EA008835B1 - Substituted sulfone and sulfonamides and pharmaceutical compositions based thereon useful for the treatment of obesity, type ii diabetes cns disorders - Google Patents

Abstract

The present invention relates to compounds of the general formula (I), wherein 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, to achieve reduction of body weight and of body weight gain.

Description

This application claims priority on the application of Sweden number 0201925-5, filed June 20, 2002, the application of Sweden number 0202908-0, filed October 1, 2002, the application of Sweden number 0202181-4, filed July 11, 2002, the application of Sweden number 0300357 filed February 10, 2003, US provisional application 60/406120, filed August 26, 2002, US provisional application 60/434010, filed December 17, 2002, and US provisional application 60/464701, filed April 23, 2003, the contents of which are incorporated into this invention by reference.

Technical field

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 (Kia !, M. s. A1. (1993) Vusyet. Vyuruz. Kez. Sottip. 193: 268-276; 8eyep, M. e ! a1. (1994) HeigoKeroi 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 effect of a 5-HT ₆ antagonist and 5-HT ₆ antisensory oligonucleotides on the reduction of food intake by rats was described (Wepbeu, 1.C. e! A1. (1999) Vg. 1. Ryagtas. 8irp. 126, P66; Vep ! 1eu, 1.C. e! A1. (1997) 1. Rzusyoryagtaso1. 8irr1. A64, 255; ^ oo11eu M.E.e! A1. (2001) No. igoryattasodu).

Compounds with increased affinity and selectivity for the 5-HT6 receptor were identified, for example, in XVO 00/34242 and in the publication 1zaas, M. e! a1. (2000) 6-V1cus1or1regah1pu1-1atu1zi1Gopu1shbo1ez apb 6-V1sus1or1regah1pu1zu1-1-atu1zi1Gopu1tbo1ez bepuaysez az poue1. ro! ep! Apb Ze1esyue 5NT ₆ Geser! Oh ap! Adozhz! z. Vyuotdashs & Meb1ssa1 Sjet1z1tu Ljetz 10: 1719-1721 (2000).

Description of the Related Art

In the publication EMeb.Set. 1970, 13 (4), 592-598 describe P- (4 {[2- (diethylamino) ethyl] amino} -1naphthyl) amides; P- {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.

- 1 008835

\ Νϋ 98/27081 A1 describes compounds that bind to the 5-HTD receptor and are used to treat CNS disorders, and also, along with other uses, can be used to treat appetite disorders.

EP 0 701 819 describes compounds that bind to the 5-HT _1C receptor and are used to treat CNS disorders and obesity.

US Pat. Nos. 6191141 and νθ 01/12629 describe compounds that bind to the 5-HT ₆ receptor and are used to treat CNS disorders.

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, psychoses, Alzheimer's disease, Parkinson's disease, Huntington's disease and / or schizophrenia, attention deficit medicines. Weight loss and weight gain (for example, treatment of disorders associated with abnormal body weight) is achieved along with other means of 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 “C2-6 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 “C3-7cycloalkyl” refers to a cyclic alkyl group containing a ring from C3 to C7, 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 from C5 to C10. 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,

- 2 008835 pyrrolidinyl, imidazolyl, pyrazolyl, piperidyl, azepinyl, morpholinyl, pyranyl, dioxanyl, pyridazinyl, pyrimidinyl and piperazinyl.

Unless otherwise stated or indicated, the term “aryl” refers to a hydrocarbon 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 compound of formula (I) ί *

I and * *

X

Υ

¢ 1) or a pharmaceutically acceptable salt thereof, wherein ring B is

I Τ-Υ

A a

V /

D each XV independently represents -Ν-, - (CH) - or -C-, provided that in total no more than three groups of XV are -Ν- in both rings A and B at the same time,

P represents any of the groups of formula (a), (b) or (c)

BUT

3 (0) x

At

K ¹ η Ν-Η ² (Y ^ Y to ¹

5 '' °

I'm ^2nd >

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

IR, IR ³ can be attached to any carbon atom that can be substituted in one of rings A or B, or, when ring A contains at least one nitrogen atom and P represents (c), then P can also be attached to any nitrogen atom in ring B that allows substitution;

dashed lines mean that P and B ³ , respectively, can be attached to ring A or to ring B; but each P or B ³ cannot simultaneously be attached to both rings A and B;

V ¹ represents (a) S1_ ₆ alkyl, (b) S1_ ₆ alkoxyalkyl, (c) hydroxyalkyl S1_ ₆ straight or branched chain alkyl, (ά) S1.balkilgalogenidy straight or branched chain alkyl, (f) arilkarbonilmetil, (£) C3_7 cycloalkyl, which is optionally partially unsaturated, (e) C3.7cycloalkyl-C1_alkyl, where the cyclic ring is optionally partially unsaturated, or (11) an Ar group;

wherein Ar represents (a) phenyl, (b) 1-naphthyl, (c) 2-naphthyl, (ά) aryl _{S1_-6} alkyl, (e) cinnamyl, (£) 5-7-membered, optionally aromatic, partially saturated or fully saturated mono- or bicyclic heteroaryl ring, each of which contains from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms, (e) a bicyclic ring system comprising at least one heterocyclic ring corresponding to the definition of (£ ), and the group Ag, where the group Ag is substituted in one or more positions by groups (a) Η, 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;

I ² is (a) H, (b) S1_b alkyl, (c) C ₂ .b alkoxyalkyl, (b) straight or branched C] .6 hydroxyalkyl, or (e) straight or branched alkyl halides S1_ _6;

(£) Ar group, or H ¹ and H ^{2 are} connected to form the group —CH ₂ CH ₂ OCH ₂ CH ₂ —or

where ν is equal to 0-2, X and Υ are independently (a) H, (b) halogen, (c) S1_balkil, (b) CE ₃ (e) hydroxy, (£) S1_ ₆ alkoxy, (d) C ₂ . ₆ alkenyl, (11) phenyl, (ΐ) phenoxy,

()) benzyloxy, (k) benzoyl, (l) -OECEs, (w) -ΟΝ, (i) straight or branched C-hydroxyalkyl, (o) straight or branched C. '| Alkyl halides.

(P) -ΝΗ ₂ , (f -ΝΗΚ ⁴ , (d) -ΝΒ ⁴ Κ ⁵ , (8) -ΝΟ ₂ , (ΐ) -SOSH'A ³ .

(i) -ΝΗ8Ο ₂ Κ ⁴ , (ν) -ΝΒ ⁴ ΟΟΚ ⁵ , (χ) -8Ο ₂ ΝΒ ⁴ Κ ⁵ , (ζ) -С (= О) I ⁴ , (aa) -CO ₂ I ⁴ or (ab) -8 (O) _II ⁴ , where u is 0, 1, 2 or 3, (ac) -8 (C1_b) alkyl or (ab) -8CE ₃ ; and

I ⁴ and I ⁵ are independently (a) H, (b) S1_balkil, (c) C ₃ _7tsikloalkil or (b) Ar whose values defined above for R ^1;

alternatively

Z ⁴ and Z ^{5 are} connected to form the group —CH ₂ OCH ₂ -, —CH ₂ CH ₂ OCH ₂ CH ₂ - or (CH ₂ ) ₃ . ₅ ;

I ³ represents a group selected from any of the following groups:

-4008835

where R ³ is optionally substituted at each carbon atom which permits substitution groups K ,,, where venom is independently H or (C1. ₆₎ alkyl, and wherein two poison groups may be on the same carbon atom simultaneously, wherein q = 1 , 2, 3, 4, 5, or 6, t = 1 or 2 and u = 0, 1 or 2;

I ⁶ is independently (a) H, (b) linear or branched S1_ ₆ alkyl, (c) benzyl, (b) -CH ₂ -CH ₂ -OH, or (e) -CH ₂ -CH ₂ -O-C1 - ₆ alkyl;

P and R ³ can be attached to one ring or to different rings of rings A and B; provided that when P represents co ₂

K-Ν <

'(a) or (b), and P and I ³ are both attached to the ring A in the meta or para position with respect to each other, then I ^{3 is} selected from any of the following groups:

-5008835

when ring B represents and P represents

then P and H ^{3 are} simultaneously attached to the same ring A or B; when ring B is

and P represents

where y = 0, then P and I ^{3 are} attached to different rings of rings A and B, or when ring B is

and I ^{1 =} Ar is a partially saturated bicyclic heterocyclic ring containing an atom Ν, the atom N in Ar cannot be attached to the atom § in P;

with the proviso that when rings A and B are both phenyl, P represents any of the groups of formula (a) or (c) substituted at position 7 of the naphthalene ring, then R ^{3 is} not substituted at position 1 of the naphthalene ring.

In another embodiment, the invention relates to a compound of formula (I), wherein

I ¹ represents (a) C1_balkyl or (e) a group of Ar;

Ag is

-6008835 (a) phenyl, (b) 1-naphthyl, (c) 2-naphthyl or (G) 5-7 membered, optionally aromatic, partially saturated or fully saturated heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur atoms, where the Ar group is substituted in one or more positions by the groups (a) H, (b) halogen, (c) C1_b alkyl, (b) -Cr3, (D) C1_b alkoxy, (g) C ₂ .b alkenyl, (1) -OSRz, (iii) straight or branched S1_ ₆ hydroxyalkyl, (u) aryloxy, (v) benzyloxy, (ν) -ΝΚ ⁴ ΟΟΚ ^5, (x) -3Ο ΝΚ ₂ ^{4 5} Κ ;

(ζ) -C (= O) I ⁴ , (ab) -8 (O) _П I ⁴ , where u is 0, 1, 2 or 3;

(ac) -8- (. C 1 -C ₆₎ alkyl or (ab) -8SR _3;

I ² is (a) H, or (b) S1_ ₆ alkyl;

or I ¹ and I ^{2 are} connected to form the —CH ₂ CH ₂ OCH ₂ CH ₂ - group;

X and Υ are H;

I ⁴ and I ⁵ each independently represents H or C 1 alkyl; and

I am ³ selected from any of the following groups:

where R ³ can be substituted on each carbon atom, which permits substitution groups I _h where venom is independently H or S1_ ₆ alkyl, and where two groups I may be on the same carbon atom simultaneously, where | = 1 or 2, w = 1 or 2, and = 0 and

I ⁶ independently represents (a) H, (b) C1_balkyl, in particular methyl, (b) —CH ₂ —CH ₂ —OH or (e) —CH ₂ —CH ₂ —OCH ₃ .

Another preferred embodiment of the invention is a compound of formula (I), wherein I ³ is piperazine; homopiperazine; 2,6-dimethylpiperazine; 3,5-dimethylpiperazine; 2,5-dimethylpiperazine; 2 methylpiperazine; 3-methylpiperazine; 2,2-dimethylpiperazine; 3,3-dimethylpiperazine; piperidine; 1,2,3,6tetrahydropyrazine or 4-pyrrolidin-3-yloxy.

The next preferred variant of the invention relates to a compound of formula (I), where P represents ^K \

Y (c) where H ¹ , x and y have the meanings defined above. A further preferred embodiment is a compound wherein P is

K ¹

I _g η M-EG

X

O>'(a)or' (b) where I ¹ and I ² have the meanings defined in π. 1. One embodiment of the invention is a compound wherein

I ² represents N.

Another embodiment of the invention relates to a compound of general formula (II)

where I ¹ , x, y and X, Υ, I ³ have the meanings defined above. The next frequent embodiment of the invention is a compound where y = 0 and x = 2.

Another embodiment of the invention relates to a compound of general formula (III)

(Iii) where ^{1 1} , x, y and X, Υ have meanings as in π. 1, and I ³ has the meanings defined in and. 2. One preferred embodiment of the invention is a compound wherein y = 0 and x = 2. One embodiment of the invention relates to a compound of general formula (XI)

οα> · where P represents a group of formula (a) or (b), the meanings of which are defined in claim 1, preferably, where I ² represents Η, X, I ³ and Υ have the meanings defined above.

One embodiment of the invention relates to a compound which is 6-benzenesulfonyl-4-piperazin-1-ylquinoline hydrochloride;

6 - [(2-fluorophenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride;

6- (1-naphthylsulfonyl) -4-piperazin-1-ylquinoline hydrochloride;

6 - [(3,4-dichlorophenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride;

6 - [(3,5-dimethylphenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride;

6 - [(2-chloro-6-methylphenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride;

6 - [(4-chlorophenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride;

6 - [(2-methyl-1,4-tert-butylphenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride;

6 - [(3,4-dimethylphenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride;

6 - [(2,3-dichlorophenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride;

6 - [(4-tert-butylphenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride;

6 - [(4-Isopropylphenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride;

(4-piperazin-1-yl) -6- {[4- (trifluoromethyl) phenyl] sulfonyl} quinoline hydrochloride;

6 - [(4-tert-butylphenyl) sulfonyl] -4- (1,4-diazepan-1-yl) quinoline hydrochloride; or 4- (1,4-diazepan-1-yl) -6 - [(4-isopropylphenyl) sulfonyl] quinoline hydrochloride.

7- (2-chloro-6-methylbenzenesulfonyl) -1-piperazin-1-isoquinoline hydrochloride;

-8008835 7- (2-tert-butylbenzenesulfonyl) -1-piperazin-1-yl-isoquinoline hydrochloride; 7- (3,4-dichlorobenzenesulfonyl) -1-piperazin-1-yl-isoquinoline hydrochloride; 7- (2,4-dimethylbenzenesulfonyl) -1-piperazin-1-yl-isoquinoline hydrochloride; 7- (2,5-dimethylbenzenesulfonyl) -1-piperazin-1-yl-isoquinoline hydrochloride; 7- (p-chlorobenzenesulfonyl) -1-piperazin-1-yl-isoquinoline hydrochloride;

7-benzenesulfonyl-1 - [1,4] diazepan-1-isoquinoline hydrochloride;

7 - [(4-tert-butylbenzenesulfonyl) -1- [1,4] diazepan-1-yl] isoquinoline hydrochloride; 7 - [(2-chloro-6-methylbenzenesulfonyl) -1- [1,4] diazepan-1-yl] isoquinoline hydrochloride; 7 - [(3,5-dimethylbenzenesulfonyl) -1- [1,4] diazepan-1-yl] isoquinoline hydrochloride;

7 - [(3,4-dichlorobenzenesulfonyl) -1 - [1,4] diazepan-1-yl] isoquinoline hydrochloride; 7- [(4-chlorobenzenesulfonyl) -1- [1,4] diazepan-1-yl] isoquinoline hydrochloride;

7 - [(3,4-dimethylbenzenesulfonyl) -1- [1,4] diazepan-1-yl] isoquinoline hydrochloride; 7 - [(2-tert-butylbenzenesulfonyl) -1- [1,4] diazepan-1-yl] isoquinoline hydrochloride;

7-benzenesulfonyl-1-piperazinyl isoquinoline hydrochloride; or 7- (4-tert-butylbenzenesulfonyl-1-piperazinyl) isoquinoline hydrochloride.

4-chloro-Y- [4- (pyrrolidin-3-yloxy) -1-naphthyl] benzenesulfonamide hydrochloride; 4-methoxy-Y- [4- (pyrrolidin-3-yloxy) -1-naphthyl] benzenesulfonamide hydrochloride; 5-chloro-Y- [4- (pyrrolidin-3-yloxy) -1-naphthyl] thiophen-2-sulfonamide hydrochloride;

4-chloro-Y- [4- (piperidin-3-yloxy) -1-naphthyl] benzenesulfonamide hydrochloride; 4-methoxy-Y- [4- (piperidin-3-yloxy) -1-naphthyl] benzenesulfonamide hydrochloride;

5-fluoro-2-methyl-Y- [4- (piperidin-4-yloxy) -1-naphthyl] benzenesulfonamide hydrochloride; 5-chloro-Y- [4- (piperidin-4-yloxy) -1-naphthyl] thiophen-2-sulfonamide hydrochloride;

4-chloro-Y- {4 - [(38) -pyrrolidin-3-yloxy] -1-naphthyl} benzenesulfonamide hydrochloride; or 4-chloro-Y- {4 - [(3K) -pyrrolidin-3-yloxy] -1-naphthyl} benzenesulfonamide hydrochloride.

The present invention also relates to the use of a compound in the manufacture of a medicament for the treatment or prevention of disorders of the central nervous system, in particular, to the use of a compound wherein rings A and B are both phenyl, P is any group of formula (a) or (c), substituted at position 7 of the naphthalene ring, and K ³ substituted at position 1 of the naphthalene ring to obtain a medicament for the treatment or prevention of type II diabetes mellitus.

The invention also relates to the use of a compound for the manufacture of a medicament for the treatment or prevention of obesity, in order to achieve a decrease in body weight or an increase in body weight.

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 (i.e., it can be measured using some test or marker) or subjectively (i.e., the subject speaks of an indication or sensation 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 wt.% The drug, preferably in the range of 0.2-20 wt.% In preparations for parenteral use, and preferably in the range from 1 to 50 wt. preparations for oral administration.

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), which can be used to synthesize compounds that can be used later, are known in the art and include, for example,

- 9 008835 dy described in publications: Ya. Lagosk, Sotrgs11sp5p s Oggashs TgapkGogtayopk, USN RiyEyega (1989); Τ.λν. Oheepe aps! R.O.M. \ Yi15. Rgo1ssN \ s Ogirz ίη Og§ashs 8y GPNsMz, 2 ' ¹ Esk, 1o1t \ UISu aps1 8oiz (1991); B. E1ezeg aps1 M. E1ezeg, Nschsg aps1 P1ezeg'5 Yaegeri15 £ og Ogdashs 8y PShMk, 1o1t XVIsu aps1 8oiz (1994); aps1 b. Husband, to her., Epsus1oresya about £, 15 £ og Ogdashs Ξνηΐΐιεδίδ. 1Ut KhUISu aps1 8oiz (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 AsKapss 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 Regkt-E1teg 8res1git 1000 BT-1Ya spectrophotometer. The spectra of ion-spray mass spectrometry (MS) were obtained on a Rekt-E1sheg ΑΡΙ 150EX mass spectrometer. Exact mass determinations were carried out using a dual sensor M1gotaz5 LST. Preparative HPLC / MS was carried out using the system XUa1eg5 / M1sgotaz5 ΡΙηΙίοπη Ζζ). equipped with system A (column ACE 5 C8 (19x50 mm) eluents: Μίΐΐίζ) water, MeSL and Μίΐΐίφ water / MSSS). 1% TFA) and system B (column X1egga M8 C 18, 5 μm (19x50 mm), eluents: Μίΐΐίζ) water, MeSL and XN ₄ NSO ₃ (100 mM)). HPLC analysis was carried out on an ASh1sSh 1100 apparatus [ACE 3 C8 column (system A) or UMS-Rask column (system B), eluents: Μίΐ1ίζ) / 0.1% TFUK and MeSL]. Elemental analysis was performed on a Uapo E1 apparatus. Preparative flash chromatography was performed on Megk 60 silica gel (230-400 mesh).

Table 1

Example to ⁴ one 6-benzenesulfonyl-4-piperaein hydrochloride 1-ylquinoline nine 0 2 B - [(2-fluorophenyl} sulfonyl] -4 piperazin-1-ylquinoline hydrochloride 0 3 6- (1-Maftylsulfomyl) -4-piperazin-1-ylquinoline hydrochloride ¢ 0 0 4 6- ((3,4-Dichlorophenyl) sulfonyl] hydrochloride] - 4-piperazin-1-ylquinoline C1 0 5 Hydrochloride 6 - ((3,5- dimethylphenyl] sulfonyl] -4-piperazin-1- ilquinoline V 0 6 6 - ((2-Chloro-6-methyl-phenyl) -sulfonyl] -4-piperazin-1-ylquinoline hydrochloride -9s 0 7 6 - [(4-Chlorophenyl) sulfonyl] -4 piperazin-1-ylquinoline hydrochloride 0 6 6 - ((2-Methyl-4-tert-butylphenyl) sulfonyl} -4-piperazin-1ylquinoline hydrochloride £ 0 nine Hydrochloride 6 - ((3,4- diethylphenyl) sulfonyl] -4-piperaein-1- ilquinoline f 10 Hydrochloride 6 - [(2,3-Dichlorophenyl) sulfonyl] - 4-piperazin-1-ylquinoline 9s> f eleven Hydrochloride 6 - [(4-tert- butidophenyl) sulfonyl] -4-piperazin-1- iphinoline 5 f

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12 Hydrochloride 6 “[(4- isopropylphenyl) sulfonyl] -4-piperain-1ylquinoline $ 0 thirteen Hydrochloride (4 ~ pilerazin-1-ichcb- {[4- (trifluoromethyl} phenyl] with ul phyl} chin one a 0 14 hydrochloride 6 - [(4-tert- butylphenyl) sulfonyl) -4- (1,4-diaelan-1- silt) quinoline ί FROM) fifteen 4 * (1, 4-diazepai-1-id) -6- [(4- 'y' ieopropylphenyl) sulfonyl] quinoline hydrochloride Γη 1 ^U ABOUT

Scheme 1

Explanations for Scheme 1: ί) hydrogen gas, Ρά / С, methanol; i) sodium nitrite, sulfuric acid, various thiols (Κ'-δΗ), 3 hours; ίίί) methachloroperoxybenzoic acid (w-CPBA), dichloromethane (CH ₂ Cl ₂ ), overnight; ίν) phosphorus oxychloride (РОСЬ ₃ ), acetonitrile (СН ₃ СКГ), 80 ° С, 2 h; ν) aliphatic cyclic amines (Я ² ), 80 ° С, 0Ή ₃ 0'Ν: νί) НС1 in diethyl ether.

Methods

The proposed structures are confirmed by standard methods of spectroscopy and elemental analysis and / or high-resolution MS.

NMR spectra were obtained on Vgikeg 500 MHz or XEOI 270 MHz spectrometers at 25 ° C; chemical shifts were recorded in parts per million (δ). The MS spectra were obtained on 2690 Gerard Mos1i1s (\ Ya1sg5) with ΡΙαίΓοηη LX (M1gosh88). Flash chromatography was carried out on silica gel 60 (Megsk) or Ysygorger Yar-18 (Megsk). HPLC analysis was performed on an HP 8sps5 1100 apparatus, with a column СЯОМ-81Ь 100 ОЭ8-0 АВ (4.6x50 mm). Purification by HPLC was carried out on a preparative HPLC / MS system using a Column No. 0 of Sochi rger OE8-AO (56x20 mm), SpEop pumps. detector Ouiashakh iU-1 and Mass detector Gshshdai. H ₂ O and ΟΗ ₃ ΟΝ, both with the addition of 0.1% TFA, were used as eluents. The purity of the compounds was determined by HPLC. Elemental analysis was performed on a 81gis! Ig1 device Syepyygu OyraysheSh, Vuyuygit AB, 8yusk1yuyt. The melting points, when given, were obtained on an apparatus for determining the melting point of Visa or CaNeicatr and were not adjusted.

Intermediate 1 Synthesis of 6-aminoquinoline

A suspension of 6-nitroquinoline (8.7 g, 5 mmol) using palladium on carbon (10%) (0.1 g) in methanol (0.2 L) was hydrogenated at room temperature for 24 hours with stirring. The catalyst was removed by filtration and the solvent was evaporated, yielding a yellow solid. Crystallization from ethyl acetate afforded the pure title compound as a pale yellow solid (3.3 g, 46%). MS w / ζ 145 [M + H +]. 'H-NMR (270 MHz, CHC1 _3- δ δ ppm 3.89 (s, 2H), 6.87 (d, 1 = 2.64 Hz, 1H), 7.14 (dd, 1 = 8.97, 2.64 Hz, 1H), 7.25 (dd, 1 = 8.44, 4.22 Hz, 1H), 7.88 (dd, 1 = 7.92, 1.58 Hz, 1H ), 7.90 (d, 1 = 8.97 Hz, 1H), 8.63 (dd, 1 = 4.22, 1.58 Hz, 1H).

Intermediate 2

Synthesis of 6-phenylsulfanylquinoline

A solution of sodium nitrite (1 g, 14 mmol) in water (6 ml) is slowly added with stirring to a solution of 6-aminoquinoline (1.44 g, 10 mmol) in sulfuric acid (50%) (8 ml). During the addition, the temperature is maintained below 5 ° C. The reaction mixture was poured into a solution of potassium hydroxide (9 g, 16 mmol) and thiophenol (1 ml, 9 mmol) in water (30 ml). The reaction mixture was refluxed for 3 hours, cooled and extracted with diethyl ether. Insoluble materials are removed by filtration. During the filtering process, most of the substance is captured by the solid phase. The filtrate was evaporated and the residue was purified by column chromatography ₍₂ occupies 8, EtOAc-hexane 1: 2) to give a colorless oil (100 mg, 4% P8: low yield is due to losses during the filter

-11 008835 vania). MS t / ζ 238 [M + H +]. Ή-NMR (270 MHz, СО ₃ С1) δ ppm 7.34 (m, 4H), 7.42 (m, 2H), 7.57 (dd, 1 = 8.97, 2.11 Hz, 1H), 7.67 (d, 1 = 2.11 Hz) , 1H), 7.99 (m, 2H), 8.84 (dd, 1 = 4.22, 1.58 Hz, 1H).

Intermediate 3

Synthesis of 6-benzenesulfonylquinoline 1-oxide

A solution of m-chloroperbenzoic acid (1 g, 5.8 mmol) in DCM (10 ml) was added with stirring to a solution of 6-phenylsulfanylquinoline (0.25 g, 1 mmol) and No. 1CH 0 ₃ (0.5 g) in DCM (10 ml). The reaction mixture was stirred overnight, washed with water, a solution of No. ₁ HCO ₃ and evaporated. After trituration of the residue in diethyl ether, the pure title product is obtained as a pale yellow solid (0.14 g, 30%). MS t / ζ 287 [M + H +].

Intermediate 4

Synthesis of 6-benzenesulfonyl-4-chloroquinoline

A solution of 6-benzenesulfonylquinoline 1-oxide (135 mg, 0.47 mmol) in POC1 ₃ (4 ml) is heated to 90 ° C and maintained at this temperature for 2 hours, after which the solution is poured into ice, ammonium hydroxide is added and extracted DXM. The organic phase is dried (No. 8O |). volatile solvents were evaporated and the residue was purified by column chromatography (§ίθ ₂ , ethyl acetate: petroleum ether, 1: 1) to give the product as a white solid (39 mg, 27%). MS t / ζ 305 [M + H +].

Example 1. Synthesis of 6-benzenesulfonyl-4-piperazin-1-ylquinoline hydrochloride

A solution of 6-benzenesulfonyl-4-chloroquinoline (35 mg, 0.11 mmol) and piperazine (0.5 g, 2.5 mmol) in acetonitrile (2 ml) was heated at 80 ° C. overnight. The mixture was extracted with toluene and water. The organic phase is purified by silica gel chromatography, eluting with CHC1 ₃ , saturated ΝΗ ₃ (gas.). The purified product is dissolved in ethyl acetate and HC1 (gas.) In diethyl ether is added. The resulting oily residue was dissolved in methanol and ethyl acetate and evaporated to give a white solid (24 mg, 77%). MS w / ζ 354 [M + H +]. Ή-NMR (270 MHz, CH ₃ OH-O ₄ ) δ ppm 3.52 (m, 4H), 4.13 (m, 4H), 7.36 (d, 1 = 7.18 Hz, 1H), 7.57 (m, 3H), 8.01 (m, 1 = 12.25, 8.54 Hz, 3H), 8.28 (d, 1 = 8.9 Hz, 1H), 8.63 (d, 1 = 6.68 Hz,

2a n = o 2b, n = 1

Explanations for Scheme 2: ί) ΝηίΒιιΟ. Ρά (ΡΡ1ι ₃ ) ₄ , n-ViOH, diamines containing protective BOC groups; i) tert-butylpiperazine-1-carboxylate or tert-butyl-1,4-diazepan-1-carboxylate, triethylamine or K ₂ CO ₂ , DMSO, thiols; ίν) TFA, Н ₂ О ₂ , ΝηΟΗ: ίν) НС1.

Method A. Obtaining thiol derivatives of tert-Butyl-4- (6-bromoquinolin-4-yl) -1,4-diazepan-1-carboxylate (0.5 g, 1.23 mmol) is mixed with thiol (1 equiv.), ΝηΟίΒιι (2 equiv.), Ρά (ΡΡ1ι ₃ ) ₄ (0.05 equiv.) And n-ViOH (5 ml) in a reaction vessel. Ν ₂ (gas.) Is passed through the mixture for 30 minutes. The reaction mixture is heated to 120 ° C and maintained at this temperature overnight. The precipitate was filtered and the reaction mixture was concentrated in vacuo. The residue was dissolved in EuAc and washed with H ₂ O, dried (Mg§ ₄ ) and evaporated. Purification by flash chromatography using a mixture of DCM: MeOH 98: 2 as eluent gives the title product, which is used in the next step without further purification.

Method B. Oxidation of thiol derivatives to sulfone derivatives

Suitable thiophenol derivatives are dissolved in TFA (5 ml) and stirred for 15 minutes at room temperature. H ₂ O ₂ (2 ml) was added and the reaction mixture was stirred overnight. The reaction mixture was evaporated and the residue was partitioned between diethyl ether and water. The layers were separated, the aqueous layer was extracted with diethyl ether and made basic by the addition of 1M ΝηΟΗ. Extraction of DCM, drying of Mg§ ₄ and evaporation afforded the products in the form of free bases, which were dissolved in MeOH, an excess of HCl / ether (2M) was added and the solvent was evaporated. The residues were purified by preparative HPLC / MS (X1egg MS C18 column, 5 μm, elution with a gradient of 10-40% MeCl-water with 0.1% HO Ac, for 10 min). Pure fractions are combined and lyophilized. The residues were dissolved in MeOH and treated with excess HCl / ether (2M). After evaporation of the solvent, solids are obtained, which are triturated in diethyl ether to give the desired products as HCl salts.

Intermediate 5. tert-Butyl-4- (6-bromoquinolin-4-yl) piperazine-1-carboxylate

6-Bromo-4-chloroquinoline (5.0 g, 20.6 mmol), tert-butyl-1-piperazine (4.1 g, 22 mmol), triethylamine (3 ml, 22 mmol) and DMSO (20 ml) mix and incubate in an oil bath at 100 ° C overnight.

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The reaction mixture was cooled, diluted with diethyl ether, washed with water (5x), dried (MD80 ₄ ) and evaporated. The residue was filtered through a short silica gel column (elution with a gradient of 2.5-5% MeOH in CH ₂ Cl ₂ ) and evaporated to give 8.02 g of product (97%) as a brown liquid. HPLC 98%, Jt = 3.01 (System A1, 10-97% MECA for 3 min). Ή-NMR (400 MHz, SES1 ₃ ) δ ppm 1.52 (s, 9H), 3.12-3.17 (m, 4H), 3.69-3.75 (m, 4H), 6.86 (d, 1 = 5.0 Hz, 1H) 7.72 (dd, 1 = 9.0, 2.26 Hz, 1H), 7.92 (d, 1 = 8.8 Hz, 1H), 8.14 (d, 1 = 2.3 Hz, 1H), 8.73 (d, 1 = 5.0 Hz, 1H). MS (Ε8Ι +) for С ₁₈ Н ₂₂ ВгЫ ₃ 0 ₂ t / ζ 392.2 (М + Н ⁺ ).

Example 2. Hydrochloride 6 - [(2-fluorophenyl) sulfonyl] -4-piperazin-1-ylquinoline

The total amount of suitable thiophenol is 2.25 mmol, the reaction is carried out for 8 hours. The oxidation step is carried out for 24 hours at room temperature. Purification by silica gel column chromatography (10-20% MeOH in DCM) affords the free amine, which is further purified by preparative HPLC. 15 mg (4%) of the product are obtained in the form of a yellow solid. HPLC 95%, I _t = 2.33 (System A1, 10-97% MECA for 3 min). Ή-NMR (400 MHz, DMSO-b ₆ ) δ ppm 3.30-3.42 (m, 4H), 3.51-3.62 (m, 4H), 7.28 (d, 1 = 5.27 Hz, 1H), 7.42 (dd, 1 = 10.29, 8.78 Hz, 1H), 7.52 (t, 1 = 7.28 Hz, 1H), 7.77-7.84 (m, 1H), 8.04-8.21 (m , 3H), 8.62 (s, 1H), 8.87 (d, 1 = 5.27 Hz, 1H), 9.82 (br s, 2H). MS (Ε8Ι +) for C1 ₉ H ₁₈ EU ₃ 0 ₂ 8 t / ζ 372.0 (M + H ⁺ ). HRMS for C1 ₉ H ₁₈ EU ₃ 0 ₂ 8: calculated: 371.1104; Found: 371.1102.

Example 3. 6- (1-Naphthylsulfonyl) -4-piperazin-1-ylquinoline hydrochloride

The total amount of suitable thiophenol is 2.25 mmol, the reaction is carried out for 8 hours. The oxidation step is carried out for 24 hours at room temperature. Purification by silica gel column chromatography (10-20% MeOH in DCM) affords the free amine, which is converted to the HCl salt. 14 mg (4%) of the product are obtained in the form of a gray solid. HPLC 95%, I _t = 2.54 (System A1, 10-97% MECA for 3 min). Ή-NMR (400 MHz, DMSO-b ₆ ) δ ppm 3.33 (s, 4H), 4.06 (s, 4H), 7.38 (d, 1 = 6.78 Hz, 1H), 7.65 (d, 1 = 7.53 Hz, 1H), 7.69-7.75 (m, 1H), 7.82 (t, 1 = 7.78 Hz, 1H), 8.12 (d, 1 = 8.03 Hz, 1H), 8.21-8 30 (m, 2H), 8.38 (d, 1 = 8.03 Hz, 1H), 8.56 (t, 1 = 8.53 Hz, 2H), 8.74-8.79 (m, 2H), 10.05 (s, 2H). MS (Ε8Ι +) for С ₂₃ Н ₂₁ Н ₃ 0 ₂ 8 t / ζ 404.4 (М + Н ⁺ ) MSR for С ₂₃ Н ₂₁ Н ₃ 0 ₂ 8: calculated: 403.1354; Found: 403.1365.

Example 4. Hydrochloride 6 - [(3,4-dichlorophenyl) sulfonyl] -4-piperazin-1-ylquinoline

The total amount of suitable thiophenol is 2.25 mmol, the reaction is carried out for 8 hours. The oxidation step is carried out for 24 hours at room temperature. Purification by silica gel column chromatography (10-20% MeOH in DCM) affords the free amine, which is converted to the HCl salt. 15 mg (3%) of the product are obtained in the form of a yellow solid. Ή-NMR (400 MHz, DMSO-b ₆ ) δ ppm 3.35-3.41 (m, 4H), 4.06-4.15 (m, 4H), 7.40 (d, 1 = 6.78 Hz, 1H), 7.93 (d, 1 = 8.53 Hz, 1H), 8.04 (dd, 1 = 8.53, 2.01 Hz, 1H), 8.27 (d, 1 = 9.03 Hz, 1H), 8.32 (d, 1 = 2.01 Hz, 1H), 8.36-8.42 (m, 1H), 8.73 (d, 1 = 1.51 Hz, 1H), 8.82 (d, 1 = 6.53 Hz, 1H), 9.86 (s, 2H). MS (Ε8Ι +) for С ₁₉ Н ₁₇ С1 ₂ Н ₃ 0 ₂ 8 t / ζ 422.2 (М + Н ⁺ ). HRMS for С1 ₉ Н ₁₇ С1 ₂ Н ₃ 0 ₂ 8: calculated: 421.0419; Found: 421.0422. HPLC 95%, I _t = 2.69 (System A1, 10-97% MECA for 3 min).

Example 5. Hydrochloride 6 - [(3,5-dimethylphenyl) sulfonyl] -4-piperazin-1-ylquinoline

The oxidation step is carried out for 2 hours at room temperature. Purification by silica gel column chromatography with 10-20% MeOH in DCM affords the free amine, which is converted to the HCl salt to give a gray solid. Obtain 0.007 g (2%) of the product as a yellow solid. HPLC 90% R _T = 2.57 (System A1, Mesa 10-97% for 3 min). MS (Ε8Ι +) for С ₂ 1Н ₂₃ ЕЫ ₃ 0 ₂ 8 t / ζ 382.2. HRMS for C ₂ 1H ₂₃ YO ₃ 0 ₂ 8: calculated: 381.1511; Found: 381.1521.

Example 6. Hydrochloride 6 - [(2-chloro-6-methylphenyl) sulfonyl] -4-piperazin-1-ylquinoline

The total amount of suitable thiophenol is 2.25 mmol, the reaction is carried out for 8 hours. An additional amount of H ₂ 0 ₂ (1 ml) is added and the reaction mixture is stirred at 50 ° C for an additional 48 hours. Purification by silica gel column chromatography (10- 20% MeOH in DCM) yields a free amine, which is converted to the HCl salt. Obtain 33 mg (7.5%) of product as a white solid. Ή-NMR (400 MHz, DMSO-b ₆ ) δ ppm 2.13 (s, 3H), 2.98 (s, 4H), 3.72 (s, 4H), 7.06 (d, 1 = 6.78 Hz, 1H), 7.14 (dd, 1 = 11.54, 8.03 Hz, 2H), 7.23 (t, 1 = 7.78 Hz, 1H), 7.89 (d, 1 = 8.78 Hz, 1H), 7.94-8 00 (m, 1H), 8.24 (s, 1H), 8.45 (d, 1 = 6.78 Hz, 1H), 9.68 (s, 2H). MS (Ε8Ι +) for С ₂₀ Н ₂₀ С1Ы ₃ 0 ₂ 8 t / ζ 402.2 (М + Н ⁺ ). HRMS for С ₂₀ Н ₂₀ СЫЫ ₃ 0 ₂ 8: calculated: 401.965; Found: 401.967. HPLC 95%, I _t = 2.55 (A1 system, 10-97% MECA for 3 min).

Example 7. Hydrochloride 6 - [(4-chlorophenyl) sulfonyl] -4-piperazin-1-ylquinoline

The total amount of suitable thiophenol is 2.25 mmol, the reaction is carried out for 8 hours. The oxidation step is carried out for 24 hours at room temperature. Purification by silica gel column chromatography (10-20% MeOH in DCM) affords the free amine, which is converted to the HCl salt. Obtain 14 mg (3%) of the product as a yellow solid. HPLC 95%, I _t = 2.66 (A1 system, 10-97% MECA for 3 min). MS (Ε8Ι +) for С _{! 9} Н ₁₈ СЫЫ ₃ 0 ₂ 8 t / ζ 388.2 (M + H ⁺ ). HRMS for С _{! 9} Н ₁₈ СЫЫ ₃ 0 ₂ 8: calculated: 387.0808; Found: 387.0821.

Example 8. Hydrochloride 6 - [(2-methyl-4-tert-butylphenyl) sulfonyl] -4-piperazin-1-ylquinoline

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The oxidation step is carried out for 2 hours at room temperature. Purification by silica gel column chromatography (10-20% MeOH in DCM) affords the free amine, which is converted to the HCl salt to give a gray solid. 17 mg (4%) of product are obtained. HPLC 95%, K. _t = 2.81 (A1 system, 10-97% MECA for 3 min). MS (Ε8Ι +) for C ₂₄ H ₂₉ N ₃ 0 ₂ 8 t / ζ 424.2 (M + H ⁺ ). HRMS for C ₂₄ H ₂₉ N ₃ 0 ₂ 8: Calculated: 423.1980; Found: 423.1969.

Example 9. Hydrochloride 6 - [(3,4-dimethylphenyl) sulfonyl] -4-piperazin-1-ylquinoline

The oxidation step is carried out for 2 hours at room temperature. Purification by silica gel column chromatography (10-20% MeOH in DCM) affords the free amine, which is converted to the HCl salt. Obtain 33 mg (8%) of the product as a yellow solid. Ή NMR (400 MHz, DMSO-b ₆ ) δ ppm 2.27 (d, 1 = 6.27 Hz, 6H), 3.34 (s, 4H), 4.12 (s, 4H), 7.39 (dd, 1 = 7.40, 2.13 Hz , 2H), 7.75 (d, 1 = 7.78 Hz, 1H), 7.81 (s, 1H), 8.32 (s, 2H), 8.61 (s, 1H), 8.78 (d, 1 = 6.78 Hz, 1H), 10.18 (s, 2H). MS (Ε8Ι +) for С ₂ 1Н ₂₃ Н ₃ 0 ₂ 8 t / ζ 382.2 (М + Н ⁺ ). HRMS for С ₂ 1Н ₂₃ Н ₃ 0 ₂ 8: calculated: 381.1511; Found: 381.1519. HPLC 95%, B = 2.54 _m (A1 system Mesa 10-97% for 3 min).

Example 10. Hydrochloride 6 - [(2,3-dichlorophenyl) sulfonyl] -4-piperazin-1-ylquinoline

The total amount of suitable thiophenol is 2.25 mmol, the reaction is carried out for 8 hours. The oxidation step is carried out for 24 hours at room temperature. Purification by silica gel column chromatography (10-20% MeOH in DCM) affords the free amine, which is converted to the HCl salt. 15 mg (3%) of the product are obtained in the form of a yellow solid. ¹ H-NMR (400 MHz, DMSO-b6) δ ppm 3.36 (m, 4H), 4.10 (m, 4H), 7.42 (d, 1 = 6.78 Hz, 1H), 7.75 (t, 1 = 8.03 Hz, 1H), 8.07 (d, 1 = 8.03 Hz, 1H), 8.24 (d, 1 = 9.04 Hz, 1H), 8.33 (dd, 1 = 13.93, 8.41 Hz, 2H ), 8.70 (s, 1H), 8.82 (d, 1 = 6.78 Hz, 1H), 10.00 (s, 2H). MS (Ε8Ι +) for С19Н17С12Ы3028 t / ζ 422.2 (M + H ⁺ ). HRMS for С19Н ₁₇ С1 ₂ Н ₃ 0 ₂ 8: calculated: 421.0419; Found: 421.0408. HPLC 95%, K. _t = 2.50 (A1 system, 10-97% MECA for 3 min).

Example 11. Hydrochloride 6 - [(4-tert-butylphenyl) sulfonyl] -4-piperazin-1-ylquinoline tert-Butyl-4- {6 - [(4-tert-butylphenyl) thio] quinolin-4-yl} piperazine -1-carboxylate (0.60 g, 1.3 mmol) was dissolved in TFA (12 ml) and stirred for 30 minutes, then H ₂ 0 ₂ (0.65 ml,

6.3 mmol). The mixture was stirred for 2 hours, then water (5 ml) was added. The mixture was evaporated, the residue was taken up in water and washed with diethyl ether (2x). The pH of the aqueous phase was adjusted to 10 by adding 1N Na0H, the mixture was extracted with CH ₂ Cl ₂ (2x), dried (MD80 ₄ ) and evaporated. The residue was diluted with CH2C12, 1.3 ml of 2H HCl in diethyl ether was added with vigorous stirring, the mixture was evaporated again, the residue was washed with diethyl ether (2x) and dried. 0.40 g (69%) of the product is obtained in the form of a gray solid. HPLC 95%, K. _t = 2.77 (A1 system, 10-97% MECA for 3 min). ¹ NNMR (400 MHz, DMSO-b ₆ ) δ ppm 1.23 (s, 9H), 3.38 (s, 4H), 4.08 (s, 4H), 7.39 (d, 1 = 7.03 Hz, 1H), 7.65 (d, 1 = 8.53 Hz, 2H), 7.96 (d, 1 = 8.53 Hz, 2H), 8.25 (d, 1 = 8.78 Hz, 1H), 8.30-8.36 (m , 1H), 8.66 (d, 1 = 1.76 Hz, 1H), 8.81 (d, 1 = 7.03 Hz, 1H), 9.85 (br s, 2H). MS (Ε8Ι +) for C ₂₃ H ₂₇ N ₃ 0 ₂ 8 t / ζ 410.4 (M + H ⁺ ).

Example 12. 6 - [(4-Isopropylphenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride

4-Isopropylthiophenol (0.152 g, 1.0 mmol) is added dropwise to a suspension of tert-butyl 4- (6 bromoquinolin-4-yl) piperazine-1-carboxylate (0.2 g, 0.51 mmol), Na-tert -butoxide (0.192 g, 2.0 mmol) and Pb [P (Pb) ₃ ] ₄ (0.030 g, 0.025 mmol) in ethanol (3 ml) at 90 ° C and the mixture is stirred for 18 hours. The mixture is diluted with THF, filtered through a layer of silicon dioxide and evaporated. The crude product was dissolved in TFA (5 ml) and stirred for 15 minutes, after which 30% H202 (1 ml) was added. The mixture was stirred for 2 hours and evaporated.

The residue was dissolved in water and washed with CH ₂ Cl ₂ (2x), then 2N Na0H was added until pH = 10, the mixture was extracted with CH ₂ Cl ₂ (3x), dried (MD80 ₄ ) and evaporated. The crude product was purified by preparative HPLC (5-95 water / acetonitrile), collecting t / ζ 395.2. After evaporation, the free amine is dissolved in CH2C12, an excess of HC1 in diethyl ether is added and the mixture is evaporated again. 0.015 g (7%) of product is obtained. Ή-NMR (400 MHz, DMSO-be) δ ppm 1.17 (d, 1 = 7.03 Hz, 6H), 2.90-3.02 (m, 1H), 3.343.42 (m, 4H), 4.03-4.12 (m, 4H) , 7.39 (d, 1 = 6.78 Hz, 1H), 7.51 (d, 1 = 8.28 Hz, 2H), 7.96 (d, 1 = 8.53 Hz, 2H), 8 26 (d, 1 = 9.03 Hz, 1H), 8.29-8.36 (m, 1H), 8.66 (s, 1H), 8.80 (d, 1 = 6.78 Hz, 1H), 9.85-9.97 (m, 2H). HPLC 95%, K. _t = 2.65 (A1 system, 10-97% MECA for 3 min).

Example 13. 4-piperazin-1-yl-6 - [[4- (trifluoromethyl) phenyl] sulfonyl} quinoline hydrochloride

4-Trifluoromethylthiophenol (0.178 g, 1.0 mmol) is added dropwise to a suspension of tert-butyl 4- (6 bromoquinolin-4-yl) piperazine-1-carboxylate (0.2 g, 0.51 mmol), tert-butoxide sodium (0.192 g, 2.0 mmol) and Pb [P (PY) ₃ ] ₄ (0.030 g, 0.025 mmol) in ethanol (3 ml) at 90 ° C and the resulting mixture was stirred for 18 hours. The mixture was diluted with THF, filtered through a loose pad of silica and evaporated. The crude product was dissolved in TFA (5 ml) and stirred for 15 minutes, after which 30% H202 (1 ml) was added. The mixture was stirred for 2 hours and evaporated. The residue was dissolved in water, washed with CH ₂ Cl ₂ (2x), 2N Na0H was added until pH = 10, after which the mixture was extracted with CH ₂ Cl ₂ (3x), dried (MD80 ₄ ) and evaporated. The crude product was purified by preparative HPLC (5-95 water / acetonitrile), collecting t / ζ 421.1. The mixture was evaporated, the free amine was dissolved in CH ₂ Cl ₂ , excess HC1 was added in diethyl ether and the mixture was evaporated again. Obtain 0.024 g (10%) of the product as a yellow oil. Ή-NMR (400 MHz, DMSO-b ₆ ) δ ppm 3.33-3.40 (m, 4H), 4.13-4.21 (m, 4H), 7.42 (d,

- 14 008835

1 = 7.03 Hz, ΙΗ), 8.02 (d, 1 = 8.53 Hz, 2H), 8.25-8.35 (m, ZN), 8.37-8.53 (m, 1H ), 8.76 (d, 1 = 1.76 Hz, 1H), 8.80 (d, 1 = 7.03 Hz, 1H), 9.95-10.05 (m, 2H). HPLC 95%, _W = 2.66 (system A1, Mesa 10-97% for 3 min).

Intermediate 6. tert-Butyl-4- (6-bromoquinolin-4-yl) -1,4-diazepan-1-carboxylate

6-Bromo-4-chloroquinoline (3.5 g, 14.5 mmol) is reacted with tert-butyl-1,4-diazepane-1 carboxylate (3.7 g, 18.8 mmol) and K ₂ CO ₃ (4 g, 29 mmol) in DMSO at 100 ° C. overnight. The mixture was cooled, poured into water and extracted with DCM. The organic layer was washed with water, dried (MgSO ₄ ) and evaporated. The residue was purified by flash chromatography (elution with a gradient: E1OAc: hexane 1: 1 to 2: 1) to obtain 2.1 g of the product (36%) as a yellow oil. 'H-NMR (400 MHz, COC1 ₃ ) δ ppm 1.47 (d, 1 = 5.5 Hz, 9H), 2.08-2.16 (m, 2H), 3.35-3.44 (m, 4H), 3.60-3.73 ( m, 4H), 6.87 (d, 1 = 5.5 Hz, 1H), 7.69 (dd, 1 = 9.0, 2.0 Hz, 1H), 7.88 (d, 1 = 8 5 Hz, 1H), 8.16 (s, 1H), 8.65 (d, 1 = 5.0 Hz, 1H). MS (Ε8Ι +) for Οι ₉ Η ₂₄ ΒγΝ ₃ 0 ₂ w / ζ 406.4 (M + H) ⁺ . HRMS (ΕΙ) calculated for Οι ₉ Η ₂₄ ΒγΝ ₃ : 405.1052, found 405.1045.

Intermediate 7. tert-Butyl-4 {3 - [(4-tert-butylphenyl) thio] quinolin-5-yl} -1,4-diazepan1-carboxylate (General Method A)

The compound is prepared from tert-butyl- (6-bromoquinolin-4-yl) -1,4-diazepan-1-carboxylate (0.5 g, 1.23 mmol) and p-tert-butylbenzenethiol (0.2 g, 1 23 mmol). 0.27 g (44%) of the title compound is obtained. HPLC 89%, R _t: 3.76 min (5-99% Meslin containing 0.1% TFA over 3 min).

Intermediate 8. tert-Butyl-4- {3 - [(4-isopropylphenyl) thio] quinolin-5-yl} -1,4-diazepan1-carboxylate (General Method A)

The compound is prepared from tert-butyl-4- (6-bromoquinolin-4-yl) -1,4-diazepan-1-carboxylate (0.5 g, 1.23 mmol) and 4-isopropylbenzenethiol (0.19 g, 1 23 mmol). 0.27 g (46%) of the title compound is obtained, which is used in the next step without further purification. HPLC 89%, R _t: 3.67 min. (5-99% ΜεΟΝ containing 0.1% TFA for 3 minutes); MS (Ε8Ι +) for €. ' _2Χ Η ₃₃ Ν ₃ Ο ₂ 8 w / ζ 478.2 (M + H) ⁺ .

Example 14. Hydrochloride 6 - [(4-tert-Butylphenyl) sulfonyl] -4- (1,4-diazepan-1-yl) quinoline (General Method B)

The compound is synthesized from tert-butyl-4 {3 - [(4-tert-butylphenyl) thio] quinolin-5-yl} -1,4-diazepan1-carboxylate (0.27 g, 0.55 mmol). 20 mg (8%) of the title compound are obtained. ¹ H-NMR (270 MHz, DMSO-bb) δ ppm 1.25 (s, 9H), 2.31 (broad s, 2H), 3.25 (broad s, 2H), 3.49 (broad s, 2H), 4.11 broad s, 2H ), 4.26 (br s, 2H), 7.16 (d, 1 = 7.1 Hz, 1H), 7.65 (d, 1 = 8.2 Hz, 2H), 7.94 (d , 1 = 8.2 Hz, 2H), 8.19 (d, 1 = 8.7 Hz, 1H), 8.26 (d, 1 = 8.7 1H), 8.62 (d, 1 = 6 , 3 Hz, 1H), 8.75 (s, 1H), 9.65 (br s, 2H). MS (Ε8Ι +) for 024Η29Ν3028 t / ζ 424.2 (M + H) ⁺ . HPLC 93%, W: 2.79 min. (5-99% MCH for 3 minutes).

Example 15. 4- (1,4-Diazepan-1-yl) -6 - [(4-isopropylphenyl) sulfonyl] quinoline hydrochloride (General Method B)

The compound is prepared from tert-butyl-4 {3 - [(4-isopropylphenyl) thio] quinolin-5-yl} -1,4-diazepan-1 carboxylate (0.27 g, 0.57 mmol). 15 mg (6%) of the title compound are obtained; 'H-NMR (270 MHz, DMSO-bb) δ ppm 1.16 (d, 1 = 6.9 Hz, 6H), 2.31 (br s, 2H), 2.96 (m, 1H), 3.25 (br s, 2H), 3.49 (broad s, 2H), 4.11 (broad s, 2H), 4.26 (broad s, 2H), 7.16 (d, 1 = 6.9 Hz, 1H), 7.51 ( d, 1 = 8.2 Hz, 2H), 7.94 (d, 1 = 8.2 Hz, 2H), 8.18 (d, 1 = 8.7 Hz, 1H), 8.30 (d, 1 = 8.4Hz, 1H), 8.62 (d, 1 = 6.1 Hz, 1H), 8.75 (s, 1H), 9.62 (br s, 2H). MS (Ε8Ι +) for €. ' ₂₃ Η ₂ -Ν ₃ Ο ₂ 8 w / ζ 410.4 (M + H) ⁺ . HPLC 93%, _W: 2.70 min. (5-99% MCH for 3 minutes).

table 2

Example to' to ¹ sixteen 7- (2-Chloro-6-methylbeneolsulfonyl) -1-piperaein-1 or isoquinoline hydrochloride 'F f 17 7- (2-Tert-butylbenzenesulfonyl) -1-piperazin-1 or isoquinoline hydrochloride 0

-15 008835

eighteen 7- (3,4-Dichlorobenzenesulfonyl) -1-piperazine-1 or isoquinoline hydrochloride 0 nineteen 7- (3,4dimethylbenzenesulfonyl) -1-piperazine-1 or isoquinoline hydrochloride & 0 twenty Hydrochloride 7- (2,5- dimethylbenzenesulfonyl) -1-piperazin-1- iloquinoline V 0 21 7- (p-chlorobenzenesulfonyl) -1 piperazin-1-yl-isoquinoline hydrochloride nine 0 22 7-benzenesulfonyl-1- hydrochloride [1,4] diazepan-1-yl-isoquinoline nine 0 23 7- (4-Tert-butylbenzenesulfonyl) -1- [1,4] diazepan-1 or isoquinoline hydrochloride $ 0 24 7- (2-Chloro-6-methylbenzenesulfonyl) -1- [1,4] diazepan-1 or isoquinoline hydrochloride 0 25 7- (3,5dimethylbenzenesulfonyl) -1- [1,4] diaeepan1-yl-isoquinoline hydrochloride V about and—. 26 Hydrochloride 7- (3,4- dichlorobenzenesulfonyl) -1- [1,4] diazepan-1 or eioquinoline 0 27 7- (4-Chlorobenzenesulfonyl) -1- hydrochloride [1,4] diazepan-1-yl-isoquinoline 0 28 Hydrochloride 7- (3,4- dimethylbenzenesulfonyl) -1- [1,4] diazepan- 1-isoquinoline & about 29th 7- (2-Tert-butylbenzenesulfonyl) -1- [1,4] diazepan-1 or isoquinoline hydrochloride 99 0 thirty 7-Beneolsulfonyl-1- hydrochloride piperazinyl isoquinoline nine 0

Hydrochloride 7- (4-tert-

but thi lbe and zo l sul f o nor l -1 pipera zinylisoquinoline

ABOUT

- 16008835

Scheme 3

Explanations

DMF, BOC diamines; ίίί) Pc1 (PP11z) ₄ : n-ViOH; ίν) TFUK, Н ₂ О ₂ ; ν) HC1 in diethyl ether.

Intermediate 9. 7-Bromo-1-Chloroisoquinoline

To phosphorus oxychloride (46.6 ml, 0.5 mol) at room temperature, 7-bromo-1-hydroxyisoquinoline (11.2 g, 0.05 mol) was added in small portions. The mixture is heated to 100 ° C and maintained at this temperature for 90 minutes with vigorous stirring. After cooling to room temperature, the mixture was carefully poured into ice / water (200 ml). The pH of the mixture was adjusted to 8 by adding dropwise an aqueous solution of ammonia, the precipitate formed was collected by filtration and washed with chilled water. The solid was dried under reduced pressure at 45 ° C for 12 hours. The product was isolated as a beige solid (13.86 g, 115%). 'H-NMR (DMSO-ss) δ 8.4 (s, 1H), 8.34-8.38 (d, 1 = 6 Hz, 1H), 8.03-8.07 (m, 2H), 7.91-7.96 (d, 1 = 6 Hz, 1H); HPLC: 96%; LCMS: 242, 244, 246.

3: ί) POC1 ₃ ; η)

K ₂ CO ₃ ,

ΝηΙ-Q & A. thiophenols,

Nucleophilic Chlorine Substitution

Intermediate 10. 4- (7-Bromisoquinolin-1-yl) piperazine-1 carboxylic acid tert-butyl ester

To a suspension of 7-bromo-1-chloroisoquinoline (3.14 g, 1.3 mmol) in DMSO (20 ml), either tert-butyl- (BOC) piperazine (7.23 g, 38.8 mmol) is added at room temperature or BOC-homopiperazine (7.77 g, 38.8 mmol) and then potassium carbonate (5.36 g, 39 mmol). The mixture was heated to 110 ° C and held at this temperature for 24 hours. After cooling, the reaction mixture was poured into ice / water (50 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic phases are washed with water (50 ml) and brine (50 ml), then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a crude product. Purification is carried out by applying the crude product to a loose layer of silica in a filter funnel and eluting with a heptane / ethyl acetate (2: 1) mixture to obtain 2.73 g (54%) of the product as a yellow oil. 'H-NMR (COC1 ₃ ) δ 8.20-8.22 (m, 1H), 8.138.18 (d, 1 = 6 Hz, 1H), 7.65-7.71 (dd, 1 = 12, 3 Hz, 1H), 7.59-7.65 (d, 1 = 12 Hz, 1H), 7.21-7.25 (m, 1H), 3.64-3.73 (m, 4H), 7.27-7.36 (m, 4H); 1.49 (s, 9H); LCMS: 392, 394, 395.

- 17008835

Intermediate 11. 4- (7-Bromisoquinolin-1-yl) - [1,4] diazepan-1 carboxylic acid tert-butyl ester

2.75 g (52%) of the product are isolated as a yellow oil. 'H-NMR (SEST,) δ 8.19-8.24 (m, 1H), 8.068.12 (d, .19 Hz, 1H), 7.54-7.68 (m, 2H), 7, 11 (m, 1H), 3.47-3.74 (m, 8H), 1.98-2.16 (m, 2H), 1.48 (s, 9H); LCMS: 406, 407, 408.

Catalytic binding of aryl to thiol using a palladium catalyst

Sodium tert-butoxide (481 mg, 5 mmol), thiol (1.5 mmol) and tetrakis-triphenylphosphine palladium (1) were added to 7-bromo-1-chloroisoquinoline (1 mmol) in butan-1-ol (20 ml) at room temperature. 60 mg, catalytic). The mixture was heated to 120 ° C and held at this temperature for 16 hours. After cooling to room temperature, the mixture was filtered through silica, eluting with THF. The solvent was removed under reduced pressure to give a crude product, which was used in the next step without further purification.

Intermediate 12. 4- [7- (2-Chloro-6-methylphenylsulfanyl) isoquinolin-1-yl] piperazine-1-carboxylic acid tert-butyl ester

A mixture of 4- (7-bromoisoquinolin-1-yl) piperazine-1-carboxylic acid tert-butyl ester (0.5 g,

1.3 mmol), 2-chloro-6-methylthiophenol (0.206 g, 1.3 mmol), ΝαϊΒιιϋ (0.44 g, 4.5 mmol), Pb (PP ₃ ) ₄ (74 mg, 0.065 mmol) in n-ViOH (10 ml) was heated to 110 ° C and maintained at this temperature for 3 hours. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase is washed with water (50 ml x 3), separated, dried (MD8O ₄ ), filtered. Volatile solvents were evaporated and the residue was purified by flash column chromatography (81O ₂ , n-heptane: ethyl acetate 8: 2) to give 530 mg of the title compound as a colorless oil (86.4% yield). 'H-NMR (COS1 ₃ ) δ 8.05 (d, 1H), 7.65 (d, 1H), 7.20-7.45 (m, 5H), 7.15 (d, 1H), 3 26-3.40 (m, 4H); 3.10-3.20 (m, 4H); 2.5 (s, 3H); 1.38 (s, 9H).

Intermediate 13: 4- [7- (2-tert-butylphenylsulfanyl) isoquinolin1-yl] piperazine-1-carboxylic acid tert-butyl ester

A mixture of 4- (7-bromoisoquinolin-1-yl) piperazine-1-carboxylic acid tert-butyl ester (0.5 g,

1.3 mmol), 2-tert-butylthiophenol (0.216 g, 1.3 mmol) and ΝαϊΒιιΟ (0.44 g, 4.5 mmol), Pb (PP ₃ ) ₄ (74 mg, 0.065 mmol) in n- ViOH (10 ml) is heated to 110 ° C and maintained at this temperature for 3 hours. The reaction mixture is filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase is washed with water (50 ml x 3), separated, dried (MD8O ₄ ), filtered. Volatile solvents were evaporated and the residue was purified by flash column chromatography (81O ₂ , n-heptane: ethyl acetate 8: 2) to give 440 mg of the title compound as a colorless oil (71% yield). 'H-NMR (COS1 ₃ ) δ 8.00-8.10 (m, 2H), 7.15-7.65 (m, 7H), 3.60-3.70 (m, 1H), 3, 30-3.45 (m, 4H), 3.05-3.20 (m, 3H), 1.55 (s, 9H), 1.50 (s, 9H).

Intermediate 14. 4- [7- (3,4-Dichlorophenylsulfanyl) isoquinolin-1yl] piperazine-1-carboxylic acid tert-butyl ester

A mixture of 4- (7-bromisoquinolin-1-yl) piperazine-1-carboxylic acid tert-butyl ester, (0.5 g,

1.3 mmol), 3,4-dichlorothiophenol (165 μl, 1.3 mmol), No. 11ViO (0.44 g, 4.5 mmol) and RB (PP ₃ ) ₄ (74 mg, 0.065 mmol) in n -Vion (10 ml) is heated to 110 ° C and maintained at this temperature for 3 hours. The reaction mixture is filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase is washed with water (50 ml x 3), separated, dried (MD8O ₄ ), filtered. Volatile solvents were evaporated and the residue was purified by flash column chromatography (81O ₂ , n-pentane: ethyl acetate 9.5: 0.5 ^ 8: 2) to give 230 mg of the title compound as a colorless oil (36% yield). ^! H-NMR (SPS1 ₃ ) δ 8.10-8.20 (m, 2H), 7.90 (br s, 1H), 7.65-7.75 (m, 2H), 7.10-7 55 (m, 3H), 3.50-3.65 (m, 4H), 3.20-3.30 (m, 4H), 1.50 (s, 9H).

Intermediate 15. 4- [7- (3,4-Dimethylphenylsulfanyl) isoquinolin1-yl] piperazine-1-carboxylic acid tert-butyl ester

A mixture of 4- (7-bromoisoquinolin-1-yl) piperazine-1-carboxylic acid tert-butyl ester (0.5 g,

1.3 mmol), 3,4-dimethylthiophenol (175 μl, 1.3 mmol), No. 11ViO (0.44 g, 4.5 mmol) and RB (PP ₃ ) ₄ (74 mg, 0.065 mmol) in n -Vion (10 ml) is heated to 110 ° C and maintained at this temperature for 3 hours. The reaction mixture is filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase is washed with water (50 ml x 3), separated, dried (MD8O ₄ ), filtered. Volatile solvents were evaporated and the residue was purified by flash column chromatography (81O ₂ , n-pentane: ethyl acetate 9.5: 0.5 ^ 8: 2) to give 260 mg of the title compound as a colorless oil (44% yield). ¹ NNMR (SPS1 ₃ ) δ 8.00-8.10 (m, 2H), 7.55-7.65 (m, 3H), 7.40-7.50 (m, 1H), 7.10- 7.30 (m, 2H), 3.30-3.40 (m, 4H), 3.10-3.20 (m, 4H), 2.30 (s, 3H), 2.25 (s, 3H), 1.50 (s, 9H).

Intermediate 16. 4- [7- (3,5-Dimethylphenylsulfanyl) isoquinolin1-yl] piperazine-1-carboxylic acid tert-butyl ester

A mixture of 4- (7-bromoisoquinolin-1-yl) piperazine-1-carboxylic acid tert-butyl ester (0.5 g,

1.3 mmol), 3,5-dimethylthiophenol (180 mg, 1.3 mmol), No. 11ViO (0.44 g, 4.5 mmol) and RB (PP ₃ ) ₄ (74 mg, 0.065 mmol) in n -Vion (10 ml) is heated to 110 ° C and maintained at this temperature for 3 hours. Reaction

- 18 008835 the new mixture is filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase is washed with water (50 ml x 3), separated, dried (MD80 ₄ ), filtered. Volatile solvents were evaporated and the residue was purified by flash column chromatography (8ίΟ _2, n-pentane: ethyl acetate 9.8: 0.2 ~ 8: 2) to give 380 mg of the title compound as a colorless oil (yield 65%). 'H-NMR (ΟΌΟ1 ₃ ) δ 8.05-8.10 (m, 1H), 7.80-7.85 (m, 1H), 7.60-7.75 (m, 1H), 7, 17-7.25 (m, 1H), 7.10 (br s, 2H), 7.00 (br s, 1H), 3.40-3.50 (m, 4H), 3.10- 3.20 (m, 4H), 2.25 (br s, 6H), 1.50 (s, 9H).

Intermediate 17. 4- [7- (p-Chlorophenylsulfanyl) isoquinolin-1yl] piperazine-1-carboxylic acid tert-butyl ester

A mixture of 4- (7-bromoisoquinolin-1-yl) piperazine-1-carboxylic acid tert-butyl ester (0.5 g,

1.3 mmol), p-chlorothiophenol (188 mg, 1.3 mmol), ΝαϊΒιιΟ (0.44 g, 4.5 mmol) and Pb (PP ₃ ) ₄ (74 mg, 0.065 mmol) in n-ViOH ( 10 ml) is heated to 110 ° C and maintained at this temperature for 3 hours. The reaction mixture is filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase is washed with water (50 ml x 3), separated, dried (MD80 ₄ ), filtered. Volatile solvents were evaporated and the residue was purified by flash column chromatography (8ίΟ _2, n-pentane: ethyl acetate 9.5: 0.5 ~ 8: 2) to give 300 mg of the title compound as a colorless oil (yield 50%). '11-51MR (СОС1 ₃ ) δ 8.05-8.15 (m, 2Н), 7.60-7.70 (m, 2Н), 7.40-7.50 (m, 2Н), 7, 15-7.30 (m, 3H), 3.45-3.55 (m, 4H), 3.10-3.15 (m, 4H), 1.50 (s, 9H).

Intermediate 18.

4- (7-Phenylsulfanylisoquinolin-1-yl) piperazine-1-carboxylic acid tert-butyl ester

LCMS: 422,423.

Intermediate 19.

4- [7- (4-tert-butylphenylsulfanyl) isoquinolin-1-yl] piperazine-1-carboxylic acid tert-butyl ester

LCMS: 478.479.

Intermediate 20.

4- (7-Phenylsulfanylisoquinolin-1-yl) - [1,4] diazepan-1-carboxylic acid tert-butyl ester MS: 368,369,370.

Intermediate 21.

4- [7- (4-tert-butylphenylsulfanyl) isoquinolin-1-yl] - [1,4] diazepan-1 carboxylic acid tert-butyl ester

MS: 424, 425, 426.

Intermediate 22.

4- [7- (2-Chloro-6-methylphenylsulfanyl) isoquinolin-1-yl] - [1,4] diazepan-1 carboxylic acid tert-butyl ester

MS: 416, 417, 418.

Intermediate 23.

4- [7- (3,4-dimethylphenylsulfanyl) isoquinolin-1-yl] - [1,4] diazepan-1 carboxylic acid tert-butyl ester

MS: 396,397,398.

Intermediate 24.

4- [7- (3,4-Dichlorophenylsulfanyl) isoquinolin-1-yl] - [1,4] diazepan-1 carboxylic acid tert-butyl ester

MS: 436,437,438.

Intermediate 25.

4- [7- (4-Chlorophenylsulfanyl) isoquinolin-1-yl] - [1,4] diazepan-1-carboxylic acid tert-butyl ester

MS: 402, 404.

Intermediate 26.

4- [7- (3,4-dimethylphenylsulfanyl) isoquinolin-1-yl] - [1,4] diazepan-1 carboxylic acid tert-butyl ester

LCMS: 464, 465, 466.

Intermediate 27.

4- [7- (2-tert-butylphenylsulfanyl) isoquinolin-1-yl] - [1,4] diazepan-1 carboxylic acid tert-butyl ester

LCMS: 492, 493, 494.

Introduction of BOC protection and oxidation of thiols to sulfonic derivatives

Each thiol (0.2-1.14 mmol) was dissolved in trifluoroacetic acid (1.5 ml) at 0 ° C and stirred for 15 minutes at this temperature. A 33% aqueous solution of hydrogen peroxide (5-100 ml) was added to the mixture. The resulting mixture was stirred at room temperature for 90 minutes and then treated with sodium hydroxide solution (1M, 25 ml). The mixture was extracted with ethyl acetate (3 x 50 ml), then the combined organic layers were washed with brine (50 ml). Organi

The 19008835 extracts were dried over anhydrous sodium sulfate and then the solvent was removed under reduced pressure. The crude product is purified by preparative LCMS. Processing the purified product with a mixture of HC1 / ether (1M, 1 ml) gives the final product as a white solid.

Example 16. 7- (2-Chloro-6-methylbenzenesulfonyl) -1-piperazin-1-yl-isoquinoline hydrochloride

A mixture of 4- [7- (2-chloro-6-methylphenylsulfanyl) isoquinolin-1-yl] piperazine-1-carboxylic acid tert-butyl ester (160 mg, 0.340 mmol), H ₂ O ₂ (30% in water, 200 μl) and trifluoroacetic acid (2 ml) are heated to 50 ° C and maintained at this temperature for 2 hours. An aqueous NaOH solution (1N) (pH = 14) is added, ethyl acetate and the organic phase are separated, dried (MD8O ₄ ), filtered. The filtrate was concentrated and the residue was purified by flash column chromatography (81O ₂ , dichloromethane: methanol 8: 2) to obtain 77 mg of the product in the form of a free base (yield 56%). The free base is converted to hydrochloride by treatment with HCl in diethyl ether. ¹ H-NMR (CH ₃ OH-b ₄ ) δ 8.88 (br s, 1H), 8.05-8.20 (m, 3H), 7.65 (d, 1H), 7.35- 7.55 (m, 3H), 3.85-3.95 (m, 4H), 3.00-3.15 (m, 4H), 2.95 (s, 3H).

Example 17. 7- (2-tert-Butylbenzenesulfonyl) -1-piperazin-1-yl-isoquinoline hydrochloride

A mixture of 4- [7- (2-tert-butylphenylsulfanyl) isoquinolin-1-yl] piperazine-1-carboxylic acid tert-butyl ester (273 mg, 0.571 mmol), H ₂ O ₂ (30% in water, 1 ml) and trifluoroacetic acids (3 ml) are heated to 50 ° C and maintained at this temperature for 2 hours. The reaction mixture is maintained overnight at 35 ° C. An aqueous solution of NaOH (1N) (pH = 14) was added, ethyl acetate and the organic phase were separated, dried (MD8O ₄ ), filtered. The filtrate was concentrated and the residue was purified by flash column chromatography (81O ₂ , dichloromethane: methanol 8: 2) to give 50 mg of the title compound as a free base (yield 56%). The free base is converted to hydrochloride by treatment with HCl in diethyl ether. Ή-NMR (CH ₃ OH-b ₄ ) δ 8.55 (d, 1H), 8.25 (d, 1H), 7.95-8.10 (m, 3H), 7.55 (d, 1H) ), 7.55-7.65 (m, 2H), 7.4 (d, 1H), 3.60-3.75 (m, 4H), 3.40-3.50 (m, 4H), 1.55 (s, 9H).

Example 18. 7- (3,4-Dichlorobenzenesulfonyl) -1-piperazin-1-yl-isoquinoline hydrochloride

A mixture of 4- [7- (3,4-dichlorophenylsulfanyl) isoquinolin-1-yl] piperazine-1-carboxylic acid tert-butyl ester (230 mg, 0.47 mmol), Н ₂ О ₂ (30% in water, 0.5 ml) and trifluoroacetic acid (1.5 ml) are heated to 50 ° C and maintained at this temperature for 2 hours. The reaction mixture is maintained overnight at 35 ° C. An aqueous solution of NaOH (1N) (pH = 14) was added, ethyl acetate and the organic phase were separated, dried (MD8O ₄ ), filtered. The filtrate was concentrated and the residue was purified by flash column chromatography (81O ₂ , dichloromethane: methanol 9: 1). The free base is converted to the hydrochloride by treatment with HCl in diethyl ether to give 45 mg of the title compound. ¹ H-NMR (CH ₃ OH-b ₄ ) δ 8.75-8.85 (m, 1H), 8.10-8.30 (m, 4H), 7.90-8.00 (m, 1H ), 7.75-7.85 (m, 1H), 7.50-7.60 (m, 1H), 3.85-3.90 (m, 4H), 3.50-3.70 (m , 4H).

Example 19. 7- (3,4-Dimethylbenzenesulfonyl) -1-piperazin-1-yl-isoquinoline hydrochloride

A mixture of 4- [7- (3,4-dimethylphenylsulfanyl) isoquinolin-1-yl] piperazine-1-carboxylic acid tert-butyl ester (260 mg, 0.58 mmol), Н ₂ О ₂ (30% in water, 0.5 ml) and trifluoroacetic acid (1.5 ml) are heated to 50 ° C and maintained at this temperature for 2 hours. The reaction mixture is maintained overnight at 35 ° C. An aqueous solution of NaOH (1N) (pH = 14) was added, ethyl acetate and the organic phase were separated, dried (MD8O ₄ ), filtered. The filtrate was concentrated and the residue was purified by flash column chromatography (81O ₂ , dichloromethane: methanol 9: 1). The free base is converted to the hydrochloride by treating HCl in diethyl ether to give 20 mg of the title compound. ¹ H-NMR (CH ₃ OH-b ₄ ) δ 8.75-8.80 (m, 1H), 8.10-8.25 (m, 3H), 7.70-7.85 (m, 2H ), 7.60-7.70 (m, 1H), 7.35-7.40 (m, 1H), 3.90-4.00 (m, 4H), 3.55-3.65 (m 4H); 2.35 (br s, 6H).

Example 20. 7- (2,5-Dimethylbenzenesulfonyl) -1-piperazin-1-yl-isoquinoline hydrochloride

A mixture of 4- [7- (2,5-dimethylphenylsulfanyl) isoquinolin-1-yl] piperazine-1 carboxylic acid tert-butyl ester (380 mg, 0.846 mmol), H2O2 (30% in water, 0.5 ml) and trifluoroacetic acid (3 ml) was heated to 50 ° C and maintained at this temperature for 2 hours. The reaction mixture was kept overnight at 35 ° C. An aqueous solution of NaOH (1N) (pH = 14) was added, ethyl acetate, the organic phase was separated, dried (MDO ₄ ), filtered. The filtrate was concentrated and the residue was purified by flash column chromatography (81O ₂ , dichloromethane: methanol 9, 8: 0.2 ^ 9.5: 0.5). The free base is converted to the hydrochloride by treating HCl in diethyl ether to give 120 mg of the title compound. Я-NMR (CH ₃ OH-b ₄ ) δ 8.75-8.80 (m, 1H), 8.25-8.30 (m, 1H), 8.05-8.20 (m, 2H) 7.60-7.70 (m, 3H), 7.3007.35 (m, 1H), 4.00-4.10 (m, 4H), 3.60-3.70 (m, 4H), 2 30-1.35 (br s, 6H).

Example 21. 7- (p-Chlorobenzenesulfonyl) -1-piperazin-1-yl-isoquinoline hydrochloride

A mixture of 4- [7- (p-chlorophenylsulfanyl) isoquinolin-1-yl] piperazine-1-carboxylic acid tert-butyl ester (297 mg, 0.65 mmol), H ₂ O ₂ (30% in water, 0.5 ml) , trifluoroacetic acid (3 ml) is heated to 50 ° C and maintained at this temperature for 2 hours. The reaction mixture is maintained overnight at 35 ° C. An aqueous solution of NaOH (1N) (pH = 14) was added, ethyl acetate, the organic phase was separated, dried (MDO ₄ ), filtered. The filtrate was concentrated and the residue was purified by flash column chromatography (81O ₂ , dichloromethane: methanol 9.5: 0.5 ^ 9.0: 1.0). The free base was converted to hydrochloride by treatment with HCl in diethyl ether to give 70 mg of the title compound .

- 20 008835 'H-NMR (CH ₃ OH-b ₄ ) δ 8.75-8.85 (m, 2H), 8.10-8.25 (m, 3H), 8.00-8.08 ( m, 2H), 7.60-7.68 (m, 3H), 3.85-3.95 (m, 4H), 3.55-3.65 (m, 4H).

Example 22. 7-Benzenesulfonyl-1- [1,4] diazepan-1-yl-isoquinoline hydrochloride

30 mg of product are isolated. 'H-NMR (DMSO-s.) Δ 9.3 (s, 1H), 8.58 (s, 1H), 8.26-8.30 (d, 1 = 9 Hz, 1H), 8.1 -8.13 (m, 2H), 8.01-8.06 (d, 1 = 6 Hz, 1H), 7.6-7.76 (m, ZN), 7.53-7.58 (d , 1 = 6 Hz, 1H), 3.70-3.90 (m, 4H), 3.58-3.66 (m, 2H), 3.29-3.40 (m, 2H); LCMS: 368.369; HPLC: 98%.

Example 23. 7- (4-tert-Butylbenzenesulfonyl) -1- [1,4] diazepan-1-yl-isoquinoline hydrochloride

69 mg of product are isolated. 'H-NMR (DMSO-s1 ₆ ) δ 9.2 (s, 1H), 8.65 (s, 1H), 8.09-8.15 (d, 1 = 6 Hz, 1H), 8.03 -8.08 (d, 1 = 15 Hz, 1H), 7.89-7.96 (d, 1 = 9 Hz, 2H), 7.60-7.67 (d, 1 = 9 Hz, 2H) 7.33-7.38 (d, 1 = 9 Hz, 1H), 4.01-4.09 (m, 2H), 3.83-3.91 (m, 2H), 3.43-3 52 (m, 2H); 3.23-3.33 (m, 2H); 1.25 (s, 9H); LCMS: 424, 425, HPLC: 97%.

Example 24. 7- (2-Chloro-6-methylbenzenesulfonyl) -1- [1,4] diazepan-1-yl-isoquinoline hydrochloride

27 mg of product are isolated. 'H-NMR (DMSO-b ₆ ) δ 8.81 (s, 1H), 8.28 (m, 1H), 8.10-8.18 (d, 1 = 6 Hz, 1H), 7.94 -8.08 (m, 2H), 7.45-7.62 (m, 3H), 7.36-7.42 (d, 1 = 6 Hz, 1H), 3.75-3.86 (m , 2H), 3.41-3.51 (m, 2H), 3.18-3.32 (m, 2H), 2.86 (s, 3H), 2.14-2.19 (m, 2H) ); LCMS: 416, 418; HPLC: 98%.

Example 25. 7- (3,5-Dimethylbenzenesulfonyl) -1- [1,4] diazepan-1-yl-isoquinoline hydrochloride

62 mg of product are isolated. 'H-NMR (DMSO-b ₆ ) δ 9.35 (s, 1H), 8.67 (m, 1H), 8.00-8.18 (m, 3H), 7.587.69 (m, 2H) 7.45-7.41 (d, 1 = 6 Hz, 1H), 7.30-7.35 (m, 1H), 4.06-4.14 (m, 2H), 3.86-3 97 (m, 2H), 3.42-3.52 (m, 2H), 3.23-3.31 (m, 2H), 2.33 (s, 6H), 2.23-2.25 (m, 2H); LCMS: 436.438; HPLC: 95%.

Example 26. 7- (3,4-Dichlorobenzenesulfonyl) -1- [1,4] diazepan-1-yl-isoquinoline hydrochloride

11 mg of product are isolated. 'H-NMR (CO ₃ OO) δ 8.88 (m, 1H), 8.23-8.29 (d, 1 = 12 Hz, 1H), 8.13-8.16 (d, 1 = 3 Hz, 1H), 8.04-8.10 (d, 1 = 9 Hz, 1H), 7.88-7.94 (d, 1 = 9 Hz, 1H), 7.79-7.84 (d , 1 = 6 Hz, 1H), 7.67-7.73 (d, 1 = 9 Hz, 1H), 7.42-7.46 (d, 1 = 6 Hz, 1H), 4.28-4 35 (m, 2H); 4.09-4.16 (m, 2H); 3.69-3.75 (m, 2H); 2.33-2.46 (m, 2H); LCMS: 368.369; HPLC: 97%.

Example 27. 7- (4-Chlorobenzenesulfonyl) -1- [1,4] diazepan-1-yl-isoquinoline hydrochloride

41 mg of product are isolated. 'H-NMR (DMSO-b ₆ ) δ 9.27 (s, 1H), 8.68 (m, 1H), 7.99-8.17 (m, 5H), 7.667.75 (d, 1 = 9 Hz, 2H), 7.33-7.39 (d, 1 = 6 Hz, 1H), 4.03-4.11 (m, 2H), 3.83-3.93 (m, 2H), 3.43-3.53 (m, 2H); 3.233.32 (m, 2H); 2.19-2.30 (m, 2H); LCMS: 402.404; HPLC: 98%.

Example 28. 7- (3,4-Dimethylbenzenesulfonyl) -1- [1,4] diazepan-1-yl-isoquinoline hydrochloride

10 mg of product are isolated. 'H-NMR (DMSO-b ₆ ) δ 9.41 (s, 1H), 8.67 (s, 1H), 8.00-8.16 (m, 3H), 7.767.82 (m, 1H) 7.68-7.77 (d, 1 = 9 Hz, 1H), 7.32-7.42 (d, 1 = 9 Hz, 2H), 3.99-4.40 (m, 4H), 3.49 (m, 2H); 3.33 (m, 2H); 2.29 (s, 3H); 2.25 (s, 3H); LCMS: 396, 397; HPLC: 92%.

Example 29. 7- (2-tert-Butylbenzenesulfonyl) -1- [1,4] diazepan-1-yl-isoquinoline hydrochloride

5 mg of product are isolated. 'H-NMR (DMSO-b ₆ ) δ 9.27 (s, 1H), 8.52 (s, 1H), 8.06-8.16 (m, 2H), 7.97-7.97 ( m, 2H), 7.72-7.78 (m, 1H), 7.61-7.70 (m, 1H), 7.40-7.45 (d, 1 = 9 Hz, 2H), 3 69-3.99 (m, 4H), 3.43 (s, 2H), 3.25 (s, 2H), 2.05-2.26 (m, 2H), 1.52 (s, 9H) ); LCMS: 424.425; HPLC: 90%.

Example 30. 7-Benzenesulfonyl-1-piperazinyl isoquinoline hydrochloride

10 mg of product are isolated. 'H-NMR (DMSO-b ₆ ) δ 9.04 (s, 1H), 8.65 (s, 1H), 8.12-8.16 (d, 1 = 6 Hz, 1H), 7.98 -8.05 (m, 5H), 7.58-7.72 (m, 2H), 7.32-7.36 (d, 1 = 6 Hz, 1H), 3.98-4.04 (m 4H); 3.80-3.86 (m, 4H); LCMS: 354.355; HPLC: 98%.

Example 31. 7- (4-tert-Butylbenzenesulfonyl-1-piperazinyl isoquinoline hydrochloride

10 mg of product are isolated. 'H-NMR (DMSO-b ₆ ) δ 9.33 (s, 1H), 8.57 (s, 1H), 8.24-8.29 (d, 1 = 9 Hz, 1H), 8.11 (m, 2H), 7.91-7.97 (d, 1 = 9 Hz, 2H), 7.60-7.66 (d, 1 = 12 Hz, 2H), 7.52-7.57 ( d, 1 = 6 Hz, 1H), 3.59-3.68 (m, 4H), 3.29-3.40 (m, 4H), 1.24 (s, 9H); LCMS: 410, 411; HPLC: 90%.

Table 3

EXAMPLE TITLE K ¹ to ⁵ 32 Hydrochloride 4-chlorOr-C- (4- {pyrrolidin-3-yloxy) -1naphthyl] benzenesulfonamide f C1

-21 008835

33 4-methoxy-M- hydrochloride [4- (pyrrolidin-3-yloxy) -1naphthyl] benzenesulfonamide f OMe 34 5-Chloro-Y- hydrochloride [4- (pyrrolidin-3-yloxy) - 1-naphthyl] thiophen-2-sulfonamide -ARA 35 4-Chloro-Y- hydrochloride [4- (piperidin-3-yloxy) -1naphthyl] benzenesulfonamide F C | 36 4-methoxy-K- hydrochloride [4- (piperidine - 3-yloxy) -1naphthyl] benzenesulfonamide f OMe 37 Hydrochloride 5 ~ fluoro-2-methyl-I- [4- (piperidin-4-yloxy) -1- naphthyl] benzenesulfonamide V 38 5-chloro-M- hydrochloride [4- (piperidin-4-yloxy) -1- naphthyl] thiophene-2-sulfonamide 39 4-chloro-K- {4 - [(33) pyrrolidin-3-yloxy] -1-naphthyl} benzenesulfonamide hydrochloride 4 g * '0' ό Α 40 Hydrochloride 4-chloro-y- {4 - [(ZK) - pyrrolidin-3-yloxy] -1- naphthyl} benzenesulfonamide ή

Scheme 4

Bos bos

-22008835

Explanations for Scheme 4: (1) tert-butyl-3-hydroxypyrrolidine-1-carboxylate or tert-butyl-4-hydroxypiperidin-1-carboxylate, PP ₃ , ΌΕΛΌ, THF; (ίί) H ₂ (gas.), Pb / C, MeOH; (w) I ₁ -8O ₂ -C1, pyridine, CH ₂ Cl ₂ ; (ίν) HC1 in diethyl ether.

General method C.

In accordance with the Mitsonobu reaction, 4-nitro-1-naphthol with BOC-protected 3-hydroxypyrrolidine and 4-hydroxypiperidine 4-nitro-1-naphthol (1 eq.) Was dissolved in THF (3 ml / mmol), tert-butyl-3- was added hydroxypyrrolidine-1-carboxylate (2 eq.), then PP ₃ (2 eq.). The solution was kept in an atmosphere of Ν ₂ and cooled in an ice bath. Diethyl azodicarboxylate (ΌΕΆΌ; 2 equiv.) Was added dropwise. The ice bath was removed after 10 minutes and the reaction mixture was stirred at room temperature overnight. The solution was evaporated and the residue was redissolved in ESAc. The precipitate formed is collected by filtration. The solution was concentrated in vacuo and purified by flash chromatography (8x10 ₂ , EuAc: isohexane 2: 8 → EuAc).

General way Ό. Reduction of nitronaphthalene derivatives

To a solution of the corresponding nitronaphthalene (1 equiv.) (Obtained by general method A) in MeOH (2 ml / mmol) was added Pb / C (10%) and the reaction mixture was stirred overnight in a hydrogen atmosphere (1 atm). The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the corresponding aminonaphthalene derivative.

General Method E. Interaction of Aminonaphthalene Derivatives with Sulfonyl Chlorides

To solutions of aminonaphthalene derivatives (1 equiv.) In CH ₂ Cl ₂ (8 ml / mmol) pyridine (3 equiv.) Is added, then the corresponding sulfonyl chloride (1.2 equiv.). The mixture was stirred at room temperature overnight, washed with HCl (1M) (2 ml) and dried (MgO ₄ ). Volatile solvents were removed in vacuo to give a crude product which was purified by flash chromatography ₍₂ occupies 8, EYuAs: isohexane 1: 4) to afford the desired sulfonamide.

General Method D. Removal of the BOC Protective Group

Sulfonamide derivatives (prepared by General Method C) are dissolved in a small amount of MeOH and treated with excess HCl in diethyl ether (1M). Stirring at room temperature overnight resulted in the formation of a precipitate, which was collected by filtration to obtain the title compounds in the form of hydrochloride salts.

General method O.

3-Hydroxypyrrolidine (1 eq.) Was dissolved in MeOH (1 ml / mmol) and cooled in an ice bath. (BOC) ₂ O (1.1 equiv.) Was added to the mixture, and the resulting mixture was stirred for 2 hours at room temperature. Pyridine / water (10/10 ml) was added to the resulting mixture, and the mixture was stirred overnight. Evaporation of the solvents and co-evaporation with toluene affords the desired BOC-protected 3-hydroxypyrrolidine.

Intermediate 28. Tert-Butyl-3 - [(4-nitro-1-naphthyl) oxy] pyrrolidine-1-carboxylate (General Method C)

The crude product is purified by column chromatography. The compound was prepared from 4-nitro-1-naphthol (2.85 g, 15.1 mmol). The product thus obtained is dissolved in a small amount of EyAc and isohexane is added. The resulting solid precipitate was collected by filtration and triturated with MeOH to give 4.6 g (85%) of the pure title compound. HPLC 99%, I _t = 2.70 (A1 system, 1097% MeCN for 3 min). '11-51MR (400 MHz, SRS) δ ppm 1.46 (d, 1 = 7.03 Hz, 9H), 2.26-2.38 (m, 2H), 3.60-3.81 (m, 4H), 5.20 (br s, 1H), 6.76 (d, 1 = 8.53 Hz, 1H), 7.58 (t, 1 = 7.53 Hz, 1H), 7.73 (t, 1 = 7.53 Hz, 1H) 8.34 (dd, 1 = 20.33, 8.78 Hz, 2H); 8.75 (d, 1 = 9.04 Hz, 1H). MS (Ε8Ι +) for C1 RAO ·. t / ζ 376.2 (Μ + ΝΉ) ⁺ , 359.2 (M + H) ⁺ , 303.2 (M-1Bi) ⁺ . HPLC 99%, And 2.78 min (B1 system, 10-90% GeCN for 3 min).

The intermediate product 29. tert-Butyl-3 - [(4-amino-1-naphthyl) oxy] pyrrolidine-1-carboxylate (General method Ό)

The compound was prepared from intermediate 1 (2.6 g, 7.2 mmol). 2.1 g (87%) of the title compound are obtained as a red solid. HPLC 96%, I _t = 1.768 min. (A1 system, 10-97% GeCN for 3 min). HPLC 95%, I _t = 1.604 min (B1 system, 10-90% GeCN for 3 min). Ή-NMR (400 MHz, DMSO-b ₆ ) δ ppm 1.37 (d, 1 = 22.59 Hz, 9H), 2.12 (s, 2H), 3.43-3.46 (m, 4H), 4.96 (s, 1H), 5.50 (s, 2H), 6.63 (d, 1 = 8.03 Hz, 1H), 6.81 (d, 1 = 8.03 Hz, 1H), 7.41 (dd, 1 = 6.02, 3.01 Hz, 2H); 7.94-8.01 (m, 2H). MS (Ε8Ι +) for C1 RACE t / ζ 329.2 (M + H) ⁺ , 273.2 (M-1Bi) ⁺ , 229.2 (M-Boc) ⁺ .

The intermediate product 30. tert-Butyl-3 - [(4 - {[(4-chlorophenyl) sulfonyl] amino} -1naphthyl) oxy] pyrrolidine-1-carboxylate (General method E)

The compound was prepared from intermediate 2 (0.2 g, 0.61 mmol). The crude product was triturated with CH3CA to give 0.14 g (46%) of the title compound as a pale pink solid. HPLC 97%, I _t = 2.703 min (A1 system, 10-97% GeCN for 3 min). Ή-NMR (400 MHz, С15СР) δ ppm 1.46 (d, 1 = 4.02 Hz, 9H), 2.18-2.30 (m, 2H), 3.54-3.76 (m, 4H), 5.05 (br s, 1H), 6.62-6.65 (m, 1H), 6.74-6.76 (m, 1H), 7.17-7.23 (m, 1H), 7.32 (d, 1 = 9.04 Hz, 2H), 7.39-7.45 (m, 2H), 7.62 (d, 1 = 8.53 Hz, 2H), 7.68-7.72 (m, 1H), 8.16-8.19 (m, 1H). MS (Ε8Ι +) for С ₂₅ Н ₂₇ СШ ₂ О ₅ 8 t / ζ 520.2 (М + ΝΉΉ, 447.0 (М1Ви) ⁺ . HPLC 98%, I _t = 2.738 min (system B1, 10-90 % GeCN for 3 min).

- 23 008835

Intermediate 31. tert-Butyl-3 - [(4 - {[(4-methoxyphenyl) sulfonyl] amino} -1naphthyl) oxy] pyrrolidine-1-carboxylate (General Method E)

The compound was prepared from intermediate 2 (0.2 g, 0.61 mmol). 0.2 g (66%) of the title compound are obtained in the form of a pink oil. HPLC 98%, And _t = 2.617 min. (A1 system, 1097% MECA for 3 min). Ή-NMR (400 MHz, C1) C1 _; ) δ 1.45 (d, 1 = 5.02 Hz, 9H), 2.14-2.31 (m, 2H), 3.543.76 (m, 4H), 3.79 (s, 3H), 5 04 (br s, 1H), 6.60-6.65 (m, 2H), 6.81 (d, 1 = 8.53 Hz, 2H), 7.15-7.24 (m, 1H) ), 7.38-7.44 (m, 2H), 7.60-7.64 (m, 2H), 7.71-7.76 (m, 1H), 8.14-8.18 (m , 1H). MS (Ε8Ι +) for С ₂₆ Н ₃₀ Н ₂ 0 ₆ 8 t / ζ 516.4 ((М + НН ₄ ) ⁺ , 443.0 ((М-! Ви) ⁺ , 399.2 (М-ВС) ⁺ .

Intermediate 32. Tert-Butyl-3 - [(4 - {[(5-chloro-2-thienyl) sulfonyl] amino} -1naphthyl) oxy] pyrrolidine-1-carboxylate (General Method E)

The compound was prepared from intermediate 2 (0.2 g, 0.61 mmol). 0.21 g (68%) of the title compound are obtained as a yellow solid. HPLC 99%, K. _t = 2.777 min (B1 system, 10-90% МеСЫ for 3 min). Я-NMR (400 MHz, C12CE) δ ppm 1.46 (d, 1 = 6.02 Hz, 9H), 2.16-2.30 (m, 2H), 3.55-3.74 (m, 4H), 5.07 (br s, 1H), 6.67-6.70 (m, 1H), 6.75 (d, 1 = 4.02 Hz, 1H), 6.77 (br s, 1 H), 7.13 (br s , 1H), 7.28-7.35 (m, 1H), 7.46-7.48 (m, 2H), 7.75-7.79 (m, 1H), 8.19-8.22 (m, 1H). MS (Ε8Ι +) for С ₂₃ Н ₂₅ С1Ы ₂ 0 ₅ 8 ₂ t / ζ 526.2 (M + ON ₄ ) ⁺ , 453.0 (M-! Vi) ⁺ , 409.2 (M-Boc) ⁺ . HPLC 99%, _W == 2.767 min (A1 system Mesa 10-97% for 3 min).

Intermediate 33. Tert-Butyl-4 - [(4-nitro-1-naphthyl) oxy] piperidine-1-carboxylate (General Method C)

The compound is obtained from 4-nitro-1-naphthol (2 g, 10.6 mmol). The product obtained after flash chromatography is not pure enough to conduct NMR studies. Recrystallization from ΕΐΟAc / isohexane gave 2.3 g (62%) of the title compound as a yellow solid. HPLC 98%, _W = 2.842 min (A1 system Mesa 10-97% for 3 min). Ή-NMR (400 MHz, SOSB) δ ppm 1.48 (s, 9H), 1.99 (m, 4H), 3.54 (m, 2H), 3.70 (m, 2H), 4.87 (m, 1H), 6.82 (d , 1 = 9.04 Hz, 1H), 7.59 (m, 1H), 7.74 (m, 1H), 8.38 (d, 1 = 8.53 Hz, 2H), 8.77 (d , 1 = 8.53 Hz, 1H). MS (Ε8Ι +) for С ₂₀ Н ₂₄ Н ₂ 0 ₅ t / ζ 373.0 (М + Н) ⁺ , 390.2 (М + НН4) ⁺ , 317.0 (М-! Ви) ⁺ . HPLC 98%, W == 2.973 min (B1 system, 10-90% МеСЫ for 3 min).

Intermediate 34. Tert-Butyl-4 - [(4-amino-1-naphthyl) oxy] piperidine-1-carboxylate (General Method C)

The compound was prepared from intermediate 6 (2.3 g, 7.0 mmol). 2 g (95%) of the product are obtained in the form of rose oil. HPLC 94%, And _t = 2.885 min (B1 system, 10-90% MeCY for 3 min). Ή NMR (400 MHz, C12CE) δ ppm 1.46 (s, 9H), 1.80-1.98 (m, 4H), 3.35-3.41 (m, 2H), 3.46 (s, 3H), 3.69-3, 75 (m, 2H), 3.88 (br s, 1H), 4.50-4.54 (m, 1H), 7.45-7.50 (m, 2H), 7.79-7, 81 (m, 1H), 8.22-8.24 (m, 1H). MS (Ε8Ι +) for С ₂₀ Н ₂₆ Н ₂ 0 ₃ t / ζ 343.2 (М + Н) ⁺ . HPLC 94%, = 2.735 min. (A1 system, 10-97% МеСЫ for 3 minutes).

Intermediate 35. tert-Butyl-4 - [(4 - {[(4-chlorophenyl) sulfonyl] amino} -1naphthyl) oxy] piperidine-1-carboxylate (General Method E)

The compound is obtained from intermediate 7 (0.25 g, 0.73 mmol). 0.29 g (77%) of product is obtained. HPLC 98%, And _t = 2.906 min (A1 system, 10-97% MeCY for 3 min). Ή-NMR (400 MHz, SOSB) δ ppm 1.47 (s, 9H), 1.88 (m, 2H), 1.98 (m, 2H), 3.47 (m, 2H), 3.68 (m, 2H), 4.69 (m , 1H), 6.61 (s, 1H), 6.70 (d, 1 = 8.03 Hz, 1H), 7.17 (d, 1 = 8.03 Hz, 1H), 7.32 (m , 2H), 7.43 (m, 2H), 7.62 (m, 2H), 7.70 (m, 1H). MS (Ε8Ι +) for C ₂₆ H _2E S1Y ₂ 0 ₅ 8 t / ζ 534,0 (M + NH ₄₎ ^+, 461.2 (M! Bu) ^+. HPLC 98%, And 2.843 min (B1 system, 10-90% MECA for 3 min).

Intermediate 36. Tert-Butyl-4 - [(4 - {[(4-methoxyphenyl) sulfonyl] amino} -1naphthyl) oxy] piperidine-1-carboxylate (General Method E)

The compound is obtained from intermediate 7 (0.25 g, 0.73 mmol). 0.21 g (56%) of the title compound are obtained as a pink solid. HPLC 100%, _W = 2.755 min (A1 system Mesa 10-97% for 3 min). Ή-NMR (400 MHz, C1) C1 _; ) δ ppm 1.47 (s, 9H), 1.86-2.01 (m, 4H), 3.43-3.49 (m, 2H), 3.65-3.71 (m, 2H), 3, 79 (s, 3H), 4.65-4.70 (m, 1H), 6.58 (s, 1H), 6.69 (d, 1 = 8.53 Hz, 1H), 6.83-6 79 (m, 2H), 7.17 (d, 1 = 8.03 Hz, 1H), 7.39-7.44 (m, 2H), 7.61-7.64 (m, 2H), 7.75-7.77 (m, 1H); 8.21-8.24 (m, 1H). MS (Ε8Ι +) for С ₂₇ Н ₃₂ Н ₂ 0 ₆ 8 t / ζ 530.2 (М + НН ₄ ) ⁺ , 457.2 (М-! Ви) ⁺ , 413.4 (М-Bos) ⁺ . HPLC 99%, And _m = 2,668 min (B1 system, 10-90% MeCY for 3 min).

Intermediate 37. tert-Butyl-4 - [(4 - {[(5-fluoro-2-methylphenyl) sulfonyl] amino} -1naphthyl) oxy] piperidine-1-carboxylate (General Method E)

The compound is prepared from tert-butyl-4 - [(4-amino-1-naphthyl) oxy] piperidine-1-carboxylate (0.25 g, 0.73 mmol). 0.24 g (64%) of the title compound are obtained as a pink solid. HPLC 99%, And _t = 2.809 min (B1 system, 10-90% MeCY for 3 min). Ή-NMR (400 MHz, SOSB) δ ppm 1.46 (s, 9H), 1.83-1.98 (m, 4H), 2.54 (s, 3H), 3.42-3.48 (m, 2H), 3.63-3, 69 (m, 2H), 4.64-4.68 (m, 1H), 6.64-6.68 (m, 2H), 7.03 (d, 1 = 8.53 Hz, 1H), 7 10 (m, 1H), 7.22 (dd, 1 = 8.53, 5.02 Hz, 1H), 7.44-7.48 (m, 2H), 7.55 (dd, 1 = 8 53, 2.51Hz, 1H), 7.83-7.86 (m, 1H), 8.24 (m, 1H). MS (Ε8Ι +) for С ₂₇ Н ₃₁ ЕЫ ₂ 0 ₅ 8 t / ζ 532.2

- 24 008835 (Μ + ΝΗ ₄ ) ⁺ , 459.2 (M-! Bi) ⁺ , 415.2 (M-Boc) ⁺ . HPLC 100%, And _t = 2.877 min (A1 system, 10-97% MeCN for 3 min).

Intermediate 38. tert-Butyl-4 - [(4 - {[(5-chloro-2-thienyl) sulfonyl] amino} -1naphthyl) oxy] piperidine-1-carboxylate (General Method E)

The compound is prepared from tert-butyl-4 - [(4-amino-1-naphthyl) oxy] piperidine-1-carboxylate (0.25 g, 0.73 mmol). 0.25 g (65%) of the title compound are obtained as a pink solid. HPLC 98%, And _t = 2.827 min. (B1 system, 10-90% GeCN for 3 min). Ή-NMR (400 MHz, SES1 ₃ ) δ ppm 1.47 (s, 9H), 1.86-2.03 (m, 4H), 3.45-3.51 (m, 2H), 3.66-3.72 (m, 2H), 4, 69-4.74 (m, 1H), 6.66 (s, 1H), 6.74-6.76 (m, 2H), 7.14 (d, 1 = 4.02 Hz, 1H), 7 30 (d, 1 = 8.03 Hz, 1H), 7.45-7.50 (m, 2H), 7.76-7.79 (m, 1H), 8.25-8.28 (m , 1H). MS (Ε8Ι +) for С ₂₄ Н ₂₇ СШ ₂ 0 ₅ 8 ₂ t / ζ 540.4 (Μ + ΝΉ ₄ ) ⁺ , 467.2 (Μ-ίΒιι) '. HPLC 99%, K. _t = 2.910 min (A1 system, 10-97% SEC for 3 min).

Intermediate 39. Tert-Butyl- (3H) -3-hydroxypyrrolidine-1-carboxylate (General Method C)

The compound is prepared from (3I) -3-hydroxypyrrolidine (5 g, 57.4 mmol). 9.6 g (90%) of the title compound are obtained. Ή-NMR (400 MHz, SES1 ₃ ) δ ppm 1.43 (s, 9H), 1.90-1.98 (m, 2H), 3.27-3.47 (m, 4H), 4.40 (br s, 1H).

Intermediate 40. Tert-Butyl- (38) -3-hydroxypyrrolidine-1-carboxylate (General Method C)

The compound is prepared from (38) -3-hydroxypyrrolidine (5 g, 57.4 mmol). 8 g (86%) of the title compound are obtained. Ή-NMR (400 MHz, SES1 ₃ ) δ ppm 1.40 (s, 9H), 1.86-1.91 (m, 2H), 3.24-3.42 (m, 4H), 4.36 (br s, 1H).

Intermediate 41. tert-Butyl- (38) -3 - [(4-nitro-1-naphthyl) oxy] pyrrolidine-1 carboxylate (General Method C)

The compound is prepared from tert-butyl- (3I) -3-hydroxypyrrolidin-1-carboxylate (3.56 g, 19 mmol) and 4-nitro-1-naphthol (3 g, 15.9 mmol). 5 g (88%) of the title compound are obtained as a yellow oil. ^! H-NMR (400 MHz, SES1 ₃ ) δ ppm 1.45 (d, 1 = 7.03 Hz, 9H), 2.22-2.38 (m, 2H), 3.54-3.83 (m, 4H), 5.18 (br s, 1H), 6.74 (d, 1 = 8.53Hz, 1H), 7.56 (t, 1 = 7.78 Hz, 1H), 7.71 (t, 1 = 7.78 Hz, 1H), 8.29 (d, 1 = 8.53 Hz, 1H), 8.33 (d, 1 = 8.53 Hz, 1H), 8.72 (d, 1 = 8.53 Hz, 1H). MS (Ε8Ι +) for С11.Л0, t / ζ 376.2 (Μ + ΝΉ ₄ ) ⁺ , 303.2 (M-ΐΒιι) '. HPLC 100%, And 2.768 min (A1 system, 10-97% GeCN for 3 min).

Intermediate 42. tert-Butyl- (3I) -3 - [(4-nitro-1-naphthyl) oxy] pyrrolidine-1 carboxylate (General Method C)

The compound is prepared from tert-butyl- (38) -3-hydroxypyrrolidine-1-carboxylate (3.56 g, 19 mmol) and 4-nitro-1-naphthol (3 g, 15.9 mmol). 2.8 g (49%) of the title compound are obtained as a yellow oil. ^! H-NMR (400 MHz, SES1 ₃ ) δ ppm 1.46 (d, 1 = 7.03 Hz, 9H), 2.26-2.38 (m, 2H), 3.55-3.81 (m, 4H), 5.20 (br s, 1H), 6.77 (d, 1 = 8.53 Hz, 1H), 7.59 (t, 1 = 7.53 Hz, 1H), 7.72-7.76 (m, 1H), 8, 32 (d, 1 = 8.03 Hz, 1H), 8.37 (d, 1 = 8.53 Hz, 1H), 8.76 (d, 1 = 8.53 Hz, 1H). HPLC 95%, And _t = 2.775 min (A1 system, 10-97% GeCN for 3 min).

Intermediate 43. Tert-Butyl- (38) -3 - [(4-amino-1-naphthyl) oxy] pyrrolidine-1 carboxylate (General Method Ό)

The compound is prepared from tert-butyl- (38) -3 - [(4-nitro-1-naphthyl) oxy] pyrrolidine-1-carboxylate (5 g, 14 mmol). 3.5 g (76%) of the title compound are obtained as a dark pink solid. Ή-NMR (400 MHz, SES1 ₃ ) δ ppm 1.46 (d, 1 = 14.56 Hz, 9H), 2.08-2.13 (m, 1H), 2.27-2.30 (m, 1 = 13.05 Hz, 1H), 3 54-3.77 (m, 4H), 3.88 (broad s, 2H), 4.96 (broad s, 1H), 6.65-6.70 (m, 2H), 7.45 -7.51 (m, 2H), 7.79-7.81 (m, 1H), 8.15-8.19 (m, 1H). MS (Ε8Ι +) for C11 _; A 0 _; t / ζ 329.2 (M + H) ⁺ , 273.2 (M-! Vi) ⁺ , 229.2 (M-Boc) ⁺ . HPLC 95%, And _t = 1.854 min (A1 system, 10-97% GeCN for 3 min).

Intermediate 44. Tert-Butyl- (3I) -3 - [(4-amino-1-naphthyl) oxy] pyrrolidine-1 carboxylate (General Method Ό)

The compound is prepared from tert-butyl- (3I) -3 - [(4-nitro-1-naphthyl) oxy] pyrrolidine-1-carboxylate (2.8 g, 7.8 mmol). 1.8 g (72%) of the title compound are obtained as a dark pink solid. Ή-NMR (400 MHz, SES1 ₃ ) δ ppm 1.46 (d, 1 = 14.56 Hz, 9H), 2.07-2.14 (m, 1H), 2.272.30 (m, 1H), 3.54-3.77 (m, 4H) 3.93 (br s, 2H), 4.96 (br s, 1H), 6.65-6.70 (m, 2H), 7.45-7.51 (m, 2H), 7.797 81 (m, 1H); 8.16-8.18 (m, 1H). MS (Ε8Ι +) for C11 _; L0 _; t / ζ 329.2 (M + H) ⁺ , 273.2 (M-! Vi) ⁺ , 229.2 (MVOS) ⁺ . HPLC 94%, And _t = 1.751 min. (A1 system, 10-97% GeCN for 3 min).

Intermediate 45. tert-Butyl- (38) -3 - [(4 - {[(4-chlorophenyl) sulfonyl] amino} -1naphthyl) oxy] pyrrolidine-1-carboxylate (General Method E)

The compound is prepared from tert-butyl- (38) -3 - [(4-nitro-1-naphthyl) oxy] pyrrolidine-1-carboxylate (0.3 g, 0.9 mmol) and 4-chlorophenylsulfonyl chloride (0.23 g 1.1 mmol). 0.23 g (50%) of the title compound is obtained. Ή-NMR (400 MHz, SES1 ₃ ) δ ppm 1.46 (d, 1 = 4.52 Hz, 9H), 2.15-2-34 (m, 2H), 3.543.74 (m, 4H), 5.05 (br s, 1H), 6 62-6.71 (m, 2H), 7.17-7.23 (m, 1H), 7.33 (d, 1 = 8.53 Hz, 1H), 7.39-7.43 (m , 2H), 7.62-7.64 (m, 2H), 7.65-7.70 (m, 1 = 6.02 Hz, 1H), 8.18 (d, 1 = 8.53 Hz, 1H). MS (Ε8Ι +) for С ₂₅ Н ₂₇ СШ ₂ 0 ₂ 8 t / ζ 520.2 (M + IN ₄ ) ⁺ , 447.0 (M-! Vi) ⁺ . HPLC 100%, And 2.772 min (A1 system, 10-97% GeCN for 3 min).

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Intermediate 46. tert-Butyl- (3K) -3 - [(4 - {[(4-chlorophenyl) sulfonyl] amino} -1naphthyl) oxy] pyrrolidine-1-carboxylate (General Method E)

The compound is prepared from tert-butyl- (3K) -3 - [(4-nitro-1-naphthyl) oxy] pyrrolidine-1-carboxylate (0.3 g, 0.9 mmol) and 4-chlorophenylsulfonyl chloride (0.23 g 1.1 mmol). 0.4 g (87%) of the title compound are obtained. Ή-NMR (400 MHz, SES1 _; ) δ ppm 1.46 (d, 1 = 4.52 Hz, 9H), 2.15-2.34 (m, 2H), 3.543.74 (m, 4H), 5.05 (br s, 1H), 6 , 60-6.66 (m, 2H), 7.17-7.23 (m, 1H), 7.33 (d, 1 = 8.53 Hz, 1H), 7.39-7.43 (m , 2H), 7.62-7.64 (m, 2H), 7.65-7.70 (m, 1 = 6.02 Hz, 1H), 8.18 (d, 1 = 8.53 Hz, 1H). MS (Ε8Ι +) for С ₂₅ Н ₂₇ С1Ы ₂ О ₅ 8 t / ζ 520.2 (Μ + ΝΗ ₄ ) ⁺ , 447.0 (М-! Ви) ⁺ . HPLC 100%, AND 2.769 min (A1 system, 10-97% MECA for 3 min).

Example 32. 4-Chloro-Y- [4- (pyrrolidin-3-yloxy) -1-naphthyl] benzenesulfonamide hydrochloride (General Method D)

The compound was prepared from intermediate 3 (0.13 g, 0.26 mmol). The solid product was further purified by trituration in diethyl ether to give 0.11 g (95%) of the title compound as a white solid. HPLC 98%, And _t = 1.810 min. (A1 system, 10-97% МеСЫ for 3 minutes). Ή-NMR (400 MHz, DMSO-b ₆ ) δ ppm 2.21-2.26 (m, 2H), 3.32-3.37 (m, 2H), 3.48-3.50 (m, 2H), 5.28 (br s, 1H), 6.91-6.98 (m, 2H), 7.44-7.50 (m, 2H), 7.56-7.64 (m, 4H), 7.88-7.90 (m, 1H ), 8.20-8.23 (m, 1H). MS (Ε8Ι +) for С ₂₀ Н ₁₉ С1Ы ₂ О ₃ 8 t / ζ 401.2 (М + Н) ⁺ . HPLC 98%, And _t = 1.651 min (B1 system, 10-90% МеСЫ for 3 min).

Example 33. 4-Methoxy-Y- [4- (pyrrolidin-3-yloxy) -1-naphthyl] benzenesulfonamide hydrochloride (General Method D)

The compound was prepared from intermediate 4 (0.18 g, 0.36 mmol). 0.12 g (76%) of the title compound are obtained as a white solid. HPLC 100%, And _t = 1.490 min (B1 system, 10-90% МеСЫ for 3 min). Ή-NMR (400 MHz, DMSO-b ₆ ) δ ppm 2.20-2.25 (m, 2H), 3.31-3.53 (m, 4H), 3.78 (s, 3H), 5.27 (br s, 1H), 6.90- 6.97 (m, 2H), 7.00 (d, 1 = 8.53 Hz, 2H), 7.43-7.48 (m, 2H), 7.57 (d, 1 = 8.53 Hz, 2H), 7.93-7.96 (m, 1H), 8.19-8.22 (m, 1H), 9.63 (br s, 2H). MS (Ε8Ι +) for С ₂ ; Н ₂₂ Н ₂ О ₄ 8 t / ζ 409.2 (М + Н) ⁺ . HPLC 100%, And _t = 1,639 min (A1 system, 10-97% МеСЫ for 3 min).

Example 34. 5-Chloro-Y- [4- (pyrrolidin-3-yloxy) -1-naphthyl] thiophen-2-sulfonamide hydrochloride (General Method D)

The compound was prepared from intermediate 5 (0.20 g, 0.39 mmol). 0.14 g (80%) of the title compound is obtained as a solid off-white solid. HPLC 99%, And _t = 1.651 min (B1 system, 10-90% МеСЫ for 3 min). Ή-NMR (400 MHz, DMSO-b ₆ ) δ ppm 2.23-2.26 (m, 2H), 3.28-3.39 (m, 2H), 3.40-3.56 (m, 2H), 5.32 (br s, 1H), 6.99 (d, 1 = 8.53 Hz, 1H), 7.13 (d, 1 = 8.03 Hz, 1H), 7.15 (d, 1 = 4.02 Hz, 1H), 7, 26 (d, 1 = 4.02 Hz, 1H), 7.48-7.52 (m, 2H), 7.92 (dd, 1 = 6.53, 3.01 Hz, 1H), 8.25 (dd, 1 = 6.53, 3.01 Hz, 1H), 9.60 (s, 1H). MS (Ε8Ι +) for C; ₈ H ₁₇ Cl ₂ O ₃ 8 ₂ t / ζ 409.2 (M + H) ⁺ . HPLC 99%, And _t = 1.818 min. (A1 system, 10-97% МеСЫ for 3 minutes).

Example 35. 4-Chloro-Y- [4- (piperidin-3-yloxy) -1-naphthyl] benzenesulfonamide hydrochloride (General Method D)

The compound was prepared from intermediate 8 (0.26 g, 0.50 mmol). 0.12 g (53%) of the title compound are obtained as a white solid. HPLC 100%, And _t = 1.872 min (A1 system, 10-97% MeCSA for 3 min). Ή-NMR (400 MHz, DMSO-b ₆ ) δ ppm 1.95-1.99 (m, 2H), 2.14-2.19 (m, 2H), 3.11 (br s, 2H), 3.26 (br s, 2H), 4, 84 (br s, 1H), 6.92-6.99 (m, 2H), 7.44-7.51 (m, 2H), 7.57-7.65 (m, 4H), 7, 91 (d, 1 = 7.53 Hz, 1H), 8.17 (d, 1 = 7.03 Hz, 1H), 8.94 (br s, 1H), 9.05 (br s, 1H ), 10.11 (s, 1H). MS (Ε8Ι +) for С ₂ ; Н ₂₁ СЫЫ ₂ О ₃ 8 t / ζ 415.2 (М + Н) ⁺ . HPLC 99%, And _t = 1.657 min (B1 system, 10-90% MECA for 3 min).

Example 36. 4-Methoxy-Y- [4- (piperidin-3-yloxy) -1-naphthyl] benzenesulfonamide hydrochloride (General Method D)

The compound was prepared from intermediate 9 (0.19 g, 0.37 mmol). 0.15 g (90%) of the title compound is obtained as a white solid. HPLC 97%, And _t = 1.508 min (B1 system, 10-90% МеСЫ for 3 min). Ή-NMR (400 MHz, DMSO-b ₆ ) δ ppm 1.96 (m, 2H), 2.16 (m, 2H), 3.10 (m, 2H), 3.26 (m, 1 = 6.02 Hz, 2H), 3.78 (s, 3H ), 4.82 (m, 1H), 6.95 (q, 1 = 8.20 Hz, 1H), 7.01 (d, 1 = 9.04 Hz, 2H), 7.47 (m, 2H) ), 7.57 (m, 2H), 7.96 (m, 1H), 8.16 (m, 1H), 8.96 (s, 1H), 9.07 (s, 1H), 9.81 (s, 1H). MS (Ε8Ι +) for C ₂₂ H ₂₄ N ₂ O ₄ 8 t / ζ 413.4 (M + H) ⁺ . HPLC 97%, And _t = 1.713 min (A1 system, 10-97% MECA for 3 min).

Example 37. 5-Fluoro-2-methyl-Y- [4- (piperidin-4-yloxy) -1-naphthyl] benzenesulfonamide hydrochloride (General Method D)

The compound was prepared from intermediate 10 (0.24 g, 0.47 mmol). 0.21 g (99%) of the title compound are obtained in the form of a solid off-white solid. HPLC 100%, And _t = 1.823 min (A1 system, 10-97% MeCA for 3 min). Ή-NMR (400 MHz, CH ₃ OH-b ₄ ) δ ppm 2.13 (m, 4H), 2.42 (s, 3H), 3.18 (m, 2H), 3.37 (m, 2H), 4.83 (m, 1H), 6.81 (d , 1 = 8.53 Hz, 1H), 6.97 (d, 1 = 8.03 Hz, 1H), 7.10 (m, 1H), 7.24 (m, 1 = 8.53, 5, 52Hz, 1H), 7.35 (m, 3H), 7.83 (m, 1H). MS (Ε8Ι +) for С ₂₂ Н ₂₃ ГЫ ₂ О ₃ 8 t / ζ 415.2 (М + Н) ⁺ . HPLC 96%, _W = 1.628 min (B1 system Mesa 10-90% for 3 min).

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Example 38. 5-Chloro-Y- [4- (piperidin-4-yloxy) -1-naphthyl] thiophen-2-sulfonamide hydrochloride (General Method E)

The compound is prepared from tert-butyl-4 - [(4 - {[(5-fluoro-2-methylphenyl) sulfonyl] amino} -1naphthyl) oxy] piperidine-1-carboxylate (0.24 g, 0.46 mmol). 0.16 g (76%) of the title compound is obtained as a white solid. Ή-NMR (DMSO-b ₆ ) δ ppm 1.96-2.03 (m, 2H), 2.16-2.22 (m, 2H), 3.09-3.14 (m, 2H), 3.25-3.31 (m, 2H) ), 4.86-4.89 (m, 1H), 7.04-7.11 (m, 2H), 7.16 (d, 1 = 4.02 Hz, 1H), 7.26 (d, 1 = 4.02 Hz, 1H), 7.48-7.53 (m, 2H), 7.92-7.94 (m, 1H), 8.19-8.21 (m, 1H), 9 06 (br s, 1H); 10.36 (br s, 1H). MS (Ε8Ι +) for С1 ₉ Н ₁₉ С1Ы ₂ О ₃ 8 ₂ ш / ζ 423.0 (М + Н) ⁺ . HPLC 99%, I _t = 1.861 min (A1 system, 1097% MECA for 3 min).

Example 39. 4-Chloro-Y- {4 - [(38) -pyrrolidin-3-yloxy] -1-naphthyl} benzenesulfonamide hydrochloride (General Method E)

The compound is prepared from tert-butyl- (38) -3 - [(4 - {[(4-chlorophenyl) sulfonyl] amino} -1naphthyl) oxy] pyrrolidine-1-carboxylate (0.22 g, 0.44 mmol). 0.15 g (78%) of the title compound is obtained as a yellow solid. Ή-NMR (400 MHz, CH ₃ OH-b ₄ ) δ ppm 2.37-2.49 (m, 2H), 3.52-3.56 (m, 2H), 3.61-3.71 (m, 2H), 5.37 (br s, 1H), 6.87 (d, 1 = 8.03 Hz, 1H), 7.14 (d, 1 = 8.03 Hz, 1H), 7.38-7.47 (m, 4H), 7.61 (d , 1 = 8.53 Hz, 2H), 7.83 (d, 1 = 8.03 Hz, 1H), 8.22 (d, 1 = 8.03 Hz, 1H). MS (Ε8Ι +) for С ₂₀ Н ₁₉ С1Ы ₂ О ₃ 8 ш / ζ 403.2 (М + Н) ⁺ . HPLC 100%, I _t = 1.826 min (A1 system, 10-97% MECA for 3 min).

Example 40. 4-Chloro-Y- {4 - [(W) pyrrolidin-3-yloxy] -1-naphthyl} benzenesulfonamide hydrochloride (General Method E)

The compound is prepared from tert-butyl- (3A) -3 - [(4 - {[(4-chlorophenyl) sulfonyl] amino} -1naphthyl) oxy] pyrrolidine-1-carboxylate (0.37 g, 0.74 mmol). 0.27 g (82%) of the title compound are obtained in the form of a solid off-white solid. Ή-NMR (400 MHz, CH ₃ OH-b ₄ ) δ ppm 2,372.49 (m, 2H), 3.52-3.56 (m, 2H), 3.61-3.71 (m, 2H), 5.37 (br s, 1H), 6.88 ( d, 1 = 8.53 Hz, 1H), 7.15 (d, 1 = 8.03 Hz, 1H), 7.39-7.47 (m, 4H), 7.60-7.62 (m , 2H), 7.83 (d, 1 = 7.53 Hz, 1H), 8.22 (d, 1 = 8.03 Hz, 1H). MS (Ε8Ι +) for С ₂₀ Н ₁₉ С1Ы ₂ О ₃ 8 ш / ζ 403.2 (М + Н) ⁺ . HPLC 100%, I _t = 1.815 min (A1 system, 10-97% MECA for 3 min).

Scheme 5

Explanations for Scheme 5: ί) Little new acid, pyridine, piperidine, heating; i) ethyl chloroformate, acetone, Na ₃ , -10 ° C; ίίί) diphenyl ether, 220 ° C; ίν) POC1 ₃ , heating; ν) gaseous 8О ₂ , n-VI, Нхл illosuccinimide, СН ₂ С1 ₂ ; νί) K'-UNG, pyridine; νίί) AE ³ , K ₂ CO 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%). Ή-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 over MgSO ₄ , filtered and the solvent removed to give 0.96 g (83.4%) of the product. Ή-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 = 15.57Hz, 1H); MS 258.1 (M-H) ⁺ ; purity (HPLC) 65%.

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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 CH3OH-b4) 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%.

Intermediates 51 and 52. 4-Chlortieno [3,2-c] pyridin-2-sulfonyl chloride and 2-bromo-4chlortieno [3,2-c] pyridin-3-sulfonyl chloride n-Butyl lithium (1.5 ml, 2, 4 mmol) is added to 2-bromo-4-chlorothieno [3,2-c] pyridine (0.5 g, 2 mmol) dissolved in dry THF (15 ml) at -78 ° C under 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: Y-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 (3 x 50 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.

Intermediates 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) is added to a solution of 4-chlorothieno [3,2-c] pyridin-2sulfonyl 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-2sulfonic acid p-tolylamide hydrochloride and 2-bromo-4- (4-methylpiperazin-1- hydrochloride p-tolylamide il) thieno [3,2c] pyridin-3-sulfonic acid

A mixture of 4-chloro-2-thieno [3,2-c] pyridin-2-sulfonic acid p-tolylamide and 2-bromo-4-chlorothieno [3,2-c] pyridin-3-sulfonic acid p-tolylamide (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) are heated to 100 ° C and maintained at this temperature for nights. The reaction mixture was dissolved in water and extracted with ethyl acetate (3x10 ml). The organic layers were combined and the solvent was removed. The products were purified by HPLC to give 1.9 mg of 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-b ₄ ) 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- (4-methylpiperazin-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: ¹ 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 TPZATTE ™ (~ 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).

- 28 008835

Binding to 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.) Were 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 8reaUas 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) -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%). ¹ H-NMR (270 MHz CH ₃ OH-a ₄ ) δ ppm 8.13 (d, D = 5.81 Hz, 1H), 7.67 (s, 1H), 7.54 (d, D = 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-2sulfonic acid amide hydrochloride (3-fluoro-5-trifluoromethylphenyl) amide 4- [2- (3-fluoro-5-trifluoromethylphenylsulfamoyl) thieno [3,2-c] pyridin-4yl] piperazine-1-carboxylic acid (0.235 mmol, 1 equiv.) is used as thienopyridine in the H-b method. Yield: 25.7 mg. HPLC: C = 3.395 (system: from 5% to 50% ΑCN for 3 min, C8), purity: 100%, LC / MS: ΐρ = 1.375 (system: from 30% to 60% ΑCN for 1.5 min, NuregSCh8), purity: 99%. MS: 461 (M + 1). ^! H-NMR (270 MHz CH ₃ OND 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, t = 6.33 Hz, 1H).

Example 45. Hydrochloride of (4-chlorophenyl) amide 4-piperazin-1-yl-thieno [3,2-c] pyridin-2sulfonic acid (3-Fluoro-5-trifluoromethylphenyl) amide 4-chlorothieno [3,2-c] pyridin-2-sulfonic acid (0.208 mmol, 1 equiv.) is used as thienopyridine in the method H-b. Yield: 7.2 mg. HPLC: C = 3.039 (system: 5 to 50% ΑCN for 3 min, C8), purity: 100%, LC / MS: 1 _K = 0.905 (system: 30 to 60% ΑCN for 1.5 min , NuregShΒΌ8), purity: 97%. MS: 409 (M + 1). ¹ H-NMR (270 MHz, CH ₃ OH-th ₄ ) δ ppm 3.50 (m, 4H), 3.91 (m, 4H), 7.25 (m, 4H), 7.71 (dd, .1 (ν + ν 0.53Hz, 1H), 7.96 ( d, t = 0.79 Hz, 1H), 8.04 (d, .16> Hz, 1H).

Example 46. Hydrochloride of (4-isopropylphenyl) amide 4-piperazin-1-ylthieno [3,2-s] pyridin-2sulfonic acid (4-Isopropylphenyl) amide 4-chlorothieno [3,2-s] pyridin-2-sulfonic acid (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% ΑCN for 3 min, C8), purity: 95%, LC / MS: C = 1.255 (system: 30 to 60% ΑCN for 1.5 min , NuregSh ΒΌ8), purity: 98%, MS: 417 (M + 1). ^! H-NMR (270 MHz, CH ₃ OH-th ₄ ) δ ppm 1.18 (d, ^ = 6.86 Hz, 6H), 2.83 (m, 2H), 3.52 (m, 4H), 4.00 (m, 4H), 7.14 (m, 3H ), 7.75 (d, ^ = 6.60Hz, 1H), 8.02 (m, 1H).

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

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 E1OAc (100 ml) and washed with brine (2 x 50 ml). The organic phase is dried SchA ₂ 8O ₄ ) and concentrated. The crude intermediate was purified by silica column chromatography using E1OAc / n-pentane (1: 1) as an eluent. The intermediate was dissolved in E1OAc / MeOH 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 NMR (DMSO-a ₆ , 25 ° C, 270.17 MHz) δ 10.61 (br s, 1H), 9.23 (br s , 2H), 8.13 (d, ^ = 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 (E81 +) 399 (M + H).

- 29 008835

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

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 25.6 mg. ¹ H-NMR (270 MHz, DMSO-to 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-to 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. 4- (4-Methylpiperazin-1-yl) -I- [1- (1-naphthyl) ethyl] thieno [3,2-c] pyridin-2sulfonamide hydrochloride

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 20.1 mg. ^! 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-to 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. ^! 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 the solvent signal); 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

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-a 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 [3,2s] 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-ae) 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-1ylethyl) 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. ^! H-NMR (270 MHz, DMSO-a 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

- 30 008835 (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); LCMS 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-a 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. 'H-NMR (270 MHz, DMSO-a 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-2sulfonamide

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. Я-NMR (270 MHz, CH ₃ OH-a 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. Hydrochloride Y- (2,4-difluorophenyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-2sulfonamide

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-a 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-Y- [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-a 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-a 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-2sulfonamide

The synthesis is carried out essentially in accordance with the method of method H-b. Yield: 7.7 mg (3.6%). ¹ NNMR (270 MHz, CH ₃ OH-a 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-2sulfonamide

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-a 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), 7.30-

7.29 (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 method of method Hb from tert-butyl ether 4 [2- (3,4-dihydro-1H-isoquinolin-2-sulfonyl) thieno [3,2-c] pyridin-4-yl] piperazine-1-carboxylic acid (0.235 mmol, 1 equiv.). Yield: 4.0 mg. LC / MS: ΐ _κ = 0.801 (system: from 30 to 60% ASA for 1.5 min,

- 31 008835

Nuregay Βϋδ), 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 procedure of method Hb from 4 [2- (2-thiophen-2-yl-ethylsulfamoyl) thieno [3,2-c] pyridin-4-yl] piperazine-1-carboxylic acid tert-butyl ester (0.235 mmol, 1 equiv.). Yield: 8.7 mg. LC / MS: 1 ^ = 0.430 (system: from 30 to 60% ASA for 1.5 min, NuregSh Βϋδ), purity: 93%. MS: 409 (M + 1). Ή-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 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] piperazin-1- carboxylic acid (0.112 mmol, 1 equiv.), which is used as thienopyridine in method C. Yield: 14.7 mg. LC / MS: 1B = 0.610 (system: from 30 to 60% ASA for 1.5 minutes, UMS), purity: 92%. MS: 469 (M + 1). Ή-NMR (270 MHz, DMSO-sG) 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 tert-butyl ether 4 (2-phenethylsulfamoylthieno [3,2-c] pyridin-4-yl) piperazine-1-carboxylic acid (0.112 mmol, 1 equiv.). Yield: 3.8 mg. LC / MS: 1 ^ = 0.410 (system: 30 to 60% ASA for 1.5 minutes, 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-2sulfonic acid

The synthesis is carried out essentially in accordance with the method of method Hb from 4 [2- (2,6-diethylphenylsulfamoyl) thieno [3,2-c] pyridin-4-yl] piperazine-1-carboxylic acid tert-butyl ester (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-E 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. 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 tert-butyl ether 4 [2- (3-phenylpropylsulfamoyl) thieno [3,2-c] pyridin-4-yl] piperazine-1-carboxylic acid (0.112 mmol, 1 equiv.). Yield: 13.0 mg. LC / MS: 1 ^ = 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 4-piperazin-1-ylthieno [3,2-c] pyridin-2sulfonic acid

The synthesis is carried out essentially in accordance with the method of method Hb from tert-butyl ether 4 [2- (3,3-diphenylpropylsulfamoyl) thieno [3,2-c] pyridin-4-yl] piperazine-1-carboxylic acid (0.112 mmol, 1 equiv.). Yield: 14.4 mg. LC / MS: 1 ^ = 1.109 (system: 30 to 60% ASA for 1.5 minutes, UMS), purity: 93%. MS: 493 (M + 1). Ή-NMR (270 MHz, DMSO-b 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 [3,2c] 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 ^ = 0.364 (system: 30% to 60% ASA for 1.5 minutes, UMS), purity: 91%. MS: 472 (M + 1). Ή-NMR (270 MHz, CH ₃ OH-b 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).

- 32 008835

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 method 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:! _K = 0.771 (system: from 30 to 60% ASA for 1.5 min, UMS), purity 91%. MS: 457 (M + 1). Ή-NMR (270 MHz, CH ₃ OH-b 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:! _K = 0.930 (system: from 30 to 60% ASA for 1.5 minutes, UMS), purity: 95%. MS: 417 (M + 1) Ή-NMR (270 MHz, CH ₃ OH-b 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 = 6.60Hz, 1H), 8.14 (s, 1H).

Intermediate 55. Tert-Butyl-4- (3 - {[((3-ethylphenyl) amino] sulfonyl} thieno [3,2c] 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 = 7.5 Hz, 3Н), 1.48 (s, 9Н), 2.47 (q, 1 = 7.7 Hz, 2Н ), 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 (Ε8Ι +) t / ζ 503.2 (M + H); HPLC 97%, CT: 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-b 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, 0 = 6.0 Hz, 1H), 8.36 (d, 1 = 6.0 Hz, 1H); 8.49 (s, 1H). MS (Ε8Ι +) t / ζ 403.2 (M + H) ⁺ . HPLC 95%, CT: 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-butyl piperazine-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 H2O 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%. CT: 3.27 min. (5-99% MECA for 3 minutes). ¹ H-NMR (400 MHz, CH 3 OH-b4) δ 1.48 (s, 9H), 3.21 (br s, 4H), 3.71 (s br, 4H), 7.61 (d, 1 = 5.6 Hz, 1H), 7.72 (s, 1H), 8.08 (d, 1 = 5.6 Hz, 1H). MS (Ε8Ι +) 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 a solid off-white solid 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-b ₄ ) δ 1.48 (s, 9H), 3.22 (br s, 4H), 3.72 (s br, 4H), 7.60 ( d, 1 = 5.5 Hz, 1H), 8.06 (d, 1 = 5.5 Hz, 1H), 8.14 (s, 1H). MS (Ε8Ι +) t / ζ 384.0 (M + H) ⁺ . HPLC CT: 2.62 min. (5-99% MECA for 3 minutes).

Intermediate Product 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, 7.06 mmol (3.126 g crude mixture product)) in DCM (40 ml) at 0 ° C add Yxlorosuccinimide (1.338 g, 10.0 mmol). 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. Combined Organic Wash Extracts

- 33 008835 is saturated with brine and dried over MgO 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%). 'H-NMR (400 MHz, CH ₃ OH-b ₄ ) δ 1.47 (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 (Ε8Ι +) t / ζ 418.2 (M + H) ⁺ ; HPLC 92%, I _t : 3.76 min. (5-99% MeCl for 3 min).

Intermediate 59. tert-Butyl-4- (3 - {[((4-isopropylphenyl) amino] sulfonyl} thieno [3,2c] pyridin-4-yl) piperazin-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). 'H-NMR (400 MHz, ΓΌΟ,) δ 1.12 (d, 1 = 7.0 Hz, 6H), 1.47 (s, 9H), 2.76 (sept, 1 = 6.9Hz, 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 (Ε8Ι +) t / ζ 517.2 (M + H) ⁺ ; HPLC 97%, I _t : 4.01 min. (5-99% ΜεΟΝ for 3 minutes).

Example 78. L- (4-Isopropylphenyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-3sulfonamide hydrochloride

The expected product is obtained from tert-butyl 4- (3 - {[((4-isopropylphenyl) amino] sulfonyl} thieno [3,2s] 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. 'H-NMR (400 MHz, CH ₃ OH-b ₄ ) δ 1.16 (d, 1 = 7.0 Hz, 6H), 2.81 (sept, 1 = 6.8 Hz, 1H), 3, 59 (br. 8H), 7.00 (d, 1 = 8.0 Hz, 2H), 7.10 (d, 1 = 8.0 Hz, 2H), 8.07 (br. 1H ), 8.37 (s br., 1H), 8.50 (s, 1H). MS (Ε8Ι +) w / ζ 417.2 (M + H) ⁺ ; HPLC 94%, I _t : 3.14 min. (5-99% MeCl for 3 min).

Example 79. L- (4-methylphenyl) -4- (pyrrolidin-3-yloxy) thieno [3,2-c] pyridin-2sulfonamide hydrochloride

4-chloro-1 \ G- (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%). 'H-NMR (270 MHz, CH ₃ OH-b ₄ ) δ ppm 8.09 (s, 1H), 7.71 (d, 1 = 6.93 Hz, 1H), 7.46 (d, 1 = 6.93 Hz, 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 (M-H) ⁺ ; purity (HPLC) 99%.

Example 80. Hydrochloride L- (4-methylphenyl) -4- (piperidin-4-yloxy) thieno [3,2-c] pyridin-2sulfonamide

The synthesis is carried out essentially in accordance with the procedure for the preparation of N- (4 methylphenyl) -4- (pyrrolidin-3-yloxy) thieno [3,2-c] pyridin-2-sulfonamide hydrochloride. Yield: 16.2 mg (22.7%). ^! Η NMR (270 MHz, CH ₃ OH-b 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, ZN), 2.06-2.03 (m, 2H), 2.01-1.71 (m, 2H); LC-MS 404 (ΜΗ) ⁴ ; purity (HPLC) 99%.

Example 81. Hydrochloride] I- (2,3-difluorobenzyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-2sulfonamide

Yield: 74.4 mg (39.2%). 'H-NMR (270 MHz, CH ₃ OH-b ₄ ) δ ppm 8.10-8.03 (m, 2H), 7.81 (d, 1 = 6.68 Hz, 1H), 7.16-7.05 (m, ZN), 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. M- (3-chlorobenzyl) -4-piperazin-1-ylthieno [3,2-c] pyridin-2-sulfonamide hydrochloride

Yield: 74.4 mg (44.7%). 'H-NMR (270 MHz, CH ₃ OH-b ₄ ) δ ppm 8.04-8.01 7.85 (d, 1 = 6.93 Hz, 1H), 7.22-

7.15 (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%.

Scheme 6

Explanations for Scheme 6: ί) amines containing a protective BOC group (I ⁴ ), K ₂ CO ₃ , DMSO; i) thiophenols (Y'-BN), Cu ₂ (1) O, DMF; ίίί) ΝηΟΑο. 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%. 'H-NMR (270 MHz, COC1 ₃ ) δ 1.48 (s, 9H),

-34008835

1.52-1.63 (m, 1H), 3.42-3.47 (m, 4H), 3.61-3.64 (m, 4H), 7.22 (dd, 1 = 5.4 , 1 Hz, 1H), 7.35 (d, 1 = 1 Hz, 1H), 8.04 (d, 1 = 5.4 Hz, 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, СОСР) 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), v / ζ = 411.97 (M + H).

Thiophenol Binding (Method M)

The intermediate product 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), powdered KOH (0.084 g, 1.5 mmol) and Cu ₂ (1) O (0 , 1 g, 0.75 mmol) is mixed with DMF (1 ml) and a solution of benzenediol (0.016 g, 1.5 mmol) in DMF (1 ml) is added. The reaction mixture was heated to 120 ° C and held 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%. Ή-NMR (270 MHz, C1) C1 _; ) δ 1.37 (s, 4.5H), 1.43 (s, 4.5H), 1.972.10 (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 No. OAc (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 (MdO ₄ ) and the solvent was evaporated, yielding 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). Я-NMR (270 MHz, SES1 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 = 5.4 Hz, 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-s] pyridine hydrochloride tert-butyl-4- (2-phenylsulfonyl) thieno [3,2-s ] 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%). Ή-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 4 Hz, 1H), 8.11 (dd, 1 = 5.4, 1 Hz, 1H), 8.41 (d, 1 = 1 Hz, 1H), v / ζ = 374.09 (M + H -CH1).

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. Я-NMR (270 MHz, SES1 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). 111 // 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), NOAc (0.5 g) in NaOH (2 ml, followed by reverse phase chromatography (40 ^ 70)), 6 mg of product are obtained. Yield 17%, purity 98%). Я-NMR (270 MHz, СОСР) δ 1.32 (s, 9Н), 1.35 (s, 9Н), 2.05-2.15 (m, 2Н), 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). ι / ζ = 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 gave

- 35 008835 NIU 0.022 g (95% purity) of the product. Я-NMR (270 MHz, SIS) 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, 1Hz, 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 [3,2c] pyridin-4-yl) -1,4-diazepan-1-carboxylate ( 0.022 g, 0.047 mmol), oxone (0.11 g, 0.19 mmol) and NaOAc (0.5 g) in NaO (2 ml), followed by reverse phase chromatography (40 ^ 70), 9 mg of product are obtained ( yield 38%, purity 92%). Ή-NMR (270 MHz, C1) C1 _; ) δ 1.35 (s, 9H), 2.08-2.20 (m, 2H), 2.33 (s, 6H),

3.52-3.59 (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

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%. Ή-NMR (270 MHz, SIS) 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, 1Hz, 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). m ^ = 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-4-yl) -

1,4-diazepane-1-carboxylate (0.055 g, 0.112 mmol), oxone (0.27 g, 0.448 mmol) and NaOAc (0.5 g) in NaO (2 ml), followed by reverse phase chromatography (40 ^ 70), 15 mg of product are obtained. Yield 26%, purity 93%. Ή-NMR (270 MHz, C1) C1 _; ) δ 1.34 (s, 9H), 2.06-2.10 (m, 2H), 3.48-3.62 (m, 2H), 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). m ^ = 524.22 (M + H);

Example 84. 4- (1,4-Diazepan-1-yl) -2 - [(3,4-dichlorophenyl) sulfonyl] thieno [3,2-c] pyridine 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 solid beige in accordance with the general methods A and B described above. Ή-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, obtaining 12 mg of the target product (yield 90%, purity 95%). Ή-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 [3.2s] 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-a 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 obtained from tert-butyl-4 - ([2- (3,4dimethylphenyl) 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 target product (yield 88%, purity 89%). Я-NMR (270 MHz, CH ₃ OH-a 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).

- 36 008835

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

Trifluoroacetic acid (1 ml) is slowly added to a 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. ¹ H-NMR (270 MHz, CH ₃ OH-a ₄ ) δ 8.41 (s, 1H), 8.06-7.99 (m, 2H), 7.92 (d, ^ = 6.86 Hz , 1H), 7.87-7.80 (m, 2H), 7.66 (d, t = 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 the starting material has been consumed, two peaks in the chromatogram indicate the presence of the product and Ν-oxide. After purification by preparative HPLC, the resulting Boc product was 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 with 8Uas. Yield 18%, purity (HPLC) = 98%, t / ζ 360.0 (M + H). Ή-NMR (270 MHz, CH ₃ OND ₄ ) δ ppm 3.56 (m, 4H), 4.08 (m, 4H), 7.68 (m, 4H), 7.77 (dd, ^ = 6.60, 0.79Hz, 1H), 8.04 ( d, .Ι6Γ3 Hz, 1Н), 8.12 (m, 2Н), 8.39 (d, ^ = 0.79 Hz, 1Н).

Example 90. 2- (3-Methoxybenzenesulfonyl) -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride 4- [2- (3-methoxyphenylsulfanyl) thieno [3,2-c] pyridine tert-butyl ester -4-yl] piperazin-1 carboxylic acid (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. ¹ H-NMR (270 MHz, SESE) 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); MSt / 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. ¹ H-NMR (270 MHz, CO ₃ , OE) δ 8.31 (s, 1H), 8.09 (d, ^ = 6.33 Hz, 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] pyridine tert-butyl ester -4-yl] piperazin-1 carboxylic acid (100 mg, 42%) is 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 the 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, ^ = 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. Ή-NMR (270 MHz, SPS1 ₃ ) δ 1.48 (s, 9H), 3.67-3.91 (m, 11H), 7.01 (d, ^ = 8.97 Hz, 2H), 7 27-7.37 (m, 1H); 7.93 (d, t = 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 (С'П ₃ ОО) δ 8.25 (s, 1Н), 8.09-7.89 (m, 3Н), 7.69 (d, ^ = 6.33 Hz, 1Н), 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 [3,2c] 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 min and H2O2 (100 μl) was added. 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-f) δ ppm 9.79 (s, 1H), 8.56 (s, 1H), 8.35 (d, ^ = 8.44 Hz, 2H), 8.12-8.05 (m, 3H), 7.79 (d, .1 6% 3 Hz, 1H), 3.98-3.96 (m, 4H), 3.32-3.31 (m, 4H); LC-MS 428 (M-H) ⁺ ; purity (HPLC) 95%

Example 93. 2 - [(2-tert-Butylphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride. The title compound was prepared according to method M-O. Yield: 10.6 mg (6.3%) of 2 - [(2-tert-butylphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine hydrochloride. Ή-NMR (270 MHz, DMSO-a 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%.

- 37 008835

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

The title compound was prepared according to method M-0. 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 pH ~ 6 by adding sodium oxide acetate and 2 - [(4-tert-butylphenyl) thio] -4 is added to the solution piperazin-1ylthieno [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%). Я-NMR (500 MHz, CH ₃ 0H-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%.

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

The title compound was prepared according to method M-0. 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 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 0 (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 0 ₂ (100 μl) was added and the mixture was stirred at room temperature overnight. 2M Na0H 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 method M-0. 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 2 - [(2-methoxyphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2-c] pyridine

The title compound was prepared according to method M-0. 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. Hydrochloride 2 - [(2,4-dimethoxyphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2с] pyridine

The title compound was prepared according to method M-0. 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 [3,2s] pyridine hydrochloride

The title compound was prepared according to method M-0. 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. Hydrochloride 2 - [(2,5-dimethylphenyl) sulfonyl] -4-piperazin-1-ylthieno [3,2с] pyridine

The title compound was prepared according to method M-0. 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%.

- 38 008835

Example 103. Hydrochloride 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-sr.) 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-Vi1l, diethyl ether, and) 8O 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 Ν 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. 8O ₂ (gas) was bubbled through the reaction mixture for 1 hour. After bubbling stopped, the reaction mixture stirred for one hour at -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. Ή-NMR (270 MHz, DMSO-f) 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 ζ))

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 HC1 / diethyl ether (1 ml, 1.0 M) at room temperature and stirred for 16 hours. Removal of 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-4yl] 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 ζ). Yield: 0.009 g (7% after two stages). Ή-NMR (300 MHz, СОС1 ₃ ) δ 8.14 (d, 1 = 5.5 Hz 1Н), 7.27-7.40 (m, 5Н), 7.15-7.21 (m, 2Н) ), 4.45 (s, 2H), 3.503.56 (m, 4H), 3.40-3.45 (m, 4H), 1.49 (s, 9H); MS (Ε8Ι +) for С ₂₃ Н ₂₇ М ₃ О ₄ 8 ₂ ш / ζ 474 (М + Н) ⁺ . HPLC 77%. R _t: 3.93 min (ASEZ C8 50x4 mm, 5-50% acetonitrile for 3 min).

Intermediate 72. tert-Butyl-4- (2 - {[4- (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 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 ζ) Ε. Yield: 0.02 g (16% for two stages). The solid is beige. Ή-NMR (300 MHz, СОС1 ₃ ) δ 8.16 (d, 1 = 6 Hz, 1Н), 7.53-7.61 (d, 1 = 9 Hz 2Н), 7.49 (s, 1Н) 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 (Ε8Ι +) for Ε ₂₄ Η ₂₆ Ε ₃ Ν ₃ Ο ₄ 8 ₂ t / ζ 542 (M + H) ⁺ ; HPLC 71%, I _t : 4.07 min (ASEZ 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 ζ). Yield: 0.023 g (10% for two stages).

-39008835

The solid is beige. Ή-NMR (300 MHz, CPC1 ₃ ) 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 (Ε8Ι +) for C ₂₃ H ₂₆ Br = 0 ₄ 8 ₂ m / ζ 554 (M + H) ^+; HPLC 77%, I: 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 [3,2c] 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 p. Yield: 0.023 g (10% for two stages). The solid is beige. Ή-NMR (300 MHz, CPC1 ₃ ) 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 (Ε8Ι +) for C ₂₄ H ₂₆ P ₃ ^ 0 ₄ 8 ₂ t / ζ 542 (M + H) ⁺ ; HPLC 85%, I: 2.13 min (UMS 0-8 Ar, 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 reacted with tert-butylpiperazine-1-carboxylate in accordance with method p. Yield: 0.01 g (4% for two stages). The solid is beige. Я-NMR (300 MHz, CPC1 ₃ ) δ 8.16 (d, 1 = 5.8Hz, 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 C ₂₅ H ₂₅ E ₆ No. _! 0 ₄ 8 ₂ t / ζ 610 (M + H) ⁺ ; HPLC 73%, I: 2.36 min (UMS 0-8 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-butyl piperazine-1- carboxylate in accordance with method p. Yield: 0.005 g (3% for two stages). The solid is beige. Я-NMR (300 MHz, CPC1 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 ₂ ^ ₃ 0 ₄ 8 ₂ t / ζ 488 (M + H) ⁺ ; HPLC 69%, I: 2.06 min. (UMS 0–8 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 subjected interaction with tert-butylpiperazine-1-carboxylate in accordance with method p. Yield: 0.019 g (7.5% for two stages). The solid is beige. Ή-NMR (300 MHz, CPC1 ₃ ) 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 С ₂₄ Н ₂₅ С1Е; No. 0 ₄ 8 ₂ t / ζ 576 (М + Н) ⁺ . HPLC 74%, I: 2.30 min (UMS 0-8 Ar, 33x3 mm, 10-90% 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 3.4bis (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: 0.014 g (6% for two stages). The solid is beige. Я-NMR (300 MHz, CPC1 ₃ ) 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 С ₂₃ Н ₂₅ Е ^ ₃ 0 ₄ 8 ₂ t / ζ 510 (М + Н) ⁺ . HPLC 64%, I: 2.02 min (UMS 0-8 Ar, 33x3 mm, 10-90% acetonitrile for 3 min).

Intermediate 79. tert-Butyl-4- {2 - [(3,5-dimethoxybenzyl) 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 3,5 dimethoxybenzyl 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. Yield: 0.02 g (10% for two stages). The solid is beige. Я-NMR (300 MHz, CPC1 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 C ₂₅ H ₃₁ No. 0 ₆ 8 ₂ t / ζ 534 (M + H) ⁺ . HPLC 69%, YAG 1.99 min (UMS 0–8 Ar, 33x3 mm, 10-90% acetonitrile for 3 min).

Example 104. 4- (piperazinyl) -2- (3-methoxybenzylsulfonyl) thienopyridine

A mixture (1: 1) of lithium 4-chlorothienopyridin-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

- 40 008835 at this temperature over 2 hours. BOC-piperazine (546 mg, 2.94 mmol) was added to the mixture and the reaction mixture was heated at 110 ° C for 1.5 hours. The solvent was removed and the crude product was purified by preparative HPLC to obtain 17.4 mg of 4- (4-tert-butyloxycarbonylpiperazinyl) -2- (3methoxybenzylsulfonyl) 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- (3methoxybenzylsulfonyl) thienopyridine. ¹ H-NMR (SP ₃ OD / E ₂ 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), 3.64-3 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-4yl] 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 in accordance with method O. Yield: 0.00 g of product (7% for two stages). The solid is beige. ¹ H-NMR (300 MHz, SES13) 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), 3.50-3.56 (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).

Example 105. 2- (Benzylsulfonyl) -4-piperazin-1-ylthieno [3,2-s] pyridine hydrochloride tert-Butyl-4- [2- (benzylsulfonyl) thieno [3,2-s] pyridin-4-yl ] piperazine-1-carboxylate (0.01 g, 0.02 mmol) is treated in accordance with method K to obtain the desired product as a white solid. Yield: 0.009 g (100%). Я-NMR (300 MHz, DMSO-a 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 (Ε8Ι +) for С1 ₈ Н ₁₉ Н ₃ О ₂ 8 ₂ , С1 Н t / ζ 374 (М + Н) ⁺ . HPLC 90%, R _t 2.91 min (C8 ASE3 50h4 mm, 5-50% acetonitrile for 3 min).

Intermediate 81. tert-Butyl-4- (2 - {[4- (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 4 (trifluoromethyl) benzyl bromide (0.59 mmol) in accordance with method P described above, and then reacted with tert- butylpiperazine-1-carboxylate according to method O. 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), 7.53-7.61 (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), 3.363.49 (m, 4H), 1.49 (s 9H); MS (Ε8Ι +) for С24Н26Б3Ы3О482 t / ζ 542 (M + H) ⁺ . HPLC 71%, CT 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 [3,2c] pyridine tert-butyl-4- (2 - {[4- (trifluoromethyl) benzyl] hydrochloride] sulfonyl} thieno [3,2-c] pyridin-4-yl) piperazin-1-carboxylate (0.02 g, 0.03 mmol) is treated in accordance with method K to obtain the desired product as a white solid. Yield: 0.014 g (100%). The solid is white. ¹ H-NMR (300 MHz, DMSO-a 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 (Ε8Ι +) for С1 ₉ Н ₁₈ Б ₃ Ы ₃ О ₂ 8 ₂ , С1 Н t / ζ 442 (М + Н) ⁺ . HPLC 90%, CT 3.53 min (ACE3 C8 50x4.6 mm, 5-50% acetonitrile for 3 min).

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 O. Yield: 0.023 g (10% for two stages). The solid is beige. ¹ H-NMR (300 MHz, SES13) 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 (Ε8Ι +) for С23Н26ВгЫ3О482 t / ζ 554 (M + H) ⁺ . HPLC 77%, CT 4.07 (ACE3 C8 50x4.6 mm, 5-50% acetonitrile for 3 minutes).

Example 107. Hydrochloride 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} piperazin-1-carboxylate (0.023 g, 0.04 mmol) is treated in accordance with method K to obtain the desired product as a white solid. Yield: 0.013 g (67%). The solid is white. ¹ H-NMR (300 MHz, DMSO- ₆ ) δ 9.19 (s, 1H), 8.18 (d, 1 = 6 Hz, 1H), 8.05 (s, 1H), 7.70 (d, 1 = 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 (Ε8Ι +) for С1 ₈ Н ₁₈ ВгЫ ₃ О ₂ 8 ₂ . C1 N t / ζ 452 (M + H) \ HPLC 90%, K _t 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 3.4bis (trifluoromethyl) benzyl bromide (0.59 mmol) in accordance with method P described above, and

- 41 008835 are then reacted with tert-butylpiperazine-1-carboxylate in accordance with method p. Yield: 0.014 g (6% for two stages). The solid is beige. Я-NMR (300 MHz, SES1 ₃ ) 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 С ₂₃ Н ₂₅ Е ₂ Н ₃ 0 ₄ 8 ₂ t / ζ 510 (М + Н) ⁺ . HPLC 64%, K 2.02 min (UMS 0-8 Ar, 33x3 mm, 10-90% acetonitrile for 3 min).

Example 108. Hydrochloride 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 [3.2s] pyridin-4-yl} piperazine-1-carboxylate according to method K. Yield: 0.068 g (100%). The solid is white. Ή-NMR (300 MHz, DMSO-b ₆ ) δ 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 (Ε8Ι +) for С1 ₈ Н ₁₇ Б ₂ Ы ₃ 0 ₂ 8 ₂ , С1 Н t / ζ 410 (М + Н) ⁺ . HPLC 90%, K 1.07 min (UMS 0-8 Ar, 33x3 mm, 20-50% acetonitrile for 1.5 min).

Example 109. Hydrochloride 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 protective BOC group is removed in accordance with method K. Yield: 0.024 g (12% for three stages). The solid is white. Ή NMR (300 MHz, DMSO-b ₆ ) 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 С ₁₈ Н ₁₈ ВгЫ ₃ 0 ₂ 8 ₂ , С1 Н t / ζ 454 (М + Н) ⁺ . HPLC 90%. To 1.24 min (UMS 0–8 Ar, 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) 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 reacted with tert-butylpiperazine-1-carboxylate in accordance with method p. Yield: 0.01 g (4% for two stages). The solid is beige. Я-NMR (300 MHz, SES1 ₃ ) 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 C ₂₅ H ₂₅ N ₆ B 0 _{3 4} 8 ₂ m / ζ 610 (M + H) ^+. HPLC 73%, K 2.36 min (UMS 0-8 Ar, 33x3 mm, 10-90% acetonitrile for 3 min).

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

Yield: 0.024 g (100%). The solid is white. Ή-NMR (300 MHz, DMSO-b ₆ ) 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), 3.243.33 (m, 4H); MS (Ε8Ι +) for C ₂₀ H ₁₇ B ₆ S ₃ 0 ₂ 8 ₂ . C1 H t / ζ 510 (M + H) ⁺ . HPLC 90%, K 1.08 min (UMS 0-8 Ar, 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-butyl piperazine-1- carboxylate in accordance with method p. Yield: 0.005 g (3% for two stages). The solid is beige. Я-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 S ₃ 0 ₄ 8 ₂ t / ζ 488 (M + H) ⁺ . HPLC 69%, K 2.06 min (UMS 0-8 Ar, 33x3 mm, 1090% 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 [3,2c] pyridin-4-yl} piperazine-1-carboxylate in accordance with method K. Yield: 0, 05 g (75%). The solid is white. Я-NMR (300 MHz, DMSO-b 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 0 ₂ 8 ₂ . C1 H t / ζ 388 (M + H) ⁺ . HPLC 90%, K 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 subjected interaction with tert-butylpiperazine-1-carboxylate in accordance with method p. Yield: 0.019 g (7.5% for two stages). The solid is beige. Я-NMR (300 MHz, SES1 ₃ ) 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

- 42 008835 (s, 9H); MS (Ε8Ι +) for C ₂₄ H ₂₅ S1R ₃ N ₃ O ₄ 8 ₂ m / ζ 576 (M + H) ^+. HPLC 74%, K _T 2.30 min (UMS O118 Ar, 33x3 mm, 10-90% acetonitrile for 3 min).

Example 112. Hydrochloride 2 - {[5-chloro-2- (trifluoromethyl) benzyl] sulfonyl} -4-piperazin-1ylthieno [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. Я-NMR (300 MHz, DMSO-b ₆ ) 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 C1 ₉ H ₁₇ C1E ₃ N ₃ O ₂ 8 ₂ . C1 H t / ζ 476 (M + H) ⁺ . HPLC 90%, K _T 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 [3,2c] 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-butyl piperazine- 1-carboxylate in accordance with method p. Yield: 0.02 g (10% for two stages). The solid is beige. Я-NMR (300 MHz, SESE) 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%, K _T 1.99 min (UMS OE8 Ar, 33x3 mm, 10-90% acetonitrile for 3 min).

Example 113. Hydrochloride 2 - [(3,5-dimethoxybenzyl) sulfonyl] -4-piperazin-1-ylthieno [3,2с] 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 K. Yield: 0.01 g (62%). The solid is white. Я-NMR (300 MHz, DMSO-b ₆ ) δ 9.09 (s, 1H), 8.18 (d, 1 = 6.7 Hz, 1H), 8.02 (s, 1H), 7.69 (d, 1 = 6.7 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 (Ε8Ι +) for С ₂₀ Н ₂₂ Н ₃ О ₄ 8 ₂ t / ζ 434 (М + Н) ⁺ . HPLC 90%, K _T 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 method RC to obtain 12.4 mg of the expected 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 was used according to method PK to obtain 4.8 mg of the expected product. Ή-NMR (270 MHz, CH ₃ OH-b 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. 1- (4-Pyrrolidin-1-yl-phenyl) -2 - [(4-piperazin-1-ylthieno [3,2-c] pyridin2-yl) sulfonyl] ethanone hydrochloride

2-Bromo-1- (4-pyrrolidin-1-ylphenyl) ethanone was used in accordance with method PK to obtain 19.6 mg of the expected product. Ή-NMR (270 MHz, CH ₃ OH-b 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 according to method PK to obtain 9.0 mg of the expected product. Ή-NMR (500 MHz, CH ₃ OH-b ₄ ) δ ppm 1.16 (t, 1 = 7.06 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. ¹ H-NMR (270 MHz, CH 3 OH-b4) 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-b 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, 2.24Hz, 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-b 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 = 7.39 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.

- 43 008835

Scheme 8

K4

Explanations for Scheme 8: ί) Ethyl chloroformate, TEM, acetone, ΝηΝ ₃ : π) Βη ₃ Ν, DCM and diphenylether; ίίί) POC1 ₃ , ΝηΟΗ: ίν) amines containing a protective BOC group (B ⁴ ), K ₂ CO ₃ , DMSO; ν) ΝΗ ₂ (gas.), Na, ΝΗ ₄ Ο1, THF; νί) sulfonyl chloride (B ¹ ), ΝηΗ. THF; νίί) HC1 / diethyl ether, methanol.

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

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 No. 1Ν 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 prepared in accordance with publication procedure C. Oisgoss |: E. B1capd1; 1-M, Yuk! E; I. MnreIeg; Tsjaysbgop. Yo1. 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) w / ζ 225 (w + H); Я-NMR (DMSO-SB, 25 ° C, 270.16) δ 10.84 (br s, 1H), 7.43-7.14 (m, 6H), 7.00 (d, 1 = 7.12 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. ΝηΟΗ (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), K ₂ CO ₃ (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. An additional amount of 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 (СО ₃ ОО) δ 7.87-7.85 (m, 1Н), 7.25-7.24 (m, ЗН), 7.04-6.98 (m, ЗН), 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-s ] pyridin-4-yl) piperazin-1-carboxylate (383 mg, 0.488 mmol) was dissolved in THF (6 ml) and liquid ammonia (10 ml) in a 30 ml reactor. Xa (67 mg, 2.93 mmol) was added in several portions, and the reaction mixture turned violet. After 30 min, ΝΗ ₄ α (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. Ή-NMR

-44008835 (CO ₃ OE) 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) piperazine-1 carboxylate (total 1.391 mmol, 1 equiv.) Was dissolved in THF (14 ml) and transferred into vials 10 ml, equipped with threaded caps. A suspension of NaH (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-4yl] piperazine-1-carboxylate

Recrystallization after removal of the BOC protecting group results in 16 mg (56%) of the product. Ίΐ-NMR (SPS1 ₃ ) δ 8.03-8.01 (m, 1H), 7.89-7.86 (m, 2H), 7.57-7.39 (m, 5H), 6.67 -6.64 (m, 1H), 3.553.52 (m, 8H), 1.47 (s, 9H); MS (Ε8Ι) 443 (M + H) ⁺ ; purity (HPLC, ACE column) 95%.

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

Purification by preparative HPLC after removal of the BOC-protecting group yields 4 mg (11%) of the product. Ή-NMR (СОС1 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 (Ε8Ι) 377 (M + H) ⁺ ; purity (HPLC, ACE column) 95%.

Intermediate 95. tert-Butyl-4- {1 - [(4-methoxyphenyl) sulfonyl] -1H-pyrrolo [3,2c] 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. Ί Ι-NMR (СОС1 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 (Ε8Ι) 473 (M + H) ⁺ ; purity (HPLC, ACE column) 95%.

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

Purification by preparative HPLC after removal of the BOC-protecting group affords 8.6 mg (25%) of the product. ¹ H-NMR (SPS1 ₃ ) δ 8.14-8.11 (m, 1H), 8.01-7.94 (m, 2H), 7.89-7.72 (m, 3H), 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 (Ε8Ι) 511 (M + H) ⁺ ; purity (HPLC, ACE column) 95%.

Intermediate 97. tert-Butyl-4- {1 - [(2-methoxy-5-methylphenyl) sulfonyl] -1Npyrrolo [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. ¹ H-NMR (SPS1 ₃ ) δ 7.95-7.92 (m, 2H), 7.74-7.72 (m, 1H), 7.44-7.40 (m, 2H), 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 (Ε8Ι) 487 (M + H) ⁺ ; purity (HPLC, ACE column) 95%.

Example 121. 4-piperazin-1-yl-1- (toluene-4-sulfonyl) -1H-pyrrolo [3,2-c] pyridine p-toluenesulfonyl chloride hydrochloride (24.6 mg) was added to tert-butyl-4- (1H-pyrrolo [3,2-c] pyridin-4yl) piperazine-1-carboxylate to give the title compound (4.3 mg). LC / MS _t I: 1,374 (system: Mesa 10-40% for 1.5 min, ACE C8), purity 91%. MS: 357 (M + 1). ¹ H-NMR (ΟΟ ₃ ΟΌ) 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 [3.2s] pyridine hydrochloride

3-Chloro-2-methylbenzenesulfonyl chloride (29.0 mg) was added to tert-butyl-4- (1H-pyrrolo [3,2s] pyridin-4-yl) piperazine-1-carboxylate to give the title compound (6, 3 mg). LC / MS R _t: 1.563 (system: Mesa 10-40% for 1.5 min, ACE C8), purity 96%. MS: 392 (M + 1).

Example 123. 1- (3,4-Dimethoxybenzenesulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3.2s] pyridine hydrochloride

3,4-Dimethoxybenzenesulfonyl chloride (30.5 mg) was added to tert-butyl 4- (1H-pyrrolo [3,2c] pyridin-4-yl) piperazine-1-carboxylate to give the title compound (8.5 mg) ) LC / MS R _t: 1.284 (system: Mesa 10-40% for 1.5 min, ACE C8), purity 92%. MS: 404 (M + 1). ¹ H-NMR (C1TO1)) δ 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).

- 45 008835

Example 124. 4- (4-piperazin-1-ylpyrrolo [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 K. _t : 1.150 (system: 10-40% MECA for 1.5 min, ACE C8), purity 93%. MS: 369 (M + 1). Ή-NMR (SE 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 [3,2c] pyridine hydrochloride

4,5-Dichlorothiophen-2-sulfonyl chloride (32.4 mg) was added to tert-butyl-4- (1H-pyrrolo [3,2s] pyridin-4-yl) piperazine-1-carboxylate to give the title compound ( 0.3 mg). LC / MS K _t : 1.119 (system: 10-40% MECA 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 [3.2s] pyridine hydrochloride

2-Chloro-4-fluorobenzenesulfonyl chloride (29.5 mg) was added to tert-butyl-4- (1H-pyrrolo [3,2s] pyridin-4-yl) piperazine-1-carboxylate to give the title compound (2, 4 mg). LC / MS K _t : 1.361 (system: 10-40% MECA for 1.5 min, ACE C8), purity 90%. MS: 396 (M + 1). Ή-NMR (SE ₃ OE) δ ppm 3.51 (m, 4H), 4.08 (m, 4H), 7.23 (dd, 1 = 3.96, 0.49Hz, 1H), 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% MECA 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 [3.2s] 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% MECA for 1.5 min, ACE C8), purity 97%. MS: 483 (M + 1).

Example 129. 1- (4-Butylbenzenesulfonyl) -4-piperazin-1-yl-1H-pyrrolo [3.2s] pyridine hydrochloride

4-Y-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% MeCY for 1.5 min, ACE C8), purity 95%. MS: 400 (M + 1) Ή-NMR (SE 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 [3.2s] pyridine (4-phenoxybenzene) sulfonyl chloride hydrochloride (34.7 mg) was added to tert-butyl 4- ( 1H-pyrrolo [3.2s] pyridin-4-yl) piperazine-1-carboxylate to give the title compound (12.8 mg). LC / MS C _t : 1.839 (system: 10-40% MECA for 1.5 min, ACE C8), 95% purity. MS: 436 (M + 1). Ή-NMR (SE ₃ OE) 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 (Ε8Ι) 343.1 (M + H) ⁺ ; purity (HPLC, ACE column) 94%.

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

Purification by preparative HPLC after removal of the protective BOC group yields 4 mg (11%) of the product. MS (Ε8Ι) 377 (M + H) ⁺ ; purity (HPLC, ACE column) 96%.

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

Purification by recrystallization (MeOH / ether) after removal of the BOC protecting group affords 21 mg (67%) of the product. MS (Ε8Ι) 373 (M + H) ⁺ ; purity (HPLC, ACE column) 92%.

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

Purification by preparative HPLC after removal of the protective BOC group yields 10.3 mg (32%) of the product. MS (Ε8Ι) 387 (M + H) ⁺ ; purity (HPLC, ACE column) 95%.

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

Purification by preparative HPLC after removal of the protective BOC group yields 8.6 mg (25%) of the product. MS (Ε8Ι) 411 (M + H) ⁺ ; purity (HPLC, ACE column) 94%.

- 46 008835

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 νινο and ίη νίΐΓΟ, which are known in the art.

(a) 5-HT ₆ Binding Reaction

Experience to determine the binding affinity of 5-HT ₆ receptor is carried out on HEK293 cells transfected with 5-HT ₆ receptor using (3H) -b & 0 as labeled ligand according to the general method described in publications Voekk D.6. e1 a1. No. igoryagtas1o§u νο1. 36 (4/5) 713-720, 1997.

Materials

Cell culture

The HEK-293 cell line, transfected with the 5-HT ₆ receptor, is grown in Enlessoc MobSheb Wad1ec Mebst medium containing 5% dialyzed fetal bovine serum (61bcoc Vlb 10106-169), 0.5 mM sodium pyruvate and 400 μg / ml Opeyst (6 -418) (61bco VKSh0131-019). Cells are subcultured 1:10 twice a week.

Chemical substances

The radioligand [ ³ H] L8P 60-240 Ci / mmol obtained from AtegkNat RNagtas1aVu1es11 (Wisktkapkge, 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

The compounds are diluted in polypropylene 96-well plates with a U-shaped bottom Sok1ag (Sogshpd 1ps. Sok1ag, United States). Samples were incubated in the Raskagb OrPr1a1e incubator (Raskagb 1pkyitepr V.U., Ogoshpdep, Netherlands). The total amount of added radioligand is determined in Raskagb 24-well plates (Wageh, Raskagb EMgitepR W.U., Ogoshpdep, The Netherlands) in the presence of scintillation fluid Myugokst! ™ 20 (Raskagb Vukaepse, Mepbep, St, USA).

Buffer

The binding buffer consists of 20 mM HΕPΕ8, 150 mM No. C1, 10 mM MDCl ₂ and 1 mM RetL, pH 7.4.

Methods

Membrane preparation

Cells are grown to about 90% confluence on culture plates 24.5 x 24.5 x 6. The medium is aspirated and after washing with PB8, ice-cold, the cells are cleaned using 25 ml Tris buffer (50 mM Tris-HC1, 1 mM BETA, 1 mM ΕΘ ^, 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 / d 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 Po1u1gop homogenizer and bound to 8PA wheat seed agglutinin granules (Ategkyat IgE 8c1epsek, SagbggGG, 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 was carried out in accordance with the original 8PA method, with the difference that the membranes were obtained from HEK293 cells expressing the 5Ht ₆ human receptor, and not from HeLa cells (Όίπΐι OM, 2 ogogkk1 P6, 6111 68, 8сЫсЫе 8К, Лагокоп SG, 8шЬЬ М \ W. Uaibayop OG Nntap 5-HT ₆ Gesergyrgrkkeb and Nebse11 tarte: CaEiopop bibbidibib, cactiocodulocarum rbcbbbbbbpbbpbbbpbbpbbpbbpbbpbbbpbbpbbpbbpbbpbbpbbpbbpbbpbbpbbpbbpbbpbbpbbpbbpbbpbbpbbpbbpbbpbbpbbpbbpbbpbbpfbpbpfbpfbp. 27). The specific binding of [ ³ H] L8P is saturable, while the non-specific binding increases linearly with the concentration of the added radioligand. The [ ³ H] L8P bond has a high affinity for 5-HT ₆ receptors. The value of K _b , as established on the basis of four independent experiments, is 2.6 ± 0.2 nM.

The total binding at 3 nM [ ³ H] L8P, the concentration of the radioligand used in the comparative experiments, is usually 6000 Brit and the specific binding is more than 70%. 5-HT causes concentration-dependent inhibition of [ ³ H] L8P binding at average K ₁ values above 236 nM when tested on two different membrane preparations. The coefficient of variation of CS for three different experiments is 10% with average K1 values of 173 nM (8Ό30) and Gill coefficient (Н111) of 0.94 (8Ό0.09). The internal variation of the experiment is 3% (n = 4). The values of K ₁ for a limited set of control compounds with a known affinity for binding to the 5-HT6 receptor are presented in table. 7. All unlabeled ligands replace the specific binding of [ ³ H] L8P with concentration dependent on

- 47 008835 at once, although with different powers. 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 were determined according to the method ΒίοΚηά Ρτοΐείη Azza (MM Vgas1Gogs1 A πιρίά APS 5sp51Y \ with ιηείΐιοά ίοτ 11yu with | IAP Ia1 ίο η οί ppsgsschgat ςιιηηΐίΐίοδ οί ρτοΐείη ιιΐίΐίζίπβ Πιε ρπηοίρΙε οί rgoΙείη-άνε 6ίηάίη§ Aia1 Βίοοίιειη 1976.!;!. 72: 248-54). Bovine serum albumin is used as a standard.

Scintillation reading

Radioactivity is determined using a scintillation counter Rask gc1 TorSoshy ™ (Raskata ΙηδΙπιιηεηΚ Μεήάεη, CT, 118 A) 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 ,, is determined from non-linear regression analysis using equation 1. Lb represents the concentration of the unbound radioligand, and y represents the bound amount.

β TTX - 1m

B + + Κά (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 the specific binding of the radioligand by 50% is determined from non-linear regression analysis, and the value of K; calculated using the method [Syey§ US. Βίοοίιειη. Ryapiaso 1. 22. 3099-3108, 1973] in accordance with equation 2.

1C &

Κΐ ~ —D

(equation 2)

B is the concentration of the radioligand;

Cd - radioligand affinity (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 content in HEK293 cells expressing the 5-HT ₆ receptor (see Voebb c1 a1. (1997) No. 11passo1ou 36: 713-720). That is, HEK293 / 5-HT ₆ cells are seeded in 96 well plates coated with polylysine at a seeding density of 25,000 / well and grown in EMEM (Oi1esso'b Μοάίίίεά Ea§1e MccHp) (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 aspirated and replaced with 0.1 ml of the experimental medium (Naike Ba1aise 8a11 8O1u1uy solution containing 20 mM HEPE8, 1.5 mM isobutylmethylxanthine and 1 mg / ml bovine serum albumin). After adding test compounds dissolved in 50 μl of test medium, the cells are incubated for 10 min at 37 ° C in an incubator with 5% CO ₂ . The medium is again aspirated and the cAMP content is determined using a set of radioactive cAMP (Ashegeiash Ryapias 1a Βίοίοοίι. ΒΙΟΤΚ.ΑΚ KPA 559). The strength of the antagonists is quantified by finding the concentration that causes 50% inhibition of the increase in cAMP caused by 5-HT (at [5-HT] = 8 x EC ₅₀ ), using the formula 1C _{50> CO} g = 1C ₅ o / (1+ [5HT] / EC ₅ o).

The compounds of this invention have selective affinity for 5-HT ₆ receptors with values of K and 1C5o, _C ogg in the range from 0.5 nM to 5 μM or exhibit inhibition of [ ³ H] L8O> 20% at 50 nM and are antagonists, agonists or partial agonists in relation to 5HT ₆ . The compounds exhibit good selectivity for 5-HT1 _and 5-HT _2a, 5-HT _2b and 5-HT _2c.

(c) Experience in reducing food intake under ίη νίνη

A review of the effects of serotonin on food intake is presented in publication B1ieb11, 1.E. aps1 Na1ίοτά, 1.C.6. (1998) δετοίοηίη ас1 Αρρείίίε Ке§и1а1уп. 1shrysayop8 Gog Ιΐιε P11agtasooshchota1 TgsaOpsgP οί Оее8йу. ΟΝ8 ϋπι§8 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.

-48008835

In all studies used male mice (obese S57V / 6LZot ^LEP-ob field and suffering from leanness C57B1 / 6LZot; VopyyuIkdaap !, Oeptagk) aged 8-9 weeks with an average body weight of 50 g (for obese) and 25 g (for sufferers thinness). 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 / methanesulfonic acid, and a 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 Αΐζεΐ osmotic mini-pumps (Μοάεΐ 200 Yu, infusion rate of 8 μl / h) and fill them essentially in accordance with the recommendations of the technical manual Αΐζεΐ (А1га δοίεηНпс РгобисЕ. 1997; Т11сси \\ s5. Ε. Apb Wash, 8.1. Ail. Ed. 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). Zga 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 using scales equipped with a computer MsShsg To1sbo RV 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 electrospray mode of positive ions and the control of many reactions (Mi1br1e Yaasboyi Mopyopid). 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 with the help of Kg5ka1- \ Va1P5 ops - \\ ay ΑΝΟνΑ using a percentage of the initial values. If the statistical significance reaches a level of p <0.05, the Mapp- \ U1Shpsu test I is carried out for statistical comparison of the control group and the group treated with drugs.

The compounds of this invention exhibit an effect in the range of 5-200 mg / kg.

Table 7. Biological data Ιη νίΐτο binding to human 5-HT ₆ receptor

Example Κι (nM) 5-HTE human receptor one 10 eleven 6, 5 twenty 10.5 40 7.5 131 5

131 ----- 1 ......- - - -

Performance Data ΐη νίνο Example % reduction in food intake * Saz, and (μM) one 12 0.44 eleven 47.1 0.02 40 44 0, 2

* The effect of reducing food intake in b / o mice with a single dose of 50 mg / kg / day, measured in a stable state

Claims (17)

CLAIM 1. The compound of formula (I) -49008835 or a pharmaceutically acceptable salt thereof, wherein ring B represents each XV independently represents -Ν-, - (CH) - or -C-, provided that a total of not more than three groups of XV are -Ν- in both rings A and B at the same time, P represents any of the groups of formula (a), (b) or (c) In ¹ i am ¹ ? = Oh η Ν-Κ ^: • Mu o * ⁵ y (a) (b) (c) where x = 0, 1 or 2 and y = 0, 1 or 2; and P and K ³ can be attached to any carbon atom that can be substituted in one of rings A or B, or, when ring A contains at least one nitrogen atom and P represents (c), then P can also be attached to any nitrogen atom in ring B that allows substitution; dashed lines mean that P and K ^3, respectively, can be attached to ring A or to ring B; but each P or H ³ cannot simultaneously be attached to both rings A and B; I ¹ represents: (a) C1_b alkyl, (b) C1_b alkoxyalkyl, (c) C1_b straight or branched chain hydroxyalkyl, (ά) C1_b straight or branched chain alkyl halides, (e) arylcarbonylmethyl, (£) C3_7 cycloalkyl, which is optionally partially unsaturated , (§) C3_7 cycloalkyl-C1_b alkyl, where the cyclic ring is optionally partially unsaturated, or (i) a group Ar; where Ar is: (a) phenyl, (b) 1-naphthyl, (c) 2-naphthyl, (ά) aryl-C1_b alkyl, (e) cinnamyl, (£) 5-7 membered, optionally aromatic, partially saturated or fully saturated mono - or a bicyclic heteroaryl ring, each of which contains from 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen atoms, (§) a bicyclic ring system comprising at least one heterocyclic ring corresponding to the definition of paragraph (£), and the group Ar where the group Ag is substituted in one or more positions by groups: (a) Η, 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; I ² represents: (a) H, (b) C1_b alkyl, (c) C ₂ .b alkoxyalkyl, (ά) straight or branched C] .6 hydroxyalkyl, or (e) straight or branched C] .6 alkyl halides; (£) the group Ar, -50008835 or K ¹ and K ^{2 are} connected with the formation of the group -CH2CH2OCH2CH2- or where ν is 0-2, X and Υ independently represent: (a) H, (b) halogen, (c) C1_b alkyl, (ά) CE ₃ , (e) hydroxy, (£) C1_b alkoxy, (g) C ₂ .b alkenyl, (i) phenyl, (ί) phenoxy 0) benzyloxy, (k) benzoyl, (l) -OCE ₃ , (w) -ΟΝ, (i) straight or branched C] .6 hydroxyalkyl, (o) straight or branched C] .6 alkyl halides, (P) - νη ₂ , (ф -ΝΗΚ ⁴ , (d) -ΝΚ ⁴ Κ ⁵ , (8) -ΝΟ ₂ , (ΐ) -ΟΟΝΚ ⁴ Κ ⁵ , (и) -ΝΗ8Ο ₂ Κ ⁴ , (ν) -ΝΚ ⁴ ΟΟΚ ⁵ , (χ) -8Ο ₂ ΝΚ ⁴ Κ ⁵ , (ζ) -С (= О) К ⁴ , (aa) -СО ₂ К ⁴ or (ab) -8 (О) _П Я ⁴ , where u is 0 , 1, 2 or 3, (ac) -8 (C1_b) alkyl or (af -8CE ₃ ; and K ⁴ and K ⁵ independently represent: (a) H, (b) S1_b alkyl, (c) _C3 _7 cycloalkyl or (ά) Ar, the values of which are as defined above for R ^1; alternatively, K ⁴ and K ^{5 are} connected to form the —CH ₂ OCH ₂ -, —CH ₂ CH ₂ OCH ₂ CH ₂ - or (CH ₂ ) ₃ group. ₅ ; I ³ represents a group selected from any of the following groups: -51 008 835 where R ³ is optionally substituted at each carbon atom which permits substitution groups I _h, where R independently represents H or (S1_ _b) alkyl, and wherein two poison groups may be on the same carbon atom simultaneously, wherein q = 1 2, 3, 4, 5 or 6, w = 1 or 2 and u = 0, 1 or 2; I ⁶ independently represents: (a) H, (b) linear or branched C] .6 alkyl, (c) benzyl, (b) -CH ₂ -CH ₂ -OH, or (e) -CH ₂ -CH _{2 -O-C1-C6alkyl} ; P and R ³ can be attached to one ring or to different rings of rings A and B; with the proviso that when P represents both P and R ³ , both are attached to ring A in a meta or para position with respect to each other, then R ^{3 is} selected from any of the following groups: when ring B is -52008835 ABOUT and P represents to ¹ Ko? o (G— '(a). then P and H ^{3 are} simultaneously attached to the same ring A or B; when ring B is (BUT and P represents ⁱⁿ \> where y = 0, then P and H ^{3 are} attached to different rings of rings A and B, or, when ring B is and H ^{1 =} Ar is a partially saturated bicyclic heterocyclic ring containing an atom N, the N atom in Ag cannot be attached to atom 8 in P; with the proviso that when rings A and B are both phenyl, P represents any of the groups of formula (a) or (c) substituted at position 7 of the naphthalene ring, then R ^{3 is} not substituted at position 1 of the naphthalene ring. 2. The compound according to claim 1, where I ¹ represents: (a) C1_b alkyl or (e) a group of Ar; Ag 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 atoms , nitrogen and sulfur, where the group Ag is substituted in one or more positions by groups: (a) H, (b) halogen, (c) S1_b alkyl, (d) -SGz, (ί) S1_b alkoxy, (d) C ₂ .b alkenyl, (1) -OSEz, (iii) straight or branched S1_ ₆ hydroxyalkyl, (i) phenyloxy, (o) benzyloxy, (ν) -II ⁴ SOY ⁵ , (x) -8О ₂ Ш 'Я ³ : (ζ) -C (= O) I ⁴ , (ab) -8 (O) _П I ⁴ , where u is 0, 1, 2 or 3; (ac) -8- (C1_b) alkyl or (ay) -8CE ₃ ; I ² represents: (a) H, or (b) S1_ ₆ alkyl; or I ¹ and I ^{2 are} connected to form the —CH ₂ CH ₂ OCH ₂ CH ₂ - group; X and Υ are H; I ⁴ and I ⁵ , each independently, represents H or C]. ₃ alkyl and -53 008835 I am ³ selected from any of the following groups: where I ³ can be substituted on each carbon atom, which allows the substitution of groups I ,,. where R independently represents H or S1_ ₆ alkyl, and where two groups I may be on the same carbon atom simultaneously, where | = 1 or 2, m = 1 or 2, u = 0 and I ⁶ independently represents: (a) H, (b) C1_balkyl, in particular methyl, (b) -CH ₂ —CH ₂ —OH or (e) —CH ₂ —CH ₂ —OCH ₃ . 3. The compound according to claim 1 or 2, where I ³ represents piperazine; homopiperazine; 2,6dimethylpiperazine; 3,5-dimethylpiperazine; 2,5-dimethylpiperazine; 2-methylpiperazine; 3methylpiperazine; 2,2-dimethylpiperazine; 3,3-dimethylpiperazine; piperidine; 1,2,3,6-tetrahydropyrazine or 4-pyrrolidin-3-yloxy. 4. The compound according to any one of pi. 1-3, where P represents ^k '\ ^{8 (} Ch1, (0 where H ¹ , x uy have the meanings defined in paragraph 1. 5. The compound according to any one of pi. 1-3, where P represents K ¹ I 2 - Ν-Κ ² o ^<5 y k ' Who _r ? ^r about K — Ν ^, ί-ι N -u (a) or where I ¹ and I ² have the meanings defined in π. one. 6. The compound according to and 5 where I ² represents N. 7. The compound according to and.4 of the general formula (II) (b) where H ¹ , x, y and X, Υ have the meanings as in π. 1 and I ³ has the meanings defined in and. 2. 8. The compound according to claim 1, where y = 0 and x = 2. 9. The compound according to and.4 of the general formula (III) (III) where I ¹ , x, y and X, Υ have the meanings as in π. 1 and I ³ has the meanings defined in and. 2. 10. The compound according to claim 9, where y = 0 and x = 2. 11. Connection by and. 6 general formula (XI) -54008835 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, X and Υ have the meanings defined in claim 1, and I ³ has the meanings defined in clause 4. 12. The compound according to claim 7, which is a 6-benzenesulfonyl-4-piperazin-1-ylquinoline hydrochloride; 6 - [(2-fluorophenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride; 6- (1-naphthylsulfonyl) -4-piperazin-1-ylquinoline hydrochloride; 6 - [(3,4-dichlorophenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride; 6 - [(3,5-dimethylphenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride; 6 - [(2-chloro-6-methylphenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride; 6 - [(4-chlorophenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride; 6 - [(2-methyl-1,4-tert-butylphenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride; 6 - [(3,4-dimethylphenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride; 6 - [(2,3-dichlorophenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride; 6 - [(4-tert-butylphenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride; 6 - [(4-Isopropylphenyl) sulfonyl] -4-piperazin-1-ylquinoline hydrochloride; (4-piperazin-1-yl-6 - {[4- (trifluoromethyl) phenyl] sulfonyl} quinoline hydrochloride; 6 - [(4-tert-butylphenyl) sulfonyl] -4- (1,4-diazepan-1-yl) quinoline hydrochloride or 4- (1,4-diazepan-1-yl) -6 - [(4- isopropylphenyl) sulfonyl] quinoline. 13. The compound of claim 9, which is 7- (2-chloro-6-methylbenzenesulfonyl) -1-piperazin-1-yl-isoquinoline hydrochloride; 7- (2-tert-butylbenzenesulfonyl) -1-piperazin-1-yl-isoquinoline hydrochloride; 7- (3,4-dichlorobenzenesulfonyl) -1-piperazin-1-yl-isoquinoline hydrochloride; 7- (2,4-dimethylbenzenesulfonyl) -1-piperazin-1-yl-isoquinoline hydrochloride; 7- (2,5-dimethylbenzenesulfonyl) -1-piperazin-1-yl-isoquinoline hydrochloride; 7- (p-chlorobenzenesulfonyl) -1-piperazin-1-yl-isoquinoline hydrochloride; 7-benzenesulfonyl-1 - [1,4] diazepan-1-isoquinoline hydrochloride; 7 - [(4-tert-butylbenzenesulfonyl) -1- [1,4] diazepan-1-yl] isoquinoline hydrochloride; 7 - [(2-chloro-6-methylbenzenesulfonyl) -1- [1,4] diazepan-1-yl] isoquinoline hydrochloride; 7 - [(3,5-dimethylbenzenesulfonyl) -1- [1,4] diazepan-1-yl] isoquinoline hydrochloride; 7 - [(3,4-dichlorobenzenesulfonyl) -1 - [1,4] diazepan-1-yl] isoquinoline hydrochloride; 7 - [(4-chlorobenzenesulfonyl) -1- [1,4] diazepan-1-yl] isoquinoline hydrochloride; 7 - [(3,4-dimethylbenzenesulfonyl) -1- [1,4] diazepan-1-yl] isoquinoline hydrochloride; 7 - [(2-tert-butylbenzenesulfonyl) -1- [1,4] diazepan-1-yl] isoquinoline hydrochloride; 7-benzenesulfonyl-1-piperazinyl isoquinoline hydrochloride; or 7- (4-tert-butylbenzenesulfonyl-1-piperazinyl) isoquinoline hydrochloride. 14. The compound according to claim 11, which is 4-chloro-no. [4- (pyrrolidin-3-yloxy) -1-naphthyl] benzenesulfonamide hydrochloride; 4-methoxy-hydrochloride [4- (pyrrolidin-3-yloxy) -1-naphthyl] benzenesulfonamide hydrochloride; 5-chloro-no. [4- (pyrrolidin-3-yloxy) -1-naphthyl] thiophen-2-sulfonamide hydrochloride; 4-chloro-no. [4- (piperidin-3-yloxy) -1-naphthyl] benzenesulfonamide hydrochloride; 4-methoxy-hydrochloride [4- (piperidin-3-yloxy) -1-naphthyl] benzenesulfonamide; 5-fluoro-2-methyl-no. [4- (piperidin-4-yloxy) -1-naphthyl] benzenesulfonamide hydrochloride; 5-chloro-no. [4- (piperidin-4-yloxy) -1-naphthyl] thiophen-2-sulfonamide hydrochloride; 4-chloro-No hydrochloride {4 - [(38) -pyrrolidin-3-yloxy] - 1-naphthyl} benzenesulfonamide or 4-chloro-No hydrochloride {4 - [(3Я) -pyrrolidin-3-yloxy] -1- naphthyl} benzenesulfonamide. 15. The use of a compound according to any one of claims 1 to 14 in the preparation of a medicament for the treatment or prevention of disorders of the central nervous system. 16. The use of the compounds according to any one of claims 1 to 14, where rings A and B are both phenyl, P is any group of formula (a) or (c) substituted at position 7 of the naphthalene ring, and I ^{3 is} substituted at position 1 naphthalene ring, to obtain a medicine for the treatment or prevention of type II diabetes mellitus. 17. The use of a compound according to any one of claims 1 to 14, for the manufacture of a medicament for the treatment or prevention of obesity, in order to achieve a decrease in body weight or an increase in body weight.