UA81755C2 - Derivates of 3,4-dihydro-1h-isoquinoline-2-yl - Google Patents

Abstract

The present invention relates to novel compounds of formula I wherein the radicals groups are as defined in the claims or in a pharmaceutically acceptable acid addition salt thereof. The compounds of the invention are NKantagonists

Description

Description of the invention

The compounds of this invention belong to a new group of 3,4-dihydro-1H-isoquinolin-2-yl derivatives, which have 2 affinity to the neurokinin 2 (MK2) receptor. The compounds are MK2 antagonists and are useful in the treatment of diseases involving the MK2 receptor, such as asthma and CNS diseases. These new 3,4-dihydro-1H-isoquinolin-2-yl derivatives are able to penetrate the blood-brain barrier and are therefore useful in the treatment of various CNS diseases.

Three tachykinins, substance P (ZR), neurokinin A (MKA) and neurokinin B (MKB), are widely distributed in the peripheral and central nervous system. The biological effects of the indicated neuropeptides are carried out by binding to their predominant receptors, MK, MK2 and MKZ |Sptsaga, 5. apa UUaivop, 5.R. Meyhospet. Yippee 1991, 18, 149). Substance P shows the highest affinity for MK receptors, while MKA and MKV preferentially bind to MK2 and MKZ receptors, respectively. The selectivity of endogenous ligands in relation to their corresponding receptors is not absolute (review by Keodoi, YuO. ei ai. Rpagtasoi. Kem. 1994, 46, Mo. 4, 551 and Vgeteg, 75 A.A. ei a). Ashg u). Rpagtasoi 2001, 423, 143). Three subtypes of receptors belong to the superfamily associated with

C-protein receptors, and they have been cloned in various species, including mice, rats, and humans. ISiagaipa, 0. A.

M. eg a. Ogydz oyi (te Eshige 1997, 22, 1235 and references in the specified publications).

Activation of tachykinin receptors affects a wide range of biological actions, including pain transmission, vasodilation, smooth muscle contraction, saliva secretion, bronchostenosis, activation of the immune system (inflammatory pain), neurogenic inflammation, and neurotransmission (|Raiasspipi, K. ei Maoddi, S.A. Eig. y). RNagtasoi. 2001, 429, 13; Iopditoge, 9. ей аЙ. Sap. 9. RNuzioi. Rpagtasoi 1997, 75, 612; Siagaipa, S. A. M. ei aiYi. YuOgoidve oi (She Eshige 1997, 22, 1235 and references in the specified publications).

The expression of MK2 receptors in humans is quite controversial. The receptor is usually expressed in small amounts in the CNS, and autoradiographic studies failed to show MK2 receptors in the human brain. with

However, in a recent study based on polymerase chain reaction with reverse transcriptase (3 (CT-RSK), detectable expression of MK2 receptor mRNA was found in various areas of the human brain, including the caudate nucleus, shell, hippocampus, substantia nigra, and cerebral cortex (Vepzaid, M. oh oh

Meishgovsi. And hey. 2001, 303, 25).

Upregulation of preprotachykinin genes (PRT) and mRNA of neurokinin receptors occurs both in animal models of the disease (Rizspeg, A. ei aiYi. 9. Siip. Ipmevi 1996, 98, 2284) and in human diseases such as asthma |Adsosk , I. M. ei a). 9. Mine. Epdoshypo 1993, 11, 1).

MK antagonists have been studied and are still being studied in relation to the treatment of a large number of diseases - related to both the central nervous system and the peripheral nervous system. A number of preclinical studies have been conducted to "- evaluate the involvement of MK and MK2 receptors in the mediation and modulation of diseases associated with anxiety and/or depression (|OgiereI, b. ei aYi. RevusporpagtasoYodu, 2001, 158, 241; MUaIvp, O M. ei aYi Rzusporpaptasyodu so 1995, 121, 186; Kirpiak, M. M. ei aYi. Meigorpagtasyodu 2000, 39, 1413; Kirpiak, M. M. ei Kgateg, M. 5. TiR5 1999, 20, 485; Siagaipa, Fr. A. M. egai. Ogydz Eshige 1997,22,1235 and references in the specified publications).

These studies suggest that MK2 antagonists may be useful in the treatment or prevention of many brain disorders, including depression, manic depression, bipolar 0 disorder, psychotic depression, mixed anxiety and depressive disorder, generalized anxiety disorder, and social anxiety disorder. disorder, panic anxiety disorder, post-traumatic stress disorder, "obsessive-compulsive disorder, acute stress disorder, phobia, premenstrual dysphoric disorder, " psychosis and Huntington's disease, as well as Parkinson's disease, adjustment disorder, pain, vomiting, migraine, epilepsy, obesity , asthma and cerebrovascular disease. However, peripheral diseases such as inflammation, inflammatory bowel disease, hypertension, arthritis, cardiovascular disease, neuritis, co neuralgia, urticaria, incontinence, gastrointestinal disease, influenza, allergy, pulmonary allergy and - carcinoma/tumor growth, also can be directly influenced by MK2 antagonists. -1 IP patent O5 C 994 891) declared tetrahydroisoquinolines of the general formula 1 (l

F) ko 60 b5

C p, -0 p, where K means hydrogen or methyl, and b means MH or CH". Dihydroxy compounds are described as effective vasodilators, while dimethoxy compounds are intermediates in the production of dihydroxy compounds. at

Therefore, there is a need for new compounds that are antagonists of the MK receptor.

The purpose of this invention is to obtain compounds that are antagonists of the MK2 receptor.

Another object of the present invention is to obtain compounds with such activities that have increased solubility, metabolic stability and/or bioavailability compared to compounds of the prior art. yu

Thus, the present invention relates to new compounds of the formula tr and re so - yaz: - 1 «sl | IS

F, where is B! means the group В""СО-, ЕК" С85-, К"1805-, В" OsСО-, В" 8СО- or К"!СО-СВ "ВЗ. where EK"! is C1-4o-alkyl, C1-4o-alkenyl, C1-8-alkynyl, C1-6-cycloalkyl, C1-6-cycloalkyl-C1-6-alkyl, aryl, aryl-C1-6-alkyl, heteroaryl, heteroaryl -C.-6-alkyl, tetrahydropyranyl, 1,2,3,4-tetrahydronaphthalenyl or 4H-benzo|1,3)dioxynyl, optionally substituted by halogen, where each of the indicated C 4 6-alkyl, aryl, heteroaryl and C3 1-cycloalkyl groups are independently unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, C 4-6 alkyl, C 1-6 -alkyl, aryl-C 1-6 -alkyl, C 1-6 -alkylsulfanyl , aryl and aryloxy group, where the specified aryl and aryloxy group are independently unsubstituted or substituted by one or more halogen atoms, and B": and B"Z independently are hydrogen or C 1 -alkyl; or B" is the group K'"B"5МСО- , В'ЕВ'5МС8-, where K/Y and 75 are independently hydrogen,

C3-alkyl, C3-alkenyl, C3-alkynyl, C3-cycloalkyl, C3-cycloalkyl-C3-alkyl, aryl or aryl-C3-alkyl, where each of the indicated C .beta.-alkyl, aryl and C3-d-cycloalkyl groups are independently unsubstituted or substituted by one or more substituents selected from the group consisting of halogen,

C-alkyl and C-alkyloxy groups, or BK" and KZ, together with the M atom to which they are connected, form a pyrrolidinyl, piperidinyl or perhydroazepinyl group;

IN? is selected from hydrogen, trifluoromethyl, and C. c-alkyl; 3-5 vya, t, va and v are independently selected from hydrogen, halogen, cyano group, nitro group, C..i.v.-alkyl,

C. d-alkenyl, C3-alkynyl, C3-c-cycloalkyl, C3-cycloalkyl-C; c-alkyl, amino group, C. c-alkylamino group, di(C 4 c-alkyl)amino group, C. c-alkylcarbonyl, aminocarbonyl, C. c-alkylaminocarbonyl, di(Ci.-c-alkyl)aminocarbonyl, C. c- alkoxy group, C. v-alkylthio group, hydroxy group, trifluoromethyl, trifluoromethylsulfonyl and C. d-alkylsulfonyl; t is equal to 2-6; /5 AR means benzyl, benzoyl, 2,3-dihydrobenzofuranyl or mono- or bicyclic aryl or heteroaryl, where each benzyl, benzoyl, aryl or heteroaryl is optionally substituted by one or more substituents selected from halogen, cyano group, nitro group, C. C-alkyl, C-C-alkenyl, C-C-alkynyl, C-C-C-cycloalkyl,

Cz.v-cycloalkyl-C. 6-alkyl, amino group, C. c-alkylamino group, di(C..c-alkyl)amino group, C. c-alkylcarbonyl, aminocarbonyl, C. c-alkylaminocarbonyl, di(C..c-alkyl)aminocarbonyl, C. .b-alkyl group, C..b-alkylthio group, hydroxy group, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl;

O means C, M or SVO; where CO is selected from hydrogen, halogen, cyano group, nitro group, C. v-alkyl, Co v-alkenyl, Co v-alkynyl,

C. v-cycloalkyl, Cz.v-cycloalkyl-C. c-alkyl, amino groups, C. c-alkylamino groups, di(C.-c-alkyl)lamino groups,

C. β-alkylcarbonyl, aminocarbonyl, C. β-alkylaminocarbonyl, di(Ci-β-alkyl)aminocarbonyl, urine

C-C-Alkoxy group, C-C-alkylthio group, hydroxy group, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethylsulfonyl, -MEZ9SOVZ! group, where KZ is hydrogen or C-C-alkyl and CZ! is C. c-alkyl, the group o -COOV 5, where K "5 means hydrogen or C. c-alkyl, or the group -SOMA "BB", where EK" and KZ are independently selected from hydrogen and C. c-alkyl or B" ii KZ together with the nitrogen atom to which they are attached form piperidinyl, piperazinyl or morpholinyl, where the indicated piperidinyl, piperazinyl and morpholinyl are unsubstituted or substituted which,

C. by alkyl; у or КЗ ии КО together with the carbon atom to which they are attached form a cyclic structure selected from the group consisting of: - «-- г (ге) жх су ји А « хо 2 se де - с ' 2» 1 ) 2) Z) co

railway

- o; m, (l and y where 0 means a carbon atom shared with the piperidine ring, so that the indicated cyclic structure together with the indicated piperidine ring forms a spiro-structure; and (F; X, M and 7 are independently selected from O; MAE"? SV ?Zv?y; 5(0), and the bond; where B is selected from hydrogen, C.v.-alkyl, C. d-alkenyl, C.v.-alkynyl, C.v.-cycloalkyl, C.v. -cycloalkyl-C. in-alkyl, trifluoromethyl, acyl, thioacyl and trifluoromethylsulfonyl, or KK" is the group К?О5О2-, КРООСО- or К?О5СО-, where KO means C. in-alkyl, 60 C. in" alkenyl, C.v.-alkynyl, C.v.-cycloalkyl, C.v.-cycloalkyl-C.v.-alkyl or aryl, or KU is the group К7"К??7МСО- or

In ?MSV-, where VC? is she 8? independently denote hydrogen, C-alkyl, C-alkenyl, C-alkynyl,

C. c-cycloalkyl, C3.c-cycloalkyl-C.sub.6-alkyl or aryl, where the specified aryl is unsubstituted or substituted by one or more substituents selected from C..c-alkyl or halogen; or, together with the M atom to which they are connected, form a pyrrolidinyl, piperidinyl or perhydroazepinyl group; Sv is independently selected from hydrogen, halogen, cyano group, nitro group, C. c-alkyl, C. c-alkenyl, C. c-alkynyl, C. c.-cycloalkyl,

C3.6-cycloalkyl-C.46-alkyl, aryl, heteroaryl, where the indicated aryl is unsubstituted or substituted by one or more substituents selected from C.6-alkyl or halogen, amino group, C.6-alkylamino group, group

ME?9B?6, where ?5 1 and?b are independently selected from C. c-alkyl, C. c-alkylcarbonyl, aminocarbonyl,

C. d-alkylaminocarbonyl, di(C. c-alkyl) aminocarbonyl, C. c- alkoxy group, C. c- alkylthio group, hydroxy group, trifluoromethyl, trifluoromethylsulfonyl and C. c- alkylsulfonyl, or EC? and K26 together with the M atom to which they are connected form a pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group, or B 23 and 224 together are an oxo group; and n is equal to 0, 1 or 2; provided that no more than one of X, M, and 7 may be a bond, and provided that two adjacent groups of X, Y, or 7 cannot be simultaneously selected from 0 and 5; and then A", A?, AZ and A? are independently selected from M and CE", where BC?" means hydrogen, halogen, cyano group, nitro group,

C. v'alkyl, Czv-alkenyl, Czv-alkynyl, Czv-cycloalkyl, Czv-cycloalkyl-C. β-alkyl, C. β-alkylcarbonyl, aminocarbonyl, C. β-alkylaminocarbonyl, di(C.4.β-alkyl)aminocarbonyl, C. β-alkyl group, C..β-alkylthio group, hydroxy group, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethylsulfonyl, C. v-alkylsulfonyl, /5 amino group or group MK?UB29, where B? and 79 are independently selected from hydrogen and C-C-alkyl or K78 and B? together with the atom

M, with which they are connected, form a pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group; provided that only one of A", A?2, AZ and A? can be M; and a dotted line departing from C) means a bond when C) is C, and is not a bond, when CO is CE "9 or M; or their pharmaceutically acceptable acid addition salts.

C. 12o-alkyl groups specified in the definition of "BE" are preferably selected from C. 1-0-alkyl, more preferably C. 6-alkyl and most preferably C. 3-c-alkyl.

In one version, the present invention relates to such compounds, where C) is SV 9, and KU and KO together with the carbon atom to which they are connected form a bicyclic structure: с 4 о у зд2 а

Kh.. - -Az y od shchy cha ch- 1 ), (he) where C means a carbon atom shared with the piperidine ring, so that the indicated bicyclic structure together with the indicated piperidine ring forms a spiro-structure; and

X, Y and 7 are independently selected from O; ME"U; SK?ZE?ya and 5(O)4, where KU is selected from hydrogen, S. in -alkyl, Co in -alkenyl, "

C3-alkynyl, C3-cycloalkyl, C3-cycloalkyl-C. β-alkyl, trifluoromethyl, acyl, thioacyl, and - with trifluoromethylsulfonyl, or KVK" is the group КО 505-, К2ОСО- or К?О5СО-, where КО means C. б-alkyl, з" C. б-alkenyl, Со .b-alkynyl, C3-b-cycloalkyl, C3.b-cycloalkyl-C..b-alkyl or aryl, or KU is the group К7"К??МСО- or

BB? Ministry of the Interior, where is BC?! ii V? independently denote hydrogen, C.v.-alkyl, C.v.-alkenyl, C.v.-alkynyl,

C. c-cycloalkyl, C3.c-cycloalkyl-C.sub.6-alkyl or aryl, where the specified aryl is unsubstituted or substituted by one or

Go! several substituents selected from C. b6-alkyl or halogen; or lead together with the M atom to which they are connected form a pyrrolidinyl, piperidinyl or perhydroazepinyl group; BZ and 827 are independently selected from hydrogen, halogen, cyano group, nitro group, C.v.-alkyl, C.v.-alkenyl, C.v.-alkynyl, C.v.-cycloalkyl, -I C.v.-cycloalkyl-C.46-alkyl, aryl, heteroaryl, where the indicated aryl is unsubstituted or substituted with one or more substituents selected from C.v.-alkyl or halogen, amino group, C.v.-alkylamino group, group

MA29B26, where 25 and K26 are independently selected from Si. в-alkyl, or K?5 and KE? together with the M atom to which they are bound, sp form a group of pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl, C. c-alkylcarbonyl, aminocarbonyl, C. c-alkylaminocarbonyl, di(C..c-alkyl)aminocarbonyl, C. .b-alkyl group, C..b-alkylthio group, hydroxy group, trifluoromethyl, trifluoromethylsulfonyl and C.b-alkylsulfonyl, or KZ and B? together is 29 oxo group; and n is equal to 0, 1 or 2; and communication; provided that no more than one of X, Y, and 7 can be a bond,

GF! and provided that two adjacent groups X, Y or 7 cannot be simultaneously selected from O and 5; and

A", A?, AZ and A? are independently selected from M and CE", where BK" means hydrogen, halogen, cyano group, nitro group, C. c-alkyl, C. c-alkenyl, C-alkynyl, C. β-cycloalkyl, C3.β-cycloalkyl-C.β-alkyl, amino group, MKK group, 6o where 28 | i29 are independently selected from hydrogen and C1-6-alkyl or B28 and 29 together with the M atom with which they are connected bound, form a pyrrolidinyl, piperidinyl, perhydroazepinyl, or morpholinyl group; C. c-alkylcarbonyl, aminocarbonyl, C. c-alkylaminocarbonyl, di(C.4.c-alkyl)aminocarbonyl, C. c.-alkyl group, C..c.-alkylthio group , a hydroxy group, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethylsulfonyl or C. 6-alkylsulfonyl; or provided that only one of A", A?, AZ and A? may be M. 65 In a preferred embodiment, the present invention relates to such compounds where X, M and 7 are selected from one of the combinations: X is oxygen, Y is a bond and 7 is CE?ZB?Y: X is CA?ZB ?I, U is a bond and 7 is an oxygen; X is ME "U, U is a connection and 7 is SEZ X is SAM, U is a connection and 7 is ME "U; X is CO, Y is a bond and 7 is ME "Y; X is 80", Y is a bond and 7 is

MA 79; X is 50, Y is a bond and 7 is MV"; X is SEZ, Y is a bond and 7 is 5; X is SV, Y is a bond 7 is ZO; X is

Stk2Zdoya, U is a connection and 7 is 502; where B" is hydrogen, acetyl or methylsulfonyl, and BZ | 22" is independently selected from hydrogen, methyl, isobutyl, cyclohexyl and 4-fluorophenyl.

In another preferred embodiment, this invention relates to such compounds where -X-U-2- together form a group selected from: -0O-SVK2ZV2Ya-, -sv23v2-0o-, -MV'Z-sv2Zv., stv. BABY. -сО-МА79-, -502-MA U. -50-ME 79-, -"СВ23в24-8-, -СВ23821-50-, -"СВ2324-805-; where BZ is hydrogen, acetyl or methylsulfonyl, and B23 /0 and 724 are independently selected from hydrogen, methyl, isobutyl, cyclohexyl and 4-fluorophenyl.

In another preferred embodiment, the present invention relates to such compounds where АЗ is M or СВ2", where В?! means a halogen, a cyano group, a nitro group, a ME?829 group, where K28 and K?9 are independently selected from hydrogen and C. v6- alkyl or 8 Its BZ, together with the M atom to which they are bound, form a group of pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl, C. c-alkylcarbonyl, aminocarbonyl, Ci-c-alkylaminocarbonyl, 75 DdYy(Ci-c-alkyl)uaminocarbonyl, C..v-alkyl group, hydroxy group, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethylsulfonyl or C.v.-alkylsulfonyl.

In another preferred embodiment, this invention relates to such compounds where A 1 A? АЗиАЙ independently selected from SV", where B?" has the values defined above.

In a more preferred embodiment, the present invention relates to such compounds where the bicyclic structure described above is selected from the group consisting of:

KO da de sch o o) fun s ; Consolidation a) 5) c) "-- where VU means acetyl or methylsulfonyl, BU means hydrogen or methyl, B2/ means hydrogen or (0 fluorine, KO" means hydrogen, fluorine, methyl or isopropyl, K2" means hydrogen, fluorine or trifluoromethyl.

In another variant, the present invention relates to such compounds, where VZ, together with the carbon atom to which they are connected, form a cyclic structure selected from the group consisting of: « | - i (х чино что что) proe o z y - 2) 3) 4) o where 0 is a carbon atom shared with the piperidine ring, so that the indicated cyclic structure together with the indicated piperidine ring forms a spiro-structure.

In another embodiment, the present invention relates to such compounds, where Kc C is benzyl, benzoyl, 2,3-dihydrobenzofuran-7-yl or mono- or bicyclic aryl or heteroaryl, where each benzyl, benzoyl, aryl or heteroaryl is optionally substituted by one or more substituents selected from halogen, cyano group, nitro group, C.v.-alkyl, C.v.-alkenyl, C.v.-alkynyl, C.v.-cycloalkyl, C.v.-cycloalkyl-C. d-alkyl, amino group, o C. c-alkylamino group, di(C..c-alkyl)amino group, C. c.6-alkylcarbonyl, aminocarbonyl, C..c-alkylaminocarbonyl, ke di(Ci.-c-alkyl)aminocarbonyl , C. β-alkyl group, C. β-alkylthio group, hydroxy group, trifluoromethyl, difluoromethyl, fluoromethyl, and trifluoromethylsulfonyl. 60 In another variant, the present invention relates to such compounds, where EC? means 2,3-dihydrobenzofuran-7-yl, benzyl or benzoyl, wherein said benzyl or benzoyl is unsubstituted or substituted by one or more halogen atoms in the phenyl groups, or KU is mono- or bicyclic aryl or heteroaryl selected from the group consisting of from phenyl, indolyl, pyridyl, thiophenyl, and benzisoxazolyl, where each aryl or heteroaryl is optionally substituted with one or more substituents selected from halogen, cyano, or nitro, C.v.-alkyl, C.v.-alkenyl, C.v.-alkynyl, C3.c-cycloalkyl, C3-c-cycloalkyl-C. d-alkyl, amino groups,

C. c-alkylamino group, di(C..c-alkyl)amino group, C. c.6-alkylcarbonyl, aminocarbonyl, C..c-alkylaminocarbonyl, di(Ci.-c-alkyl)aminocarbonyl, C. c-alkyl group, C β-alkylthio group, hydroxy group, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl.

In a preferred embodiment, the present invention relates to such compounds where the indicated mono- or bicyclic aryl or heteroaryl is selected from the group consisting of phenyl, indol-3-yl and benzisoxazol-3-yl, where the indicated phenyl, indol-3-yl or benzisoxazol-3-yl is optionally substituted with one or more substituents selected from halogen, cyano group, nitro group, C.v.-alkyl, C.v.-alkenyl, C.v.-alkynyl, C.v.-cycloalkyl,

C3.v-cycloalkyl-Si 6-alkyl, amino group, C. v-alkylamino group, di(C.v-alkyl)damino group, C. v-alkylcarbonyl, 70 aminocarbonyl, C. v-alkylaminocarbonyl, di(C..v -alkyl)aminocarbonyl, C..v.-alkyl group, C..v.-alkylthio group, hydroxy group, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl.

In an even more preferred version, the present invention relates to such compounds where the specified optional substituents are selected from the group consisting of halogen, phenyl and methyl.

In yet another variant, the present invention relates to such compounds, where OO means SK 10 where B7O is selected from 75 hydrogen, Cu c-alkylcarbonyl, hydroxy group, group -MVZOSOVZ!, where ZO means hydrogen or C. c-alkyl and B! means C. c-alkyl of the group -SOOK "E, where VK "Z is C. c-alkyl, or of the group -"SOMA "B", where B" and KZ together with the nitrogen atom to which they are connected form piperidinyl, piperazinyl or morpholinyl, wherein said piperidinyl, piperazinyl and morpholinyl are unsubstituted or substituted by C 1-6 alkyl.

In a preferred version, this invention relates to such compounds where K 10 is selected from hydrogen, acetyl, hydroxy group, -MESOSOVZ group, where BO is hydrogen and KZ! is methyl, the group -"SOOV E, where B"5 means ethyl, or the group -"SOMA"B'Z, where B"/ and VK'Z together with the nitrogen atom to which they are connected form piperidinyl. or 4-methylpiperazinyl.

In another preferred embodiment, the present invention relates to compounds where t is 2, 3 or 4, more preferably t is 2. c

In another variant, the present invention relates to such compounds where B! is the group В"!СО-, В"ОСО-, where В!! (o) means C1-6-alkyl, C1-6-cycloalkyl, C3-cycloalkyl-C-6-alkyl, phenyl, phenyl-C-6-alkyl, pyridyl, furanyl, benzo|1,2,5|oxadiazolyl, quinoxalinyl, benzo |B) hyophenyl or naphthalenyl, where each of the indicated groups of C 1 -C 6 -alkyl, phenyl, pyridyl and furanyl is independently unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, C 4.6 -alkyl, C 6 -C 6 -alkyl , phenyl and phenoxy group, where the indicated phenyl and phenoxy group are independently unsubstituted or substituted by one halogen; or B! is io) the group KYAV5MSO-, where B" and BZ independently mean hydrogen, C. 6-alkyl, aryl or aryl-C. 6-alkyl, where each p of the specified C. 6-alkyl and aryl groups is independently unsubstituted or substituted by one substituent selected from the group consisting of halogen and C. 6b-alkyl group. --

In another embodiment, the present invention relates to compounds where B2 is hydrogen. with

In yet another embodiment, the present invention relates to such compounds where VZ is hydrogen.

In another embodiment, the present invention relates to such compounds where VE is hydrogen or a methoxy group.

In another variant, the present invention relates to such compounds, where VE? is hydrogen or a methoxy group. 20 In yet another embodiment, the present invention relates to compounds where 25 is hydrogen. With c In yet another variant, the present invention relates to such compounds where ai c is hydrogen.

In another embodiment, the present invention relates to such compounds where Ba and 85 are hydrogen. ;" Preferred compounds of this invention are the compounds numbered 1-209, which are described in the experimental section, as well as the compounds indicated in the following list: 1-(1-42-i(4-(5-fluoro-1H-indol-3-yl) )piperidin-1-ylethyl)-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone 1-cyclopentyl-1-(1-12-I( 4-(5-fluoro-1H-indol-3-yl)utperidin-1-ilyethyl)-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)m-ethanone-I 1-cyclopentyl-1 -(1-12-Ib-fluorospiro(isobenzofuran-1(ZH), "4-piperidin-1'-ilyethyl)-5-chloro-3,4-dihydro-1H-isoboro inolin-2-ylumethanone 1 1- (4-fluorophenyl)-1-(1-2-16-fluorospiro(isobenzofuran-1(3H),4-piperidin-1'-yl|ethyl)-5-chloro-3,4-dihydro-1H-is sl oquinolin-2-yl)umethanone 1-cyclopentyl-1-(1-12-I(b-trifluoromethylspiro|(isobenzofuran-1(3H),4-piperidin-1'-ilyethyl)-5-chloro-3,4- dihydro -1H-isoquinolin-2-yl)umethanone 1-(4-fluorophenyl)-1-(1-2-(b-trifluoromethylespiro(isobenzofuran-1(ZH), 4-piperidin-1'-ilyethyl)-5- chloro-3,4-dihydro-THN-isoquinolin-2-yl)umethanone (F) IM-(1-4422-(2-(1-cyclopentylmethanol)-1,2,3,4-tetra hydroisoquinolin-1-yl)ethyl)-4-(3-fluorophenyl)piperidin-4-ylylacetamide

IM-(1-422-(2-(1-(4-fluorophenyl)methanol)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-(3-fluorophenyl)piperidin-4-yl because |acetamide

IM-(1-4422-(2-(1-cyclopentylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-ylethyl)-4-phenylpiperidin-4-ylylacetamide

IM-(1-422-(2-(1-(4-fluorophenyl)methanol)-1,2,3,4-tetrahydroisoquinolin-1-yl)|ethyl)-4-phenylpiperidin-4-ilyacetamide 1-cyclopentyl- 1-11-/1-acetylstro|2,3-dihydro-1H-indole-3,4"-piperidin-1-yl|yl|-5-chloro-3,4-dihydro-1H-isoquinoline-2- Ilumethanone 65 1--4-fluorophenyl)-141-P1-acetylspiro|2,3-dihydro-1H-indole-3,4-piperidin-1-yl|ethyl|-5-chloro-3,4-dihydro-1H - isoquinoline-2-ilumethanone

1-cyclopentyl-1-11-P1-acetylspiro (2,3-dihydro-5-fluoro-1H-indole-3,4"-piperidin-1'-yl|ethyl|-5-chloro-3,4-dihydro -1H-isoquinoline-2-ylumethanone 1--4-fluorophenyl)-1471-/1-acetylspiro/2,3-dihydro-5-fluoro-1H-indole-3,4-piperidin-1'-yl|ethyl| -5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 1-cyclopentyl-1-(1-2-I(4-(3-trifluoromethylphenyl)piperidin-1-ylylethyl)-5- chloro-3,4-dihydro-1H-isoquinolin-2-yl)m-ethanone 1-4-fluorophenyl)-1-(1-2-14-(3-trifluoromethylphenyl)piperidin-1-yl|1-ethyl)-5 -chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone 70 1-(1-2-(4-(6-fluorobenzo|d|isoxazol-3-yl)piperidin-1-ilyethyl)-5 -chloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone 1-(1-2-(4-(6-fluorobenzo|d|isoxazol-3-yl)piperidine -1-ylethyl)-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone 1-(4-fluorophenyl)-1-(1-2-I5,6 -difluorospiro|benzofuran-1(ZH),4-piperidin-1"-yl|ivatyl)-5-chloro-3,4-dihydro-1H-i 7/5 ZoHquinoline-2-ylumethanone 1-(4-fluorophenyl) -1-(12-Ib-fluorospiro(benzofuran-1(ZN),4-piperidin-1'-yl|ethyl)-5-chloro-3,4-dihydro-1H-isoquine o lin-2-yl)umethanone 1-cyclopentyl-1-(1-12-15,b-difluorospiro(benzofuran-1(ZN),4-piperidin-1-yl|1ethyl)-5-chloro-3,4 -dihydro-1H-isoquinolin-2-yl)umethanone 1-cyclopentyl-1-(12-Ib-fluorospiro(benzofuran-1(3H),4-piperidin-1'-yl)|ethyl)-5-chloro- 3,4-dihydro-1H-isoquinol n-2-yl)umethanone 1-(1-42-i(4-(5-fluoro-1H-indol-3-yl)piperidin-1-yl|Hethyl)-3 ,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone 1-cyclopentyl-1-(1-12-I(4-(5-fluoro-1H-indole -3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl) c g methanone 1-cyclopentyl-1-(1-12-1b-fluorospiro isobenzofuran-1(ZH), "4-piperidin-1'-ilyethyl)-3,4-dihydro-5-fluoro-1H-isox (8) inolin-2-yl)umethanone 1-(4-fluorophenyl)-1 -(1-2-16-fluorospiro(isobenzofuran-1(3H),4-piperidin-1-yl|ethyl)-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)umethanone 1-cyclopentyl-1-(1-12-I(b-trifluoromethylspiro|(isobenzofuran-1(3H),4-piperidin-1'-yl|ethyl)-3,4-dihydro-5-fluoro-1H-isoquinoline -2-yl)umethanone io) 1-(4-fluorophenyl)-1-(1-2-I(b-trifluoromethylespiro(isobenzofuran-1(ZH), 4 - Piperidine-1'-ylethyl)-3,4-dihydro-5-methyl-or-1H-isoquinolin-2-yl)umethanone

IM-(1-422-(2-(1-cyclopentylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-(3-fluorophenyl)piperidin-4-yl|h-acetamide so

IM-(1-422-(2-(1-(4-fluorophenyl)methanol)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-(3-fluorophenyl)piperidin-4-yl acetamide

IM-(1-4422-(2-(1-cyclopentylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-ylethyl)-4-phenylpiperidin-4-ylylacetamide

IM-(11-42-(2-(1-(4-fluorophenyl)methanol)-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-4-phenylpiperidin-4-yl)iacetamide « 1- cyclopentyl-1-11-/1-acetylspiro|(2,3-dihydro-1H-indole-3,4"-piperidin-1'-ylethyl/|-3,4-dihydro-5-fluoro-1H-iz c oquinoline-2-ilumethanone 1-(4-fluorophenyl)-1471-1-acetylspiro|2,3-dihydro-1H-indol-3,4-piperidin-1"-yl|HyethylI-3,4-dihydro-5 -fluoro-1H-; t isoquinolin-2-ylumethanone 1-cyclopentyl-1-11-(1-acetylspiro|(2,3-dihydro-5-fluoro-1H-indol-3,4-piperidin-1'-yl |Ieutyl|-3,4-dihydro-5-phto

B-1H-isoquinoline-2-ilumethanone so 1-(4-fluorophenyl)-1471-1-acetylspiro|2,3-dihydro-5-fluoro-1H-indole-3,4-piperidin-1-yl|ethyl) |-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)umethanone-y 1-cyclopentyl-1-(1-2-(4-(3-trifluoromethylphenyl)piperidin-1-yl|ethyl) )-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)m-1 ethanone 1-(4-fluorophenyl)-1-(1-2-I4-(3-trifluoromethylphenyl)piperidine-1- yl|Liethyl)-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl 1)methanone sl 1-(1-2-(4-(6-fluorobenzo|d|isoxazol-3-yl)piperidine -1-yl|ethyl)-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone 1-(1-2-(4-(6-fluorobenzo| d|isoxazol-3-yl)piperidin-1-ylethyl)-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone 1-(4-fluorophenyl)-1 -(1-2-(5,6-difluorospiro|Ibenzofuran-1(3H),4-piperidin-1'-ilyethyl)-3,4-dihydro-5-fluoro-1H-i

HF) zoquinolin-2-yl)umethanone

F 1-(4-fluorophenyl)-1-(12-I(b-fluorospiro(benzofuran-1(ZH) 4-piperidin-1'-yl|IIethyl)-3,4-dihydro-5-fluoro-1H- isoquinolin-2-yl)umethanone in 1-cyclopentyl-1-(1-2-15,6-difluorospiro

Ibenzofuran-1(3H),4-piperidin-1'-ilyethyl)-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)umethanone 1-cyclopentyl-1-(12-Ib-fluorospiro(benzofuran -1(3H),4-piperidin-1'-ilyethyl)-3,4-dihydro-5-fluoro-1H-isoquinol n-2-yl)umethanone 1-(1-42-i4-(5-fluoro- 1H-indol-3-yl)piperidin-1-ylethyl)-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro 65 phenyl)methanone 1-cyclopentyl- 1-(1-2-I(4-(5-fluoro-1H-indol-3-yl)piperidin-1-yl|ethyl)-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2

-ilumethanone 1-cyclopentyl-1-(1-12-Ib-fluorospiro(isobenzofuran-1(ZH), "4-piperidin-1'-ilyethyl)-5,b-dichloro-3,4-dihydro-1H- isoquinoline -2-yl)umethanone 1-(4-fluorophenyl)-1-(1-2-(b-fluorospiro(isobenzofuran-1(ZH),4-piperidin-1-yl|ethyl)-5,6-dichloro- 3,4-dihydro-1

N-isoquinolin-2-yl)umethanone 1-cyclopentyl-1-(1-2-I(b-trifluoromethylspiro|(isobenzofuran-1(ZH),4-piperidin-1'-ilyethyl)-5,6-dichloro- 3,4-dihydro-1H-isoquinolin-2-yl)umethanone 1-(4-fluorophenyl)-1-(1-2-Ib-trifluoromethylespiro(isobenzofuran-1(ZH), 4-piperidin-1'-ilyethyl) )-5,6b-dichloro-3,4-d 7/0 Mhydro-TH-isoquinoline-2-ylumethanone

IM-(1-422-(2-(1-cyclopentylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-(3-fluorophenyl)piperidin-4-yl acetamide

IM-(1-422-(2-(1-(4-fluorophenyl)methanol)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-(3-fluorophenyl)piperidin-4-yl

Iacetamide

IM-(1-4422-(2-(1-cyclopentylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-ylethyl)-4-phenylpiperidin-4-ylylacetamide

IM-(1-422-(2-(1-(4-fluorophenyl)methanol)-1,2,3,4-tetrahydroisoquinolin-1-yl)|ethyl)-4-phenylpiperidin-4-ilyacetamide 1-cyclopentyl- 1-11-/1-acetylspiro|2,3-dihydro-1H-indole-3,4"-piperidine-1'-ylethyl/|-5,6-dichloro-3,4-dihydro-1

N-isoquinoline-2-ylumethanone 1--4-fluorophenyl)-1471-P1-acetylespiro|2,3-dihydro-1H-indole-3,4-piperidin-1-yl|ethyl/|-5,6-dichloro -3,4-dihydro 207 H-isoquinoline-2-ilumethanone 1-cyclopentyl-1-11-P1-acetylspiro (2,3-dihydro-5-fluoro-1H-indole-3,4"-piperidine-1'- iliethyl|-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 1-(4-fluorophenyl)-1471-1-acetylspiro|2,3-dihydro-5-fluoro-1H- Indole-3,4-piperidin-1"-yl|ethyl|-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)umethanone with 1-cyclopentyl-1-(1-2-( 4-(3-trifluoromethylphenyl)piperidin-1-yl|ethyl)-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone (8) 1-(4-fluorophenyl)-1- (1-(2-I4-(3-trifluoromethylphenyl)piperidin-1-yl|IIethyl)-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 1-(1-2- (4-(6-fluorobenzo|d|isoxazol-3-yl)piperidin-1-yl|ethyl)-5,b-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-1 yzo 7 ((4-fluorophenyl)methanone 1-(1-2-(4-(6-fluorobenzo|d|isoxazol-3-yl)piperidin-1-yl|ethyl)-5,b-dichloro-3,4-dihydro -1H-isoquinolin-2-yl)-1io)-(cyclopentyl)methanone y- 1-(4-fluorophenyl)-1-(1-2-15,6-diphth orspiro|benzofuran-1(ZN),4-piperidin-1'-yl|ethyl)-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)umethanone h- 1-(4-fluorophenyl )-1-(12-1b-fluorospiro(benzofuran-1(ZN),4-piperidin-1'-ylethyl)-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl) umethanone 1-cyclopentyl-1-(1-12-15,b-difluorospiro(benzofuran-1(ZH),4-piperidin-1-yl|ethyl)-5,6-dichloro-3,4-dihydro-1H - isoquinolin-2-yl)umethanone 1-cyclopentyl-1-(12-I(b-fluorospiro

Ibenzofuran-1(3H),4-piperidin-1'-ylethyl)-5,6b-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)umethanone with 1(142-14-(5-fluoro -1H-indol-3-yl)piperidin-1-yl|ethyl)-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)umethanone; t 1-cyclopentyl-1-(1-12-I(4-(5-fluoro-1H-indol-3-yl)piperidin-1-yl|Hiethyl)-5,6-difluoro-3,4-dihydro- 1H-isoquinolin-2-ilumethanenone 1-cyclopentyl-1-(1-12-1b-fluorospiro(isobenzofuran-1(Z3H), 4-piperidin-1-yl|ethyl)-5,6-difluoro-3,4- dihydro-1H-so isoquinolin-2-yl)umethanone 1-(4-fluorophenyl)-1-(1-2-16-fluorospiro(isobenzofuran-1(ZN),4-piperidin-1-yl|ethyl)-5 ,6-difluoro-3,4-dihydro-1-y H-isoquinolin-2-yl)umethanone-1 1-cyclopentyl-1-(1-12-I(b-trifluoromethylespiro|(isobenzofuran-1(Z3H), 4-piperidin-1'-ylethyl)-5,6-difluoro-3,4-digbohydro-1H-isoquinolin-2-ylumethanone 1 1-(4-fluorophenyl)-1-(1-2-I(b -trifluoromethylespiro(isobenzofuran-1(ZN),4-piperidin-1'-ylethyl)-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)umethanone

IM-(1-4422-(2-(1-cyclopentylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-yl)|ethyl)-4-(3-fluorophenyl)piperidin-4-ylylacetamide

IM-(1-422-(2-(1-(4-fluorophenyl)methanol)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-(3-fluorophenyl)piperidin-4-yl

Iacetamide

HF) IM-(1-4422-(2-(1-cyclopentylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-ylethyl)-4-phenylpiperidin-4-ylylacetamide

F IM-(1-422-(2-(1-(4-fluorophenyl)methanol)-1,2,3,4-tetrahydroisoquinolin-1-yl)|ethyl)-4-phenylpiperidin-4-ilyacetamide 1-cyclopentyl -1-11-(1-acetylspiro|2,3-dihydro-1H-indole-3,4"-piperidin-1-yl|ethylI-5,6-difluoro-3,4-dihydro-1boH-isoquinoline -2-yl)umethanone 1--4-fluorophenyl)-1471-/1-acetylspiro/2,3-dihydro-1H-indole-3,4-piperidin-1'-yl|ethyl|-5,6-difluoro -3,4-dihydro -1H-isoquinoline-2-ilumethanone 1-cyclopentyl-1-11-/1-acetylspiro|(2,3-dihydro-5-fluoro-1H-indole-3,4"-piperidine-1 -yl|ethyl|-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 65 1--4-fluorophenyl)-1471-1-acetylspiro|2,3-dihydro-5 -fluoro-1H-indole-3,4-piperidin-1-ylethyl|-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)umethanone

1-cyclopentyl-1-(1-12-(4-(3-trifluoromethylphenyl)piperidin-1-yl|ethyl)-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1 -(4-fluorophenyl)-1-(1-2-14-(3-trifluoromethylphenyl)piperidin-1-yl|1-ethyl)-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl) umethanone 1-(1-2-(4-(6-fluorobenzo|d|isoxazol-3-yl)piperidin-1-yl|ethyl)-5,b-difluoro-3,4-dihydro-1H-isoquinoline-2 -yl)-1-(4-fluorophenyl)methanone 1-(1-2-(4-(6-fluorobenzo|d|isoxazol-3-yl)piperidin-1-yl|ethyl)-5,b-difluoro- 3,4-dihydro-1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone 70 1-(4-fluorophenyl)-1-(1-2-15,6-difluorospiro|benzofuran-1(ZH), 4-piperidin-1'-ylethyl)-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 1-(4-fluorophenyl)-1-(12-Ib-fluorospiro(benzofuran- 1(ZH),4-piperidin-1'-ylethyl)-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 1-cyclopentyl-1-(1-12-I5, b-difluorospiro(benzofuran-1(ZH),4-piperidin-1'-yl|ethyl)-5,6-difluoro-3,4-dihydro-1H 75 "Isoquinolin-2-yl)umethanone and 1-cyclopentyl- 1-(12-Ib-fluorospiro(benzofuran-1(Z3H),4-piperidin-1'-ylethyl)-5,6-difluoro-3,4-dihydro-1 N-isohynolin-2-yl)umethanone.

The compounds of the present invention are antagonists of MK receptors, having a binding affinity to human MK (IC50) of 5 μM or less, usually 1 μM or less, preferably 200 nM or less, more preferably 5 ONM or 20 less and most preferably 1 ONM or less.

Thus, the compounds of the present invention are expected to be useful in the treatment of a variety of CNS disorders such as depression, manic depression, bipolar disorder, psychotic depression, mixed anxiety and depressive disorder, generalized anxiety disorder, social anxiety disorder, panic anxiety disorder, and post-traumatic stress disorder. , obsessive-compulsive disorder, acute stress disorder, sch phobia, premenstrual dysphoric disorder, psychosis and Huntington's disease, as well as Parkinson's dementia, adjustment disorder, pain, vomiting, migraine, epilepsy, obesity, cerebrovascular disease. (at)

In particular, the compounds of this invention are considered useful in the treatment of depression, manic depression, bipolar disorder, psychotic depression, mixed anxiety and depressive disorder, generalized anxiety disorder, social anxiety disorder, panic anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, acute stress disorder, phobia, premenstrual dysphoric disorder and psychosis. what,

Thus, in another aspect, the present invention provides a pharmaceutical composition containing at least one compound of formula I as defined above, or a pharmaceutically acceptable acid addition salt thereof in a therapeutically effective amount and in combination with one or more pharmaceutically acceptable (same carriers or diluents

In the next aspect, the present invention relates to the use of a compound of formula I as defined above, or its acid addition salt for the manufacture of a pharmaceutical preparation for the treatment of the above-mentioned disorders.

Compounds of the general formula | can exist in the form of optical isomers, and such optical isomers are also included in the invention. In this description and in the claims, references to specific compounds refer to c racemates, unless otherwise specified.

The term "C. 6 -alkyl" refers to a branched or unbranched alkyl group containing from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2- butyl, 2-methyl-2-propyl and 2-methyl-1-propyl. The terms "C1-4 alkyl", "C40-alkyl" and "C1-42-alkyl", respectively, also refer to a branched or unbranched alkyl group containing from one to eight, ten or twelve carbon atoms inclusive , respectively.

Likewise, "Co d -alkenyl" and "Co b -alkynyl", respectively, mean groups containing from two to six carbon atoms, including one double bond and one triple bond, respectively, such as ethenyl , -1 propenyl, butenyl, ethynyl, propynyl and butynyl.

The term "C3-8-cycloalkyl" means a monocyclic or bicyclic carbocycle containing from three to eight C atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, and the like. sl Halogen means fluorine, chlorine, bromine or iodine.

As used herein, the term "acyl" refers to a formyl,

C. γ-alkylcarbonyl arylcarbonyl, aryl-C. β-alkylcarbonyl, C3.8-cycloalkylcarbonyl or

C3.b-cycloalkyl-C4 6b-alkylcarbonyl group, and the term "thidnzacil" means the corresponding acyl group in which the carbonyl group is replaced by a thiocarbonyl group.

GF) The terms "Cu c-alkyl group", "C c c-cycloalkyl-C c alkyl", "C c alkylsulfonyl", "C c alkylamino group",

F "Ci-6-alkylcarbonyl" and the like mean such groups in which the C 4-6-alkyl and the C 3-1-cycloalkyl group have the meanings as defined above. The term "aryl" refers to a carbocyclic aromatic group such as phenyl or naphthyl, especially phenyl.

The term "heteroaryl" refers to 5-membered monocyclic rings such as 1H-tetrazolyl,

ZH-1,2,3-oxathiazolyl, 1H-1,2,4-oxathiazolyl, 1H-1,2,5-oxathiazolyl, 1,3,2-oxathiazolyl, 1,3,4-oxathiazolyl, 1,4, 2-oxathiazolyl, 1H-1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,4,2-dioxazolyl, 1H-1,2,3-dithiazolyl, 1H-1,2,4-dithiazolyl, 1,93,2-dithiazolyl, 1,4,2-dithiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 65 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1 ,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1H-1,2,3-triazolyl, 1H-1,2,4-triazolyl , isoxazolyl, oxazolyl, isothiazolyl, thiazolyl,

1H-imidazolyl, 1H-pyrazolyl, 1H-pyrrolyl, furanyl, thienyl, 1H-pentazole; to β-membered monocyclic rings such as 1,2,3-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl, 1,3,5-oxathiazinyl, 1,4,2 -oxathiazinyl, 1,4,3-oxathiazinyl, 1,2,3-dioxazinyl, 1,2,4-dioxazinyl, AN-1,3,2-dioxazinyl,

AN-1,3,5-dioxazinyl, 1,4,2-dioxazinyl, 2H-1,5,2-dioxazinyl, 1,2,3-dithiazinyl, 1,2,4-dithiazinyl,

AN-1,3,2-dithiazinyl, AN-1,3,5-dithiazinyl, 1,4,2-dithiazinyl, 2H-1,5,2-dithiazinyl, 2H-1,2,3-oxadiazinyl, 2H- 1,2,4-oxadiazinyl, 2Н-1,2,5-oxadiazinyl, 2Н-1,2,6-oxadiazinyl, 2Н-1,3,4-oxadiazinyl, 2Н-1,3,5-oxadiazinyl, 2Н- 1,2,3-thiadiazinyl, 2Н-1,2,4-thiadiazinyl, 2Н-1,2,5-thiadiazinyl, 2Н-1,2,6-thiadiazinyl, 2Н-1,3,4-thiadiazinyl, 2Н- 1,3,5-thiadiazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 70 1,3,5-triazinyl, 2H-1,2-oxazinyl, 2H-1,3-oxazinyl, 2H -1,4-oxazinyl, 2H-1,2-thiazinyl, /-2H-1,3-thiazinyl, 2H-1,4-thiazinyl, pyrazinyl, pyridazinyl, pyrimidyl, pyridyl, 2H-pyranyl, 2H-thiinyl; and to bicyclic rings such as 1H-1,2,3-benzoxathiazolyl, 1,3,2-benzodioxazolyl, 1H-1,2,3-benzodithiazolyl, 1,3,2-benzodithiazolyl, benzofurazanil, 1,2,3 -benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, 1H-benzotriazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, benzoxazolyl, 1,2-benzisbthiazolyl, 2,1-benzisothiazolyl, benzothiazolyl . -benzodithiolyl, 1,3-benzodithiolyl, 1H-indolyl, 2H-isoindolyl, benzofuranyl, isobenzofuranyl, 1-benzothienyl, 2-benzothienyl, 1H-2,1-benzoxazinyl, 1H-2,3-benzoxazinyl, 2H-1,2 -benzoxazinyl, 2Н-1,3-benzoxazinyl, 2Н-1,4-benzoxazinyl, 2Н-3,1-benzoxazinyl, 1Н-2,1-benzothiazinyl, 1Н-2,3-benzothiazinyl, 2Н-1,2-benzothiazinyl . 1H-2-benzothiopyranil or 2H-1-benzothiopyranil.

Acid addition salts of the compounds of this invention are pharmaceutically acceptable salts formed with non-toxic acids. Examples of such organic salts are maleic, fumaric, benzoic, ascorbic, amber, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, milky, malic, almond, cinnamon, citraconic, aspartic salts. , stearic, palmitic, ithaconic, glycolic, p-aminobenzoic, (o) glutamic, benzenesulfonic and theophylline acetic acids, as well as formed with 8-halotheophyllines, for example, 8-bromoteophylline. Typical examples of inorganic salts are salts of hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids. Pharmaceutical compositions according to the present invention or pharmaceutical compositions prepared according to the present invention can be administered by any suitable route, for example, orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for other ections Methods well known in the art can be used to prepare such compositions, and any pharmaceutically acceptable carriers, diluents, excipients or other additives commonly used in the art can be used. co

For convenience, the compounds of the present invention are administered in a unit dosage form containing the specified compounds in an amount of approximately 0.01 to 10 µg.

The total daily dose is usually in the range of about 0.05-500Omg and most preferably from about 0.1 to 5Omg of the active compound of this invention. "

The compounds of the invention can be obtained as follows: - c 1) Alkylation of piperazine, piperidine or tetrahydropyridine of the formula PP with an alkylating derivative of the formula II: z o -j - 1 sp (Ф) io) bo b5

Ba ke di

I / t t 7 where on s shch (1) (p) o where K"-KZ and O are as defined above, and | is a leaving group, such as, for example, halogen, mesylate or tosylate; 2) Reductive alkylation of the amine of the formula I with the reagent of the formula IM:

ЧИ со дл / х - I и о, и . 7 MA in so ke - - t (a) c 50 where K"-KU | O are as defined above, and E is an aldehyde or an activated carboxylic acid; "sl C) Acylation of an amine of formula M using a carboxylic acid and oxidizing reagent, activated ester, acid chloride, isocyanate, carbamoyl chloride, or in a two-stage way by treatment with phosgene followed by the addition of an amine:

F) ko 60 b5

; p» re vk» e

F | be and "t" EE c (U 5) where B!-B8Z and O are as defined above, with further isolation of the compound of formula I in the form of a free base or its pharmaceutically acceptable acid addition salt.

Alkylation according to method 1) is easily carried out in an organic solvent, such as alcohol or ketone boiling at the appropriate temperature, preferably in the presence of an organic or inorganic base Mu (potassium carbonate, diisopropylethylamine or triethylamine) at reflux temperature. Alternatively, the alkylation can be carried out at a constant temperature, which is different from the boiling point, in one of the above-mentioned solvents or in dimethylformamide (DMF), dimethylsulfoxide (DMSO) or

M-methylpyrrolidin-2-one (MMP), preferably in the presence of a base. Alkylating agents of formula II can be prepared by methods similar to those described in the examples, or can be synthesized using methods described in standard works such as Noshrep-U/eu!I, Meijodep deg ogdapizspep Spetij (Meijodz Ogdapis Spetivighu),

Seogod-Gpiete-Megiad, Zishydag Oghdapis Keasiopv, add. UMUyeu 5 Bopv, Ips. Mem MogK, namely under such reaction conditions that are known and suitable for such reactions. Amines of formula I are either commercially available or described in the literature, or can be obtained by methods similar to those described in the literature, for example, Magheg eyi 740 a... Ogd. Spent 1975, 40, 1427, Rashat ei aYi. U. Ogd. Spent 1976, 41.2628 and Vatseg ei a). U. Mea. Spent shi p 1976,19,1315, Maiiidgez ei aiYi. Teiapedgoop 1997,53,10983 and Sped ei a). That's it. 1997. 41,1218-1235), or can be synthesized by methods described in standard works such as

I(Noirep-UUeu!, Meijodep deg ogdapizspep Spetiye (Meijodv Ogdapis Spetivigu), Seogod-Ppiete-Megiad, ZYishkdagi;

Ogdapis Keasiopv, add. UMPeu 5 Bopv, Ips. Mem/ MogKk)|), namely under such reaction conditions that are known and suitable for such reactions. - Reductive alkylation according to method 2) is carried out according to standard methods described in the literature, or as described in standard works, such as |Notsrep-U/eu!Y, Meijpodep deg ogdapizspep Spetie (Mejodz Ogdapis - Spetivigu), beogd-Tpiete-Megpiad , Trouble; Ogdapis Keasipv, add. UMPeu 5 Bopv, Ips. Mem/ HogKk), namely under such reaction conditions that are known and suitable for such reactions. The reaction can be carried out in two stages, for example, by combining amines of formula PI with a reagent of formula IM by standard methods using carboxylic acid chloride, activated esters or using carboxylic acids in combination with coupling reagents such as, for example, dicyclohexylcarbodiimide, with subsequent reduction of the resulting amide with lithium aluminum hydride or alane. Carboxylic acids of formula IM are either commercially available or can be obtained by methods similar to those described in the literature (for example, Tei Ie. 37, 1996, pp. 5453-5456; Tei Ie. 35, 1994, pp. 6567-6570; 9 May. Spet. 25, 1982, pp. 1235-1240; Zupipevz 1987, pp. 474-477). Acylation according to method 3) is easily carried out by standard methods using carboxylic acid chloride, activated esters or using carboxylic acids in combination with binding reagents, such as, for example, dicyclohexylcarbodiimide. In the case when the acylating reagents are carbamoyl chlorides or isocyanates, acylation gives urea derivatives. Urea derivatives can also be obtained by a two-stage method, which consists in treatment with phosgene followed by the addition of an amine.

Intermediate compounds of formula M are prepared as described in methods 1) and 2), where B2-KU, O, 1 and E are as defined above, and ' is a protecting group. Said protecting group may be selected from protecting groups commonly used to protect amino groups. Those skilled in the art are well aware of how to select appropriate protecting groups and how to protect and deprotect amines in the case of said protecting groups.

Experimental section

Melting points were determined on the Wyspi BMR-20 apparatus and were not corrected. LC-MS analysis data were obtained on the RE Zsiekh АРИ 150ЭХ device, equipped with the Iopbrgau source and the 5pitaidga IС-8А/5I С-10А РХ system. Conditions

PH (column С18 4.х3О0mm with a particle size of 3.5μm) had a linear elution gradient from a mixture of water/acetonitrile/trifluoroacetic acid (90:10:0.05) to a mixture of water/acetonitrile/trifluoroacetic acid (10:90:0, 03) for 4 minutes at 2 ml/min. Purity was determined by integrating the UV curve (254 nm). Holding time,

KE, expressed in minutes. 70 Mass spectra were obtained by the method of reverse-progressive scanning to obtain information about the molecular mass. The molecular ion, MH, was obtained at a low voltage on the diaphragm (5-208) and fragmentation - at a high voltage on the diaphragm (100-2008).

Preparative LC-MS separation was performed on the same device. The LC conditions (column C18 20 x 50 mm with a particle size of 5 μm) had a linear elution gradient from a mixture of water/acetonitrile/trifluoroacetic acid (75 80:20:0.05) to a mixture of water/acetonitrile/trifluoroacetic acid (5:95:0.03 ) for 7 minutes at 22.7 ml/min.

Fractional collection was performed using MO-detection of a branched flow.

TN-NMR spectra were recorded at 500.13 MHz on a Vgykeg Amapse OVH5O0O device or at 250.13 MHz on a VgyKeg AS 250 device. Deuterated chloroform (99.895 0) or dimethyl sulfoxide (99.995 0) were used as solvents. As an internal standard, tetramethylsilane ( TM5). The values of 20 chemical shifts were expressed in parts per million (ppm). The following abbreviations were used to denote the multiplicity of NMR signals: c - singlet, d - doublet, t - triplet, k - quartet, q - quintet, d - heptet, dd - double doublet, dt - double triplet, dk - double quartet, tt - triplet of triplets, m - multiplet. NMR signals corresponding to acidic protons were practically neglected. Silica gel of the Kieseide type was used for column chromatography! 60,230-400 mesh according to A5BTM. For ion exchange with 25 chromatography, the following materials were used: ZSX columns (1g) from Magpap Meda Wopia Ash, Spgotrask catalog number 220776. Before use, 5SX columns were pre-conditioned at 1095 with a solution of acetic acid in methanol (Zml).

Preparation of intermediate compounds

Alkylating reagents of the formula ІІ о) 30 1. Tert-butyl ester of (K5)-1-(2-bromo-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid

Tetrahydroisoquinolinic acid (10g) was suspended in tetrahydrofuran, THF (100ml). Triethylamine (9 mL) and di-tert-butyl dicarbonate (14.3 g) were added and the mixture was stirred at room temperature for 16 hours. -

The mixture was concentrated in vacuo, re-dissolved in ethyl acetate (25 Oml) and washed twice with an aqueous solution of 0.5 M KZNO (200 ml), dried over magnesium sulfate and evaporated in vacuo to give the tert-butyl ester

1-carboxymethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid with a quantitative yield in the form of a transparent oil, which crystallized on standing. The protected amino acid was dissolved in anhydrous tetrahydrofuran under a nitrogen atmosphere, cooled to 02С, and 1M borane in tetrahydrofuran (41.5 ml) was slowly added under a nitrogen atmosphere over 15 min. The mixture was heated to room temperature and stirred for 1 hour. Excess borane was carefully destroyed by slowly adding 5 ml of a 1:1 water/tetrahydrofuran mixture. The mixture was alkalinized to pH 40 by adding a saturated solution of potassium carbonate and extracted with diethyl ether (2 hbBOml). The combined organic phase was dried (magnesium sulfate) and evaporated in vacuo to give 1-(2-hydroxyethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester as a clear oil (8.4g). The protected amino alcohol was dissolved in anhydrous tetrahydrofuran (15 Oml) together with triethylamine (5.bml) and cooled to 02C in a nitrogen atmosphere. Methanesulfonyl chloride (2.64 mL) was added dropwise over 15 minutes in anhydrous

THF (3 mL), the mixture was heated to room temperature and stirred for 30 min. After filtration and concentration under vacuum, the clear oily residue was dissolved in acetone (300 ml), lithium bromide (14.6 g) was added and the mixture was refluxed for 1 hour. The mixture was filtered, evaporated in vacuo, and the product was purified by chromatography on a column with silica gel, using a mixture of ethyl acetate/heptane (1:1) as eluent, and the fractions containing the product were combined and evaporated in vacuo, obtaining 50 c of tert-butyl (K5)-1-(2-bromo-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid ester in the form of a transparent oil (8g), which crystallized on standing. sl In a similar way, the following compound was obtained:

Tert-butyl ester (K5)-1-(2-bromo-ethyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid.

Piperidines of formula PI

Piperidine derivatives of the formula I, where X means oxygen, 7 means SEUB'O, Y means a bond, A", A? and A?

ГФ) mean CH, AZ means CE", that is, spiro(isobenzofuran-1(ZN),4-piperidines) are obtained according to the methods,

Ф described | Magheg ей айЙ. U. Ogd. Spent 1975,40, 1427, Ratat ei aY. U. Ogd. Spent 1976,41,2628 and Vatseg ei ai.

U. Med. Spent 1976,19,1315). 60 The following compounds were obtained in a similar way: b-fluorospiro(isobenzofuran-1(Z3H),4"-piperidine b-trifluoromethylspiro|(isobenzofuran-1(ZH),4-piperidine b-fluoro-3-methylspiro|(isobenzofuran-1( ЗН),4-piperidine b-trifluoromethyl-3-methylspiro(isobenzofuran-1(З3Н),4-piperidine 65 5-methylspiro(isobenzofuran-1(ЗН),4-piperidine b-fluoro-3-isobutylspiro|(isobenzofuran- 1(Z3H),4"-piperidines b-fluoro-3-cyclohexylspiro(isobenzofuran-1(ZH),4-piperidines and b-fluoro-3-(4-fluorophenyl)spiro(isobenzofuran-1(ZH),4- piperidine|.

Piperidine derivatives of the formula II, where X means SEUV "9, 7 means ME, Y means bond, A", A? and A? mean СН,АЗmeans СК" and Кк"! is fluorine or trifluoromethyl, obtained according to the methods described by IMaijdgev et al.

Teigapedgop 1997,53,10983, and Spepo ei ai. Tei. And ek. 1997, 38, 1497).

In a similar way, the following compound was obtained: 1-acetyl-5-fluorospiro|2,3-dihydro-1H-indole-3,4"-piperidine.

Piperidine derivatives of the formula I, where X means SVEUV"O, 7 means oxygen, Y means a bond, A", A? and A? 70 means CH, AZ means SW", i.e. 2,3-dihydrospiro(benzofuran-3,4-piperidines), obtained according to the methods described | Spep, Mepao-Nvip; Abgapat, Chuoypp A. Teigapedgop Gay. 1996, 37, 5233 -5234 and Biade, R.O. ei a). U. Med. Spet. 1998, 41, 1218-1235).

The following compounds were obtained in a similar way: 2,3-dihydro-5-fluorospiro|(benzofuran-3,4-piperidine and 15 2,3-dihydro-5,6-difluorospiroIbenzofuran-3,4''-piperidine.

Substituents K -K are introduced using appropriately substituted starting compounds in methods similar to those indicated above.

Amines of formula M

The amine of the formula M was obtained by the following method: 20 A mixture of the amine of the formula SH (Immol), tert-butyl ester (k5)-1-(2-bromo-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (1 .3mmol) and potassium carbonate (1.3mmol) in acetonitrile (2Oml) was heated to 859 for b hours. The mixture was cooled to room temperature and evaporated in vacuo to give a yellow oily residue. The product was re-dissolved in dichloromethane (10ml), anisole (0.2bml) and trifluoroacetic acid (10ml) were added, and the mixture was stirred at room temperature with 25°C for 90h. The mixture was evaporated in vacuo. The product was either purified by chromatography or (He) was used directly in the next step without purification.

The following compounds were purified by chromatography before further use: (k5)-1-42-I4-(5-fluoro-1H-indol-3-yl)piperidin-1-yl|ethyl-1,2,3,4-tetrahydroisoquinoline (k5 )-1-2-Ib-fluorospiro|(isobenzofuran-1(Z3H),4-piperidin-1-yl|ethyl)-1,2,3,4-tetrahydroisoquinoline. yuyu 30 Enantiomeric forms of amines of the formula M yu

Enantiomer 1 and enantiomer 2M-4-(3-fluorophenyl)-1-(2-(1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl|piperidine-4-ilyacetamide -

Racemic M-(4-(3-fluorophenyl)-1-(2-(1,2,3,4-tetrahydroisoquinolin-1-yl)lethyl|Ipiperidin-4-ylacetamide) was separated by chiral HPLC using a supercritical liquid chromatography SiVop 35 ZEZ, equipped with Spigaise columns (4.mm x 25 cm for analytical and 1 mm x 25 cm for preparative separation). The particle size in the columns was 10 μm. The solution of the racemic compound

M-14-(33-fluorophenyl)-1-(2-(1,2,3,4-tetrahydroisoquinolin-1-yl)lethyl|piperidin-4-yl) acetamide (1 g) in methanol (1 mL) was injected portions of 40 μl per preparative column. The column was eluted with a mixture of carbon dioxide and modifier (75:25). The modifier was 2-propanol with diethylamine (0.595) and trifluoroacetic acid (0.596). Consumption was 18.9 ml/min. at 20 MPa. Fractional collection was determined using UV detection with C (210nm). Fractions containing separate products were combined and evaporated in a vacuum, obtaining enantiomers. c» The first eluted enantiomer was named enantiomer 1, and the second eluted enantiomer was named /2M-14-(3-fluorophenyl)-1-(2-(1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl|piperidin- 4-iliacetamide.

Enantiomers were estimated by HPLC to give an enantiomeric excess greater than 95965.

The following enantiomers were similarly obtained: enantiomer 1 and enantiomer 2M-4-(phenyl)-1-(2-(1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl|piperidin-4-yl)iacetamide. Examples

Preparation of compounds of the invention

Sh- The compounds of this invention were obtained by one of two general methods: c 20 Method A: Alkylation of piperidine of formula II with an alkylating derivative of formula II:

A mixture of piperidine of the formula Ш (1 mmol), tert-butyl ester of sl (K,5)-1-(2-bromomethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (1.3 mmol) and potassium carbonate ( 1.3 mmol) in acetonitrile (2 Oml) was heated at 859 for b hours. The mixture was cooled to room temperature and evaporated in vacuo. The product was purified by chromatography either on silica gel using a mixture of 59 ethyl acetate/triethylamine (99:1) as eluent, or by HPLC. Fractions containing the product were combined and evaporated in

HF) vacuum.

Method B: Acylation of an amine of formula M using a carboxylic acid and a binding reagent such as an activated ester, acid chloride, or isocyanate:

The amine of formula M (prepared as described above; Tmmol) and triethylamine (bmmol) were dissolved in anhydrous acetonitrile (10ml). Appropriately substituted acid chloride (mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. Methanol (0.5 ml) was added to the reaction mixture followed by evaporation in a vacuum. The product was purified by chromatography either on silica gel using a mixture of ethyl acetate/triethylamine (99:1) as eluent, or by HPLC. Fractions containing the product were combined and evaporated in vacuo and characterized by HPLC-UV-EIA 50-MS. The measured HPLC retention time, measured molecular weight and purity in UV and EI 50 are shown in Table 1.

The following compounds were prepared according to the methods indicated in Table 1. Analytical data are shown in Table 1.

Compounds 1...1-(142-I4-(5-Fluoro-1H-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-1 -(4-fluorophenyl)methanone 2. 1-cyclopentyl-1-(1-(2-I(4-(5-fluoro-1H-indol-3-yl)piperidin-1-yl|ethyl)-3,4 -dihydro-1H-isoquinolin-2-yl)umethanone

C. Phenethylamide of 1-2-I4-(5-fluoro-1H-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4. 1-( 142-I4-(5-Fluoro-1H-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-1-phenylmethanone 5. 1-(1 -432-I(4-(5-Fluoro-1H-indol-3-yl)piperidin-1-ylethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-1--2-fluorophenyl)methanone 70 6. 1-(1-42-I(4-(5-Fluoro-1H-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl) -3-phenylpropan-1-one 7. (3-Chloropropyl)amide 1-2-I4-(5-fluoro-1H-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro- 1H-isoquinoline-2-carboxylic acid 8. (2-Methoxyphenyl)amide 1-2-I4-(5-fluoro-1H-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro- 1H-isoquinoline-2-carboxylic acid 9. Tert-butyl ester 1-2-I4-(5-fluoro-1H-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-1H- of isoquinoline-2-carboxylic acid 10.

3-Chloro-1-(1-2-I4-(5-fluoro-1H-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)- 2,2-dimethylpropan-1-one 12. 1-Cyclopentyl-1-(1-72-(b-fluorospiro(isobenzofuran-1(ZH),4-piperidin-1'-yl|ethyl)-3,4- dihydro-1H-isoquinolin-2-yl)methanone 13. 1--2--4-Chlorophenoxy)pyridin-3-ylI-1-(1-2-|Ib-fluorospiro(isobenzofuran-1(ZH), 4 - piperidan-1-yl|ethyl)-3,4-dihydro c two 71 H-isoquinoline-2-ylumethanone 14. Tert-butyl ester (8) 1-2-Ib-fluorospiro(isobenzofuran-1(Z3H),4- piperidin-1'-ylethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 15. 1-(1-2-(6-Fluorospiro(isobenzofuran-1(ZH),4"-piperidine- 1'-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-1-phenylmethanone 16. that 1-(1-2-(6-Fluorospiro(isobenzofuran-1(ZH),4 -piperidin-1'-ylethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-1-paratolylmio)ethanone y- 17. 1-(1-2-(6-Fluorospiro(isobenzofuran- 1(3H),4-piperidin-1'-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-1-(2-methoxy h-phendmethanone so 1-Cycloheptyl-1-(1 -(2-Ib-fluorospiro|(isobenzofuran-1(Z3H),4-piperidine-1'-ilyethyl)-3,4-d hydro-1H-isoquinolin-2-yl)methanone 19.1--2-Fluorophenyl)-1-(1-(2-(b-fluorospiro(isobenzofuran-1(3H),4-piperidin-1"-yl|ethyl) -3,4-dihydro-1H-isoquinolin-2-yl)umethanone from p 20. 1--2-Chlorophenyl)-1-(1-2-Ib-fluorospiro(isobenzofuran-1(ZH),4- piperidin-1'-ilyethyl)-3,4-dihydro-1H-isoquinoline-2-zyl)umethanone 21. 1--4-Fluorophenyl)-1-(1-2-(b-fluorospiro (isobenzofuran-1 ЗН), 4-piperidin-1'-ylethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone oo 22. 1--4-Chlorophenyl)-1-(1-2-Ib-fluorospiro isobenzofuran-1(ZH),4-piperidine-1'-ilyethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone-1 23. Phenethylamide 1-2-Ib-fluorospiro(isobenzofuran-1 (ZH),4-piperidin-1"-yl|ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1 24. 1-(1-2-(6-Fluorospiro sl (isobenzofuran-1( ЗН), 4-piperidin-1'-ilyethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-1--4-methoxyphenyl)methanone 25. 1-(1-2-(6-Fluorospiro 26.

HF) 2-ethyl-1-(1-2-(b-fluorospiro(isobenzofuran-1(ZH),4-piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl) butan-1-one 27. with 1-(1-2-(6-Fluorospiro(isobenzofuran-1(Z3H),4-piperidin-1'-yl|ethyl)-3,4-dihydro-1H-isoquinoline-2 -yl)-1-"3-methoxy-phenyl)methanone 28. 1-(1-2-(6-Fluorospiro(isobenzofuran-1(Z3H),4-piperidin-1'-yl|ethyl)-3,4 -dihydro-1H-isoquinolin-2-yl)-2-phenylethanone 29. 3-Cyclohexyl-1-(1-2-(b-fluorospiro(isobenzofuran-1(ZH),4-piperidin-1-yl|Iethyl) -3,4-dihydro-1H-isoquinolin-2-yl 65)propan-1-one 30.

2-(4-Fluorophenyl)-1-(1-(2-(b-fluorospiro(isobenzofuran-1(ZH),4-piperidin-1'-yl|ethyl)-3,4-dihydro-1H-isoquinoline- 2-yl)ethanone 31. (3,4-Dichlorophenyl)amide 1-2-Ib-fluorospiro(isobenzofuran-1(ZH),4-piperidin-1"-yl|Hethyl)-3,4-dihydro-1H- of isoquinoline-2-carboxylic acid 32. 1-Cyclopropyl-1-(1-(2-(b-fluorospiro(isobenzofuran-1(ZH),4-piperidin-1'-yl|ethyl)-3,4-dihydro- 1H-isoquinolin-2-yl)methanone 33. 70 1-(1-2-(6-Fluorospiro(isobenzofuran-1(ZH),4-piperidin-1'-ylethyl)-3,4-dihydro-1H -isoquinolin-2-yl)-1-pyridin-3-ylmethanone 34. 1-(5-«4-Chlorophenyl)-2-methylfuran-3-yl|-1-(1-2-Ib-fluorospiro(isobenzofuran- 1(ZH),4-piperidin-1-yl|ethyl)-3,4-dighydro-1H-isoquinolin-2-yl)umethanone 35. 2-(4-Chlorophenyl)-1-(1-2-I6 -fluorospiro (isobenzofuran-1(ZH),4-piperidin-1'-ilyethyl)-3,4-dahydro-1H-isoquinolin-2-yl)ethanone 36. 1-(1-2-(6-Fluorospiro(isobenzofuran -1(ZH),4-piperidin-1'-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-2-methylpropan-1-one 37. (2-Ethylphenyl)amid- 1-(2-Ib-fluorospiro(isobenzofuran-1(ZH),4-piperidin-1'-ilyethyl)-3,4-dihydro-1H-is oquinoline-2-k arbonic acid 38.

IM-(1-422-(2-(1-Cycloheptylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-yl|butyl)-4-(3-fluorophenyl)piperidine-4-ilyacetamide with 39. that 1 -Cyclopentyl-1-(1-72-(b-fluoro-3Z-methylespiro(isobenzofuran-1-(ZH),4"-piperidin-1'-yl||ethyl)-3,4-dihydro-1H-isochy (8) nolin-2-yl)umethanone 40. 1-Cycloheptyl-1-11-(/1-acetylspiro|(2,3-dihydro-1H-indol-3,4"-piperidin-1-yl|Ivethyl| -3,4-dihydro-1H-isoquinoline-2-yu

Zoyl)methanone 41... M-(1-22-(2-(1-cycloheptylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-ylylethyl)-4-phenylpiperidin-4-yl)acetamido) 42. 1-Cycloheptyl-1-(1-(2-Ib-fluorospiro|(isobenzofuran-1(Z3H),4-piperidin-1'-ilyethyl)-3,4-dihydro-6,7-dimethoxy-1H- and that zoquinolin-2-yl)umethanone h- 13. (ee) 1--4-Fluorophenyl)-1-(1-72-(b-fluoro-3Z-methylespiro(isobenzofuran-1(ZH),4-piperidine -1'-ilyethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 44. 1-Cycloheptyl-1-(1-(2-(5-fluoro-1-methanesulfonylspiro(|2,3 -dihydro-1H-indol-3,4-piperidin-1-yl|ethyl)-3,4-dihydro « 40. 9-1H-isoquinolin-2-ylumethanone from p 45. 1-(1-42-(2 -(1-cycloheptylmethanol)-1,2,3,4-tetrahydroisoquinoline-1-ylethyl)-4-phenylpiperidin-4-yl)-1-piperidin-:3-ylmethanone 46. 1-x4-Fluorophenyl)- 1-(1-(2-(5-fluoro-1-methanesulfonylpyro|2,3-dihydro-1H-indole-3,4-piperidin-1-yl|ethyl)-3,4-dihydro-1H- isoquinolin-2-yl)umethanone 47. 1-Cycloheptyl-1-(1-42-(4--2-methyl-1H-indol-3-yl)piperidin-1-yl|ethyl)-3,4 -dihydro-1H-isoquinolin-2-yl)umethanone -1 48. doro 1-Cycloheptyl-1-(1 -42-I4-(3-trifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-ylumethanone 1 49. sl 1-Cyclopentyl-1-(1-72-(b- fluoro-33-methylespiro(isobenzofuran-1(ZH),4-piperidin-1'-ilyethyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)umethanone 50. 1-Cyclopentyl -1-1 1-Ispiro(2,3-dihydro-1H-indole-3,4-piperidin-1-yl|ethyl/|-3,4-dihydro-1H-isoquinoline-2-ylumethanone 51. 1-Cyclopentyl -1-(1-2-15-fluoro-1-methanesulfonylspiro|2,3-dihydro-1H-indole-3,4"-piperidin-1-yl

HF) ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone t 52. 1--4-Fluorophenyl)-1-(1-72-I(b-fluoro-3Z-methylspiro(isobenzofuran- 1(ZH),4-piperidin-1'-ylethyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-ylumethanone 53. 1--2-Fluorophenyl)-1-( 1-72-(b-fluorospiro(isobenzofuran-1(ZH),4-piperidin-1'-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)methanone 54. 65 1-cycloheptyl- 1-(1-72-(spiro(isobenzofuran-1(Z3H), "4-piperidin-1'-ilyethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 55.

1-cycloheptyl-1-(1-72-(b-fluoro-3Z-methylespiro(isobenzofuran-1(ZH),4-piperidin-1'-ilyethyl)-3,4-dihydro-6,7-dimethoxy- 1H-isoquinolin-2-yl)umethanone 56. 1-(1-42-I(4-(4-Chlorophenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl) -1-cycloheptylmethanone 57. and 1-Cyclopentyl-1-(1-72-(5-isopropylspiro(isobenzofuran-1(ZH),4-piperidin-1'-yl|ethyl)-3,4-dihydro-1H- isoquinoline -2-yl)umethanone 58.

IM-(1-422-(2-(1-cyclopentylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-(3-fluorophenyl)piperidin-4-ilyacetamide 70 59. 1- Cycloheptyl-1-11-(2-(4-phenylpiperidin-1-yl)ethyl|-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 60. 1-Cycloheptyl-1-(1-(2- I(b-fluoro-3-methylspiro(isobenzofuran-1(ZH), "4-piperidin-1'-ilyethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 61. 75. 1- Cyclopentyl-1-(1-42-I4-(3-trifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-ylumethanone 62. 1-Cyclopentyl-1-(1-72 -(b-fluorospiro(isobenzofuran-1(ZH),4-piperidin-1'-ilyethyl)-3,4-dihydro-6,7-dimethoxy-1H-i zoquinolin-2-yl)umethanone 63. 1-- 4-Fluorophenyl)-1-(1-52-(b-fluorospiro(isobenzofuran-1(Z3H),4-piperidin-1'-yl|Iethyl)-3,4-dihydro-6,7-dimethoxy-1H - isoquinolin-2-yl)umethanone 64. 1-(1-2-(4-(6-Fluorobenzo|4|isoxazol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinoline -2-yl)-1-(4-fluorophenyl)m ethanone ch 65. 1-(1-(-2-2-(1--4-Fluorophenyl)methanol||-1,2,3,4-tetrahydroisoquinoline -1-yl)ethyl)-4-phenylpiperidin-4-yl|-1-piperidine (8) n-1-ylme tanone 66. 1-Cyclopentyl-1-(1-2-(4-(3-fluorophenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 67. zo 8 -2-(2-(1-Cycloheptylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-1-phenyl-1,3,8-triazaspiro|4,5)|decane-4- He is 68. 1-cycloheptyl-1-(1-72-(b--rifluoromethylspiro|(isobenzofuran-1(Z3H), 4-piperidin-1-yl|ethyl)-3,4-dihydro-6,7- dimetho-xy-1H-isoquinolin-2-yl)umethanone 69. h- 1-(1-«-2-42-(1--2-Fluorophenyl)methanoyl|/|-1,2,3,4- Tetrahydroisoquinolin-1-yl)ethyl)-4-phenylpiperidin-4-yl|-1-(4-methylsopiperazin-1-yl)umethanone 70. Ethyl ester 1-2-(2-(1-cycloheptylmethanol)-1 ,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-phenylpiperidine-4-carboxylic acid 71...1-(142-(2-(1-cycloheptylmethanol)-1,2,3,4- Tetrahydroisoquinolin-1-yl|ethyl)-4-phenylpiperidin-4-yl)ethanone « 72. sho c 1-cyclopentyl-1-(1-12-I(b-trifluoromethylspiro|(isobenzofuran-1(ZH),4- piperidin-1'-ylethyl)-3,4-dihydro-b6,7-dimethyl-1H-isoquinolin-2-yl)umethanone from 73. 1-Cyclopentyl-1-(1-2-I4-(2 -methyl-1H-indol-3-yl)piperidin-1-yl| Ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 74... 1-(1-42-(2--1-CDiclopentylmethanol)-1,2,3,4-tetrahydroisoquinoline-1- yl)|Hyl)-4-phenylpiperidin-4-yl)ethanone 75. sa 1--4-Fluorophenyl)-1-(1-2-(b-trifluoromethylspiro|(isobenzofuran-1(3H),4-piperidine- 1-yl|ethyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)umethanone -1 76. 1-(1-42-I(4-(4-Chlorophenyl )piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone 77. 1 20 1-(1-42-(2-«1- cycloheptylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-ylylethyl)piperidin-4-yl)-1-(4-fluorophenyl)methanone 78. ma 1-(1-42-(2-«1-cycloheptylmethanol) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-phenylpiperidin-4-yl)-1-(4-methylpiperazin-1-yl)umethanone 79. 1-( 1-42-(4--4-Chlorophenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-1-diclopentylmethanone 80.

HF) 1--4-Fluorophenyl)-1-(1--2-I(4--"3--trifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dehydro-1H-isoquinoline-2- yl)umethanone 81. with 1--4-Fluorophenyl)-1-(1-2-Ispiro(isobenzofuran-1(Z3H), 4-piperidin-1'-ilyethyl)-3,4-dihydro-1H-isoquinoline- 2-yl)umethanone 82. 70 1-cyclopentyl-1-(1-12-(I4-fluorospiro(isobenzofuran-1(Z3H), 4-piperidin-1'-ilyethyl)-3,4-dihydro-1H-isoquinoline -2-yl)methanone 83. 1--2-Fluorophenyl)-1-(1-72-I(b-fluoro-3-methylespiro(isobenzofuran-1(ZH),4-piperidin-1'-ilyethyl)- 3,4-dihydro-6,7-dime 65 toxy-1H-isoquinolin-2-yl)umethanone 84. M-I4-(3-Fluorophenyl)-1-(2-2-1-(4-fluorophenyl)methanol |-1,2,3,4-tetrahydroisoquinolin-1-yl ethyl)piperidin-4-yl|acetamide 1--2-Fluorophenyl)-1-11-|Ispiro(2,3-dihydro-1H-indole-3 ,4-piperidin-1'-yl|ethyl1-3,4-dihydro-1H-isoquinolin-2-ylumethanone 86. and 1-cycloheptyl-1-(1-2-15-fluoro-1-methanesulfonylspiro|2,3 -dihydro-1H-indol-3,4"-piperidin-1-yl|butyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)umethanone 87. 1-(1- 42-(2-"1-cycloheptylmethanol)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline -1-yl|ethyl)-4-phenylpiperidin-4-yl 7/0. )-1-piperidin-1-ylmethanone 88... 1-11-(2-(4-Benzylpiperidin-1-yl)ethyl/|-3,4-dihydro-1H-isoquinolin-2-yl)-1- dcycloheptylmethanone 89. 1--2-Fluorophenyl)-1-(1-2-(b-trifluoromethylspiro(isobenzofuran-1(ZH),4-piperidin-1'-ilyethyl)-3,4-dihydro-6,7- dimethoxy-1H-isoquinolin-2-yl)umethanone 90. 1-41-42-(Chlorotrifluoromethylphenyl)hydroxypiperidin-1-yl|ethyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2- yl)-1-C cycloheptylmethanone 91. 1-(1-42-(4--4-Chlorophenyl)-4-hydroxypiperidin-1-yl|ethyl)-6,7-dimethoxy-3,4-dihydro-1H- isoquinolin-2-yl)-1-cycloheptylmethanone 92. 1-Cycloheptyl-1-(1-2-I(4--2-13opropoxyphenyl)piperidin-1-yl|Hethyl)-3,4-dipdro-1H -isoquinolin-2-yl)umethanone 93... 1-(1-42-I4-(7-Chloro-1H-indol-3-yl)piperidin-1-yl|Iethyl)-3,4-dihydro-1H -isoquinolin-2-yl)-1-diclopentylmethanone 94. 1-cyclopentyl-1-(1-12-I4-(2,3-dihydrobenzofuran-7-yl)piperidin-1-yl|ethyl)-3,4- dihydro-1H-isoquinolin-2-yl)umethanone with 95. that 1-(1-2-(4-(2,3-Dihydrobenzofuran-7-yl)piperidin-1-ylylethyl)-3,4-dihydro-1H -isoquinolin-2-yl)-1-(4-fluorophenyl)meth (8) anon 96. LA-(1-4 2-(2--1-cycloheptylmethanol)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-ylethyl)-4-(3 -fluorophenyl)piperidin-4-isoylacetamide 97. 1-(4-Fluorophenyl)-1-11-(2-(4-phenylpiperidin-1-yl)ethyl|-3,4-dihydro-1H-isoquinoline-2 -yl)umethanone io) 98. i- 1-(1-42-(4-(6-Chloro-1H-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-1H- isoquinolin-2-yl)-1-(4-fluorophenyl)methanone 99. 1-(4-Fluorophenyl)-1-(1-2-14-(3-fluorophenyl)piperidin-1-yl|ethyl)-3, 4-dihydro-1H-isoquinolin-2-yl)umethanone h- 100. so 1-Cycloheptyl-1-(1-|Ispiro(2,3-dihydro-1H-indole-3,4-piperidin-1-yl| iethyl/|-3,4-dihydro-b6,7-dimethoxy-1H-isoquinolin-2-yl|methanone 101.

M-(1--2-42-(1-cyclopentylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-phenylpiperidin-4-yl)acetamide « 102. - c 1-( 1-2-(4-(6-Fluorobenzo|4|isoxazol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-1-(2-fluorophenyl) )m ethanone;" 103. 1-cycloheptyl-1-(1-72-I(spiro(isobenzofuran-1(ZH), "4-piperidin-1'-ilyethyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquino /Lin-2-ylumethanone oo 104. Ethyl ester of 1-2-(2-(1-cyclopentylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-4-phenylpiperidine-4-carboxylic acid - 105. -1 1-(1-42-(4--4-Dimethylaminophenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-1--4-fluorophenyl) methanone 106. 1-cyclopentyl-1-(1-12-(4-(4-isopropylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 1 107. 1 -(1-(2-42-| 1--4-Fluorophenyl)methanol/|-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-4-phenylpiperidin-4-yl]iethanone cl 108. .1-(1--2-42-1-(2-Fluorophenyl)methanol|)-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-4-phenylpiperidin-4-yl|Ivtanone 109, 1-(1-(-2-2-(1--2-Fluorophenyl)methanol|-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-4-phenylpiperidin-4-yl|-1- piperids two H-1-yl-methanone 110. 1-cyclopentyl-1-41-(2-(4-phenylpiperidin-1-yl)ethyl/|-3,4-dihydro-1H-isoquinolin-2-ylumethanone (F ) 111.

F 1--2-Fluorophenyl)-1-(1-72-(b-fluoropyro(isobenzofuran-1(ZH),4-piperidin-1'-yl|ethyl)-3,4-dihydro-6,7- dimethoxy-1H-isoquinolin-2-yl)umethanone 60 112. 1--4-Fluorophenyl)-1-(1-2-I(5,6-difluorospiroI(benzofuran-1(3H),4-piperidine-1' -ylethyl)-3,4-dihydro-1H-isoquinoline-2-yl-methanone 113. 1--4-Fluorophenyl)-1-(2-Ib-fluorospiro|(benzofuran-1(3H),4-piperidine- 1'-ylethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umet b/anone 114.

3,3-Dimethyl(|1-(2-Ispiro(5-fluorobenzofuran-2H-3,4"-piperidin-1'"-yl))ethyl)-3,4-dihydro-1H-isoquinolin-2-yl )butan-1-one

Cyclohexyl|1-2-(spiro(5-fluorobenzofuran-2H-3,4"-piperidin-1'-yl))ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 116.

Cyclohexyl(1-12-Ispiro(5-methylisobenzofuran-ZH-1,4"-piperidin-1'-yl/ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)methanone 117. Cyclohexyl(| 1-72-Ispiro(benzofuran-ZN-1,4"-ylperidin-1'-yl)ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 118. Cyclohexyl (1-(2- 14-(2-methyl-1H-indol-3-yl)/piperidin-1-yl|1ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 70 119... M-11-( 2-(2-Cyclohexanecarbonyl-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-4-phenylpiperidin-4-ylyl acetamide 120. 3,3-Dimethyl-1-(1-72-I4-(Z -trifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)butan-1-one 121. Cyclohexyl(1-2-I4-(3-trifluoromethylphenyl)piperidine-1- yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 122. Cyclohexyl(1-(2-I(4--(4-dimethylaminophenyl)piperidin-1-yl|Iethyl)-3, 4-dihydro-1H-isoquinolin-2-yl)umethanone 123.

3-Phenyl-1-(2-Ispiro(5-fluorobenzofuran-2H-3,4"-piperidin-1'-yl))|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)|Ipropanone 124. (1-2-I(4-(4-Chloro-3-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl|ethyl)-6, 7-dimethoxy-3,4-dihydro-1H-isoquinoline-2 - yl)ucyclohexylmethanone 125. 2-Phenoxy|1-12-Ispiro(5-fluorobenzofuran-2H-3,4-piperidin-1-yl)Dethyl)-3,4-dihydro-1H-isoquinolin-2-yl|Ethane- 1-on 126.

Benzo!|1,2,5|oxadiazol-5-yl(1-(2-Ispiro(5-methylisobenzofuran-ZH-1,4"-piperidin-1'-yl))|ethyl)-3,4-dihydro -1H-isoquinolin-2-yl)umethanone c 127. Cyclohexyl(1-12-14-(4-isopropylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl) umethanone 128. o) 2-propyl|1-42-I(Ispiro(5-fluorobenzofuran-2H-3,4-piperidin-1-yl)lethyl)-3,4-dihydro-1H-isoquinolin-2-yl) |pentan-1-one 129. 2,2-Dimethyl-3-chloro(|1-(2-Ispiro(5-fluorobenzofuran-2H-3,4-piperidin-1-yl)ethyl)-3,4-dihydro -1H-isoquinolin-2-yl isopropan-1-one 130. Io)

Cyclohexyl(1-12-I4-(2,3-dihydrobenzofuran-7-yl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone i- 131. 3,3 -Dimethyl(1-(2-(Ispiro(5-methylisobenzofuran-ZH-1,4"-piperidin-1'-yl))'ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)but h - an-1-on 132. so

Benzo!|1,2,5|oxadiazol-5-yl(1-2-(4-(3-trifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl) methanone 133... 2-Ethyl-1-(1-2-I4-(3-trifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)butan-1 -on « 134. - c 2-Benzyloxy(1-12-Ispiro(5-methylisobenzofuran-ZH-1,4"-piperidin-1'-yl))|ethyl)-3,4-dihydro-1H-isoquinoline- 2-il)et an-1-on;" 135.

Benzo!|1,2,5|oxadiazol-5-yl|1-2-Ispiro(5-fluorobenzofuran-2H-3,4-piperidin-1'-yl))ethyl)-3,4-dihydro-1H- isochino

Lin-2-yl)methanone so 136. (1--2--4--4-Chlorophenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)ucyclohexylmethanone 1387. 1-(1-42-(4-(4-Chlorophenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-3,3-dimethylbutan-1-one - 138. -1 3,5,5-Trimethyl|1-12-Ispiro(5-fluorobenzofuran-2H-3,4-piperidin-1 -ylDethyl)-3,4-dihydro-1H-isoquinolin-2-yl)hex b5r /an-1-one 1 139, sl 3,5,5-Trimethyl(1-(2-Ispiro(5-methylisobenzofuran-ZH-1,4"-piperidin-1"-yl/ethyl)-3,4 -dihydro-1H-isoquinolin-2-yl) hexan-1-one 140. two 2-Phenoxy(1 --2-(spiro(5-methylisobenzofuran-3H-1,4"-piperidin-1"-yl)) ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)ethan-1-one (F) 141.

F (1-2-I(4-(4-Chlorophenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-(2,2-dichlorocyclopropyl)methanone 142. bo 2-Benzyloxy|1 --2-I(spiro(5-fluorobenzofuran-2H-3,4-piperidin-1'-yl)|)ethyl)-3,4-dihydro-1H-isoquinolin-2-yl|Ethane -1-one 143. 1-(1-42-(4--4-Chloro-3-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl|ethyl)-6,7-dimethoxy-3,4-dihydro-1H -isoquinolin -2-yl)-3,3-dimethylbutan-1-one 144. 65 1-(1-2-(4-(2,3-Dihydrobenzofuran-7-yl)piperidin-1-yl|ethyl)- 3,4-dihydro-1H-isoquinolin-2-yl)-3,3-dimethylbutan-1-one 145.

3,5,5- Trimethyl-1-(1-42-I(4--Z3--rifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)hexane- 1-one 2,2-Dimethyl(|1-2-|Ispiro(5-fluorobenzofuran-2H-3,4-piperidin-1 -yl)Lethyl)-3,4-dihydro-1H-isoquinolin-2-yl| propan-1-one 147.

3-cyclohexyl-1-(1-2-14-(3-trifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-7Y isoquinolin-2-yl)upropan-1-one 148.

Furan-2-yl1--2-(spiro(5-fluorobenzofuran-2H-3,4"-piperidin-1-yl))ethyl)-3,4-dihydro-1H-isoquinolin-2-ylimethanone 149.

M-(4-Phenyl-1-12-(2-(3,5,5-trimethylhexanoyl)-1,2,3,4-tetrahydroisoquinolin-1-ylylethyl)piperidin-4-yl)acetamide 150.

Quinoxalin-2-yl1-(2-I(spiro(5-fluorobenzofuran-2H-3,4-piperidin-1'-yl)|)ethyl)-3,4-dihydro-1H-isoquinolin-2-yl|Imethanone 151. 7/5 З-Cyclohexyl|1 --2-(spiro(5-fluorobenzofuran-2H-3,4-piperidin-1'-yl)|ethyl)-3,4-dihydro-1H-isoquinolin-2- il|Ipropa n-1-on 152.

Benzo!|1,2,5|oxadiazol-5-yl(1-(2-I(4-(2,3-dihydrobenzofuran-7-yl)piperidin-1-yl|ethyl)-3,4-dihydro- 1H-isoquinoline -2-yl)umethanone 153. Benzo|1,2,5|oxadiazol-5-yl(1-2-(4-(2-methyl-1H-indol-3-yl)piperidin-1-yl ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 154. (Tetrahydropyran-4-yl)-(1-42-(4-(3-trifluoromethylphenyl)piperidin-1-yl|Iethyl)- 3,4-dihydro-1H-isoquinolin-2-yl)umethanone 155... 2-Propyl-1-(1--2-I(4--"3-trifluoromethylphenyl)piperidin-1-yl|Iethyl)- 3,4-dihydro-1H-isoquinolin-2-yl)pentan-1-one c 156. 2-ethyl1-(2-Ispiro(5-fluorobenzofuran-2H-3,4"-piperidin-1'-yl)) ethyl)-3,4-dihydro-1H-isoquinolin-2-ylIbrbutan-1-one (8) 157. 3-Phenyl-1-(1-2-I4-(3-trifluoromethylphenyl)piperidin-1-yl|Iethyl )-3,4-dihydro-1H-isoquinolin-2-yl)upropan-1-one 158. 3,3-Dimethyl-1-(1-72-I4-(2-methyl-1H-indol-3-yl) )piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)butan-1-one 159, (1-2-I(4-(4-Chloro-3-trifluoromethylphenyl) -4-hydroxypiperidin-1-yl|ethyl)-6, 7-dimethoxy-3,4-dihydro-1H-isoquinolin-2 io)-yl)-(2,2-dichlorocyclopropyl)methanone i- 160. 1,2,3,4-Tetrahydronaphthalene-2-yl(1-12-I(Ispiro(5-methylisobenzofuran-ZH-1,4"-piperidin-1-yl)|ethyl)-3,4-dihydro -1H- h- isoquinolin-2-yl)umethanone so 161. (4-Methylsulfanylphenyl)-(1-(2-I4--"3-trifluoromethylphenyl)piperidin-1-yl|Iethyl)-3,4-dihydro- 1H-isoquinolin-2-yl)methanone 162. « 40. C,5,2- Grimethyl-1-(1-(2-(4-(2-methyl-1H-indol-3-yl)piperidin-1) -yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)hexan-1-one from 163. 3-Phenyl(1-(2-Ispiro(5-methylisobenzofuran-ZH-1,4" -piperidin-1'-yl)|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)upropan-z 1-one 164. Furan-2-yl(1-2-I(4-(Z3 -trifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 165. 2-Beuyloxy-1-(1-2-14-(2-methyl-1H-indole) -3-yl)/piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)ethanone so 166. 1-(1--2-(4--4-Chlorophenyl)piperidine -1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-2-phenoxyethanone 167. Quinoxalin-2-yl(1-2-(spiro(5-methylisobenzofuran-ZH-1 ,4-piperidin-1'-yl)|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl-1)methanone 168. 1 2,2-Dimethyl-1-(1-2 -I4-(3-trifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)y-propan-1-one cl 169, (2,2-Dichlorocyclopropyl)-( 1-2-I4-(3-trifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 5B 170. 4-Methylsulfanylphenyl(1-(2-Ispiro 5-methylisobenzofuran-ZH-1,4"-piperidin-1-yl)ethyl)-3,4-dihydro-1H-isoquinol

HF) n-2-yl)umethanone t 171. (2,2-Dichlorocyclopropyl)-(1-12-I4-(2,3-dihydrobenzofuran-7-yl)piperidin-1-yl|ethyl)-3,4 -dihydro-1H-isoquinolin-2-bolyl)methanone 172...1-(1-42-(4-(4-Isopropylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinoline -2-yl)-3,5,5-trimethylhexan-1-one 173. 2,2-Dichlorocyclopropyl(1-(2-Ispiro(isobenzofuran-ZH-1,4"-piperidin-1'-yl)|ethyl )-3,4-dihydro-1H-isoquinolin-2-yl) methanone 65 174.

M-(4-phenyl-1-(2-(2-(1,2,3,4-tetrahydronaphthalene-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-ylylethyl)piperidine-4-

il)uacetamide

Benzo!|1,2,5|oxadiazol-5-yl(1-2-14-(4-chlorophenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 176... Mm-(1-2-(2-(3,3-Dimethylbutyryl)-1,2,3,4-tetrahydroisoquinolin-1-ilyethyl)-4-phenyl-piperidin-4-yl)iacetamide 177.

3-Chloro-2,2-dimethyl-1-(1-2-I4-(3-trifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)upropan-1 -one 178. 7/0 Tetrahydropyran-4-yl/1 --2-(spiro(5-fluorobenzofuran-2H-3,4-piperidin-1'-yl)|ethyl)-3,4-dihydro-1H- isoquinoline-2-and libutan-1-one

The following compounds were obtained in the form of enantiomers by method B, starting from enantiomer 2 of the corresponding amines of formula B. Analytical data are shown in Table 1.

Compounds 179.

M-(4-(3Z-fluorophenyl)-1-72-(2-(2-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-ylylethyl)piperidin-4-yl)acetamide (e enantiomer) 180 ... M-(4-(3-fluorophenyl)-1-(2-(2-(2-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)piperidin-4-yl) acetamide (enantiomer) 181.

IM-(11-42-(2-(4-chlorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-(3-fluorophenyl)piperidin-4-ylacetamide (enantiomer) 182.

I-(11-42-(2-(4-bromobenzo)-1,2,3,4-tetrahydroisoquinolin-1-ylethyl)-4-(3-fluorophenyl)piperidine-4-ylideacetamide (enanth isomer) 7 t , i)

IM-(1-42-(2-(4-fluorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-ilyethyl)-4-(3-fluorophenyl)piperidin-4-yl|Iacetamide (enantiomer) 184. uzo m/-K4-(3-fluorophenyl)-1-12-(2-(4-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-ylylethyl)piperidin-4-yl)uacetamide (enantiomer) ) io) 185. i-

M-(4-(3-fluorophenyl)-1-2-(2-(4-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)piperidin-4-yl)acetamide (enantiomer) h- 186. so

IM-(11-42-(2-(3-chlorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-(3-fluorophenyl)piperidin-4-ylacetamide (enantiomer) 187. .. M-(1-2-(2-(2-bromobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-ilyethyl)-4-(3-fluorophenyl)piperidin-4-yl acetamide (enantiomer) " 188... M-(1-2-(2-(4-bromobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-ilyethyl)-4-phenylpiperidin-4-yl)acetamide with (enantiomer) p 189 .;

IM-(1-42-(2-(2,4-dichlorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl|-4-(3-fluorophenyl)piperidin-4-yl coacetamide ( enantiomer) 191. -th IM-(11-42-(2-(benzo|1,2,5)oxadiazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4 -(3Z-fluorophenyl)piperides -1 n-4-yl|Iidacetamide (enantiomer) 192. 1 M-(4-(Z-fluorophenyl)-1-2-(2-(naphthalene-1-carbonyl)-1, 2,3,4-tetrahydroisoquinolin-1-yl|ethyl)piperidin-4-yl)acetami d (enantiomer) p 193.

I-(1-(2--2-cyclopentanecarbonyl-1,2,3,4-tetrahydroisoquinolin-1-yl)ethylI-4-(3-fluorophenyl)piperidin-4-yl)iacetamide dv (enantiomer) 194.. M-(1-42-(2-(4-chlorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-phenylpiperidin-4-yl)acetamide

HF) (enantiomer) t 195.

I-(11-42-(2-(benzo|bithiophen-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|Hethyl)-4-(3-fluorophenyl)piperidin-4-yl| but Chetamide (enantiomer) 196.

IM-(11-42-(2-(6-fluoro-4H-benzo/|1,3)dioxin-8-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|Hethyl)-4- (3Z-fluorophenyl)piperidine-4-ilyacetamide (enantiomer) 197. 65 I-(11-42-(2-(3-bromobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)- 4-(3-Fluorophenyl)piperidine-4-ilyacetamide (enan thiomer)

I-(11-42-(2-(2-fluorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-ylethyl)-4-(3-fluorophenyl)piperidin-4-ylylacetamide (enan thiomer) 199,

M-(1442-(2-(4-methylbenzoyl)-1)2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-phenylpiperidin-4-yl)acetamide (enantiomer) 200.

IM-(11-42-(2-(2-chlorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-ylethyl)-4-(3-fluorophenyl)piperidin-4-ylylacetamide (enan thiomer) 70 201.

M-(4-(33-fluorophenyl)-1-72-(2-(4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-ylethyl)piperidin-4-yl)acetamide (e enantiomer) 202 .

IM-(1-72-(2-(3-chlorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-phenylpiperidin-4-yl)uacetamide (enantiomer) 203.

IM-(1-72-(2-(4-fluorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-ylethyl)-4-phenylpiperidin-4-yl)acetamide (enantiomer) 204.

M-41-(2-(2-cycloheptanecarbonyl-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl|-4-phenylpiperidin-4-ilyacetamide (enantiomer) 205.

IM-(1-72-(2-(3-bromobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-phenylpiperidin-4-yl)iacetamide (enantiomer) 206. 2-M -(4-(3-fluorophenyl)-1-2-(2-(3-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)piperidin-4-yl)acetamide (enantiomer) c 207.

M-(4-(3-fluorophenyl)-1-72-(2-(thiophen-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl/piperidin-4-yl)acetamide ( 8) (enantiomer) 208... M-(4-(3-fluorophenyl)-1-72-(2-(4-pyrazol-1-ylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) (ethyl) piperidin-4-yl) acetamide (enantiomer) 209.

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Pharmacological testing

The compounds of this invention were tested using a well-known and reliable test. The test consisted of the following: Inhibition of 722I-MKA binding to human MK2 receptors

It was found that the compounds of this invention strongly inhibit the binding of 722I-MKA to the human MK2 receptor.

This method determines the inhibition of 722I-MKA binding by drugs to the membranes of cloned CHO cells that express the human MK2 receptor.

Briefly, the affinity of the compounds was measured by their ability to replace 7292I-MKA when CHO membranes expressing human MK2 were incubated with the compounds and the radioligand at room temperature for 60 minutes. Incubation was stopped by rapid filtration through CP/C filters, and the filters were counted on a UMaiIyas Ttykh scintillation counter. IC50 values for the Mo1-209 compounds exemplified above were determined to be 200 nm or less. Most of the compounds had IC 50 values of 5 ONM or less, and a large group of compounds had IC 50 values of 1 ONM or less. 70 Examples of compositions

The pharmaceutical compositions of this invention can be prepared by conventional methods used in this field.

For example: tablets can be obtained by mixing the active ingredient with conventional adjuvants and/or diluents and then pressing the mixture in a conventional tableting 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 this purpose, such as dyes, flavorings, preservatives, etc., may be used provided they are compatible with the active ingredients.

Solutions for injections can be prepared by dissolving the active ingredient and possible additives in part of the solvent for injection, preferably sterile water, bringing the solution to the required volume, sterilizing the solution and filling it into appropriate ampoules or vials. Any suitable additives commonly used in the art, such as isotonicity agents, preservatives, antioxidants, etc., may be added.

Typical examples of recipes for the composition of this invention are the following: Ha 1) Tablets containing 5.0mg of the compound of this invention calculated on the free basis: o

Compound Ta or 16 B,.Omg

Lactose bomg

Corn starch ZOmg IT c)

Hydroxypropyl cellulose 2, AmMg

Microcrystalline cellulose 19.2 mg

Croscarmellose sodium salt type A 2.4 mg

Magnesium stearate O.v4mMg «- 2) Tablets containing 0.5 mg of the compound of this invention calculated on the free basis: so

Compound Ta or 16 O, Bmg

Lactose 4b, UMG

Corn starch 23.5 mg

Povidone 1.vmg w-in s Microcrystalline cellulose 14 4mMg

Sodium salt of croscarmellose type A 1.8mg:z» Magnesium stearate 0.6bZmg

C) Syrup containing per milliliter: so Compound Ta or 16 25mg Sorbitol BOOmg

Hydroxypropyl cellulose 1Bmg - Glycerin Bomg 1 20 Methylparaben 1mg

Propylparaben O mg sp

Ethanol O, bo5 ml

Flavoring O,Oo5mg

Sodium salt of saccharin O, Bmg

Water to ml and 4) Solution for injection containing per milliliter:

Compound Ta or 16 O, Bmg or Sorbit B1mg

Acetic acid O, OBmg

Sodium salt of saccharin 0O, Bmg

Water up to ml b5

Claims (1)

The formula of the invention 1. Derivatives of 3,4-dihydro-1H-isoquinolin-2-yl of general formula 9. .-, В ОсСО-, В" 5СО- or В"!СО-СВ "В. where K" represents C 4-125-alkyl, C 6-alkenyl, C 6-alkynyl, C 6-cycloalkyl, C 6-cycloalkyl-C 6-alkyl, aryl, aryl-C 6-alkyl, heteroaryl, heteroaryl- C. c-alkyl, tetrahydropyranyl, 1,2,3,4-tetrahydronaphthalenyl or 4H-benzo|1,3|dioxynyl, optionally substituted by halogen, where each of the indicated C..c-alkyl, aryl, heteroaryl and C3 1-cycloalkyl groups is independently unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, C 1-6-alkyl, C-C-Alkoxy group, aryl-C-C-Alkoxy group, C-C-Alkylsulfanyl, aryl and aryloxy group, where the indicated aryl and aryloxy group are independently unsubstituted or substituted by one or more halogen atoms, and 272 is independently hydrogen or C. in-alkyl; or BK" is the group К"В'МСО-, В"В'ЗМСВ8 -, where B" and VK! are independently hydrogen, C3-alkyl, C3-alkenyl, C3-alkynyl, C3-cycloalkyl, C3-cycloalkyl-C3-alkyl, aryl or aryl-C3-alkyl, where each of the indicated C C-alkyl, aryl, and C3-d-cycloalkyl groups are independently (8) unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, C1-6 alkyl, and C1-6-alkyl groups, or B? and B" ? together with the M atom to which they are connected, form a pyrrolidinyl, piperidinyl or perhydroazepinyl group; yuyu V? selected from hydrogen, trifluoromethyl and C. c-alkyl; 3-9, vya, KR, ba | NPs are independently selected from hydrogen, halogen, cyano group, nitro group, C. c-alkyl, which C. d-alkenyl, C3-alkynyl, C3-c-cycloalkyl, C3-cycloalkyl-C; c-alkyl, amino group, C. c-alkylamino group, Its di(C 4 c-alkyl)amino group, C. c-alkylcarbonyl, aminocarbonyl, C c-alkylaminocarbonyl, «- di(Ci.-c-alkyl)aminocarbonyl, C C-Alkoxy group, C-C alkylthio group, hydroxy group, trifluoromethyl, trifluoromethylsulfonyl and C-C-alkylsulfonyl; so t is equal to 2-6; IN? means benzyl, benzoyl, 2,3-dihydrobenzofuranyl or mono- or bicyclic aryl or heteroaryl, where each benzyl, benzoyl, aryl or heteroaryl is optionally substituted by one or more substituents selected from halogen, cyano group, nitro group, C. c- alkyl, C6-alkenyl, C6-alkynyl, C3-6-cycloalkyl, Cz.v-cycloalkyl-C. 6-alkyl, amino group, C. c-alkylamino group, di(C..c-alkyl)amino group, C. c-alkylcarbonyl, c. aminocarbonyl, C. c-alkylaminocarbonyl, di(C..c-alkyl)aminocarbonyl, C..v-alkyl groups, C..v-alkylthio groups, "» hydroxy groups, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl; "O means C, M or CBO; 415 where KO is selected from hydrogen, halogen, cyano group, nitro group, C 1 -alkyl, C 1 -alkenyl, C 1 -alkynyl, C 1 -cycloalkyl, C 3 -cycloalkyl-C 1 -alkyl, amino group, C β-alkylamino groups, di(C-β-alkyl)amino groups, C. v-alkylcarbonyl, aminocarbonyl, C. v-alkylaminocarbonyl, di(Ci-v-alkyl)aminocarbonyl, -y C) v- alkyl group, C. v-alkylthio group, hydroxy group, trifluoromethyl, difluoromethyl, fluoromethyl, -1 trifluoromethylsulfonyl, of the group -MEZ9SOVZ!, where KZ is hydrogen or C. v-alkyl and KZ! is C. c-alkyl, group 50 -COOV 5, where KZ means hydrogen or C. c-alkyl, or group -SOME B, where B" and 878 are independently selected from hydrogen o and C4.c-alkyl or B" and KZ, together with the nitrogen atom to which they are attached, form piperidinyl, piperazinyl, or morpholinyl, where the specified piperidinyl, piperazinyl, and morpholinyl are unsubstituted or substituted by C 1 -alkyl; or KZ and KO, together with the carbon atom to which they are attached, form a cyclic structure selected from 22 groups consisting of: , K. 1) 2 Е b5 И о и и з Ми 9): where 0 means a carbon atom shared with the piperidine ring, so that the indicated cyclic structure together with the 70 indicated piperidine ring forms a spiro-structure; and X, M and 7 are independently selected from O; ME"; SV?Zv?y: 8(0), and connection; where B is selected from hydrogen, C is alkyl, C. d-alkenyl, Co-v-alkynyl, C3.v-cycloalkyl, C3.v-cycloalkyl-C. γ-alkyl, trifluoromethyl, acyl, thioacyl and trifluoromethylsulfonyl, or КК" is the group К?О5О2-, КРООСО- or К?О5СО-, where КО means C. б-alkyl, 18 C, б-alkenyl, Со.в -alkynyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C6-6-alkyl or aryl, or KU is the group К7"Т??МСО- or В" в?Мс8-, where EC! and EC? independently stand for hydrogen, C3-alkyl, C3-alkenyl, C3-alkynyl, C3-cycloalkyl, C. c-cycloalkyl-C. β-alkyl or aryl, where said aryl is unsubstituted or substituted by one or more substituents selected from C-6-alkyl or halogen; or left together with the M atom to which they are connected form a pyrrolidinyl, piperidinyl or perhydroazepinyl group; KZ and 8?b are independently selected from hydrogen, halogen, cyano group, nitro group, C.v.-alkyl, C.v.-alkenyl, C.v.-alkynyl, C.v.-cycloalkyl, C3.6-cycloalkyl-C.46-alkyl, aryl, heteroaryl, where the specified aryl is unsubstituted or substituted by one or more substituents selected from C.6-alkyl or halogen, amino group, C.6-alkylamino group, ME group? 9B?6, where ?5 1 and?b are independently selected from C. c-alkyl, C. c-alkylcarbonyl, aminocarbonyl, C. c-alkylaminocarbonyl, di(C.. c-alkyl)aminocarbonyl, C. c- alkoxy group, C. c-alkylthio group, hydroxy group, trifluoromethyl, trifluoromethylsulfonyl and Cc-alkylsulfonyl, or 22 and 226 together with the M atom, to which they (U are bonded) form a pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group, or BZ and 84 together are an oxo group; and n is 0, 1 or 2; provided that not more than one of X, M and 7 may be a bond, and provided that two adjacent groups X, Y or 7 cannot be simultaneously selected from 0 and 5; and ю A", A?, AZ and A? are independently selected from M and SV", where K2 / means hydrogen, halogen, cyano group, nitro group, C. c-alkyl, C. c-alkenyl, C. c-alkynyl, C. c-c-cycloalkyl, C. c-c-cycloalkyl- C. c-alkyl, C. c-alkylcarbonyl, io) aminocarbonyl, C. c-alkylaminocarbonyl, di( C.4.v-alkyl)aminocarbonyl, C.v-alkyl group, C..v-alkylthio group, m. hydroxy group, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethylsulfonyl, C.v-alkylsulfonyl, amino group or group MV29229, where 28 Her K29 independently selected from hydrogen and C u -alkyl, or 28 129 together with the 77 M atom to which they are bound, form a pyrrolidinyl, piperidinyl, perhydroazepinyl or co morpholinyl group; provided that only one of A", A?, AZ and A? can be M; and the dashed line extending from CO) means a bond when C is C, and is not a bond when C is SVO or M; or their pharmaceutically acceptable acid addition salts." 2. The compound according to claim 1, which differs in that O is SV 79, and KZ and 79, together with the carbon atom 70 to which they are attached, form a bicyclic structure: З с Кк хз» И здеши ша А - де С means a carbon atom shared with a piperidine ring, so that the specified bicyclic structure together with -1 specified piperidine ring forms a spiro structure; and X, X and 7 are independently selected from O; ME"U; SVZE?I and 5(O)n, where V"? selected from hydrogen, C3-alkyl, C3-alkenyl, C3-alkynyl, C3-cycloalkyl, C3-cycloalkyl-C. β-alkyl, trifluoromethyl, acyl, thioacyl and c trifluoromethylsulfonyl, or КК" is the group К?О5О2-, КРООСО- or К?О5СО-, where КО means C. б-alkyl, C, б-alkenyl, Со.в -alkynyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C6-6-alkyl or aryl, or KU is the group К7"Т??МСО- or В" в?Мс8-, where EC! and EC? independently mean hydrogen, C. c-alkyl, C. c-alkenyl, C. c-alkynyl, C. c.-cycloalkyl, 25 C. c.-cycloalkyl-C 1 c-alkyl or aryl, where the indicated aryl is unsubstituted or substituted by one or more HF ) by substituents selected from C..6-alkyl or halogen; or B, together with the M atom to which they are bound, F form a pyrrolidinyl, piperidinyl, or perhydroazepinyl group; KZ and 8?b are independently selected from hydrogen, halogen, cyano group, nitro group, C.v-alkyl, C.v-alkenyl, C.v-alkynyl, C.v.-cycloalkyl, because C.v.-cycloalkyl-C4.v-alkyl, aryl, heteroaryl, where the indicated aryl is unsubstituted or substituted by one or by several substituents selected from C-6-alkyl or halogen, amino group, C-6-alkylamino group, Me?9226 group, where 2 25 and 176 are independently selected from C. v-alkyl, or B? ii 229, together with the M atom to which they are bound, form a group of pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl, C. c-alkylcarbonyl, aminocarbonyl, C. c-alkylaminocarbonyl, di(C..c-alkyl)aminocarbonyl, C ..b-alkyl group, C..b-alkylthio group, 65 hydroxy group, trifluoromethyl, trifluoromethylsulfonyl and C.b-alkylsulfonyl, or KZ and B? together is an oxo group; and n is equal to 0, 1 or 2; and communication; provided that no more than one of X, Y, and 7 can be a bond, and provided that two adjacent groups X, Y or 7 cannot be simultaneously selected from O and 5; and A", A?, AZ and A? are independently selected from M and CE", where BC?" means hydrogen, halogen, cyano group, nitro group, C. c-alkyl, C. c-alkenyl, C. c-alkynyl, C3.c-cycloalkyl, C3.c-cycloalkyl-C. β-alkyl, amino group, MKK group, where K28 | B29 are independently selected from hydrogen and C16-alkyl or 28 and 29 together with the M atom to which they are connected form a pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group; C. c-alkylcarbonyl, aminocarbonyl, C. c-alkylaminocarbonyl, di(C.4.c-alkyl)aminocarbonyl, C. c-alkyl group, C..c-alkylthio group, hydroxy group, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethylsulfonyl or C 6-alkylsulfonyl; or under the condition that only one of A", A?, AZ and A? can be M. C. The compound of claim 2, wherein X, M, and 7 are selected from one of the following combinations: X is oxygen, M is a bond, and 7 is SVC. X is SV?ZN2Ya., U is a bond and 7 is oxygen; X is ME "U, U is a connection and 7 is SEZ; X is sv, U is a connection and 7 is ME "U; X is CO, Y is a bond and 7 is MV"; X is 505, M is a bond and 7 is MA "Y; X is 50, Y is a bond and 7 is ME"; X is SKZE?Y, Y is a bond 7 is 5; X is 75 SV, Y is a bond and 7 is 50; X is SVKZERIA, Y is a bond and 7 is 505, wherein KU is hydrogen, acetyl or methylsulfonyl and KZ and 227 are independently selected from hydrogen, methyl, isobutyl, cyclohexyl and 4-fluorophenyl. 4. The compound according to claim 2, which differs in that -Х-У-7- together form a group selected from: -О-СКЗЕ., -Ст?зд2.о-, МЕС? Saints? MV. -сО-Мв79-, -8025-МВ79-, -8О-М"9-, -СВ?З82ы.8-, -СВЗ. 80.-, uy -St2zd2180.-; where V"? means hydrogen, acetyl, or methylsulfonyl, and 223 and 2524 are independently selected from hydrogen, methyl, isobutyl, cyclohexyl, and 4-fluorophenyl. 5. A compound according to any one of claims 2-4, which differs in that AZ is M or СВЕ2", where 227 means a halogen, a cyano group, a nitro group, a ME?9E29 group, where K28 and K?9 are independently selected from hydrogen and C. 6-alkyl or K?8 and E?9, together with the M atom to which they are bound, form a pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group, C. v-alkylcarbonyl, aminocarbonyl, C. v-alkylaminocarbonyl, di(C1-C6-alkyl)aminocarbonyl, C16-Alkoxy group, hydroxy group, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethylsulfonyl or i) SuC6-alkylsulfonyl. 6. A compound according to any of claims 2-5, which differs in that A", A?2, AZ | A? are independently selected from CE2", where B?! is as defined above. i am 7. The compound according to claim 2, which differs in that the indicated bicyclic structure is selected from the group consisting of: ю Яє" Я (Я 2 Яє" Я (Я 2 є-ego to я poho, - р) в з И в a so kv vah - Still bo go and ne pe v g v s) 8 s , 2" where KE"?! means acetyl or methylsulfonyl, B" means hydrogen or methyl, K2" means hydrogen or fluorine, B2"" means hydrogen , fluorine, methyl or isopropyl, K2"" means hydrogen, fluorine or trifluoromethyl. 8. The compound according to claim 1, which differs in that vivo together with the carbon atom to which they are attached form a cyclic structure selected from the group consisting of: - r - r. P - 0. not I not I MS ru. OO ru. ОО 1 2 z 9 z z) 9 «sl | Syshe S o no Gaki, 52 2 z 2 o , Ho) where C is a carbon atom shared with the piperidine ring, so that the specified cyclic structure together with the specified piperidine ring forms a spiro-structure. 60 9. The compound according to claim 1, which is characterized by the fact that KZ is benzyl, benzoyl, 2,3-dihydrobenzofuran-7-yl or mono- or bicyclic aryl or heteroaryl, where each benzyl, benzoyl, aryl or heteroaryl is optionally substituted by one or more substituents selected from halogen, cyano group, nitro group, C3-alkyl, C3-alkenyl, C3-alkynyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C. γ-alkyl, amino groups, C. c-alkylamino group, di(C..c-alkyl)amino group, C. c.6-alkylcarbonyl, aminocarbonyl, C..c-alkylaminocarbonyl, di(C.i.c-alkyl)aminocarbonyl, C. c-alkylcarbonyl, C. β-alkylthio group, hydroxy group, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl. 10. The compound according to claim 9, which differs in that He is 2,3-dihydrobenzofuran-7-yl, benzyl or benzoyl, where the specified benzyl or benzoyl is unsubstituted or substituted by one or more halogen atoms in the phenyl groups, or KZ is mono- or bicyclic aryl or heteroaryl selected from the group consisting of phenyl, indolyl, pyridyl, thiophenyl and benzisoxazolyl, where each aryl or heteroaryl is optionally substituted with one or more substituents selected from halogen, cyano, nitro, C. c- alkyl, C-6-alkenyl, C-6-alkynyl, C-6-cycloalkyl, C-8-cycloalkyl-C-6-alkyl, amino group, C-6-alkylamino group, di(C 4-alkyl)amino group, C-6-alkylcarbonyl, aminocarbonyl, C1-6-alkylaminocarbonyl, di(C1-6-alkyl)aminocarbonyl, C. c-alkyl group, C. c-alkylthio group, hydroxy group, trifluoromethyl, 70 difluoromethyl, fluoromethyl and trifluoromethylsulfonyl. 11. The compound according to claim 10, which is characterized in that the indicated mono- or bicyclic aryl or heteroaryl is selected from the group consisting of phenyl, indol-3-yl and benzisoxazol-3-yl, where the indicated phenyl, indol-3-yl or benzisoxazol-3-yl optionally substituted with one or more substituents selected from halogen, cyano, nitro, C.sub.-alkyl, C.sub.-alkenyl, C.sub.-alkynyl, C.sub.3-d-cycloalkyl, C.sub.3-cycloalkyl-C . c-alkyl, 75 amino groups, C. c-alkylamino groups, di(C.4 c-alkyl)amino groups, C. c-alkylcarbonyl, aminocarbonyl, C. β-alkylaminocarbonyl, di(C..β-alkyl)aminocarbonyl, C. β-6-alkyl group, C. β-alkylthio group, hydroxy group, trifluoromethyl, difluoromethyl, fluoromethyl and trifluoromethylsulfonyl. 12. The compound according to claim 11, which is characterized in that the specified optional substituents are selected from the group consisting of halogen, phenyl and methyl. 13. A compound according to any one of claims 9-12, characterized in that O is an IED, where 'i is selected from hydrogen, S. in alkylcarbonyl, hydroxy group, group -MEOSOVU!, where KZ? means hydrogen or C..v-alkyl and KU! means S. valkyl, groups -SOOV"U, where VK"? is C..in-alkyl, or the group -SOME'"B"YAU, where KI and "9, together with the nitrogen atom to which they are bound, form piperidinyl, piperazinyl, or morpholinyl, where piperidinyl, piperazinyl, and c morpholinyl are indicated are unsubstituted or substituted by C..v.-alkyl. 14. The compound according to claim 13, which differs in that KO is selected from hydrogen, acetyl, a hydroxy group, group (8)-MAVZOSOV, where KO is hydrogen and B! is methyl, the group -"СООВЕ, where ВЗ means ethyl, or the group -"СОМА"В8, where К 17 | В78 together with the nitrogen atom to which they are attached form piperidinyl or 4-methylpiperazinyl. 15. A compound according to any of claims 1-14, which differs in that t is equal to 2, З or 4. IS c) 16. Compound according to claim 15, which differs in that t is equal to 2 17. The compound according to any of claims 1-16, which differs in that VE! is the group В'"СО-, В''ОСО-, where 2"! means C 1 -alkyl, C 1 -cycloalkyl, C 1 -cycloalkyl-C 1 -alkyl, phenyl, phenyl-C 1 -alkyl, pyridyl, furanyl, i-benzo|1,2,5|oxadiazolyl, quinoxalinyl, benzo|B) hyophenyl or naphthalenyl, wherein each of the indicated C 1 -C 6 -alkyl, -phenyl, pyridyl and furanyl groups is independently unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, C 4-6 -alkyl, C 4- γ-Alkoxy group, phenyl and phenoxy group, where the indicated phenyl and phenoxy group are independently unsubstituted or substituted by one halogen atom; or В is the group В'"В'ЗМСО-, where В"! and B" are independently hydrogen, C1-6-alkyl, aryl, or aryl-C1-6-alkyl, wherein each of said C1-6-alkyl and aryl groups is independently unsubstituted or substituted by one substituent selected from the group, " Ф, consisting of a halogen and C. 6-alkoxy group. 18. A compound according to any of claims 1-17, which differs in that B? is hydrogen. З U ud , dr ; Shh d s 19. A compound according to any of claims 1-18, which differs in that WZ is hydrogen. ;" 20. The compound according to any one of claims 1-19, which differs in that B" is hydrogen or a methoxy group. 21. A compound according to any of claims 1-20, which differs in that E? is hydrogen or a methoxy group. 22. A compound according to any one of claims 1-21, characterized in that 25 is hydrogen. so 23. A compound according to any of claims 1-22, which differs in that K "2 and 2? is hydrogen. - 24. A compound according to any of claims 1-23, which differs in that Ka and 85 is hydrogen. 25. The compound according to claim 1, which differs in that it is selected from the group containing: - and 1-(1-42-i(4-(5-fluoro-1H-indol-3-yl)piperidin-1- yl|Iethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone with 20 1-cyclopentyl-1-(1-2-I(4-(5-fluoro- 1H-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone phenethylamide 1-2-I4-(5-fluoro-1H-indol-3- yl)piperidin-1-ylethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-(1-42-4-(5-fluoro-1H-indol-3-yl)piperidine -1-yl|Hiethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-1-phenylmethanone 1-(1-42-i(4-(5-fluoro-1H-indol-3-yl) piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-1-(2-fluorophenyl)methanone 52 1-(1-42-i(4-(5-fluoro-1H -indol-3-yl)piperidin-1-ylethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-3-phenylpropan-1-one o (3-chloropropyl)amide 1-2-I4 -(5-fluoro-1H-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid co (2-methoxyphenyl)amide 1-2-I4- (5-fluoro-1H-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 60 tert- 3-Chloro-1-butyl ester of 1-2-I4-(5-fluoro-1H-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (1-2-I4-(5-fluoro-1H-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-2,2-dimethylpropane -1-one 1-cyclopentyl-1-(1-12-1b-fluorospiro(isobenzofuran-1(3H), 4-piperidin-1'-ylIIethyl)-3,4-dihydro-1H-isoquinoline bo -2-ylumethanone 1-(2-(4-chlorophenoxy)pyridin-3-ylI-1-(1-12-I(b-fluorospiro(isobenzofuran-1(Z3H), "4-piperidin-1"-ylID|ethyl)-3 ... -dihydro-1H-isoquinoline-2-carboxylic acid 1-(1-2-(b-fluorospiro(isobenzofuran-1(ZH),4"-piperidin-1"-yl|ethyl)-3,4-dihydro-1H -isoquinolin-2-yl)-1-phenyl methanone 1-(1-2-(b-fluorospiro(isobenzofuran-1(ZH),4"-piperidin-1"-yl|ethyl)-3,4-dihydro- 1H-isoquinolin-2-yl)-1-parat olylmethanone 70 1-(1-2-(b-fluorospiro(isobenzofuran-1(ZH),4"-piperidin-1"-yl|ethyl)-3,4- dihydro-1H-isoquinolin-2-yl)-1-(2-me toxyphenyl)methanone 1-cycloheptyl-1-(1-2-(b-fluorospiro(isobenzofuran-1(ZH),4-piperidine-1'- yl1|ethyl)-3,4-dihydro-1H-isoquinoline-2-yl)umethanone 1-(2-fluorophenyl)-1-(1-2-16-fluorospiro(isobenzofuran-1(3H),4-piperidine- 1'-ylIIethyl)-3,4-dihydro-1H-isoquinol 75. In-2-ilumethanone 1-(2-chlorophenyl)-1-(1-2-1b-fluorospiro(isobenzofuran-1(3H),4-piperidin-1'-ylIIethyl)-3,4-dihydro-1H -isoquinol in-2-yl)umethanone 1-(4-fluorophenyl)-1-(1-2-16-fluorospiro(isobenzofuran-1(3H),4-piperidin-1'-ylIIethyl)-3,4-dihydro -1H-isoquinol in-2-yl)umethanone 1-(4-chlorophenyl)-1-(1-2-1b-fluorospiro(isobenzofuran-1(3H),4-piperidin-1'-ylIIethyl)-3,4 -dihydro-1H-isoquinol yn-2-yl)umethanone phenethylamide 1-2-(b-fluorospiro(isobenzofuran-1(ZH),4-piperidin-1"-yl|ethyl)-3,4-dihydro-1H- isoquinoline-2-carboxylic acid 1-(1-2-(b-fluorospiro(isobenzofuran-1(ZH),4"-piperidin-1"-yl|ethyl)-3,4-dihydro-1H-isoquinoline-2- yl)-1-(4-mesov toxyphenyl)methanone 1-(1-2-(b-fluorospiro(isobenzofuran-1(ZH),4-piperidin-1"-yl|ethyl)-3,4-dihydro -1H-isoquinolin-2-yl)-3 (8)-phenylpropan-1-one 2-ethyl-1-(1-2-16b-fluorospiro(isobenzofuran-1(3H),4-piperidin-1'-yl) |ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)butan-1-one uzo 1-(1-2-(b-fluorospiro(isobenzofuran-1(ZH),4"-piperidine- 1"-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-methoxyphenyl)meth anonio) 1-(1-2-(b-fluorospiro(isobenzofuran-1(3H),4-piperidin-1'-ylIIIethyl)-3,4-dihydro-1H-y-isoquinolin-2-yl)-2 -phenylethanone Z-cyclohexyl-1-(1-12-|1b-fluorospiro(isobenzofuran-1(ZH) 4-piperidin-1'-yl||ethyl)-3,4-dihydro-1H-isoquinoline h- -2 -yl)propan-1-one so 2-(4-fluorophenyl)-1-(1-72-(b-fluorospiro(isobenzofuran-1(ZH),4-piperidin-1"-yl|ethyl)-3, 4-dihydro-1H-isoquinol yn-2-yl)ethanone (3,4-dichlorophenyl)amide 1-42-I6-fluorospiro(isobenzofuran-1(ZN),4-piperidin-1'-ylI|)ethyl)- 3,4-dihydro-1H-isoquinoline-2-carboxylic acid "1-cyclopropyl-1-(1-2-I(b-fluorospiro(isobenzofuran-1(ZH),4-piperidin-1'-ylI|ethyl) -3,4-dihydro-1H-isoquinoline with c -2-yl)umethanone 1-(1-2-(b-fluorospiro(isobenzofuran-1(ZH),4"-piperidin-1"-yl|ethyl)- 3,4-dihydro-1H-isoquinolin-2-yl)-1-pyride; t in-3-ylmethanone 1-I5-(4-chlorophenyl)-2-methylfuran-3-ylI-1-(1-72-(b-fluorospiro(isobenzofuran-1(ZH),4"-piperidine-1" -yl|ethyl)-Z"4-dihydro-1H-isoquinolin-2-yl)umethanone with 2-(4-chlorophenyl)-1-(1-72-(b-fluorospiro(isobenzofuran-1(ZH),4 -piperidin-1"-yl|ethyl)-3,4-dihydro-1H-isoquinol in-2-yl)ethanone -y 1-(1-2-(b-fluorospiro(isobenzofuran-1(Z3H),4- piperidin-1'-ylethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1 propan-1-one (2-ethylphenyl)amide 1 1-2-(b-fluorospiro(isobenzofuran -1(ZH),4-piperidin-1"-yl|ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid sl IM-(1-22-(2-(1-cycloheptylmethanol)-1 . 1-(3H), 4-piperidin-1"-yl|ethyl)-3,4-dihydro-1H-i dv Zoquinoline-2-ylumethanone 1-cycloheptyl-1-71-/1-acetylspiro|2,3- dihydro-1H-indole-3,4-piperidin-1'-ylethyl|-3,4-dihydro-1H-isoquinol HF) n-2-ylimethanone М-11-42-(2-(1-cycloheptylmethanol)- 1,2,3,4-tetrahydroisoquinoline-1-ylethyl)-4-f enylpiperidin-4-yl) acetamide 1-cycloheptyl-1-(1-2-(b-fluorospiro(isobenzofuran-1(ZH),4-piperidin-1"-yl)ethyl)-3,4-dihydro-b6, 7-dimethoxy bo 0/7 H-isoquinoline-2-ilumethanone 1-(4-fluorophenyl)-1-(1-2-16-fluoro-3-methylespiro(isobenzofuran-1(ZH),4-piperidine-1" -ylI|ethyl)-3,4-dihydro-1H- isoquinolin-2-yl)umethanone 1-cycloheptyl-1-(1-2-I5-fluoro-1-methanesulfonylspiro|2,3-dihydro-1H-indole- 3,4"-piperidin-1"-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 65 1-(1-42-(2-"1-cycloheptylmethanol)-1, 2,3,4-tetrahydroisoquinoline-1-ylethyl)-4-phenylpiperidin-4-yl)-1-piperidin-1-ylmethanone 1--4-fluorophenyl)-1-(1-2-I(5-fluoro-1-methanesulfonylspiro|2,3-dihydro-1H-indole-3,4-piperidin-1"-ylI|ethyl)-3 ,4-dihydro-1H-isoquinolin-2-yl)umethanone 1-cycloheptyl-1-(1-2-14-(2-methyl-1H-indol-3-yl)piperidin-1-yl|Hethyl)-3 ,4-dihydro-1H-isoquinolin-2-yl)umethanone 1-cycloheptyl-1-(1-2-I4-(3-trifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinoline -2-yl)umethanone 1-cyclopentyl-1-(1-12-1b-fluoro-3-methylespiro(isobenzofuran-1(3H),4-piperidin-1"-yl|ethyl)-3,4-dihydro- 6b, 7-d ethoxy-1H-isoquinolin-2-yl)umethanone 1-cyclopentyl-1-11-(spiro(2,3-dihydro-1H-indole-3,4"-piperidin-1-yl|ethyl) |-3,4-dihydro-1H-isoquinolin-2-ylum ethanone 70 1-cyclopentyl-1-(1-2-(5-fluoro-1-methanesulfonylspiro|2,3-dihydro-1H-indole-3,4 -piperidin-1"-yl||ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 1-(4-fluorophenyl)-1-(1-2-16-fluoro-3-methylespiro (isobenzofuran-1(3H),4-piperidin-1'-yl||ethyl)-3,4-dihydro-6, 7-dimethoxy-1H-isoquinolin-2-yl)umethanone 1-(2-fluorophenyl)- 1-(1-2-16-fluorospiro(isobenzofuran-1(3H),4-piperidin-1'-ylIIethyl)-3,4-di hydro-1H-isoquinol 75. In-2-ylumethanone 1-cycloheptyl-1-(1-72-(spiro(isobenzofuran-1(Z3H), "4-piperidin-1'-ylI|ethyl)-3,4-dihydro-1H-isoquinoline -2-yl)methanone 1-cycloheptyl-1-(1-72-(b-fluoro-3-methylspiro|(isobenzofuran-1(3H),4-piperidin-1'-yl||ethyl)-3,4 -dihydro-6b,7-d ethoxy-1H-isoquinolin-2-yl)umethanone 1-(1-42-i(4-(4-chlorophenyl)piperidin-1-yl|ethyl)-3,4-dihydro- 1H-isoquinolin-2-yl)-1-cycloheptylmethanone 1-cyclopentyl-1-(1-12-15-isopropylspiro(isobenzofuran-1(3H),4-piperidin-1'-yl1|ethyl)-3,4- dihydro-1H-isoquinolin-2-yl)umethanone IM-(1-4422-(2-(1-cyclopentylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-yl)|ethyl)-4-(3 -fluorophenyl)piperidin-4-ylylacetamide c 1-cycloheptyl-1-11-(2-(4-phenylpiperidin-1-yl)ethyl/|-3,4-dihydro-1H-isoquinolin-2-ylumethanone 1-cycloheptyl -1-(1-72-(b-fluoro-3Z-methylespiro(isobenzofuran-1(ZH),4-piperidin-1"-yl|ethyl)-3,4-dihydro-1H-iz (8) oquinoline- 2-yl)umethanone 1-cyclopentyl-1-(1-2-I4-(3-trifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 1-cyclopentyl -1-(1-12-Ib-fluorospiro(i isobenzofuran-1(Z3H), 4-piperidin-1'-ylethyl)-3,4-dihydro-6,7-dimethoxy y 30/71 H-isoquinoline-2-ylumethanone 1-(4-fluorophenyl)-1-( 1-2-16-fluorospiro(isobenzofuran-1(ZN),4-piperidin-1'-yl|ethyl)-3,4-dihydro-6,7-dimethocyl)si-1H-isoquinolin-2-yl) umethanone y- 1-(1-2-(4-(6-fluorobenzo|d|isoxazol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)- 1-(4-rtorphenyl)methanone h- 1-(1-(-2-22-(1-(4-fluorophenyl)methanol|)-1,2,3,4-tetrahydroisoquinolin-1-yl)oethyl) -4-phenylpiperidin-4-yl|-1-pipesoridin-1-ylmethanone 1-cyclopentyl-1-(1-2-I(I4-(3-fluorophenyl)piperidin-1-yl|ethyl)-3, 4-dihydro-1H-isoquinolin-2-yl)umethanone 8-2-(2-(1-cycloheptylmethanoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-1-phenyl-1,3 ,8-triazaspiro|4,5)|deca n-4-one "1-cycloheptyl-1-(1-72-(b--riftomethylspiro(isobenzofuran-1(ZH), "4-piperidin-1'-yl) |ethyl)-3,4-dihydro-6b,7-d with c imethoxy-1H-isoquinolin-2-yl)umethanone 1-(1-«-2-42-(1-(2-fluorophenyl)methanol)|- 1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-4-phenylpiperidin-4-yl|-1-(4-m with ethylpiperazin-1-yl)um ethanone ethyl ester of 1-2-(2-(1-cycloheptylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-ylethyl)-4-phenylpiperidine-4-carboxylic acid so 1-(1-42-( 2-"1-cycloheptylmethanol)-1,2,3,4-tetrahydroisoquinoline-1-ilyethyl)-4-phenylpiperidin-4-yl)ethanone 1-cyclopentyl-1-(1-12-I(b-trifluoromethylspiro|isobenzofuran -1(3H),4"-piperidin-1'-yl||ethyl)-3,4-dihydro-6b,7-d -y ethoxy-1H-isoquinolin-2-yl)umethanone -1 1-cyclopentyl- 1-(1-2-(4-(-2-methyl-1H-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 1- (1-42-(2-"1-cyclopentylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-yl)|Yuethyl)-4-phenylpiperidin-4-yl)ethanone 1 1-(4-fluorophenyl)- 1-(1-2-I(b-trifluoromethylspiro|(isobenzofuran-1(ZH),4-piperidin-1"-ylI|ethyl)-3,4-dihydro-6,7sl-dimethoxy-1H-isoquinoline- 2-yl)umethanone 1-(1-42-i(4-(4-chlorophenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-1--4- fluorophenyl)methanone 1-(1-42-(2-"1-cycloheptylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-ylylethyl)piperidin-4-yl)-1-(4-fluorophenyl)m dv ethanone 1-(1-42-(2-«1-cycl logheptylmethanol)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-phenylpiperidine-HF) 4-yl)-1-(4-methylpiperazin-1-yl)umethanone F 1-(1-42-(4-(4-chlorophenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-1-diclopentylmethanone 1-(4-fluorophenyl)- 1-(1-2-14-(3-trifluoromethylphenyl)piperidin-1-yl|1ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone in 1-(4-fluorophenyl)-1-( 1-2-Ispiro(isobenzofuran-1(ZN),4-piperidin-1'-yl||ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1-cyclopentyl-1-(1 -12-I4-fluorospiro(isobenzofuran-1(Z3H), 4-piperidin-1'-ylIIethyl)-3,4-dihydro-1H-isoquinoline -2-yl)umethanone 1-(2-fluorophenyl)-1-( 1-2-I6-fluoro-3-methylespiro(isobenzofuran-1(Z3H),4-piperidin-1'-yl||ethyl)-3,4-dihydro-6,7 65-dimethoxy-1H-isoquinoline-2 -yl)umethanone IM-(4-(3-fluorophenyl)-1-(2-42-11-(4-fluorophenyl)methanol/|-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)piperidine -4-il Acetamide 1-(2-fluorophenyl)-1-71-Ispiro(2,3-dihydro-1H-indole-3,4-piperidin-1'-yl|Hyethyl|-3,4-dihydro-1H-isoquinoline-2 -yl)methanone 1-cycloheptyl-1-(1-2-15-fluoro-1-methanesulfonylspiro|2,3-dihydro-1H-indol-3,4"-piperidin-1"-yl|ethyl)-3, 4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)umethanone 1-(1-42-(2-«1-cycloheptylmethanol)-6,7-dimethoxy-1,2,3,4- Tetrahydroisoquinolin-1'-yl)ethyl)-4-phenylpiperidin-4-yl)-1-piperidin-1-ylmethanone 1-71-(2-(4-benzylpiperidin-1-yl)ethyl)-3,4 -dihydro-1H-isoquinolin-2-yl)-1-cycloheptylmethanone 70 1-(2-fluorophenyl)-1-(1-2-I(b-trifluoromethylespiro(isobenzofuran-1(ZH),4-piperidine-1' -yl||ethyl)-3,4-dihydro-b,7-dimethoxy-1H-isoquinolin-2-yl)umethanone 1-41-42-(chlorotrifluoromethylphenyl)hydroxypiperidin-1-yl|ethyl)-6,7- dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-cycloheptylmethanone 1-(1-42-i(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl|ethyl)-6, 7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-cyclohexylmethanone 1-cycloheptyl-1-(1-22-14-(2-isopropoxyphenyl)piperidin-1-yl)ethyl )-3,4-digy dro-1H-isoquinolin-2-yl)umethanone 1-(1-42-i(4-(7-chloro-1H-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro- 1H-isoquinolin-2-yl)-1-diclopentylmethanone 1-cyclopentyl-1-(1-12-I4-(2,3-dihydrobenzofuran-7-yl)piperidin-1-yl|ethyl)-3,4-dihydro -1H-isoquinolin-2-yl)m ethanone 1-(1-2-(4-(2,3-dihydrobenzofuran-7-yl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinoline -2-yl)-1-4-fluorophenyl)methanone IM-(1-422-(2-(1-cycloheptylmethanol)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl) |ethyl)-4-(3-fluorophenyl)piperidin-4-yl|Iiacetamide 1--4-fluorophenyl)-1-11-(2-(4-phenylpiperidin-1-yl)ethyl|-3,4- dihydro-1H-isoquinolin-2-yl)umethanone with 1-(1-42-i(4-(6-chloro-1H-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro -1H-isoquinolin-2-yl)-1-(4-rtorphenyl)methanone 1-(4-fluorophenyl)-1-(1-2-I4-(3-fluorophenyl)piperidin-1-yl|ethyl)-3 ,4-dihydro-1H-isoquinolin-2-yl)umethanone (8) 1-cycloheptyl-1-11-Ispiro(2,3-dihydro-1H-indol-3,4"-piperidin-1'-yl|Hiethyl |-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-ylumethanone M-(1-42-(2-(1-cyclopentylmethanol)-1,2,3,4-tetrahydro Zoquinolin-1-ylethyl)-4-phenylpiperidin-4-yl)acetamide )-3,4-dihydro-1H-isoquinolin-2-yl)-1-(2-fluorophen yl)methanone io) 1-cycloheptyl-1-(1-72-(spiro(isobenzofuran-1(Z3H), 4 -piperidin-1'-yl(ethyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)umethanone ethyl ester h-1-2-(2-(1-cyclopentylmethanol) )-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-4-phenylpiperidine-4-carboxylic acid so 1-(1-42-(4--4-dimethylaminophenyl)piperidin-1-yl|ethyl) )-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone 1-cyclopentyl-1-(1-12-(4-(4-isopropylphenyl)piperidin-1-yl) Ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 1-(1-(-2-2-(1-(4-fluorophenyl)methanol|)-1,2,3,4-tetrahydroisoquinoline -1-yl)ethyl)-4-phenylpiperidin-4-yl|butanone 1-11-(2-2-(1-(2-fluorophenyl)methanol/-1,2,3,4-tetrahydroisoquinolin-1-yl) )ethyl)-4-phenylpiperidin-4-yl|iethanone « 1-(1-«-2-22-(1-(2-fluorophenyl)methanoyl|)-1,2,3,4-tetrahydroisoquinolin-1-yl )oethyl)-4-phenylpiperidin-4-yl|-1-piperidine-1-yl l-methanone 1-cyclopentyl-1-11-(2-(4-phenylpiperidin-1-yl)ethyl/|-3,4-dihydro-1H-isoquinolin-2-yl)umethanone; t 1-(2-fluorophenyl)-1-(1-2-16-fluorospiro(isobenzofuran-1(ZH),4-piperidin-1"-yl|ethyl)-3,4-dihydro-6,7-dimethoc si-1H-isoquinolin-2-yl)umethanone 1-(4-fluorophenyl)-1-(1-2-I(5,6-difluorospiro|benzofuran-1(ZH),4-piperidin-1"-ylI| ethyl)-3,4-dihydro-1H-isoquinosolin-2-yl)y-methanone 1-(4-fluorophenyl)-1-(2-(b-fluorospiro|(benzofuran-1(ZH),4- piperidin-1"-yl|ethyl)-3,4-dihydro-1H-isoquinoline-2-y l)methanone-1 3,3-dimethyl(1-12-|Ispiro(5-fluorobenzofuran-2H-3 ,4-piperidin-1"-yl)ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)butyric acid /an-1-one 1 cyclohexyl(1-(2-Ispiro(5-fluorobenzofuran -2H-3,4-piperidin-1'-yl)ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)meth slanone cyclohexyl(1-(2-Ispiro(5-methylisobenzofuran-ZH- 1,4"-piperidin-1'-yl)ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)methanone cyclohexyl(1-(2-Ispiro(benzofuran-ZH-1,4"-piperidine -1'-yl)ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone cyclohexyl(1-12-I(4--2-methyl-1H-indol-3-yl)piperidin- 1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone HF) M-41-(2-(2-cyclohexanecarbonyl-1,2,3,4-tetra hydroisoquinolin-1yl)ethyl)-4-phenylpiperidin-4-ilyacetamide F 3,3-dimethyl-1-(1-2-14-(3-trifluoromethylphenyl)piperidin-1-ylethyl)-3,4-dihydro -1H-isoquinolin-2-yl)butan-1-one cyclohexyl(1-12-(4-(3-trifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl )umethanone in cyclohexyl(1-12-(4--4-dimethylaminophenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 3-phenyl(|1-12- Ispiro(5-fluorobenzofuran-2H-3,4-piperidin-1'-yl)|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl|Inpropanone (1-2-I(4-(4- chloro-3-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl|ethyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinol in-2-yl)ucyclohexylmethanone 2-phenoxy|1-2-Ispiro( 5-fluorobenzofuran-2H-3,4-piperidin-1'-yl)|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl|Ietane-Thon 65 benzo|1,2,5|oxadiazole-5 -yl(1-12-|Ispiro(5-methylisobenzofuran-ZH-1,4"-piperidin-1'-yl))ethyl)-3,4-dihydro-TIN -isoquinolin-2-yl)umethanone cyclohexyl (1 -12-(4-(4-isopropylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 2-propyl(1--2-I(Ispiro(5- Fluoride enzofuran-2H-3,4"-piperidin-1'-yl)ethyl)-3,4-dihydro-1H-isoquinolin-2-yl|Ipentan-1-one 2,2-dimethyl-3-chloro(| 1-2-Ispiro(5-fluorobenzofuran-2H-3,4-piperidin-1'-yl)lethyl)-3,4-dihydro-1H-isoquinolin-2-yl|propan-1-one cyclohexyl(1-( 2-I4-(2,3-dihydrobenzofuran-7-yl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 3,3-dimethyl(1-12-| Ispiro(5-methylisobenzofuran-ZN-1,4-piperidin-1-yl)lethyl)-3,4-dihydro-.-7/7-isoquinolin-2-yl)butan-1-one 70 benzo|1,2 ,5|oxadiazol-5-yl(1-12-14-(3-trifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-.:7/7-isoquinolin-2-yl)umethanone 2- ethyl-1-(1-2-(4-(3-trifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-7/-isoquinolin-2-yl)butan-1-one 2-benzyloxy( 1-(2-Ispiro(5-methylisobenzofuran-ZH-1,4"-piperidin-1'-yl)|ethyl)-3,4-dihydro-. 7/7-isoquinolin-2-yl)ethan-1-one benzo|1,2,5)oxadiazol-5-yl|1-2-(spiro(5-fluorobenzofuran-2H-3,4-piperidin-1' -yl)|ethyl)-3,4-dihydro- :- 7/7 -isoquinolin-2-yl|methanone (1-2-I4-(4-chlorophenyl)piperidin-1-yl|Iethyl)-3,4 -dihydro-7A-isoquinolin-2-yl)ucyclohexylmethanone 1-(1-2-(4-(4-chlorophenyl)piperidin-1-yl|ethyl)-3,4-dihydro-77-isoquinolin-2-yl) -3,3-dimethylbutan-1-one 3,5,5-trimethyl|1-(2-Ispiro(5-fluorobenzofuran-2H-3,4'-piperidin-1-yl)Letyl)-3,4-dihydro -. 7/7 2o isoquinolin-2-yl)hexan-1-one 3,5,5-trimethyl(1-(2-(Ispiro(5-methylisobenzofuran-ZH-1,4"-piperidin-1'-yl)) |ethyl)-3,4-dihydro-.7/7-isoquinolin-2-yl)hexan-1-one 2-phenoxy(1-(2-(Ispiro(5-methylisobenzofuran-ZH-1,4"-piperidine -1'-yl)|ethyl)-3,4-dihydro-..-7/7-isoquinolin-2-yl)ethan-1-one c (1-2-I(4-(4-chlorophenyl)piperidine -1-yl|Iethyl)-3,4-dihydro-77A-isoquinolin-2-yl)-(2,2-dichlorocyclopropyl)methanone 2-benzyloxy|1-12-Ispiro(5-fluorobenzofuran-2H-3,4 (-piperidin-1-yl)ethyl)-3,4-dihydro-.: 7/7 (8)-isoquinolin-2-yl|Hiethan-1-one 1-(1-42-(4-(4- chloro-3-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl|ethyl)-6, 7-dimethoxy-3,4-dihydro-.:7/7-isoquinolin-2-yl)-3,3-dimethylbutan-1 -one yuzo 1-(1-2-(4-(2,3-dihydrobenzofuran-7-yl)piperidin-1-yl|ethyl)-3,4-dihydro-.7/7-isoquinolin-2-yl )-3,3-dimethylbutan-1-one and) 3,5,5-trimethyl-1-(1-2-I4-(3-trifluoromethylphenyl)piperidin-1-yl|Iethyl)-3,4-dihydro- . 7/7 i--isoquinolin-2-yl)hexan-1-one 2,2-dimethyl(1-(2-Ispiro(5-fluorobenzofuran-2H-3,4'-piperidin-1-yllethyl)-3, 4-dihydro-.7/7 h- -isoquinolin-2-yl|Ipropan-1-one so 3-cyclohexyl-1-(1-12-(4-(3-trifluoromethylphenyl)piperidin-1-yl|ethyl) -3,4-dihydro-.7/7-isoquinolin-2-yl)upropan-1-one furan-2-yl(1-(2-Ispiro(5-fluorobenzofuran-2H-3,4-piperidin-1' -yl)|ethyl)-3,4-dihydro-.-7A-isoquinolin-2-yl|Imethanone L(4-phenyl-1-12-(2-(3,5,5-trimethylhexanoyl)-1,2 ,3,4-tetrahydroisoquinolin-1-yl|ethyl)piperidin-4-yl)acetamide " quinoxalin-2-yl1-(2-I(spiro(5-fluorobenzofuran-2H-3,4'-piperidin-1-yl) )ethyl)-3,4-dihydro-.-7/7 z -isoquinolin-2-yl|methanone 3-cyclohexyl-2-Ispiro(5-fluorobenzofuran-2H-3,4-piperidin-1'-yl) )ethyl)-3,4-dihydro-. -dihydrobenzofuran-7-yl) piperidin-1-yl| -12-14-(2-methyl-7A-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-7/7-isoquinolin-2-yl)meth anon -y (tetrahydropyran-4-yl)-(1--2-I(4--"3--fluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-7-1-isoquinoline-2 -yl)umethanone 2-propyl-1-(1--2-(4--3--trifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-7A-isoquinolin-2-yl)upentane- 1-one 1 2-ethyl-1-(2-Ispiro(5-fluorobenzofuran-2H-3,4'-piperidin-1-yl)lethyl)-3,4-dihydro-.-7A-isoquinolin-2-yl|Ibutane -1-one sl 3-phenyl-1-(1-2-14-(3-trifluoromethylphenyl)piperidin-1-yl|1ethyl)-3,4-dihydro-7A-isoquinolin-2-yl)upropan-1- one 3,3-dimethyl-1-(1-12-14-(2-methyl-7A-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-7A-isoquinoline-2- yl)butan-1-one (1-2-14-(4-chloro-3-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl|ethyl)-6,7-dimethoxy-3,4-dihydro-.-7 /7 two Tizoquinolin-2-yl)-(2,2-dichlorocyclopropyl)methanone 1,2,3,4-tetrahydronaphthalen-2-yl(1-2-Ispiro(5-methylisobenzofuran-ZH-1,4"-piperidine -1'-yl)ethyl)-3,4-dihydro-HF)7H-isoquinolin-2-yl)umethanone F (4-methylsulfanylphenyl)-(1-2-(4-(3-trifluoromethylphenyl)piperidine-1 -yl|ethyl)-3,4-dihydro-.-7/7-isoquinolin-2-yl)umethanone in 3.5 ,5-trimethyl-1-(1-2-I4-(2-methyl-7A-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-7/7-isoquinoline-2- yl)hexan-1-one Z-phenyl(1-(2-Ispiro(5-methylisobenzofuran-ZH-1,4"-piperidin-1'-yl))ethyl)-3,4-dihydro-. 7-isoquinolin-2-yl)upropan-1-one furan-2-yl(1-42-(4--(3-trifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-7A-isoquinoline -2-yl)umethanone 65 2-benzyloxy-1-(1-2-I4-(-2-methyl-1H-indol-3-yl)piperidin-1-ylHyethyl)-3,4-dihydro-1H-isoquinoline -2-yl)ethanone 1-(1-42-(4-(4-chlorophenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-2-phenoxyethanone quinoxalin- 2-yl(1-72-(spiro(5-methylisobenzofuran-ZH-1,4-piperidin-1'-yl))ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 2,2 -dimethyl-1-(1-(2-(4-(3-trifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl-propan-1-one (2, 2-dichlorocyclopropyl)-(1-2-I(4--"3--fluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)methanone 4-methylsulfanylphenyl(1 -/2-(spiro(5-methylisobenzofuran-ZH-1,4-piperidin-1'-yl))ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)umethanone (2,2-dichlorocyclopropyl )-(1-2-I4-(2,3-dihydrobenzofuran-7-yl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinol 7/0. H-2-yl)methanone 1-(1-42-i(4-(4-isopropylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro-1H-isoquinolin-2-yl)-3,5 ,5-trimethylhexan-1-one 2,2-dichlorocyclopropyl(1-12-|Ispiro(isobenzofuran-ZH-1,4"-piperidin-1'-yl))|ethyl)-3,4-dihydro-1H- isoquinoline-2-ylumethanone M-(4-phenyl-1-(2-(2-(1,2,3,4-tetrahydronaphthalene-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) Ethyl) 7/5 Piperidin-4-yl)acetamide benzo|1,2,5|oxadiazol-5-yl(1-12-I4-(4-chlorophenyl)piperidin-1-yl|ethyl)-3,4- dihydro-1H-isoquinolin-2-yl)umethanone IM-(1-72-(2-(3,3-dimethylbutyryl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-phenyl- piperidin-4-yl)acetamide 3-chloro-2,2-dimethyl-1-(1-2-I4-(3-trifluoromethylphenyl)piperidin-1-yl|Iethyl)-3,4-dihydro-1H-isoquinoline- 2-yl)propan-1-one tetrahydropyran-4-yl1-2-Ispiro(5-fluorobenzofuran-2H-3,4"-piperidin-1'-yl)|ethyl)-3,4-dihydro-1H -isoquinoline -2-yl|Ibutan-1-one 1-(1-42-i(4-(5-fluoro-1H-indol-3-yl)piperidin-1-ylylethyl)-5-chloro-3,4 -dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone 1-cyclopentyl-1-(1-42-I4-(5-fluoro-1H-indol-3-yl) /piperidin-1-yl|ethyl)-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl) c g methanone 1-cyclopentyl-1-(1-12-Ib-fluorospiro(isobenzofuran-1( 3H), 4-piperidin-1"-yl(ethyl)-5-chloro-3,4-dihydro-1H-iso (8) quinolin-2-yl)umethanone 1-(4-fluorophenyl)-1-(1 -2-16-fluorospiro(isobenzofuran-1(ZN),4-piperidin-1"-yl|ethyl)-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)umethanone zo 1- cyclopentyl-1-(1-12-I(b-trifluoromethylspiro|(isobenzofuran-1(ZH),4-piperidin-1'-yl||ethyl)-5-chloro-3,4-dihydro o-1H-isoquinoline -2-yl)umethanone io) 1-(4-fluorophenyl)-1-(1-2-I(b-trifluoromethylespiro(isobenzofuran-1(ZH), 4-piperidin-1'-yl||ethyl)-5 -chloro-3,4-dihydro-1H-isoquinolin-2-yl)umethanone IM-(1-4422-(2-(1-cyclopentylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-yl) )|ethyl)-4-(3-fluorophenyl)piperidin-4-yl-acetamide with IM-(1-422-(2-(1-(4-fluorophenyl)methanol)-1,2,3,4- tetrahydroisoquinolin-1-yl|ethyl)-4-(3-fluorophenyl)piperidin-4-yl Acetamide IM-(1-4422-(2-(1-cyclopentylmethanol)-1,2,3,4-tetrahydroisoquinolin-1- ylethyl)-4-phenylpiperidin-4-ylylacetamide IM-(11-42-(2-(1 -(4-fluorophenyl)methanol)-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-4-phenylpiperidin-4-yl)iacetamide « 1-cyclopentyl-1-11-(1-acetylspiro|2 ,3-dihydro-1H-indole-3,4"-piperidine-1'-ilyethyl|-5-chloro-3,4-dihydro-1H-isoquinoline-2-ylumethanone 1-(4-fluorophenyl)- 1471-/1-acetylspiro|2,3-dihydro-1H-indole-3,4-piperidin-1'-yl|ethyl|-5-chloro-3,4-dihydro-1H-; t isoquinoline-2-ylumethanone 1-cyclopentyl-1-11-/1-acetylspiro|(2,3-dihydro-5-fluoro-1H-indole-3,4-piperidin-1'-yl|Ivethyl|-5- chloro-3,4-dihydro o-1H-isoquinoline-2-ilumethanone so 1--4-fluorophenyl)-1471-/1-acetylspiro/2,3-dihydro-5-fluoro-1H-indole-3,4- piperidin-1'-yl|ethyl|-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)umethanone-y 1-cyclopentyl-1-(1-2-I(4-(Z- trifluoromethylphenyl)piperidin-1-ylethyl)-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)m-1ethanone 1-4-fluorophenyl)-1-(1-2-I4-(Z -trifluoromethylphenyl)piperidin-1-yl|ethyl)-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl 1)methanone sl 1-(1-2-(4-(6-fluorobenzo|d| isoxazol-3-yl)piperidin-1-ylethyl)-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone 1-(1-2-(4- (6-fluorobenzo|d|isoxazol-3-yl)piperidin-1-ylethyl)-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(cyClOopentyl)methanone 1-«( 4-fluorophenyl)-1-(1-2-(5,6-difluorospiro|Ibenzofuran-1(3H),4-piperidin-1'-yl||ethyl)-5-chloro-3,4-dihydro-1H - HF) isoquinolin-2-yl)umethanone F 1-(4-fluorophenyl)-1-(12-Ib-fluorospiro(benzofuran-1(ZH) 4-piperide) in-1'-yl|ethyl)-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)umethanone in 1-cyclopentyl-1-(1-12-15,b-difluorospiro|(benzofuran -1(3H),4-piperidin-1"-yl|ethyl)-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 1-cyclopentyl-1-(12-Ib-fluorospiro (benzofuran-1(3H),4-piperidin-1'-yl||ethyl)-5-chloro-3,4-dihydro-1H-isoquinol in-2-yl)umethanone 1-(1-42-i( 4-(5-fluoro-1H-indol-3-yl)piperidin-1-yl|ethyl)-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl 65 l)methanone 1-cyclopentyl-1-(1-12-I(4-(5-fluoro-1H-indol-3-yl)piperidin-1-yl|Hyethyl)-3,4-dihydro-5-fluoro- 1H-isoquinolin-2-yl) methanone 1-cyclopentyl-1-(1-12-Ib-fluorospiro(isobenzofuran-1(ZH), 4-piperidin-1'-ylI|ethyl)-3,4-dihydro-5-fluoro-1H-isoquinoline- 2-yl)umethanone 1-(4-fluorophenyl)-1-(1-2-16-fluorospiro(isobenzofuran-1(3H),4-piperidin-1'"-yl1|1ethyl)-3,4-dihydro- 5-fluoro-1H-isoquinolin-2-yl)umethanone 1-cyclopentyl-1-(1-2-I(b-trifluoromethylespiro|(isobenzofuran-1(ZH),4-piperidin-1'-yl|)| ethyl)-3,4-dihydro-5-fluoro p-1H-isoquinolin-2-yl)umethanone 1-(4-fluorophenyl)-1-(1-2-(b-trifluoromethylespiro(isobenzofuran-1(ZH), 4-piperidin-1'-yl||ethyl)-3,4-dihydro-5-f 70. thor-1H-isoquinolin-2-ylumethanone IM-(1-4422-(2-(1-cyclopentylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-yl)|ethyl)-4-(3- fluorophenyl)piperidin-4-ylylacetamide IM-(1-422-(2-(1-(4-fluorophenyl)methanol)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-(Z -fluorophenyl)piperidin-4-yl Iacetamide IM-(1-4422-(2-(1-cyclopentylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-ylylethyl)-4-phenylpiperidin-4-ylIacetamide IM-( 1-422-(2-(1-(4-fluorophenyl)methanol)-1,2,3,4-tetrahydroisoquinolin-1-yl)|ethyl)-4-phenylpiperidine-4-ilyacetamide 1-cyclopentyl-1-11 -/1-acetylspiro|(2,3-dihydro-1H-indole-3,4-piperidin-1'-yl|Hyethyl|-3,4-dihydro-5-fluoro-1H-isoquinoline-2-ylumethanone 1 -(4-fluorophenyl)-1471-1-acetylspiro|2,3-dihydro-1H-indole-3,4-piperidin-1"-yl|Hyethyl-3,4-dihydro-5-fluoro-1H-2o Isoquinoline -2-yl)umethanone 1-cyclopentyl-1-11-(1-acetylspiro|(2,3-dihydro-5-fluoro-1H-indole-3,4-piperidin-1'-yl|Hyethyl|-3, 4-dihydro-5-fluoro p-1H-isoquinoline-2-ilumethanone 1--4-fluorophenyl)-1471-1-acetylspiro|2,3-dihydro-5-fluoro-1H-indole-3,4-piperidine- 1'-yl|ethyl/|-3,4- dihydro-5-fluoro-1H-isoquinolin-2-yl)umethanone with 1-cyclopentyl-1-(1-2-(4-(3-trifluoromethylphenyl)piperidin-1-yl|ethyl)-3,4-dihydro -5-fluoro-1H-isoquinolin-2-yl)m-ethanone o 1-(4-fluorophenyl)-1-(1-2-14-(3-trifluoromethylphenyl)piperidin-1-yl|1-ethyl)-3,4 -dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone 1-(1-2-(4-(6-fluorobenzo|d|isoxazol-3-yl)piperidin-1-yl|ethyl)-3, 4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-1-(4-isofluorophenyl)methanone 1-(1-2-(4-(6-fluorobenzo|d|isoxazol-3-yl) piperidin-1-ylethyl)-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-1-(cyclo)clopentyl)methanone y- 1-(4-fluorophenyl)-1-(1- 2-(5,6-difluorospiro|Ibenzofuran-1(3H),4-piperidin-1-yl||ethyl)-3,4-dihydro-5-fluoro-1H-i zoquinolin-2-yl)umethanone h- 1-(4-fluorophenyl)-1-(12-1b-fluorospiro(benzofuran-1(ZH)4-piperidin-1'-yl|ethyl)-3,4-dihydro-5-fluoro-1H-isoquinoline -2-yl)umethanone 1-cyclopentyl-1-(1-12-15,b-difluorospiro(benzofuran-1(ZH),4-piperidin-1"-yl|ethyl)-3,4-dihydro-5- fluoro-1H-isoquinolin-2-yl)umethanone 1-cyclopentyl-1-(12-1b-fluorospiro(benzofuran-1(ZN),4-piperidin-1'-yl)eth yl)-3,4-dihydro-5-fluoro-1H-isoquinol " In-2-ylumethanone with c 1-(1-42-i4-(5-fluoro-1H-indol-3-yl)piperidin-1- ilyethyl)-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone; t 1-cyclopentyl-1-(1-2-I(4-(5-fluoro-1H-indol-3-yl)piperidin-1-yl|ethyl)-5,6-dichloro-3,4-dihydro- 1H-isoquinolin-2-ilumethanenone 1-cyclopentyl-1-(1-12-1b-fluorospiro(isobenzofuran-1(3H),4-piperidin-1'-ylIIIethyl)-5,6-dichloro-3,4-dihydro -TH co-isoquinolin-2-yl)umethanone 1-(4-fluorophenyl)-1-(1-2-16-fluorospiro(isobenzofuran-1(ZN),4-piperidin-1"-yl|ethyl)-5 ,6-dichloro-3,4-dihydro- and 1H-isoquinolin-2-yl)umethanone-1 1-cyclopentyl-1-(1-2-I(b-trifluoromethylespiro|(isobenzofuran-1(ZH),4 -piperidin-1'-yl||ethyl)-5,6-dichloro-3,4-di vo Hydro-1H-isoquinolin-2-ylumethanone 1 1-(4-fluorophenyl)-1-(1-2-Ib -trifluoromethylspiro|(isobenzofuran-1(ZN),4-piperidin-1-yl||ethyl)-5,b-dichloro-3,4-d slyhydro-1H-isoquinolin-2-yl)umethanone IM-(1 -4422-(2-(1-cyclopentylmethanol)-1,2,3,4-tetrahydroisoquinolin-1-yl||ethyl)-4-(3-fluorophenyl)piperidin-4-yl acetamide IM-(1-422- (2-(1-(4-fluorophenyl)methanol)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-(3-fluorophenyl)piperidin-4-yl Acetamide HF) IM-(1 -4422-(2-(1-cyclopentylmethanol)-1,2,3,4-tetrahydroisoquinoline- 1-ylethyl)-4-phenylpiperidin-4-ylylacetamide FIM-(1-422-(2-(1-(4-fluorophenyl)methanol)-1,2,3,4-tetrahydroisoquinolin-1-yl)|ethyl) )-4-phenylpiperidine-4-ilyacetamide 1-cyclopentyl-1-11-/1-acetylspiro|(2,3-dihydro-1H-indol-3,4-piperidin-1'-yl|Hyethyl|-5,6 -dichloro-3,4-dihydro-1 boH-isoquinolin-2-yl)umethanone 1-(4-fluorophenyl)-1471-1-acetylspiro|2,3-dihydro-1H-indole-3,4-piperidine- 1-yl|ethyl/|-5,6-dichloro-3,4-dihydro-1H-isoquinoline-2-ylumethanone 1-cyclopentyl-1-11-(1-acetylspiro|(2,3-dihydro-5-fluoro -1H-indole-3,4-piperidin-1'-yl|ethyl|-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 65 1-(4-fluorophenyl)- 1471-1-acetylspiro|2,3-dihydro-5-fluoro-1H-indole-3,4-piperidin-1"-yl|ethyl|-5,6-dichloro-3,4- dihydro-1H-isoquinoline- 2-yl)umethanone 1-cyclopentyl-1-(1-2-(4-(3-trifluoromethylphenyl)piperidin-1-yl|ethyl)-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone 1 -(4-fluorophenyl)-1-(1-2-14-(3-trifluoromethylphenyl)piperidin-1-yl|1ethyl)-5,6b-dichloro-3,4-dihydro-1H-isoquinolin-2-yl) umethanone 1-(1-2-(4-(6-fluorobenzo|d|isoxazol-3-yl)piperidin-1-yl|ethyl)-5,b-dichloro-3,4-dihydro-1H-isoquinoline-2 -yl)-1-(4-fluorophenyl)methanone 1-(1-2-(4-(6-fluorobenzo|d|isoxazol-3-yl)piperidin-1-yl|ethyl)-5,b-dichloro- 3,4-dihydro-1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone 70 1-(4-fluorophenyl)-1-(1-2-I(5,6-difluorospiro|benzofuran-1(ZH ),4-piperidin-1'-yl||ethyl)-5,6-dichloro-3,4-dihydro -1H-isoquinolin-2-yl)umethanone 1-(4-fluorophenyl)-1-(12-Ib -fluorospiro(benzofuran-1(ZH) 4-piperidin-1'-yl|ethyl)-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)umethanone 1-cyclopentyl-1-( 1-12-I5,b-difluorospiro(benzofuran-1(ZH),4-piperidin-1"-yl|ethyl)-5,6b-dichloro-3,4-dihydro-1 75. N-isoquinolin-2-ylumethanone 1-cyclopentyl-1-(12-Ib-fluorospiro(benzofuran-1(Z3H),4-piperidin-1'-yl||ethyl)-5,6-dichloro-3, 4-dihydro-1H-isoinolin-2-yl)umethanone 1-(1-42-I(4-(5-fluoro-1H-indol-3-yl)piperidin-1-yl|Hyethyl)-5,b -difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone 1-cyclopentyl-1-(1-12-I(4-(5-fluoro-1H-indole) -3-yl)piperidin-1-yl|ethyl)-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-ilumethanenone 1-cyclopentyl-1-(1-12-Ib-fluorospiro(isobenzofuran- 1(3H), 4-piperidin-1'-yl(ethyl)-5,6-difluoro-3,4-dihydro-TIN-isoquinolin-2-yl)umethanone 1-(4-fluorophenyl)-1-(1 -2-16-fluorospiro(isobenzofuran-1(ZN),4-piperidin-1"-yl|ethyl)-5,6-difluoro-3,4-dihydro-s two H-isoquinoline-2-ylumethanone 1-cyclopentyl -1-(1-2-I(b-trifluoromethylspiro|(isobenzofuran-1(ZH),4-piperidin-1'-yl||ethyl)-5,6-difluoro-3,4-di (8) hydro -1H-isoquinolin-2-yl)umethanone 1-(4-fluorophenyl)-1-(1-2-(b-trifluoromethylspiro(isobenzofuran-1(Z3H), "4-piperidin-1'-ylID|ethyl)- 5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)umethanone yzo IM-(1-422-(2-(1-cyclopentyl) methanol)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-(3-fluorophenyl)piperidin-4-yl acetamide is) IM-(1-422-(2-(1-(4 -fluorophenyl)methanol)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-(3-fluorophenyl)piperidin-4-yl y-acetamide IM-(1-4422-(2-(1 -cyclopentylmethanol)-1,2,3,4-tetrahydroisoquinoline-1-ylethyl)-4-phenylpiperidin-4-ylylacetamide h- IM-(1-422-(2-(1-(4-fluorophenyl)methanol)-1 ,2,3,4-tetrahydroisoquinolin-1-yl)|ethyl)-4-phenylpiperidin-4-ilyacetamide co 1-cyclopentyl-1-11-(1-acetylspiro|(2,3-dihydro-1H-indole-3 ,4"-piperidine-1'-ilyethyl|-5,6-difluoro-3,4-dihydro-1H-isoquinoline-2-ylumethanone 1--4-fluorophenyl)-1471-/1-acetylspiro/2,3 -dihydro-1H-indole-3,4-piperidin-1'-yl|ethyl|-5,6-difluoro-3,4-dihydro -1H-isoquinoline-2-ylumethanone « 1-cyclopentyl-1-11-/ 1-Acetylspiro|(2,3-dihydro-5-fluoro-1H-indole-3,4"-piperidin-1"-yl|HyethylI|-5,6-difluoro-3,4-dy z c hydro-1H -isoquinolin-2-yl)umethanone 1--4-fluorophenyl)-1471-/1-acetylspiro(2,3-dihydro-5-fluoro-1H-indole-3,4-piperidin-1'-yl|ethyl| -5,6-difluoro-3,4-; t dihydro-1H-isoquinolin-2-yl)umethanone 1-cyclopentyl-1-(1-12-(4-(3-trifluoromethylphenyl)piperidin-1-ylethyl)-5,6-difluoro-3,4- dihydro-1H-isoquinolin-2-l)methanone so 1-(4-fluorophenyl)-1-(1-2-14-(3-trifluoromethylphenyl)piperidin-1-yl|1ethyl)-5,6-difluoro-3 ,4-dihydro-1H-isoquinolin-2-yl)umethanone-y 1-(1-2-(4-(6-fluorobenzo|d|isoxazol-3-yl)piperidin-1-yl|ethyl)-5, b-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-1 -1 -(4-fluorophenyl)methanone 1-(1-2-(4-(6-fluorobenzo|d|isoxazol-3- yl)piperidin-1-yl|ethyl)-5,b-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-1 1 -(cyclopentyl)methanone sl 1-(4-fluorophenyl)-1- (1-2-15,6-difluorospiro|benzofuran-1(ZN),4-piperidin-1"-yl|ethyl)-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl) umethanone 1-"(4-fluorophenyl)-1-(12-I(b-fluorospiro(benzofuran-1(ZH) 4-piperidin-1'-yl|ethyl)-5,6-difluoro-3,4-dihydro -1H-iz dv oquinolin-2-ilumethanone 1-cyclopentyl-1-(1-12-15,b-difluorospiro(benzofuran-1(ZH),4-piperidin-1"-yl|ethyl)-5,6- difluoro-3,4-dihydro-1 HF) N-isoquinolin-2-yl)umethanone F 1-cyclopentyl-1-(12-Ib-fluorospiro(benzofuran- 1(3H),4-piperidin-1'-yl||ethyl)-5,6-difluoro-3 4'"dihydro-1H-isox inolin-2-yl)umethanone in M-(4-(3-fluorophenyl) )-1-72-(2-(2-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-ylylethyl)piperidin-4-yl)uacetamide (enantiomer) M-(4-(3-fluorophenyl) -1-72-(2-(2-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-ylylethyl)piperidin-4-yl)uacetamide (enantiomer) IM-(11-42-(2-( 4-chlorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-ylethyl)-4-(3-fluorophenyl)piperidin-4-ylacetamide 65 (enantiomer) I-(11-42-(2-(4 -bromobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-(3-fluorophenyl)piperidine-4-ilyacetamide -BO0- (enantiomer) IM-(1-42-(2-(4-fluorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-ylethyl)-4-(3-fluorophenyl)piperidin-4-yl|acetamide (enantiomer ) M-K4-(3-fluorophenyl)-1-12-I(I2-(4-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-ilyethyl)piperidin-4-yl)acetamide (enantiomer) M-(4-(3-fluorophenyl)-1-2-(2-(4-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)piperidin-4-yl)acetamide (enantiomer) IM-(11-42-(2-(3-chlorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-(3-fluorophenyl)piperidin-4-ylIacetamide 7/0 (enantiomer ) I-(11-42-(2-(2-bromobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-(3-fluorophenyl)piperidine-4-ilyacetamide (enantiomer) IM -(1-72-(2-(4-bromobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-phenylpiperidin-4-yl)acetamide (enantiomer) IM-(1-72 -(2-(2,4-dichlorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-ylethyl)-4-phenylpiperidin-4-yl)acetamide /5 (enantiomer) IM-(1-(2-( 2-(2,4-dichlorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-(3-fluorophenyl)piperidin-4-yl)acetate copper (enantiomer) I-(11- 42-(2 -(benzo|1,2,5)oxadiazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-(3-fluorophenyl)piperidin-4-yl|acetamide ( enantiomer) M-(4-(3-fluorophenyl)-1-2-(2-(naphthalene-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-ylylethyl)piperidin-4-yl)acetamide (enantiomer) I-(1-(2--2-cyclopentanecarbonyl-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl I|-4-(3-fluorophenyl)piperidine-4-ilyaceta copper (enantiomer) IM -(1-72-(2-(4-chlorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-ylethyl)-4-phenylpiperidin-4-yl)uaacetamide (enantiomer) with IM-(11-42- (2-(benzo|bithiophene-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-(3-fluorophenyl)piperidin-4-yl|acetamide (enantiomer) (8) IM-(11-42-(2-(6-fluoro-4H-benzo/|1,3)dioxin-8-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4- (Z-fluorophenyl)piperidin-4-yl)| acetamide (enantiomer) I-(11-42-(2-(3-bromobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-(3-fluorophenyl)piperidine-4-ilyacetamide zo (enantiomer) I-(11-42-(2-(2-fluorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-ylethyl)-4-(3-fluorophenyl)piperidin-4-yl|acetamido ) (enantiomer) y-IM-(1-72-(2-(4-methylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-phenylpiperidin-4-yl)acetamide (enantiomer ) h- IM-(1-72-(2-(2-chlorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-ilyethyl)-4-(3-fluorophenyl)piperidine-4-ilyacetamide co (enantiomer) M-(4-(3-fluorophenyl)-1-72-(2-(4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-ylylethyl)piperidin-4-yl)uacetamide (enantiomer) M -(1-22-(2-(3-chlorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-4-phenylpiperidin-4-ylluacetamide (enantiomer) « IM-(1-72- (2-(4-fluorobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-phenylpiperidin-4-yl)oacetamide (enantiomer) with М-41-(2-(2- cycloheptanecarbonyl-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl|-4-phenylpiperidin-4-ilyacetamide (enantiomer); t IM-(1-72 -(2-(3-bromobenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)-4-phenylpiperidin-4-yl)acetamide (enantiomer) 2-M-(4-(3-fluorophenyl) )-1-2-(2-(3-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-ylylethyl)ipiperidin-4-yl)acetamide (enantiomer) co M-(4-(3-fluorophenyl) )-1-2-(2-(thiophen-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)piperidin-4-yl)aceta copper (enantiomer)-th M-(4 -(3-fluorophenyl)-1-72-(2-(4-pyrazol-1-ylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl|ethyl)piperidin-4-yl)a-1 cetamide (enantiomer) M-(1-72-(2-(naphthalene-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-ylethyl)-4-phenylpiperidin-4-yl)acetamide 1 (enantiomer). sl 26. A pharmaceutical composition that contains the compound specified in any of claims 1-25 in a therapeutically effective amount together with one or more pharmaceutically acceptable carriers or diluents. 27. Use of the compound specified in any of claims 1-25 for the manufacture of a pharmaceutical preparation for the treatment of a central nervous system disorder. 28. Application according to claim 27, characterized in that the disorder is selected from the group consisting of depression, HF) manic depression, bipolar disorder, psychotic depression, mixed anxiety and depressive disorder, generalized anxiety disorder, social anxiety disorder, panic anxiety disorder , post-traumatic stress disorder, obsessive-compulsive disorder, acute stress disorder, phobia, premenstrual dysphoric disorder, psychosis and Huntington's disease, as well as Parkinson's dementia, adjustment disorder, pain, vomiting, migraine, epilepsy, obesity and cerebrovascular disease. 29. The application according to claim 28, characterized in that the disorder is selected from the group consisting of depression, manic depression, bipolar disorder, psychotic depression, mixed anxiety and depressive disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, 65 post-traumatic stress disorder stress disorder, obsessive-compulsive disorder, acute stress disorder, phobia, premenstrual dysphoric disorder, and psychosis. 30. Use of the compound specified in any one of claims 1-25 in the treatment of a disorder of the central nervous system. 31. Use according to claim 3, characterized in that the disorder is selected from the group consisting of depression, manic depression, bipolar disorder, psychotic depression, mixed anxiety and depressive disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder stress disorder, obsessive-compulsive disorder, acute stress disorder, phobia, premenstrual dysphoric disorder, psychosis and Huntington's disease, as well as Parkinson's dementia, adjustment disorder, pain, vomiting, migraine, epilepsy, obesity and cerebrovascular disease. 70 32. The application according to claim 31, characterized in that the disorder is selected from the group consisting of depression, manic depression, bipolar disorder, psychotic depression, mixed anxiety and depressive disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder stress disorder, obsessive-compulsive disorder, acute stress disorder, phobia, premenstrual dysphoric disorder, and psychosis. 0. and and and and. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2008, MZ, 11.02.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. c 7 o Io) Io) che «-- Zo so - and? so - - 1 (l ko 60 b5