixture of HCl / ether (2 ml) was added. After 45 minutes, the solvent was removed.

Intermediate 93. tert-Butyl-4- [1- (phenylsulfonyl) -1H-pyrrolo [3,2-c] pyridin-4-yl] piperazine-1-carboxylate.

Recrystallization after removal of the BOC protecting group results in 16 mg (56%) of the product. ^! H-NMR (СРС1 ₃ ) δ 8.03-8.01 (m, 1Н), 7.89-7.86 (m, 2Н), 7.57-7.39 (m, 5Н), 6.67 -6.64 (m, 1H), 3.553.52 (m, 8H), 1.47 (s, 9H); MS (E8C 443 (M + H) ⁺ ; purity (HPLC, ACE column) 95%.

Intermediate 94. tert-Butyl-4- {1 - [(4-chlorophenyl) sulfonyl] -1H-pyrrolo [3,2-c] pyridin-4-yl} piperazin-1-carboxylate.

Purification by preparative HPLC after removal of the BOC-protecting group yields 4 mg (11%) of the product. ^! H-NMR (СРС1 ₃ ) δ 8.03-7.51 (m, 7Н), 6.89-6.87 (m, 1Н), 3.91-3.66 (m, 8Н), 1.47 (s, 9H); MS (E8T) 377 (M + H) ⁺ ; purity (HPLC, ACE column) 95%.

Intermediate 95. tert-Butyl-4- {1 - [(4-methoxyphenyl) sulfonyl] -1H-pyrrolo [3,2-c] pyridin-4-yl} piperazine-1-carboxylate.

Purification by recrystallization (MeOH / ether) after removal of the BOC-protecting group affords 21 mg (67%) of the product. ^! H-NMR (СРС1 ₃ ) δ 8.02-8.00 (m, 1Н), 7.84-7.80 (m, 2Н), 7.48-7.46 (m, 1Н), 7.41 -7.38 (m, 1H), 6.92-6.86 (m, 2H), 6.64-6.62 (m, 1H), 3.79 (s, 3H), 3.57-3 52 (m, 8H); 1.48 (s, 9H); MS (E8T) 473 (M + H) ⁺ ; purity (HPLC, ACE column) 95%.

Intermediate 96. tert-Butyl-4- (1 - {[[2- (trifluoromethyl) phenyl] sulfonyl} -1H-pyrrolo [3,2-c] pyridin-4-yl) piperazine-1-carboxylate.

Purification by preparative HPLC after removal of the BOC-protecting group affords 8.6 mg (25%) of the product. ^! H-NMR (СРС1 ₃ ) δ 8.14-8.11 (m, 1Н), 8.01-7.94 (m, 2Н), 7.89-7.72 (m, 3Н), 7.37 -7.34 (m, 1H), 6.89-6.88 (m, 1H), 3.93-3.89 (m, 4H), 3.71-3.67 (m, 4H), 1 47 (s, 9H); MS (E8C 511 (M + H) ⁺ ; purity (HPLC, ACE column) 95%.

Intermediate 97. tert-Butyl-4- {1 - [(2-methoxy-5-methylphenyl) sulfonyl] -1H-pyrrolo [3,2-c] pyridin-4-yl} piperazine-1-carboxylate.

Purification by preparative HPLC after removal of the protective BOC group yields 10.3 mg (32%) of the product. ^! H-NMR (СРС1 ₃ ) δ 7.95-7.92 (m, 2Н), 7.74-7.72 (m, 1Н), 7.44-7.40 (m, 2Н), 6.85 -6.77 (m, 2H), 3.92-3.88 (m, 4H), 3.70 (s, 3H), 3.69-3.66 (m, 4H), 2.39 (s , 3H); 1.47 (s, 9H); MS (E8T) 487 (M + H) ⁺ ; purity (HPLC, ACE column) 95%.

Example 121. 4-piperazin-1-yl-1- (toluene-4-sulfonyl) -1H-pyrrolo [3,2-c] pyridine hydrochloride. p-Toluenesulfonyl chloride (24.6 mg) was added to tert-butyl-4- (1H-pyrrolo [3,2-c] pyridin-4-yl) piperazine-1-carboxylate to give the title compound (4.3 mg ) LC / MS S _T : 1.374 (system: 10-40% MeCI for 1.5 minutes, ACE C8), purity 91%. MS: 357 (M + 1). ^! H-NMR (SR ₃ OR) δ ppm 2.39 (s, 3H), 3.48 (m, 4H), 4.06 (m, 4H), 7.22 (d, 1 = 3.71 Hz, 1H), 7.43 (d, 1 = 8.16 Hz, 2H), 7.95 (m, 5H).

Example 122. 1- (3-Chloro-2-methylbenzenesulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride.

3- Chloro-2-methylbenzenesulfonyl chloride (29.0 mg) was added to tert-butyl-4- (1H-pyrrolo [3,2-c] pyridin-4-yl) piperazine-1-carboxylate to give the title compound ( 6.3 mg). LC / MS S _T : 1.563 (system: 10-40% MeCI for 1.5 min, ACE C8), 96% purity. MS: 392 (M + 1).

Example 123. 1- (3,4-Dimethoxybenzenesulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride.

3,4-Dimethoxybenzenesulfonyl chloride (30.5 mg) was added to tert-butyl-4- (1H-pyrrolo [3,2-c] pyridin-4-yl) piperazine-1-carboxylate to give the title compound (8, 5 mg). LC / MS S _T : 1.284 (system: 10-40% MeCI for 1.5 min, ACE C8), purity 92%. MS: 404 (M + 1). ¹ H-NMR (SR ₃ OR) 8 ppm 3.50 (m, 1 = 4.21 Hz, 2H), 3.85 (d, 1 = 3.22 Hz, 4H), 4.10 (m, 1 = 3.96 Hz, 2H), 7, 11 (d, 1 = 8.66 Hz, 1H), 7.23 (d, 1 = 3.46 Hz, 1H), 7.48 (d, 1 = 1.73 Hz, 1H), 7.74 ( dd, 1 = 8.54, 1.86 Hz, 1H), 7.92 (s, 2H), 8.07 (d, 1 = 3.46 Hz, 1H).

Example 124. 4- (4-Piperazin-1-yl-pyrrolo [3,2-c] pyridin-1-sulfonyl) benzonitrile hydrochloride.

4- Cyanobenzenesulfonyl chloride (26.0 mg) was added to tert-butyl 4- (1H-pyrrolo [3,2-c] pyridin-4yl) piperazine-1-carboxylate to give the title compound (9.1 mg). LC / MS Y _T : 1,150

- 38 011581 (system: 10-40% CeCN for 1.5 min, ACE C8), purity 93%. MS: 369 (M + 1). 'H-NMR (CO ₃ OE) δ ppm 3.50 (m, 4H), 4.08 (m, 4H), 7.29 (d, 1 = 3.71 Hz, 2H), 7.98 (m, 4H), 8.29 (d, 1 = 8.66 Hz, 2H).

Example 125. 1- (4,5-Dichlorothiophen-2-sulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride.

4,5-Dichlorothiophen-2-sulfonyl chloride (32.4 mg) was added to tert-butyl-4- (1H-pyrrolo [3,2-c] pyridin-4-yl) piperazine-1-carboxylate to give the title compound (0.3 mg). LC / MS K _t : 1.119 (system: 10-40% GeCN for 1.5 min, ACE C8), purity 92%. MS: 418 (M + 1).

Example 126. 1- (2-Chloro-4-fluorobenzenesulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride.

2-Chloro-4-fluorobenzenesulfonyl chloride (29.5 mg) was added to tert-butyl-4- (1H-pyrrolo [3,2-c] pyridin-4-yl) piperazine-1-carboxylate to give the title compound ( 2.4 mg). LC / MS K _t : 1,361 (system: 10-40% GeCN for 1.5 min, ACE C8), purity 90%. MS: 396 (M + 1). Ή-NMR ΉΌΉΌ) δ ppm 3.51 (m, 4H), 4.08 (m, 4H), 7.23 (dd, 1 = 3.96, 0.49 Hz, 14), 7.47 (m, 1H), 7.55 (dd, 1 = 8.41, 2.47 Hz, 2H), 7.62 (d, 1 = 6.93 Hz, 1H), 7.91 (d, 1 = 7.18 Hz, 1H), 8 06 (d, 1 = 3.96 Hz, 1H).

Example 127. 1-Phenylmethanesulfonyl-4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride.

Phenylmethanesulfonyl chloride (24.6 mg) was added to tert-butyl-4- (1H-pyrrolo [3,2-c] pyridin-4yl) piperazine-1-carboxylate to give the title compound (0.2 mg). LC / MS K _t : 1.007 (system: 10-40% GeCN for 1.5 min, ACE C8), purity 90%. MS: 357 (M + 1).

Example 128. 1- (5-Chlorothiophen-2-sulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride.

5-Chlorothiophen-2-sulfonyl chloride (28.0 mg) was added to tert-butyl-4- (1H-pyrrolo [3,2-c] pyridin4-yl) piperazine-1-carboxylate to give the title compound (7, 2 mg). LC / MS K _t : 1.381 (system: 10-40% GeCN for 1.5 min, ACE C8), purity 97%. MS: 483 (M + 1).

Example 129. 1- (4-Butylbenzenesulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride.

4-No. Butylbenzenesulfonyl chloride (30.0 mg) was added to tert-butyl-4- (1H-pyrrolo [3,2-c] pyridin4-yl) piperazine-1-carboxylate to give the title compound (11.9 mg) . LC / MS K _t : 1.904 (system: 10-40% GeCN for 1.5 min, ACE C8), 95% purity. MS: 400 (M + 1) Ή-NMR (CO ₃ OE) δ ppm 0.90 (t, 1 = 7.18 Hz, 3H), 1.31 (m, 2H), 1.55 (m, 2H), 2.67 (m, 2H), 3.50 (m, 4H ), 4.09 (m, 1 = 3.96 Hz, 4H), 7.25 (d, 1 = 3.71 Hz, 2H), 7.44 (d, 1 = 8.16 Hz, 2H), 7.91 (m, 2H); 8.02 (m, 2H).

Example 130. 1- (4-Phenoxybenzenesulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride.

(4-Phenoxybenzene) sulfonyl chloride (34.7 mg) was added to tert-butyl 4- (1H-pyrrolo [3,2-c] pyridin-4-yl) piperazine-1-carboxylate to give the title compound (12 8 mg). LC / MS K _t : 1.839 (system: 10-40% GeCN for 1.5 min, ACE C8), 95% purity. MS: 436 (M + 1). Ή-NMR ΉΌΉΌ) δ ppm 3.50 (m, 1 = 3.96 Hz, 4H), 4.09 (m, 1 = 4.45 Hz, 4H), 7.05 (dd, 1 = 8.16, 6.43 Hz, 2H ), 7.26 (m, 2H), 7.44 (t, 1 = 7.79 Hz, 2H), 7.90 (m, 3H), 8.01 (d, 1 = 3.71 Hz, 2H) ), 8.07 (d, 1 = 8.91 Hz, 2H).

Example 131. 1- (Phenylsulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride.

Purification by recrystallization after removal of the BOC protecting group affords 16 mg (56%) of the product. MS (EM) 343.1 (M + H) ⁺ ; purity (HPLC, ACE column) 94%.

Example 132. Hydrochloride of 1 - [(4-chlorophenyl) sulfonyl] -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine.

Purification by preparative HPLC after removal of the protective BOC group yields 4 mg (11%) of the product. MS (EM) 377 (M + H) ⁺ ; purity (HPLC, ACE column) 96%.

Example 133. Hydrochloride of 1 - [(4-methoxyphenyl) sulfonyl] -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine.

Purification by recrystallization (MeOH / ether) after removal of the BOC protecting group affords 21 mg (67%) of the product. MS (E§ [) 373 (M + H) ⁺ ; purity (HPLC, ACE column) 92%.

Example 134. Hydrochloride of 1 - [(2-methoxy-5-methylphenyl) sulfonyl] -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine.

Purification by preparative HPLC after removal of the protective BOC group yields 10.3 mg (32%) of the product. MS (EM) 387 (M + H) ⁺ ; purity (HPLC, ACE column) 95%.

Example 135. 4-piperazin-1-yl-1 - [[2- (trifluoromethyl) phenyl] sulfonyl} -1H-pyrrolo [3,2-c] pyridine hydrochloride.

Purification by preparative HPLC after removal of the protective BOC group yields 8.6 mg (25%) of the product. MS (EM) 411 (M + H) ⁺ ; purity (HPLC, ACE column) 94%.

Biological tests

The ability of a compound of this invention to bind a 5-HT ₆ receptor and be pharmaceutically useful can be determined using tests under the conditions ίη νίνο and ίη νίΐτο, which are known in the art.

(a) 5-HT6 binding reaction.

- 39 011581

An experiment to determine the affinity for binding of the 5-HT ₆ receptor is performed on HEK293 cells transfected with the 5-HT ₆ receptor using (3H) -BBO as a labeled ligand in accordance with the general method described in the publication B.O. Woeck. e (a1. No. igoryagtasodu νοί. 36 (4/5) 713-720, 1997.

Materials

Cell culture

The HEK-293 cell line, transfected with the 5-HT ₆ receptor, is grown in an ECBessoc MobShebEad1ec Mobility medium containing 5% dialyzed fetal bovine serum (01bCo VKB 10106-169), 0.5 mM sodium pyruvate and 400 μg / ml Opeyst (0 -418) (01bco VKB10131-019). Cells are subcultured 1:10 twice a week.

Chemical substances

The radioligand [ ³ Η ^ 8Ό 60-240 Ci / mmol obtained from AtegkNat Ryagtaa Vu1es11 (Wisktjapkge, England) was stored in ethanol at -20 ° C. Unlabeled ligands, representing profiles of different selectivity, are presented in table. 1. The compounds are dissolved in 100% DMSO and diluted with binding buffer.

Expendable materials

Compounds are diluted in polypropylene 96-well plates with a ν-shaped bottom Sok! Ag (Sogshpd 1ps. Sok! Ag, ΝΥ, USA). Samples are kept in the Raskagb OrPr1a1e incubator (Raskagb 1pk1gnteSk V.M., Ogoptdep, Netherlands). The total amount of added radioligand is determined in Raskagb 24-well plates (Wageh, Raskagb 1pc! Gitep! To W / ν., Ogoptdep, the Netherlands) in the presence of Myogokst! ™ 20 scintillation fluid (Raskagb Wyukscheps, Mepbepp, ST, USA).

Buffer

The binding buffer consists of 20 mM NEREB, 150 mM No. C1, 10 mM MdCl ₂ and 1 mM рН, pH 7.4.

Methods

Membrane preparation

Cells are grown to about 90% confluence on culture dishes 24.5x24.5 ΝϋΝΟ The medium is aspirated and after rinsing with RVB, chilled with ice, the cells are cleaned using 25 ml Tris buffer (50 mM Tris-HC1, 1 mM ΕΌΤΑ, 1 mM ΕΟΤΑ , pH 7.4) and window scraper. Then the cells are placed in a Po1uhom homogenizer and the remaining particles of the substance are removed by low-speed centrifugation (1000 xd for 5 min). Finally, the membranes are collected by high speed centrifugation (20,000 x d), suspended in binding buffer and frozen in aliquots at -70 ° C.

Radioligand binding

Frozen cell membranes are thawed, immediately re-homogenized in a Po1uhop homogenizer and bound to BRA wheat seedlings agglutinin granules (ATEGKNat BaGe Baepsek, SagbyR, England) for 30 min with continuous shaking of the tubes. After binding, the granules are centrifuged for 10 min at 1000 d and then suspended in 20 ml of binding buffer on a 96 well plate. The binding reaction is initiated by adding to the suspension containing granule membranes, a radioligand and test compounds. After incubation at room temperature, the experimental plates are read on a scintillation counter. The experiment is carried out in accordance with the original ARB method, with the difference that the membranes are obtained from HEK293 cells expressing the 5HT ₆ human receptor, and not from HeBa cells (Όίΐ'ΐΐι OM, 2a \\ ogcc | PO, 0111 OB, Bsyasyeg BK Ba \\ 'cop sat, Btyy M \ V Va1 baΐ ^ ^ οp og Nitap 5-HT ₆ Gesar (WGC ehrgekkeb w sky se11 tetgapek:. kaShgaOop shbshd to ib1ek, rNagtaso1od1sa1 rgoGPek to exhaust (CNN apbagb adegIk APB BRA! . beνe1οrteηΐ TNE ir) SNPs Sotrapu Tes1nnsa1 Keroy 7295-95-064 1995;. 27 Oeseteg) Specific binding of | ^3H | EBO is saturable, while non-specific binding of age is a linear function of the concentration of added radioligand. ^[3 H ^ BO bond has high affinity for 5-HT ₆ receptors. K _b value as set on the basis of four independent experiments, equal to 2.6 ± 0.2 nM.

The total binding at 3 nM [ ³ H ^ BO, the concentration of the radioligand used in the comparative experiments, is usually 6000 gt, and the specific binding is more than 70%. 5-HT causes concentration-dependent inhibition of [ ³ H ^ BO binding at average K ₁ values above 236 nM when tested on two different membrane preparations. The coefficient of variation CV for three different experiments is 10% with average K values _of 1,173 nM (BE 30) and a Gill coefficient (H111) of 0.94 (BE 0.09). The internal variation of the experiment is 3% (n = 4). The values of K ₁ for a limited set of control compounds with known affinity for binding to the 5-HT6 receptor are presented in table. 7. All unlabeled ligands replace specific binding of [ ³ H ^ BO in a concentration-dependent manner, albeit with different forces. The binding strength order for the compounds is: methiotepine (2 nM)> mianserin (190 nM) -5-HT (236 nM)> methysergide (482 nM)> mesulerguide (1970 nM).

Determination of protein concentrations

Protein concentrations are determined in accordance with the method of WuKab Prigo! Akkau (VgabGogb MM. And Garbb apb kepyteyub Gog Not c. . Apa1 WusNet 1976; 72: 248-54). Bovine cheese albumin is used as a standard.

- 40 011581 cranks.

Scintillation reading

Radioactivity is determined using a Raskagb TorCoip1 ™ scintillation counter (Raskagb 1p8 (gtep18, Mepbep, ST, I8A) with a reading efficiency of about 20%. Reading efficiency is determined in separate series of experiments.

Saturation Experiments

In experiments on determining saturation, at least 6 concentrations in the doublets of the radioligand (0.1-20 nM [ ³ H] L8O) are used. Specific binding is calculated as the difference between total binding and non-specific binding, which is defined as radioligand binding in the presence of 5 μM lysuride. In _max and dissociation constant, K _b is determined from nonlinear regression analysis using equation 1. Lb represents the concentration of the unbound radioligand, and y represents the bound amount.

^Y ~ 1m + K <1 (equation 1)

Comparative experiments

The total and nonspecific binding of each radioligand is determined in eight repeated experiments. Samples containing the test compound were tested twice at 11 concentrations. Inoculation is carried out at room temperature for 3 hours. The value is 1C ₅₀ , i.e. the concentration of the experimental compound, at which it inhibits specific binding of the radioligand by 50%, is determined from nonlinear regression analysis, and the value of K _{1 is} calculated using the method [Syepd U.S. Vusyet. P11agtaso 1. 22. 3099-3108, 1973] in accordance with equation 2.

Κϊ = (equation 2) ¹⁺ K

B = concentration of radioligand;

Kb = affinity of the radioligand.

(b) Experience in determining the internal activity of 5-HT ₆ .

Antagonists with respect to the 5-HT ₆ receptor are characterized by measuring the inhibition of the 5-HT-induced increase in cAMP in HEK293 cells expressing the 5-HT ₆ receptor (see Boeu8 e1 a1. (1997) Leigoryagtasodu 36: 713-720). That is, HEK293 / 5-HT ₆ cells are plated in 96 well plates coated with polylysine at a seeding density of 25,000 / well and grown in EMEM (Unobenz MobSheb Ead1e Mebst) (without phenol red) containing 5% dialyzed bovine serum for 48 hours at 37 ° C in an incubator with 5% CO ₂ . Then the medium is suctioned off and replaced with 0.1 ml of the test medium (Napkk Ba1aps 8a11 8o1i1yup solution containing 20 mM HEPE8, 1.5 mM isobutyl methylxanthine and 1 mg / ml bovine serum albumin). After adding test compounds dissolved in 50 μl of test medium, the cells were incubated for 10 min at 37 ° C in an incubator with 5% CO2. The medium is again sucked off and the cAMP content is determined using a set of radioactive cAMP (AtheNat Ryagtaa Vu1esy, VYUTKAK KRA559). The strength of antagonists is quantified by finding the concentration that causes 50% inhibition of the increase in cAMP caused by 5-HT (at [5-HT] = 8xEC ₅₀ ), using the formula 1C ₅₀ , _co1T = 1C ₅₀ / (1+ [5HT] / EU ₅₀ ).

The compounds of this invention have selective affinity for 5-HT ₆ receptors with values of K ₁ and 1C ₅₀ , _co1T in the range from 0.5 nM to 5 μM or show inhibition of [ ³ H] L8O> 20% at 50 nM and are antagonists , agonists or partial agonists in relation to 5-HT ₆ . The compounds exhibit good selectivity for 5-HT _1a , 5-HT _2a , 5-HT _2b , 5-HT _2c .

(c) Experience in reducing food intake in the setting of u1uo.

A review of the effects of serotonin on food intake is presented in B1ipbe11, 1.E. Apb Na1Gogb. 1. S.S. (1998) 8th September 2003 APB Arre1be Keschbabop. 1tr11sa (ju8 Gog (Not P11agtasooshchos1 Tgea1tep1 oG Oe8yu. CU8 9: 473-495.

As a primary animal model, a mouse with signs of obesity (b / b) is selected, since such a mouse mutant consumes large amounts of food, causing a high signal in the noise ratio. To further confirm and obtain comparative efficacy data, the effect of compounds on food intake is also studied in field mice (C57BB / 61). The amount of food consumed within 15 hours of infusion of the compounds is recorded.

All studies used male mice (obese S57V / 61Vot ^EEP-ob and suffering thinness field C57B1 / 6 A;! Votyo118daagb, Eeptagk) 8-9 weeks with an average body weight of 50 g (for the obese) and 25 g (for thin people). Animals are kept separately in cages at 23 ± 1 ° C, 40-60% humidity and have free access to water and a standard laboratory diet. A 12/12-hour light / dark cycle was established with the lights off at 17 o’clock. Animals were kept under such conditions for at least one week before the start of the study.

Test compounds are dissolved in solvents suitable for each particular compound, such as cyclodextrin, a mixture of cyclodextrin / methanesulfonic acid, polyethylene glycol

- 41 011581 col / methanesulfonic acid, salt solution. Fresh solutions are prepared for each study. Use doses of 30, 50 and 100 mg kg ^-1 day ^-1 . The degree of purity of the test compounds is analytically pure.

Animals are weighed at the beginning of the study and randomly distributed based on body weight. Use A1xe1 osmotic mini-pumps (Mobe1 2001Ό, infusion rate of 8 μl / h) and fill them, essentially, in accordance with the recommendations of the A1xe1 technical manual (A1xa 8s1epNPs Rgobis1k, 1997; T11eei \ uek. R. Ap Uat, 8.1. App. Wute. Ep. 4 (4), 343-353, 1976). A continuous subcutaneous infusion of 24 hours is used. The mini-pumps are filled either with solutions of the test compounds of different concentrations in the carrier, or only with carriers that are previously held at 37 ° C (approx. 1 hour). Minipumps are implanted subcutaneously in the neck / back using short-term anesthesia (metofan / enflurane). This surgery lasts approximately 5 minutes. Uniform connection delivery is established within approximately 3 hours.

The mass of food pellets is determined at 17 and 20 hours for two days before implantation (baseline) and within one day after implantation of osmotic mini-pumps. Weighing is carried out with the help of scales equipped with a computer Mob1eg To1ebo RK 5002. A correction is made for the case of leakage. At the end of the study, the animals are killed by displacement of the cervical vertebrae and a stem blood sample is taken for further analysis on the content of the drug in the plasma.

Proteins of the plasma sample are precipitated with methanol, centrifuged, the supernatant is transferred to an HPLC vessel and injected into the liquid chromatography / mass spectrometry system. The mass spectrometer is set to the mode of electrospray of positive ions and the control of many reactions (Mi1br1e Keasbop Mopboppd). To calculate the concentrations of unknown samples, a linear regression analysis of standards forcedly injected through the source is used.

Food intake over 15 hours is determined over three consecutive days, and food consumption is determined for each animal as a percentage of the relative baseline level during the day before and after treatment. The obtained values are expressed as mean values of ± 8Ό and ± 8EM for eight animals per dose. Statistical evaluation is carried out using Kgikka1-WaShk ope - \\ ^g ay AYOUA using a percentage of the initial values. If the statistical significance reaches a level of p <0.05, the Mapp-U1Shpeu test is carried out and for statistical comparison of the control group and the group,

Claims (14)

CLAIM 1. The compound of formula (I) or its pharmaceutically acceptable salt, where the ring Ό is a 5-membered heterocyclic or heteroaryl ring, and the specified ring includes one or two atoms selected from the group comprising atoms of nitrogen, sulfur and oxygen, provided that that when Ό contains an oxygen atom, Ό is heteroaryl; each ν is independently -Ы-, - (СН) - or -С-, provided that at least one group ν is -Ы-; P represents a group of formula (a), (b) or (c), or> (a) (b) (c) where x = 0, 1 or 2 and y = 0; and P and K ³ can be attached to any carbon atom that allows substitution, or - 42 011581 when P is (c), then P can also be attached to any nitrogen atom in the ring Ό that allows substitution; I ¹ is (e) arylcarbonylethyl, (d) C _3-7 cycloalkyl-C 1 _-6 alkyl, where the cyclic ring is optionally partially unsaturated, or (11) the group Ar; wherein Ar represents (a) phenyl, (b) 1-naphthyl, (c) 2-naphthyl, (ά) aryl-C1 _-6 alkyl, (ί) 5-7-membered, optionally aromatic, partially saturated or fully saturated a mono- or bicyclic heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (e) a bicyclic ring system comprising at least one heterocyclic ring corresponding to the definition of (ί) and the group Ar, where the group Ar is substituted in one or several positions by the groups (a) H, X or Υ or (b) 5-7-membered, optionally an aromatic, partially saturated or fully saturated heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; I ² is (a) H or (b) C _1-6 alkyl, or I ¹ and I ^{2 are} joined to form the group —CH ₂ CH ₂ OCH ₂ CH ₂ - or where ν is 0-2, Υ and X are independently (a) H, (b) halogen, (c) C1 _-6 alkyl, (ά) HTF, (ί) _C1-6 alkoxy, (ί) phenoxy, (r) -SY ( o) straight or branched C1-6 alkyl halides, (d) -YY ⁴ I ⁵ , I ⁴ and I ⁵ independently represent (b) C _1-6 alkyl; I ³ is a group selected from any of the following groups: where I ³ is optionally substituted on each carbon atom, which allows the substitution of I _h groups, where I independently represents H or (C _{-2 -2} ) alkyl, and where two I groups can be on the same carbon atom at the same time, where c. = 1 or 2, t = 1 or 2 and I ⁶ independently represents (a) H, (b) linear or branched C1-6 alkyl. 2. The compound according to claim 1, where I ¹ represents the group Ar; - 43 011581 Ar is (a) phenyl, (b) 1-naphthyl, (c) 2-naphthyl or (ί) 5-7-membered, optionally aromatic, partially saturated or fully saturated heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, wherein the group Ar is substituted in one or more positions of the groups (a) H, (b) halogen, (c) C1 _-6 alkyl, (b) -SEe, (ί) C1 _-6 alkoxy , (n) phenyloxy, B ² represents (a) H, or (b) C1 _-6 alkyl; X and Υ are H; In ³ selected from any of the following groups: where t = 1 or 2, and B ⁶ independently represents (a) H, (b) C 1-6 alkyl, in particular methyl. 3. The compound according to any one of claims 1 to 2, where is pyrrolyl, thienyl or furanyl. 4. The compound according to any one of claims 1 to 3, where P is where B ¹ , x and y have the meanings defined in claim 1. 5. The compound according to any one of claims 1 to 3, where P is a 6. The compound according to claim 5, where In ² represents N. 7. The compound according to claim 4 of the general formula (IV) 8. The compound according to any one of paragraphs.5 or 6 of the general formula (VI) 10. The compound according to claim 7, which is 4- (1,4-diazepan-1-yl) -2- (phenylsulfonyl) thieno [3,2-c] pyridine hydrochloride; 4- (1,4-diazepan-1-yl) -2 - [(3,4-dichlorophenyl) sulfonyl] thieno [3,2-c] pyridine hydrochloride; 4- (1,4-diazepan-1-yl) -2- [4-tert-butylphenylsulfonyl] thieno [3,2-c] pyridine hydrochloride; 4- (1,4-diazepan-1-yl) -2- [4-tert-butylphenylsulfonyl] thieno [3,2-c] pyridine hydrochloride; - 44 011581 4- (1,4-diazepan-1-yl) -2- [3,4-dimethylphenylsulfonyl] thieno [3,2-c] pyridine hydrochloride; 2 - [(4-bromophenyl) sulfonyl] -4- (1,4-diazepan-1-yl) thieno [3,2-c] pyridine hydrochloride; 2- (phenylsulfonyl) -4-piperazin-1 -thyleno [3,2-c] pyridine hydrochloride; 2- (3-methoxy-benzenesulfonyl) -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride; 2- (4-methoxybenzenesulfonyl) -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride; 4-piperazin-1 -yl-2 - {[(4-trifluoromethyl) phenyl] sulfonyl} thieno [3,2-c] pyridine hydrochloride; 2 - [(2-tert-butylphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride; 2 - [(3,4-dichlorophenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonamide hydrochloride; 2 - [(4-tert-butylphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride; 2- (1-naphthylsulfonyl) -4-piperazin-1 -thyleno [3,2-c] pyridine hydrochloride; 2 - [(3-fluorophenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonamide hydrochloride; 2- (mesitylsulfonyl) -4-piperazin-1 -thyleno [3,2-c] pyridine hydrochloride; 2 - [(2-methoxyphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride; 2 - [(2,4-dimethoxyphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride; 2 - [(2,4-dimethylphenyl) sulfonyl] -4-piperazine-1 -thyleno [3,2-c] pyridine hydrochloride; 2 - [(2,5-dimethylphenyl) sulfonyl] -4-piperazine-1 -thyleno [3,2-c] pyridine hydrochloride; 2 - [(2-ethylphenyl) sulfonyl] -4-piperazin-1 -thyleno [3,2-c] pyridine hydrochloride; 4- (piperazinyl) -2- (3-methoxybenzylsulfonyl) thienopyridine hydrochloride; 2- (benzylsulfonyl) -4-piperazin-1 -thyleno [3,2-c] pyridine hydrochloride; 4-piperazin-1-yl-2 - {[4- (trifluoromethyl) benzyl] sulfonyl} thieno [3,2-c] pyridine hydrochloride; 2 - [(3-bromobenzyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride; 2 - [(2,3-difluorobenzyl) sulfonyl] -4-piperazin-1 -thyleno [3,2-c] pyridine hydrochloride; 2 - [(4-bromobenzyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride; 2 - {[2,5-bis (trifluoromethyl) benzyl] sulfonyl} -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride; 2 - [(4-methylbenzyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride; 2 - {[5-chloro-2- (trifluoromethyl) benzyl] sulfonyl} -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride; 2- [(3,5-dimethoxybenzyl) sulfonyl] -4-piperazin-1 -thyleno [3,2-c] pyridine hydrochloride; 2 - [(2-naphthylmethyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride; 4-piperazin-1 -yl-2- {[4- (1,2,3-thiadiazol-4-yl) benzyl] sulfonyl} thieno [3,2-c] pyridine hydrochloride; 1- (4-pyrrolidin-1-ylphenyl) -2 - [(4-piperazin-1-ylthieno [3,2-c] pyridin-2-yl) sulfonyl] ethanone hydrochloride; or 1- [4- (diethylamino) phenyl] -2 - [(4-piperazin-1-ylthieno [3,2-c] pyridin-2-yl) sulfonyl] ethanone hydrochloride; or its pharmaceutically acceptable salt. 11. The compound according to claim 7, which is 1- (4-methylphenylsulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; 1- (3-chloro-2-methylphenylsulfonyl) -4-piperazin-1 -yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; 1- (3,4-dimethoxyphenylsulfonyl) -4-piperazin-1 -yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; 4- (4-piperazin-1-ylpyrrolo [3,2-c] pyridin-1-sulfonyl) benzonitrile hydrochloride; 1- (4,5-dichlorothiophen-2-sulfonyl) -4-piperazin-1 -yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; 1- (2-chloro-4-fluorophenylsulfonyl) -4-piperazin-1 -yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; 1-phenylmethanesulfonyl-4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; 1- (5-chlorothiophen-2-sulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; 1- (4-Butylbenzenesulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; 1- (4-phenoxybenzenesulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; 1- (Phenylsulfonyl) -4-piperazin-1 -yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; 1 - [(4-chlorophenyl) sulfonyl] -4-piperazin-1 -yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; 1 - [(4-methoxyphenyl) sulfonyl] -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; 1 - [(2-methoxy-5-methylphenyl) sulfonyl] -4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine hydrochloride; or 4-piperazin-1-yl-1 - {[2- (trifluoromethyl) phenyl] sulfonyl} -1H-pyrrolo [3,2-s] pyridine hydrochloride; or its pharmaceutically acceptable salt. 12. The compound of claim 8, which is L- (4-methylphenyl) -4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine-2-sulfonamide hydrochloride; p-tolyl amide hydrochloride 2-bromo-4- (4-methylpiperazin-1-yl) thieno [3,2-s] pyridine-3-sulfonic acid; 4- (4-methylpiperazin-1-yl) -n-phenylthieno [3,2-c] pyridine-2-sulfonamide hydrochloride; 4-piperazin-1-ylthieno [3,2-c] pyridine-2 sulfonic acid hydrochloride (3-fluoro-5-trifluoromethylphenyl) amide; 4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonic acid hydrochloride (4-chlorophenyl) amide; 4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonic acid hydrochloride (4-isopropylphenyl) amide; - 45 011581 p-tolylamide hydrochloride 4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonic acid; 4- (4-methylpiperazin-1-yl) -N (2-cyclohex-1-ene-1-el-ethyl) thieno [3,2-c] pyridine-2-sulfonamide hydrochloride; 2- (4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridin-2-ylsulfonyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride; 4- (4-methylpiperazin-1-yl) -N (2-thien-2-yl-ethyl) thieno [3,2-c] pyridine-2-sulfonamide hydrochloride; 4- (4-methylpiperazin-1-yl) -N [1- (1-naphthyl) ethyl] thieno [3,2-c] pyridine-2-sulfonamide hydrochloride; 4- (4-methylpiperazin-1-yl) -No (4-hexylphenyl) thieno [3,2-c] pyridine-2-sulfonamide hydrochloride; N- (3-chlorobenzyl) -4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine-2-sulfonamide; 4- (4-methylpiperazin-1-yl) -N [1- (4-fluorophenyl) ethyl] thieno [3,2-c] pyridine-2-sulfonamide hydrochloride; hydrochloride no. (2,3-difluorobenzyl) -4- (4-methylpiperazin-1-yl) thieno [3,2-s] pyridine-2-sulfonamide; 4- (4-methylpiperazin-1-yl) -No (4-chloro-2,5-dimethoxyphenyl) thieno [3,2-c] pyridine-2-sulfonamide hydrochloride; 2-bromo-4- (4-methylpiperazin-1 -yl) -No (2-cyclohex-1-ene-1-ethyl) thieno [3,2-c] pyridine-3-sulfonamide hydrochloride; 2-bromo-4- (4-methylpiperazin-1-yl) -No [(18) -1 - (2-naphthyl) ethyl] thieno [3,2-c] pyridine-3sulfonamide hydrochloride; 2-bromo-4- (4-methylpiperazin-1 -yl) -No. [1- (4-fluorophenyl) ethyl] thieno [3,2-c] pyridine-3sulfonamide hydrochloride; 2-bromo-4- (4-methylpiperazin-1-yl) -N (2,4,5-trimethoxyphenyl) thieno [3,2-c] pyridine-3-sulfonamide; hydrochloride no. (3,4-dichlorophenyl) -4-piperazin-1 -thyleno [3,2-c] pyridine-2-sulfonamide; hydrochloride no. (2,4-difluorophenyl) -4-piperazin-1 -thyleno [3,2-c] pyridine-2-sulfonamide; 4-piperazin-1-yl-no. [3- (trifluoromethyl) phenyl] thieno [3,2-c] pyridine-2-sulfonamide hydrochloride; N- (3-ethylphenyl) -4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonamide hydrochloride; hydrochloride no. (3,4-dimethoxyphenyl) -4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonamide; hydrochloride no. (4-bromo-2-methylphenyl) -4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonamide; 2- (4-piperazin-1 -thyleno [3,2-c] pyridin-2-sulfonyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride; 4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonic acid hydrochloride (2-thiophen-2-ylethyl) amide; 4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonic acid hydrochloride (4-chloro-2,5-dimethoxyphenyl) amide; phenethyl amide hydrochloride 4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonic acid; 4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonic acid hydrochloride (2,6-diethylphenyl) amide; 4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonic acid hydrochloride (3-phenylpropyl) amide; 4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonic acid hydrochloride (3,3-diphenylpropyl) amide; 4-piperazin-1-ylthieno [3,2-c] pyridine-2 sulfonic acid hydrochloride [2- (5-methoxy-1H-indole-3-yl) ethyl] amide; 4-trifluoromethyl-benzylamide 4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonic acid hydrochloride; 4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonic acid benzyl ethyl amide hydrochloride; hydrochloride no. (3-ethylphenyl) -4-piperazin-1-ylthieno [3,2-c] pyridine-3-sulfonamide; hydrochloride no. (4-isopropylphenyl) -4-piperazin-1 -thyleno [3,2-c] pyridine-3-sulfonamide; hydrochloride no. (4-methylphenyl) -4- (pyrrolidin-3-yloxy) thieno [3,2-c] pyridine-2-sulfonamide; hydrochloride no. (4-methylphenyl) -4- (piperidin-4-yloxy) thieno [3,2-c] pyridine-2-sulfonamide; hydrochloride no. (2,3-difluorobenzyl) -4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonamide; N- (3-chlorobenzyl) -4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonamide hydrochloride; 4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonic acid phenylamide hydrochloride; (4-tert-butylphenyl) amide hydrochloride 4-piperazin-1-ylthieno [3,2-c] pyridine-2-sulfonic acid; 4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine-2-sulfonic acid hydrochloride; 4- (4-methylpiperazin-1-yl) thieno [3,2-s] pyridine-2-sulfonic acid hydrochloride (3-chlorophenyl) amide; 2-bromo-4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine-3-sulfonic acid hydrochloride phenylamide; 4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine-3-sulfonic acid hydrochloride (4-methylphenyl) amide; or phenyl-7-piperazin-1-ylthieno [2,3-c] pyridine-2-sulfonamide hydrochloride; or its pharmaceutically acceptable salt. 13. The use of a compound according to any one of claims 1 to 12 for the manufacture of a medicament for - 46 011581 use in the treatment or prevention of disorders of the central nervous system. 14. The use of a compound according to any one of claims 1 to 12 for the preparation of a medicament for use in the treatment or prophylaxis of type II diabetes mellitus. 15. The use of a compound according to any one of claims 1 to 12 for the preparation of a medicament for use in the treatment or prevention of obesity, for achieving a reduction in body weight and an increase in body weight.