UA74830C2 - Indole derivatives being useful for the treatment of cns disorders, a pharmaceutical composition and a method for the treatment of diseases - Google Patents

Abstract

The present invention relates to dopamine and serotonin receptor ligands having the general formula (I) wherein one of Y1 and Y2 is N, which is bound to Y4, Y3 is Z-CH2, CH2-Z or CH2CH2 and the further meanings of Y1, Y2, Y3, Y4, Z, W, n, m, X, R1-R9 and R10 are as given in the claims and the description. The compounds of the invention are useful in the treatment of certain psychiatric and neurological disorders, i.e. schizophrenia, other psychoses, anxiety disorders, depression, migraine, cognitive disorders, ADHD and sleep improvement. (I)

Description

Description of the invention

This invention relates to a new class of indole derivatives having affinity for the O/-dopamine 2 receptor. These compounds have an antagonistic effect on the O)-dopamine receptor and are thus suitable for the treatment of certain mental and neurological disorders, in particular, psychoses. Some of these compounds also have affinity for the 103-dopamine receptor, the 5-HT2 receptor, and/or the 5-HT10 receptor, and some of these compounds are serotonin reuptake inhibitors.

Ligands of Y/-dopamine receptors related to the compounds of this invention are known from M/O 98/28293. Derivatives 70 of indane and dihydroindole, which are described here, have the general formula: where A is indole and Y is an indane or dihydroindole terminating group and the other substituents are c 29 as defined in the application. Gee)

MO 00/23441 describes compounds of the general formula о ее о и д- / ТЯ осо щ-- СН ж s (Kan « s o

M -

Kk " where the substitutes K., Ko, Kz, t, p and r are as defined in the application. These compounds are said to show high affinity for 100-dopamine receptors and to be serotonin reuptake inhibitors. The object of the claimed invention is that these compounds are "" suitable for the treatment of schizophrenia and other mental disorders. " Other compounds structurally related to the compounds of this invention are described in UUO 99/58525. It is about the fact that the compounds described in the specified document are 5-HT od ligands and serotonin reuptake inhibitors and have the general formula - .

V o i B

In (Snamint (o) Z rache

The substituents are as defined in the application. It is said that these compounds are suitable for the treatment of schizophrenia.

MO 00/31074 refers to compounds of the general formula b5 or ; "ak (Snap ,

Kk,'

M a and 70 | | X ores I not Y 75 where X represents CO or 50 5 and M represents M-K 4 or СВ7РВ5 and the substituents are as defined in the application. It is about the fact that these compounds are active in relation to the 5-HT od-receptor, have inhibitory activity in relation to the reuptake of 5-HT and enhance the release of 5-HT.

Applications UUO 94/18197, ER 329168, MO 93/16073, ER 732332, UMO 98/37893 and MO 95/11680 describe ligands

O;-dopamine receptors, which, like the compounds of this invention, are substituted derivatives of tetrahydroquinolinone and tetrahydroisoquinolinone. However, these compounds do not contain indole, unlike the compounds of the present invention. It is about the fact that these compounds are ligands of O y-dopamine receptors, suitable as antipsychotic drugs. It is also claimed that the compounds described in MO 93/16073 have antagonistic activity in relation to 5-H T»-receptors.

О/-dopamine receptors belong to the subfamily of ОО 5-dopamine receptors, which are believed to be responsible for the antipsychotic effect of neuroleptics. The side effect of neuroleptic drugs, which primarily act through antagonism in relation to Я»о-receptors, is due, as is known, to antagonism in relation to Яо-receptor in the atrial (striatal) areas of the brain. However, O y-dopamine receptors are located, mainly, not in the atria, but in other areas of the brain, and this allows us to make an assumption that antagonists of the Y;-dopamine receptor will not cause extrapyramidal side effects. This is evident from the antipsychotic effect of clozapine, which shows a higher affinity for ОО y- than for Хо-receptors, and does not cause extrapyramidal side effects (Map ТойЙ ей а). Maishge 1991, 550,610; Nadieu MeaiisipaI Kezeagsp (O

Kemiemuv 1996,16, 507-526 and Zappeg Ehr. Orip. Tag. Rayepiv 1998, 8, 383-393). co

It was shown that a number of О/-ligands, which were claimed to be selective antagonists of О//-receptors (I-745,879 and 0-101958), have antipsychotic activity. 200). However, recently it was reported that these compounds in various experiments to determine the effectiveness of ip mygo ich show themselves to be partial agonists of ХО /-receptors (Sally ey ai. Vg. )In RIagtasoi. 1998,124, 889-896 and scores of A. Hg. 9). RIpapgtasoi. 1999, 128, 613-620). In addition, it has been shown that clozapine, which is an effective antipsychotic agent, is also a latent antagonist of |Sa?i ei aI. Hg. 9. Rpagtasoi. 1999, 128, 613-620). 20 Thus, O,-ligands, which are partial agonists or antagonists of O,-receptors, may have advantages in terms of effectiveness against psychosis. c Dopamine O antagonists may also be suitable for the treatment of cognitive impairments: c" Mepivsi ei ai., Rvusporpaptasoiido, 1999, 142, 78-84).

In addition, the published confirmation of the genetic link between the "primary inattention" subtype of attention deficit hyperactivity disorder (ADHD) and the polymorphism of tandem copies in the gene encoding the Y/-dopamine receptor - IMeStaskep ei aiI. My. Rzuspiai 2000, 5, 531-536). This clearly indicates the presence of a connection between the Y /-dopamine receptor and ASNO, and ligands acting on this receptor may be suitable for the treatment of this specific disorder. o О3-dopamine receptors also belong to the subfamily of 10-dopamine receptors, and they are mainly located in the limbic areas of the brain (ZokoYoi ei aiYi., Maiyshge, 1990, 347, 146-151), such as o pysygyes and assythrepsis, and the blockade of dopamine receptors associated with antipsychotic activity about HMMpeg, Ipi. Siipisai Rzusporpagtasoyodu, 1997, 12, 297-308). In addition, leveling up has been described

Oz-receptors in the limbic part of the brain of patients suffering from schizophrenia

Agsp. Sept. Rzuspiaigu, 1997, 54, 225-324).

Therefore, antagonists of Oz-receptors can provide an opportunity for effective antipsychotic therapy, free from extrapyramidal side effects of classical antipsychotic drugs that show their effect, (F; mainly, with the help of blockade of U»o-receptors | 1998, 135, 1-16;

GI zZspuagig ei a!., Vgaip Kezeagsp Kemiem/v, 2000, 31, 277-287).

Moreover, the blockade of Yuz receptors leads to a slight stimulation in the prefrontal cortex of the brain IMegsnap. Segebga! Sopeh, 1996, 6, 561-570), which could be useful for negative symptoms and cognitive impairment associated with schizophrenia. In addition, antagonists of dopamine ХО3 can return 0» antagonist-induced ERZ | MiMPap ei ai., Eig. U. Riaptasoi!., 1997, 321, K7-K9| and do not cause changes in prolactin. Ex. Tpeg., 2000, 294, 1154-165). Therefore, the O3-antagonistic properties of an antipsychotic drug could reduce negative symptoms and cognitive impairment and lead to an improved side effect profile in terms of ESR and hormonal changes.

Agonists of dopamine OZ were also considered suitable for the treatment of schizophrenia (M/ivyom ei ai., Sigtepi

Rpagtaseciisa! Oevzidp, 1997, Z, 391-404).

Various effects of compounds that are ligands of different subtypes of the serotonin receptor are known. Regarding the 5-HT receptor, which was previously referred to as the 5-HT receptor, the following effects are known, for example: antidepressant effect and improvement of sleep quality. YuOgyd. OEM Kez. 1989,18, 119), weakening of the negative symptoms of schizophrenia and extrapyramidal side effects caused by the use of classical neuroleptics by patients with schizophrenia | Seidege Vgyizy 3. Reuspiayu 1989, 755 (see. 5), 33). In addition, selective antagonists of 5-HTod can be effective for the prevention and treatment of migraine | Zshir Kerogi; "Midgaipe-Sygttepi (hepaz ip gezeagspy apa igeaitepi"; ROV Rybiisayope a. Mau 1991) and for the treatment of the state of /o anxiety |SoiIrag ei ai. Rezusporpagtasoydu 1985, 86, 303-305 and Regtedaagy ei a). Sitepi Oripiop ip

Tpegaretsiis Raifepiv 1993, 1, 101-128.

Some clinical studies consider the involvement of the 5-HT o-receptor subtype in aggressive behavior. Moreover, atypical serotonin-dopamine antagonist neuroleptics have antagonistic effects on the 5-HT 2 receptor in addition to blocking properties on dopamine and, as described, have /5 anti-aggressive behavior |Soppog ei ai. Ex. Orip. Tneg. Rayepov 1998, 8(4), 350-3511.

Recently, evidence has also accumulated that substantiates the feasibility of using selective 5-HTod antagonists as drugs suitable for the treatment of positive symptoms of psychosis | eusep ei ai Sstepi

Rpagtaseciisa! Oevidp 1997, 5,367-390 and Sagizwop Sitepi Oripiop ip SRMZ Ipmeviidaiopa! YuOgidve 2000, 2(1), 22-24).

Compounds that are 5-HT reuptake inhibitors are well known as antidepressants.

5-HT 2 ligands have been shown to potentiate the effects of 5-HT reuptake inhibitors in microdialysis and animal experiments, and compounds exhibiting inhibitory effects on 5-HT reuptake combined with affinity for 5-HT os -receptor, may, therefore, be particularly suitable for the treatment of depression and other disorders that are amenable to treatment with serotonin reuptake inhibitors (international application PCT/OKOO0/00671). high school

Therefore, β-dopamine receptor ligands are potential drugs for the treatment of schizophrenia and other psychoses, and compounds with combined effects on the 5-HT transporter may have additional i) advantages in terms of improved effects on depressive and negative symptoms in patients suffering from for schizophrenia Compounds with a combined effect on the β-dopamine receptor and the 5-HT receptor may have additional advantages in terms of improved effects on positive and negative symptoms of schizophrenia, and additional advantages in terms of effects on symptoms of depression and anxiety. In addition, the antipsychotic drug's antipsychotic antipsychotic antagonist properties may reduce the negative symptoms and cognitive deficits of schizophrenia and improve the side effect profile. co

The purpose of the present invention is to obtain compounds that are partial agonists or antagonists of the O /-dopamine receptor, and similar compounds with combined effects in relation to the Y;-dopamine receptor, the receptor "

Oz, 5-HTod-receptor, 5-HT»os-receptor and/or 5-HT-transporter. uh-

Another goal of the present invention is to create compounds with the specified properties, which have improved solubility in comparison with compounds known from the state of the art.

Accordingly, this invention relates to new compounds of the formula - c v i-i i i i i i not k | what? - и х же в ники ия Inni pni Goi Ya tr, M./ 1 so ko M y go | () o 1 then o Kk where (a) one of U! and U? represents M, which is connected to U 7, and the other to U! and 2 is CO, C8, 50 or 505, and M" sv IS CH"; (B) one of U" and U? represents M, which is connected to U 7, and the other to U! and U? is SN", and U? is

F) СО, С5, 80 or 50"; or ko (s) one of U! and U? represents M, which is connected to U", and the other from U! and y? represents CH", and 7 represents

SN"; 60 UZ represents 7-CH», CH»-7 or CH» CH», and 7 represents O or 5; provided that, when U represents M, then UZ may not be 2-CH";

MU is a bond or group О, 5, СО, С5, 50 or 505; n equals 0-5, t equals 0-5, and type equals 1-10; provided that when M/ represents O or 5, then n » 2, and t » 1; when MU is CO, С5, 5О or 505, then n» 1, and t » 1; because X represents C, CH or M; provided that when X represents C, then the dashed line represents a bond, and when X represents M or CH, then the dashed line is not a bond;

B!-K9 are independently selected from hydrogen, halogen, cyano group, nitro group, amino group, hydroxyl group,

C, v-alkylamine, di-Ci-v-alkylamine, C-v-alkyl, Cv-alkenyl, Cv-alkynyl, Cv-alkoxy, Cv-alkylthio,

Si. β-alkyl substituted by a hydroxyl group or a thiol group, C3 β-cycloalkyl,

Cz c-cycloalkyl-Ci c-alkyl, acyl group, thioacyl group, aryl group, trifluoromethyl group, trifluoromethylsulfonyl group and Ci c d-alkylsulfonyl;

BO is hydrogen, C 4 -alkyl, C 6 -alkenyl, C 6 -alkynyl, C 6 -alkyl substituted by a hydroxyl group or a thiol group, C 6 -cycloalkyl, C 6 -cycloalkyl-C-6-alkyl, aryl group, aryl-C; β-alkyl, acyl 70 group, thioacyl group, Si. β-alkylsulfonyl, trifluoromethylsulfonyl or arylsulfonyl group, or to their pharmaceutically acceptable acid addition salts.

In the first specific embodiment of the present invention, the indole is linked to the X to C position of the indole.

In the second embodiment of the present invention, one of U and U2 is M, which is connected to U 7, and the other to U! and y2 is CO, and U" is CH." t Ut ianti of the reactions U andU2 is M, which is connected to M 7, and in another variant of the implementation of the present invention, one of ,; ,;

C 1 U2 is CH", and U" is CO.

In the fourth embodiment of the present invention, U is a nitrogen that is bound to U, and one of Ulim?2 is CO, and the other is CH."

In the fifth embodiment of the present invention, U represents nitrogen, which is bound to 7, 2 represents CO, and U" represents CH".

In the sixth embodiment of the present invention, U is a nitrogen that is connected to U 7, U? is

CH, and U" is CO.

In the seventh embodiment of the present invention, U? is nitrogen, which is connected to U 4, and one of which is CO, and the other is CH." at

In the eighth embodiment of the present invention, U? is a nitrogen atom that is connected to U 7, U! is SN", and U? is SO.

In the ninth embodiment of the present invention, U 2 is a nitrogen atom that is connected to U 7, U! represents av! is CO, and U" is CH". p

In the tenth embodiment of the present invention, one of U and U2 is M, which is connected to U 4, and the other 3 1 m2 is CH 2, | M? is CH 5. These compounds are mainly in the form of their co-pharmaceutically acceptable double salts. "AND

In yet another variant of the implementation of the present invention, UZ is СНоСН» or СН2Й. m

In further embodiments of the present invention, X is C, X is M or X is CH.

Substituents '-B9, in particular, are selected from hydrogen, halogen, cyano group, nitro group, amino group,

C, d-alkylamine, di-C. β-alkylamine, C.β-alkyl, C3-β-cycloalkyl and trifluoromethyl group, and BO is hydrogen, C.β-alkyl or an acyl group, and/or MU is a bond, and Pt is from 1 to 6, in particular, from Z « dOb. o, c The compounds of this invention are partial agonists or antagonists of the O/-dopamine receptor. Many compounds have a combined action on the ХО/-dopamine receptor and affinity for the Х-dopamine receptor, "» affinity for the 5-HT»о-receptor, affinity for the 5-HT2-receptor and/or action on inhibiting the reuptake of 5-HT .

Accordingly, the compounds of the present invention are considered suitable for the treatment of positive and negative -I symptoms of schizophrenia, other psychoses, anxiety disorders such as generalized anxiety disorder, panic disorder and obsessive-compulsive disorder, depression, aggression, side effects induced by conventional t-antipsychotics agents, migraine, cognitive disorders, AONO, as well as to improve sleep. In another aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of formula I as defined above or a pharmaceutically acceptable acid addition salt thereof in a therapeutically effective amount and in combination with one or more pharmaceutically acceptable carriers or diluents.

In yet another aspect, this invention relates to the use of a compound of formula I as defined above, or an acid addition salt thereof, for the manufacture of a pharmaceutical preparation for the treatment of the above-mentioned disorders.

Compounds of the general formula | can exist in the form of optical isomers, and these optical isomers are also within the scope of the present invention. iF) The term "C1-6 alkyl" refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1-propyl, pentyl and hexyl. Similarly, the terms "Co v -alkenyl" and "Co v -alkynyl", respectively, refer to groups having from two to six carbon atoms, comprising one double bond and one triple bond, respectively, such such as ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.

The terms "C.v.-alkyl", "C.v.-alkylthio", "C.v.-alkylsulfonyl", "C.v.-alkylamino", "C.v.-alkylcarbonyl" etc. denote such groups in which the alkyl group is C. γ-alkyl, as defined above. 65 The term "C3-d-cycloalkyl" denotes a monocyclic or bicyclic carbocycle having from three to eight

C atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, etc.

The term "aryl" refers to a carbocyclic aromatic group, such as phenyl, naphthyl, in particular, phenyl, including phenyl substituted with methyl, or naphthyl.

Halogen means fluorine, chlorine, bromine or iodine.

As used herein, the term "acyl" refers to formyl, C 4 in -alkylcarbonyl, arylcarbonyl, aryl-C. γ-alkylcarbonyl, C3.8-cycloalkylcarbonyl or Su γ-cycloalkyl-C. γ-alkylcarbonyl group, and the term "thioacyl" denotes the corresponding acyl group in which the carbonyl group is replaced by a thiocarbonyl group.

Acid addition salts of compounds according to the present invention are pharmaceutically acceptable salts obtained by interaction with non-toxic acids. Examples of such organic salts are maleic, fumaric, 70 benzoic, ascorbic, amber, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, lemon, gluconic, milky, malic, almond, cinnamon, citraconic, aspartic salts. , stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophyllineacetic acids, as well as formed with 8-halotheophyllines, for example, 8-bromotheophylline. Examples of such inorganic salts are 7/5 salts of hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids.

Pharmaceutical compositions of the present invention or compositions obtained according to this invention can be administered by any suitable route, for example, orally in the form of tablets, capsules, powders, syrups, etc. or parenterally in the form of a solution for injection. Methods well known in the art may be used to prepare such compositions, and any pharmaceutically acceptable carriers, diluents, fillers, and other additives commonly used in the art may be used.

The compounds of the invention are conveniently administered in a unit dosage form containing said compounds in an amount of about 0.01 to 10 ug.

The total daily dose is usually from about 0.05 to about 50 Ωg, and most preferably it is from about 0.1 to about 5 Ωg of the active compound of the invention. high school

The compounds according to the invention can be obtained as follows: 1) Alkylation of piperazine, piperidine or tetrahydropyridine of formula II with the help of alkylating i) derivative of formula I:

Ge

In them about in KE « | so g i

J

Her. / x U t d) ry CHI W 7. .

In M 4 g in: - -

Pov a vkyno v 10 v v v (SHKO shi h» where K!-8'9, X, U, mg, UZ mia, MU, p, t and the dashed line are as defined above, and | is a group , " which is removed, such as a halogen, mesylate or tosylate; 2) By re-alkylation of an amine of formula II with the help of a reagent of formula IM: ik МН in-ChSNu is M (СН ры M / in

V M o Re v also (0 where where B-BO, X, U, mg, M, y, M, n, t and the dashed line are as defined above, and E represents either an aldehyde or an activated carboxyl group 60 C) Alkylation of the compound of the formula M with the help of an alkylating derivative of the formula MI: b5 c?

Eh Di Kk 7'

TY shi M-A-A- (СН M --(СН)ty 7 7 re M / y Y no Z in d2

I

Sh- 3 p

U) o z ( where K!-B79, X, MUZ, Mu, n, t and the dashed line are as defined above, one of U? and 9 is MH or

M-, and the other with M? and Mb is CO, C5, 5O, 5O" or CH" and Y is a leaving group such as halogen, mesylate or tosylate; or so 4) Restoration of the double bond in the tetrahydropyridinyl ring in the derivatives of the following formula MI!:

II / In the "

MAACHSNa yam SN r. y - p s v! M with vk Gu : -1 where 27-89, u, mg, Z, U, MU, p and t are as defined above; 5) By reduction of amide carbonyl in the compound of the formula MIP:

According to: ts M--с0О- (СН M (СН r 1 o in Hu ko a |»

Kk Kk (M) bo where 27-89, y, mg, m, M, p, t, MU and the dotted line are as defined above; 6) Reduction of the amide group of the compound of formula IX: b5 di to z cha i nu ve

I|--ya /k x a ' uv kg 7 mtenattt sn, M

M / ch yuyu cht Y o Kk ne vya ah de B!-879, X, M, U2, Z, p, t, MU and the dotted line are as defined above; 19 7) Reductive alkylation of a derivative of the formula Ma with the help of an acylating derivative of the formula X: ro o in KE

KK

. , o x sew, m-n zd M -SNe r. or o v! M schi de I, o o so ni (ee) 4 ge "I 7 th-

U « -- uv d2 - c i, (Ua) z n where K!-879, X, UZ, Mu, n, t and the dotted line are as defined above, one of U / and UZ is a MN, and the other of M" and u8 represents CH", and E represents an aldehyde or an activated carboxylic acid group; -I 8) Acylation of an amine of the formula Ma with the help of a reagent of the formula X: t" (ee) o 50 "2 (F) ko because b5 in 2 i k 7

Hey shk / r M / in M in I, (X) ge ki

Ki

Kk cho 7 h same s

Sh- no 5) vk a (Ua) o where B!-879, X, UZ, MU, n, t and the dotted line are as defined above, one of U and UZ represents MN, and c the other of U " and x8 represents CH", and E represents an aldehyde or an activated carboxylic acid group; 9) By splitting the polymer bond of the derivative of the formula XI: so x - vro v3 M.

UZ

Ge toy / M a ; "

PO zu2 I ih MAACHSNI WE (SN - s , M m/ iy te A. -i c) ok FO) iz de B!-89, m, mg, UZ, X, MU, t and p are as defined above, and E'OH represents hydroxyethyl- or hydroxymethylpolystyrene, U/apd resin or similar polyethylene glycol-polystyrene resins; after which the compound of formula I! isolated in the form of a free base or its pharmaceutically acceptable acid additive salt.

Ha 50 Alkylation according to methods 1) and 3) is conveniently carried out in an inert organic solvent, such as alcohol or a ketone, which has a suitable boiling point, preferably in the presence of an organic or inorganic base (potassium carbonate, diisopropylethylamine or triethylamine) at the reflux temperature. Alternatively, the alkylation can be carried out at a fixed temperature, which is different from the boiling point, in one of the solvents listed above or in dimethylformamide (DMF), dimethylsulfoxide (DMSO) or 595 M-methylpyrrolidin-2-one (NMP), preferably in the presence of a base.

GF) The synthesis of amines of formula (I), 3-(piperidin-4-yl)-1H-indoles and 3-(3,6b-dihydro-2H-pyridin-4-yl)-1H-indoles is described in the literature | see for example, EP-A1-465398|. Alkylating reagents of formula (III) are known from the literature, see Oz5 Pigot ei a). 9). Honey. Spent 2000, 43, 177-189 and EP-B 1-512525)| or they can be obtained by methods obvious to a specialist in the field of chemistry (see, for example, Komuaizki ei ai. 9. Nei(egosusiis Spet. 60 2000, 37, 187-189, Mokgoz2 ei a. Riagtalie 1997, 52, 423-428 and Mivla!ei Am Mea Spect Bez 1992, 2, 82-87|.Alkylating reagents of formula (MI) can be prepared by methods known to a person skilled in the field of chemistry, and amines of formula (M) are commercially available or described in the literature.

Reductive alkylation according to methods 2) and 7) is carried out according to standard methods described in the literature.

The reaction can be carried out in two stages, for example, by combining the derivatives of the formula PIIL/a and the reagent of the formula bo|M/X by standard methods with the help of carboxylic acid chloride, or by using coupling reagents such as dicyclohexylcarbodiimide, followed by the reduction of the resulting amide with the help of lithium aluminum hydride or alane. This reaction can also be carried out by a standard method in one reactor. Carboxylic acids or aldehydes of the formula IM/X can be obtained by obvious methods

For a specialist in the field of chemistry.

Alkylation according to method 3) is conveniently carried out as described above, or by the interaction of nitrogen anion M with MI.

The nitrogen anion M can be prepared in an inert organic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) or M-methylpyrrolidin-2-one (NMIP) with a strong base such as Mann before alkylation. 70 The reduction of the double bond according to method 4) is usually carried out by catalytic hydrogenation at low pressure (less than Zatm.) in a Steam apparatus or with the help of reducing agents, such as diborane or hydrogen bromide derivatives, which are obtained directly from Mavn, in trifluoroacetic acid, in inert solvents such as tetrahydrofuran (THF), dioxane or diethyl ether. Starting substances of the formula (MI) can be obtained by methods 1), 3), 7) and 8).

Reduction of amide groups according to methods 5) and 6) is most easily carried out with the help of lithium aluminum hydride or alane in an inert organic solvent, such as, for example, tetrahydrofuran (THF) or diethyl ether, at a temperature from 09C to the reflux temperature. Starting substances of the formula (MI) can be obtained by methods 2) and 3), while starting substances of the formula (IX) can be obtained by methods 1), 7) and 8).

The interaction according to method 8) is conveniently carried out with the help of binding reagents, such as, for example, dicyclohexylcarbodiimide.

Derived structures (XI) are obtained using the solid-phase synthesis sequence presented in Scheme 1, below. The first building block (XII), obtained by methods obvious to a skilled chemist, is usually attached to a resin (ethyl-4-nitrophenylcarbonate bonded to polystyrene) using a base, for example, M,M-dimethylaminopyridine and M, M-diisopropylethylamine, at an elevated temperature (for example, 50-1002С) in an aprotic solvent (for example, DMF or DMSO), with the production of (HIPI). After deprotection of the amino group with trifluoroacetic acid (KHIM resin), a second diversifying building block is introduced by alkylation. Alkylation is carried out at an elevated temperature (50-100 22) in an aprotic solvent, such as DMF, acetone or acetonitrile, as a result of which resin (XM) is obtained. (av)

After deprotection of the carboxylic acid ester with trifluoroacetic acid (XMI resin), using a standard sequence of amide-forming reactions, for example, conversion of the carboxylic acid into the corresponding acid chloride using thionyl chloride at low temperature in dichloromethane, (se) acetonitrile, or DMF, followed by amine, the third diversifying building block of the formula "(Ma) is introduced. The final product is separated from the resin using dilute sodium methoxide in a methanol/tetrahydrofuran mixture at room temperature. uh-

Scheme 1 - p. and? -I sh" (ee) at 50 (42)

F) name) 60 b5 ve ve re

Y ry 1) BOS,

DL, 2) (c) in M and t5 | hi k-vosken 7 sho KHIM: Vih Ne SOSNA)

HU: You (SNO MASNI SO Ve, Ki - S(ODO(SNI(BB) sch

HUST of the entire SN SOON, VOYU RI) svi in i

F M schiva Y | so /t im chi

And h-

III l with A. so --x MA SNoa-- m ---(СНо у « ry х / Z t EI Ha che y Iy (Hv, zo EMmS(ОЮ(СНО РЕ), P5 and Polystyrene abosmola Mapy -o c Experimental section: c» Melting points were determined on a Vyspi B-540 instrument and were not corrected. Mass spectra were obtained using the Otsaigo M5-M5 system from the company MO Vioyesi, Rizopz Ipzigitepiv. Analytical data of LC-MS were obtained on a RE apparatus 5x АРИ 150ЭХ supplied by the source of ion sputtering and the РХ system of Zpitaidga - 15 ІС-ВА/5І С-10A. Liquid chromatography (LC) was performed (50x4bmm MMC О05-А with a particle size of 5 μm) eluting with a linear gradient with a mixture of water/acetonitrile/trifluoroacetate acid (gradient from 90:10:0.05 t. to 10:90:0.03) for 7 minutes at 2 ml/min. Purity was determined by integration of the UV trace (254 nm). Retention time K, so was expressed in minutes. Preparative LC -MSOS-distribution was carried out on the same apparatus. Conditions of RH (50 x 20 mm

MMC O05-A with a particle size of 100 µm) was eluted with a linear gradient with a mixture of water/acetonitrile/trifluoroacetic acid (gradient from 80:20:0.05 to 5:95:0.03) for 7 minutes at 22.7 ml /min. Fractional collection was performed using MO-detection of a branched flow.

H NMR spectra were recorded at 250.13 MHz on a Vgykeg AS 250 device or at 500.13 MHz on a Vgykeg device

OKH 500. Deuterated chloroform (99.8956 U) or dimethyl sulfoxide (99.9965 0) were used as solvents. TM5 was used as an internal standard. The values of chemical shifts were expressed in m.h. (million"). The following abbreviations were used to denote different NMR signals: c - singlet, d - doublet, t - triplet, kv

F, - quartet, kvi - quintet, g - heptet, dd - double doublet, dt - double triplet, dkv - double quartet, ime) tt - triplet of triplets, m - multiplet, width. - wide NMR signals corresponding to acidic protons were usually neglected. The water content in crystalline compounds was determined by Karl Fischer titration. Silica gel of the Kieseide type was used for column chromatography! 60, 40-60 mesh for AZTM. The following material was used for ion exchange chromatography: 5CX-columns (1g) from the company Magiap Meda Vopa EitsiF),

SpgotraskK, catalog number 220776. Before use, the LC-column was pre-conditioned with a 1090 solution of acetic acid in methanol (Zml).

Examples 65 Preparation of intermediate compounds

A. Alkylating reagents

1-(2-chloroethyl)-3,4-dihydroquinolin-2(1H)-one

A suspension of sodium hydride (3.0g, 6095 in mineral oil) and dimethylformamide (10O0ml) was kept at 15-1892С7, after which a solution of 3,4-dihydroquinolin-2(1H)-one (10.0g) in dimethylformamide (15Oml) was added. . The resulting mixture was stirred at room temperature for 60 minutes, after which a solution of 2-chloroethyl acetate (10.0 g) in dimethylformamide (5 Oml) was added at a temperature of 2020. The resulting mixture was heated to 802C for 2.5 hours, cooled and poured onto ice. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine, dried (M950 5) and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel (eluent: ethyl acetate/heptane, 1:11) to give crude 70. 1-(2-acetoxyethyl)-3,4-dihydroquinolin-2(1H)-one (10.2g). A mixture of crude 1-(2-acetoxyethyl)-3,4-dihydroquinolin-2(1H)-one, sodium methylate (2.5 mL, 3095 in methanol) and methanol (250 mL) was stirred at room temperature for 16 hours and then concentrated under vacuum conditions. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate/heptane, 1:11) to obtain the corresponding alcohol as a red crystalline compound (4.9 g). This alcohol was dissolved in tetrahydrofuran 75 (10 Oml), after which triethylamine (8.2 ml) was added. The resulting mixture was cooled to 5-69, after which a solution of methanesulfonic acid chloride (2 ml) in tetrahydrofuran (25 ml) was added. The mixture was filtered and evaporated to dryness under vacuum conditions. The residue was dissolved in dimethylformamide (50 ml), after which lithium chloride (4.9 g) was added and the resulting mixture was heated to 702 for 5 minutes. The mixture was poured into brine and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (Mo 5 O)), filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate/heptane, 1:1) to give the product as a red oil (2.9 g). 1-(3-bromopropan-1-yl)-3,4-dihydroquinolin-2(1H)-one

A suspension of sodium hydride (6b, 8g, 6095 in mineral oil) and dimethylformamide (200ml) was kept at 20-252C, after which a solution of 3,4-dihydroquinolin-2(1H)-one (25.0g) in dimethylformamide (18Oml) was added. . c 25 The resulting mixture was stirred at room temperature for 10 minutes, after which a solution of Ge) 1,3-dibromopropane (172g) in dimethylformamide (150ml) was added at a temperature of 20-359C. The resulting mixture was stirred at 302C for 20 minutes and concentrated under vacuum conditions. The residue was poured onto ice and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried (MozoO) and concentrated under vacuum conditions. The crude product was purified by flash chromatography on silica gel (eluent: 30% ethyl acetate/heptane, 1:1) to give the product as a yellow oil (27 g). co

The following compounds were obtained in a similar way: 1-(4-bromobutan-1-yl)-3,4-dihydroquinolin-2(1H)-one co from 3,4-dihydroquinolin-2(1H)-one and 1,4-dibromobutane "I 1-(5-bromopentan-1-yl)-3,4-dihydroquinolin-2(1H)-one

Zo from 3,4-dihydroquinolin-2(1H)-one and 1,5-dibromopentane t 4-(4-bromobutan-1-yl)-3,4-dihydro-2H-1,4-benzoxazin-3(4H )-one from 3,4-dihydro-2H-1,4-benzoxazin-3(4H)-one and 1,4-dibromobutane 2-(3-hydroxypropan-1-yl)-3,4-dihydroisoquinoline-1( 2H)-one from 3,4-dihydroisoquinolin-1(2H)-one and 3-bromopropanol 37Z 2-(4-bromobutan-1-yl)-3,4-dihydroisoquinolin-1(2H)-one from 3 ,4-dihydroisoquinolin-1(2H)-one and 1,4-dibromobutane; z» 1-(3-bromopropan-1-yl)-3,4-dihydroisoquinolin-1(2H)-one

The compound 2-(3-hydroxypropan-1-yl)-3,4-dihydroisoquinolin-1(2H)-one was dissolved in tetrahydrofuran (10 Oml), after which triethylamine (5.2 ml) was added. The resulting mixture was cooled to 6-112C, after which a solution of methanesulfonic acid chloride (1.4ml) in tetrahydrofuran (25ml) was added. The mixture was stirred at 59C for 10 minutes, filtered and concentrated under vacuum conditions. The residue was dissolved in acetone (250 ml), after which lithium bromide (6.5 g) was added and the resulting mixture was refluxed for 2 hours. The mixture was poured into brine and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (MazO)), filtered and concentrated under vacuum conditions. The residue was purified by flash chromatography (95) on silica gel (eluent: ethyl acetate/heptane, 1:2) to give the product as a yellow oil (2.7). o 3-chloro-1-(3,4-dihydro-1H-isoquinolin-2-yl)upropan-1-one

A solution of 3-chloropropanoyl chloride (10.5 g) in tetrahydrofuran (400 ml) was cooled to 6°C, after which a solution of 3,4-dihydro-1H-isoquinoline (10.0 g) was added. The resulting mixture was stirred at 102 for 30 minutes, 5B was filtered and concentrated under vacuum conditions. The residue was subjected to standard aqueous work-up, after which it was purified by flash chromatography on silica gel (eluent: ethyl acetate/heptane, 1:1) to give the product (F) as a colorless oil (10 g). The following compounds were obtained in a similar way:

3-bromo-1-(3,4-dihydro-1H-isoquinolin-2-yl)upropan-1-one 60 from 3,4-dihydro-1H-isoquinoline and 3-bromopropanoyl chloride 4-chloro-1-(3, 4-dihydro-1H-isoquinolin-2-yl)butan-1-one from 3,4-dihydro-1H-isoquinoline and 4-chlorobutanoyl chloride 4-chloro-1-(3,4-dihydro-2H-quinolin-1- yl)butan-1-one from 3,4-dihydro-2H-quinoline and 4-chlorobutanoyl chloride 65 Preparation of intermediate compounds on a solid basis

Production of 4-nitrophenyloxycarbonyloxyethylpolystyrene

A 2 L flask with a round bottom was loaded with hydroxyethyl polystyrene (62.9 g, 83 Zmmol, sold by

Carr Roiutege, cat. Mo NA 140000), M-methylmorpholine (200 ml, 183 mmol) and dry dichloromethane (900 ml).

The suspension was cooled in an ice bath and 4-nitrophenyl chloroformate dissolved in

In dry dichloromethane (40O0ml). The mixture was stirred at room temperature for 16 hours. The resin was filtered and washed with dry dichloromethane (5x200ml). The resin was dried under vacuum conditions (202C, 72 hours) to obtain the title resin (79.6g).

Preparation of 7-chloro-3-(piperidin-4-yl)-1H-indole bound to a polymer 100 ml round-bottomed flask was charged with 4-nitrophenyloxycarbonyloxyethyl polystyrene (4.OHg, 7/0 4.Zmmol), 7- chloro-3-(1-tert-butoxycarbonylpiperidin-4-yl)-1H-indole (2.7g, 8.1mmol), diisopropylethylamine (3.5ml, 20.2mmol), 4-dimethylaminopyridine (0.5g, 4mmol) and dry dimethylformamide (5 Oml). The mixture was stirred at 909C for 72 hours. After cooling to room temperature, the resin was filtered and washed with dry dimethylformamide (3x25ml), dry acetonitrile (3x25ml) and dry dichloromethane (3x25ml). The resin was transferred to a 250 ml glass cylinder with a frit and a triple adapter for 75 days. The resin was then treated for 20 minutes with bOml of a 1:1 mixture of dichloromethane and trifluoroacetic acid containing anisole (295 w/w) and methionine (0.290 w/w), using a stream of nitrogen to stir the resin (warning: release of carbon dioxide ). The resin was filtered and washed with dry dichloromethane (25ml), 111 mixture of dichloromethane:triethylamine (3x25ml) and dry dichloromethane (3x25ml). The resin was dried under vacuum conditions (202C, 20 hours) to obtain the resin specified in the title (3Z, 8Hg). 20 The following compounds bound to the polymer were obtained in a similar way: 4-chloro-3-(piperidin-4-yl)-1H-indole, 4-fluoro-3-(piperidin-4-yl)-1H-indole, 5-chloro-3-(piperidin-4-yl)-1H-indole, 5-fluoro-3-(piperidin-4-yl)-1H-indole, c 25 b-chloro-3-(piperidin-4-yl) )-1H-indole. at

Preparation of 3-I4-(7-chloro-1H-indol-3-yl)piperidin-1-yl|Ipropionic acid. polymer-bound 25 mL round-bottom flask was charged with polymer-bound 7-chloro-3-(piperidin-4-yl)-1H-indole (1.0 g, 0.98 mmol), triethylamine (80.2 mL) , tert-butyl-3-bromopropionate and dry acetonitrile (5 ml). The mixture was stirred at 802 for 3 hours. After cooling to room temperature, the resin was filtered at 30° and washed with dry acetonitrile (3x10ml) and dry dichloromethane (3x10ml). The resin was treated for 20 s minutes with ml of a 1:1 mixture of dichloromethane and trifluoroacetic acid containing anisole (295 w/w) and methionine (0.295 w/w) (warning: release of carbon dioxide). The resin was filtered and washed with dry dichloromethane (1Oml), a 1:11 mixture of dichloromethane:triethylamine (3X1!Oml) and dry dichloromethane (3X1Oml). "w

The resin was dried under vacuum conditions (202C, 20 hours) to obtain the resin specified in the title (1.0OHg).

The following compounds bound to the polymer were obtained in a similar way: -1H-indol-3-yl)piperidin-1-yl|Ipropionic acid, 3-I4-(5-fluoro-1H-indol-3-yl)piperidin-1-yl|Ipropionic acid, « 3-I4-( 6β-chloro-1H-indol-3-yl)/piperidin-1-yl|propionic acid, 37Z 4-(4-(4-chloro-1H-indol-3-yl)piperidin-1-yl)butyric acid, c 4-(4-(4-fluoro-1H-indol-3-yl)piperidin-1-ylbutyric acid, ; c» 4-I4-(5-chloro-1H-indol-3-yl)piperidin-1- yl)butyric acid, 4-I4-(5-fluoro-1H-indol-3-yl)piperidin-1-ylbutyric acid, 4-I4-(7-chloro-1H-indol-3-yl)piperidin-1- yl)butyric acid, 5-I4-(4-chloro-1H-indol-3-yl)/piperidin-1-yl|pentanoic acid, - 5-I4-(5-fluoro-1H-indol-3-yl) Piperidin-1-yl|pentanoic acid, t» 5-I4-(7-chloro-1H-indol-3-yl)/piperidin-1-yl|pentanoic acid, 6-I4-(4-fluoro-1H-indole -3-yl)piperidine-1-ylhexanoic acid,

Co 6-I4-(4-chloro-1H-i -3-yl)pi -1-indol-3-yl)piperidin-1-ylhexanoic acid, (4) 50 6-I4-(5-fluoro- 1H-indol-3-yl)piperidin-1-ylhexanoic acid, 6-I(4-(6b-chloro-1H-indol-3-yl)piperidin-1-ylhexanoic acid, c 6-I4-(7-chloro -1H-indol-3-yl)piperidin-1-ylhexanoic acid.

Preparation of the compounds of this invention

Example 1 99 Ta, 5-fluoro-3-11-(2-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)lethyl|piperidin-4-yl)-1H-indole hydrochloride

GF) Mixture of /5-fluoro-3-(piperidin-4-yl)-1H-indole (0.3g), 1-(2-chloroethyl)-3,4-dihydroquinolin-2(1H)-one (041g) and triethylamine (0.75g) in dimethylformamide (bml) and butanone (10ml) were refluxed for b hours. The mixture was concentrated under vacuum conditions, and the residue was purified by flash chromatography on silica gel (eluent: ethyl acetate/ethanol/triethylamine, 90:10:5) to obtain a crude product, which was isolated from acetone in the form of a hydrochloride salt as a white crystalline compound ( 0.04g). "H NMR (DMSO-dv): 2.00-2.25 (m, 4H); 2.60 (t, 2H); 2.90 (t, 2H); 2.95-3.10 (m, 1H); 3.10-3.30 (m, 4H); 3.70 (d, 2H); 4.35 (t, 2H); 6.90 (t, 1H); 7.05 (t, 1H ); 7.15-7.40 (m, 5H); 7.50 (d, 1H); 10.95 (width, 1H); 11.05 (s, 1H), MS t/: 392 ( МН), 174. v The following compounds were obtained in a similar way:

IV, 5-fluoro-3-11-I3-(1-oxo-3,4-dihydro-1H-quinolin-2-yl)propan-1-yl|Ipiperidin-4-yl)-1H-indole oxalate from B -fluoro-3-(piperidin-4-yl)-1H-indole and 1-(3-bromopropan-1-yl)-3,4-dihydroisoquinolin-1(2H)one. NN NMR (DMSO-4v): 1.90-2.15 (m, 6Н); 2.95-3.15 (m, 7H); 3.55-3.60 (m, 6H); 6.90 (t, 1H); 7.20 (s, 1H); 7.30 (d, 1H); 7.30-7.40 (m, 4H); 7.45-7.50 (m, 1H); 7.90 (d, 1H); 11.05 (s, 1H), MS t/: 406 (MH), 188. 1s, hydrochloride 5-fluoro-3-11-I(4-(1-oxo-3,4-dihydro-1H-quinoline- 2-yl)butan-1-yl)|piperidin-4-yl)-1H-indole from B-fluoro-3-(piperidin-4-yl)-1H-indole and 2-(4-bromobutan-1-yl) )-3,4-dihydroisoquinolin-1(2H)one. NO NMR (DMSO-iv): 1.55-1.70 (m, 2H); 1.70-1.85 (m, 2H); 2.05 (d, 2H); 2.10-2.25 (m, 2H); 2.90-3.15 (7H); 3.40-3.65 (m, 6H); 6.90 (t, 1H); 7.20 (c, 1); 7.30 (d, 1H); 7.30-7.40 (m, 2H); 7.40-7.55 (m, 2H); 7.90 (d, 1H); 10.75 (width, 1H); 11.05 (s, 1H), MS t/7: 420 (MH). 70 Example 2 2a, 5-fluoro-3-11-I3-(2-oxo-3.4-dihydro-2H-quinolin-1-yl)/propan-1-yl|piperidin-4-yl)-1H-indole hydrochloride

A mixture of 5-fluoro-3-(piperidin-4-yl)-1H-indole (5.0 g), 1-(3-bromopropan-1-yl)-3,4-dihydroquinolin-2(1H)-one (7 .77) and potassium carbonate (7.0g) in dimethylformamide (40ml) was heated to 1009 for 2.5 hours. The mixture was cooled, filtered and concentrated under vacuum. The residue was purified by flash chromatography on 75 silica gel (eluent: ethyl acetate, then ethyl acetate/ethanol, 90:10) to give the product as an orange oil (9.1 g). The title compound (1.8 g of free base) was isolated as a hydrochloride salt from tetrahydrofuran as a white crystalline compound (1.5 g). T. pl. 210-2122С. 7N

NMR (DMSO-α): 2.00-2.20 (m, 6Н); 2.60 (t, 2H); 2.90 (t, 2H); 2.95-3.10 (m, ZN); 3.10-3.20 (m, 2H); 3.55 (d, 2H); 3.95 (t, 2H); 6.90 (t, 1); 7.05 (t, 1); 7.15-7.30 (m, 4H); 7.30-7.40 (m, 1H); 7.50 (d, 1H); 10.55 (width, 1H); 11.05 (s, 1H), MS t/: 406 (MN.Yu).

The following compounds were obtained in a similar way: 26, 5-fluoro-3-11-I5-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)upentan-1-yl|piperidin-4-yl) hydrochloride -1H-indole from 5-fluoro-3-(piperidin-4-yl)-1H-indole and 1-(5-bromopentan-1-yl)-3,4-dihydroquinolin-2(1H)-one. /T. sq. 199-20052, "H NMR (DMSO-iv): 1.30-1.0 (m, 2H); 1.55-1.60 (m, 2H); 1.70-1.80 (m, 2H ); 2.05-2.15 (m, 4H); s 2.55 (t, 2H); 2.85 (t, 2H); 2.95-3.10 (m, 5H); 3.55 (d, 2H); 3.90 (t, 2H); 6.90 (t, 1); 7.00 (t, 18); 715 OO (d, 1); 7.20-7.30 (m , ZN); 7.30-7.35 (m, 1H); 7.50 (d, 1H); 12.20 (width, 1H); 11.05 (s, 1H), MS t/: 434 (MH Kk). 2c, 5-chloro-3-11-(3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)upropan-1-yl|piperidin-4-yl) hydrochloride )-1H-indole from 5-chloro-3-(piperidin-4-yl)Y-1H-indole and 1-(3-bromopropan-1-yl)-3,4-dihydroquinolin-2(1H)-one. TT. pl. o 1342-146b9b, "H NMR (DMSO-yv): 1.95-2.15 (m, 6Н); 2.60 (t, 2H); 2.90 (t, 2H); 2.95-3.15 (ZN); 3.15-3.20 (m, 2H); 3.55 (d, 2H); 3.95 (t, 2H); 7.00-7.10 (m, 2H); 7.20-7.30 (m, 4H); 7.35 (d, 1H); 7.75 (s, 1H), 11.30 o (lat.s, 1H); 11.15 (s, 1H), MS t/: 422 (MH), 188. Ge) 24, 5-chloro-3-11-(4-(2-oxo-3,4-dihydro-2H-quinoline) hydrochloride -1-yl)butan-1-ylIpiperidin-4-yl)-1H-indole from B-chloro-3-(piperidin-4-yl)-1H-indole and 1-(4-bromobutan-1-yl)- 3,4-dihydroquinolin-2(1H)-one. T.pl. 229-23120. /N Z

NMR (DMSO-Idv): 1.55-1.65 (m, 2H); 1.70-1.80 (m, 2H); 2.00-2.15 (m, 4H); 2.55 (t, 2H); 2.85 (t, 2H); i- 2.95-3.15 (m, 5H); 2.55 (d, 2H); 3.95 (t, 2H); 7.00 (t, 1H); 7.05 (d, 1H); 7.15 (d, 1H); 7.20-7.30 (m, ZN); 7.40 (d, 1H); 7.75 (c, 1H); 10.05 (width, 1H); 11.10 (s, 1H), MS t/2: 436 (MN Kk). 2e, 5-chloro-3-11-15-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)pentan-1-yl|piperidin-4-yl)-1H-indole hydrochloride 5-chloro-3-(piperidin-4-yl)Y-1H-indole and 1-(5-bromopentan-1-yl)-3,4-dihydroquinolin-2(1H)-one. TT. sq. 206-20902, "H NMR (DMSO-iv): 1.30-1.40 (m, 2H); 1.55-1.65 (m, 2H); 1.70-1.80 (m, 2H ); 2.00-2.15 (m, 4H); c) s 2.55 (t, 2H); 2.85 (t, 2H); 2.95-3.10 (m, 4H); 3 ,10-3.25 (m, 1H); 3.55 (d, 2H); 3.90 (t, 2H); 7.00 (t, 1H); "from 7.05 (d, 1); 7.15 (d, 71Н); 7.20-7.30 (m, ZN); 7.40 (d, 1H); 7.75 (c, 1H); 11.20 (latitude, 1H); 11.15 (s. MH), " MeSti/: 450 (MH), 299. 21, hydrochloride 7-chloro-3-11-14-(2-oxo-3,4-dihydro-2H-quinoline-1- yl)butan-1-yl|piperidin-4-yl)-1H-indole 75 3 7-chloro-3-(piperidin-4-yl)-1H-indole and 1-(4-bromobutan-1-yl)- 3,4-dihydroquinolin-2(1H)-one. TT. pl. im 253-2542s. "H NMR (DMSO-iv): 1.55-1.65 (m, 2H); 1.75-1.85 (m, 2H); 2.05-2.25 (m, 4H); 2.55 (t, 2H); 2.90 (t, 2H); 2.95-3.15 (m, 5H); 3.55 (d, 2H); 3.95 (t, 2H); 6.95-7.05 (m, 2H); 7.15-7.30 (m, 5H); 7.70 (d, tn); so 10.60 (width s, 1H); 11.30 (s, 1H), MS t/: 436 (MH), 289. 29, hydrochloride B-fluoro-3-11-I4-(3-oxo-3,4-dihydro-2H-1,4- benzoxazin-4-yl) 1, and (95) butan-1-yl|piperidin-4-yl)-1H-indole o with B5-fluoro-3-(piperidin-4-yl)-1H-indole and 4 -(4-bromobutan-1-yl)-3,4-dihydro-2H-1,4-benzoxazin-3(4H)-one.

T. pl. 83-92, IN NMR (DMSO-iv): 1.60-1.70 (m, 2H); 1.75-1.85 (m, 2H); 2.00-2.20 (m, 4H); 2.95-3.15 (m, 5H); 3.55 (d, 2H); 3.95 (t, 2H); 4.65 (c, 2H); 6.90 (t, 1H); 7.00-7.05 (m, 2H); 7.05-7.15 (m, 71Н); 7.20 (c, vv 1H); 725 (d, 1H); 7.30-7.40 (m, 1H); 7.50 (d, 1H); 10.45 (width, 1H); 11.05 (s, 1H), MS t/2: 422 (MNu), 273. 2p, hydrochloride (F. 5-chloro-3-11-I4-(3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-4-yl)butan-1-yl|Ipiperidin-4-yl)-1H-indole with 5-chloro-3-(piperidin-4-yl)-1H-indole and 4-(4 -bromobutan-1-yl)-3,4-dihydro-2H-1,4-benzoxazin-3(4H)-one.

T. pl. 222-2242p. "H NMR (DMSO-div): 1.60-1.70 (m, 2H); 1.75-1.85 (m, 2H); 2.05-2.15 (m, 4H); 3, 00-3.15 (m, 6vo ZN); 3.55 (d, 2H); 3.95 (t, 2H); 4.65 (s, 2H); 7.00-7.10 (m, 4H ); 7.20 (s, 1H); 7.25 (d, 1H); 7.40 (d, 1H); 7.75 (s, 1H); 10.30 (width, 1H); 11 ,15 (c, 1H), MS t/l: 438 (MN), 291, 204.

Example C

Za, oxalate 5-fluoro-3-11-3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propan-1-yl|-3,6-dihydro-2H-pyridin-4 -yl)-1H-indole 65 A mixture of 5-fluoro-3-(3,6-dihydro-2H-pyridin-4-yl)-1H-indole (3.0g) and potassium carbonate (6.2g) in butanone ( 250ml) was heated to boiling temperature under reflux, after which it was added

1-(3-bromopropan-1-yl)-3,4-dihydroquinolin-2(1H)-one (5.0g) in butanone (50ml). The resulting mixture was refluxed for 10 hours, filtered and concentrated under vacuum (7.7 g). The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate/triethylamine, 100:5) to obtain a crude product, which was crystallized from a mixture of tetrahydrofuran/ethyl acetate. The title compound was isolated from acetone/tetrahydrofuran in the form of an oxalate salt as a yellowish crystalline compound (1.7 g).

T. pl. 203-20620. "H NMR (DMSO-iv): 1.95-2.05 (m, 2H); 2.55 (t, 2H); 2.75 (s, 2H); 2.85 (t, 2H); 3 .15 (t, 2H); 3.35 (s, 2H); 3.80 (s, 2H); 3.95 (t, 2H); 6.05 (s, 1H); 6.95-7, 05 (m, 2H); 7.15-7.30 (m, ЗН); 7.35-7.45 (m, 1H); 7.50-7.60 (m, 2H); 11.50 ( s, 1H), MS t/: 404 (MN), 218.

The following compounds were obtained in a similar way:

Zp, 5-fluoro-3-(1-I4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-ylI-3,6-dihydro-2H-pyridin-4-yl hydrochloride )-1H-indole 3B-fluoro-3-(3,6-dihydro-2H-pyridin-4-yl)-1H-indole and /1-(4-bromobutan-1-yl)-3,4-dihydroquinoline -2(1H)-one.

T. pl. 124-125960. "IN NMR (DMSO-yv): 1.55-1.65 (m, 2H); 1.80 (k, 2H); 2.55 (t, 2H); 2.75 (d, 1H); 2 ,85-2,95 75 (m, ЗН); 3,15-3,30 (m, ЗН); 3,55-3,65 (m, 1Н); 3,75 (d, 1Н); 3, 90-4.00 (m, ZN); 6.10 (s, 1H); 6.95-7.05 (m, 2H); 7.15 (d, 1H); 7.20-7.30 ( m, 2H); 7.40-7.45 (m, 1H); 7.55-7.65 (m, 2H); 10.70 (width, 1H); 11.50 (s, 1H) ,

MS t/l: 418 (MN), 231.

Cs, oxalate 5-fluoro-3-11-(5-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)upentan-1-yl|-3,6-dihydro-2H-pyridin- 4-yl)-1H-indole from 5-fluoro-3-(3,6-dihydro-2H-pyridin-4-yl)-1H-indole and 1-(5-bromopentan-1-yl)-3,4 -dihydroquinolin-2(1H)-one.

T. pl. 205-2072C. "IN NMR (DMSO-div): 1.35 (t, 2H); 1.55 (t, 2H); 1.75 (t, 2H); 2.55 (t, 2H); 2.75 (s , 2H); 2.85 (t, 2H); 3.10 (t, 2H); 3.35 (s, 2H); 3.80 (s, 2H); 3.90 (t, 2H); 6 .10 (c, 1); 6.95-7.05 (m, 2H); 7.15 (d, 1); 7.20-7.30 (m, 2H); 7.40-7.45 (m, 1H); 7.55-7.60 (m, 2H); 11.50 (s, 1H), MS t/: 432 (MH), 245.

Example 4 with 4, 5-fluoro-3-7-(4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl|Ipiperidin-4-yl)-1H hydrochloride -indole o

Mixture

B-fluoro-3-11-I4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-ylI|-3,6-dihydro-2H-pyridin-4-yl) -1-H-indole (3.5 g), ethanol (100 ml), acetic acid (100 ml) and platinum oxide (0.4 g) were shaken under the atmosphere. within 16 hours.

The mixture was filtered, evaporated under vacuum to approximately 100 ml, then poured onto ice and added (2 aqueous ammonia solution to alkaline pH. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine, dried (Mo5O4) and concentrated under The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate/triethylamine, 100:4) to obtain the crude product g) (2.0 g). The title compound was isolated from ethyl acetate in the form of a hydrochloride salt as a white crystalline compound (2.0 g). T. pl. 212-21320. "H NMR (DMSO-iv): 1.55-1.65 (m, 2H); 1.75-1.85

Zo (m, 2H); 2.00-2.20 (m, 4H); 2.55 (t, 2H); 2.85 (t, 2H); 2.95-3.15 (m, 5H); 3.55 (d, 2H); 3.95 (t, 2H); 6.90 - (t, 1); 7.00 (t, 1H); 7.15-7.30 (m, 4H); 7.30-7.40 (m, 1H); 7.50 (d, 1H); 10.55 (width, 1H); 11.05 (c, 1H),

MS t/: 420 (MN), 273, 202.

Example 5 « ba, oxalate 5-fluoro-1-methyl-3-11-(3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)upropan-1-yl|Ipiperidin-4- yl)-1H-indole

A suspension of sodium hydride (0.5 g, 6095 in mineral oil) and dimethylformamide (bOml) was maintained at 3 s 22-24, after which the solution was added; c» 5-fluoro-3-11-3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propan-1-yl|Ipiperidin-4-yl)-1H-indole (4, 9g) in dimethylformamide (5 Oml). The resulting mixture was stirred at room temperature for 25 minutes, after which a solution of methyl iodide (2.0 g) in dimethylformamide (15 ml) was added at a temperature of 22-272С. The resulting mixture -1 395 was stirred at 2292 for 1 hour and poured onto ice. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine, dried (Mo5O/) and concentrated under vacuum conditions. The crude product was purified by flash chromatography on silica gel (eluent: ethyl acetate/heptane/triethylamine, SO 50:50:5) to give the product as an orange oil (2.4 g). The title compound was isolated from acetone in the form of an oxalate salt as a white crystalline compound (0.6 g). T. pl. at 188-18922. "H NMR (DMSO-in): 1.85-2.05 (m, 4H); 2.10 (d, 2H); 2.55 (t, 2H); 2.90 (t, 2H); 2 .95-3.05 (m, o ZN); 3.10 (t, 2H); 3.50 (d, 2H); 3.75 (s, ZN); 3.95 (t, 2H); 6 .95-7.05 (m, 2H); 7.15-7.30 (m, 4H); 7.35-7.45 (m, 2H), MS ti/l: 420 (MH), 188.

The following compounds were obtained in a similar way: 55, 5-fluoro-1-methyl-3-11-I4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl|piperidin- 4-yl)-1nH-indole

F) from 5-fluoro-3-11-I4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl|Ipiperidin-4-yl)-1H-indole and methyl iodide . name) T. pl. 177-17960. "YAN NMR (DMSO-dv): 1.55-1.65 (m, 2H); 1.75-1.85 (m, 2H); 2.00-2.15 (m, 4H); 2, 55 (t, 2H); 2.90 (t, 2H); 2.95-3.15 (m, 5H); 3.55 (d, 2H); 3.75 (s, ЗН); 3.95 (t, 2H); 6.95-7.05 (m, 2H); 7.15 (d, 1H); in 7.20-7.30 (m, ЗН); 7.35-7.45 ( m, 1H); 7.55 (d, 1H); 11.40 (width, 1H), MS t/z:: 434 (MN).

Bbs, oxalate 1-(butan-1-yl)-5-fluoro-3-11-I(4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl| -3,6-dihydro-2H-pyridin-4-yl)-1nH-indole from 5-fluoro-3-11-I4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butane -1-yl|-3,6-dihydro-2H-pyridin-4-yl)-1H-indole and butyl bromide. T. pl. 152-15496, IN nMR (DMSO-α): 0.90 (t, ZN); 1.20-1.30 (m, 2H); 1.55-1.65 (m, 2H); 65 1.65-1.80 (m, 4H); 2.55 (t, 2H); 2.75 (c, 2H); 2.85 (t, 2H); 3.10 (t, 2H); 3.35 (c, 2H); 3.80 (c, 2H); 3.95 (t, 2H); 4.15 (t, 2H); 6.10 (c, 1H); 6.95-7.05 (m, 2H); 7.15 (d, 71Н); 7.20-7.30 (m, 2H); 7.50-7.55 (m, 1);

7.55-7.70 (m, 2H), MS t/l: 474 (MN), 231.

Example 6 ba, 5-fluoro-3-11-(3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxopropan-1-yl|piperidin-4-yl)-1H-indole oxalate

A mixture of 5-fluoro-3-(piperidin-4-yl)-1H-indole (3.0g), butanone (200ml), tetrahydrofuran (100ml), methanol (BOml) and triethylamine (2.4ml) was heated to boiling point with under reflux, after which a solution of 3-chloro-1-(3,4-dihydro-1H-isoquinolin-2-yl)upropan-1-one (3.5 g) in butanone (bOml) was added. The mixture was refluxed for 30 hours, after which an additional amount was added

C-chloro-1-(3,4-dihydro-1H-isoquinolin-2-yl)upropan-1-one (2.0g) and triethylamine (1.bml) in tetrahydrofuran 7/0 (bOml). The resulting mixture was refluxed for another 12 hours. The mixture was cooled, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate/ethanol/triethylamine, 100:4:4) to obtain the crude product. The title compound was isolated from acetone in the form of an oxalate salt as a white crystalline compound (0.75 g). T. pl. 206-20922. "H NMR (DMSO-yv): 1.95 (k, 2H); 2.05-2.15 (m, 2H); 2.80 (t, 0O,8H); 2.90 (t, 1, 2H); 2.90-3.10 75 (m, 5H); 3.30 (t, 2H); 3.55 (d, 2H); 3.70 (t, 2H); 4.65 (s, 1.20Н); 4.70 (s, 0.8Н); 6.85-6.95 (m, 1Н); 7.15-7.25 (m, 5Н); 7.30-7.40 ( m, 1H); 7.40 (d, 1H); 11.05 (s, 1H), MS t/l: 406 (MH), 231.

The following compounds were obtained in a similar way: br, hydrochloride 7-chloro-3-11-3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxopropan-1-yl|piperidin-4-yl)- of 1H-indole from 7-chloro-3-(piperidin-4-yl)-1H-indole and 3-bromo-1-(3,4-dihydro-1H-isoquinolin-2-yl)propan-1-one. "NN NMR (DMSO-α): 2.05-225 (m, 4); 2.80 (t, 08Н); 2.95 (t, 1.2Н); 3.00-320 (m, 5Н) ; 3.30-3.45 (m, 2H); 3.55-3.65 (m, 2H); 3.65-3.75 (m, 2H); 4.65 (s, 12H); 4 .75 (s, 08H); 7.00 (t, 1H); 7.15-7.25 (m, 6H); 7.70 (d, 1H); 10.70 (width, 1H); 11.30 (s, 1H), MS p/z: 422 (MH), 247. bs, hydrochloride 5-chloro-3-11-I4-(3,4-dihydro-2H-quinolin-1-yl)- 4-oxobutan-1-yl|Ipiperidin-4-yl)-1H-indole from B-chloro-3-(piperidin-4-yl)-1H-indole and /4-chloro-1-(3,4-dihydro -2H-quinolin-1-yl)butan-1-one. m.p. SM 29 158-16290. "YAN NMR (DMSO-yv): 1.85-1.95 (m, 2H); 1.95-2.20 (m, 6H); 2.60-2.75 (m, 4H); 2.95-3.15 (m, 5H); d) 3.55 (d, 2H); 3.70 (t, 2H); 7.05-7.25 (m, 6H); 7.40 (d, 1H); 7.75 (c, 1H); 1045 (width p, 1H); 11.15 (c, 1H),

MS t/l: 436 (MN), 303.

Example 7 7, 5-fluoro-3-11-I4-(3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutan-1-yl|Ipiperidin-4-yl)-1H-indole o

A mixture of 5-fluoro-3-(piperidin-4-yl)-1H-indole (3.0 g), butanone (200 ml), tetrahydrofuran (200 ml), methanol (30 ml), potassium iodide (11.4 g) and triethylamine (7.bml) was heated to boiling temperature under reflux, after which a solution of 4-chloro-1-(3,4-dihydro-1H-isoquinolin-2-yl)butan-1-one (14.6g) in aq. butanone (5 Oml). The mixture was refluxed for 2 hours, filtered while hot and concentrated under vacuum. The residue was purified by flash chromatography on silica gel 3o (eluent: ethyl acetate/ethanol/triethylamine, 100:5:5) to obtain a crude product. The title compound was isolated from ethyl acetate in the form of a free base as a white crystalline compound (0.9 g). T. pl. 146-1482 p. "H NMR (DMSO-iv): 1.55-1.70 (m, 2H); 1.70-1.80 (m, 2H); 1.85-1.95 (m, 2H); 2, 00 (K, 2H); 2.30 (K, 2H); 2.35-2.45 (m, 2H); 2.60-2.70 (m, 1H); 2.75 (t, 0, 8H); 2.80-3.00 (m, 3.2H); 3.65 (t, 2H); 4.60 (s, « 1.2H); 4.70 (s, 0.8H); 6.85-6.95 (m, 1H); 7.10-7.20 (m, 5H); 7.25 (d, 1H); 7.30-7.35 (m, 1H); 10, 85 (s, 1H), -o 70 Me ptu/g: 420 (MH), 202.s Example 8 :z» 8,5-chloro-3-11-I4-(3,4-dihydro-1H-isoquinoline -2-yl)-4-oxobutan-1-yl|pteridin-4-yl)-1H-indole

A mixture of 5-fluoro-3-(piperidin-4-yl)-1H-indole (3.0 g), butanone (200 ml) and triethylamine (8.9 ml) was heated to boiling temperature with a reflux condenser, after which a solution of -1 15 4-chloro-1-(3,4-dihydro-1H-isoquinolin-2-yl)butan-1-one (15.2g) in butanone (80ml). The mixture was refluxed for 6 hours. The resulting mixture was filtered and concentrated under vacuum conditions. Remainder

It was purified by flash chromatography on silica gel (eluent: ethyl acetate/ethanol/triethylamine, 100:4:4) to obtain a crude product. The title compound was isolated from acetone in the form of a free base as a white crystalline compound (0.6 g). T. pl. 172-17590. NMR (DMSO-yv): 1.55-1.65 (m, 2H); 1.65-1.75 (95) (m, 2H); 1.90 (s, 2H); 2.00 (k, 2H); 2.30 (k, 2H); 2.40 (k, 2H); 2.65-2.80 (m, 1.8H); 2.80-3.00 (m, 3 ,2H); o 3.70 (t, 2H); 4.60 (s, 12H); 4.70 (s, 08H); 7.05 (d, 1H); 7.10-7.25 (m , 5H); 7.35 (d, 71H); 7.55 (s, 1H); 11.00 (s, 1H), MS t/: 436 (MN), 202.

Example 9

Za, 5-fluoro-3-11-I3-(3,4-dihydro-2H-quinolin-1-yl)/propan-1-yl|piperidin-4-yl)-1H-indole dihydrochloride

A suspension of lithium aluminum hydride (0.94 g) in tetrahydrofuran (40 ml) was stirred at 52C, after which (F) concentrated sulfuric acid (1.2 g) in tetrahydrofuran (200 ml) was added. The mixture was stirred at 72C for 60 minutes, after which 5-fluoro-3-11-3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propan-1-yl|Ipiperidin-4 was added -yl)-1H-indole (2.0g) in tetrahydrofuran (bbml). The resulting mixture was stirred at 59C for 60 minutes, after which it was processed in the standard way. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate) to give the crude product as a colorless oil. The title compound was isolated from tetrahydrofuran in the form of a dihydrochloride salt as a white crystalline compound (1.0 g). T. pl. 230-23620. "H NMR (DMSO-iv): 1.95 (t, 2H); 2.00-2.30 (m, 4H); 2.75 (t, 2H); 2.95-3.20 (m, 5H); 3.30 (t, 65 2H); 3.40 (t, 2H); 3.55 (d, 2H); 6.20 (width, 1H); 6.70 (width, 1H); 6.95 (m, 2H); 7.00 (d, 1H); 7.10 (t, 1H); 7.20 (s, 1H); 7.30-7.40 (m, 1H ); 7.50 (d, 1H); 10.95 (width, 1H); 11.05 (s, 1H), MS t/2: 392 (MN), 259.

The following compounds were obtained in a similar way: 90, dihydrochloride 5-fluoro-3-(1-I4-(3,4-dihydro-2H-quinolin-1-yl)butan-1-yl|piperidin-4-yl)-1H- indole from B-fluoro-3-11-I4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl)piperidin-4-yl-1H-indole. T. pl. 207-21220. /H NMR (DMSO-II6): 1.65 (s, 2H); 1.80-1.p90 (m, 2H); 1.95 (c, 2H); 2.05 (d, 2H); 2.20 (k, 2H); 2.65-2.80 (m, 2H); 2.95-3.25 (m, 4H); 3.15-3.25 (m, 1H); 3.35 (c, 4H); 3.55 (d, 2H); 4.65 (width s); 5.55-6.95 (m, ZN); 7.00 (c, 18); 7.10 (c, 1H); 7.20 (s, 1H); 7.30-7.40 (m, 1H); 7.55 (d, 1H); 11.75 (width, 1H); 11.05 (s, 1H), MS t/2: 406 (MH), 274.

Us, 5-fluoro-3-11-(5-(3,4-dihydro-2H-quinolin-1-yl)upentan-1-yl|piperidin-4-yl)-1nH-indole dihydrochloride 70 with B-fluoro -3-11-I5-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)upentan-1-yl|Ipiperidin-4-yl-1H-indole. T. pl. 155-1582C. /N

NMR (DMSO-ydv): 1.30-145 (m, 2H); 1.65 (c, 2H); 1.75-1.80 (m, 2H); 1.95 (c, 2H); 2.20 (k, 2H); 2.75 (c, 2H); 2.95-3.10 (m, 5H); 3.35 (c, 4H); 3.55 (d, 2H); 5.05 (width s); 6.70-7.15 (m, 4H); 6.90 (t, 1H); 7.20 (s, 1H); 7.30-7.40 (m, 1H); 7.50 (d, 1H); 10.75 (width, 1H); 11.05 (s, 1H), MS t/2: 420 (MH), 287.

Za, dihydrochloride 5-chloro-3-11-I(3-(3,4-dihydro-2H-quinolin-1-yl)/propan-1-yl|piperidin-4-yl)-1nH-indole with B- chloro-3-11-I3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propan-1-yl|Ipiperidin-4-yl)-1H-indole. T. pl. 201-20420. 7N

NMR (DMSO-α): 1.95 (t, 2H); 2.00-2.25 (m, 6H); 2.75 (t, 2H); 3.00-3.20 (m, 5H); 3.30 (t, 2H); 3.40 (t, 2H); 3.55 (d, 2H); 640 (width p); 6.65 (c, 1H); 6.85 (c, 1H); 6.95 (d, 1H); 7.00-7.10 (m, 2H); 7.20 (s, 1H); 7.40 (d, 1H); 7.75 (c, 1H); 10.85 (width, 1H); 11.20 (s, 1H), MS t/: 408 (MN yu), 275.

Ze, 5-chloro-3-11-I4-(3,4-dihydro-2H-quinolin-1-yl)butan-1-yl|Ipiperidin-4-yl)-1H-indole dihydrochloride with B-chloro-3 -11-14-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-ylIpiperidin-4-yl)-1H-indole. T. pl. 140-14520. /N

NMR (IDMSO-γ): 1.65 (c2H); 1.80-1.90 (m, 2H); 1.95 (c, 2H); 2.00-2.25 (m, 4H); 2.75 (c, 2H); 2.95-3.25 (m, 5H); 3.35 (c, 4H); 3.55 (d, 2H); 6.75 (width, 1H); 6.90 (width, 1H); 7.00 (c, 1H); 7.05-7.15 (m, 2H); 7.20 (s, 1H); 7.40 (d, 1H); 7.80 (c, 1H); 10.70 (width, 1H); 11.20 (s, 1H), MS t/: 422 (MH), 289, 188. 9, dihydrochloride 5-chloro-3-11-I5-(3,4-dihydro-2H-quinolin-1-yl) upentan-1-yl|piperidin-4-yl)-1H-indole c z. B-chloro-3-41-15-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)pentan-1-yl|Ipiperidin-4-yl)-1H-indole. T. pl. 101-1062C. /N He)

NMR (DMSO-α): 1.30-145 (m, 2H); 1.65 (c2H); 1.70-1.85 (m, 2H); 1.95 (c, 2H); 2.00-2.25 (m, 4H); 2.75 (c, 2H); 2.95-3.25 (m, 5H); 3.35 (c, 4H); 3.55 (d, 2H); 6.80 (width, 1H); 6.90-7.15 (m, 4H); 7.20 (s, 1H); 7.35 (d, 1H); 7.75 (c, 1H); 10.70 (width, 1H); 11.20 (s, 1H), MS t/: 436 (MH Kk), 303. yes, dihydrochloride 7-chloro-3-11-I4-(3,4-dihydro-2H-quinolin-1-yl)butane -1-yl|piperidin-4-yl)-1H-indole o with 7-chloro-3-11-I4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1- yl|piperidin-4-yl)-1H-indole.T. sq. 214-21990. "But

NMR (DMSO-α): 1.65 (c2H); 1.80-1.90 (m, 2H); 1.95 (c, 2H); 2.00-2.15 (m, 2H); 2.15-2.30 (m, 2H); 2.70 (c, 2H); 2.95-3.15 (m, 5H); 3.35 (c, 4H); 3.55 (d, 2H); 6.70 (width, 1H); 6.85 (width, 1H); 6.95-7.05 (m, so 2H); 7.10 (c, 1H); 7.15-7.25 (m, 2H); 7.70 (d, 1H); 10.80 (width, 1H); 11.30 (c, 1H), MS t/: 422 (MN), 289, 188. "I

Zp, 5-fluoro-1-methyl-3-11-(3-(3,4-dihydro-2H-quinolin-1-yl)upropan-1-yl|Ipiperidin-4-yl)-1H-indole dihydrochloride with 5-Fluoro-1-methyl-3-11-I3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)upropan-1-yl|piperidin-4-yl)-1H-indole. t. - sq. 202-20626p. "H NMR (DMSO-iv): 1.85-1.95 (m, 2H); 2.00-2.10 (m, 4H); 2.10-2.25 (m, 2H); 2, 65-2.75 (m, 2H); 2.95-3.15 (m, 5H); 3.25-3.35 (m, 2H); 3.35-3.40 (m, 2H); 3.55 (d, 2H); 3.75 (s, ZN); 6.65 (width, 1H); 6.80 (width, 1H); 6,90-7,10 (m, ЗН); 7.20 (s, 1Н); 7.35-7.45 (m, 1Н); 7.55 (d, 1Н); 10.90 (width с, 1), MS t/: 20 406 (MN), 273. -o

Z, 5-fluoro-1-methyl-3-11-I4-(3,4-dihydro-2H-quinolin-1-yl)butan-1-yl|Ipiperidin-4-yl)-1H-indole oxalate 5-fluoro-1-methyl-3-(1-I4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl|Ipiperidin-4-yl)-1H-indole . TT. sq. from 123-12520. "H NMR (DMSO-iv): 1.50-1.60 (m, 2H); 1.65-1.75 (m, 2H); 1.80-1.90 (m, 2H); 1, 90-2.00 (m, 2H); 2.10 (d, 2H); 2.60-2.70 (m, 2H); 2.95-3.10 (m, 5H); 3.20- 3.30 (m, 4H); 3.50 (d, 2H); 3.75 (s, ЗН); 6.45 (t, 455 1H); 6.60 (d, 1H); 6.85 ( d, 1H); 6.95-7.05 (m, 2H); 7.20 (s, 1H); 7.40-7.45 (m, 2H), MS t/g: 420 (MH), 287. -I 9), dihydrochloride 5-fluoro-3-11-I4-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)butan-1-yl|piperidin-4-yl)- 1nH-indole from 5-fluoro-3-11-I4-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)butan-1-yl|Ipiperidin-4-yl)- yH-indole. TT. pl. ve 179-18620. "H NMR (DMSO-yv): 1.55-1.65 (m, 2H); 1.75-1.90 (m, 2H); 2.00-2.10 (m, 2H); 2.15-2.25 (m, 2H); o 2.95-3.25 (m, 5H); 3.25-3.40 (m, 4H); 3.55 (d, 2H); 4.15-425 (m, 2H); 6.55 (t, 1H); 6.65 (d, 1H); 6.70-6.80 (m, 2H); 6.90 (t, 1H); 7.20 (s, 1H); 7.30-7.40 (m, 1H); 7.55 (d, 1H); 10.80 (width, 1H); 11.05 (s, 1H), MS t/:

Mami 408 (MN.Yu, 273, 190. o OK, dihydrochloride 5-chloro-3-11-I4-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)butan-1-yl| Ipiperidin-4-yl)-1nH-indole from 5-chloro-3-11-14-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)butan-1-yl| piperidine-4-yl-1H-indole. TT. sq. 186-19022. "H NMR (DMSO-iv): 1.55-1.65 (m, 2H); 1.70-1.85 (m, 2H); 2.00-2.20 (m, 4H); 2, 95-3.25 (m, 5H); 3.25-3.40 (m, 4H); 3.55 (d, 2H); 4.15-420 (m, 2H); 6.55 (t, 1H); 6.65 (d, 1H); 6.70-6.80 (m, 2H); 7.05 (d, 1H); 7.20 (s, 1H); 7.40 (d, 1H ); 7.75 (s, 1H); 10.50 (width, 1H); 11.15 (s, 1H), MS t/: 424 (MN), 289, 190.

IF) 9I, dihydrochloride ime) 5-fluoro-3-11-I3-(3,4-dihydro-2H-quinolin-1-yl)propan-1-yl|-3,6-dihydro-2H-pyridin-4 -yl)-1H-indole from 5-fluoro-3-11-I3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)upropan-1-yl|-3,6-dihydro- 2H-pyridin-4-yl)-1H-indole. 60 square meters 220-2239b. "H NMR (DMSO-div): 1.85-2.00 (m, 2H); 2.05-2.10 (m, 2H); 2.70-2.80 (m, 4H); 2, 90-3.00 (m, 1H); 3.15-3.30 (m, 2H); 3.30-3.35 (m, 2H); 3.40 (t, 2H); 3.55- 3.65 (m, 1H); 3.70-3.80 (m, 1H); 4.00 (d, 1H); 6.10 (s, 1); 6.70 (width, 1H) 6.90 (width, 1H); 6.95-7.05 (m, 2H); 7.05-7.10 (m, 71H); 7.40-7.45 (m, 1) ; 7.55-7.65 (m, 2H); 11.10 (width, 1H); 11.60 (s, 1H), MS t/:: 390 (MN), 203, 146.

Ut, dihydrochloride 65 5-fluoro-3-(1-I4-(3,4-dihydro-2H-quinolin-1-yl)butan-1-yl)|-3,6-dihydro-2H-pyridin-4- yl)-1nH-indole from 5-fluoro-3-11-I4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-ylI|-3,6-dihydro-2H -pyridin-4-yl)-1H-indole.

T. pl. 198-2002 p. "H NMR (DMSO-dv): 1.60-1.75 (m, 2H); 1.80-1.90 (m, 2H); 1.95 (s, 2H); 2.70-2, 80 (m, 4H); 2.85-3.00 (m, 71H); 3.15-3.30 (m, 4H); 3.30-3.40 (m, 2H); 3.55- 3.65 (m, 71H); 3.70-3.80 (m, 1H); 3.95 (d, 1H); 6.10 (s, 1h); 6.80 (width, 1H) ; 6.90-7.20 (m, ZN); 7.00 (t, 1H); 7.40-7.45 (m, 1H); 7.55-7.65 (m, 2H); 10 .95 (width, 1H); 11.55 (s, 1H), MS t/l: 404 (MN), 271, 217.

Zp, 5-fluoro-3-11-(5-(3,4-dihydro-2H-quinolin-1-yl)upentan-1-yl|-3,6-dihydro-2H-pyridin-4-yl) dihydrochloride -1H-indole z. 5-fluoro-3-11-I5-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)upentan-1-yl|-3,6-dihydro-2H-pyridin-4-yl) -1H-indole.

T. pl. 167-16990. "H NMR (DMSO-iv): 1.30-145 (m, 2H); 1.70 (s, 2H); 1.75-1.90 (m, 2H); 2.00 (s, 2H) ; 70 2.710-2.85 (m, ZN); 2.85-3.00 (m, 1H); 3.05-3.20 (m, 2H); 3.20-3.30 (m, 1 ); 3.35 (s, 2H); 3.55-3.65 (m, 1H); 3.70-3.80 (m, 1H); 3.95 (d, 1H); 6.10 ( s, 1H); 6.80-7.25 (m, 4H); 7.00 (t, 1); 7.40-7.45 (m, 1); 7.55-7.65 (m, 2H); 11.00 (s, width s, 1H); 11.60 (s, 1H), MS t/: 418 (MN), 231, 188.

Example 10 1ba, 4-fluoro-3-11-3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxopropan-1-yl|piperidin-4-yl)-1H-indole 3- (1-(4-fluoro-1H-indol-3-yl)piperidin-1-yl)propionic acid bound to the polymer (0.1g, 0.08mmol) and dry dichloromethane (ml) were mixed in a chemical test tube . The mixture was cooled to 02C and treated for 2 hours with a 2M solution of thionyl chloride (0.4ml, 0.8mmol) in dichloromethane. The resin was filtered and washed with dry dichloromethane (3x 1ml), resuspended in dichloromethane (ml) and treated at room temperature for 3 hours with 3,4-dihydro-1H-isoquinoline (0.05g, 04mmol). The resin was filtered and washed with dichloromethane (3x1ml), a 1:11 mixture of dichloromethane:triethylamine (3x1ml) and dry dichloromethane (3x1ml).

The resin was treated for 1 hour with a mixture of sodium methoxide (2ml, 5M solution of sodium methoxide in methanol), methanol (5Oml) and tetrahydrofuran (5Oml). After filtration, the resin was washed with methanol (ml).

The combined filtrates were loaded into a pre-conditioned ion-exchange column (500 mg ZX-column, sold by the company Apaiuis! Ipvigitepiv, MO batch 1210-2040), washed with acetonitrile (ml) and methanol with (1 ml). The product was eluted with a 4M solution of ammonia in methanol. After evaporation of the volatile solvents, the crude product was purified by reverse-phase preparative HPLC. The resulting solution was then loaded into a pre-conditioned ion exchange column, washed with acetonitrile (ml) and methanol (ml). The product was eluted with a 4M solution of ammonia in methanol. After evaporation of volatile solvents, the title compound was obtained as a yellow oil (5 mg, 12 μmol). LC/MS (t/:) 406 (MN), CT-3.61, o purity: 6695. so

The following compounds were obtained in a similar way (106-10t) or using 3,4-dihydro-2H-quinoline (10p-1052): so 106, 4-fluoro-3-11-I4-(3,4-dihydro-1H- isoquinolin-2-yl)-4-oxobutan-1-yl|Ipiperidin-4-yl)-1H-indole «g

LC/MS (t/2) 420 (MN), CT-3.69, purity: 93905.

Zo 10c, 4-fluoro-3-11-(6-(3,4-dihydro-1H-isoquinolin-2-yl)-6-oxohexan-1-yl|Ipiperidin-4-yl)-1H-indole -

LC/MS (t/2) 448 (MN), CT-3.81, purity: 97905. 10a, 4-chloro-3-11-I4-(3,4-dihydro-1H-isoquinolin-2-yl) -4-oxobutan-1-yl|Ipiperidin-4-yl)-1H-indole

LC/MS (t/2) 436 (MN), CT-3.86, purity: 97905. « 1be, 4-chloro-3-11-(5-(3,4-dihydro-1H-isoquinoline-2- yl)-5-oxopentan-1-yl|Ipiperidin-4-yl)-1H-indole

LC/MS (t/z) 450 (Mn.yu), CT-3.87, purity: 8195. With p 107, 4-chloro-3-11-I6-(3,4-dihydro-1H-isoquinoline- 2-yl)-6-oxohexan-1-yl|piperidin-4-yl)-1H-indole "» LC/MS (ti/2) 464 (MH), CT-3.97, purity: 86905. " 109 , 5-fluoro-3-11-I5-(3,4-dihydro-1H-isoquinolin-2-yl)-5-oxopentan-1-yl|piperidin-4-yl)-1H-indole

LC/MS (t/2) 434 (MN), CT-3.67, purity: 93905. 10p, 5-fluoro-3-11-I6-(3,4-dihydro-1H-isoquinolin-2-yl) -6-oxohexan-1-yl|piperidin-4-yl)-1H-indole - LC/MS (t/2) 448 (MH), CT-3.79, purity: 89905. 15" 10, b-chloro -3-11-I3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxopropan-1-yl|piperidin-4-yl)-1H-indole

LC/MS (t/2) 422 (MN), CT-3.80, purity: 8595. so 10). b-chloro-3-11-I(I6-(3,4-dihydro-1H-isoquinolin-2-yl)-6-oxohexan-1-yl|Ipiperidin-4-yl)-1H-indole about 70 РХ/ MS (t/z) 464 (Mn.yu, CT-3.98, purity: 8795. 1OK, 7-chloro-3-11-I4-(3,4-dihydro-1H-isoquinolin-2-yl)- 4-oxobutan-1-yl|piperidin-4-yl)-1H-indole with LC/MS (t/2) 436 (MH), CT-3.85, purity: 98905. 101, 7-chloro-3- 41-(5-(3.4-dihydro-iH-isoquinolin-2-yl)-5-oxopentan-1-yl|Ipiperidin-4-yl)-1H-indole

LC/MS (t/z2) 450 (MN), CT-3.85, purity: 96905. 10t, 7-chloro-3-11-I(I6-(3,4-dihydro-1H-isoquinoline-2- yl)-6-oxohexane-1-yl|Ipiperidin-4-yl)-1H-indole

F! LC/MS (ti/z2) 464 (MN), CT-3.96, purity: 97905. 10p, 4-fluoro-3-11-I3-(3,4-dihydro-2H-quinolin-1-yl) -3-oxopropan-1-yl|piperidin-4-yl)-1H-indole by LC/MS (t/2) 406 (MH), CT-3.67, purity: 82905. 100, 4-fluoro-3 -11-I4-(3,4-dihydro-2H-quinolin-1-yl)-4-oxobutan-1-yl|piperidin-4-yl)-1H-indole 60 LC/MS (ti/g) 420 ( МН, ВТ-3.78, purity: 8495. 10р, 4-chloro-3-11-I3-(3,4-dihydro-2H-quinolin-1-yl)-3-oxopropan-1-yl|piperidine- 4-yl)-1H-indole

LC/MS (t/2) 422 (MN), CT-3.85, purity: 97905. 109, 4-chloro-3-11-I4-(3,4-dihydro-2H-quinolin-1-yl) -4-oxobutan-1-yl|piperidin-4-yl)-1H-indole

LC/MS (t/2) 436 (MN), CT-3.97, purity: 92905. bo 10g, 5-fluoro-3-11-I3-(3,4-dihydro-2H-quinolin-1-yl )-3-oxopropan-1-yl|piperidin-4-yl)-1H-indole

LC/MS (t/2) 406 (MN), CT-3.63, purity: 97905.

105. 5-fluoro-3-11-I4-(3,4-dihydro-2H-quinolin-1-yl)-4-oxobutan-1-yl|Ipiperidin-4-yl)-1H-indole

LC/MS (t/2) 420 (MN), CT-3.73, purity: 96905. 106, 5-fluoro-3-11-(5-(3,4-dihydro-2H-quinolin-1-yl) )-5-oxopentan-1-yl|piperidin-4-yl)-1H-indole

LC/MS (t/2) 434 (MN), CT-3.76, purity: 97905. 10y, 5-fluoro-3-11-(6-(3,4-dihydro-2H-quinolin-1-yl) )-6-oxohexan-1-yl|piperidin-4-yl)-1H-indole

LC/MS (t/2) 448 (MN), CT-3.88, purity: 97905. 10m, b-chloro-3-11-IZ3-(3,4-dihydro-2H-quinolin-1-yl) -3-oxopropan-1-yl|Ipiperidin-4-yl)-1H-indole

LC/MS (ti/2) 422 (MN), CT-3.88, purity: 90905. 70 10, b-chloro-3-11-(6-(3,4-dihydro-2H-quinoline-1- yl)-6-oxohexane-1-yl|piperidin-4-yl)-1H-indole

LC/MS (t/z2) 464 (MN), CT-4.09, purity: 96905. 10x, 7-chloro-3-71-I4-(3,4-dihydro-2H-quinolin-1-yl) -4-oxobutan-1-yl|piperidin-4-yl)-1H-indole

РХ/MS (t/2) 436 (MN), KT-3.91, purity: 98905. 1bu. 7-chloro-3-11-I5-(3,4-dihydro-2H-quinolin-1-yl)-5-oxopentan-1-yl|piperidin-4-yl)-1H-indole 15 LC/MS (t /z2) 450 (MH), CT-3.93, purity: 96905. 102, 7-chloro-3-11-(6-(3,4-dihydro-2H-quinolin-1-yl)-6-oxohexane -1-yl|Ipiperidin-4-yl)-1H-indole

LC/MS (t/z2) 464 (MN), CT-4.05, purity: 97905.

Example 11 11a, 5-fluoro-3-71-I(4-(3,4-dihydro-1H-isoquinolin-2-yl)butan-1-yl|piperidin-4-yl)-1H-indole dioxalate 20 Mixture 5-fluoro-3-(piperidin-4-yl)-1H-indole (5.0g), triethylamine (b.3bml) and tetrahydrofuran (500ml) were cooled to 72C, and then a mixture of succinic anhydride (2.5g) was added in tetrahydrofuran (5 Oml). The mixture was stirred at 8-109С7 for 2 hours and the solvent was removed under vacuum. The residue was dissolved in ethyl acetate and the organic phase was washed with cold 2M aqueous hydrochloride solution and brine.

The organic phase was dried (Ma5O)), filtered and concentrated under vacuum (6.4 g). The residue (1.5) and c 25 C,4-dihydro-1H-isoquinoline (0.63g) were dissolved in a mixture of acetonitrile (25ml) and dimethylformamide (10ml) and the resulting mixture was cooled (592), and then 1,3- dicyclohexylcarbodiimide (1.0 g). The mixture was stirred at i) room temperature for 16 hours, filtered and poured into a saline solution. The aqueous phase was extracted with ethyl acetate and tetrahydrofuran, and the combined organic phase was washed with brine, dried (M9503) and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluent: 3 30 ethyl acetate) to give a white solid (1.0 g), which was then added to a mixture of alane in tetrahydrofuran (100 Oml) at 5-10. Alan was obtained from lithium aluminum hydride (0.55 g) and concentrated sulfuric acid (0.72 g). The mixture was quenched by adding water (ml), 1595 aqueous sodium hydroxide solution (0.5 ml) and water (ee) (2.5 ml) and the resulting mixture was dried (Ma5O5)), filtered and concentrated under vacuum conditions. The title compound was crystallized from acetone in the form of a dioxalate salt (0.8 g). T. pl. 105-11120. "N NMR

Zo (DMSO-a5): 1.75 (s, 4H); 1.85-2.05 (m, 2H); 210 (d, 2H); 2.90-3.20 (m, 9H); 3.25 (t, 2H); 3.50 (d, 2H); in. 4.15 (c, 2H); 6.85-6.95 (m, 1H); 7.10-7.25 (m, 5H); 7.30-7.45 (m, 2H); 11.05 (s, 1H), MS t/: 406 (MN), 273, 188.

The following compound was obtained in a similar way: 116, dioxalate "

B-fluoro-3-11-I4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)butan-1-yl|piperidin-4-yl)-1nH-indole Z z B -fluoro-3-(piperidin-4-yl)-1H-indole and 6,7-dimethoxy-3,4-dihydro-1H-isoquinoline. T. pl. 98-1052C. "H NMR s (DMSO-yv): 1.75 (s, 4H); 1.85-2.00 (m, 2H); 2.10 (d, 2H); 2.90-3.15 (m , 9H); 3.30 (c, 2H); 3.50 (d, 2H); "from 3.75 (d, 6H); 4.10 (c, 2H); 6.75 (c, 1H); 6.80 (c, 1H); 6.90-6.95 (m, 1H); 7.20 (s, 1H); 7.30-7.45 (m, 2H); 11.05 (s, 1H), MS t/: 466 (MN), 273, 248.

Pharmacological testing - I 75 The compounds of the present invention were tested according to well-known and reproducible methods. The tests were as follows.

Inhibition of the binding of (-НIUM-09151-2) to human О/-dopamine receptors в Using this method, under conditions of ip migo, the inhibition by drugs of the binding of НIUM-09151-2 (0.06 nM) to the membrane of cloned О 2 was determined. -dopamine receptors of humans, expressed in

СНоО-cells. Modified method from MEM, Zsiepse Rgodysiv, Ips., certificate of technical data on RS2533-10/96. o Table 1, below, presents the results of the tests: уй о ю »1791 81 ввв я |в 915801 ж 1766 мж 11 бе ото | 77yu1yuya towers 1111

Table 1: Binding data (value of IC so in NM or 95 inhibition of binding in BONM) (pi. means "not tested")

The compounds of this invention have been found to strongly inhibit the binding of tritiated UM-09151-2

With 0/-dopamine receptors.

Compounds were also evaluated in a functional assay described by Sally et al. in Vg. U. RIagptsoi, 1999, 128, 613-620. In this test, the compounds were shown to be partial agonists or antagonists of 0)-dopamine receptors.

The compounds of this invention were also tested in the following tests:

The compounds of the present invention were screened for affinity for the ХО»-dopamine receptor by determining their ability to inhibit binding | ZNIpiperon with Oo-receptors, according to the method described by Nucei! her a). U. Meyhospet. 1985, 44, 1615.

Inhibition of binding ("NIspiperon" with Oz-receptors

With the help of this method, IPM inhibition by binding drugs was determined ZNIpiperone (0.3nM) with membranes of human cloned Yuz3-dopamine receptors expressed in CHO cells. The method is modified according to MasKept?ie eyi a. Yeig U. Rpagt.-My. Rpagt. Zes. 1994, 266, 79-85.

Inhibition of serotonin uptake by synaptosomes of intact rat brain

The compounds were tested for their inhibitory effect on the reuptake of 5-HT by measuring their ability to inhibit the reuptake of | Ni-Serotonin by synaptosomes of intact rat brain under conditions of IP myo. This analysis was performed as described by Nucei! in Rzusporpagtasoiiodu 1978, 60, 13.

Inhibition of binding (NI-ketanserin with 5-HTod receptors

The compounds were evaluated in relation to their affinity for 5-H Tod receptors by determining their ability to inhibit the binding of ZNI-ketanserin (0.50 nM) to the membranes of the brain (cortex) of the rat and mouse. The method is described in . Disgust Yuem. Kev. 1991, 22, 239-250. (8)

Efficiency in relation to 5-HT»os-receptors according to the results of fluorometry

The compounds were tested for their efficacy against CHO cells expressing 5-HT»os receptors using a fluorometric visual plate reader (VGIRC) assay. This study was performed according to the instructions of Moiesciag Oemisez Ips. for their RR Saisisht Avvzau KI ii with modification for

Rohieg her aii. Vgyivp doshigpa! oi Rpagtasoiodo 1999, 128:13. at

It was established that these compounds have insignificant or very weak affinity in relation to co

Bo-dopamine receptor.

Many compounds have been found to inhibit the binding of | "NIspiperon with Oz-dopamine receptor, M some of the compounds inhibit the reuptake of serotonin, and some of the compounds are ligands of 5-HT receptors and/or ligands of 5-HT» receptors.

As mentioned above, the compounds of this invention are well soluble in water compared to related compounds described in UUO 98/28293. Accordingly, these compounds are expected to have improved bioavailability.

Thus, the compounds of this invention are considered suitable for the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders such as generalized anxiety disorder, panic disorder and obsessive-compulsive disorder, depression, side effects induced by conventional drugs. antipsychotic agents, migraine, AONO, as well as to improve sleep. In particular, the compounds of this invention are considered suitable for the treatment of positive and negative symptoms of schizophrenia without the development of 5 extrapyramidal side effects. -I Examples of pharmaceutical forms

The pharmaceutical preparations of this invention can be prepared by methods commonly used in the art. (ee) For example, tablets can be prepared by mixing the active ingredient with conventional adjuvants and/or diluents, followed by compression of the mixture in a conventional tableting machine. Examples of adjuvants or

Examples of diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums and similar substances. Any other adjuvants or additives commonly used for such purposes, such as dyes, flavorings, preservatives, etc., may be used, provided they are compatible with the active ingredients.

Solutions for injections can be obtained by dissolving the active ingredient and possible additives in part of the solvent for injections, preferably in sterile water, after which the solution is brought to the required volume, sterilized and injected into ampoules or bottles. Any acceptable additives commonly used in the art may be used, such as isotonicity agents, preservatives, antioxidants, and the like.

Typical examples of prescriptions for compounds according to the present invention are as follows. in 1) Tablets containing 5.Omg of the compound according to this invention in terms of free base:

Compound B,.Omg

Lactose bomg

Corn starch ZOmg 65 Hydroxypropyl cellulose 2.Amg

Microcrystalline cellulose 19.2 mg

Croscarmellose sodium salt type A 2.4 mg

Magnesium stearate O, in 4 mg 2) Tablets containing 0.5 mg of the compound according to this invention, calculated on the free basis:

Compound O, Bmg

Lactose Ab, Umg

Corn starch 23, BmMg

Povidone 1.mg 70 Microcrystalline cellulose 14 A4mg

Croscarmellose sodium salt type A. 1.8 mg

Magnesium stearate O.6Zmg

C) Syrup containing per milliliter:

Compound 25mg

Sorbitol BOOmg

Hydroxypropyl cellulose 1Bmg

Glycerin Bomg

Methylparaben 1 mg

Propylparaben 0 1 mg

Ethanol O, bo5 ml

Flavoring O, OBmg

Sodium salt of saccharin O, Bmg p

Water to ml of He) 4) Solution for injections containing in milliliters:

Compound O, Bmg (ав)

Sorbitol B1Mg so

Acetic acid O, OBmg

Sodium sulsaccharin 0O.5mg so

Water up to ml "Her and -

Claims (19)

The formula of the invention 1. Substituted indole derivatives of formula | « in , shi - 5 z shЯ i» rі i tu ydi h -sn-khm (sn la t wo - M і r E! і" and so e Vo de o (a) one of U іі у? represents M, which is bonded to U 7 and the other to U" and U? is CO, C8, 50 or 50", and x "2 is CH"; or (B) one of U" and U? is is M, which is connected to U 7, and the other of U! and U? represents CH", and U? represents СО, С5, 50 or 50", UZ represents 7-СН», СНо-7 or СНоСН», and 7 represents О or 5; provided that when У! represents M, ГФ) then УЗ cannot be 2-СН»; MU is a bond or group О, 5, СО, С5, 50 or 505; o n equals 0 - 5, t equals 0 - 5, and tp equals Z - b for (a), and tep equals 1 - 10 for (B); provided that when MU is O or 5, then claim 2 2, and t 2 1; when M/ represents СО, С5, 5О or 505, then claim 2 bo 1, at g 1; X is C, CH or M; provided that when X represents C, then the dashed line represents a bond, and when X represents M or CH, then the dashed line is not a bond; B!-K9 are independently selected from hydrogen, halogen, cyano group, nitro group, amino group, hydroxyl group, 65 C, C 1 -alkylamine, di-Ci 6 -alkylamine, C 1 -alkyl, C 6 -alkenyl, C 6 -alkynyl, Ci-C-Alkoxy, Su-C-Alkylthio, Si. β-alkyl substituted by a hydroxyl group or a thiol group, C3 β-cycloalkyl, Cz c-cycloalkyl-Ci c-alkyl, acyl group, thioacyl group, aryl group, trifluoromethyl group, trifluoromethylsulfonyl group and Ci c d-alkylsulfonyl; BO is hydrogen, C 4 -alkyl, C 6 -alkenyl, C 6 -alkynyl, C 6 -alkyl substituted by a hydroxyl group or a thiol group, C 6 -cycloalkyl, C 6 -cycloalkyl-C 6 -alkyl, aryl group, aryl-Cu-alkyl, acyl group, thioacyl group, C-C-alkylsulfonyl, trifluoromethylsulfonyl or arylsulfonyl group, or their pharmaceutically acceptable acid addition salts. 2. The compound according to claim 1, where the indole is linked to X at the C position of the indole. 3. Compound according to claim 1 or 2, where is one of U and U? represents M, which is connected to U 7, and another to U! IN? is 70. CO, and U" represents CH". 4. Compound according to claim 3, where U! is nitrogen, which is bound to U", 2 is CO, and U" is CH". 5. Compound according to claim 3, where U? is a nitrogen atom that is bound to U, U is CO, and U? is SN". 6. Compound according to claim 1 or 2, where is one of U and U? represents M, which is connected to U 7, and another to U! IN? is CH", and 7 is CO. 7. Compound according to claim 6, where U! is a nitrogen that is connected to 7, U? is SN", and U? is SO. 8. Compound according to claim 6, where U? is a nitrogen atom, which is connected to 7, U! is SN", and U? is Co. 9. A compound according to any of claims 1 - 8, where the UZ is a "SN" or a "SNO". 10. A compound according to any of claims 1 - 9, where X is C. 11. The compound according to any of claims 1 - 9, where X is M. 12. A compound according to any of claims 1 - 9, where X is CH. 13. The compound according to any one of claims 1 - 12, where K 1.89 is independently selected from hydrogen, halogen, cyano group, nitro group, amino group, C.sub.6-alkylamine, di-Ci.sub.6-alkylamine, C.sub.6-alkyl, C3-C-cycloalkyl and trifluoromethyl o group, and BK'9 represents hydrogen, C 34 6-alkyl or an acyl group, or its pharmaceutically acceptable acid addition salt. 14. The compound according to claim 13, where MU is a bond. 15. Compound according to claim 14, where put is equal to З - 6. o 16. The compound according to claim 1, which is selected from: 5-fluoro-3-11-3-(1-oxo-3,4-dihydro-1H-quinolin-2-yl)propan-1-yl|piperidin- 4-yl)-1H-indole, B-fluoro-3-11-I4-(1-oxo-3,4-dihydro-1H-quinolin-2-yl)butan-1-yl|Ipiperidin-4-yl) -1H-indole, so 5-fluoro-3-11-3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propan-1-yl|piperidin-4-yl)-1H- indole, "g 5-fluoro-3-11-15-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)pentan-1-yl|piperidin-4-yl)-1H-indole, Zo 5-chloro-3-11-3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)propan-1-yl|piperidin-4-yl)-1H-indole, i- 5 -chloro-3-11-I4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl|Ipiperidin-4-yl)-1H-indole, 5-chloro-3 -11-I|I5-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)pentan-1-yl|piperidin-4-yl)-1H-indole, 7-chloro-3-11 -I4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl|Ipiperidin-4-yl)-1H-indole, "B-fluoro-3-11-I4- (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)butan-1-yl|Ipiperidin-4-yl)-1H-indole, 5-chloro-3-11-I4- (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)butan-1-yl|Ipiperidin-4-ylI-1H-indole, C c 5-fluoro-3-11-I3 -(2-o xo-3,4-dihydro-2H-quinolin-1-yl)propan-1-yl(-3,6-dihydro-2H-pyridin-4-yl)-1H-indole, "» B-fluoro-3- 11-I(4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-ylI|-3,6-dihydro-2H-pyridin-4-yl)-1H-indole , " 5-fluoro-3-11-I5-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)pentan-1-yl|-3,6-dihydro-2H-pyridin-4- yl)-1H-indole, B-fluoro-3-11-I4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl|Ipiperidin-4-yl)-1H -indole, 5-fluoro-1-methyl-3-11-I3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)upropan-1-yl|piperidin-4-yl)-1H -indole, w- B-fluoro-1-methyl-3-11-I4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-yl|piperidin-4-yl) -1H-indole, their 1-(butan-1-yl)-5-fluoro-3-11-I4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)butan-1-ylI |-3,6-dihydro-2H-pyridin-4-yl)-1H-indole, so 5-fluoro-3-11-IZ3-(3,4-dihydro-1H-isoquinolin-2-yl)-3- oxopropan-1-yl|piperidin-4-yl)-1H-indole, 2) 20 7-chloro-3-11-3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxopropan- 1-yl|piperidin-4-yl)-1H-indole, 5-chloro-3-11-I4-(3,4-dihydro-2H-quinolin-1-yl)-4-oxobutan-1-yl|Ipiperidine -4-yl)-1H-indole, m e, B-fluoro-3-11-I4-(3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutan-1-yl|Ipiperidin-4-yl)-1H-indole, 5-chloro -3-11-I4-(3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutan-1-yl|Ipiperidin-4-yl)-1H-indole, 4-fluoro-3-11- I3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxopropan-1-yl|piperidin-4-yl)-1H-indole, 59 4-fluoro-3-11-I4-(3 ,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutan-1-yl|piperidin-4-yl)-1H-indole, HF) 4-fluoro-3-11-(6-(3,4 -dihydro-1H-isoquinolin-2-yl)-6-oxohexan-1-yl|piperidin-4-yl)-1H-indole, 4-chloro-3-11-I4-(3,4-dihydro-1H- isoquinolin-2-yl)-4-oxobutan-1-yl|piperidin-4-yl)-1H-indole, where 4-chloro-3-11-(I5-(3,4-dihydro-1H-isoquinoline-2 -yl)-5-oxopentan-1-yl|piperidin-4-yl)-1H-indole, 4-chloro-3-11-(I6-(3,4-dihydro-1H-isoquinolin-2-yl)- b-oxohexan-1-yl|piperidin-4-yl)-1H-indole, 6o 5-fluoro-3-11-I5-(3,4-dihydro-1H-isoquinolin-2-yl)-5-oxopentan- 1-yl|piperidin-4-yl)-1H-indole, 5-fluoro-3-11-I6-(3,4-dihydro-1H-isoquinolin-2-yl)-6-oxohexan-1-yl|piperidine -4-yl)-1H-indole, b-chloro-3-11-3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxo propan-1-yl|piperidin-4-yl)-1H-indole, b-chloro-3-11-I6-(3,4-dihydro-1H-isoquinolin-2-yl)-6-oxohexan-1-yl |piperidin-4-yl)-1H-indole, 7-chloro-3-11-I4-(3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutan-1-yl|Ipiperidin-4- yl)-1H-indole, because 7-chloro-3-11-15-(3,4-dihydro-1H-isoquinolin-2-yl)-5-oxopentan-1-yl|piperidin-4-yl)-1H -indole, 7-chloro-3-11-I6-(3,4-dihydro-1H-isoquinolin-2-yl)-6-oxohexan-1-yl|piperidin-4-yl)-1H-indole, 4-fluoro-3 -11-I3-(3,4-dihydro-2H-quinolin-1-yl)-3-oxopropan-1-yl|piperidin-4-yl)-1H-indole, 4-fluoro-3-11-I4- (3,4-dihydro-2H-quinolin-1-yl)-4-oxobutan-1-yl|piperidin-4-yl)-1H-indole, 4-chloro-3-11-I3-(3,4- dihydro-2H-quinolin-1-yl)-3-oxopropan-1-yl|piperidin-4-yl)-1H-indole, 4-chloro-3-11-I4-(3,4-dihydro-2H-quinoline -1-yl)-4-oxobutan-1-yl|piperidin-4-yl)-1H-indole, 5-fluoro-3-11-I3-(3,4-dihydro-2H-quinolin-1-yl) -3-oxopropan-1-yl|piperidin-4-yl)-1H-indole, B-fluoro-3-11-I4-(3,4-dihydro-2H-quinolin-1-yl)-4-oxobutan- 1-yl|Ipiperidin-4-yl)-1H-indole, 5-fluoro-3-11-I5-(3,4-dihydro-2H-quinolin-1-yl)-5-oxopentan-1-yl|piperidine -4-yl)-1H-indole, 70 5-fluoro-3-11-I6-(3,4-dihydro-2H-quinolin-1-yl)-6-oxohexan-1-yl|piperidin-4-yl )-1H-indole, b-chloro-3-11-3-(3,4-dihydro-2H-quinolin-1-yl)-3-oxopropan-1-yl|piperidin-4-yl)-1H-indole , b-chloro-3-11-I6-(3,4-dihydro-2H-quinolin-1-yl)-b-oxohexan-1-yl|Ipiperidin-4-yl)-1H-indole, 7-chloro p-3-11-I4-(3,4-dihydro-2H-quinolin-1-yl)-4-oxobutan-1-yl|Ipiperidin-4-yl)-1H-indole, 7-chloro-3-11 -I5-(3,4-dihydro-2H-quinolin-1-yl)-5-oxopentan-1-yl|piperidin-4-yl)-1H-indole and 7-chloro-3-11-I6-(3 ,4-dihydro-2H-quinolin-1-yl)-b-oxohexan-1-yl|Ipiperidin-4-yl)-1H-indole, or their pharmaceutically acceptable salts. 17. A pharmaceutical composition, characterized in that it contains a therapeutically effective amount of a compound according to any one of claims 1 - 16 in combination with one or more pharmaceutically acceptable carriers or diluents. 18. Use of a compound according to any one of claims 1 - 16 for the production of a medicinal product suitable for the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders such as generalized anxiety disorder, panic disorder and obsessive-compulsive disorder, depression, aggression , side effects induced by conventional antipsychotic agents, migraine, cognitive disorders, AONO, and to improve sleep. with 19. Method of treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalized anxiety disorder, panic disorder and obsessive-compulsive disorder, depression, i) aggression, side effects induced by conventional antipsychotic agents, migraine, cognitive disorders, ARNO , as well as for improving sleep, in which a therapeutically effective amount of the compound according to any of claims 1 - 16 is administered. -I sh» (ee) o 50 (42) F) ime) 60 b5