SK402003A3

SK402003A3 - Indole derivatives, pharmaceutical composition comprising same and their use

Info

Publication number: SK402003A3
Application number: SK40-2003A
Authority: SK
Inventors: Benny Bang-Andersen; Jakob Felding; Jan Kehler; Kim Andersen
Original assignee: Lundbeck & Co As H
Priority date: 2000-06-14
Filing date: 2001-06-13
Publication date: 2003-07-01
Also published as: PL358967A1; CN1446211A; IL153234A; ZA200209958B; EA006315B1; BR0111764A; IL153234A0; UA74830C2; HK1059086A1; EA200300019A1; CN100415737C; IS6643A

Description

Indolové deriváty, farmaceutický prostriedok s ich obsahom a ich použitieIndole derivatives, pharmaceutical composition containing them and their use

Oblasť technikyTechnical field

Predkladaný vynález sa týka novej skupiny indolových derivátov, ktoré majú afinitu k dopamínovému D₄ receptoru. Zlúčeniny majú antagonistický účinok na dopamínový D₄ receptor a sú teda vhodné na liečenie niektorých psychických a neurologických porúch, najmä psychóz. Niektoré z týchto zlúčenín majú afinitu k dopamínovému D₃ receptoru, 5-HT₂a receptoru a/alebo 5-HT₂c receptoru a niektoré z týchto zlúčenín sú inhibítormi reabsorpcie serotonínu.The present invention relates to a novel class of indole derivatives having affinity for the dopamine D ₄ receptor. The compounds have a dopamine D ₄ receptor antagonistic effect and are thus useful in the treatment of certain psychological and neurological disorders, particularly psychoses. Some of these compounds have affinity for the dopamine D ₃ receptor, _{5-HT2-receptor} and / or 5-HT _2c receptor and some of the compounds are serotonin reuptake inhibitors.

Doterajší stav technikyBACKGROUND OF THE INVENTION

Dopamínové D₄ ligandy príbuzné zlúčeninám podľa vynálezu sú známe zWO 98/28293. Indánové a dihydroindolové deriváty tu opísané majú všeobecný vzorecDopamine D ₄ ligands related to the compounds of the invention are known from WO 98/28293. The indane and dihydroindole derivatives described herein have the general formula

kde A je indol a Y je skupina doplňujúca indán, alebo dihydroindol a iné substituenty sú určené v prihláške. ^! ,wherein A is indole and Y is an indane supplementing group, or dihydroindole and other substituents are defined in the application. ^! .

WO 00/23441 opisuje zlúčeniny všeobecného vzorcaWO 00/23441 discloses compounds of the general formula

R² R ²

-2kde substituenty R¹, R², R³, m, n a p sú určené v prihláške. Uvádza sa, že zlúčeniny vykazujú vysokú afinitu k dopamínovým D2 receptorom a tiež, že sú inhibítormi reabsorpcie serotonínu. Zlúčeniny sú nárokované na použitie na liečenie schizofrénie a iných psychických porúch.Where the substituents R ¹ , R ² , R ³ , m, n and p are as defined in the application. The compounds are said to exhibit high affinity for dopamine D2 receptors and also to be serotonin reuptake inhibitors. The compounds are claimed for use in the treatment of schizophrenia and other psychiatric disorders.

Iné zlúčeniny štruktúrne príbuzné zlúčeninám podľa vynálezu sú opísané voWO 99/58525. Uvádza sa, že zlúčeniny tu opísané sú 5-HT₂a ligandami a inhibítormi reabsorpcie serotonínu a majú všeobecný vzorecOther compounds structurally related to the compounds of the invention are described in WO 99/58525. The compounds described herein are said to be 5-HT ₂ and serotonin reuptake inhibitors and inhibitors and have the general formula:

kde substituenty sú určené v prihláške. Uvádza sa, že zlúčeniny sú užitočné na liečenie schizofrénie.wherein the substituents are as defined in the application. The compounds are said to be useful for the treatment of schizophrenia.

WO 00/31074 sa týka zlúčenín všeobecného vzorcaWO 00/31074 relates to compounds of the general formula

kde X je CO alebo SO₂ a Y je N-R⁴ lebo CR⁴R⁴ a substituenty sú určené v prihláške. Uvádza sa, že zlúčeniny majú účinok na 5-HT_2A receptor, majú inhibičnú aktivitu na reabsorpciu 5-HT a zvyšujú uvoľňovanie 5-HT.wherein X is CO or SO ₂ and Y is NR ⁴ or CR ⁴ R ⁴ and substituents are defined in the application. The compounds are said to have 5-HT _2A receptor activity, inhibit 5-HT reuptake inhibitory activity, and enhance 5-HT release.

Patentové prihlášky, WO 94/18197, EP 329168, WO 93/16073, EP 732332,Patent applications, WO 94/18197, EP 329168, WO 93/16073, EP 732332,

WO 98/37893 a WO 95/11680, opisujú dopamínové D4 Ugandy, ktoré podobne ako zlúčeniny podľa vynálezu, sú substituované tetrahydrochinolinónové a tetrahydroizochinolinónové deriváty. Tieto zlúčeniny však neobsahujú indol ako zlúčeniny podľa vynálezu. Uvádza sa, že zlúčeniny sú dopamínovými D₄ ligandamiWO 98/37893 and WO 95/11680 disclose dopamine D4 Ugands which, like the compounds of the invention, are substituted tetrahydroquinolinone and tetrahydroisoquinolinone derivatives. However, these compounds do not contain indole as the compounds of the invention. The compounds are said to be dopamine D ₄ ligands

-3užitočnými ako antipsychotiká. Nárokuje sa, že zlúčeniny podľa WO 93/16073 majú tiež antagonistickú aktivitu k 5-HT2 receptorom.Useful as antipsychotics. It is claimed that the compounds of WO 93/16073 also have 5-HT 2 receptor antagonistic activity.

Dopamínová D₄ receptory patria k dopamínovej D₂ podskupine receptorov, ktorá je zodpovedná za antipsychotické účinky neuroleptík. Vedľajšie účinky neuroleptických liečiv, ktoré uplatňujú svoj účinok najmä cez antagonizmus D₂receptorov, sú známe, že pôsobia na antagonizmus D₂ receptora v priečne prúžkovaných oblastiach mozgu. Avšak, dopamínová D₄ receptory sú umiestnené najmä v oblastiach mozgu iných ako je prúžkované teleso, čo naznačuje, že antagonistom dopamínu D₄ receptora budú chýbať extrapyramidálne vedľajšie účinky. To ilustruje antipsychotický klozapín, ktorý má vyššiu afinitu k D₄ receptorom ako k D₂ receptorom a chýbajú extrapyramidálne vedľajšie účinky (Van Tol a ďalší, Náture 1991, 350, 610; Hadley Medicinal Research Reviews, 1996, 16, 507 - 526 a Sanner Exp. Opin. Ther. Patents, 1998, 8, 383 - 393).Dopamine D ₄ receptors belong to the dopamine D ₂ receptor subgroup, which is responsible for the antipsychotic effects of neuroleptics. Side effects of neuroleptic drugs, which exert their effect mainly through D ₂ receptor antagonism, are known to act on D ₂ receptor antagonism in the cross-striated areas of the brain. However, dopamine D ₄ receptors are mainly located in areas of the brain other than the banded body, suggesting that dopamine D ₄ receptor antagonists will lack extrapyramidal side effects. This illustrates antipsychotic clozapine, which has a higher affinity for D ₄ receptors than for D ₂ receptors and lacking extrapyramidal side effects (Van Tol et al., Nature 1991, 350, 610; Hadley Medicinal Research Reviews, 1996, 16, 507-526 and Sanner Exp Opin Ther. Patents, 1998, 8, 383-393).

Veľa D₄ ligandov, u ktorých sa požadovalo, aby boli selektívnymi D₄receptorovými antagonistami (L-745,879 a U-101958) má antipsychotický účinok (Mansbach a ďalší, Psychopharmacology, 1998, 135, 194 -200). Avšak, nedávno bolo uvedené, že tieto zlúčeniny sú čiastočné D₄ receptorové agonisty v rôznych in vitro skúškach na ich účinnosť (Gazi a ďalší, Br. J. Pharmacol. 1998, 124, 889 - 896 a Gazi a ďalší, Br. J. Pharmacol., 1999, 128, 613 - 620). Okrem toho, bolo uvedené, že klozapín, ktorý je účinne antipsychotický, je tichý antagonista (Gazi a ďalší, Br. J. Pharmacol., 1999, 128, 613 - 620).Many D ₄ ligands that were required to be selective D ₄ receptor antagonists (L-745,879 and U-101958) have antipsychotic effect (Mansbach et al., Psychopharmacology, 1998, 135, 194-200). However, it has recently been reported that these compounds are partial D ₄ receptor agonists in various in vitro assays for their efficacy (Gazi et al., Br. J. Pharmacol. 1998, 124, 889-896 and Gazi et al., Br. J. Pharmacol., 1999, 128, 613-620). In addition, clozapine, which is effectively antipsychotic, has been reported to be a silent antagonist (Gazi et al., Br. J. Pharmacol., 1999, 128, 613-620).

Takže, D₄ ligandy, ktoré sú čiastočnými D₄ receptorovými agonistami alebo antagonistami, môžu mať blahodarné účinky proti psychózam.Thus, D ₄ ligands that are partial D ₄ receptor agonists or antagonists can have beneficial effects against psychoses.

Dopamínové D₄ antagonisty môžu byť vhodné aj na liečenie kognitívnych porúch (Jentsch a ďalší, Psychopharmacology, 1999, 142, 78 - 84).Dopamine D ₄ antagonists may also be useful in the treatment of cognitive disorders (Jentsch et al., Psychopharmacology, 1999, 142, 78-84).

Ďalej bol publikovaný dôkaz genetickej súvislosti medzi „prvotne nepozorným“ subtypom ADHD (hyperaktívna porucha nedostatočnej pozornosti) a tandemovým duplikačným polymorfizmom v géne, ktorý kóduje dopamínový D₄receptor (McCraken a ďalší, Mol. Psychiat. 2000, 5, 531 až 536). To jasne indikuje súvislosť medzi dopamínovým D₄ receptorom a ADHD, a ligandy, ktoré ovplyvňujú tento receptor môžu byť užitočné na liečenie tohto špecifického ochorenia.Furthermore, evidence of a genetic link between the "initially inattentive" subtype of ADHD (hyperactive attention deficit disorder) and the tandem duplication polymorphism in the gene encoding the dopamine D ₄ receptor has been reported (McCraken et al., Mol. Psychiat. 2000, 5, 531-536). This clearly indicates the association between the dopamine D ₄ receptor and ADHD, and the ligands that affect this receptor may be useful in the treatment of this specific disease.

-4Dopamínové D₃ receptory patria taktiež do podskupiny receptorov dopamínu D2 a sú prednostne umiestnené v iimbických oblastiach mozgu (Sokoloff a ďalší, Náture, 1990, 347, 146 - 151), ako je napríklad nucleus accumbens, kde blokáda dopamínového receptora bola spojená s antipsychotickou účinnosťou (Willner Int. Clinical Psychopharmacology, 1997, 12, 297 - 308). Okrem toho bolo uvedené zvýšenie úrovne D₃ receptorov v limbickej časti schizofrenického mozgu (Gurevich a ďalší, Árch. Gen. Psychiatry 1997, 54, 225 - 232). Z toho dôvodu, D₃ receptorové antagonisty môžu poskytnúť potenciálnu antipsychotickú terapiu bez extrapyramidálnych vedľajších účinkov klasických antipsychotických liečiv, ktoré uplatňujú svoje účinky blokádou D2 receptorov (Shafer a ďalší, Psychopharmacology, 1998, 135, 1 - 16; Schwartz a ďalší, Brain Research Reviews 2000, 31,277-287).The dopamine D ₃ receptors also belong to the dopamine D2 receptor subset and are preferably located in the iimbic brain regions (Sokoloff et al., Nature, 1990, 347, 146-151), such as the nucleus accumbens, where dopamine receptor blockade has been associated with antipsychotic efficacy (Willner Int. Clinical Psychopharmacology, 1997, 12, 297-308). In addition, an increase in the D ₃ receptor level in the limbic portion of the schizophrenic brain has been reported (Gurevich et al., Ar. Gen. Psychiatry 1997, 54, 225-232). Therefore, D ₃ receptor antagonists can provide potential antipsychotic therapy without the extrapyramidal side effects of classical antipsychotic drugs that exert their effects by blocking D2 receptors (Shafer et al., Psychopharmacology, 1998, 135, 1-16; Schwartz et al., Brain Research Reviews 2000, 31, 277-287).

Okrem toho, blokáda D₃ receptora vedie k miernej stimulácii v prefrontálnom kortexe (Merchant a ďalší, Cerebral Cortex 1996, 6, 561 - 570), ktorá by mohla byť blahodarná na negatívne symptómy a kognitívne deficity spojené so schizofréniou. Okrem toho, dopamínové D₃ antagonisty môžu obrátiť D2 antagonistom indukovaný EPS (Millan a ďalší, Eur. J. Pharmacol. 1997, 321, R7 - R9) a nespôsobujú zmeny v prolaktíne (Reavill a ďalší, J. Pharmacol. Exp. Ther. 2000, 294, 1154 - 1165). Takže D₃ antagonistické vlastnosti antipsychotických liečiv by mohli zmenšiť negatívne symptómy a kognitívne deficity a mohli by mať za následok zlepšenie profilu vedľajších účinkov ohľadne EPS a hormonálnych zmien.In addition, blockade of the D ₃ receptor leads to mild stimulation in the prefrontal cortex (Merchant et al., Cerebral Cortex 1996, 6, 561-570), which could be beneficial for the negative symptoms and cognitive deficits associated with schizophrenia. Furthermore, dopamine D ₃ antagonists can reverse D 2 antagonist-induced EPS (Millan et al. Eur. J. Pharmacol. 1997, 321, R7 - R9) and do not cause changes in prolactin (Reavill et al, J. Pharmacol. Exp. Ther. 2000, 294, 1154-1165). Thus, D ₃ antagonistic properties of antipsychotic drugs could reduce negative symptoms and cognitive deficits and could result in improved side effects profile with respect to EPS and hormonal changes.

Dopamínové D₃ agonisty boli tiež považované za dôležité na liečenie schizofrénie (Wustow a ďalší, Current Pharmaceutical Design 1997, 3, 391 - 404).Dopamine D ₃ agonists have also been considered important in the treatment of schizophrenia (Wustow et al., Current Pharmaceutical Design 1997, 3, 391-404).

Sú známe rôzne účinky v súvislosti so zlúčeninami, ktoré sú ligandami rozličných subtypov serotonínových receptorov. Čo sa týka 5-HT₂a receptora, ktorý bol predtým uvádzaný ako 5-HT2 receptor, boli opísané nasledujúce účinky, napr.: Antidepresívne účinky a zlepšenie kvality spánku (Meert a ďalší, Drug. Dev. Res., 1989, 18, 119), zníženie negatívnych symptómov schizofrénie a extrapyramidálnych vedľajších účinkov spôsobených liečením klasickými neuroleptikami u schizofrenických pacientov (Gelders, British J. Psychiatry, 1989, 155 (dodatok 5), 33). Selektívne 5-HT2A antagonisty môžu byť tiež užitočné na prevenciu a liečenie migrény (Script Report, „Migraine - Current trends in research and treatment“, PJBVarious effects are known with respect to compounds which are ligands of various serotonin receptor subtypes. With respect to 5-HT ₂ and the receptor previously referred to as 5-HT 2 receptor, the following effects have been described, e.g.: Antidepressant effects and improved sleep quality (Meert et al., Drug. Dev. Res., 1989, 18, 119), reducing the negative symptoms of schizophrenia and extrapyramidal side effects caused by treatment with classical neuroleptics in schizophrenic patients (Gelders, British J. Psychiatry, 1989, 155 (Appendix 5), 33). Selective 5-HT 2A antagonists may also be useful for the prevention and treatment of migraine (Script Report, "Migraine - Current Trends in Research and Treatment", PJB

-5Publications Ltd., May 1991) a úzkosti (Colpart a ďalší, Psychopharmacology, 1985, 86, 303 až 305 a Perregaard a ďalší, Current Opinion in Therapeutic Patents, 1993, 1, 101 až 128).-5Publications Ltd., May 1991) and anxiety (Colpart et al., Psychopharmacology, 1985, 86, 303-305 and Perregaard et al., Current Opinion in Therapeutic Patents, 1993, 1, 101-128).

Niektoré klinické štúdie implikujú 5-HT₂ receptorový subtyp pri agresívnom správaní. Ďalej, atypické serotonín-dopamínové antagonistické neuroleptiká majú antagonistický účinok na 5-HT₂ receptor, okrem ich dopamín blokujúcich vlastností a bolo uvedené, že majú antiagresívne správanie. (Connor a ďalší Exp. Opin. Ther. Patents. 1998, 8(4), 350 až 351).Some clinical studies imply a 5-HT ₂ receptor subtype in aggressive behavior. Further, atypical serotonin-dopamine antagonist neuroleptics have 5-HT ₂ receptor antagonistic activity in addition to their dopamine blocking properties and have been reported to have anti-aggressive behavior. (Connor et al. Exp. Opin. Ther. Patents. 1998, 8 (4), 350-351).

Nedávno sa taktiež nahromadili dôkazy, ktoré podporujú názor, že selektívneRecently, evidence has also accumulated to support the view of being selective

5-HT_2a antagonisty sú liečivá schopné liečiť pozitívne symptómy psychózy (Leysen a ďalší Current Pharmaceutical Design 1997, 3, 367 až 390 a Carlsson Current Opinion in CPNS Investigational Drugs 2000, 2(1), 22 až 24).5-HT _2A antagonists are drugs capable of treating the positive symptoms of psychosis (Leysen et al. Current Pharmaceutical Design 1997, 3, 367-390 and Carlsson Current Opinion in CPNS Investigational Drugs 2000, 2 (1), 22-24).

Zlúčeniny, ktoré sú inhibítormi reabsorpcie 5-ΗΤ sú dobre známymi antidepresívnymi liečivami.Compounds which are inhibitors of 5-β re-uptake are well known antidepressant drugs.

Zistilo sa, že 5-HT₂c ligandy zvyšujú účinok inhibítorov reabsorpcie 5-ΗΤ v mikrodialýzových experimentoch a zvieracích modeloch, a zlúčeniny, ktoré majú inhibičný účinok na reabsorpciu 5-HT spojený s afinitou k5-HT₂c receptoru môžu byť preto obzvlášť užitočné na liečenie depresie a iných ochorení kladne reagujúcich na inhibítory reabsorpcie serotonínu (PCT patentová prihláška č. PCT/DK00/00671).It was found that 5-HT _2c ligand increase the activity as inhibitors of serotonin 5-ΗΤ in microdialysis experiments and animal models, and compounds having an inhibitory effect on the reuptake of 5-HT related to the affinity of K5-HT _2c receptor may therefore be particularly useful for the treatment of depression and other diseases responsive to serotonin reuptake inhibitors (PCT Patent Application No. PCT / DK00 / 00671).

Okrem toho, dopamínové D₄ receptorové ligandy sú potenciálnymi liečivami na liečenie schizofrénie a iných psychóz, a zlúčeniny s kombinovanými účinkami naIn addition, dopamine D ₄ receptor ligands are potential drugs for the treatment of schizophrenia and other psychoses, and compounds with combined effects on

5-HT prenášač môžu poskytovať ďalší úžitok zo zlepšeného účinku na depresívne a negatívne symptómy u pacientov so schizofréniou. Zlúčeniny s kombinovaným účinkom na dopamínový D₄ receptor a 5-HT_2A receptor môžu poskytovať úžitok zo zlepšeného účinku na pozitívne a negatívne symptómy schizofrénie a úžitok z účinku na depresívne alebo úzkostné symptómy. Okrem toho, dopamínové D₃antagonistické vlastnosti antipsychotických liečiv môžu znížiť negatívne symptómy a kognitívne deficity schizofrénie a vyústiť tak do zlepšeného profilu vedľajších účinkov.The 5-HT transporter can provide additional benefit from an improved effect on depressive and negative symptoms in patients with schizophrenia. Compounds with a combined effect on the dopamine D ₄ receptor and the 5-HT _2A receptor can provide the benefit of an improved effect on the positive and negative symptoms of schizophrenia and the benefit of an effect on depressive or anxiety symptoms. In addition, dopamine D ₃ antagonistic properties of antipsychotic drugs can reduce the negative symptoms and cognitive deficits of schizophrenia, resulting in an improved side effect profile.

-6Cieľom tohto vynálezu je poskytnúť zlúčeniny, ktoré sú čiastočnými agonistami alebo antagonistami dopamínového D4 receptora, D₃ receptora, 5-ΗΪ2Α receptora, 5-HT2C receptora a/alebo 5-HT prenášača.It is an object of the present invention to provide compounds that are partial agonists or antagonists of the dopamine D4 receptor, the D ₃ receptor, the 5-Α2A receptor, the 5-HT2C receptor, and / or the 5-HT transporter.

Ďalším cieľom vynálezu je poskytnúť zlúčeniny s takýmito účinkami, ktoré majú zlepšenú rozpustnosť v porovnaní s doteraz známymi zlúčeninami.It is a further object of the invention to provide compounds with such effects, which have improved solubility compared to the prior art compounds.

Podstata vynálezuSUMMARY OF THE INVENTION

Podstatou vynálezu sú indolové deriváty všeobecného vzorca IThe invention relates to indole derivatives of the general formula I

kdewhere

a) jeden z Y¹ a Y² je N, ktorý je naviazaný na Y⁴ a druhý z Y¹ a Y² je CO, CS, SO alebo SO2 a Y⁴ je CH₂;(a) one of Y ¹ and Y ² is N which is bound to Y ⁴ and the other of Y ¹ and Y ² is CO, CS, SO or SO 2 and Y ⁴ is CH ₂ ;

b) jeden z Y¹ a Y² je N, ktorý je naviazaný na Y⁴ a druhý z Y¹ a Y² je CH2 a Y⁴ je CO, CS, SO alebo SO2; alebob) one of Y ¹ and Y ² is N, which is bound to Y ⁴ and the other of Y ¹ and Y ² is CH ² and Y ⁴ is CO, CS, SO or SO 2; or

c) jeden z Y¹ a Y² je N, ktorý je naviazaný na Y⁴ a druhý z Y¹ a Y² je CH2 a Y⁴ je CH₂;c) one of Y ¹ and Y ² is N, which is bound to Y ⁴ and the other of Y ¹ and Y ² is CH ² and Y ⁴ is CH ₂ ;

Y³ je Z-CH2, CH2-Z alebo ΟΗ2ΟΗ2 a Z je O alebo S; pod podmienkou, že keď Y¹ je N, Y³ nemôže byť Z-CH2;Y ³ is Z-CH 2, CH 2 -Z or ΟΗ2-2 and Z is O or S; with the proviso that when Y ¹ is N, Y ³ cannot be Z-CH 2;

W je väzba alebo O, S, CO, CS, SO alebo SO₂ skupina;W is a bond or O, S, CO, CS, SO or SO ₂ group;

n je 0 až 5, m je 0 až 5 a m + n je 1 až 10; pod podmienkou, že keď W je O alebo S, potom n > 2 a m > 1; keď W je CO, CS, SO alebo SO₂, potom n > 1 a m > 1;n is 0 to 5, m is 0 to 5, and n is 1 to 10; with the proviso that when W is O or S, then n> 2 and m>1; when W is CO, CS, SO or SO ₂ , then n> 1 and m>1;

X je C, CH alebo N; pod podmienkou, že keď X je C, čiarkovaná čiara znamená väzbu a keď X je N alebo CH, čiarkovaná čiara nie je väzba;X is C, CH or N; with the proviso that when X is C, the dashed line is a bond and when X is N or CH, the dashed line is not a bond;

-7R¹ až R⁹ sú nezávisle vybrané zo skupiny zahrnujúcej: vodík, halogén, kyano, nitro, amino, hydroxy, C^ealkylamino, di-Ci.₆alkylamino, Ci.₆alkyl, C2-6alkenyl, C2-6alkinyl, Ci.₆alkoxy, Ci_6alkyltio, C^alkyl substituovaný hydroxyskupinou alebo tiolom, C₃.₈cykloalkyl, C₃.₈cykloalkyl-Ci.₈alkyl, acyl, tioacyl, aryl, trifluórmetyl, trifluórmetylsulfonyl a Ci-6alkylsulfonyl;7R ¹ to R ⁹ are independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, C ^ alkylamino, di-C. ₆ alkylamino; ₆ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C. ₆ alkoxy, Ci_6alkyltio, C ^ alkyl substituted with hydroxy or thiol, C _3. ₈ cycloalkyl, C _3. ₈ cycloalkyl-C 1. ₈ alkyl, acyl, thioacyl, aryl, trifluoromethyl, trifluoromethylsulfonyl and C 6 alkylsulfonyl;

R¹⁰ je vodík, C^alkyl, C2-6alkenyl, C₂-6alkinyl, C-i_₆alkyl substituovaný hydroxyskupinou alebo tiolom, C₃.₈cykloalkyl, C₃.₈cykloalkyl-Ci-6alkyl, aryl, aryl-Ci.₆alkyl, acyl, tioacyl, Cvealkylsulfonyl, trifluórmetylsulfonyl alebo arylsulfonyl;R ¹⁰ is hydrogen, alkyl, C 2-6 alkenyl, C ₂ -6alkinyl C _{i_-6} alkyl substituted with hydroxy or thiol, C _3. ₈ cycloalkyl, C _3. ₈ cycloalkyl-C 1-6 alkyl, aryl, aryl-C 1-6 alkyl; ₆ alkyl, acyl, thioacyl, Cvealkylsulfonyl, trifluoromethylsulfonyl or arylsulfonyl;

alebo ich farmaceutický prijateľné adičné soli s kyselinou.or a pharmaceutically acceptable acid addition salt thereof.

V prvom výhodnom uskutočnení vynálezu, je indol naviazaný na X cez polohu 3 indolu.In a first preferred embodiment of the invention, the indole is bonded to X through the 3-position of the indole.

V druhom uskutočnení vynálezu, jeden z Y¹ a Y² je N, ktorý je naviazaný na Y⁴ a druhý z Y¹ a Y² je CO a Y⁴ je CH₂.In a second embodiment of the invention, one of ^Y1 and ^Y2 is N, which is bound to Y ⁴ and the other of Y ¹ and Y ² is CO and Y ⁴ is CH _second

V treťom uskutočnení vynálezu, jeden z Y¹ a Y² je N, ktorý je naviazaný na Y⁴a druhý 2 Y¹ a Y² je CH₂ a Y⁴ je CO.In a third embodiment of the invention, one of Y ¹ and Y ² is N, which is bound to Y ⁴ and the other 2 Y ¹ and Y ² is CH ₂ and Y ⁴ is CO.

Vo štvrtom uskutočnení vynálezu, Y¹ je dusík naviazaný na Y⁴ a jeden z Y⁴a Y² je CO a druhý je CH₂.In a fourth embodiment of the invention, Y ¹ is nitrogen bonded to Y ⁴ and one of Y ⁴ and Y ² is CO and the other is CH ₂ .

V piatom uskutočnení vynálezu, Y¹ je dusík naviazaný na Y⁴, Y² je CO a Y⁴je CH₂.In a fifth embodiment of the invention, Y ¹ is nitrogen bonded to Y ⁴ , Y ² is CO and Y ⁴ is CH ₂ .

V šiestom uskutočnení vynálezu, Y¹ je dusík naviazaný na Y⁴, Y² je CH₂ a , Y⁴ je CO.In a sixth embodiment of the invention, Y ¹ is nitrogen bonded to Y ⁴ , Y ² is CH ₂ and, Y ⁴ is CO.

V siedmom uskutočnení vynálezu, Y² je dusík naviazaný na Y⁴ a jeden z Y¹a Y⁴ je CO a druhý je CH₂.In a seventh embodiment of the invention, Y ² is nitrogen bonded to Y ⁴ and one of Y ¹ and Y ⁴ is CO and the other is CH ₂ .

V ôsmom uskutočnení vynálezu, Y² je dusík naviazaný na Y⁴, Y¹ je CH₂ a Y⁴ je CO.In an eighth embodiment of the invention, Y ² is nitrogen bonded to Y ⁴ , Y ¹ is CH ₂ and Y ⁴ is CO.

V deviatom uskutočnení vynálezu, Y² je dusík naviazaný na Y⁴, Y¹ je CO a Y⁴ je CH₂.In a ninth embodiment of the invention, Y ² is nitrogen bonded to Y ⁴ , Y ¹ is CO and Y ⁴ is CH ₂ .

V desiatom uskutočnení vynálezu, jeden z Y¹ a Y² je N, ktorý je naviazaný na Y⁴ a druhý z Y¹ a Y² je CH2 a Y⁴ je CH2. Takéto zlúčeniny sú výhodné vo forme ich farmaceutický prijateľných dvojsolí.In a tenth embodiment of the invention, one of Y ¹ and Y ² is N which is bonded to Y ⁴ and the other of Y ¹ and Y ² is CH ² and Y ⁴ is CH 2. Such compounds are preferred in the form of their pharmaceutically acceptable di-salts.

V ďalšom uskutočnení vynálezu, Y³ je CH₂CH₂ alebo CH₂Z.In another embodiment of the invention, Y ³ is CH ₂ CH ₂ or CH ₂ Z.

V ešte ďalšom uskutočnení vynálezu, X je C, X je N alebo X je CH.In yet another embodiment of the invention, X is C, X is N or X is CH.

-8Substituenty R¹ až R⁹ sú výhodne vybrané zo skupiny zahrnujúcej: vodík, halogén, kyano, nitro, amino, Ci_₆alkylamino, di-C-|.₆alkylamino, C-|.₆alkyl, C₃.₈cykloalkyl a trifluórmetyl a R¹⁰ je vodík, Ci-ealky! alebo acyl a/alebo W je väzba a n + m je 1 až 6, výhodne 3 až 6.The substituents R ¹ to R ⁹ are preferably selected from the group consisting of: hydrogen, halogen, cyano, nitro, amino, C _1-6 alkylamino, di-C 1-7. ₆ alkylamino, C _1-6 alkyl. ₆ alkyl, C _3. _And cycloalkyl and trifluoromethyl; and R ¹⁰ is hydrogen, C 1-6 alkyl. or acyl and / or W is a bond and n and m is 1 to 6, preferably 3 to 6.

Zlúčeniny podľa vynálezu sú čiastočnými agonistami alebo antagonistami dopamínového D₄ receptora. Veľa zlúčenín má kombinovaný účinok na afinitu k dopamínovému D₄ receptoru a dopamínovému D₃ receptoru, na afinitu k 5-HT₂a receptoru, na afinitu k 5-HT₂c receptoru a/alebo inhibičný účinok na 5-HT reabsorpciu.The compounds of the invention are partial dopamine D ₄ receptor agonists or antagonists. Many compounds have combined effect at the dopamine D affinity ₄ receptors and dopamine D ₃ receptor, the affinity for _{5-HT2-receptor,} the affinity for 5-HT _2c receptor and / or inhibitory effect on 5-HT reuptake.

Okrem toho, zlúčeniny podľa vynálezu sa považujú za užitočné na liečenie pozitívnych a negatívnych symptómov schizofrénie, iných psychóz, úzkostných porúch, ako je všeobecná úzkostná porucha, panická porucha, a obsedantnokompulzívna porucha, depresie, agresie, vedľajších účinkov indukovaných bežnými antipsychotickými látkami, migrény, kognitívnych porúch, ADHD a na zlepšenie spánku.In addition, the compounds of the invention are considered useful for the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders such as general anxiety disorder, panic disorder, and obsessive-compulsive disorder, depression, aggression, side effects induced by common antipsychotics, cognitive disorders, ADHD and sleep improvement.

Z iného hľadiska poskytuje tento vynález farmaceutické prostriedky, ktoré obsahujú najmenej jednu zlúčeninu všeobecného vzorca I ako je uvedené vyššie alebo jej farmaceutický prijateľnú adičnú soľ s kyselinou v terapeuticky účinnom množstve spolu s jedným alebo viacerými farmaceutický prijateľnými nosičmi alebo riedidlami.In another aspect, the invention provides pharmaceutical compositions comprising at least one compound of Formula I as defined above, or a pharmaceutically acceptable acid addition salt thereof, in a therapeutically effective amount together with one or more pharmaceutically acceptable carriers or diluents.

Z ďalšieho hľadiska poskytuje tento vynález použitie zlúčeniny všeobecného vzorca I uvedenej vyššie alebo jej adičnej soli s kyselinou na výrobu lieku na liečenie vyššie uvedených porúch.In another aspect, the invention provides the use of a compound of Formula I above or an acid addition salt thereof for the manufacture of a medicament for the treatment of the above disorders.

Niektoré zlúčeniny všeobecného vzorca I existujú ako ich optické izoméry a takéto optické izoméry sú tiež obsiahnuté vynálezom.Certain compounds of formula I exist as optical isomers thereof, and such optical isomers are also contemplated by the invention.

Termín Cve-alkyl sa týka rozvetvenej alebo nerozvetvenej alkylovej skupiny, ktorá má od jedného do šiestich atómov uhlíka vrátane, ako je napríklad metyl, etyl,The term Cve-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-metyl-2-propyl, 2-metyl-1 -propyl, pentyl a hexyl.1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1-propyl, pentyl and hexyl.

Podobne C₂.s-alkenyl alebo C₂._e-alkinyl znamenajú také skupiny, ktoré majú od dvoch do šiestich atómov uhlíka, obsahujúce jednu dvojitú väzbu alebo trojitú väzbu, ako je napríklad etenyl, propenyl, butenyl, etinyl, propinyl a butinyl.Similarly, _C2 s-alkenyl, or C _2nd _ε- alkynyl means those groups having from two to six carbon atoms containing one double bond or triple bond, such as ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.

-9Výrazy C-i_₆-alkoxy, C-i-e-alkyltio, C-i-6-alkylsulfonyl, Cve-alkylamino, C-i_6-alkylkarbonyl a podobne znamenajú také skupiny, v ktorých Ci-6-alkylová skupina je určená vyššie.The terms C _1-6 -alkoxy, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkylamino, C 1-6 -alkylcarbonyl and the like mean those groups in which the C 1-6 -alkyl group is as defined above.

Výraz C3.ecykloalkyl znamená monocyklický alebo bicyklický karbocyklus, ktorý má tri až 8 C-atómov, ako je napríklad cyklopropyl, cyklopentyl, cyklohexyl a podobne.The term C 3-8 cycloalkyl means a monocyclic or bicyclic carbocycle having three to 8 C-atoms, such as cyclopropyl, cyclopentyl, cyclohexyl and the like.

Výraz aryl znamená karbocyklickú aromatickú skupinu, ako je napríklad fenyl, naftyl, výhodne fenyl, ktorý zahrnuje metylom substituovaný fenyl alebo naftyl.The term aryl means a carbocyclic aromatic group such as phenyl, naphthyl, preferably phenyl, which includes methyl substituted phenyl or naphthyl.

Halogén znamená fluór, chlór, bróm alebo jód.Halogen means fluorine, chlorine, bromine or iodine.

Ako bolo použité v tomto dokumente termín acyl sa týka formylu alebo Ci.₆alkylkarbonylu, arylkarbonylu, aryl-Ci.₆alkylkarbonylu, C₃.₈cykloalkylkarbonylu alebo C3-8cykloalkyl-Ci.6alkylkarbonylu a termín tioacyl je príslušný acyl, v ktorom je karbonylová skupina nahradená tiokarbonylovou skupinou.As used herein, the term acyl refers to formyl or C 1. ₆ alkylcarbonyl, arylcarbonyl, aryl-C 1-6 alkyl; ₆ alkylcarbonyl, C _3. _And cycloalkylcarbonyl or C 3-8 cycloalkyl-C 1-6 alkylcarbonyl and the term thioacyl is the corresponding acyl in which the carbonyl group is replaced by a thiocarbonyl group.

Adičné soli zlúčenín s kyselinami podľa vynálezu môžu byť farmaceutický prijateľné soli tvorené s netoxickými kyselinami. Príkladmi takýchto organických solí sú soli s kyselinou maleínovou, fumárovou, benzoovou, askorbovou, jantárovou, šťaveľovou, bismetylénsalicylovou, metánsulfónovou, etándisulfónovou, octovou, propiónovou, vinnou, salicylovou, citrónovou, glukónovou, mliečnou, jablčnou, mandľovou, škoricovou, citrakónovou, asparágovou, steárovou, palmitovou, itakónovou, glykolovou, p-aminobenzoovou, glutámovou, benzénsulfónovou a teofylínoctovou kyselinou ako aj s 8-halogénteofylínmi, napríklad s 8-brómteofylínom. Príkladmi anorganických adičných solí sú soli s kyselinou chlorovodíkovou, bromovodíkovou, sírovou, sulfámovou, fosforečnou a dusičnou.The acid addition salts of the compounds of the invention may be pharmaceutically acceptable salts formed with non-toxic acids. Examples of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartar, salicylic, citric, gluconic, lactic, citric, malic, mandaric, mandaric, mandaric, mandaric, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, as well as with 8-halo-thiophylenes, for example with 8-bromothiophyline. Examples of inorganic addition salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

Farmaceutické prostriedky podľa vynálezu alebo tie, ktoré sa vyrobili v súlade s týmto vynálezom sa môžu podávať akýmkoľvek vhodným spôsobom, napríklad orálne vo forme tabliet, kapsúl, práškov, sirupov, atď., alebo parenterálne vo forme roztokov pre injekcie. Na prípravu takýchto farmaceutických prostriedkov sa môžu použiť spôsoby dobre známe v danej oblasti techniky, a môžu sa použiť farmaceutický prijateľné nosiče, riedidlá, excipienty alebo iné prídavné látky bežne používané v danej oblasti techniky.The pharmaceutical compositions of the invention or those made in accordance with the invention may be administered by any suitable means, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. Methods well known in the art may be used to prepare such pharmaceutical compositions, and pharmaceutically acceptable carriers, diluents, excipients, or other additives commonly used in the art may be used.

Bežne sa zlúčeniny podľa vynálezu podávajú v jednotkovej dávkovej forme, ktorá obsahuje uvedené zlúčeniny v množstve približne 0,01 až 100 mg.Typically, the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 0.01 to 100 mg.

-10Celková denná dávka je bežne v rozmedzí približne 0,05 až 500 mg, a výhodnejšie približne 0,1 až 50 mg aktívnej zlúčeniny podľa vynálezu.The total daily dose is conveniently in the range of about 0.05 to 500 mg, and more preferably about 0.1 to 50 mg of the active compound of the invention.

Zlúčeniny podľa vynálezu sa môžu pripraviť nasledujúcim spôsobom:The compounds of the invention can be prepared as follows:

1) Alkyláciou piperazínu, piperidínu alebo tetrahydropyridínu všeobecného vzorca II s alkylačným derivátom všeobecného vzorca III1) Alkylation of piperazine, piperidine or tetrahydropyridine of formula II with an alkylating derivative of formula III

kde R¹ až R¹⁰, X, Y¹, Y², Y³, Y⁴, W, n, m a čiarkovaná čiara sú určené vyššie, a L je odštiepiteľriá skupina, ako je napríklad halogén, mesilát alebo tosilát;wherein R ¹ to R ¹⁰ , X, Y ¹ , Y ² , Y ³ , Y ⁴ , W, n, m and the dotted line are as defined above, and L is a leaving group such as halogen, mesylate or tosylate;

2) Redukčnou alkyláciou amínu všeobecného vzorca II s reakčným činidlom všeobecného vzorca IV2) Reductive alkylation of an amine of formula II with a reagent of formula IV

kde R¹ až R¹⁰, X, Y¹, Y², Y³, Y⁴, W, n, m a čiarkovaná čiara sú určené vyššie, a E je aldehydová skupina alebo skupina aktivovanej karboxylovej kyseliny;wherein R ¹ to R ¹⁰ , X, Y ¹ , Y ² , Y ³ , Y ⁴ , W, n, m and the dotted line are as defined above, and E is an aldehyde or activated carboxylic acid group;

3) Alkyláciou zlúčeniny všeobecného vzorca V s alkylačným derivátom všeobecného vzorca VI3) Alkylating a compound of formula V with an alkylating derivative of formula VI

-11 R⁵ -11 R ⁵

kde R¹ až R¹⁰, X, Y³, W, n, m a čiarkovaná čiara sú určené vyššie, jeden z Y⁵ a Y⁶ je NH alebo N' a druhý z Y⁵ a Y⁶ je CO, CS, SO, SO₂ alebo CH₂, a L je odštiepiteľná skupina, ako je napríklad halogén, mesilát alebo tosilát; alebowherein R ¹ to R ¹⁰ , X, Y ³ , W, n, m and the dotted line are as defined above, one of Y ⁵ and Y ⁶ is NH or N 'and the other of Y ⁵ and Y ⁶ is CO, CS, SO, SO ₂ or CH ₂ , and L is a leaving group such as halogen, mesylate or tosilate; or

4) Redukciou dvojitej väzby v tetrahydropyridinylovom kruhu u derivátov nasledujúceho všeobecného vzorca VII4) Reduction of the double bond in the tetrahydropyridinyl ring for derivatives of the following formula (VII)

kde R¹ až R¹⁰, Y¹, Y², Y³, Y⁴, W, n a m sú určené vyššie;wherein R ¹ to R ¹⁰ , Y ¹ , Y ² , Y ³ , Y ⁴ , W, n and m are as defined above;

5) Redukciou amidkarbonylu v zlúčenine všeobecného vzorca VIII5) Reduction of amidocarbonyl in the compound of formula VIII

-12kde R¹ až R¹⁰, Y¹, Y², Y³, Y⁴, n, m, W a čiarkovaná čiara sú určené vyššie;-12where R ¹ to R ¹⁰ , Y ¹ , Y ² , Y ³ , Y ⁴ , n, m, W and the dotted line are as defined above;

6) Redukciou amidovej skupiny v zlúčeninách všeobecného vzorca IX6) Reduction of the amide group in compounds of formula IX

kde R¹ až R¹⁰, X, Y¹, Y², Y³, n, m, W a čiarkovaná čiara sú určené vyššie;wherein R ¹ to R ¹⁰ , X, Y ¹ , Y ² , Y ³ , n, m, W and the dotted line are as defined above;

7) Redukčnou alkyláciou derivátu všeobecného vzorca Va s acylačným derivátom všeobecného vzorca X7) Reductive alkylation of a derivative of formula Va with an acylating derivative of formula X

(Va) kde R¹ až R¹⁰, X, Y³, W, n, m a čiarkovaná čiara sú určené vyššie, jeden z Y⁷ a Y^{8 *} je NH a druhý z Y⁷ a Y⁸ je CH₂ a E aldehyd alebo aktivovaná karboxylová kyselina;(Va) wherein R ¹ to R ¹⁰ , X, Y ³ , W, n, m and the dotted line are as defined above, one of Y ⁷ and Y ^{8 *} is NH and the other of Y ⁷ and Y ⁸ is CH ₂ and E aldehyde or an activated carboxylic acid;

8) Acyláciou amínu všeobecného vzorca Va s reakčným činidlom všeobecného vzorca X8) Acylating the amine of formula Va with a reagent of formula X

kde R¹ až R¹⁰, X, Y³, W, n, m a čiarkovaná čiara sú určené vyššie, jeden z Y⁷ a Y⁸ je NH a druhý z Y⁷ a Y⁸ je CH₂ a E aldehyd alebo aktivovaná karboxylová kyselina;wherein R ¹ to R ¹⁰ , X, Y ³ , W, n, m and the dotted line are as defined above, one of Y ⁷ and Y ⁸ is NH and the other of Y ⁷ and Y ⁸ is CH ₂ and E aldehyde or activated carboxylic acid ;

9) Štiepením polymérom viazaného derivátu všeobecného vzorca XI9) Cleavage of the polymer-bound derivative of formula XI

kde R¹ až R⁹, Y¹, Y², Y³, X, W, n a m sú určené vyššie a ROH je hydroxyetyl- alebo hydroxy metyl polystyrén, Wangova živica alebo živica podobná polyetylénglykolpolystyrénovej živici;wherein R ¹ to R ⁹ , Y ¹ , Y ² , Y ³ , X, W, n and m are as defined above and ROH is hydroxyethyl or hydroxy methyl polystyrene, Wang resin or polyethylene glycol polystyrene-like resin;

a hneď nato sa zlúčenina všeobecného vzorca I izoluje ako voľná báza alebo ako jej farmaceutický prijateľná adičná soľ s kyselinou.and immediately thereafter, the compound of formula I is isolated as the free base or as a pharmaceutically acceptable acid addition salt thereof.

Alkylácia podľa spôsobu 1) a 3) sa obyčajne uskutočňuje v inertnom organickom rozpúšťadle, napríklad vo vhodnom vriacom alkohole alebo ketóne, výhodne v prítomnosti organickej alebo anorganickej bázy (uhličitan draselný,The alkylation according to methods 1) and 3) is usually carried out in an inert organic solvent, for example in a suitable boiling alcohol or ketone, preferably in the presence of an organic or inorganic base (potassium carbonate,

- 14diizopropyletylamín alebo tríetylamín). Alternatívne sa môže alkylácia uskutočniť pri konštantnej teplote, ktorá je odlišná od teploty varu, v jednom z vyššie uvedených rozpúšťadiel alebo v dimetylformamide (DMF), dimetylsulfoxide (DMSO), alebo Nmetylpyrolidín-2-óne (NMP), výhodne v prítomnosti bázy.- 14diisopropylethylamine or triethylamine). Alternatively, the alkylation can be carried out at a constant temperature other than boiling point in one of the above solvents or in dimethylformamide (DMF), dimethylsulfoxide (DMSO), or N-methylpyrrolidin-2-one (NMP), preferably in the presence of a base.

Syntéza amínov všeobecného vzorca II, 3-(piperidín-4-yl)-1 /7-indolov a 3(3,6-dihydro-2Ä7-pyridín-4-yl)-1 /7-indolov bola opísaná v literatúre (pozri napríklad EP-A1-465398). Alkylačné reakčné činidlá všeobecného vzorca III sú známe z literatúry (pozri Oshiro a ďalší J. Med. Chem. 2000, 43, 177 - 189 a EP-B1512525) alebo sa môžu pripraviť spôsobmi zrejmými odborníkom v danej oblasti techniky (pozri napríklad Kowalski a ďalší J. Heterocyclic Chem. 2000, 37, 187 189, Mokrosz a ďalší Pharmazie 1997, 52, 432 - 428 a Misztal a ďalší Med. Chem. Res. 1992, 2, 82 - 87). Alkylačné činidlá všeobecného vzorca VI sa môžu pripraviť spôsobmi známymi odborníkom v danej oblasti techniky a amíny všeobecného vzorca V sú komerčne dostupné alebo sú opísané v literatúre.The synthesis of amines of formula II, 3- (piperidin-4-yl) -1 H -indoles and 3- (3,6-dihydro-2 H -pyridin-4-yl) -1 H -indoles has been described in the literature (see e.g. EP-A1-465398). Alkylating reagents of formula III are known in the literature (see Oshiro et al. J. Med. Chem. 2000, 43, 177-189 and EP-B1512525) or may be prepared by methods apparent to those skilled in the art (see, for example, Kowalski et al. J. Heterocyclic Chem. 2000, 37, 187 189, Mokrosz et al. Pharmazie 1997, 52, 432-428 and Misztal et al. Med. Chem. Res. 1992, 2, 82-87). Alkylating agents of formula VI can be prepared by methods known to those skilled in the art and amines of formula V are commercially available or are described in the literature.

Redukčná alkylácia opísaná v spôsoboch 2) a 7) sa uskutočňuje štandardnými známymi spôsobmi. Reakcia sa môže uskutočniť v dvoch krokoch, napríklad väzbovou reakciou derivátov všeobecného vzorca ll/Va a reakčného činidla všeobecného vzorca IV/X štandardnými spôsobmi pomocou chloridu karboxylovej kyseliny alebo použitím väzbových reakčných činidiel, ako je napríklad dicyklo-hexylkarbodiimid, po ktorej nasleduje redukcia výsledného amidu hydridom hlinito-lítnym alebo alánom. Reakcia sa môže tiež uskutočniť štandardným jednonádobovým spôsobom. Karboxylové kyseliny alebo aldehydy všeobecného vzorca IV/X sa môžu pripraviť spôsobmi známymi odborníkom v danej oblasti techniky.The reductive alkylation described in methods 2) and 7) is carried out by standard known methods. The reaction may be carried out in two steps, for example, by coupling the derivatives of formula II / Va and reagent of formula IV / X by standard methods using carboxylic acid chloride or by using coupling reagents such as dicyclohexylcarbodiimide followed by reduction of the resulting amide lithium aluminum hydride or alane. The reaction can also be carried out using a standard one-pot method. Carboxylic acids or aldehydes of formula IV / X may be prepared by methods known to those skilled in the art.

Alkylácia podľa spôsobu 3) sa bežne uskutočňuje ako je opísané vyššie alebo reakciou dusíkového aniónu zlúčeniny všeobecného vzorca V so zlúčeninou všeobecného vzorca VI. Dusíkový anión zlúčeniny všeobecného vzorca V sa môže pripraviť v inertnom organickom rozpúšťadle, napríklad dimetylformamide (DMF), dimetylsulfoxide (DMSO) alebo W-metylpyrolidín-2-óne (NMP), použitím silnej bázy, napríklad NaH, pred alkyláciou.The alkylation according to method 3) is conveniently carried out as described above or by reacting the nitrogen anion of a compound of formula V with a compound of formula VI. The nitrogen anion of the compound of formula V can be prepared in an inert organic solvent, for example dimethylformamide (DMF), dimethylsulfoxide (DMSO) or N-methylpyrrolidin-2-one (NMP), using a strong base, for example NaH, prior to alkylation.

Redukcia dvojitej väzby podľa spôsobu 4) sa všeobecne uskutočňuje pomocou katalytickej hydrogenácie pri nízkom tlaku (<0,303 MPa (<3 atm)) v Parrovom prístroji alebo použitím redukčných činidiel, ako je diborán aleboThe reduction of the double bond according to method 4) is generally carried out by catalytic hydrogenation at low pressure (< 0.303 MPa (< 3 atm)) in a Parr apparatus or by using reducing agents such as diborane;

- 15hydroboritanové deriváty, ktoré sú vyrobené in situ z NaBH₄ v kyseline trifluóroctovej v inertnom rozpúšťadle, ako je tetrahydrofurán (THF), dioxán alebo dietyléter. Východiskové zlúčeniny všeobecného vzorca VII sa môžu pripraviť spôsobmi 1), 3), 7) a 8).15 borohydride derivatives which are produced in situ from NaBH ₄ in trifluoroacetic acid in an inert solvent such as tetrahydrofuran (THF), dioxane or diethyl ether. The starting compounds of formula VII can be prepared by methods 1), 3), 7) and 8).

Redukcia amidových skupín podľa spôsobov 5) a 6) je najbežnejšie uskutočnená s hydridom hlinitolítnym alebo alánom v inertnom organickom rozpúšťadle, ako je napríklad tetrahydrofurán (THF) alebo dietyléter od 0 °C do teploty refluxu. Východiskové zlúčeniny všeobecného vzorca VIII sa môžu pripraviť spôsobmi 2) a 3), zatiaľ čo východiskové zlúčeniny všeobecného vzorca IX sa môžu pripraviť spôsobmi 1), 7) a 8).The reduction of the amide groups according to Methods 5) and 6) is most conveniently performed with lithium aluminum hydride or an alkane in an inert organic solvent such as tetrahydrofuran (THF) or diethyl ether from 0 ° C to reflux temperature. The starting compounds of formula VIII can be prepared by methods 2) and 3), while the starting compounds of formula IX can be prepared by methods 1), 7) and 8).

Väzbová reakcia podľa spôsobu 8) sa bežne uskutočňuje použitím väzbových činidiel, ako je dicyklohexylkarbodiimid.The coupling reaction of method 8) is conveniently performed using coupling agents such as dicyclohexylcarbodiimide.

Deriváty všeobecného vzorca XI sú pripravené pomocou krokov syntézy v tuhej fáze ako je znázornené v schéme 1 nižšie. Na prvý stavebný blok vzorca XII, pripravený spôsobmi zrejmými odborníkom v danej oblasti techniky, sa obvykle pôsobí živicou (polystyrénom viazaný etyl-4-nitrofenylkarbonát) za použitia bázy, napríklad A/,A/-dimetylaminopyridínu a A/./V-diizopropyletylamínu pri zvýšenej teplote (napríklad 50 až 100 °C) v aprotickom rozpúšťadle (napríklad DMF alebo DMSO) za vzniku zlúčeniny všeobecného vzorca XIII. Po odstránení ochranných skupín pomocou kyseliny trifluóroctovej (živica vzorca XIV), sa druhý rozširujúci stavebný blok sa zaviedol alkyláciou. Alkylácia sa uskutočnila pri zvýšenej teplote (50 až 100 °C) v aprotickom rozpúšťadle, ako je DMF, acetón alebo acetonitril za vzniku živice všeobecného vzorca XV. Po odstránení esteru kyseliny karboxylovej pomocou kyseliny trifluóroctovej (živica XVI), sa tretí rozširujúci stavebný blok všeobecného vzorca Va zaviedol pomocou krokov štandardnej reakcie tvorby amidu, napríklad konvertovaním karboxylovej kyseliny na zodpovedajúci chlorid kyseliny použitím tionylchloridu pri nízkej teplote v dichlórmetáne, acetonitrile alebo DMF, po čom nasleduje pôsobenie amínom. Finálny produkt sa odštiepil zo živice použitím zriedeného metoxidu sodného v zmesi metanol/tetrahydrofurán pri teplote okolia.The derivatives of formula XI are prepared by solid phase synthesis steps as shown in Scheme 1 below. The first building block of formula XII, prepared by methods apparent to those skilled in the art, is usually treated with a resin (polystyrene bonded ethyl 4-nitrophenyl carbonate) using a base such as N, N -dimethylaminopyridine and N, N -diisopropylethylamine for at an elevated temperature (e.g. 50-100 ° C) in an aprotic solvent (e.g. DMF or DMSO) to give a compound of formula XIII. After deprotection with trifluoroacetic acid (resin of formula XIV), the second extension building block was introduced by alkylation. The alkylation was carried out at an elevated temperature (50 to 100 ° C) in an aprotic solvent such as DMF, acetone or acetonitrile to give a resin of formula XV. After removal of the carboxylic acid ester with trifluoroacetic acid (resin XVI), the third extension building block of formula (Va) was introduced by standard amide formation reaction steps, for example by converting the carboxylic acid to the corresponding acid chloride using low temperature thionyl chloride in dichloromethane, acetonitrile or DMF. followed by amine treatment. The final product was cleaved from the resin using dilute sodium methoxide in methanol / tetrahydrofuran at ambient temperature.

XII: R' = BOC, R = H — XIII: R” = BOC, R = C(O)O(CH₂)2(PS) — XIV: R' = H, R = C(0)0(CH₂)₂(PS)XII: R = BOC, R = H - XIII: R '= Boc, R-C (O) O _(CH2) 2 (PS) - XIV: R = H, R = C (0) 0 (CH ₂₎ ₂ (PS)

1) SOCI₂ SOCI ₂

2) (Va)2) (Va)

-S»XV: R” = (CH2)_n-W-(CH₂)_m-COO-tBu, R = C(O)O(CH 2)2 (PS)-S »XV: R 1 = (CH 2) _n -W- (CH ₂ ) _m -COO-tBu, R = C (O) O (CH 2) 2 (PS)

XVI:R^D'=(CH2)n-W-(CH2)ra-COOH,R^,,=C(O)O(CH2)₂(PS) r·XVI: R ^D '= (CH 2) n W- (CH 2) m - COOH, R ^,, = C (O) O (CH ₂ ) ₂ (PS) r ·

R'-C(O)O(CH₂)₂(PS), PS = polystyrén alebo Wangova živica Príklady uskutočnenia vynálezuR'-C (O) O (CH ₂ ) ₂ (PS), PS = polystyrene or Wang resin

Experimentálna časťExperimental part

Teploty topenia sa stanovili na prístroji Biichí B-540 a sú nekorigované. Hmotnostné spektrá sa získali na Quattro MS-MS systéme z VG Biotech, Fisons Instruments. Analytické LC-MS dáta sa získali na zariadení PE Sciex API 150EX, vybavenom zdrojom lonSpray a Shimadzu LC-8A/SLC-1OA LC systémom. LC podmienky (50 x 4,6 mm YMC ODS-A s 5 gm veľkosťou častíc) boli lineárna gradientová elúcia so zmesou voda/acetonitril/kyselina trifluóroctová (90:10:0,05) až zmesou voda/acetonitril/kyselina trifluóroctová (10:90:0,03) v priebehu 7 minút pri 2 ml/min. Čistota sa stanovila integráciou UV záznamu (254 nm). Retenčné časy R_t sú vyjadrené v minútach. Preparatívna LC-MS-separácia sa uskutočňovala na tom istom prístroji. LC podmienky (50 x 20 mm, YMC ODS-A s 5 gm veľkosťou častíc) boli lineárna gradientová elúcia so zmesou voda/acetonitril/kyselina trifluór-octová (80:20:0,05) až zmesou voda/acetonitril/kyselina trifluóroctová (5:95:0,03) vMelting points were determined on a Biichi B-540 instrument and are uncorrected. Mass spectra were obtained on a Quattro MS-MS system from VG Biotech, Fisons Instruments. Analytical LC-MS data was obtained on a PE Sciex API 150EX instrument equipped with a lonSpray source and a Shimadzu LC-8A / SLC-1OA LC system. LC conditions (50 x 4.6 mm YMC ODS-A with 5 gm particle size) were linear gradient elution with water / acetonitrile / trifluoroacetic acid (90: 10: 0.05) to water / acetonitrile / trifluoroacetic acid (10 : 90: 0.03) over 7 minutes at 2 mL / min. Purity was determined by integration of a UV record (254 nm). Retention times R _t are expressed in minutes. Preparative LC-MS-separation was performed on the same instrument. LC conditions (50 x 20 mm, YMC ODS-A with 5 gm particle size) were linear gradient elution with water / acetonitrile / trifluoroacetic acid (80: 20: 0.05) to water / acetonitrile / trifluoroacetic acid ( 5: 95: 0.03) v

- 17priebehu 7 minút pri 22,7 ml/min. Zbieranie frakcií sa uskutočňovalo pomocou splitflow MS detekcie.- 17 over 7 minutes at 22.7 ml / min. Fraction collection was performed by splitflow MS detection.

¹H NMR spektrá sa zaznamenávali pri 250,13 MHz na prístroji Bruker AC 250 alebo pri 500,13 MHz na prístroji Bruker Avance DRX 500. Deuterovaný chloroform (98,8 % D) alebo dimetylsulfoxid (99,9 % D) sa použili ako rozpúšťadlá. TMS sa použil ako vnútorný referenčný štandard. Hodnoty chemického posunu sú vyjadrené v ppm hodnotách. Pre multiplicitu NMR signálov sú použité nasledovné skratky: s = singlet, d = dublet, t = triplet, q = kvartet, qui = kvintet, h = heptet, dd = dvojitý dublet, dt = dvojitý triplet, dq = dvojitý kvartet, tt = triplet tripletov, m = multiplet a b = široký singlet. NMR signály zodpovedajúce protónom kyseliny sú všeobecne vynechané. Obsah vody v kryštalických zlúčeninách sa stanovil prostredníctvom Karí Fischerovej titrácie. Na stĺpcovú chromatografiu sa použil silikagél typu Kieselgel 60, 40 až 60 mesh ASTM. Pre iónovo-výmennú chromatografiu sa použil nasledovný materiál: SCX-kolóny (1 g) od Varian Mega Bond Elut®, Chrompack kat. č. 220776. Pred použitím sa SCX-kolóny pre-kondicionovali s 10% roztokom kyseliny octovej v metanole (3 ml). ¹ H NMR spectra were recorded at 250.13 MHz on a Bruker AC 250 instrument or at 500.13 MHz on a Bruker Avance DRX 500 instrument. Deuterated chloroform (98.8% D) or dimethylsulfoxide (99.9% D) were used as solvents. TMS was used as an internal reference standard. Chemical shift values are expressed in ppm values. The following abbreviations are used for multiplicity of NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = heptet, dd = double doublet, dt = double triplet, dq = double quartet, tt = triplet triplets, m = multiplet and b = broad singlet. NMR signals corresponding to acid protons are generally omitted. The water content of the crystalline compounds was determined by Karl Fischer titration. Kieselgel 60, 40-60 mesh ASTM was used for column chromatography. The following material was used for ion exchange chromatography: SCX columns (1 g) from Varian Mega Bond Elut®, Chrompack cat. no. 220776. Prior to use, SCX columns were preconditioned with 10% acetic acid in methanol (3 mL).

Príprava medzi produktovPreparation between products

A) Alkylačné reakčné činidláA) Alkylating reagents

-(2-Chlóretyl)-3,4-dihydrochinolín-2(1 H)-ón- (2-Chloroethyl) -3,4-dihydroquinolin-2 (1H) -one

Suspenzia hydridu sodného (3,0 g, 60% v minerálnom oleji) a dimetylformamidu (100 ml) sa udržiavala pri 15 až 18 °C, potom sa pridal roztok 3,4dihydrochinolín-2(1/-/)-ónu (10,0 g) v dimetylformamide (150 ml). Výsledná zmes sa miešala pri teplote miestnosti 60 minút a potom sa pridal roztok 2-chlóretylacetátu (10,0 g) v dimetylformamide (50 ml) pri teplote 20 °C. Výsledná zmes sa zahrievala na 80 °C 2½ hodiny, potom sa ochladila a naliala na ľad. Vodná fáza sa extrahovala s etylacetátom a spojené organické fázy sa premyli soľankou, vysušili sa nad MgSO₄ a koncentrovali vo vákuu. Surový produkt sa čistil pomocou bleskovej chromatografie na silikagéli (eluent: etylacetát/heptán 1:1) za vzniku surového 1-(2acetoxyetyl)-3,4-dihydrochinolín-2(1/-/)-ónu (10,2 g). Zmes surového 1-(2-acetoxy- 18etyl)-3,4-dihydrochinolín-2(1/-/)-ónu, metanolátu sodného (2,5 ml, 30% v metanole) a metanolu (250 ml) sa miešala pri teplote miestnosti 16 hodín a následne na to sa skoncentrovala vo vákuu. Zvyšok sa čistil pomocou bleskovej chromatografie na silikagéli (eluent: etylacetát/heptán 1:1) za vzniku príslušného alkoholu ako červenej kryštalickej látky (4,9 g). Tento alkohol sa rozpustil v tetrahydrofuráne (100 ml) a potom sa pridal trietylamín (8,2 ml). Výsledná zmes sa ochladila na 5 až 6 °C, potom sa pridal roztok chloridu metánsulfónovej kyseliny (2 ml) v tetrahydrofuráne (25 ml). Zmes sa prefiltrovala a odparila do sucha vo vákuu. Zvyšok sa rozpustil v dimetylformamide (50 ml), potom sa pridal chlorid litny (4,9 g) a výsledná zmes sa zahrievala na 70 °C 5 minút. Zmes sa naliala do soľanky a vodná fáza sa extrahovala s etylacetátom. Spojené organické fázy sa sušili (MgSO₄), filtrovali a koncentrovali vo vákuu. Zvyšok sa čistil bleskovou chromatografiou na silikagéli (eluent: etylacetát/heptán 1:1) za vzniku produktu ako červeného oleja (2,9 g).A suspension of sodium hydride (3.0 g, 60% in mineral oil) and dimethylformamide (100 mL) was maintained at 15-18 ° C, then a solution of 3,4-dihydroquinolin-2 (1 H) -one (10, 0 g) in dimethylformamide (150 mL). The resulting mixture was stirred at room temperature for 60 minutes, and then a solution of 2-chloroethyl acetate (10.0 g) in dimethylformamide (50 mL) was added at 20 ° C. The resulting mixture was heated at 80 ° C for 2½ hours, then cooled and poured onto ice. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over MgSO ₄ and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluent: ethyl acetate / heptane 1: 1) to give crude 1- (2-acetoxyethyl) -3,4-dihydroquinolin-2 (1 H) -one (10.2 g). A mixture of crude 1- (2-acetoxy-18-ethyl) -3,4-dihydroquinolin-2 (1 H) -one, sodium methoxide (2.5 mL, 30% in methanol) and methanol (250 mL) was stirred at at room temperature for 16 hours and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate / heptane 1: 1) to give the corresponding alcohol as a red crystalline solid (4.9 g). This alcohol was dissolved in tetrahydrofuran (100 mL) and then triethylamine (8.2 mL) was added. The resulting mixture was cooled to 5-6 ° C, then a solution of methanesulfonic acid chloride (2 mL) in tetrahydrofuran (25 mL) was added. The mixture was filtered and evaporated to dryness in vacuo. The residue was dissolved in dimethylformamide (50 mL), then lithium chloride (4.9 g) was added and the resulting mixture was heated at 70 ° C for 5 minutes. The mixture was poured into brine and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo. 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-Brómpropán-1-yl)-3,4-dihydrochinolín-2(1/7)-ón1- (3-Bromopropan-1-yl) -3,4-dihydroquinoline-2 (1/7) -one

Suspenzia hydridu sodného (6,8 g, 60% v minerálnom oleji) a dimetylformamidu (200 ml) sa udržiavala pri teplote 20 až 25 °C, potom sa pridal roztok 3,4-dihydrochinolín-2(1H)-ónu (25,0 g) v dimetylformamide (180 ml). Výsledná zmes sa miešala pri teplote miestnosti 10 minút, potom sa pridal roztok 1,3-dibrómpropánu (172 g) v dimetylformamide (150 ml) pri teplote 20 až 35 °C. Výsledná zmes sa miešala pri teplote 30 °C 20 minút a skoncentrovala sa vo vákuu. Zvyšok sa nalial na ľad a vodná fáza sa extrahovala s etylacetátom. Spojené organické fázy sa premyli soľankou, sušili (MgSO₄) a koncentrovali vo vákuu. Surový produkt sa čistil pomocou bleskovej chromatografie na silikagéli (eluent: etylacetát/heptán 1:1) za vzniku produktu ako žltého oleja (27 g).A suspension of sodium hydride (6.8 g, 60% in mineral oil) and dimethylformamide (200 mL) was maintained at 20-25 ° C, then a solution of 3,4-dihydroquinolin-2 (1H) -one (25, 0 g) in dimethylformamide (180 mL). The resulting mixture was stirred at room temperature for 10 minutes, then a solution of 1,3-dibromopropane (172 g) in dimethylformamide (150 mL) was added at 20-35 ° C. The resulting mixture was stirred at 30 ° C for 20 minutes and concentrated in vacuo. The residue was poured on ice and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluent: ethyl acetate / heptane 1: 1) to give the product as a yellow oil (27 g).

Nasledujúce zlúčeniny sa pripravili podobným spôsobom:The following compounds were prepared in a similar manner:

-(4-Brómbután-1 -yl )-3,4-d ihyd roch inol í n-2 (1 /-/)-ón z 3,4-dihydrochinolín-2(1/-/)-ónu a 1,4-dibrómbutánu- (4-Bromobutan-1-yl) -3,4-dihydroquinolin-2 (1 H) -one from 3,4-dihydroquinolin-2 (1 H) -one and 1, 4-dibromobutane

-(5-Brómpentán-1 -yl)-3,4-dihydrochinolín-2(1 H)-ón z 3,4-dihydrochinolín-2(1/7)-ónu a 1,5-dibrómpentánu- (5-Bromopentan-1-yl) -3,4-dihydroquinolin-2 (1H) -one from 3,4-dihydroquinolin-2 (1/7) -one and 1,5-dibromopentane

- 194-(4-Brómbután-1 -yl )-3,4-d i hyd ro-2/-/-1,4-benzoxazín-3(4B)-ón z 3,4-dihydro-2/-/-1,4-benzoxazín-3(1/-/)-ónu a 1,4-dibrómbutánu194- (4-Bromobutan-1-yl) -3,4-dihydro-2H-1,4-benzoxazin-3 (4B) -one from 3,4-dihydro-2 H- 1,4-benzoxazine-3 (1H) -one and 1,4-dibromobutane

2-(3-Hydroxypropán-1 -yl )-3,4-d ihyd roizochinol ín-1 (2/-/)-ón z 3,4-dihydroizochinolín-1(2/-/)-ónu a 3-brómpropanolu2- (3-Hydroxypropan-1-yl) -3,4-dihydroisoquinolin-1 (2H) -one from 3,4-dihydroisoquinolin-1 (2H) -one and 3-bromopropanol

2- (4-Brómbután-1 -yl)-3,4-dihydroizochinolín-1 (2H)-ón z 3,4-dihydroizochinolín-1(2/-/)-ónu a 1,4-dibrómbutánu2- (4-Bromobutan-1-yl) -3,4-dihydroisoquinolin-1 (2H) -one from 3,4-dihydroisoquinolin-1 (2H) -one and 1,4-dibromobutane

1-(3-Brómpropán-1-yl)-3,4-dihydroizochinolín-1(2Z7)-ón1- (3-Bromopropan-1-yl) -3,4-dihydroisoquinoline-1 (2Z7) -one

Zlúčenina 2-(3-hydroxypropán-1 -yl )-3,4-d ihyd roizochinol í n-1 (2/-/)-ón sa rozpustil v tetrahydrofuráne (100 ml), potom sa pridal trietylamín (5,2 ml). Výsledná zmes sa ochladila na 6 až 11 °C a potom sa pridal roztok chloridu metánsulfónovej kyseliny (1,4 ml) v tetrahydrofuráne (25 ml). Zmes sa miešala pri 5 °C 10 minút, potom sa prefiltrovala a skoncentrovala vo vákuu. Zvyšok sa rozpustil v acetóne (250 ml), potom sa pridal bromid lítny (6,5 g) a výsledná zmes sa nechala vrieť za refluxu 2 hodiny. Zmes sa naliala do soľanky a vodná fáza sa extrahovala s etylacetátom. Spojené organické fázy sa sušili (MgSO₄), filtrovali a koncentrovali vo vákuu. Zvyšok sa čistil pomocou bleskovej chromatografie na silikagéli (eluent: etyl-acetát/heptán 1:2) za vzniku produktu ako žltého oleja (2,7 g).2- (3-Hydroxypropan-1-yl) -3,4-dihydroisoquinolin-1 (2H) -one was dissolved in tetrahydrofuran (100 mL) then triethylamine (5.2 mL) was added. ). The resulting mixture was cooled to 6-11 ° C and then a solution of methanesulfonic acid chloride (1.4 mL) in tetrahydrofuran (25 mL) was added. The mixture was stirred at 5 ° C for 10 minutes, then filtered and concentrated in vacuo. The residue was dissolved in acetone (250 mL), then lithium bromide (6.5 g) was added and the resulting mixture was allowed to boil under reflux for 2 hours. The mixture was poured into brine and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate / heptane 1: 2) to give the product as a yellow oil (2.7 g).

3- Chlór-1 -(3,4-dihydro-1 /-/-izochinolín-2-yl)propán-1 -ón3-Chloro-1- (3,4-dihydro-1H-isoquinolin-2-yl) propan-1-one

Roztok 3-chlórpropanoylchloridu (10,5 g) v tetrahydrofuráne (400 ml) sa ochladil pod 6 °C, potom sa pridal roztok 3,4-dihydro-1H-izochinolínu (10,0 g). Výsledná zmes sa miešala pri 10 °C 30 minút, potom sa prefiltrovala ^:a skoncentrovala vo vákuu. Zvyšok sa podrobil štandardnému vodnému spôsobu, po ktorom nasledovalo čistenie bleskovou chromatografiou na silikagéli (eluent: etylacetát/heptán 1:1) za vzniku produktu ako bezfarebného oleja (10 g).A solution of 3-chloropropanoyl chloride (10.5 g) in tetrahydrofuran (400 mL) was cooled below 6 ° C, then a solution of 3,4-dihydro-1H-isoquinoline (10.0 g) was added. The resulting mixture was stirred at 10 ° C for 30 minutes, then filtered ^: and concentrated in vacuo. The residue was subjected to a standard aqueous method followed by purification by flash chromatography on silica gel (eluent: ethyl acetate / heptane 1: 1) to give the product as a colorless oil (10 g).

3-Bróm-1-(3,4-dihydro-1/-/-izochinolín-2-yl)propán-1-ón z 3,4-dihydro-1/-/-izochinolínu a 3-brómpropanoylchloridu3-Bromo-1- (3,4-dihydro-1H-isoquinolin-2-yl) propan-1-one from 3,4-dihydro-1H-isoquinoline and 3-bromopropanoyl chloride

-204-Chlór-1 -(3,4-dihydro-l /-/-izochinolín-2-yl)bután-1 -ón z 3,4-dihydro-l H-izochinolínu a 4-chlórbutanoylchloridu-204-Chloro-1- (3,4-dihydro-1H-isoquinolin-2-yl) butan-1-one from 3,4-dihydro-1H-isoquinoline and 4-chlorobutanoyl chloride

4-Chlór-1 -(3,4-dihydro-2H-chinolín-1 -yl)bután-1 -ón z 3,4-dihydro-2/7-chinolínu a 4-chlórbutanoylchloridu4-Chloro-1- (3,4-dihydro-2H-quinolin-1-yl) butan-1-one from 3,4-dihydro-2H-quinoline and 4-chlorobutanoyl chloride

Príprava tuhých podporných medzi produktovPreparation of solid support products

Príprava 4-nitrofenyloxykarbonyloxyetylpolystyrénu litrová banka s guľatým dnom sa naplnila hydroxyetylpolystyrénom (62,9 g, mmol, komerčne dostupný od Rapp Polymere, kat. č. HA 1 400 00), /V-metylmorfolínom (20 ml, 183 mmol) a suchým dichlórmetánom (900 ml). Suspenzia sa ochladila na ľadovom kúpeli a v priebehu 5 minút sa pridal 4-nitrofenylchlórformiát rozpustený v suchom dichlórmetáne (400 ml). Zmes sa miešala pri teplote miestnosti 16 hodín. Živica sa odfiltrovala a premyla suchým dichlórmetánom (5 x 200 ml). Živica sa vysušila vo vákuu (20 °C, 72 hodín) za vzniku v nadpise uvedenej živice (79,6 g).Preparation of 4-nitrophenyloxycarbonyloxyethylpolystyrene A 1 liter round bottom flask was charged with hydroxyethylpolystyrene (62.9 g, mmol, commercially available from Rapp Polymere, Cat. No. HA 1 400 00), N-methylmorpholine (20 mL, 183 mmol) and dry dichloromethane (900 mL). The suspension was cooled in an ice bath and 4-nitrophenyl chloroformate dissolved in dry dichloromethane (400 mL) was added over 5 minutes. The mixture was stirred at room temperature for 16 hours. The resin was filtered off and washed with dry dichloromethane (5 x 200 mL). The resin was dried under vacuum (20 ° C, 72 hours) to give the title resin (79.6 g).

Príprava polymérom viazaného 7-chlór-3-(piperidín-4-yl)-1 H-indoluPreparation of polymer-bound 7-chloro-3- (piperidin-4-yl) -1H-indole

100 ml banka s guľatým dnom sa naplnila 4-nitrofenyloxykarbonyloxyetylpolystyrénom (4,0 g, 4,3 mmol), 7-chlór-3-(1-terc-butoxykarbonylpiperidín-4-yl)-1Hindolom (2,7 g, 8,1 mmol), diizopropyletylamínom (3,5 ml, 20,2 mmol), 4-dimetylaminopyridínom (0,5 g, 4 mmol) a suchým dimetylformamidom (50 ml). Zmes sa miešala pri 90 °C 72 hodín. Po ochladení na teplotu miestnosti, sa živica odfiltrovala a premyla suchým dimetylformamidom (3 x 25 ml), suchým acetonitrilom (3 x 25 ml) a suchým dichlórmetánom (3 x 25 ml). Živica sa preniesla do skleneného valca s fritou a trojcestnou spojkou v spodnej časti. Na živicu sa potom pôsobilo 20 minút 60 ml zmesi 1:1 dichlórmetán a kyselina trifluóroctová obsahujúca anizol (2 %, objem.) a metionín (0,2 %, objem.) za použitia prúdu dusíka na miešanie živice (Pozor: vývoj oxidu uhličitého). Živica sa potom odfiltrovala a premyla suchým dichlórmetánom (25 ml) a zmesou 1:1 dichlórmetán:trietylamín (3 x 25 ml) a suchýmA 100 mL round bottom flask was charged with 4-nitrophenyloxycarbonyloxyethyl polystyrene (4.0 g, 4.3 mmol), 7-chloro-3- (1- tert -butoxycarbonylpiperidin-4-yl) -1H-indole (2.7 g, 8, 1 mmol), diisopropylethylamine (3.5 mL, 20.2 mmol), 4-dimethylaminopyridine (0.5 g, 4 mmol) and dry dimethylformamide (50 mL). The mixture was stirred at 90 ° C for 72 hours. After cooling to room temperature, the resin was filtered off and washed with dry dimethylformamide (3 x 25 mL), dry acetonitrile (3 x 25 mL) and dry dichloromethane (3 x 25 mL). The resin was transferred to a glass cylinder with a frit and a three-way connector at the bottom. The resin was then treated for 20 minutes with 60 mL of a 1: 1 mixture of dichloromethane and trifluoroacetic acid containing anisole (2% v / v) and methionine (0.2% v / v) using a stream of nitrogen to stir the resin (Caution: carbon dioxide evolution) ). The resin was then filtered off and washed with dry dichloromethane (25 mL) and 1: 1 dichloromethane: triethylamine (3 x 25 mL) and dry

- 21 dichlórmetánom (3 x 25 ml). Živica sa sušila vo vákuu (20 °C, 20 hodín) za vzniku v nadpise uvedenej živice (3,8 g).- 21 dichloromethane (3 x 25 mL). The resin was dried under vacuum (20 ° C, 20 hours) to give the title resin (3.8 g).

Nasledujúce polymérom viazané zlúčeniny za pripravili podobným spôsobom: 4-chlór-3-(piperidín-4-yl)-1/7-indolThe following polymer-bound compounds were prepared in a similar manner: 4-chloro-3- (piperidin-4-yl) -1 H -indole

4- fluór-3-(piperidín-4-yl)-1 /7-indol4-Fluoro-3- (piperidin-4-yl) -1 H -indole

5- chlór-3-(piperidín-4-yl)-1 /7-indol5-chloro-3- (piperidin-4-yl) -1 H -indole

5- fluór-3-(piperidín-4-yl)-1/7-indol5-fluoro-3- (piperidin-4-yl) -1 H -indole

6- chlór-3-(piperidín-4-yl)-1/7-indol6-chloro-3- (piperidin-4-yl) -1 H -indole

Príprava polymérom viazanej kyseliny 3-[4-(7-chlór-1/7-indol-3-yl)piperidín-1-yljpropiónovej ml banka s guľatým dnom sa naplnila polymérom viazaným 7-chlór-3(piperidín-4-yl)-1/7-indolom (1,0 g, 0,98 mmol), trietylamínom (80,2 ml), ŕerc-butyl-3brómpropionátom a suchým acetonitrilom (5 ml). Zmes sa miešala pri 80 °C 3 hodiny. Po ochladení na teplotu miestnosti sa živica odfiltrovala a premyla suchým acetonitrilom (3 x 10 ml) a suchým dichlórmetánom (3x10 ml). Na živicu sa potom pôsobilo 20 minút 8 ml zmesi 1:1 dichlórmetán a kyselina trifluóroctová obsahujúca anizol (2 %, objem.) a metionín (0,2 %, objem.) (Pozor: vývoj oxidu uhličitého). Živica sa potom odfiltrovala a premyla suchým dichlórmetánom (10 ml) a zmesou 1:1 dichlórmetán:trietylamín (3 x 10 ml) a suchým dichlórmetánom (3 x 10 ml). Živica sa sušila vo vákuu (20 °C, 20 hodín) za vzniku v nadpise uvedenej živice (1,0 g)·Preparation of Polymer-Bound 3- [4- (7-Chloro-1 H -indol-3-yl) -piperidin-1-yl] -propionic ml A round-bottomed flask was charged with polymer-bound 7-chloro-3 (piperidin-4-yl) -1 H -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 80 ° C for 3 hours. After cooling to room temperature, the resin was filtered off and washed with dry acetonitrile (3 x 10 mL) and dry dichloromethane (3 x 10 mL). The resin was then treated for 20 minutes with 8 mL of a 1: 1 mixture of dichloromethane and trifluoroacetic acid containing anisole (2% v / v) and methionine (0.2% v / v) (Caution: carbon dioxide evolution). The resin was then filtered off and washed with dry dichloromethane (10 mL) and 1: 1 dichloromethane: triethylamine (3 x 10 mL) and dry dichloromethane (3 x 10 mL). The resin was dried under vacuum (20 ° C, 20 hours) to give the title resin (1.0 g).

Nasledujúce polymérom viazané zlúčeniny sa pripravili podobným spôsobom: kyselina 3-[4-(4-chlór-1 /7-indol-3-yl)piperidín-1 -yljpropiónová kyselina 3-[4-(4-fluór-1 /7-indol-3-yl)piperidin-1 -yljpropiónová kyselina 3-[4-(5-f luór-1 /7-i ndol-3-yl)piperid í n-1 -yljpropiónová kyselina 3-[4-(6-chlór-1 /7-indol-3-yl )piperid í n-1 -yljpropiónová kyselina 4-[4-(4-chlór-1 /7-indol-3-yl )piperid í n-1 -yljmaslová kyselina 4-[4-(4-fluór-1/7-indol-3-yl)piperidín-1-yljmaslová kyselina 4-[4-(5-ch lór-1 /7-indol-3-yl )piperid í n-1 -yljmaslováThe following polymer-bound compounds were prepared in a similar manner: 3- [4- (4-chloro-1/7-indol-3-yl) piperidin-1-yl] propionic acid 3- [4- (4-fluoro-1 / 7- Indol-3-yl) piperidin-1-yl] propionic acid 3- [4- (5-fluoro-1 H -indol-3-yl) piperidin-1-yl] propionic acid 3- [4- (6- Chloro-1H-indol-3-yl) piperidin-1-yl-propionic acid 4- [4- (4-chloro-1H-indol-3-yl) piperidin-1-yl] butyric acid 4- [4- (4-Fluoro-1H-indol-3-yl) piperidin-1-yl] butyric acid 4- [4- (5-chloro-1H-indol-3-yl) piperidin-1-one -yljmaslová

-22kyselina 4-[4-(5-fluór-1 /7-indol-3-yl)piperidín-1 -yljmaslová kyselina 4-[4-(7-chlór-1 /7-indol-3-yl)piperid í n-1 -yljmaslová kyselina 5-[4-(4-chlór-1 /7-indol-3-yl )piperid í n-1 -yl]pentánová kyselina 5-[4-(5-fluór-1/7-indol-3-yl)piperidín-1-yljpentánová kyselina 5-[4-(7-chlór-1 /7-indol-3-yl )piperid í n-1 -yljpentánová kyselina 6-[4-(4-fluór-1 /7-indol-3-yl)piperidín-1-yljhexánová kyselina 6-[4-(4-chlór-1/-/-indol-3-yl)piperidín-1-yl]hexánová kyselina 6-[4-(5-fluór-1/-/-indol-3-yl)piperidín-1-yl]hexánová kyselina 6-[4-(6-chlór-1 F/-indol-3-yl)piperid í n-1 -yljhexánová kyselina 6-[4-(7-chlór-1 /7-i ndol-3-y I )piperid í n-1 -yljhexánová4- [4- (5-Fluoro-1H-indol-3-yl) piperidin-1-yl] butyric acid 4- [4- (7-chloro-1H-indol-3-yl) piperidine] n-1-yl-butyric acid 5- [4- (4-chloro-1 H -indol-3-yl) piperidin-1-yl] pentanoic acid 5- [4- (5-fluoro-1 H-) 5- [4- (7-Chloro-1 H -indol-3-yl) -piperidin-1-yl] -pentanoic acid 6- [4- (4-fluoro- indol-3-yl) -piperidin-1-yl] -pentanoic acid 1- [7-Indol-3-yl] piperidin-1-yl] hexanoic acid 6- [4- (4-chloro-1H-indol-3-yl) piperidin-1-yl] hexanoic acid 6- [4- (5-Fluoro-1H-indol-3-yl) piperidin-1-yl] hexanoic acid 6- [4- (6-chloro-1H-indol-3-yl) piperidin-1-yl- 6- [4- (7-Chloro-1H-indol-3-yl) -piperidin-1-yl] -hexanoic acid

Príprava zlúčenín podľa vynálezuPreparation of Compounds of the Invention

Príklad 1Example 1

a) 5-Fluór-3-{1 -[2-(2-oxo-3,4-dihydro-2/7-chinolín-1 -yl)etyl]piperidín-4-yl}-1 /7-indol, hydrochlorid(a) 5-Fluoro-3- {1- [2- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) ethyl] piperidin-4-yl} -1H-indole; hydrochloride

Zmes 5-fluór-3-(piperidín-4-yl)-1 /7-indolu (0,3 g), 1-(2-chlóretyl)-3,4-dihydrochinolín-2-(1/7)-ónu (0,41 g) a trietylamínu (0,75 g) v dimetylformamide (5 ml) a butanóne (10 ml) sa nechala vrieť za refluxu 6 hodín. Zmes sa potom skoncentrovala vo vákuu a zvyšok sa čistil bleskovou chromatografiou na silikagéli (eluent: etylacetát/-etanol/trietylamín 90:10:5) za vzniku surového produktu, ktorý sa izoloval ako hydrochloridová soľ z acetónu vo forme bielej kryštalickej látky (0,04 g). ¹H NMR (DMSO-de): 2,00 - 2,25 (m, 4H), 2,60 (t, 2H), 2,90 (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 (široký s, 1H), 11,05 (s, 1H). MS m/z: 392 (MH⁺), 174.5-Fluoro-3- (piperidin-4-yl) -1 H -indole (0.3 g), 1- (2-chloroethyl) -3,4-dihydroquinolin-2- (1/7) -one (0.41 g) and triethylamine (0.75 g) in dimethylformamide (5 ml) and butanone (10 ml) were allowed to boil under reflux for 6 hours. The mixture was then concentrated in vacuo and the residue was purified by flash chromatography on silica gel (eluent: ethyl acetate / ethanol / triethylamine 90: 10: 5) to give the crude product which was isolated as the hydrochloride salt from acetone as a white crystalline solid (0, 04 g). ¹ H NMR (DMSO-d 6): 2.00-2.25 (m, 4H), 2.60 (t, 2H), 2.90 (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 (broad s, 1H), 11.05 (s, 1H) ). MS m / z: 392 (MH < ^{+ >} ), 174.

1b) 5-Fluór-3-{1-[3-(1-oxo-3,4-dihydro-1/7-chinolín-2-yl)propán-1-yljpiperidín-4-yl}1/7-indol, oxalát1b) 5-Fluoro-3- {1- [3- (1-oxo-3,4-dihydro-1 H -quinolin-2-yl) -propan-1-yl] -piperidin-4-yl} -1 H -indole , oxalate

-23z 5-fluór-3-(piperidín-4-yl)-1 Η-indolu a 1-(3-brómpropán-1-yl)-3,4-dihydroizochinolín1(2H)-ónu.23-5-fluoro-3- (piperidin-4-yl) -1'-indole and 1- (3-bromopropan-1-yl) -3,4-dihydroisoquinolin-1 (2H) -one.

¹H NMR (DMSO-d₆): 1,90 - 2,15 (m, 6H), 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, 1 H), 11,05 (s, 1 H). MS m/z: 406 (MH⁺), 188. ¹ H NMR (DMSO-d ₆ ): 1.90-2.15 (m, 6H), 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 m / z: 406 (MH < ^{+ >} ), 188.

1c) 5-Fluór-3-{1-[4-(1 -oxo-3,4-dihydro-l H-chinolín-2-yl)bután-1-yl]piperidín-4-yl}-1 Hindol, hydrochlorid z 5-fluór-3-(piperidín-4-yl)-1 /-/-indolu a 2-(4-brómbután-1-yl)-3,4-dihydroizochinolín1(2H)-ónu.1c) 5-Fluoro-3- {1- [4- (1-oxo-3,4-dihydro-1H-quinolin-2-yl) butan-1-yl] piperidin-4-yl} -1 Hindole, hydrochloride from 5-fluoro-3- (piperidin-4-yl) -1 H -indole and 2- (4-bromobutan-1-yl) -3,4-dihydroisoquinolin-1 (2H) -one.

¹H NMR (DMSO-d₆): 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 (s, 1H), 7,30 (d, 1H), 7,30 - 7,40 (m, 2H), 7,40 - 7,55 (m, 2H), 7,90 (d, 1H), 10,75 (široký s, 1H), 11,05 (s, 1 H). MS m/z: 420 (MH⁺). ¹ H NMR (DMSO-d ₆ ): 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 (s, 1H), 7 30 (d, 1H), 7.30-7.40 (m, 2H), 7.40-7.55 (m, 2H), 7.90 (d, 1H), 10.75 (wide s, 1H), 11.05 (s, 1H). MS m / z: 420 (MH < ^{+ >} ).

Príklad 2Example 2

2a) 5-Fluór-3-{1 -[3-(2-oxo-3,4-dihydro-2/-/-chinolín-1 -yl)propán-1 -yl] piperid ίη-4-yl}1 H-indol, hydrochlorid2a) 5-Fluoro-3- {1- [3- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] piperidin-4-yl} -1 H-indole, hydrochloride

Zmes 5-fluór-3-(piperidín-4-yl)-1 H-indolu (5,0 g), 1-(3-brómpropán-1-yl)-3,4dihydrochinolín-2(1/-/)-ónu (7,7 g) a uhličitanu draselného (7,0 g) vdimetylformamide (40 ml) sa zahrievala pri 100 °C 2½ hodiny. Zmes sa potom ochladila, prefiltrovala a skoncentrovala vo vákuu. Zvyšok sa čistil bleskovou chromatografiou na silikagéli (eluent: etylacetát, potom etylacetát/etanol 90:10) za vzniku produktu ako oranžového oleja (9,1 g). V nadpise uvedená zlúčenina (1,8 g voľnej bázy) sa izolovala ako hydrochloridová soľ z tetrahydrofuránu ako biela kryštalická zlúčenina (1,5 g), teplota topenia 210 až 212 °C.A mixture of 5-fluoro-3- (piperidin-4-yl) -1H-indole (5.0 g), 1- (3-bromopropan-1-yl) -3,4-dihydroquinolin-2 (1 H) - One-hour (7.7 g) and potassium carbonate (7.0 g) in dimethylformamide (40 ml) were heated at 100 ° C for 2½ hours. The mixture was then cooled, filtered and concentrated in vacuo. The residue was purified by flash chromatography on 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 the hydrochloride salt from tetrahydrofuran as a white crystalline compound (1.5 g), mp 210-212 ° C.

¹H NMR (DMSO-ds): 2,00 - 2,20 (m, 6H), 2,60 (t, 2H), 2,90 (t, 2H), 2,95 - 3,10 (m, 3H), 3,10 - 3,20 (m, 2H), 3,55 (d, 2H), 3,95 (t, 2H), 6,90 (t, 1H), 7,05 (t, 1H), 7,15 7,30 (m, 4H), 7,30 - 7,40 (m, 1H), 7,50 (d, 1H), 10,55 široký s, 1H), 11,05 (s, 1H). MS m/z: 406 (MH⁺). ¹ H NMR (DMSO-d 6): 2.00-2.20 (m, 6H), 2.60 (t, 2H), 2.90 (t, 2H), 2.95-3.10 (m, 3H), 3.10-3.20 (m, 2H), 3.55 (d, 2H), 3.95 (t, 2H), 6.90 (t, 1H), 7.05 (t, 1H) 7.15 7.30 (m, 4H), 7.30-7.40 (m, 1H), 7.50 (d, 1H), 10.55 broad s, 1H), 11.05 (s , 1H). MS m / z: 406 (MH < ^{+ >} ).

-24Nasledujúce zlúčeniny sa pripravili podobným spôsobom:The following compounds were prepared in a similar manner:

2b) 5-Fluór-3-{1-[5-(2-oxo-3,4-dihydro-2/-/-chinolín-1-yl)pentán-1-yl]piperidín-4-yl}1/7-indol, hydrochlorid z 5-fluór-3-(piperidín-4-yl)-1 /-/-indolu a 1-(5-brómpentán-1-yl)-3,4-dihydrochinolín2(1H)-ónu. Teplota topenia 199 až 200 °C.2b) 5-Fluoro-3- {1- [5- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] piperidin-4-yl} -1) 7-indole, 5-fluoro-3- (piperidin-4-yl) -1 H -indole hydrochloride, and 1- (5-bromopentan-1-yl) -3,4-dihydroquinolin-2 (1H) -one. Mp 199-200 ° C.

¹H NMR (DMSO-de): 1,30 - 1,40 (m, 2H), 1,55 - 1,60 (m, 2H), 1,70 - 1,80 (m, 2H), 2,05 - 2,15 (m, 4H), 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, 1H), 7,00 (t, 1H), 7,15 (d, 1H), 7,20 - 7,30 (m, 3H), 7,30 - 7,35 (m, 1 H), 7,50 (d, 1 H), 12,20 (široký s, 1 H), 11,05 (s, 1 H). MS m/z: 434 (MH⁺). ¹ H NMR (DMSO-d 6): 1.30-1.40 (m, 2H), 1.55-1.60 (m, 2H), 1.70-1.80 (m, 2H), 2, 05-2.15 (m, 4H), 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, 1H), 7.00 (t, 1H), 7.15 (d, 1H), 7.20-7.30 (m, 3H), 7.30-7.35 (m, 1H), 7.50 (d, 1H), 12.20 (broad s, 1H), 11.05 (s, 1H). MS m / z: 434 (MH < ^{+ >} ).

2c) 5-Chlór-3-{1-[3-(2-oxo-3,4-dihydro-2/-/-chinolín-1-yl)propán-1-yl]piperidín-4-yl}1 /-/-indol, hydrochlorid z 5-chlór-3-(piperidín-4-yl)-1 /-/-indolu a 1-(3-brómpropán-1-yl)-3,4-dihydrochinolín2(1/7)-ónu. Teplota topenia 142 až 146 °C.2c) 5-Chloro-3- {1- [3- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) -propan-1-yl] -piperidin-4-yl} -1) - / - indole, 5-chloro-3- (piperidin-4-yl) -1 H -indole hydrochloride and 1- (3-bromopropan-1-yl) -3,4-dihydroquinoline2 (1/7) -one. M.p. 142-146 ° C.

¹H NMR (DMSO-de): 1,95 - 2,15 (m, 6H), 2,60 (t, 2H), 2,90 (t, 2H), 2,95 - 3,15 (3H), 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 (široký, s, 1H), 11,15 (s, 1H). MS m/z: 422 (MH⁺), 188. ¹ H NMR (DMSO-d 6): 1.95-2.15 (m, 6H), 2.60 (t, 2H), 2.90 (t, 2H), 2.95-3.15 (3H) 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 (broad, s, 1H), 11.15 (s, 1H). MS m / z: 422 (MH < ^{+ >} ), 188.

2d) 5-Chlór-3-{1-[4-(2-oxo-3,4-dihydro-2/-/-chinolín-1-yl)bután-1-yl]piperidín-4-yl}1/-/-indol, hydrochlorid z 5-chlór-3-(piperidín-4-yl)-1/-/-indolu a 1-(4-brómbután-1-yl)-3,4-dihydrochinolín2(1/-/)-ónu. Teplota topenia 229 až 231 °C.2d) 5-Chloro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} 1 / - / - indole, hydrochloride from 5-chloro-3- (piperidin-4-yl) -1 H -indole and 1- (4-bromobutan-1-yl) -3,4-dihydroquinoline2 (1 H) - ) -one. Mp 229-231 ° C.

¹H NMR (DMSO-de): 1,55 - 1,65 (m, 2H), 1,70 - 1,80 (m, 2H), 2,00 - 2,15 (m, 4H), ¹ H NMR (DMSO-d 6): 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), 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, 3H), 7,40 (d, 1H), 7,75 (s, 1H), 10,05 (široký s, 1 H), 11,10 (s, 1H). MS m/z: 436 (MH⁺).2.55 (t, 2H), 2.85 (t, 2H), 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, 3H), 7.40 (d, 1H), 75 (s, 1H), 10.05 (broad s, 1H), 11.10 (s, 1H). MS m / z: 436 (MH < ^{+ >} ).

2e) 5-Chlór-3-{1-[5-(2-oxo-3,4-dihydro-2H-chinolín-1-yl)pentán-1-yl]piperidín-4-yl}1 /-/-indol, hydrochlorid z 5-chlór-3-(piperidín-4-yl)-1 /7-indoiu a 1-(5-brómpentán-1-yl)-3,4-dihydrochinolín2(1/7)-ónu. Teplota topenia 206 až 209 °C.2e) 5-Chloro-3- {1- [5- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) -pentan-1-yl] -piperidin-4-yl} 1 H- indole, 5-chloro-3- (piperidin-4-yl) -1 H -indole hydrochloride and 1- (5-bromopentan-1-yl) -3,4-dihydroquinolin-2 (1/7) -one hydrochloride. Mp 206-209 ° C.

-25¹H NMR (DMSO-de): 1,30 - 1,40 (m, 2H), 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), 2,95 - 3,10 (m, 4H), 3,10 - 3,25 (m, 1H), 3,55 (d, 2H), 3,90 (t, 2H), 7,00 (t, 1H), 7,05 (d, 1H), 7,15 (d, 1H), 7,20 - 7,30 (m, 3H), 7,40 (d, 1H), 7,75 (s, 1H), 11,20 (široký s, 1H), 11,15 (s, 1H). MS m/z: 450 (MH⁺), 299.-25 ¹ H-NMR (DMSO-de): 1.30 to 1.40 (m, 2H), 1.55 to 1.65 (m, 2H), 1.70 - 1.80 (m, 2H); 2.00-2.15 (m, 4H), 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), 7.05 (d, 1H), 7.15 (d, 1H) 7.20 - 7.30 (m, 3H), 7.40 (d, 1H), 7.75 (s, 1H), 11.20 (broad s, 1H), 11.15 (s, 1H) ). MS m / z: 450 (MH < ^{+ >} ), 299.

2f) 7-Chlór-3-{1 -[4-(2-oxo-3,4-dihydro-2/-/-chinolín-1 -yl)bután-1 -yl]piperidín-4-yl}-1 Hindol, hydrochlorid zo 7-(chlór-3-(piperidín-4-yl)-1 /-/-indolu a 1-(4-brómbután-1-yl)-3,4-dihydrochinolín2(1/-/)-ónu. Teplota topenia 253 až 254 °C.2f) 7-Chloro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1 Hindole, hydrochloride from 7- (chloro-3- (piperidin-4-yl) -1 H -indole) and 1- (4-bromobutan-1-yl) -3,4-dihydroquinoline 2 (1 H) - Mp 253-254 ° C.

¹H NMR (DMSO-de): 1,55 - 1,65 (m, 2H), ¹ H NMR (DMSO-d 6): 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, 1H), 10,60 (široký s, 1 H), 11,30 (s, 1 H). MS m/z: 436 (MH⁺), 289.1.75-1.85 (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, 1H), 10.60 (broad s, 1H), 11.30 (s, 1H). MS m / z: 436 (MH < ^{+ >} ), 289.

2g) 5-Fluór-3-{1-[4-(3-oxo-3,4-dihydro-2/-/-1,4-benzoxazín-4-yl)bután-1-yl]piperidín4-yl}-1/-/-indol, hydrochlorid z 5-fluór-3-(piperidín-4-yl)-1 H-indolu a 4-(4-brómbután-1-yl)-3,4-dihydro-2/7-1,4benzoxazín-3(4/-/)-ónu. Teplota topenia 83 až 92 °C.2g) 5-Fluoro-3- {1- [4- (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl) butan-1-yl] piperidin-4-yl} -1H-indole, 5-fluoro-3- (piperidin-4-yl) -1H-indole hydrochloride and 4- (4-bromobutan-1-yl) -3,4-dihydro-2/7 -1,4benzoxazín-3 (4 / - /) - one. Melting point 83-92 ° C.

¹H NMR (DMSO-de): 1,60 - 1,70 (m, 2H), 1,75 - 1,85 (m, 2H), 2,00 - 2,20 (m, 4H), ¹ H NMR (DMSO-d 6): 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 (s, 2H), 6,90 (t, 1H), 7,00 - 7,05 (m, 2H), 7,05 - 7,15 (m, 1H), 7,20 (s, 1H), 7,25 (d, 1H), 7,30 - 7,40 (m, 1H), 7,50 (d, 1 H), 10,45 (široký s, 1 H), 11,05 (s, 1 H). MS m/z: 422 (MH⁺), 273.2.95-3.15 (m, 5H), 3.55 (d, 2H), 3.95 (t, 2H), 4.65 (s, 2H), 6.90 (t, 1H), 7 .00-7.05 (m, 2H), 7.05-7.15 (m, 1H), 7.20 (s, 1H), 7.25 (d, 1H), 7.30-7.40 (m, 1H), 7.50 (d, 1H), 10.45 (broad s, 1H), 11.05 (s, 1H). MS m / z: 422 (MH < ^{+ >} ), 273.

2h) 5-ChIór-3-{1-[4-(3-oxo-3,4-dihydro-2/-/-1,4-benzoxazín-4-yl)bután-1-yl]piperidín4-yl}-1/7-indol, hydrochlorid z 5-chlór-3-(piperidín-4-yl)-1 /-/-indolu a 4-(4-brómbután-1-yl)-3,4-dihydro-2/7-1,4benzoxazín-3(4H)-ónu. Teplota topenia 222 až 224 °C.2h) 5-Chloro-3- {1- [4- (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl) butan-1-yl] piperidin-4-yl} -1H-indole hydrochloride from 5-chloro-3- (piperidin-4-yl) -1H-indole and 4- (4-bromobutan-1-yl) -3,4-dihydro-2 H- 7-1,4benzoxazín-3 (4H) -one. Mp 222-224 ° C.

¹H NMR (DMSO-de): 1,60 - 1,70 (m, 2H), 1,75 - 1,85 (m, 2H), 2,05 - 2,15 (m, 4H), 3,00 - 3,15 (m, 5H), 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 (široký s, 1H), 11,15 (s, 1H). MS m/z: 438 (MH⁺), 291,204. ¹ H NMR (DMSO-d 6): 1.60-1.70 (m, 2H), 1.75-1.85 (m, 2H), 2.05-2.15 (m, 4H), 3, 00-3.15 (m, 5H), 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 (broad s, 1H), 11.15 (s, 1 H). MS m / z: 438 (MH < ^{+ >} ), 291.204.

-26Príklad 3-26Example 3

3a) 5-Fluór-3-{1-[3-(2-oxo-3,4-dihydro-2/-/-chinolín-1-yl)propán-1-yl]-3,6-dihydro-2/-/pyridín-4-yl}-1 H-indol, oxalát3a) 5-Fluoro-3- {1- [3- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] -3,6-dihydro-2 tert-Pyridin-4-yl} -1H-indole oxalate

Zmes 5-fluór-3-(3,6-dihydro-2/-/-pyridín-4-yl)-1 /7-indolu (3,0 g) a uhličitanu draselného (6,2 g) v butanóne (250 ml) sa zahriala na teplotu refluxu, nasledovalo pridanie 1-(3-brómpropán-1-yl)-3,4-dihydrochinolín-2(1H)-ónu (5,0 g) v butanóne (50 ml). Výsledná zmes sa varila za refluxu 10 hodín, prefiltrovala sa a skoncentrovala vo vákuu (7,7 g). Zvyšok sa čistil bleskovou chromatografiou na silikagéli (eluent: etylacetát/trietylamín 100:5) za získania surového produktu, ktorý sa kryštalizoval zo zmesi tetrahydrofurán/etylacetát. V nadpise uvedená zlúčenina sa izolovala ako oxalátová soľ z acetón/tetrahydrofuránu ako žltkastá kryštalická látka (1,7 g). Teplota topenia: 203 až 206 °C.A mixture of 5-fluoro-3- (3,6-dihydro-2H-pyridin-4-yl) -1 H -indole (3.0 g) and potassium carbonate (6.2 g) in butanone (250 g). mL) was heated to reflux, followed by the addition of 1- (3-bromopropan-1-yl) -3,4-dihydroquinolin-2 (1H) -one (5.0 g) in butanone (50 mL). The resulting mixture was boiled at reflux for 10 hours, filtered and concentrated in vacuo (7.7 g). The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate / triethylamine 100: 5) to give the crude product which was crystallized from tetrahydrofuran / ethyl acetate. The title compound was isolated as the oxalate salt from acetone / tetrahydrofuran as a yellowish crystalline solid (1.7 g). Mp: 203-206 ° C.

¹H NMR (DMSO-de): 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, 3H), 7,35 - 7,45 (m, 1H), 7,50 - 7,60 (m, 2H), 11,50 (s, 1H). MS m/z: 404 (MH⁺), 218. ¹ H NMR (DMSO-d 6): 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, 3H), 7.35-7.45 (m, 1H), 7.50-7.60 (m, 2H), 11.50 (m, 2H) s, 1H). MS m / z: 404 (MH < ^{+ >} ), 218.

3b) 5-Fluór-3-.{1-[4-(2-oxo-3,4-dihydro-2H-chinolín-1-yl)bután-1-yl]-3,6-dihydro-2/7pyridín-4-yl}-1 /7-indol, hydrochlorid z 5-fluór-3-(3,6-dihydro-2/7-pyridín-4-yl)-1 /7-indolu a 1-(4-brómbutánu-1-yl)-3,4dihydrochinolín-2(1H)-ónu. Teplota topenia: 124 až 125 °C.3b) 5-Fluoro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] -3,6-dihydro-2H-pyridine -4-yl} -1H-indole, 5-fluoro-3- (3,6-dihydro-2H-pyridin-4-yl) -1H-indole hydrochloride and 1- (4-bromobutane) 1-yl) -3,4dihydrochinolín-2 (1H) -one. Melting point: 124-125 ° C.

¹H NMR (DMSO-de): 1,55 - 1,65 (m, 2H), 1,80 (q, 2H), 2,55 (t, 2H), 2,75 (d, 1H), 2,85 - 2,95 (m, 3H), 3,15 - 3,30 (m, 3H), 3,55 - 3,65 (m, 1H), 3,75 (d, 1H), 3,90 4,00 (m, 3H), 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 (široký s, 1H), 11,50 (s, 1H). MS m/z: 418 (MH⁺), 231. ¹ H NMR (DMSO-d 6): 1.55-1.65 (m, 2H), 1.80 (q, 2H), 2.55 (t, 2H), 2.75 (d, 1H), 2 , 85-2.95 (m, 3H), 3.15-3.30 (m, 3H), 3.55-3.65 (m, 1H), 3.75 (d, 1H), 3.90 4.00 (m, 3H), 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 (broad s, 1H), 11.50 (s, 1H). MS m / z: 418 (MH < ^{+ >} ), 231.

3c) 5-Fluór-3-{1-[5-(2-oxo-3,4-dihydro-2/-/-chinolín-1-yl)pentán-1-yl]-3,6-dihydro-2/-/pyridín-4-yl}-1 /7-indol, oxalát3c) 5-Fluoro-3- {1- [5- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] -3,6-dihydro-2 N- (pyridin-4-yl) -1H-indole oxalate

-27z 5-fluór-3-(3,6-dihydro-2/-/-pyridín-4-yl)-1 H-indolu a 1-(5-brómpentán-1-yl)-3,4dihydrochinolín-2(1H)-ónu. Teplota topenia: 205 až 207 °C.-27z 5-fluoro-3- (3,6-dihydro-2H-pyridin-4-yl) -1H-indole and 1- (5-bromo-pentan-1-yl) -3,4-dihydroquinoline-2 ( 1H) -one. Mp .: 205-207 ° C.

¹H NMR (DMSO-de): 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 (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 - 7,60 (m, 2H), 11,50 (s, 1 H). MS m/z: 432 (MH⁺), 245. ¹ H NMR (DMSO-d 6): 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 (s, 1H), 6.95 7.05 (m, 2H), 7.15 (d, 1H), 7.20 - 7.30 (m, 2H), 7.40 - 7.45 ( m, 1H), 7.55-7.60 (m, 2H), 11.50 (s, 1H). MS m / z: 432 (MH < ^{+ >} ), 245.

Príklad 4Example 4

5-Fluór-3-{1-[4-(2-oxo-3,4-dihydro-2/-/-chinolín-1-yl)bután-1-yl]-piperidín-4-yl}-1/7indol, hydrochlorid5-Fluoro-3- {1- [4- (2-oxo-3,4-dihydro-2 / - / - quinolin-1-yl) butan-1-yl] -piperidin-4-yl} -1 / 7-indole hydrochloride

Zmes 5-fluór-3-{ 1 -[4-(2-oxo-3,4-dihydro-2/-/-chinolín-1 -yl)bután-1 -yl]-3,6-dihydro-2/-/-pyridín-4-yl}-1 /-7-indolu (3,5 g), etanolu (100 ml), kyseliny octovej (100 ml) a oxidu platnatého (0,4 g) sa trepala pri tlaku 0,303 MPa (3 atm) počas 16 hodín. Zmes sa prefiltrovala, odparila vo vákuu na približne 100 ml, ktorá sa následne naliala na ľad a pridal sa vodný roztok amoniaku do zásaditého pH. Vodná fáza sa extrahovala s etylacetátom a spojené organické fázy sa premyli soľankou, sušili (MgSO₄) a skoncentrovali vo vákuu. Zvyšok sa čistil bleskovou chromatografiou na silikagéli (eluent: etylacetát/trietylamín 100:4) za získania surového produktu (2,0 g). V nadpise uvedená zlúčenina sa izolovala ako hydrochloridová soľ z etylacetátu ako biela kryštalická látka (2,0 g). Teplota topenia 212 až 213 °C.5-Fluoro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] -3,6-dihydro-2] - / - pyridin-4-yl} -1 H -indole (3.5 g), ethanol (100 ml), acetic acid (100 ml) and platinum oxide (0.4 g) were shaken at a pressure of 0.303 MPa (3 atm) for 16 hours. The mixture was filtered, evaporated in vacuo to about 100 ml, which was then poured onto ice, and aqueous ammonia solution was added to basic pH. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate / triethylamine 100: 4) to give the crude product (2.0 g). The title compound was isolated as the hydrochloride salt from ethyl acetate as a white crystalline solid (2.0 g). Mp 212-213 ° C.

¹H NMR (DMSO-de): 1,55 - 1,65 (m, 2H), 1,75 - 1,85 (m, 2H), 2,00 - 2,20 (m, 4H), ¹ H NMR (DMSO-d 6): 1.55-1.65 (m, 2H), 1.75-1.85 (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, 1H), 7,00 (t, 1H), 7,15 - 7,30 (m, 4H), 7,30 - 7,40 (m, 1H), 7,50 (d, 1H), 10,55 (široký s, 1 H), 11,05 (s, 1 H). MS m/z: 420 (MH⁺), 273, 202.2.55 (t, 2H), 2.85 (t, 2H), 2.95-3.15 (m, 5H), 3.55 (d, 2H), 3.95 (t, 2H), 6 90 (t, 1H); 7.00 (t, 1H); 7.15-7.30 (m, 4H); 7.30-7.40 (m, 1H); 7.50 (d, 1H) 10.55 (broad s, 1H), 11.05 (s, 1H). MS m / z: 420 (MH < ^{+ >} ), 273, 202.

Príklad 5Example 5

5a) 5-Fluór-1 -metyl-3-{ 1 -[3-(2-oxo-3,4-dihydro-2H-chinolín-1 -yl)propán-1 -yl] piperidín-4-yI}-1 /7-indol, oxalát5a) 5-Fluoro-1-methyl-3- {1- [3- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) -propan-1-yl] -piperidin-4-yl} - 1/7-indole oxalate

Suspenzia hydridu sodného (0,5 g, 60% v minerálnom oleji) a dimetylformamidu (60 ml) sa udržiaval pri teplote 22 až 24 °C, nasledovalo pridanie roztokuA suspension of sodium hydride (0.5 g, 60% in mineral oil) and dimethylformamide (60 mL) was maintained at 22-24 ° C, followed by the addition of a solution.

-285-fluór-3-{ 1 -[3-(2-oxo-3,4-dihydro-2H-chinolín-1 -yl)propán-1 -yl]-piperidín-4-yl }-1 Hindolu (4,9 g) v dimetylformamide (50 ml). Výsledná zmes sa miešala pri teplote miestnosti 25 minút, nasledovalo pridanie roztoku metyljodidu (2,0 g) v dimetyiformamidu (15 ml) pri teplote 22 až 27 °C. Výsledná zmes sa miešala pri teplote 22 °C 1 hodinu a naliala sa na ľad. Vodná fáza sa extrahovala s etylacetátom a spojené organické fázy sa premyli soľankou, sušili (MgSO₄) a skoncentrovali vo vákuu. Surový produkt sa čistil bleskovou chromatografiou na silikagéli (eluent: etylacetát/heptán/trietylamín 50:50:5) za získania produktu ako pomarančového oleja (2,4 g). V nadpise uvedená zlúčenina sa izolovala ako oxalátová soľ z acetónu ako biela kryštalická látka (0,6 g). Teplota topenia: 188 až 189 °C.-285-Fluoro-3- {1- [3- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) -propan-1-yl] -piperidin-4-yl} -1 Hindole (4 , 9 g) in dimethylformamide (50 mL). The resulting mixture was stirred at room temperature for 25 minutes, followed by the addition of a solution of methyl iodide (2.0 g) in dimethyiformamide (15 mL) at 22-27 ° C. The resulting mixture was stirred at 22 ° C 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 (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluent: ethyl acetate / heptane / triethylamine 50: 50: 5) to give the product as an orange oil (2.4 g). The title compound was isolated as the oxalate salt from acetone as a white crystalline solid (0.6 g). Melting point: 188-189 ° C.

¹H NMR (DMSO-de): 1,85 - 2,05 (m, 4H), 2,10 (d, 2H), 2,55 (t, 2H), 2,90 (t, 2H), ¹ H NMR (DMSO-d 6): 1.85-2.05 (m, 4H), 2.10 (d, 2H), 2.55 (t, 2H), 2.90 (t, 2H),

2.95 - 3,05 (m, 3H), 3,10 (t, 2H), 3,50 (d, 2H), 3,75 (s, 3H), 3,95 (t, 2H), 6,95 - 7,05 (m, 2H), 7,15 - 7,30 (m, 4H), 7,35 - 7,45 (m, 2H). MS m/z: 420 (MH⁺), 188.2.95-3.05 (m, 3H), 3.10 (t, 2H), 3.50 (d, 2H), 3.75 (s, 3H), 3.95 (t, 2H), 6.95 7.05 (m, 2H), 7.15-7.30 (m, 4H), 7.35-7.45 (m, 2H). MS m / z: 420 (MH < ^{+ >} ), 188.

5b) 5-FIuór-1 -metyl-3-{ 1 -[4-(2-oxo-3,4-dihydro-2H-chinolín-1 -yl)bután-1 -yl]piperidín4-yl}-1 H-indol, hydrochlorid z 5-fluór-3-{ 1 -[4-(2-oxo-3,4-dihydro-2/7-chinolín-1 -yl)bután-1 -yl]-piperid ίη-4-yl}-1Hindolu a metyljodidu. Teplota topenia 177 až 179 °C.5b) 5-Fluoro-1-methyl-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1H 5-Fluoro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] -piperide trans-4- yl} -1Hindole and methyl iodide. Melting point: 177-179 ° C.

¹H NMR (DMSO-de): 1,55 - 1,65 (m, 2H), 1,75 - 1,85 (m, 2H), 2,00 - 2,15 (m, 4H), ¹ H NMR (DMSO-d 6): 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, 3H), 3,95 (t, 2H),2.55 (t, 2H), 2.90 (t, 2H), 2.95-3.15 (m, 5H), 3.55 (d, 2H), 3.75 (s, 3H), 3 95 (t, 2H);

6.95 - 7,05 (m, 2H), 7,15 (d, 1H), 7,20 - 7,30 (m, 3H), 7,35 - 7,45 (m, 1H), 7,55 (d, 1 H), 11,40 (široký s, 1 H). MS m/z: 434 (MH⁺).6.95-7.05 (m, 2H), 7.15 (d, 1H), 7.20-7.30 (m, 3H), 7.35-7.45 (m, 1H), 7.55 ( d, 1H), 11.40 (broad s, 1H). MS m / z: 434 (MH < ^{+ >} ).

5c) 1 -(Bután-1 -yl )-5-fluór-3-{1 -[4-(2-oxo-3,4-dihydro-2H-chinolín-1 -y I )bután-1 -yl]3,6-dihydro-2H-pyridín-4-yl}-1 /7-indol, oxalát z 5-fluór-3-{1-[4-(2-oxo-3,4-dihydro-2/7-chinolín-1-yl)bután-1-yl]-3,6-dihydro-2/7pyridín-4-yl}-1 /7-indolu a butylbromidu. Teplota topenia 152 až 154 °C.5c) 1- (Butan-1-yl) -5-fluoro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] 3,6-dihydro-2H-pyridin-4-yl} -1 H -indole oxalate from 5-fluoro-3- {1- [4- (2-oxo-3,4-dihydro-2 H-) quinolin-1-yl) butan-1-yl] -3,6-dihydro-2 H -pyridin-4-yl} -1 H -indole and butyl bromide. Mp 152-154 ° C.

¹H NMR (DMSO-de): 0,90 (t, 3H), 1,20 - 1,30 (m, 2H), 1,55 - 1,65 (m, 2H), 1,65 1,80 (m, 4H), 2,55 (t, 2H), 2,75 (s, 2H), 2,85 (t, 2H), 3,10 (t, 2H), 3,35 (s, 2H), 3,80 ¹ H NMR (DMSO-d 6): 0.90 (t, 3H), 1.20-1.30 (m, 2H), 1.55-1.65 (m, 2H), 1.65 1.80 (m, 4H), 2.55 (t, 2H), 2.75 (s, 2H), 2.85 (t, 2H), 3.10 (t, 2H), 3.35 (s, 2H) , 3.80

-29(s, 2H), 3,95 (t, 2H), 4,15 (t, 2H), 6,10 (s, 1H), 6,95 - 7,05 (m, 2H), 7,15 (d, 1H), 7,20 - 7,30 (m, 2H), 7,50 - 7,55 (m, 1 H), 7,55 - 7,70 (m, 2H). MS m/z: 474 (MH⁺), 231.-29 (s, 2H), 3.95 (t, 2H), 4.15 (t, 2H), 6.10 (s, 1H), 6.95-7.05 (m, 2H), 7, 15 (d, 1H), 7.20-7.30 (m, 2H), 7.50-7.55 (m, 1H), 7.55-7.70 (m, 2H). MS m / z: 474 (MH < ^{+ >} ), 231.

Príklad 6Example 6

6a) 5-Fluór-3-{1-[3-(3,4-dihydro-l /7-izochinolín-2-yl)-3-oxopropán-1-yl]piperidín-4yl}-1 H-indol, oxalát6a) 5-Fluoro-3- {1- [3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1H-indole, oxalate

Zmes 5-fluór-3-(piperidín-4-yl)-1 /-/-indolu (3,0 g), butanónu (200 ml), tetrahydrofuránu (100 ml), metanolu (50 ml) a trietylamínu (2,4 ml) sa zahriala na teplotu refluxu, nasledovalo pridanie roztoku 3-chlór-1 -(3,4-dihydro-lAV-izochinolín-2-yl)propán-1-ónu (3,5 g) v butanóne (60 ml). Zmes sa varila za refluxu 30 hodín, nasledovalo pridanie ďalšieho množstva 3-chlór-1-(3,4-dihydro-1/-/-izochinolín-2-yl)propán-1-ónu (2,0 g) a trietylamínu (1,6 ml) v tetrahydrofuráne (50 ml). Výsledná zmes sa varila za refluxu ďalších 12 hodín. Zmes sa ochladila, prefiltrovala, skoncentrovala vo vákuu. Zvyšok sa čistil bleskovou chromatografiou na silikagéli (eluent: etylacetát/etanol/trietylamín 100:4:4) za získania surového produktu. V nadpise uvedená zlúčenina sa izolovala ako oxalátová soľ z acetónu ako biela kryštalická látka (0,75 g). Teplota topenia: 206 až 209 °C.A mixture of 5-fluoro-3- (piperidin-4-yl) -1 H -indole (3.0 g), butanone (200 mL), tetrahydrofuran (100 mL), methanol (50 mL) and triethylamine (2, 4 mL) was heated to reflux followed by the addition of a solution of 3-chloro-1- (3,4-dihydro-1 H -isoquinolin-2-yl) propan-1-one (3.5 g) in butanone (60 mL) . The mixture was refluxed for 30 hours, followed by the addition of an additional amount of 3-chloro-1- (3,4-dihydro-1H-isoquinolin-2-yl) propan-1-one (2.0 g) and triethylamine ( 1.6 mL) in tetrahydrofuran (50 mL). The resulting mixture was refluxed for an additional 12 hours. The mixture was cooled, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate / ethanol / triethylamine 100: 4: 4) to give the crude product. The title compound was isolated as the oxalate salt from acetone as a white crystalline solid (0.75 g). Mp .: 206-209 ° C.

¹H NMR (DMSO-de): 1,95 (q, 2H), 2,05 - 2,15 (m, 2H), 2,80 (t, 0,8H), 2,90 (t, 1,2H), ¹ H NMR (DMSO-d 6): 1.95 (q, 2H), 2.05-2.15 (m, 2H), 2.80 (t, 0.8H), 2.90 (t, 1, 2H);

2,90 - 3,10 (m, 5H), 3,30 (t, 2H), 3,55 (d, 2H), 3,70 (t, 2H), 4,65 (s, 1,20H), 4,70 (s, 0,8H), 6,85 - 6,95 (m, 1H), 7,15 - 7,25 (m, 5H), 7,30 - 7,40 (m, 1H), 7,40 (d, 1H), 11,05 (s, 1 H). MS m/z: 406 (MH⁺), 231.2.90-3.10 (m, 5H), 3.30 (t, 2H), 3.55 (d, 2H), 3.70 (t, 2H), 4.65 (s, 1.20H) 4.70 (s, 0.8H), 6.85-6.95 (m, 1H), 7.15-7.25 (m, 5H), 7.30-7.40 (m, 1H) 7.40 (d, 1H); 11.05 (s, 1H). MS m / z: 406 (MH < ^{+ >} ), 231.

Nasledujúca zlúčenina sa pripravila podobným spôsobom:The following compound was prepared in a similar manner:

6b) 7-Chlór-3-{ 1 -[3-(3,4-dihydro-l /-/-izochinolín-2-yl)-3-oxopropán-1 -yIJ-piperidín-4yl}-1A7-indol, hydrochlorid ’ zo 7-fluór-3-(piperidín-4-yl)-1 H-indolu a 3-bróm-1 -(3,4-dihydro-l H-izochinolín-2-yl)propán-1-ónu.6b) 7-Chloro-3- {1- [3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1A7-indole, 7-fluoro-3- (piperidin-4-yl) -1H-indole hydrochloride and 3-bromo-1- (3,4-dihydro-1H-isoquinolin-2-yl) propan-1-one hydrochloride.

¹H NMR (DMSO-d₆): 2,05 - 2,25 (m, 4H), 2,80 (t, 0,8H), 2,95 (t, 1,2H), 3,00 - 3,20 (m, 5H), 3,30 - 3,45 (m, 2H), 3,55 - 3,65 (m, 2H), 3,65 - 3,75 (m, 2H), 4,65 (s, 1,2H), 4,75 (s, 0,8H), 7,00 (t, 1H), 7,15 - 7,25 (m, 6H), 7,70 (d, 1H), 10,70 (široký s, 1H), 11,30 (s, 1H). MS m/z: 422 (MH⁺), 247. ¹ H NMR (DMSO-d ₆ ): 2.05-2.25 (m, 4H), 2.80 (t, 0.8H), 2.95 (t, 1.2H), 3.00-3 20 (m, 5H), 3.30-3.45 (m, 2H), 3.55-3.65 (m, 2H), 3.65-3.75 (m, 2H), 4.65 (s, 1.2H), 4.75 (s, 0.8H), 7.00 (t, 1H), 7.15-7.25 (m, 6H), 7.70 (d, 1H), 10.70 (broad s, 1H); 11.30 (s, 1H). MS m / z: 422 (MH < ^{+ >} ), 247.

-306c) 5-Chlór-3-{1-[4-(3,4-dihydro-2/7-chinolín-1-yl)-4-oxobután-1-yl]-piperidín-4-yl}1 /-/-indol, hydrochlorid z 5-fluór-3-(piperidín-4-yl)-1/-/-indolu a 4-chlór-1-(3,4-dihydro-2H-chinolín-1-yl)bután-1-ónu. Teplota topenia 158 až 162 °C.-306c) 5-Chloro-3- {1- [4- (3,4-dihydro-2 H- quinolin-1-yl) -4-oxobutan-1-yl] -piperidin-4-yl} 1 / - / - indole, 5-fluoro-3- (piperidin-4-yl) -1 H -indole hydrochloride and 4-chloro-1- (3,4-dihydro-2H-quinolin-1-yl) butane -1-one. Mp 158-162 ° C.

¹H NMR (DMSO-de): 1,85 - 1,95 (m, 2H), 1,95 - 2,20 (m, 6H), 2,60 - 2,75 (m, 4H), ¹ H NMR (DMSO-d 6): 1.85-1.95 (m, 2H), 1.95-2.20 (m, 6H), 2.60-2.75 (m, 4H),

2,95 - 3,15 (m, 5H), 3,55 (d, 2H), 3,70 (t, 2H), 7,05 - 7,25 (m, 6H), 7,40 (d, 1H), 7,75 (s, 1H), 10,45 (široký s, 1H), 11,15 (s, 1H). MS m/z: 436 (MH⁺), 303.2.95-3.15 (m, 5H), 3.55 (d, 2H), 3.70 (t, 2H), 7.05-7.25 (m, 6H), 7.40 (d, 1H), 7.75 (s, 1H), 10.45 (broad s, 1H), 11.15 (s, 1H). MS m / z: 436 (MH < ^{+ >} ), 303.

Príklad 7Example 7

5-Fluór-3-{ 1 -[4-(3,4-d ih yd ro-1 /-/-izochinolín-2-yl)-4-oxobután-1 -yl] pi perid ίη-4-yl} -1Hindol5-Fluoro-3- {1- [4- (3,4-dihydro-1H-isoquinolin-2-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1Hindol

Zmes 5-fluór-3-(piperidín-4-yl)-1 H-indolu (3,0 g), butanónu (200 ml), tetrahydrofuránu (200 ml), metanolu (30 ml), jodidu draselného (11,4 g) a trietylamínu (7,6 ml) sa zahriala do refluxu, následne sa pridal roztok 4-chlór-1 -(3,4-dihydro-1 Hizochinolín-2-yl)bután-1-ónu (14,6 g) v butanóne (50 ml). Zmes sa nechala vrieť za refluxu 2 hodiny, za horúca sa prefiltrovala a skoncentrovala vo vákuu. Zvyšok sa čistil pomocou bleskovej chromatografie na silikagéli (eluent: etylacetát/etanol/trietylamín 100:5:5), čím sa získal surový produkt. V nadpise uvedená zlúčenina sa izolovala ako voľná báza z etylacetátu vo forme bielej kryštalickej látky (0,9 g). Teplota topenia 146 až 148 °C.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 (7.6 mL) was heated to reflux, followed by the addition of a solution of 4-chloro-1- (3,4-dihydro-1H-isoquinolin-2-yl) butan-1-one (14.6 g) in butanone (50 mL). The mixture was allowed to boil under reflux for 2 hours, filtered hot and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate / ethanol / triethylamine 100: 5: 5) to give the crude product. The title compound was isolated as the free base from ethyl acetate as a white crystalline solid (0.9 g). Mp 146-148 ° C.

¹H NMR (DMSO-de): 1,55 - 1,70 (m, 2H), 1,70 - 1,80 (m, 2H), 1,85 - 1,95 (m, 2H), 2,00 (q, 2H), 2,30 (q, 2H), 2,35 - 2,45 (m, 2H), 2,60 - 2,70 (m, 1H), 2,75 (t, 0,8H), ¹ H NMR (DMSO-d 6): 1.55-1.70 (m, 2H), 1.70-1.80 (m, 2H), 1.85-1.95 (m, 2H), 2, Δ (q, 2H), 2.30 (q, 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). MS m/z: 420 (MH⁺), 202.2.80-3.00 (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) ). MS m / z: 420 (MH < ^{+ >} ), 202.

Príklad 8Example 8

5-Chlór-3-{1-[4-(3,4-dihydro-1/7-izochinolín-2-yl)-4-oxobután-1-yl]piperidín-4-yl}-1/7indol5-Chloro-3- {1- [4- (3,4-dihydro-1/7-isoquinolin-2-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1 / 7IND

Zmes 5-fluór-3-(piperidín-4-yl)-1 H-indolu (3,0 g), butanónu (200 ml) a trietylamínu (8,9 ml) sa zahriala do refluxu, následne sa pridal roztok 4-chlór-1-(3,4-31 dihydro-1 H-izochinolín-2-yl)bután-1-ónu (15,2 g) v butanóne (80 ml). Zmes sa nechala vrieť za refluxu 6 hodín. Výsledná zmes sa prefiltrovala a skoncentrovala vo vákuu. Zvyšok a čistil pomocou bleskovej chromatografie na silikagéli (eluent: etylacetát/etanol/trietylamín 100:4:4), čím sa získal surový produkt. V nadpise uvedená zlúčenina sa izolovala ako voľná báza z etylacetátu vo forme bielej kryštalickej látky (0,6 g). Teplota topenia 172 až 175 °C.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 reflux, followed by the addition of a solution of 4- chloro-1- (3,4-31 dihydro-1H-isoquinolin-2-yl) butan-1-one (15.2 g) in butanone (80 mL). The mixture was allowed to boil under reflux for 6 hours. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate / ethanol / triethylamine 100: 4: 4) to give the crude product. The title compound was isolated as the free base from ethyl acetate as a white crystalline solid (0.6 g). Melting point 172-175 ° C.

¹H NMR (DMSO-d₆): 1,55 - 1,65 (m, 2H), 1,65 - 1,75 (m, 2H), 1,90 (s, 2H), 2,00 (q, 2H), 2,30 (q, 2H), 2,40 (q, 2H), 2,65 - 2,80 (m, 1,8H), 2,80 - 3,00 (m, 3,2H), 3,70 (t, 2H), 4,60 (s, 1,2H), 4,70 (s, 0,8H), 7,05 (d, 1H), 7,10 - 7,25 (m, 5H), 7,35 (d, 1H), ¹ H NMR (DMSO-d ₆ ): 1.55-1.65 (m, 2H), 1.65-1.75 (m, 2H), 1.90 (s, 2H), 2.00 (q 2H, 2.30 (q, 2H), 2.40 (q, 2H), 2.65-2.80 (m, 1.8H), 2.80-3.00 (m, 3.2H) ), 3.70 (t, 2H), 4.60 (s, 1.2H), 4.70 (s, 0.8H), 7.05 (d, 1H), 7.10 - 7.25 ( m, 5H), 7.35 (d, 1 H),

7,55 (s, 1H), 11,00 (s, 1H). MS m/z: 436 (MH⁺), 202.7.55 (s, 1 H), 11.00 (s, 1 H). MS m / z: 436 (MH < ^{+ >} ), 202.

Príklad 9Example 9

9a) 5-Fluór-3-{1-[3-(3,4-dihydro-2/7-chinolín-1-yl)propán-1-yl]piperidín-4-yl}-1/-/indol, dihydrochlorid9a) 5-Fluoro-3- {1- [3- (3,4-dihydro-2 H -quinolin-1-yl) -propan-1-yl] -piperidin-4-yl} -1 H -indole, dihydrochloride

Suspenzia hydridu hlinitolítneho (0,94 g) v tetrahydrofuráne (40 ml) sa miešala pri 5 °C, následne sa pridala koncentrovaná kyselina sírová (1,2 g) v tetrahydrofuráne (20 ml). Zmes sa miešala pri 7 °C 60 minút, následne sa pridal 5fluór-3-{ 1 -[3-(2-oxo-3,4-dihydro-2/-/-chinolín-1 -yl)propán-1 -yljpiperid ín-4-yl}-1 /-/-indol (2,0 g) v tetrahydrofuráne (60 ml). Výsledná zmes sa miešala pri 5 °C 60 minút a nasledovalo štandardné spracovanie. Zvyšok a čistil pomocou bleskovej chromatografie na silikagéli (eluent: etylacetát), čím sa získal surový produkt vo forme bezfarebného oleja. V nadpise uvedená zlúčenina sa izolovala ako dihydrochloridová soľ z tetrahydrofuránu vo forme bielej kryštalickej látky (1,0 g). Teplota topenia 230 až 236 °C.A suspension of lithium aluminum hydride (0.94 g) in tetrahydrofuran (40 ml) was stirred at 5 ° C, followed by the addition of concentrated sulfuric acid (1.2 g) in tetrahydrofuran (20 ml). The mixture was stirred at 7 ° C for 60 minutes, then 5-fluoro-3- {1- [3- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] -piperide was added. In-4-yl} -1 H -indole (2.0 g) in tetrahydrofuran (60 mL). The resulting mixture was stirred at 5 ° C for 60 minutes, followed by standard work-up. 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 as the dihydrochloride salt from tetrahydrofuran as a white crystalline solid (1.0 g). Mp 230-236 ° C.

¹H NMR (DMSO-de): 1,95 (t, 2H), 2,00 - 2,30 (m, 4H), 2,75 (t, 2H), 2,95 - 3,20 (m, 5H), 3,30 (t, 2H), 3,40 (t, 2H), 3,55 (d, 2H), 6,20 (široké s, 1H), 6,70 (široké s, 1H), ¹ H NMR (DMSO-d 6): 1.95 (t, 2H), 2.00-2.30 (m, 4H), 2.75 (t, 2H), 2.95-3.20 (m, 5H), 3.30 (t, 2H), 3.40 (t, 2H), 3.55 (d, 2H), 6.20 (broad s, 1H), 6.70 (broad s, 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 (široké s, 1H), 11,05 (s, 1H). MS m/z: 392 (MH⁺), 259.6.95 (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 (broad s, 1H); 11.05 (s, 1H). MS m / z: 392 (MH < ^{+ >} ), 259.

-329b) 5-Fluór-3-{ 1 -[4-(3,4-dihydro-2/7-chinolín-1 -yl)bután-1 -yl]piperidín-4-yl}-1 /7-indol, dihydrochlorid z 5-fluór-3-{1-[4-(2-oxo-3,4-dihydro-2/7-chinolín-1-yl)bután-1-yl]piperidín-4-yl}-1/7indolu, teplota topenia 207 až 212 °C.-329b) 5-Fluoro-3- {1- [4- (3,4-dihydro-2 H- quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1 H -indole , 5-fluoro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} dihydrochloride -1 M.p. 207 DEG-212 DEG.

¹H NMR (DMSO-dg): 1,65 (s, 2H), 1,80 - 1,90 (m, 2H), 1,95 (s, 2H), 2,05 (d, 2H), ¹ H NMR (DMSO-d 6): 1.65 (s, 2H), 1.80-1.90 (m, 2H), 1.95 (s, 2H), 2.05 (d, 2H),

2.20 (q, 2H), 2,65 - 2,80 (m, 2H), 2,95 - 3,25 (m, 4H), 3,15 - 3,25 (m, 1H), 3,35 (s,2.20 (q, 2H), 2.65-2.80 (m, 2H), 2.95-3.25 (m, 4H), 3.15-3.25 (m, 1H), 3.35 ( with,

4H), 3,55 (d, 2H), 4,65 (široké s), 5,55 - 6,95 (m, 3H), 7,00 (s, 1H), 7,10 (s, 1H),4H), 3.55 (d, 2H), 4.65 (broad s), 5.55-6.95 (m, 3H), 7.00 (s, 1H), 7.10 (s, 1H) .

7.20 (s, 1H), 7,30 - 7,40 (m, 1H), 7,55 (d, 1H), 11,75 (široké s, 1H), 11,05 (s, 1H).7.20 (s, 1H), 7.30-7.40 (m, 1H), 7.55 (d, 1H), 11.75 (broad s, 1H), 11.05 (s, 1H).

MS m/z: 406 (MH⁺), 274.MS m / z: 406 (MH < ^{+ >} ), 274.

9c) 5-Fluór-3-{ 1 -[5-(3,4-dihydro-2/7-chinolín-1 -yl)pentán-1 -yl]piperidín-4-yl}-1 Hindol, dihydrochlorid z 5-fluór-3-{1 -[5-(2-oxo-3,4-dihydro-2/-/-chinolín-1 -yl)pentán-1 -yl]piperidίη-4-yl}-1Hindolu, teplota topenia 155 až 158 °C.9c) 5-Fluoro-3- {1- [5- (3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] piperidin-4-yl} -1-Hindole dihydrochloride from 5 -fluoro-3- {1- [5- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] piperidin-4-yl} -1Hindole, m.p. Mp 155-158 ° C.

¹H NMR (DMSO-dg): 1,30 - 1,45 (m, 2H), 1,65 (s, 2H), 1,75 - 1,80 (m, 2H), 1,95 (s, 2H), 2,20 (q, 2H), 2,75 (s, 2H), 2,95 - 3,10 (m, 5H), 3,35 (s, 4H), 3,55 (d, 2H), 5,05 (široké 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 (široké s, 1H), 11,05 (s, 1H). MS m/z: 420 (MH⁺), 287. ¹ H NMR (DMSO-d 6): 1.30-1.45 (m, 2H), 1.65 (s, 2H), 1.75-1.80 (m, 2H), 1.95 (s, 2H), 2.20 (q, 2H), 2.75 (s, 2H), 2.95-3.10 (m, 5H), 3.35 (s, 4H), 3.55 (d, 2H) ), 5.05 (broad 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 (broad s, 1H), 11.05 (s, 1H). MS m / z: 420 (MH < ^{+ >} ), 287.

9d) 5-Chlór-3-{ 1 -[3-(3,4-dihydro-2/7-chinolín-1 -yl)propán-1 -yl] piperid í η-4-yl} -1 /7indol, dihydrochlorid z 5-chlór-3-{1-[3-(2-oxo-3,4-dihydro-2/7-chinolín-1-yl)propán-1-yl]piperidín-4-yl}-1/7indolu, teplota topenia 201 až 204 °C.9d) 5-Chloro-3- {1- [3- (3,4-dihydro-2 H -quinolin-1-yl) -propan-1-yl] -piperidin-4-yl} -1 H -indole, 5-Chloro-3- {1- [3- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) -propan-1-yl] -piperidin-4-yl} -1-dihydrochloride Mp 201-204 ° C.

¹H NMR (DMSO-de): 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), 6,40 (široké s), 6,65 (s, 1H), 6,85 (s, 1H), ¹ H NMR (DMSO-d 6): 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), 6.40 (broad s), 6.65 (s, 1H), 6.85 (s, 1 H),

6,95 (d, 1H), 7,00 - 7,10 (m, 2H), 7,20 (s, 1H), 7,40 (d, 1H), 7,75 (s, 1H), 10,85 (široké s, 1H), 11,20 (s, 1H). MS m/z: 408 (MH⁺), 275.6.95 (d, 1H), 7.00-7.10 (m, 2H), 7.20 (s, 1H), 7.40 (d, 1H), 7.75 (s, 1H), 10 85 (broad s, 1H); 11.20 (s, 1H). MS m / z: 408 (MH < ^{+ >} ), 275.

9e) 5-Chlór-3-{ 1 -[4-(3,4-dihydro-2/7-chinolín-1 -yl)bután-1 -yl]piperidín-4-yl}-1 /7-indol, dihydrochlorid9e) 5-Chloro-3- {1- [4- (3,4-dihydro-2 H -quinolin-1-yl) -butan-1-yl] -piperidin-4-yl} -1 H -indole, dihydrochloride

-33z 5-chIór-3-{1-[4-(2-oxo-3,4-dihydro-2/7-chinolín-1-yl)bután-1-yl]piperidín-4-yl}-1/7indolu, teplota topenia 140 až 145 °C.-33z 5-Chloro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1) M.p. 140-145 ° C.

¹H NMR (DMSO-ds): 1,65 (s, 2H), 1,80 - 1,90 (m, 2H), 1,95 (s, 2H), 2,00 - 2,25 (m, 4H), 2,75 (s, 2H), 2,95 - 3,25 (m, 5H), 3,35 (s, 4H), 3,55 (d, 2H), 6,75 (široké s, 1H), ¹ H NMR (DMSO-d 6): 1.65 (s, 2H), 1.80-1.90 (m, 2H), 1.95 (s, 2H), 2.00-2.25 (m, 4H), 2.75 (s, 2H), 2.95-3.25 (m, 5H), 3.35 (s, 4H), 3.55 (d, 2H), 6.75 (broad s, 1H),

6,90 (široké s, 1H), 7,00 (s, 1H), 7,05 - 7,15 (m, 2H), 7,20 (s, 1H), 7,40 (d, 1H), 7,80 (s, 1 H), 10,70 (široké s, 1 H), 11,20 (s, 1 H). MS m/z: 422 (MH⁺), 289, 188.6.90 (broad s, 1H), 7.00 (s, 1H), 7.05-7.15 (m, 2H), 7.20 (s, 1H), 7.40 (d, 1H), 7.80 (s, 1H), 10.70 (broad s, 1H), 11.20 (s, 1H). MS m / z: 422 (MH < ^{+ >} ), 289, 188.

9f) 5-Chlór-3-{ 1-(5-(3,4-dihydro-2/7-chinolín-1-yl)pentán-1-yl]piperidín-4-yl}-1/7indol, dihydrochlorid z 5-chlór-3-{ 1 -[5-(2-oxo-3,4-dihydro-2/7-chinolín-1 -yl)pentán-1 -yI]piperidín-4-yl}-1 Hindolu, teplota topenia 101 až 106 °C.9f) 5-Chloro-3- {1- (5- (3,4-dihydro-2 H- quinolin-1-yl) pentan-1-yl] piperidin-4-yl} -1 H -indole dihydrochloride from 5-Chloro-3- {1- [5- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] piperidin-4-yl} -1-hindole, temperature mp 101-106 ° C.

¹H NMR (DMSO-ds): 1,30 - 1,45 (m, 2H), 1,65 (s, 2H), 1,70 - 1,85 (m, 2H), 1,95 (s, 2H), 2,00 - 2,25 (m, 4H), 2,75 (s, 2H), 2,95 - 3,25 (m, 5H), 3,35 (s, 4H), 3,55 (d, 2H), ¹ H NMR (DMSO-d 6): 1.30-1.45 (m, 2H), 1.65 (s, 2H), 1.70-1.85 (m, 2H), 1.95 (s, 2H), 2.00-2.25 (m, 4H), 2.75 (s, 2H), 2.95-3.25 (m, 5H), 3.35 (s, 4H), 3.55 (d, 2H)

6,80 (široké s, 1H), 6,90 - 7,15 (m, 4H), 7,20 (s, 1H), 7,35 (d, 1H), 7,75 (s, 1H),6.80 (broad s, 1H), 6.90-7.15 (m, 4H), 7.20 (s, 1H), 7.35 (d, 1H), 7.75 (s, 1H),

10.70 (široké s, 1H), 11,20 (s, 1H). MS m/z: 436 (MH⁺), 303.10.70 (broad s, 1H); 11.20 (s, 1H). MS m / z: 436 (MH < ^{+ >} ), 303.

9g) 7-Chlór-3-{ 1 -(4-(3,4-dihydro-2H-chinolín-1 -yl)bután-1 -yl]piperidíη-4-yl}-1 H-indol, dihydrochlorid zo 7-chlór-3-{ 1 -[4-(2-oxo-3,4-dihydro-2/7-chinolín-1 -yl )bután-1 -yl] piperid í η-4-yl} -1Hindolu, teplota topenia 214 až 219 °C.9g) 7-Chloro-3- {1- (4- (3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1H-indole, dihydrochloride from 7 -chloro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1Hindole, temperature mp 214-219 ° C.

¹H NMR (DMSO-ds): 1,65 (s, 2H), 1,80 - 1,90 (m, 2H), 1,95 (s, 2H), 2,00 - 2,15 (m, 2H), 2,15 - 2,30 (m, 2H), 2,70 (s, 2H), 2,95 - 3,15 (m, 5H), 3,35 (s, 4H), 3,55 (d, 2H), ¹ H NMR (DMSO-d 6): 1.65 (s, 2H), 1.80-1.90 (m, 2H), 1.95 (s, 2H), 2.00-2.15 (m, 2H), 2.15-2.30 (m, 2H), 2.70 (s, 2H), 2.95-3.15 (m, 5H), 3.35 (s, 4H), 3.55 (d, 2H)

6.70 (široké s, 1H), 6,85 (široké s, 1H), 6,95 - 7,05 (m, 2H), 7,10 (s, 1H), 7,15 - 7,25 (m, 2H), 7,70 (d, 1H), 10,80 (široké s, 1H), 11,30 (s, 1H). MS m/z: 422 (MH⁺j, 289, 188.6.70 (broad s, 1H), 6.85 (broad s, 1H), 6.95-7.05 (m, 2H), 7.10 (s, 1H), 7.15-7.25 (m, 2H), 7.70 (d, 1H), 10.80 (broad s, 1H), 11.30 (s, 1H). MS m / z: 422 (MH ⁺ , 289, 188).

9h) 5-Fluór-1 -metyl-3-{ 1 -(3-(3,4-dihydro-2/7-chinolín-1 -yl)propán-1 -yl] piperid í η-4-yl} 1 /-/-indol, dihydrochlorid z 5-fluór-1-metyl-3-{1-[3-(2-oxo-3,4-dihydro-2/7-chinolín-1-yl)propán-1-yl]-piperidín4-yl}-1 H-indolu, teplota topenia 202 až 206 °C.9h) 5-Fluoro-1-methyl-3- {1- (3- (3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] piperidin-4-yl} -1 N -indole, dihydrochloride from 5-fluoro-1-methyl-3- {1- [3- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] 1-piperidin-4-yl} -1H-indole, mp 202-206 ° C.

-34¹H NMR (DMSO-de): 1,85 - 1,95 (m, 2H), 2,00 - 2,10 (m, 4H), 2,10 - 2,25 (m, 2H),-34 ¹ H-NMR (DMSO-de): 1.85 to 1.95 (m, 2H), 2.00 to 2.10 (m, 4H), 2.10 to 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),2.65-3.75 (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, 3H), 6,65 (široké s, 1H), 6,80 (široké s, 1H), 6,90 - 7,10 (m, 3H), 7,20 (s, 1H), 7,35 - 7,45 (m, 1H), 7,55 (d, 1H), 10,90 (široké s, 1H). MS m/z: 406 (MH⁺), 273.3.55 (d, 2H), 3.75 (s, 3H), 6.65 (broad s, 1H), 6.80 (broad s, 1H), 6.90-7.10 (m, 3H) 7.20 (s, 1H), 7.35-7.45 (m, 1H), 7.55 (d, 1H), 10.90 (broad s, 1H). MS m / z: 406 (MH < ^{+ >} ), 273.

9i) 5-Fluór-1-metyl-3-{1-[4-(3,4-dihydro-2H-chinolín-1-yl)bután-1-yl]piperidín-4-yl}1 /7-indol, oxalát z 5-fluór-1-metyl-3-{1-[4-(2-oxo-3,4-dihydro-2/7-chinolín-1-yl)bután-1-yl]-piperidín-4yl}-1 /7-indolu, teplota topenia 123 až 125 °C.9i) 5-Fluoro-1-methyl-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1,7-indole , 5-fluoro-1-methyl-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] -piperidin-4yl oxalate } -1 / 7-indole, m.p. 123-125 ° C.

¹H NMR (DMSO-de): 1,50 - 1,60 (m, 2H), 1,65 - 1,75 (m, 2H), 1,80 - 1,90 (m, 2H), ¹ H NMR (DMSO-d 6): 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, 3H), 6,45 (t, 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 m/z: 420 (MH⁺), 287.1.90-2.00 (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, 3H), 6.45 (t, 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 m / z: 420 (MH < ^{+ >} ), 287.

9j) 5-Fluór-3-{1-[4-(3,4-dihydro-2/7-1,4-benzoxazín-4-yl)bután-1-yl]piperidín-4-yl}1/7-indol, dihydrochlorid z 5-fluór-3-{ 1 -[4-(3-oxo-3,4-dihydro-2/7-1,4-benzoxazín-4-yl)bután-1 -yl]-piperidín-4yl}-1/7-indolu, teplota topenia 179 až 186 °C.9j) 5-Fluoro-3- {1- [4- (3,4-dihydro-2H-1,4-benzoxazin-4-yl) butan-1-yl] piperidin-4-yl} 1/7 -indole, 5-fluoro-3- {1- [4- (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl) butan-1-yl] -piperidine dihydrochloride M.p. 179-186 ° C.

¹H NMR (DMSO-d₆): 1,55 - 1,65 (m, 2H), 1,75 - 1,90 (m, 2H), 2,00 - 2,10 (m, 2H), 2,15 - 2,25 (m, 2H), 2,95 - 3,25 (m, 5H), 3,25 - 3,40 (m, 4H), 3,55 (d, 2H), 4,15 4,25 (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 (široké s, 1H), 11,05 (s, 1H). MS m/z: 408 (MFľ), 273, 190. ¹ H NMR (DMSO-d ₆ ): 1.55-1.65 (m, 2H), 1.75-1.90 (m, 2H), 2.00-2.10 (m, 2H), 2 15-2.25 (m, 2H), 2.95-3.25 (m, 5H), 3.25-3.40 (m, 4H), 3.55 (d, 2H), 4.15 4.25 (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 (broad s, 1H), 11.05 (s, 1H). MS m / z: 408 (MH +), 273, 190.

9k) 5-Chlór-3-{1-[4-(3,4-dihydro-2/7-1,4-benzoxazín-4-yl)bután-1-yl]piperidín-4-yl}1/7-indol, dihydrochlorid z 5-chlór-3-{1-[4-(3-oxo-3,4-dihydro-2/7-1,4-benzoxazín-4-yl)bután-1-yl]-piperidín-4yl}-1/7-indolu, teplota topenia 186 až 190 °C.9k) 5-Chloro-3- {1- [4- (3,4-dihydro-2H-1,4-benzoxazin-4-yl) butan-1-yl] piperidin-4-yl} 1/7 -indole, 5-chloro-3- {1- [4- (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl) butan-1-yl] -piperidine dihydrochloride M.p. 186-190 ° C.

¹H NMR (DMSO-de): 1,55 - 1,65 (m, 2H), 1,70 - 1,85 (m, 2H), 2,00 - 2,20 (m, 4H), ¹ H NMR (DMSO-d 6): 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 - 4,20 (m, 2H), 6,55 (t,2.95-3.25 (m, 5H), 3.25-3.40 (m, 4H), 3.55 (d, 2H), 4.15-4.20 (m, 2H), 6, 55 (t,

-351 Η), 6,65 (d, 1 Η), 6,70 - 6,80 (m, 2Η), 7,05 (d, 1H), 7,20 (s, 1H), 7,40 (d, 1H), 7,75 (s, 1 H), 10,50 (široké s, 1 H), 11,15 (s, 1 H). MS m/z: 424 (MH⁺), 289, 190.-351 Η), 6.65 (d, 1H), 6.70-6.80 (m, 2Η), 7.05 (d, 1H), 7.20 (s, 1H), 7.40 (s) d, 1H), 7.75 (s, 1H), 10.50 (broad s, 1H), 11.15 (s, 1H). MS m / z: 424 (MH < ^{+ >} ), 289, 190.

9I) 5-Fluór-3-{ 1 -[3-(3,4-d ihyd ro-2 /-/-chi nol í n-1 -yl)propán-1 -yl]-3,6-d ihyd ro-2/7pyridín-4-yl}-1 /-/-indol, dihydrochlorid z 5-fluór-3-{1-[3-(2-oxo-3,4-dihydro-2/7-chinolín-1-yl)propán-1-yl]-3,6-dihydro-2/7pyridín-4-yl}-1 /-/-indolu, teplota topenia 220 až 223 °C.9I) 5-Fluoro-3- {1- [3- (3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] -3,6-dihydro trans-2/7-Pyridin-4-yl} -1H-indole, 5-fluoro-3- {1- [3- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) -hydrochloride] dihydrochloride -yl) propan-1-yl] -3,6-dihydro-2 H -pyridin-4-yl} -1 H -indole, m.p. 220-223 ° C.

¹H NMR (DMSO-de): 1,85 - 2,00 (m, 2H), 2,05 - 2,10 (m, 2H), 2,70 - 2,80 (m, 4H), ¹ H NMR (DMSO-d 6): 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, 1H), 6,70 (široké s, 1H), 6,90 (široké s, 1H), 6,95 - 7,05 (m, 2H), 7,05 - 7,10 (m, 1H), 7,40 - 7,45 (m, 1H), 7,55 7.65 (m, 2H), 11,10 (široké s, 1H), 11,60 (s, 1H). MS m/z: 390 (MH⁺), 203, 146.2.90-3.00 (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, 1H), 6.70 (broad s, 1H), 6.90 (broad s, 1H), 6.95-7.05 (m, 2H), 7.05-7.10 (m, 1H), 7.40-7.45 (m, 1H), 7 55.65 (m, 2H), 11.10 (broad s, 1H), 11.60 (s, 1H). MS m / z: 390 (MH < ^{+ >} ), 203, 146.

9m) 5-Fluór-3-{ 1 -[4-(3,4-d ihyd ro-2ŕ7-chinol í n-1 -yl )bután-1 -yl]-3,6-d ihyd ro-2/-/pyridín-4-yl}-1 /-/-indol, dihydrochlorid z 5-fluór-3-{1-[4-(2-oxo-3,4-dihydro-2/7-chinolín-1-yl)bután-1-yl]-3,6-dihydro-2/-/pyridín-4-yl}-1 /-/-indolu, teplota topenia 198 až 200 °C.9m) 5-Fluoro-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] -3,6-dihydro-2 H- - (pyridin-4-yl) -1H-indole, 5-fluoro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) -hydrochloride} dihydrochloride butan-1-yl] -3,6-dihydro-2H-pyridin-4-yl} -1H-indole, m.p. 198-200 ° C.

¹H NMR (DMSO-de): 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, 1H), 3,15 - 3,30 (m, 4H), 3,30 - 3,40 (m, 2H), 3,55 3.65 (m, 1H), 3,70 - 3,80 (m, 1H), 3,95 (d, 1H), 6,10 (s, 1H), 6,80 (široké s, 1H), ¹ H NMR (DMSO-d 6): 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, 1H), 3.15-3.30 (m, 4H), 3.30-3.40 (m, 2H), 3.55 3.65 ( m, 1H), 3.70-3.80 (m, 1H), 3.95 (d, 1H), 6.10 (s, 1H), 6.80 (broad s, 1H),

6.90 - 7,20 (m, 3H), 7,00 (t, 1H), 7,40 - 7,45 (m, 1H), 7,55 - 7,65 (m, 2H), 10,95 (široké s, 1H), 11,55 (s, 1H). MS m/z: 404 (MH⁺), 271, 217.6.90-7.20 (m, 3H), 7.00 (t, 1H), 7.40-7.45 (m, 1H), 7.55-7.65 (m, 2H), 10.95 ( broad s, 1H), 11.55 (s, 1H). MS m / z: 404 (MH < ^{+ >} ), 271, 217.

9n) 5-Fluór-3-{ 1 -[5-(3,4-dihydro-2/-/-chinolín-1 -yl)pentán-1 -yl]-3,6-d ihyd ro-2A7pyridín-4-yl}-1 /-/-indol, dihydrochlorid z 5-fluór-3-{ 1 -[5-(2-oxo-3,4-dihydro-2/-/-chinolín-1 -yl)pentán-1 -yl]-3,6-dihydro-2/-/pyridín-4-yl}-1/-/-indolu, teplota topenia 167 až 169 °C.9n) 5-Fluoro-3- {1- [5- (3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] -3,6-dihydro-2H-pyridin-4-one; 5-fluoro-3- {1- [5- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl} -1H-indole dihydrochloride m.p. 167-169 ° C] -1,6-dihydro-2 H- pyridin-4-yl} -1 H -indole.

¹H NMR (DMSO-d₆): 1,30 - 1,45 (m, 2H), 1,70 (s, 2H), 1,75 - 1,90 (m, 2H), 2,00 (s, 2H), 2,70 - 2,85 (m, 3H), 2,85 - 3,00 (m, 1H), 3,05 - 3,20 (m, 2H), 3,20 - 3,30 (m, 1H), 3,35 (s, 2H), 3,55 - 3,65 (m, 1H), 3,70 - 3,80 (m, 1H), 3,95 (d, 1H), 6,10 (s, 1H), ¹ H NMR (DMSO-d ₆ ): 1.30-1.45 (m, 2H), 1.70 (s, 2H), 1.75-1.90 (m, 2H), 2.00 (s 2H, 2.70-3.85 (m, 3H), 2.85-3.00 (m, 1H), 3.05-3.20 (m, 2H), 3.20-3.30 (m, 1H), 3.35 (s, 2H), 3.55-3.65 (m, 1H), 3.70-3.80 (m, 1H), 3.95 (d, 1H), 6.10 (s, 1 H),

-366,80 - 7,25 (m, 4H), 7,00 (t, 1H), 7,40 - 7,45 (m, 1H), 7,55 - 7,65 (m, 2H), 11,00 (s, široké s, 1 H), 11,60 (s, 1 H). MS m/z: 418 (MH⁺), 231, 188.-366.80-7.25 (m, 4H), 7.00 (t, 1H), 7.40-7.45 (m, 1H), 7.55-7.65 (m, 2H), 11 .00 (s, broad s, 1H), 11.60 (s, 1H). MS m / z: 418 (MH < ^{+ >} ), 231, 188.

Príklad 10Example 10

II

10a) 4-Fluór-3-{1-[3-(3,4-dihydro-1/7-izochinolín-2-yl)-3-oxopropán-1-yl]piperidín-4yl}-1 /-/-indol10a) 4-Fluoro-3- {1- [3- (3,4-dihydro-1 H -isoquinolin-2-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1 H- indole

Polymérom viazaná kyselina 3-[1-(4-fluór-1/-/-indol-3-yl)piperidín-1-yl)propiónová (0,1 g, 0,08 mmol) v suchom dichlórmetáne (1 ml) sa zmiešali v reakčnej skúmavke. Zmes sa ochladila na 0 °C a 2 hodiny sa na ňu pôsobilo 2M roztokom tionylchloridu (0,4 ml, 0,8 mmol) v dichlórmetáne. Živica sa odfiltrovala a premyla suchým dichlórmetánom (3 x 1 ml), opäť suspendovala v dichlórmetáne (1 ml), a pri teplote miestnosti sa 3 hodiny na ňu pôsobilo 3,4-dihydro-1/-/-izochinolínom (0,05 g, 0,4 mmol). Živica sa odfiltrovala a premyla dichlórmetánom (3 x 1 ml), 1:1 zmesou dichlórmetánu:trietylamínu (3 x 1 ml) a suchým dochlórmetánom (3 x 1 ml). Na živicu sa pôsobilo 1 hodinu 1 ml zmesi metoxidu sodného (2 ml, 5N metoxid sodného v metanole), metanolu (50 ml) a tetrahydrofuránu (50 ml). Po filtrácii sa živica premyla metanolom (1 ml). Spojené filtráty sa vložili do vopred pripravenej ionexovej kolóny (500 mg SCX kolóna, komerčne k dispozícii z Analytical Instruments, časť č. 1210-2040), premyli acetonitrilom (1 ml) a metanolom (1 ml). Produkt sa eluoval 4M amoniakom v metanole. Po odparení prchavých rozpúšťadiel sa surový produkt čistil preparatívnou HPLC chromatografiou na reverznej fáze. Výsledný roztok sa najprv vložil do vopred pripravenej iónovo-výmennej kolóny, neskôr premyl acetonitrilom (1 ml) a metanolom (1 ml). Produkt sa eluoval 4M amoniakom v metanole. Odparením prchavých rozpúšťadiel sa poskytla v nadpise uvedená zlúčenina vo forme žltého oleja (5 mg, 12 μιτιοΙ). LC/MS (m/z) 406 (MH⁺), RT = 3,61, čistota: 66%.Polymer-bound 3- [1- (4-fluoro-1 H -indol-3-yl) piperidin-1-yl) propionic acid (0.1 g, 0.08 mmol) in dry dichloromethane (1 mL) was added and the reaction stirred overnight at room temperature. were mixed in a reaction tube. The mixture was cooled to 0 ° C and treated with a 2M solution of thionyl chloride (0.4 mL, 0.8 mmol) in dichloromethane for 2 hours. The resin was filtered off and washed with dry dichloromethane (3 x 1 mL), resuspended in dichloromethane (1 mL), and treated at room temperature with 3,4-dihydro-1 H -isoquinoline (0.05 g) for 3 hours. , 0.4 mmol). The resin was filtered off and washed with dichloromethane (3 x 1 mL), 1: 1 dichloromethane: triethylamine (3 x 1 mL) and dry dichloromethane (3 x 1 mL). The resin was treated with 1 ml of a mixture of sodium methoxide (2 ml, 5N sodium methoxide in methanol), methanol (50 ml) and tetrahydrofuran (50 ml) for 1 hour. After filtration, the resin was washed with methanol (1 mL). The combined filtrates were loaded onto a preformed ion exchange column (500 mg SCX column, commercially available from Analytical Instruments, Part # 1210-2040), washed with acetonitrile (1 mL) and methanol (1 mL). The product was eluted with 4M ammonia in methanol. After evaporation of the volatile solvents, the crude product was purified by preparative reverse phase HPLC. The resulting solution was first loaded onto a preformed ion exchange column, then washed with acetonitrile (1 mL) and methanol (1 mL). The product was eluted with 4M ammonia in methanol. Evaporation of the volatile solvents gave the title compound as a yellow oil (5 mg, 12 μιτιοΙ). LC / MS (m / z) 406 (MH ⁺ ), R T = 3.61, purity: 66%.

Nasledujúce zlúčeniny sa pripravili podobným spôsobom (10b až 10m) alebo použitím 3,4-dihydro-2/-/-chinolínu (10n až 10z):The following compounds were prepared in a similar manner (10b to 10m) or using 3,4-dihydro-2H-quinoline (10n to 10z):

-3710b) 4-Fluór-3-{ 1 -[4-(3,4-dihydro-l /7-izochinolín-2-yl)-4-oxobután-1 -y I] piperid í n-4yl}-1 /-/-indol-3710b) 4-Fluoro-3- {1- [4- (3,4-dihydro-1H-isoquinolin-2-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1 / - / - indole

LC/MS (m/z) 420 (MH⁺), RT = 3,69, čistota: 93%LC / MS (m / z) 420 (MH < ^{+ >} ), RT = 3.69, purity: 93%

10c) 4-Fluór-3-{ 1 -[6-(3,4-dihydro-l H-izochinolín-2-yl)-6-oxohexán-1 -yI]piperid ín-4yl}-1 H-indol10c) 4-Fluoro-3- {1- [6- (3,4-dihydro-1H-isoquinolin-2-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1H-indole

LC/MS (m/z) 448 (MH⁺), RT = 3,81, čistota: 97%LC / MS (m / z) 448 (MH < ^{+ >} ), RT = 3.81, purity: 97%

10d) 4-Chlór-3-{ 1 -[4-(3,4-dihydro-l H-izochinolín-2-yl)-4-oxobután-1 -yl] piperid í n-4yl}-1H-indol10d) 4-Chloro-3- {1- [4- (3,4-dihydro-1H-isoquinolin-2-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1H-indole

LC/MS (m/z) 436 (MH⁺), RT = 3,86, čistota: 97%LC / MS (m / z) 436 (MH < ^{+ >} ), RT = 3.86, purity: 97%

10e) 4-Chlór-3-{ 1 -[5-(3,4-dihydro-l /-/-izochinolín-2-yl)-5-oxopentán-1 -yl] piperid í n-4yl}-1 H-indol10e) 4-Chloro-3- {1- [5- (3,4-dihydro-1H-isoquinolin-2-yl) -5-oxopentan-1-yl] piperidin-4-yl} -1H indole

LC/MS (m/z) 450 (MH⁺), RT = 3,87, čistota: 81%LC / MS (m / z) 450 (MH < ^{+ >} ), RT = 3.87, purity: 81%

10f) 4-Chlór-3-{ 1 -[6-(3,4-dihydro-l H-izochinolín-2-yl)-6-oxohexán-1 -yl] piperid í n-4yl}-1 H-indol10f) 4-Chloro-3- {1- [6- (3,4-dihydro-1H-isoquinolin-2-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1H-indole

LC/MS (m/z) 464 (MH⁺), RT = 3,97, čistota: 86% 'LC / MS (m / z) 464 (MH ⁺ ), R T = 3.97, purity: 86% '

10g) 5-Fluór-3-{ 1 -[5-(3,4-dihydro-1 H-izochinolín-2-yl)-5-oxopentán-1 -yl]piperidín-4yl}-1 H-indol10g) 5-Fluoro-3- {1- [5- (3,4-dihydro-1H-isoquinolin-2-yl) -5-oxopentan-1-yl] piperidin-4-yl} -1H-indole

LC/MS (m/z) 434 (MH⁺), RT = 3,67, čistota: 93%LC / MS (m / z) 434 (MH < ^{+ >} ), RT = 3.67, purity: 93%

10h) 5-Fluór-3-{ 1 -[6-(3,4-dihydro-l /7-izochinolín-2-yl)-6-oxohexán-1 -yl] piperid í n-4yl}-1 H-indol10h) 5-Fluoro-3- {1- [6- (3,4-dihydro-1H-isoquinolin-2-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1H- indole

LC/MS (m/z) 448 (MH⁺), RT = 3,79, čistota: 89%LC / MS (m / z) 448 (MH < ^{+ >} ), RT = 3.79, purity: 89%

10i) 6-Chlór-3-{ 1 -[3-(3,4-dihydro-l /-/-izochinolín-2-yl)-3-oxopropán-1 -yl] piperid í n-4yl}-1 /-/-indol10i) 6-Chloro-3- {1- [3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1) - / - indole

LC/MS (m/z) 422 (MH⁺), RT = 3,80, čistota: 85%LC / MS (m / z) 422 (MH < ^{+ >} ), RT = 3.80, purity: 85%

-3810j) 6-Chlór-3-{ 1 -[6-(3,4-dihydro-1 /7-izochinolín-2-yl)-6-oxohexán-1 -yl] pi perid í n-4yl}-1 /7-indol-3810j) 6-Chloro-3- {1- [6- (3,4-dihydro-1H-isoquinolin-2-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1 / 7-indole

LC/MS (m/z) 464 (MH⁺), RT = 3,98, čistota: 87%LC / MS (m / z) 464 (MH < ^{+ >} ), RT = 3.98, purity: 87%

10k) 7-Chlór-3-{ 1 -[4-(3,4-dihydro-1 /7-izochinolín-2-yl)-4-oxobután-1 -y I] pi perid í n-4yl}-1 /7-indol10k) 7-Chloro-3- {1- [4- (3,4-dihydro-1H-isoquinolin-2-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1 / 7-indole

LC/MS (m/z) 436 (MH⁺), RT = 3,85, čistota: 98%LC / MS (m / z) 436 (MH < ^{+ >} ), RT = 3.85, purity: 98%

10l) 7-Chlór-3-{ 1 -[5-(3,4-d i hyd ro-1 A7-izochinolín-2-yl)-5-oxopentán-1 -yl] piperid í n-4yl}-1/7-indol10l) 7-Chloro-3- {1- [5- (3,4-dihydro-1H-isoquinolin-2-yl) -5-oxopentan-1-yl] piperidin-4-yl} -1 / 7-indole

LC/MS (m/z) 450 (MH⁺), RT = 3,85, čistota: 96%LC / MS (m / z) 450 (MH < ^{+ >} ), RT = 3.85, purity: 96%

10m) 7-Chlór-3-{ 1 -[6-(3,4-dihydro-1 /7-izochinolín-2-yl)-6-oxohexán-1 -yl] piperid í n-4yl}-1 /7-indol10m) 7-Chloro-3- {1- [6- (3,4-dihydro-1H-isoquinolin-2-yl) -6-oxo-hexan-1-yl] -piperidin-4-yl} -1/7 indole

LC/MS (m/z) 464 (MH⁺), RT = 3,96, čistota: 97%LC / MS (m / z) 464 (MH < ^{+ >} ), RT = 3.96, purity: 97%

10n) 4-Fluór-3-{ 1 -[3-(3,4-dihydro-2/7-chinolín-1 -yl)-3-oxopropán-1 -yl ] piperid í η-4-yl} 1/7-indol10n) 4-Fluoro-3- {1- [3- (3,4-dihydro-2- (7-quinolin-1-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1) 7-indole

LC/MS (m/z) 406 (MH⁺), RT = 3,67, čistota: 82%LC / MS (m / z) 406 (MH < ^{+ >} ), RT = 3.67, purity: 82%

10o) 4-Fluór-3-{ 1 -[4-(3,4-dihydro-2/7-chinolín-1 -yl)-4-oxobután-1 -yl] pi perid ίη-4-yl ] 1/7-indol10o) 4-Fluoro-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) -4-oxobutan-1-yl] piperidin-4-yl] 1 / 7-indole

LC/MS (m/z) 420 (MH⁺), RT = 3,78, čistota: 84%LC / MS (m / z) 420 (MH < ^{+ >} ), RT = 3.78, purity: 84%

II

10p) 4-Chlór-3-{ 1 -[3-(3,4-dihydro-2/7-chinolín-1 -yl)-3-oxopropán-1 -yl] pi perid ίη-4-yl} 1 /7-indol10p) 4-Chloro-3- {1- [3- (3,4-dihydro-2 H- quinolin-1-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1) 7-indole

LC/MS (m/z) 422 (MH⁺), RT = 3,85, čistota: 97%LC / MS (m / z) 422 (MH < ^{+ >} ), RT = 3.85, purity: 97%

10q) 4-Chlór-3-{ 1 -[4-(3,4-dihydro-2/7-chinolín-1 -yl)-4-oxobután-1 -y I] pi perid í η-4-yl} 1/7-indol10q) 4-Chloro-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) -4-oxobutan-1-yl] piperidin-4-yl} 1/7-indole

LC/MS (m/z) 436 (MH⁺), RT = 3,97, čistota: 92%LC / MS (m / z) 436 (MH < ^{+ >} ), RT = 3.97, purity: 92%

-3910r) 5-Fluór-3-{ 1-(3-(3,4-dihydro-2/7-chinolín-1-yl)-3-oxopropán-1-yl]piperidín-4-yl] 1 /7-indol-3910r) 5-Fluoro-3- {1- (3- (3,4-dihydro-2 H- quinolin-1-yl) -3-oxopropan-1-yl] piperidin-4-yl] 1/7 indole

LC/MS (m/z) 406 (Mhľ), RT = 3,63, čistota: 97%LC / MS (m / z) 406 (MH +), RT = 3.63, purity: 97%

10s) 5-Fluór-3-{ 1 -[4-(3,4-dihydro-2/-/-chinolín-1 -yI)-4-oxobután-1 -yl]piperidín-4-yl}10s) 5-Fluoro-3- {1- [4- (3,4-dihydro-2H-quinolin-1-yl) -4-oxobutan-1-yl] piperidin-4-yl}

1/7-indol1/7-indole

LC/MS (m/z) 420 (MH⁺), RT = 3,73, čistota: 96%LC / MS (m / z) 420 (MH < ^{+ >} ), RT = 3.73, purity: 96%

10t) 5-Fluór-3-{1-(5-(3,4-dihydro-2/7-chinolín-1-yl)-5-oxopentán-1-yl]piperidín-4-yl] 1/7-indol10t) 5-Fluoro-3- {1- (5- (3,4-dihydro-2H-quinolin-1-yl) -5-oxopentan-1-yl] piperidin-4-yl] 1 / 7- indole

LC/MS (m/z) 434 (MH⁺), RT = 3,76, čistota: 97%LC / MS (m / z) 434 (MH < ^{+ >} ), RT = 3.76, purity: 97%

10u) 5-Fluór-3-{1-[6-(3,4-dihydro-2/7-chinolín-1-yl)-6-oxohexán-1-yl]piperidín-4-yl} 1/7-indol10u) 5-Fluoro-3- {1- [6- (3,4-dihydro-2 H- quinolin-1-yl) -6-oxo-hexan-1-yl] piperidin-4-yl} 1 / 7- indole

LC/MS (m/z) 448 (MH⁺), RT = 3,88, čistota: 97%LC / MS (m / z) 448 (MH < ^{+ >} ), RT = 3.88, purity: 97%

10v) 6-Chlór-3-{ 1 -[3-(3,4-dihydro-2/7-chinolín-1 -yl)-3-oxopropán-1 -yl]piperidίη-4-yl} 1/7-indol10v) 6-Chloro-3- {1- [3- (3,4-dihydro-2 H- quinolin-1-yl) -3-oxopropan-1-yl] piperidin-4-yl} 1 / 7- indole

LC/MS (m/z) 422 (MH⁺), RT = 3,88, čistota: 90%LC / MS (m / z) 422 (MH < ^{+ >} ), RT = 3.88, purity: 90%

10w) 6-Chlór-3-{ 1 -(6-(3,4-d ihyd ro-2/7-chinol ín-1 -yl)-6-oxohexán-1 -yl] piperid ίη-4-yl} 1/7-indol10w) 6-Chloro-3- {1- (6- (3,4-dihydro-2 H -quinolin-1-yl) -6-oxo-hexan-1-yl] piperidin-4-yl} 1/7-indole

LC/MS (m/z) 464 (MH⁺), RT = 4,09, čistota: 96%LC / MS (m / z) 464 (MH ⁺ ), R T = 4.09, purity: 96%

10x) 7-Chlór-3-{ 1 -(4-(3,4-dihydro-2/7-chinolín-1 -yl)-4-oxobután-1 -yl]piperidín-4-yl} 1/7-indol10x) 7-Chloro-3- {1- (4- (3,4-dihydro-2 H -quinolin-1-yl) -4-oxobutan-1-yl] piperidin-4-yl} 1 / 7- indole

LC/MS (m/z) 436 (MH⁺), RT = 3,91, čistota: 98%LC / MS (m / z) 436 (MH < ^{+ >} ), RT = 3.91, purity: 98%

10y) 7-Chlór-3-{ 1 -[5-(3,4-dihydro-2/7-chinolín-1 -yl)-5-oxopentán-1 -yl] piperid í η-4-yl}10y) 7-Chloro-3- {1- [5- (3,4-dihydro-2H-quinolin-1-yl) -5-oxopentan-1-yl] piperidin-4-yl}

1/7-indol1/7-indole

LC/MS (m/z) 450 (MH⁺), RT = 3,93, čistota: 96%LC / MS (m / z) 450 (MH < ^{+ >} ), RT = 3.93, purity: 96%

-40 10z) 7-Chlór-3-{1 -[6-(3,4-d ihyd ro-2/7-ch i nol í n-1 -yl)-6-oxohexán-1 -yl] piperid í η-4-yl} 1/7-indol-40 10z) 7-Chloro-3- {1- [6- (3,4-dihydro-2 H -quinolin-1-yl) -6-oxo-hexan-1-yl] -piperidine η-4-yl} 1/7-indole

LC/MS (m/z) 464 (MH⁺), RT = 4,05, čistota: 97%LC / MS (m / z) 464 (MH < ^{+ >} ), RT = 4.05, purity: 97%

Príklad 11'Example 11 '

a) 5-Fluór-3-{ 1 -[4-(3,4-dihydro-1 /7-izochinol íη-2-yl )bután-1 -yl]piperid ίη-4-yl}-1Hindol, dioxaláta) 5-Fluoro-3- {1- [4- (3,4-dihydro-1H-isoquinolin-2-yl) butan-1-yl] piperidin-4-yl} -1Hindole, dioxalate

Zmes 5-fluór-3-(piperidín-4-yl)-1 /7-indolu (5,0 g), trietylamínu (6,35 ml) a tetrahydrofuránu (500 ml) sa ochladila na 7 °C a následne sa pridala zmes anhydridu kyseliny jantárovej (2,5 g) v tetrahydrofuráne (50 ml). Zmes sa miešala pri teplote 8 až 10 °C 2 hodiny a rozpúšťadlo sa odstránilo vo vákuu. Zvyšok sa rozpustil v etylacetáte a organická fáza sa premyla studeným 2N vodným roztokom HCl a soľanky. Organická fáza sa vysušila (MgSO₄), prefiltrovala a skoncentrovala v vákuu (6,4 g). Zvyšok (1,5 g) a 3,4-dihydro-1/7-izochinolín (0,63 g) sa rozpustili v zmesi acetonitrilu (25 ml) a dimetylformamidu (10 ml), výsledná zmes sa ochladila (5 °C) a následne sa pridal 1,3-dicyklohexylkarbodiimid (1,0 g). Zmes sa miešala pri teplote miestnosti 16 hodín, prefiltrovala a naliala do soľanky. Vodná fáza sa extrahovala etylacetátom a tetrahydrofuránom, spojená organická fáza sa premyla soľankou, vysušila (MgSO₄) a skoncentrovala vo vákuu. Zvyšok sa prečistil bleskovou chromatografiou na silikagéli (eluent: etylacetát), čím sa získala biela tuhá látka (1,0 g), ktorá sa následne pridala pri 5 až 10 °C do zmesi alánu v tetrahydrofuráne (100 ml). Alán sa pripravil z hydridu hlinitolítneho (0,55 g) a koncentrovanej kyseliny sírovej (0,72 g). Zmes sa uhasila pridaním vody (ľ ml), 15% vodného roztoku hydroxidu sodného (0,5 ml) a vody (2,5 ml), a výsledná zmes sa vysušila (MgSO₄), prefiltrovala a skoncentrovala vo vákuu. V nadpise uvedená zlúčenina sa vykryštalizovala z acetónu vo forme dioxalátovej soli (0,8 g).A mixture of 5-fluoro-3- (piperidin-4-yl) -1 H -indole (5.0 g), triethylamine (6.35 mL) and tetrahydrofuran (500 mL) was cooled to 7 ° C and then added a mixture of succinic anhydride (2.5 g) in tetrahydrofuran (50 mL). The mixture was stirred at 8-10 ° C for 2 hours and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and the organic phase was washed with cold 2N aqueous HCl and brine. The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo (6.4 g). The residue (1.5 g) and 3,4-dihydro-1 H -isoquinoline (0.63 g) were dissolved in a mixture of acetonitrile (25 mL) and dimethylformamide (10 mL), the resulting mixture was cooled (5 ° C). followed by 1,3-dicyclohexylcarbodiimide (1.0 g). The mixture was stirred at room temperature for 16 hours, filtered and poured into brine. The aqueous phase was extracted with ethyl acetate and tetrahydrofuran, the combined organic phase was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate) to give a white solid (1.0 g) which was then added at 5-10 ° C to a mixture of anane in tetrahydrofuran (100 mL). Alan was prepared from lithium aluminum hydride (0.55 g) and concentrated sulfuric acid (0.72 g). The mixture was quenched by addition of water (1 ml), 15% aqueous sodium hydroxide solution (0.5 ml) and water (2.5 ml), and the resulting mixture was dried (MgSO ₄ ), filtered and concentrated in vacuo. The title compound was crystallized from acetone as the dioxalate salt (0.8 g).

Teplota topenia 105 až 111 °C.Melting point 105-111 ° C.

¹H NMR (DMSO-de): 1,75 (s, 4H), 1,85 - 2,05 (m, 2H), 2,10 (d, 2H), 2,90 - 3,20 (m, 9H), 3,25 (t, 2H), 3,50 (d, 2H), 4,15 (s, 2H), 6,85 - 6,95 (m, 1H), 7,10 - 7,25 (m, 5H), 7,30 - 7,45 (m, 2H), 11,05 (s, 1 H). MS m/z: 406 (MH⁺), 273, 188. ¹ H NMR (DMSO-d 6): 1.75 (s, 4H), 1.85-2.05 (m, 2H), 2.10 (d, 2H), 2.90-3.20 (m, 9H), 3.25 (t, 2H), 3.50 (d, 2H), 4.15 (s, 2H), 6.85-6.95 (m, 1H), 7.10-7.25 (m, 5H), 7.30-7.45 (m, 2H), 11.05 (s, 1H). MS m / z: 406 (MH < ^{+ >} ), 273, 188.

-41 Nasledujúca zlúčenina sa pripravila podobným spôsobom:The following compound was prepared in a similar manner:

b) 5-Fluór-3-{ 1 -[4-(6,7-dimetoxy-3,4-dihydro-1 /7-izochinolín-2-yl)bután-1 -yl]piperidín-4-yl}-1 /7-indol, dioxalát z 5-fluór-3-(piperidín-4-yl)-1/7-indolu a 6,7-dimetoxy-3,4-dihydro-1/7-izochinolínu, teplota topenia 98 až 105 °C.b) 5-Fluoro-3- {1- [4- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) butan-1-yl] piperidin-4-yl} - 1/7-indole, dioxalate from 5-fluoro-3- (piperidin-4-yl) -1 H -indole and 6,7-dimethoxy-3,4-dihydro-1 H -isoquinoline, m.p. 105 ° C.

¹H NMR (DMSO-de): 1,75 (s, 4H), 1,85 - 2,00 (m, 2H), 2,10 (d, 2H), 2,90 - 3,15 (m, 9H), 3,30 (s, 2H), 3,50 (d, 2H), 3,75 (d, 6H), 4,10 (s, 2H), 6,75 (s, 1H), 6,80 (s, 1H), 6,90 - 6,95 (m, 1H), 7,20 (s, 1H), 7,30 - 7,45 (m, 2H), 11,05 (s, 1H). MS m/z: 466 (MH⁺), 273, 248. ¹ H NMR (DMSO-d 6): 1.75 (s, 4H), 1.85-2.00 (m, 2H), 2.10 (d, 2H), 2.90-3.15 (m, 9H), 3.30 (s, 2H), 3.50 (d, 2H), 3.75 (d, 6H), 4.10 (s, 2H), 6.75 (s, 1H), 6, 80 (s, 1H), 6.90-6.95 (m, 1H), 7.20 (s, 1H), 7.30-7.45 (m, 2H), 11.05 (s, 1H) . MS m / z: 466 (MH < ^{+ >} ), 273, 248.

Farmakologické testyPharmacological tests

Zlúčeniny podľa vynálezu sa testovali dobre známymi a spoľahlivými testami. Testy boli nasledovné:The compounds of the invention were tested by well known and reliable assays. The tests were as follows:

Inhibicia viazania [³H]YM-09151-2 na ľudské dopamínové D₄ receptoryInhibition of [ ³ H] YM-09151-2 binding to human dopamine D ₄ receptors

Týmto spôsobom sa pomocou liečiv určila in vitro inhibicia viazania [³H]YM09151-2 (0,06 nM) na membrány ľudských klonovaných dopamínových D₄.₂receptorov exprimovaných v CHO-bunkách. Spôsob modifikovaný z NEN Life Science Products, Inc., technických dátový certifikát PC2533-10/96.In this way, in vitro inhibition of [ ³ H] YM09151-2 (0.06 nM) binding to human cloned dopamine D ₄ membranes was determined by drugs. ₂ receptors expressed in CHO cells. Method modified from NEN Life Science Products, Inc., PC2533-10 / 96 technical data certificate.

V tabuľke 1 nižšie sú uvedené výsledky testu.Table 1 below shows the test results.

Tabuľka 1Table 1

Väzbové údaje (IC50 hodnoty v nM alebo % inhibície viazania pri 50 nM) (nt. znamená netestované)Binding data (IC 50 values in nM or% inhibition of binding at 50 nM) (nt. Means untested)

Zlúčenina č. Compound No. D₄-väzbaD ₄ -binding Zlúčenina č. Compound No. D₄-väzbaD ₄ -binding Zlúčenina č. Compound No. D₄-väzbaD ₄ -binding 1a 1 92% 92% 3a 3a 0,71 0.71 10e 10e 25% 25% 1b 1b 97% 97% 3b 3b 5,0 5.0 10f 10f 17% 17% 1c 1c 95% 95% 3c 3c 15 15 10g 10 grams 65% 65% 2a 2 0,58 0.58 4 4 4,8 4.8 10h 10h 50% 50%

2b 2b 12 12 9I 9I 0,51 0.51 10i 10i 94% 94% 2c 2c 0,69 0.69 9m 9 m 17 17 10j 10j 70% 70% 2d 2d 8,0 8.0 9n 9N 53 53 10k 10k 95% 95% 2e 2e 12 12 10a 10a 93% 93% 101 101 82% 82% 2f 2f 78% 78% 10b 10b 81% 81% 10m 10 meters 69% 69% 2g 2 g 7,5 7.5 10c 10c 21% 21% 2h 2h 10 10 10d 10d 86% 86%

Zistilo sa, že zlúčeniny podľa vynálezu sú silnými inhibítormi viazania tritiovaných YM-09151-2 na dopamínové D₄ receptory.The compounds of the invention were found to be potent inhibitors of tritiated YM-09151-2 binding to dopamine D ₄ receptors.

Zlúčeniny podľa vynálezu sa tiež testovali vo funkčnom teste opísanom Gazi a ďalší v British Journal of Pharmacology 1999, 128, 613 až 620. V tomto teste sa ukázalo, že zlúčeniny sú čiastočnými agonistami alebo antagonistami dopamínových D₄ receptorov.The compounds of the invention were also tested in the functional assay described by Gazi et al. In British Journal of Pharmacology 1999, 128, 613-620. In this assay, the compounds were shown to be partial dopamine D ₄ receptor agonists or antagonists.

Zlúčeniny podľa vynálezu sa tiež testovali nasledujúcimi testami:The compounds of the invention were also tested by the following tests:

Inhibícia viazania [³H]spiperónu na D₂ receptoryInhibition of [ ³ H] spiperone binding to D ₂ receptors

Zlúčeniny podľa vynálezu sa testovali s ohľadom na afinitu k dopamínovému D₂ receptoru určením ich schopnosti inhibovať viazanie [³H]spiperónu na D₂receptory spôsobom podľa Hyttel a ďalší J. Neurochem. 1985, 44, 1615.The compounds of the invention were tested for affinity for the dopamine D ₂ receptor by determining their ability to inhibit the binding of [ ³ H] spiperone to D ₂ receptors by the method of Hyttel et al. J. Neurochem. 1985, 44, 1615.

Inhibícia viazania [³H]spiperónu na ľudské D₃ receptoryInhibition of [ ³ H] spiperone binding to human D ₃ receptors

Týmto spôsobom sa pomocou liečiv in vitro určila inhibícia viazania [³H]spiperónu (0,3 nM) na membrány ľudských klonovaných D₃ receptorov exprimovaných v CHO-bunkách. Spôsob modifikovaný MacKenzie a ďalší, Eur. J. Pharm.-Mol. Pharm. Sec.,1994, 266, 79 až 85.In this way, inhibition of [ ³ H] spiperone (0.3 nM) binding to membranes of human cloned D ₃ receptors expressed in CHO cells was determined by in vitro drugs. The method modified by MacKenzie et al., Eur. J. Pharm. Mol. Pharm. Sec., 1994, 266, 79-85.

Inhibícia reabsorpcie [³H]serotonínu do synaptozómov celého mozgu potkanaInhibition of [ ³ H] serotonin reabsorption into rat whole brain synaptosomes

Zlúčeniny sa testovali s ohľadom na ich inhibičný účinok na 5-HT reabsorpciu pomocou merania ich schopnosti inhibovať reabsorpciu [³H]serotonínu do synaptozómov celého mozgu potkana in vitro. Test sa uskutočnil spôsobom opísaným Hyttel Psychopharmacology 1978, 60, 13.Compounds were tested for their inhibitory effect on 5-HT reabsorption by measuring their ability to inhibit [ ³ H] serotonin reabsorption into rat whole brain synaptosomes in vitro. The assay was performed as described by Hyttel Psychopharmacology 1978, 60, 13.

-43Inhibícia viazania [³H]ketánserínu na 5-ΗΪ2Α receptory-43Inhibition of [ ³ H] ketanserine binding to 5-Α2Α receptors

Zlúčeniny sa testovali s ohľadom na ich afinitu k 5-HT_2A receptorom určením ich schopnosti inhibovať viazanie [³H]ketánserínu (0,50 nM) na membrány z mozgu potkana (cortex) in vitro. Spôsob opísaný pomocou Sanchez a ďalší, Drug. Dev. Res., 1991,22, 239 až 250.Compounds were tested for their affinity for 5-HT _2A receptors by determining their ability to inhibit [ ³ H] ketanserine (0.50 nM) binding to rat brain membranes (cortex) in vitro. The method described by Sanchez et al., Drug. Dev. Res., 1991, 22, 239-250.

5-HT2C receptorová účinnosť určená fluorometriou5-HT2C receptor activity determined by fluorometry

Zlúčeniny sa testovali s ohľadom na ich účinnosť na 5-HT₂c receptorexprimujúce CHO bunky analýzou fluorometrického obrazu čítača platní (FLIPR). Tento test sa uskutočnil podľa návodu Molecular Devices Inc. pre ich kit na FLIPR kalciový test, modifikovaný Porter a ďalší, British Journal of Pharmacology 1999, 128:13.The compounds were tested with respect to their efficacy on 5-HT _2c receptorexprimujúce CHO cells were analyzed by fluorometry image plate reader (FLIPR). This test was performed according to Molecular Devices Inc. instructions. for their FLIPR calcium assay kit, modified by Porter et al., British Journal of Pharmacology 1999, 128: 13.

Zistilo sa, že zlúčeniny nemajú žiadnu podstatnú alebo len slabú afinitu k dopamínovému D₂ receptoru.The compounds were found to have no significant or only weak affinity for the dopamine D ₂ receptor.

Zistilo sa, že veľa zlúčenín inhibuje viazanie [³H]spiperónu na dopamínový D₃receptor, že niektoré zlúčeniny inhibujú reabsorpciu serotonínu, a že niektoré zlúčeniny sú 5-HT_2A receptorové ligandy a/alebo 5-HT₂c receptorové ligandy.It has been found that many of the compounds to inhibit the binding of ^[3 H] spiperone binding to the dopamine D ₃ receptor, some compounds inhibit serotonin reuptake and some of the compounds to 5-HT _2A receptor ligands and / or 5-HT _2c receptor ligands.

Ako bolo vyššie uvedené, zlúčeniny podľa vynálezu sú dobre rozpustné vo vode v porovnaní s príbuznými zlúčeninami z WO 98/28293. Preto sa očakáva, že zlúčeniny majú vyššiu biodostupnosť.As mentioned above, the compounds of the invention are well soluble in water as compared to the related compounds of WO 98/28293. Therefore, compounds are expected to have higher bioavailability.

Zlúčeniny podľa vynálezu sa teda považujú za užitočné na liečenie pozitívnych a negatívnych symptómov schizofrénie, iných psychóz, ako je všeobecná úzkostná porucha, panická porucha, a obsedantno-kompulzívna porucha, depresie, vedľajších účinkov vyvolaných bežnými antipsychotickými látkami, migrény, ADHD a na zlepšenie spánku. Zlúčeniny podľa vynálezu sa považujú za užitočné najmä na liečenie pozitívnych a negatívnych symptómov schizofrénie bez extrapyramidálnych vedľajších účinkov.Thus, the compounds of the invention are considered useful for the treatment of positive and negative symptoms of schizophrenia, other psychoses such as general anxiety disorder, panic disorder, and obsessive-compulsive disorder, depression, side effects caused by common antipsychotic agents, migraine, ADHD and sleep improvement. . The compounds of the invention are believed to be particularly useful for treating the positive and negative symptoms of schizophrenia without extrapyramidal side effects.

Príklady farmaceutických prostriedkovExamples of pharmaceutical compositions

Farmaceutické prostriedky podľa vynálezu sa môžu pripraviť bežnými spôsobmi v danej oblasti techniky.The pharmaceutical compositions of the invention may be prepared by conventional methods in the art.

-44Napríklad: Tablety sa môžu pripraviť zmiešaním aktívnej zložky s bežnými adjuvans a/alebo riedidlami a následne stlačením zmesi v bežnom tabletovacom stroji. Príklady adjuvans alebo riedidiel zahrnujú: kukuričný škrob, zemiakový škrob, mastenec, stearan horečnatý, želatínu, laktózu, gumy a podobne. Akékoľvek iné adjuvans alebo prídavné látky bežne používané na taký účel ako sú farbivá, ochucovacie látky, konzervačné látky atď. sa môžu použiť pod podmienkou, že sú kompatibilné s účinnými zložkami.For example: Tablets may be prepared by mixing the active ingredient with conventional adjuvants and / or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums and the like. Any other adjuvants or additives commonly used for such purposes as coloring agents, flavoring agents, preservatives, etc. may be used provided that they are compatible with the active ingredients.

Roztoky pre injekcie sa môžu pripraviť rozpustením aktívnej zložky a možných prídavných činidiel v časti roztoku pre injekciu, výhodne sterilnej vode, upravením roztoku na žiadaný objem, sterilizovaním roztoku a jeho plnením do vhodných ampúl a liekoviek. Môžu sa použiť¹ akékoľvek vhodné prídavné látky bežne používané v danej oblasti techniky, ako sú napríklad ionizačné činidlá, konzervačné látky, antioxidanty, atď.Solutions for injections may be prepared by dissolving the active ingredient and possible adjuvants in a portion of the solution for injection, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution and filling it in suitable ampoules and vials. ¹ may be used Any suitable additive conventionally used in the art, such as ionizing agents, preservatives, antioxidants, etc.

Typickými príkladmi receptúr pre farmaceutické prostriedky podľa vynálezu sú nasledovné:Typical examples of formulations for pharmaceutical compositions of the invention are as follows:

1) Tablety obsahujúce 5,0 mg zlúčeniny podľa vynálezu počítanej ako voľná báza 1) Tablets containing 5.0 mg of the compound of the invention calculated as the free base zlúčenina compound 5,0 mg 5.0 mg laktóza lactose 60 mg 60 mg kukuričný škrob maize starch 30 mg 30 mg hydroxypropylcelulóza hydroxypropyl 2,4 mg 2.4 mg mikrokryštalická celulóza microcrystalline cellulose 19,2 mg 19.2 mg kroskarmelóza sodná typu A croscarmellose sodium type 2,4 mg 2.4 mg stearan horečnatý magnesium stearate 0,84 mg 0.84 mg

2) Tablety obsahujúce 0,5 mg zlúčeniny podľa vynálezu počítanej ako voľná báza 2) Tablets containing 0.5 mg of a compound of the invention calculated as the free base zlúčenina compound 0,5 mg 0.5 mg laktóza lactose 46,9 mg 46.9 mg kukuričný škrob maize starch 23,5 mg 23.5 mg povidón povidone 1,8 mg 1.8 mg mikrokryštalická celulóza microcrystalline cellulose 14,4 mg 14.4 mg

kroskarmelóza sodná typu A stearan horečnatý croscarmellose sodium type magnesium stearate 1,8 mg 0,63 mg 1.8 mg 0.63 mg 3) Sirup obsahujúci na mililiter: (3) Syrup containing per milliliter: zlúčenina compound 25 mg 25 mg sorbitol sorbitol 500 mg 500 mg hydroxypropylcelulóza hydroxypropyl 15 mg 15 mg glycerol glycerol 50 mg 50 mg metyl-parabén methyl paraben 1 mg 1 mg propyl-parabén propylparaben 0,1 mg 0.1 mg etanol ethanol 0,005 ml 0,005 ml príchuť flavor 0,05 mg 0.05 mg sacharín sodný saccharin sodium 0,5 mg 0.5 mg voda Water do 1 ml to 1 ml

4) Injekčný roztok obsahujúci na mililiter: (4) Solution for injection containing per milliliter: zlúčenina compound 0,5 mg 0.5 mg sorbitol sorbitol 5,1 mg 5.1 mg kyselina octová acetic acid 0,05 mg 0.05 mg sacharín sodný saccharin sodium 0,5 mg 0.5 mg voda Water do 1 ml to 1 ml

II

Claims

1. Indolové deriváty všeobecného vzorca I kdeWhat is claimed is: 1. An indole derivative of the general formula I wherein

a) jeden z Y¹ a Y² je N, ktorý je naviazaný na Y⁴ a druhý z Y¹ a Y² je CO, CS, SO alebo SO2 a Y⁴ je CH2;a) one of Y ¹ and Y ² is N which is bonded to Y ⁴ and the other of Y ¹ and Y ² is CO, CS, SO or SO 2 and Y ⁴ is CH 2;

c) jeden z Y¹ a Y² je N, ktorý je naviazaný na Y⁴ a druhý z Y¹ a Y² je CH2 a Y⁴ je CH2;c) one of Y ¹ and Y ² is N, which is bound to Y ⁴ and the other of Y ¹ and Y ² is CH ² and Y ⁴ is CH 2;

Y³ je Z-CH2, CH2-Z alebo CH2CH2 a Z je O alebo S; pod podmienkou, že keď Y¹ je N, Y³ nemôže byť Z-CH2;Y ³ is Z-CH 2, CH 2 -Z or CH 2 CH 2 and Z is O or S; with the proviso that when Y ¹ is N, Y ³ cannot be Z-CH 2;

n je 0 až 5, m je 0 až 5 a m+n je 1 až 10; pod podmienkou, že ked W je O alebo S, potom n > 2 a m > 1; keď W je CO, CS, SO alebo SO₂, potom n > 1 a m > 1;n is 0 to 5, m is 0 to 5, and m + n is 1 to 10; with the proviso that when W is O or S, then n > 2 and m >1; when W is CO, CS, SO or SO ₂ , then n> 1 and m>1;

R¹ až R⁹ sú nezávisle vybrané zo skupiny zahrnujúcej: vodík, halogén, kyano, nitro, amino, hydroxy, Ci-6alkylamino, di-C-|.6alkylamino, Ci.₆alkyl, C₂.₆alkenyl, C₂-6alkinyl, Ci.6alkoxy, Ci.6alkyltio, C^alkyl substituovaný hydroxyskupinou alebo tiolom, C3-8cykloalkyl, C₃.₈cykloalkyl-Ci.₆alkyl, acyl, tioacyl, aryl, trifluórmetyl, trifluórmetylsulfonyl a Ci-6alkylsulfonyl;R ¹ to R ⁹ are independently selected from the group consisting of: hydrogen, halogen, cyano, nitro, amino, hydroxy, C 1-6 alkylamino, di-C 1-6 alkylamino, C 1-6 alkylamino; ₆ alkyl, _second ₆ alkenyl, C ₂ -6alkinyl, Ci.6alkoxy, Ci.6alkyltio, C ^ alkyl substituted with hydroxy or thiol, C 3-8 cycloalkyl, C _3. ₈ cycloalkyl-C 1. ₆ alkyl, acyl, thioacyl, aryl, trifluoromethyl, trifluoromethylsulfonyl and C 6 alkylsulfonyl;

-47 R¹⁰ je vodík, C-i.ealkyl, C₂_₆alkenyl, C₂.₆alkinyl, C-i_₆alkyl substituovaný hydroxyskupinou alebo tiolom, C₃.₈cykloalkyl, C₃.₈cykloalkyl-C-|.₆alkyl, aryl, aryl-Cj-ealkyl, acyl, tioacyl, Ci.₆alkylsulfonyl, trifluórmetylsulfonyl alebo arylsulfonyl;-47 R ¹⁰ is hydrogen, Ci.ealkyl, C ₂ _ ₆ alkenyl, _second ₆ alkynyl, C-i_ ₆ -alkyl substituted with hydroxy or thiol, C _3. ₈ cycloalkyl, C _3. ₈ cycloalkyl-C _1-8 . ₆ alkyl, aryl, aryl-C alkyl, acyl, thioacyl, C. ₆ alkylsulfonyl, trifluoromethylsulfonyl or arylsulfonyl;

2. Indolové deriváty podľa nároku 1, kde je indol naviazaný na X cez polohu 3 indolu.The indole derivative according to claim 1, wherein the indole is linked to X through the 3-position of the indole.

3. Indolové deriváty podľa nárokov 1 až 2, kde jeden z Y¹ a Y² je N, ktorý je naviazaný na Y⁴ a druhý z Y¹ a Y² je CO a Y⁴ je CH₂.Indole derivatives according to claims 1 to 2, wherein one of Y ¹ and Y ² is N, which is bonded to Y ⁴ and the other of Y ¹ and Y ² is CO and Y ⁴ is CH ₂ .

4. Indolové deriváty podľa nárokov 1 až 2, kde jeden z Y¹ a Y² je N, ktorý je naviazaný na Y⁴ a druhý z Y¹ a Y² je CH₂ a Y⁴ je CO.The indole derivatives of claims 1 to 2, wherein one of Y ¹ and Y ² is N, which is bonded to Y ⁴ and the other of Y ¹ and Y ² is CH ₂ and Y ⁴ is CO.

5. Indolové deriváty podľa nárokov 1 až 2, kde Y¹ je dusík naviazaný na Y⁴a jeden z Y⁴ a Y² je CO a druhý je CH₂.The indole derivatives of claims 1 to 2, wherein Y ¹ is nitrogen bonded to Y ⁴ and one of Y ⁴ and Y ² is CO and the other is CH ₂ .

6. Indolové deriváty podľa nárokov 3 a 5, kde Y¹ je dusík naviazaný na Y⁴, Y²je CO a Y⁴ je CH₂.Indole derivatives according to claims 3 and 5, wherein Y ¹ is nitrogen bonded to Y ⁴ , Y ² is CO and Y ⁴ is CH ₂ .

7. Indolové deriváty podľa nárokov 4 a 5, kde Y¹ je dusík naviazaný na Y⁴, Y²je CH₂ a Y⁴ je CO.Indole derivatives according to claims 4 and 5, wherein Y ¹ is nitrogen bonded to Y ⁴ , Y ² is CH ₂ and Y ⁴ is CO.

8. Indolové deriváty podľa nárokov 1 až 2, kde Y² je dusík naviazaný na Y⁴a jeden z Y¹ a Y⁴ je CO a druhý je CH_2i Indole derivatives according to claims 1 to 2, wherein Y ² is nitrogen bonded to Y ⁴ and one of Y ¹ and Y ⁴ is CO and the other is CH ₂

9. Indolové deriváty podľa nárokov 4 a 8, kde Y² je dusík naviazaný na Y⁴, Y¹je CH₂ a Y⁴ je CO.Indole derivatives according to claims 4 and 8, wherein Y ² is nitrogen bonded to Y ⁴ , Y ¹ is CH ₂ and Y ⁴ is CO.

10. Indolové deriváty podľa nárokov 3 a 8, kde Y² je dusík naviazaný na Y⁴, Y¹ je CO a Y⁴jeCH₂.The indole derivatives of claims 3 and 8, wherein Y ² is nitrogen bonded to Y ⁴ , Y ¹ is CO and Y ^{4 is} CH ₂ .

-4811. Indolové deriváty podľa nárokov 1 až 2, kde Y¹ a Y² je N, ktorý je naviazaný na Y⁴ a druhý z Y¹ a Y² je CH2 a Y⁴ je CH2.-4811. The indole derivatives of claims 1 to 2, wherein Y ¹ and Y ² is N, which is bonded to Y ⁴ and the other of Y ¹ and Y ² is CH ² and Y ⁴ is CH 2.

12. Indolové deriváty podľa nárokov 1 až 11, kde Y³ je CH₂CH₂ alebo CH₂Z.The indole derivative according to claims 1 to 11, wherein Y ³ is CH ₂ CH ₂ or CH ₂ Z.

13. Indolové deriváty podľa nárokov 1 až 12, kde X je C, X je N alebo X je CH.Indole derivatives according to claims 1 to 12, wherein X is C, X is N or X is CH.

14. Indolové deriváty podľa nárokov 1 až 12, kde X je N.Indole derivatives according to claims 1 to 12, wherein X is N.

15. Indolové deriváty podľa nárokov 1 až 12, kde X je CH.Indole derivatives according to claims 1 to 12, wherein X is CH.

16. Indolové deriváty podľa nárokov 1 až 15, kde R¹ až R⁹ sú vybrané zo skupiny zahrnujúcej: vodík, halogén, kyano, nitro, amino, C-|.6alkylamino, di-Cvgalkylamino, Ci.₆alkyl, Cg.gcyklo-alkyl a trifluórmetyl a R¹⁰ je vodík, C^alkyl alebo acyl, alebo ich farmaceutický prijateľné adičné soli s kyselinou.Indole derivatives according to claims 1 to 15, wherein R ¹ to R ⁹ are selected from the group consisting of: hydrogen, halogen, cyano, nitro, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, C 1-6 alkyl. ₆ alkyl, Cg.gcyklo-alkyl and trifluoromethyl, and R ¹⁰ is hydrogen, alkyl or acyl, or a pharmaceutically acceptable acid addition salts thereof.

17. Indolové deriváty podľa nárokov 1 až 16, kde W je väzba a n + m je 1 ažThe indole derivative according to claims 1 to 16, wherein W is a bond and n + m is 1 to 16

6.6th

18. Indolové deriváty podľa nárok 17, kde n + m je 3 až 6.The indole derivative according to claim 17, wherein n + m is 3 to 6.

19. Indolové deriváty podľa nároku 1, ktoré sú vybrané zo skupiny zahrnujúcej:The indole derivative according to claim 1, selected from the group consisting of:

5-fluór-3-{1-[2-(2-oxo-3,4-dihydro-2/-/-chinolín-1-yl)etyl]piperidín-4-yl}-1/-/-indol,5-Fluoro-3- {1- [2- (2-oxo-3,4-dihydro-2 / - / - quinolin-1-yl) ethyl] piperidin-4-yl} -1 / - / - indole;

5-fl uór-3-{ 1 -[3-(1 -oxo-3,4-dihydro-1 H-chinolín-2-yl)propán-1 -yl] piperid í η-4-yl}-1Hindol,5-fluoro-3- {1- [3- (1-oxo-3,4-dihydro-1H-quinolin-2-yl) propan-1-yl] piperidin-4-yl} -1Hindole,

5-fl uór-3-{1 -[4-( 1 -oxo-3,4-dihydro-1 /-/-ch inol í η-2-yI )butá n-1 -y I] piperid í η-4-yl}-1Hindol,5-Fluoro-3- {1- [4- (1-oxo-3,4-dihydro-1H-quinolin-2-yl) butan-1-yl] piperidin-4-yl- 4-yl} -1Hindol,

5-fl uór-3-{1 -[3-(2-oxo-3,4-dihydro-2/7-chinolín-1 -yl)propán-1 -yljpiperid í n-4-yl}-1 Hindol,5-Fluoro-3- {1- [3- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) -propan-1-yl] -piperidin-4-yl} -1 Hindole,

-495-fluór-3-{1-[5-(2-oxo-3,4-dihydro-2/7-chinolín-1-yl)pentán-1-yl]piperidín-4-yl}-1/7indol,-495-fluoro-3- {1- [5- (2-oxo-3,4-dihydro-2/7-quinolin-1-yl) pentan-1-yl] piperidin-4-yl} -1 / 7IND .

5-chlór-3-{1 -[3-(2-oxo-3,4-dihydro-2/7-chinolín-1 -yl)propán-1 -yl] piperid í η-4-yl}-1 /7indol,5-Chloro-3- {1- [3- (2-oxo-3,4-dihydro-2- (7-quinolin-1-yl) -propan-1-yl] -piperidin-4-yl} -1) 7IND.

5-chlór-3-{1-[4-(2-oxo-3,4-dihydro-2/7-chinolín-1-yl)bután-1-yl]piperidín-4-yl}-1/7indol,5-chloro-3- {1- [4- (2-oxo-3,4-dihydro-2/7-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1 / 7IND,

5-ch lór-3-{ 1 -[5-(2-oxo-3,4-dihydro-2/7-chinolín-1 -yl )pentá n-1 -yl] piperid ίη-4-y I}-1 /7indol,5-Chloro-3- {1- [5- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) pentan-1-yl] piperidin-4-yl} - 1 / 7indol,

7-chlór-3-{1 -[4-(2-oxo-3,4-dihydro-2H-chinolín-1-yl)bután-1 -yl]piperidín-4-yl}-1 Hindol,7-Chloro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1 Hindole,

5-fluór-3-{1-[4-(3-oxo-3,4-dihydro-2/7-1,4-benzoxazín-4-yl)bután-1-yl]piperidín-4-yl}1/7-indol,5-Fluoro-3- {1- [4- (3-oxo-3,4-dihydro-2/7-1.4-benzoxazin-4-yl) butan-1-yl] piperidin-4-yl} 1 / 7-indole.

5-chlór-3-{1 -[4-(3-oxo-3,4-dihydro-2/7-1,4-benzoxazín-4-yl)bután-1 -yl] piperid ίη-4-yl} 1/7-indol,5-Chloro-3- {1- [4- (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl) butan-1-yl] piperidin-4-yl} 1/7-indole.

5-fluór-3-{1-[3-(2-oxo-3,4-dihydro-2/7-chinolín-1-yl)propán-1-yl]-3,6-dihydro-2/7pyridín-4-yl}-1/7-indol,5-Fluoro-3- {1- [3- (2-oxo-3,4-dihydro-2/7-quinolin-1-yl) -propan-1-yl] -3,6-dihydro-2 / 7pyridín- 4-yl} -1 / 7-indole.

5-fluór-3-{1-[4-(2-oxo-3,4-dihydro-2/7-chinolín-1-yl)bután-1-yl]-3,6-dihydro-2/7pyridín-4-yl}-1 /7-indol,5-Fluoro-3- {1- [4- (2-oxo-3,4-dihydro-2/7-quinolin-1-yl) butan-1-yl] -3,6-dihydro-2 / 7pyridín- 4-yl} -1H-indole,

5-fluór-3-{1-[5-(2-oxo-3,4-dihydro-2/7-chinolín-1-yl)pentán-1-yl]-3,6-dihydro-2/7pyrid ίη-4-yl}-1 /7-indol,5-Fluoro-3- {1- [5- (2-oxo-3,4-dihydro-2 H -quinolin-1-yl) pentan-1-yl] -3,6-dihydro-2 H -pyridine -4-yl} -1H-indole,

5-fluór-3-{1-[4-(2-oxo-3,4-dihydro-2/7-chinolín-1-yl)bután-1-yl]-piperidín-4-yl}-1/7indol,5-Fluoro-3- {1- [4- (2-oxo-3,4-dihydro-2/7-quinolin-1-yl) butan-1-yl] -piperidin-4-yl} -1 / 7IND .

5-fluór-1 -metyl-3-{ 1 -[3-(2-oxo-3,4-dihydro-2/7-chinolín-1 -yl)propán-1 -yl] piperid ín-4yl}-1/7-indol,5-Fluoro-1-methyl-3- {1- [3- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) propan-1-yl] piperidin-4-yl} -1 / 7-indole.

5-fluór-1 -metyl-3-{ 1 -[4-(2-oxo-3,4-dihydro-2/7-chinolín-1 -yl)bután-1 -yl] piperi d í n-4yl}-1/7-indol,5-Fluoro-1-methyl-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1/7 -indole,

1 -(bután-1 -y I )-5-fl uór-3-{1 -[4-(2-oxo-3,4-dihydro-2/7-chinolín-1 -yl )bután-1 -yl]-3,6dihydro-2/7-pyridín-4-yl}-1/7-indol,1- (Butan-1-yl) -5-fluoro-3- {1- [4- (2-oxo-3,4-dihydro-2H-quinolin-1-yl) butan-1-yl] ] -3,6-dihydro-2/7-pyridin-4-yl} -1 / 7-indole.

5-fluór-3-{1-[3-(3,4-dihydro-l/7-izochinolín-2-yl )-3-oxopropán-1-yl]piperidín-4-yl}1/7-indol,5-fluoro-3- {1- [3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1 H -indole,

-507-chlór-3-{ 1 -[3-(3,4-dihydro-1 /7-izochinolín-2-yl)-3-oxopropán-1 -yl]-piperidín-4-yl }1/7-indol,-507-chloro-3- {1- [3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxopropan-1-yl] -piperidin-4-yl} 1 / 7- indole,

5-chlór-3-{1-[4-(3,4-dihydro-2/7-chinolín-1-yl)-4;Oxobután-1-yl]-piperidín-4-yl}-1/7indol,5-chloro-3- {1- [4- (3,4-dihydro-2/7-quinolin-1-yl) -4, oxobutan-1-yl] -piperidin-4-yl} -1 / 7IND,

5-fluór-3-{1-[4-(3,4-dihydro-1/7-izochinolín-2-yl)-4-oxobután-1-yl]piperidín-4-yl}-1/7indol,5-Fluoro-3- {1- [4- (3,4-dihydro-1/7-isoquinolin-2-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1 / 7IND,

5-chlór-3-{ 1 -[4-(3,4-dihydro-1 /7-izochinolín-2-yl)-4-oxobután-1 -yl]piperid ίη-4-yl }-1 /7 indol,5-Chloro-3- {1- [4- (3,4-dihydro-1H-isoquinolin-2-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1/7 indole .

5-fluór-3-{1-[3-(3,4-dihydro-2/7-chinolín-1-yl)propán-1-yl]piperidín-4-yl}-1/7-indol, 5-fluór-3-{1-[4-(3,4-dihydro-2/7-chinolín-1-yl)bután-1-yl]piperidín-4-yl}-1 /7-indol, 5-fluór-3-{1-[5-(3,4-dihydro-2/7-chinolín-1-yl)pentán-1-yl]piperidín-4-yl}-1/7-indol, 5-chlór-3-{ 1 -[3-(3,4-dihydro-2/7-chinolín-1 -yl)propán-1 -yl] piperid í η-4-yl}-1 /7-indol, 5-chlór-3-{ 1 -[4-(3,4-d i hyd ro-2/7-ch inol í n-1 -yl )bután-1 -yl ] pi perid í η-4-yl} -1 /-7-indol, 5-chlór-3-{1 -[5-(3,4-d ihyd ro-2/7-chinol í n-1 -yl)pentán-1 -yl] piperid í η-4-yl }-1 /7-indol, 7-chlór-3-{1-[4-(3,4-dihydro-2/7-chinolín-1-yl)bután-1-yl]piperidín-4-yl}-1 /7-indol,5-Fluoro-3- {1- [3- (3,4-dihydro-2 H -quinolin-1-yl) -propan-1-yl] -piperidin-4-yl} -1 H -indole, 5- Fluoro-3- {1- [4- (3,4-dihydro-2 H- quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1 H -indole, 5-fluoro- 3- {1- [5- (3,4-Dihydro-2H-quinolin-1-yl) -pentan-1-yl] -piperidin-4-yl} -1H-indole, 5-chloro-3- {1- [3- (3,4-Dihydro-2 H -quinolin-1-yl) -propan-1-yl] -piperidin-4-yl} -1 H -indole, 5-chloro-3- {1- [4- (3,4-dihydro-2/7-quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1H-indole 5-chloro-3- {1- [5- (3,4-dihydro-2 H -quinolin-1-yl) pentan-1-yl] piperidin-4-yl} -1 (7-Indole, 7-chloro-3- {1- [4- (3,4-dihydro-2 H -quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1/7 indole,

5-fl uór-1 -metyl-3-{ 1 -[3-(3,4-d i hyd ro-2/7-ch inol í n-1 -yl)propán-1 -yl] pi perid ίη-4-yl}-1Hindol,5-Fluoro-1-methyl-3- {1- [3- (3,4-dihydro-2 H -quinolin-1-yl) propan-1-yl] piperidine-4 yl} -1Hindol.

5-fluór-1 -metyl-3-{ 1 -[4-(3,4-dihydro-2/7-chinolín-1 -yl)bután-1 -yl]piperidín-4-yl}-1 /7indol,5-fluoro-1-methyl-3- {1- [4- (3,4-dihydro-2 H- quinolin-1-yl) butan-1-yl] piperidin-4-yl} -1 H -indole,

5-fluór-3-{1-[4-(3,4-dihydro-2/7-1,4-benzoxazín-4-yl)bután-1-yl]piperidín-4-yl}-1/7indol,5-Fluoro-3- {1- [4- (3,4-dihydro-2/7-1.4-benzoxazin-4-yl) butan-1-yl] piperidin-4-yl} -1 / 7IND,

5-chlór-3-{1-[4-(3,4-dihydro-2/7-1,4-benzoxazín-4-yl)bután-1-yl]piperidín-4-yl}-1/7indol,5-chloro-3- {1- [4- (3,4-dihydro-2/7-1.4-benzoxazin-4-yl) butan-1-yl] piperidin-4-yl} -1 / 7IND,

5-fluór-3-{ 1 -[3-(3,4-dihydro-2/7-chinolín-1 -yl)propán-1 -yl]-3,6-dihydro-2/7-pyridín-4yl}-1/7-indol,5-Fluoro-3- {1- [3- (3,4-dihydro-2H-quinolin-1-yl) -propan-1-yl] -3,6-dihydro-2H-pyridin-4-yl} -1/7 -indole,

5-fluór-3-{ 1 -[4-(3,4-dihydro-2/7-chinolín-1 -yl)bután-1 -yl]-3,6-dihydro-2/7-pyridín-4yl}-1/7-indol,5-Fluoro-3- {1- [4- (3,4-dihydro-2 H -quinolin-1-yl) butan-1-yl] -3,6-dihydro-2 H -pyridin-4-yl} -1/7 -indole,

5-fluór-3-{1-[5-(3,4-dihydro-2/7-chinolín-1-yl)pentán-1-yl]-3,6-dihydro-2/7-pyridín-4yl}-1/7-indol,5-Fluoro-3- {1- [5- (3,4-dihydro-2/7-quinolin-1-yl) pentan-1-yl] -3,6-dihydro-2/7-pyridin-4-yl} -1/7 -indole,

-51 4-fluór-3-{ 1 -[3-(3,4-dihydro-1 /7-izochinoIín-2-yl)-3-oxopropán-1 -yl]piperidín-4-yl }1/7-indol,-51 4-Fluoro-3- {1- [3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxopropan-1-yl] piperidin-4-yl} 1 / 7- indole,

4-fluór-3-{1-[4-(3,4-dihydro-1/7-izochinolín-2-yl)-4-oxobután-1-yl]piperidín-4-yl}-1/7indol,4-Fluoro-3- {1- [4- (3,4-dihydro-1/7-isoquinolin-2-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1 / 7IND,

4-fluór-3-{ 1 -[6-(3,4-dihyd ro-1 /7-izochinolín-2-yl)-6-oxohexán-1 -yl]piperidín-4-yl }-1 7indol,4-fluoro-3- {1- [6- (3,4-dihydro-1H-isoquinolin-2-yl) -6-oxo-hexan-1-yl] piperidin-4-yl} -1-indole,

4-chlór-3-{ 1 -[4-(3,4-dihydro-1 /7-izochinolín-2-yl)-4-oxobután-1 -yl] piperid í η-4-y I} -1 7indol,4-Chloro-3- {1- [4- (3,4-dihydro-1H-isoquinolin-2-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1-indole .

4-chlór-3-{ 1-(5-(3,4-dihyd ro-1 7-izochinolín-2-yl )-5-oxopentán-1 -yl]piperidín-4-yl}1 /7-indol,4-chloro-3- {1- (5- (3,4-dihydro-17-isoquinolin-2-yl) -5-oxopentan-1-yl] piperidin-4-yl} -1 H -indole,

4- chlór-3-{ 1-(6-(3,4-dihydro-1/7-izochinolín-2-yl)-6-oxohexán-1-yl]piperidín-4-yl}-1/7indol,4-Chloro-3- {1- (6- (3,4-dihydro-1H-isoquinolin-2-yl) -6-oxohexan-1-yl] piperidin-4-yl} -1H-indole,

5- fluór-3-{ 1-(5-(3,4-dihyd ro-1 7-izochinolín-2-yl)-5-oxopentán-1-yl]piperidín-4-yl}-1 Hindol,5-fluoro-3- {1- (5- (3,4-dihydro-17-isoquinolin-2-yl) -5-oxopentan-1-yl] piperidin-4-yl} -1-hindole,

5- f luór-3-{1 -(6-(3,4-dihyd ro-1 /7-izochinolín-2-yl)-6-oxohexán-1 -yl] piperid ίη-4-yl} -1 7indol,5-Fluoro-3- {1- (6- (3,4-dihydro-1H-isoquinolin-2-yl) -6-oxo-hexan-1-yl] piperidin-4-yl} -1-indole .

6- chlór-3-{ 1-(3-(3,4-dihyd ro-1 /7-izochinolín-2-yl)-3-oxopropán-1 -yl]piperidín-4-yl }17-indol,6-Chloro-3- {1- (3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxopropan-1-yl] piperidin-4-yl} 17-indole,

6- chlór-3-{ 1-(6-(3,4-dihyd ro-1 /7-izochinolín-2-yl)-6-oxohexán-1-yl]piperidín-4-yl}-1 Hindol,6-Chloro-3- {1- (6- (3,4-dihydro-1H-isoquinolin-2-yl) -6-oxo-hexan-1-yl] -piperidin-4-yl} -1-Hindole,

7- chlór-3-{ 1-(4-(3,4-dihyd ro-1 /7-izochinolín-2-yl)-4-oxobután-1-yl]piperidín-4-yl}-1 Hindol,7-Chloro-3- {1- (4- (3,4-dihydro-1 H -isoquinolin-2-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1 Hindole,

7-chlór-3-{ 1-(5-(3,4-dihydro-1 /7-izochinolín-2-yl)-5-oxopentán-1 -yl]piperidín-4-yl}17-indol,7-chloro-3- {1- (5- (3,4-dihydro-1/7-isoquinolin-2-yl) -5-oxopentan-1-yl] piperidin-4-yl} indole-17,

7-chlór-3-{ 1-(6-(3,4-dihydro-17-izochinolín-2-yl)-6-oxohexán-1-yl]piperidín-4-yl}-17indol,7-chloro-3- {1- (6- (3,4-dihydro-17-isoquinolin-2-yl) -6-oxohexane-1-yl] piperidin-4-yl} -17indol,

4-fluór-3-{1-[3-(3,4-dihydro-27-chinolín-1-yl)-3-oxopropán-1-yl]piperidín-4-yl}-17indol,4-Fluoro-3- {1- [3- (3,4-dihydro-27-quinolin-1-yl) -3-oxopropan-1-yl] piperidin-4-yl} -17indol,

4-fluór-3-{ 1-(4-(3,4-dihydro-27-chinolín-1-yl)-4-oxobután-1-yl]piperidín-4-yl}-17indol,4-Fluoro-3- {1- (4- (3,4-dihydro-27-quinolin-1-yl) -4-oxobutan-1-yl] piperidin-4-yl} -17indol,

-524-chlór-3-{ 1 -[3-(3,4-dihydro-2/7-chinolín-1 -yl)-3-oxopropán-1 -yl]piperidín-4-yl }-1 Hindol,-524-chloro-3- {1 - [3- (3,4-dihydro-2/7-quinolin-1-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1 H -indole,

4- chlór-3-{ 1 -[4-(3,4-dihydro-2/-/-chinolín-1 -yl)-4-oxobután-1 -yl jpiperid ín-4-yl}-1 /-/indol,4-chloro-3- {1 - [4- (3,4-dihydro-2 / - / - quinolin-1-yl) -4-oxobutan-1-yl jpiperid-4-yl} -1 / - / indole,

II

5- fluór-3-{1-[3-(3,4-dihydro-2/7-chinolín-1-yl)-3-oxopropán-1-yljpiperidín-4-yl}-1/-/indol,5-Fluoro-3- {1- [3- (3,4-dihydro-2/7-quinolin-1-yl) -3-oxopropan-1-yljpiperidín-4-yl} -1 / - / indole,

5-fluór-3-{ 1 -[4-(3,4-dihydro-2/-/-chinolín-1 -yl)-4-oxobután-1 -yl]piperidín-4-yl}-1 Hindol,5-Fluoro-3- {1 - [4- (3,4-dihydro-2 / - / - quinolin-1-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1 H -indole,

5-fluór-3-{ 1 -[5-(3,4-d i hyd ro-2/7-chinol ín-1 -yl)-5-oxopentán-1 -yl] piperid í η-4-yl}-1Hindol,5-Fluoro-3- {1 - [5- (3,4-di hyd ro-2/7-quinolin-1-yl) -5-oxopentan-1-yl] -piperidine-η 4-yl} - 1H-indole,

5- fluór-3-{ 1 -[6-(3,4-dihydro-2/7-chinolín-1 -yl)-6-oxohexán-1 -yl]piperidín-4-yl}-1 Hindol,5-Fluoro-3- {1 - [6- (3,4-dihydro-2/7-quinolin-1-yl) -6-oxohexane-1-yl] piperidin-4-yl} -1 H -indole,

6- chlór-3-{ 1 -[3-(3,4-dihydro-2H-chinolín-1 -yl)-3-oxopropán-1 -yl]piperidín-4-yl}-1 Hindol,6-chloro-3- {1 - [3- (3,4-dihydro-2H-quinolin-1-yl) -3-oxopropan-1-yl] piperidin-4-yl} -1 H -indole,

6- chlór-3-{ 1 -[6-(3,4-d ihyd ro-2/-/-chinol í n-1 -yl)-6-oxohexán-1 -yl] piperid í η-4-yl}-1Hindol,6-chloro-3- {1 - [6- (3,4-dihydroquinazolin ro-2 / - / - quinolin-pyrimidin-1-yl) -6-oxohexane-1-yl] -piperidine-η 4-yl } -1Hindol.

7- chlór-3-{1-[4-(3,4-dihydro-2/-/-chinolín-1-yl)-4-oxobután-1-yl]piperidín-4-yl}-1Hindol,7-chloro-3- {1- [4- (3,4-dihydro-2 / - / - quinolin-1-yl) -4-oxobutan-1-yl] piperidin-4-yl} -1Hindol,

7-chlór-3-{ 1 -[5-(3,4-dihydro-2/7-chinolín-1 -yl)-5-oxopentán-1 -yl]piperidín-4-yl}-1 Hindol,7-chloro-3- {1 - [5- (3,4-dihydro-2/7-quinolin-1-yl) -5-oxopentan-1-yl] piperidin-4-yl} -1 H -indole,

7-chlór-3-{ 1 -[6-(3,4-dihydro-2/7-chinolín-1 -yl)-6-oxohexán-1 -yl]piperidín-4-yl}-1 Hindol,7-chloro-3- {1 - [6- (3,4-dihydro-2/7-quinolin-1-yl) -6-oxohexane-1-yl] piperidin-4-yl} -1 H -indole,

5-fluór-3-{1-[4-(3,4-dihydro-1/7-izochinolín-2-yl)bután-1-yl]piperidín-4-yl}-1/-/-indol, 5-fluór-3-{1-[4-(6,7-dimetoxy-3,4-dihydro-1/-/-izochinolín-2-yl)bután-1-yl]-piperidín-4yl}-1/-/-indol, alebo ich farmaceutický prijateľné soli.5-Fluoro-3- {1- [4- (3,4-dihydro-1/7-isoquinolin-2-yl) butan-1-yl] piperidin-4-yl} -1 / - / - indole, 5 fluoro-3- {1- [4- (6,7-dimethoxy-3,4-dihydro-1 / - / - isoquinolin-2-yl) butan-1-yl] -piperidin-4-yl} -1 / - -indole, or a pharmaceutically acceptable salt thereof.

20. Farmaceutický prostriedok, vyznačujúci sa tým, že obsahuje indolový derivát podľa ktoréhokoľvek z nárokov 1 až 19 v terapeuticky účinnom množstve spolu s jedným alebo viacerými farmaceutický prijateľnými nosičmi alebo riedidlami.20. A pharmaceutical composition, characterized in that it comprises the indole derivative of any one of claims 1 to 19 in a therapeutically effective amount together with one or more pharmaceutically acceptable carriers or diluents.

-5321. Použitie indolového derivátu podľa ktoréhokoľvek nároku 1 až 19 na výrobu lieku na liečenie pozitívnych a negatívnych symptómov schizofrénie, iných psychóz, úzkostných porúch, akou je napríklad všeobecná úzkostná porucha, ' panická porucha a obsedantno-kompulzívna porucha, depresie, agresie, vedľajších účinkov vyvolaných bežnými antipsychotickými látkami, migrény, kognitívnych porúch, hyperaktívnej poruchy nedostatočnej pozornosti a na zlepšenie spánku.-5321. The use of an indole derivative according to any one of claims 1 to 19 for the manufacture of a medicament for the treatment of the positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders such as general anxiety disorder, panic disorder and obsessive-compulsive disorder, depression, aggression, antipsychotic agents, migraines, cognitive disorders, attention deficit hyperactivity disorder and sleep improvement.

22. Indolové deriváty podľa ktoréhokoľvek z nárokov 1 až 19 na použitie na liečenie pozitívnych a negatívnych symptómov schizofrénie, iných psychóz, úzkostných porúch, akou je napríklad všeobecná úzkostná porucha, panická porucha a obsedantno-kompulzívna porucha, depresie, agresie, vedľajších účinkov vyvolaných bežnými antipsychotickými látkami, migrény, kognitívnych porúch, hyperaktívnej poruchy nedostatočnej pozornosti a na zlepšenie spánku.Indole derivatives according to any one of claims 1 to 19 for use in the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders such as general anxiety disorder, panic disorder and obsessive-compulsive disorder, depression, aggression, side effects caused by common antipsychotic agents, migraines, cognitive disorders, attention deficit hyperactivity disorder and sleep improvement.