UA77958C2 - Nociseptine analogues - Google Patents

Abstract

A compound of formula (I), (II), (III) or (IV), wherein Z, A, B, C, R, R1, R2, Q, and n are as described herein. (I) (II) (III) (IV)

Description

Description of the invention

Chronic pain is a major cause of debilitation and intense suffering. Successful treatment of 2 acute and chronic pain is the primary goal of the physician, with the use of opioid analgesics as the preferred medication.

Until recently, the existence of three major classes of opioid receptors in the central nervous system (CNS) was evident, with each class having receptor subtypes. These classes of receptors were designated as u, b and k.

Since opiates have a high affinity for these receptors, while not being endogenous to the body, further research was conducted to identify and isolate endogenous ligands for these receptors. These ligands were identified as enkephalins, endorphins and dynorphins.

Recent experiments have led to the identification of a cDNA encoding an opioid receptor-like receptor (OKI 1) with a high degree of homology to known classes of receptors. This newly discovered receptor was classified as an opioid receptor based on its structure alone, as the receptor showed no pharmacological homology. First, it was shown that non-selective ligands with high affinity for rc,b and k receptors have low affinity for OKIL. This characteristic, along with the fact that the endogenous ligand has not yet been discovered, led to the term "orphan receptor".

Further research led to the isolation and establishment of the structure of the endogenous ligand of the OKI 1 receptor.

This ligand is a peptide of seventeen amino acids, structurally similar to members of the opioid peptide 720 family.

The discovery of the OKI 1 receptor provides the opportunity to discover new compounds for the development of drugs that can be administered to control pain or other syndromes modulated by this receptor.

All documents cited herein are incorporated by reference in their entirety for all purposes.

Accordingly, the purpose of some embodiments of the present invention is to provide new compounds that show high affinity for the OKI 1 receptor. (o)

The purpose of some variants of the implementation of this invention is to provide new compounds that show affinity for the OKI 1 receptor and one or more of the shob or k receptors.

It is an object of some embodiments of the present invention to provide novel compounds for the treatment of a patient suffering from chronic or acute pain by administering a compound having an affinity for the receptor

OV. what)

The purpose of some variants of the implementation of this invention is to provide new compounds that have an agonistic activity of Fo in relation to y, b and k receptors, which is greater than that of currently available compounds, for example, morphine.

The purpose of some variants of the implementation of this invention is to provide methods of treatment of chronic or acute pain by introducing compounds that have agonistic activity in relation to receptors, which is greater than that of compounds available at this time.

The purpose of some embodiments of the present invention is to provide methods of treating chronic or acute pain by administering non-opioid compounds that have agonistic activity against shock receptors and cause fewer side effects than currently available compounds.

The purpose of some variants of the implementation of this invention is to provide compounds useful as analgesics, - with anti-inflammatory agents, diuretics, anesthetics and neuroprotective agents, antihypertensive agents, sedatives; means for regulating appetite; hearing regulators; antitussives, antiasthmatics, and" motor activity modulators, cognitive and memory modulators, neurotransmitter and hormone release regulators, kidney function modulators, antidepressants, agents for the treatment of memory loss due to Alzheimer's disease or other dementias, agents against epilepsy, - And anticonvulsants, means for the treatment of alcohol and drug withdrawal, means for regulating water balance, means for regulating sodium excretion and means for regulating disorders of arterial blood. blood pressure, and methods for introducing the specified compounds. (se) The compounds of this invention are useful for modulating the pharmacodynamic response from one or more sl 50 opioid receptors (OKI1, c, b and k) of the central and/or peripheral nervous system. The response can be attributed to a compound that stimulates (agonist) or inhibits (antagonist) one or more receptors. Some compounds 42) can stimulate one receptor (for example, an ND agonist) and inhibit another receptor (for example, an OC antagonist).

Other objects and advantages of the present invention will become apparent from the following detailed description of the invention. This invention in some embodiments includes compounds having the general formula (1):

F) name) 60 b5 dyn ()

TU. in. here

I drank gas and said: "in the village

Ec. I am not from p: "In addition

I. scha

HE where

O is a 5-8-ene cycloalkyl, 5-8-ene heterocyclic or b-ene aromatic or heteroaromatic group; n is an integer from 0 to 3;

A, B and OO are, independently, hydrogen, C 4-1 alkyl, C 1-12 cycloalkyl, C 1-choralkoxy, C 12-12C 1-ClOalkoxy, c -CHNOOH, -MNBO", hydroxyC. oralalkyl-, aminocarbonyl-, C.alkylaminocarbonyl-, diC) and dalalkylaminocarbonyl-, o acylamino-, acylaminoalkyl-, amide, sulfonylaminos..alkyl-, or A-B together can form a bridge Sov or

B-O together can form a bridge Cz.7, or A-O can together form a bridge Su.v; 7 selected from the group consisting of a bond, straight or branched C/4.alkylene, -MH-, -CH»O-, -СнNoМмнН-, -СН.М(СНай)-, -МНСН»-, - СНСОМН-, -МНСННСО-, -СННСО-, -СОСН»-, -СНасОССнН»-, -СН(СНИ)-,-СН- -0- 00 1-nHOС-CH.-, in which carbon atoms and/or nitrogen are unsubstituted or substituted by one or more lower alkyl, hydroxy, halogen or alkoxy groups;

Bi is selected from the group consisting of hydrogen, C 4-zoalkyl, C 3-1ocycloalkyl, Soloralkenyl, amino, F3

Si. loalkylamino-, C3.12cycloalkylamino-, -СООМ, -С4.АСООМ., cyano, cyanos. zralkylu-, cyanoCz zocycloalkyl-, them

MN»ZO»-, MN»ZO»S. dalkilu-, МН»ьЖЗОС. dalalkyl-, aminocarbonyl-, C.alylaminocarbonyl-, dis- dalalkylaminocarbonyl-, benzyl, C3.12cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl - or heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system, and spiro-ring system of the formula (M) :

And h | ZY no il PAY -i . . . . not - . . where Hu and Ho are independently selected from the group consisting of MH, O, 5 and CH"; and in which alkyl, cycloalkyl, and alkenyl, C. 1-alkylamino-, C. 42-cycloalkylamino-, or benzyl from the KK group are specified. optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C..4alkyl, C.alkyloxy, nitro, trifluoromethyl-, cyano, -OOM1, -C1,/COOM., cyanoC. zoalkyl-, -Si 5(-O)MM 00 -C4 5MNV(-O)2MMi; 0 -С4 6МНО(-О)ММи 0 5-membered 1 20 heteroarylCo dalalkyl-, phenyl, benzyl, benzyloxy, while the specified phenyl, benzyl and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 4.ralkylu-,

Si zoalkoxy- and cyano; and where indicated C3-isocycloalkyl, C3-42cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system or spiro ring system of formula (M) is optionally substituted with 1-3 substituents selected from the group consisting of from halogen, C1-alkyl, C1-ralkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, where gF) indicated phenyl, benzyl, phenyloxy or benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of consists of halogen, S. zralkyl, S. zralcox and cyano;

MU. is hydrogen, C 4-oalkyl, C 3-42cycloalkyl, C 2-alkyloxy, C 3-4-cycloalkyl, -CHNOOH, amino, C 4-alkylamino, diC-.alkylamino- or 5-membered heteroaromatic ring, optionally substituted by 1 -3 lower alkyls;

Mi represents H, C. alkyl, C.sub.bcycloalkyl, benzyl or phenyl;

EC" is selected from the group consisting of hydrogen, C-4 alkyl, C3-12 cycloalkyl, and halogen, while the specified alkyl or cycloalkyl is optionally substituted with an oxo, amino, alkylamino, or dialkylamino group; c5 and their pharmaceutically acceptable salts and solvates.

The present invention in some embodiments includes compounds having the following general formula (IA):

hide: (A) tk) ' : i s oi I -N : Ж ш. where n is an integer from 0 to 3; ch 7 is selected from the group consisting of the bond, -CH 5-, -MH-, -CHNHO-, -CHNHCH»-, -CHNHMH-, -CHNoM(ChNH3)-, -MHneH»-, -"CHNhSOMnH -, -МНСНННСО-, -СНСО-, -СОСН»-, -СННСОСН»-, -СН(СН»У)-, -СН- and -НС-СН-, in which the carbon and/or nitrogen atoms are unsubstituted or substituted by a lower alkyl, halogen, hydroxy or alkoxy group;

Ki is selected from the group consisting of hydrogen, C4-zoalkyl, C3-1ocycloalkyl, C3-zoalkenyl, amino,

C.i.loalkylamino, C.12-cycloalkylamino, benzyl, C.12-cycloalkenyl, monocyclic, bicyclic or tricyclic Fuso aryl or heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro-ring system of the formula: o (22) : - и: I "20 where Hu and Ho are independently selected from the group consisting of MH, 0, 5 and CH"; what! in which the specified monocyclic aryl is preferably phenyl; c in which the specified bicyclic aryl is preferably naphthyl; 1" in which alkyl, cycloalkyl, alkenyl, C 4-hoalkylamino, C3 are indicated. 4l3o7cycloalkylamino or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C4-1alkyl, C1-10alkyl, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, wherein phenyl, benzyl, and benzyloxy are indicated optionally -1 but substituted with 1-3 substituents selected from the group consisting of halogen, C1-4alkyl, C1-4alkyl, and cyano; in which C3.12cycloalkyl, C3.12cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, -and heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro-ring c system of formula (M) are optionally substituted with 1-3 substituents selected from a group consisting of halogen, C. .. .. . . . . . . . . alkyl, C. . from the group consisting of halogen, C. zralkilu, C. zralcox and cyano;

K." selected from the group consisting of hydrogen, C-1 alkyl, C3-10-2 cycloalkyl and halogen, while the specified alkyl is optionally substituted with an oxo group; 5 and their pharmaceutically acceptable salts and solvates.

In some preferred embodiments of the formula (I), O is a phenyl or β-heteroaromatic (Ф) group containing 1-3 nitrogen atoms.

Ge In some preferred embodiments of formula (I) or (IA) K 41 alkyl is methyl, ethyl, propyl, butyl, pentyl or hexyl. In some preferred embodiments of formula (I) or (A), K - cycloalkyl is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl or norbornyl.

In other preferred embodiments of formula (I) or (IA), the bicyclic ring system K. is naphthyl. In other preferred embodiments of formula (I) or (IA), the bicyclic ring system K.; is tetrahydronaphthyl or decahydronaphthyl and the tricyclic ring system Ki is dibenzocycloheptyl. In other preferred embodiments, Ku is phenyl or benzyl. b5 In other preferred embodiments of formula (I) or (IA), the bicyclic aromatic ring K/ is

A 10-membered ring, preferably quinoline or naphthyl.

In other preferred embodiments of formula (I) or (IA), the bicyclic aromatic ring K/ is a 9-membered ring, preferably indenyl.

In some embodiments of formula (I) or (IA) 7 is a bond, methyl or ethyl.

In some embodiments of formula (I) or (IA), group 7 is maximally substituted, so that no hydrogen substitution is present on the main group 7. For example, if the main group 7 is -СН 5-, when substituted with two methyl groups, the hydrogens of the main -СНо-group 2 are removed.

In other preferred embodiments of formula (I) or (IA), n is equal to 0. 70 In some embodiments of formula (I) or (IA), Hu and Ho" both represent 0.

In some variants of the embodiment of formula (I), 2K 4 is cyclohexylethyl, cyclohexylmethyl, cyclopentylmethyl, dimethylcyclohexylmethyl, phenylethyl, pyrrolyltrifluoroethyl, thienyltrifluoroethyl, pyridylethyl, cyclopentyl, cyclohexyl, methoxycyclohexyl, tetrahydropyranyl, propylpiperidinyl , indolylmethyl-, pyrazolylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl- or oxocanylpropyl-.

In some variants of the embodiment of formula (I), 7K 4 is -CH COM. tetrazolylmethyl-, cyanomethyl-,

МН»ЗзО»methylu-, МН»Ометили-, aminocarbonylmethyl-, Su dalkylaminocarbonylmethyl- or diSi dalkylaminocarbonylmethyl-.

In some variants of the embodiment of formula (I), 2К4 is 3,3-diphenylpropyl, optionally substituted at the 3rd carbon atom of propyl with the group -00M., tetrazolylSO with alkyl-, cyano-, aminocarbonyl-,

Sui.dalkylaminocarbonyl- or disC../-alkylaminocarbonyl-.

The present invention in some embodiments includes compounds having the general formula (I): (1) sch y; ve o z - " p y J

Ь AN and t st She and yu where we How.

Eat! eh-! and ki Their from the 7th c. 1 "

Where -1 the dashed line is an optional double bond;

K represents hydrogen, C 10 alkyl, C 2 cycloalkyl, C 42 cycloalkyl C. dalalkyl-, C3-12cycloalkyl, C3-12cycloalkyl, C3-12cycloalkyl, C3-12cycloalkyl, C3-412cycloalkyl, C3-12cycloalkyl, substituted with 1-3 halogens, C3-412cycloalkyl -, substituted by 1-3 halogens, C.o.alkoxy, substituted by 1-3.5r Halogens, C.1ocycloalkoxy-, substituted by 1-3 halogens, -COOM, -С4иСО0ОМ3, -СННОН, -5ОЗМ(М4)», 1 hydroxyС..ralkyl -, hydroxyC3.ocycloalkyl-, cyanosCi.ralalkyl-, cyanosSu. ocycloalkyl-, -СОМ(М 1)», со МН»ЗзО»сС. dalkil-, МНЖЗОС). dalalkyl-, sulfonylaminos..ralalkyl-, diaminoalkyl-, -sulfonyl. dalkyl, b-membered heterocyclic ring, b--lenned heteroaromatic ring, b-membered heterocyclylC. lalkyl-, b-membered heteroarylsC . alkyl-, b--len aromatic ring, b--len arylC) dalalkyl-, 5--len heterocyclic ring, optionally substituted oxo or thio, 5--len heteroaromatic ring, 5--len heterocyclyl 4 .alkyl -, optionally substituted oxo or thio, b-membered heteroarylC 4alkyl-, -C45(-O)MM1 0 -C4 (MH, (F) -C4-5MNOTstoOmM,-C3 5MHO(-O)2MM1, - С45МНО(-О)ММ, where MU is hydrogen, C4-oalkyl, C3-102cycloalkyl, C3-102cycloalkyl, C3-102 cycloalkyl, C3-30 cycloalkyl, -CHNOOH, amino, C10-alkylamino-, disilylalkylamino- or 5-membered heteroaromatic ring, necessarily substituted by 1-3 lower alkyls, where each M. is independently selected from H, C. alkyl, C.sub.3-cycloalkyl, benzyl, and phenyl; n is an integer from 0 to 3;

O is a 5-8-ene cycloalkyl, 5-8-ene heterocyclic or b-ene aromatic or heteroaromatic group;

A, B and O are, independently, hydrogen, C 4.4oalkyl, C3.12cycloalkyl, C.zoalkoxy, C3.12cycloalkoxy, 65C zoalkenyl, Suzralkylidene, oxo, -СНоОН, -МНЗО», hydroxyС. zralalkyl-, aminocarbonyl-, C dalalkylaminocarbonyl-, diC-allkylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide, sulfonylaminos. "ralkyl-, or A-B together can form a bridge Sov, or B-C0 together can form a bridge Cz.7, or A-0O together can form a bridge C. c; 7 selected from the group consisting of a bond, straight or branched C/4.alkylene, -MH-, -CH»O-, 500 СНоМННн-,-СНоМ(СН»3)-, -МНОН»-, - СНоСОМН-, -МНСНННЖСО-, -СНСО-, -СОСН»-, -СН»СОСсСН»-, -СН(СНУ)-, -СНе -0- and-СНС-СН-, in which carbon atoms and/or nitrogen are unsubstituted or substituted by one or more lower alkyl, hydroxy, halogen or alkoxy groups;

Ki is selected from the group consisting of hydrogen, C4-zoalkyl, C3-42cycloalkyl, C1-zralkenyl, amino,

Si. loalkylamino-, C3.12cycloalkylamino-, -СООМ, -С4.АСООМ., cyano, cyanos. zralkylu-, cyanoCz zocycloalkyl-, 70. МН»ЗО»-, МН»ЗО»С. dalkilu-, МН»ьЖЗОС. dalalkyl-, aminocarbonyl-, C-alkylaminocarbonyl-, diC-dalkylaminocarbonyl-, benzyl, C3.412cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro-ring system of the formula (M): : school : And about;

Shchi de Hu and Ho are independently selected from the group consisting of MH, O, 5 and CH"; and in which the specified alkyl, cycloalkyl, alkenyl, C.zoalkylamino-, C.sub.12cycloalkylamino-, or benzyl from the group Ki is optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C..1alkyl, Si .1oalkoxy, nitro, trifluoromethyl-, cyano, su -COOM1 and -SiiCOOM. cyanoC)u zralalkyl-, -Si5(5О)MM1, -С4 5МН(-О)2ММи, -С415МНОВ(-О)ММи 0 of 5-membered heteroarylCo dalalkyl-, phenyl, benzyl, benzyloxy, while phenyl, benzyl and benzyloxy i9) optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 4.alkyl-,

Siloalkoxy- and cyano; and in which the indicated C 3-10 cycloalkyl, C 10-cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system c or spiro-ring system of the formula (M) is optionally substituted with 1-3 substituents selected from the group consisting of from halogen, C 4.1 alkyl, Cisraloxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and that benzyloxy, where indicated phenyl, benzyl, phenyloxy or benzyloxy are optionally substituted with 1-3 substituents, Ge) selected from the group consisting of halogen, S. .zralkilo, S.-.zralkoxy and cyano;

EC" is selected from the group consisting of hydrogen, C-4 alkyl, C3-12 cycloalkyl, and halogen, while the indicated alkyl or cycloalkyl is optionally substituted with an oxo, amino, alkylamino, or dialkylamino group; - and their pharmaceutically acceptable salts and solvates.

This invention in some embodiments includes compounds having the general formula (PA): . and: (PA) "

Wu a Z s More. s azh - y i I 1» | S ze Be za -i 7 Ku i ich" sl 50 Z (Che) y U Y yo g

I. o t ime) where 60 the dashed line represents an optional double bond; 7 selected from the group consisting of the bond, -CH»-, -MH-, -CHНХО-, -ХНХХН»о-, -ХНХМН-, -ХНХМ(ХН»)-, -МНеНН»е-, - CHНСОМнН-, -МНОННСО-, -СНСО-, -СОСН»о-, -СНСОСН»-, -СН(СНУ)-, -СН: and -НС-СН-, where the carbon and/or nitrogen atoms are unsubstituted or substituted a lower alkyl, halogen, hydroxy or alkoxy group;

K and O are the same or different and each is selected from the group consisting of hydrogen, halogen, C 4-4 alkyl, C 4-4 alkyl, C 1-4 alkylidene, C 1-12 cycloalkyl, C 1-12 alkyl, and oxo;

Ki is selected from the group consisting of hydrogen, C4-zoalkyl, C3-1ocycloalkyl, C3-zoalkenyl, amino,

Siloalkylamino-, C3-1ocycloalkylamino-, benzyl, C34ocycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, bicyclic ring system and spiro ring system of the formula (M):

ЖЕ 2 и 70 in which Х. and Хо are independently selected from the group consisting of МН, О, 5 and СН"; in which the specified monocyclic aryl is preferably phenyl; t5 in which the indicated bicyclic aryl is preferably naphthyl; in which alkyl, cycloalkyl, alkenyl, C 4.choalkylamino, C3 are indicated. 4l3o7cycloalkylamino or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C4-1alkyl, C1-10alkyl, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, wherein phenyl, benzyl, and benzyloxy are indicated optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1.4alkyl, C1.ralcoco and cyano; in which the specified C 342ocycloalkyl, C3.4o2cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro-ring system of the formula (M) are optionally substituted with 1-3 substituents selected from the group consisting of from halogen, C 1-1 alkyl, C 1 -isoalkyl, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, where the indicated phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen , S. zralkilu, S. zralkoks and cyano; (at,

Co is selected from the group consisting of hydrogen, C..alkyl, C.sub.12cycloalkyl and halogen, while the specified alkyl is optionally substituted by an oxo group; and their pharmaceutically acceptable salts. co

In some preferred embodiments, O in formulas (II) or (IA) is hydrogen or methyl.

In some preferred embodiments, K in formulas (II) or (PA) is hydrogen, methyl, ethyl or (IF) ethylidene. F

In some preferred embodiments of formula (II), O is a phenyl or 6-membered heteroaromatic group containing 1-3 nitrogen atoms. -

In some preferred embodiments of formula (II) or (PA), K 4 alkyl is methyl, ethyl, propyl, m-butyl, pentyl or hexyl.

In some preferred embodiments of formula (II) or (PA), K and cycloalkyl is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl or norbornyl.

In other preferred embodiments of formula (II) or (PA) K, the bicyclic ring system is "20 naphthyl. In other preferred embodiments of formula (I) or (PA) K, the bicyclic ring system represents is tetrahydronaphthyl or decahydronaphthyl and KK; tricyclic ring system is c dibenzocycloheptyl. In other preferred embodiments, K is phenyl or benzyl. 1» In other preferred embodiments of formula (II) or (IA) Ku bicyclic aromatic ring is a 10-membered ring, preferably quinoline or naphthyl.

In other preferred embodiments of formula (II) or (IA) Ku, the bicyclic aromatic ring is a -1 15 9-membered ring, preferably indenyl.

In some embodiments of the formula (II) or (PA) 7 is a bond, methyl or ethyl. -i In some variants of the embodiment of the formula (II) or (PA), group 7 is maximally substituted, so that there is no hydrogen substitution on the main 7c group. For example, if the main group 7 is -СН 5-, when substituted with two methyl groups, the hydrogens of the main -СНо-group 2 are removed. embodiment of the formula (II) or (PA) Hu and Ho both represent 0.

In other preferred embodiments, the dashed line represents a double bond.

In some variants of the embodiment of the formula (I), K is -CH /5С(5О)МН», -С(МН)МН», pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl, -С(5О0)СН33, -СНХСНХМНО(-О) СН3, -505СН3, СНоОСНОМНЗО»СН», furanylcarbonyl-, methylpyrrolylcarbonyl-, diazolecarbonyl-, azolemethyl-, trifluoroethyl-, hydroxyethyl-, (F) cyanomethyl-, oxoxazolemethyl- or diazolemethyl-. with In some variants of the embodiment of formula (I) 2K 4 is cyclohexylethyl, cyclohexylmethyl, cyclopentylmethyl, dimethylcyclohexylmethyl, phenylethyl, pyrrolyltrifluoroethyl, thienyltrifluoroethyl, pyridylethyl, cyclopentyl, cyclohexyl, methoxycyclohexyl, tetrahydropyranyl, propylpiperidinyl -, 60 indolylmethyl-, pyrazolylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl- or oxocanylpropyl-.

In some variants of the embodiment of formula (I), at least one of 2K 3 and K is -CH 5COOM. tetrazolylmethyl-, cyanomethyl-, MnH.zO»methyl-, MH.zO methyl, aminocarbonylmethyl,

Si l1oalkylaminocarbonylmethyl- or disC. lalylaminocarbonylmethyl-. b5 In some versions of the implementation of formula (II) 2K. is C3,3-diphenylpropyl, optionally substituted at the C carbon atom of propyl by the group -ЧАсОоОМ., tetrazolyls 4 with alkyl-, cyano-, aminocarbonyl-,

Si dalkylaminocarbonyl- or disC. dalkylaminocarbonyl-.

This invention in some embodiments includes compounds having the general formula (IP): (1)

What about and | And I'm where Shi!

IN

Ye vu where LC represents hydrogen, C4.zralalkyl, C2.cycloalkyl, C3.42cycloalkylC. lalkyl-, C..ralkoxy, c 29 C3ocycloalkoxy-, C. oalkyl, substituted by 1-3 halogens, C.zocycloalkyl, substituted by 1-3 halogens, He)

C3.12cycloalkylC and allyl-, substituted with 1-3 halogens, Sizoalkoxy, substituted with 1-3 halogens,

C3z 12cycloalkoxy-, substituted by 1-3 halogens, -COOM. -C4 SOM, -SNYON, -505M(M1)", hydroxyS. zoalkyl-, hydroxyC3 ocycloalkyl-, cyanosCu.oralkyl-, cyanoC3. ocycloalkyl-, -СОМ(М1)», МН»ЗзО»сС. dalkil-,

MN»ZOs. dalalkyl-, sulfonylaminoC)..4ralkyl-, diaminoalkyl-, -sulfonyl. alkyl, b-membered heterocyclic ring, b-membered heteroaromatic ring, b-membered heterocyclic ring, alkyl-, b-membered heteroaryl, alkyl-, b-membered aromatic ring, b-membered aryl. dalalkyl, 5-membered heterocyclic ring, optionally substituted oxo or thio, 5-membered heteroaromatic ring, 5-membered heterocyclylC. alkyl-, optionally substituted oxo or thio, 5-ene heteroarylC. dalkyl-, -С4 5(-О)ММи, -С4 (МН, -С45МНО(О)МУ, -С4 5МНО(-О)2МУХ, cha -С415МНБ(-О)МУХ, where MU is hydrogen, С 4.4 oralalkyl, C3-12cycloalkyl, C142cycloalkyl, C142cycloalkyl,

Zo -SNYON, amino, Su .dalkylamino-, dis-alkylamino- or 5-membered heteroaromatic ring, optionally substituted in 1-3 by lower alkyls; where each M. is independently selected from H, C. alkyl, C3.cycloalkyl, benzyl and phenyl; n is an integer from 0 to 3; "

O represents a 5-8-ene cycloalkyl, 5-8-ene heterocyclic or β-ene aromatic or 70 heteroaromatic group; c 7 is selected from the group consisting of a bond, straight or branched C/4.alkylene, -MH-, -CH»O-,

Из» -сСнННМн-, -СННМ(СН3)-, - МНС Но-, -СНСОМН-, -МНСНННСО-, -СННСО-, -СОСН»-, -СННСОСН»о-, -СНСН»У)-, -CH:I -0- and -HC-CH.-, where the carbon and/or nitrogen atoms are unsubstituted or substituted by one or more lower 15 alkyl, hydroxy, halogen or alkoxy groups; or 7 is a cycloalkylamino system of the formula (MI): ev. - I), 2 sya -I KA | z" se) 7 ; s | І Is p prech

F) where A, B and 0 are, independently, hydrogen, C 4-4oalkyl, C 3-12cycloalkyl, C 3-12cycloalkyl, C 3-12cycloalkyl, -CH»OH, -MNBZO», hydroxyC-zralalkyl-, aminocarbonyl-, C .alkylaminocarbonyl-, diC.-alkylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide, sulfonylaminoC..alkyl-, or A-B together can form a bridge of Sov or

B-O together can form a bridge Cz.7, or A-O can together form a bridge Su.v;

Ki is selected from the group consisting of hydrogen, C4-zoalkyl, C3-1ocycloalkyl, C3-zoalkenyl, amino,

Suloalkylamino-, C3.42cycloalkylamino-, - COOM., -C4.4COOM., cyano, cyanosC. zoalkyl-, cyanoC3 zocycloalkyl-,

MN»ZO»-, MN»ZO»S. dalkilu-, МН»ьЖЗОС. dalalkyl-, aminocarbonyl-, C.alkylaminocarbonyl-, 65diC-.alkylaminocarbonyl-, benzyl, C3.42cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro-ring system of the formula (M) : and zby U is "she i and "SHY i. and Z. Her; where Hu and Ho are independently selected from the group consisting of MH, 0, 5 and CH"; and where alkyl, cycloalkyl, alkenyl, C are indicated. zralalkylamino-, C3.12cycloalkylamino-, or benzyl from group Ki is optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C..4alkyl, C..alkyloxy, nitro, trifluoromethyl-, cyano, - СооОмМ. , -Сб4 АСОМ , cyanosСо of ralalkyl-, -С. СОМ -0031 БМН(О)2 ММ , -С4 вМНВ(ОМУ , 5-membered heteroarylCo dalalkyl-, phenyl, benzyl, benzyloxy, while phenyl, benzyl and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 4.alkyl-,

Si zoalkoxy- and cyano; and where the indicated C3-102cycloalkyl, C3-42cycloalkyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro-ring system of the formula (M) are optionally substituted with 1-3 substituents selected from the group consisting of from halogen, C1-alkyl, C1-raloxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, where the specified phenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogen , S. zralkilu, S. zralkoks and cyano;

KE" is selected from the group consisting of hydrogen, C-alkyl, C-17cycloalkyl, and halogen, while the specified --CEM alkyl or cycloalkyl is optionally substituted with an oxo, amino, alkylamino, or dialkylamino group; o and their pharmaceutically acceptable salts and solvates.

This invention in some embodiments includes compounds having the general formula (ША): (ША) (ее) и к п Тл я 5 7 . zhit a (22) de, khan ve ikh Ya gar shk y Uk yi- i u ili i Zh m. t y "7 - z A. t sho )" -I de -I p is an integer from 0 to 3; co 7 is selected from the group consisting of the bond, -CH5-, -MH-, -CHNO-, -CHNH»-, -CHNHMH-, -CHNoM(ChNH3)-, -MHenH»-, - СНСОМнН-, -МНОННСО-, -СНСО-, -СОСН»о-, -СНСОСН»-, -СН(СН3)-, -СН-, -НС-СН- and systems with 50 cycloalkylamino formula (MI): : (m . E with 59 y. and H ime) where the carbon and/or nitrogen atoms are unsubstituted or substituted by a lower alkyl, halogen, hydroxy, phenyl, 60 benzyl or alkoxy group;

K is selected from the group consisting of hydrogen, C-4 alkyl, C-4 alkyl, and C3-42 cycloalkyl;

Ki is selected from the group consisting of hydrogen, C4-zoalkyl, C3-1ocycloalkyl, C3-zoalkenyl, amino,

C3zoalkylamino-, C3ocycloalkylamino-, benzyl, C34ocycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, heterobicyclic 65 Ring system and spiro-ring system of formula (M):

strength of strength I) k. ba y.

Z and Be and (ХУ щЭ ! 70 in which X. and Xo are independently selected from the group consisting of MH, O, 5 and CH"; in which said monocyclic aryl is preferably phenyl; in which said bicyclic aryl is preferably naphthyl, in which the specified alkyl, cycloalkyl, alkenyl, C 4 -alkylamino, C 3 -4 -cycloalkylamino or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 4 -alkyl, C 1 -alkyl, nitro, 75 trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, while the specified phenyl, benzyl, and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1.4alkyl, C1.ralcoco, and cyano; in which C3-1ocycloalkyl, C3-1ocycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro-ring system of formula (M) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, Si zralkilu, Si.loralcox and, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, where the specified phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C. zralkyl, C. zralkoxy and cyano ;

Co is selected from the group consisting of hydrogen, C 1.4 alkyl, C 1-2 cycloalkyl and halogen, and the specified alkyl is optionally substituted with an oxo group; Ha and their pharmaceutically acceptable salts.

In some preferred embodiments of the formula (II), O is a phenyl or β-heteroaromatic i9) group containing 1-3 nitrogen atoms.

In some preferred embodiments of formula (III) or (PA) K, their alkyl is methyl, ethyl, propyl, butyl, pentyl or hexyl. ee)

In some preferred embodiments of formula (III) or (ША), K - cycloalkyl is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl or norbornyl. what

In other preferred embodiments of formula (II) or (PA), the bicyclic ring system K/ is Ge») naphthyl. In other preferred embodiments of formula (II) or (PA), the bicyclic ring system K is tetrahydronaphthyl or decahydronaphthyl and the tricyclic ring system Ki is dibenzocycloheptyl. In other preferred embodiments, K/ represents phenyl or benzyl. h-

In other preferred embodiments of formula (II) or (ША), the bicyclic aromatic ring K/ is a 10-membered ring, preferably quinoline or naphthyl.

In other preferred embodiments of formula (II) or (ША), the bicyclic aromatic ring K/ is a 9-membered ring, preferably indenyl.

In some embodiments of the formula (II) or (ША), 7 is a bond, methyl or ethyl. -sh c In some variants of the embodiment of the formula (II) or (ША), group 7 is maximally substituted, so that there is no hydrogen substitution on the main group 7. For example, if the main group 7 is -СН 5-, when i» is replaced by two methyl groups, hydrogens of the main -СНо-group 2 are removed.

In some versions of the embodiment of the formula (III) or (ША) 7 is a cycloalkylamino system of the formula (MI): and I t s 50

IR f) where the nitrogen atom is optionally substituted by C..alkyl, phenyl or benzyl.

In other preferred embodiments of formula (II) or (ША), n is 0.

In some embodiments of formula (III) or (PA), Hu and X" both represent 0.

In some variants of the embodiment of the formula (I), K is -CH /5С(5О)МН», -С(МН)МН», pyridylmethyl, i) cyclopentyl, cyclohexyl, furanylmethyl, -С(5О0)СН3з, -СНХСНХМНО(- О)СН3, -505СН3, СНоОСНОМНЗО»СН», co furanylcarbonyl-, methylpyrrolylcarbonyl-, diazolecarbonyl-, azolemethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxoxazolemethyl- or diazolemethyl-. 60 In some variants of the embodiment of formula (IP) 2K 3 is cyclohexylethyl-, cyclohexylmethyl-, cyclopentylmethyl-, dimethylcyclohexylmethyl-, phenylethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl-, pyridylethyl-, cyclopentyl-, cyclohexyl-, methoxycyclohexyl-, tetrahydropyranyl-, propylpiperidinyl -, indolylmethyl-, pyrazolylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl- or oxocanylpropyl-, 65 In some variants of the embodiment of formula (I), at least one of 2K 3 and K is -CH COM ), tetrazolylmethyl-, cyanomethyl-, MH.zoO»methyl-, MH»ZzO methyl, aminocarbonylmethyl,

C. dalkylaminocarbonylmethyl- or disC. dalkylaminocarbonylmethyl-.

In some embodiments of formula (III) 7K. is 3,3-diphenylpropyl, optionally substituted at the carbon atom of propyl with the group -ЧАсОоОМ., tetrazolylСО with alkyl-, cyano-, aminocarbonyl-,

Si.dalkylaminocarbonyl- or di)u dalkylaminocarbonyl-.

This invention in some embodiments includes compounds having the general formula (IM): , Si.ralkoksy, so

C2-cycloalkyl, C1-3 alkyl, substituted with 1-3 halogens, C2-cycloalkyl, substituted with 1-3 halogens,

C3z 12cycloalkylC and allyl-, substituted with 1-3 halogens, Sizoalkoxy, substituted with 1-3 halogens,

C3z 12cycloalkoxy-, substituted by 1-3 halogens, -"СООМ., -С4.АСООМ., -СННОН, -502М(М1)", hydroxyС. zoalkyl-, o hydroxynC3 ocycloalkyl-, cyanosCu.oralkyl-, cyanoC3. ocycloalkyl-, -СОМ(М1)», МН»»зО»Si dalalkyl-, ря

MN»ZOsS. dalalkyl-, sulfonylaminoC)..4ralkyl-, diaminoalkyl-, -sulfonyl. alkyl, β-membered heterocyclic ring, β-membered heteroaromatic ring, β-membered heterocyclylC". lalkyl-, b--len heteroaryls. dalkyl-, - b-membered aromatic ring, b--linen aryles. dalalkyl, 5-membered heterocyclic ring, optionally substituted oxo or thio, 5-membered heteroaromatic ring, 5-membered heterocyclylC. alkyl-, optionally substituted oxo or thio, B-membered heteroaryl C. and dalalkyl-, -С4 5Б(-О)MMХ, -С45(-МН)МУХ /-Су BMНО(-О)MM., -С45МНЯ( -0)5MMi, "Ш -С415МНБ(-О)МУХ, where MU is hydrogen, C 4.4oralalkyl, C3.12cycloalkyl, C chordaloxy, C3-142cycloalkyloxy, C10 -CH2oOH, amino, Su.dalalkylamino-, dis-alalkylamino - or a 5-membered heteroaromatic ring, optionally substituted with 1-3 lower alkyls; 1" where each M. is independently selected from H, C. .alkyl, C.sub.3-cycloalkyl, benzyl and phenyl;

O is a 5-8-ene cycloalkyl, 5-8-ene heterocyclic or b-ene aromatic or heteroaromatic group; 35 n is an integer from 0 to 3; ate A, B and O are, independently, hydrogen, C 4-4oalkyl, C3-12cycloalkyl, C3-zoalkoxy, C3-12cycloalkyl, -| -SNYON, -MNBZO», hydroxyzralkyl-, aminocarbonyl-, C) lalkylaminocarbonyl-, disC. lalkylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide, sulfonylamino. zadalkil-, or A-B together can form a bridge Sov, or B-O together can form a bridge Cz.7, or A-O together can form a bridge Su.v; (9) 50 7 selected from the group consisting of a bond, straight or branched С/4.alkylene, -МН-, -СН»О-, со -снНХМнН-, -СНХМ(СН3)-, -МНеСН» -, -СНСОМНН-, -МНОНСО-, -СНСО-, -СОСН»о-, -СНСОСН»-, -СН(СН»У)-, -СНУе, -О- ии-НС-СНУ.-, where atoms carbon and/or nitrogen are unsubstituted or substituted by one or more lower alkyl, hydroxy, halogen or oxy groups;

Ki is selected from the group consisting of hydrogen, C 4 psoalkyl, C3.1ocycloalkyl, C.zoalkenyl, amino, 59 Su loalkylamino-, C3.42cycloalkylamino-, -COOM., -C4.4COOM., cyano, cyanosC. zoalkyl-, cyanoC3 zocycloalkyl-, (F) МН»ЗО»-, МН»ЗО»С. dalkilu-, МН»ьЖЗОС. dalalkyl-, aminocarbonyl-, C. lalkylaminocarbonyl-,

He diC-.alkylaminocarbonyl-, benzyl, C3-42cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and in the spiro-ring system of the formula (M): b5 kosovky What? where Hu and Ho are independently selected from the group consisting of MH, 0, 5 and CH"; and where indicated is alkyl, cycloalkyl, 70 alkenyl, Si. lo-alkylamino-, C3-13-7-cycloalkylamino- or benzyl from group K1 is optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C1-4alkyl, C1-4alkyl, nitro, trifluoromethyl-, cyano, -COOM . -b14 SOM. , cyanosSu.oralkilu-, -S. СОМ, -б4 БМН(-О0)2ММ 4, -б41.5МНБ(-ОММ, 5-membered heteroarylCo dalalkyl-, phenyl, benzyl, benzyloxy, while the indicated phenyl, benzyl and benzyloxy are optionally substituted 1-3 by substituents selected from the group consisting of halogen, C 4-alkyl-, 75 Silo-alkyl- and cyano, and where C3-12cycloalkyl, C3-12cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system are indicated and the spiro-ring system of the formula (M) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C.alkyl, C.alkyloxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, where indicated phenyl, benzyl, phenyloxy or benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C-1-alkyl, C-1-o-alkyl and cyano;

K" is selected from the group consisting of hydrogen, C4.4-oalkyl, C3.12-cycloalkyl- and halogen, while the indicated alkyl or cycloalkyl is optionally substituted with an oxo, amino, alkylamino or dialkylamino group; and pharmaceutically acceptable salts and solvates thereof.

This invention in some embodiments includes compounds having the general formula (MA): p

Y (MA) (o,

E (and KA and IN so cho and shchi "em F

NN -

Zo Ol - i. - i" not where sh-n is an integer from 0 to 3; -I 7 is selected from the group consisting of the bond, -CH 5-, -MH-, -CHNHO-, -CHNHCH»-, -CHNHMH-, -CHNoM(ChNH3)-, -MHneH»-, -CHNHSOMnH -, -МНеНХСОо-, -СНХСО-, -СОСН»о-, -СНХСОСН»о-, -СН(СНУз)-, -СНА and -НС-СН-, where the carbon and/or nitrogen atoms are unsubstituted or substituted a lower alkyl, halogen, hydroxy or alkoxy group; c 20 K is selected from the group consisting of hydrogen, C..alkyl, C..alkyloxy and C.sub.42cycloalkyl; co Ki is selected from the group consisting of hydrogen, C 4 -zoalkyl, C 3 -10 cycloalkyl, C 1 -zoalkenyl, amino,

Si. loalkylamino-, C3.12cycloalkylamino-, benzyl, C3.12cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro-ring system of formula (M):

GF) sha: I)

Keshikhov KSHSHSHEU K psy ime) is from: VK, but also" "more

I Y o: 60 " rya y i a u p i; Ж tk. і I Still I 65 in which X. and Xo are independently selected from the group consisting of MH, O, 5 and CH"; in which the monocyclic aryl is indicated is mostly phenyl;

in which the specified bicyclic aryl is preferably naphthyl; in which alkyl, cycloalkyl, alkenyl, C 4.choalkylamino, C3 are indicated. 4l3o7cycloalkylamino or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C4-1alkyl, C1-10alkyl, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, wherein phenyl, benzyl, and benzyloxy are indicated optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1.4alkyl, C1.ralcoco and cyano; in which C 3-1ocycloalkyl, C 3-1ocycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro-ring system of formula (M) are optionally substituted with 1-3 substituents selected from the group consisting of from 7/o halogen, C1-6oalkyl, C1-6oalkyl, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, where the indicated phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 substituents selected from the group that consists of halogen, S. zralkyl, S. zralcox and cyano;

K" is selected from the group consisting of hydrogen, C. alkyl, C.sub.12-cycloalkyl and halogen, while the indicated alkyl is optionally substituted by an oxo group; and their pharmaceutically acceptable salts.

In some preferred embodiments of the formula (IM), O is a phenyl or β-heteroaromatic group containing 1-3 nitrogen atoms.

In some preferred embodiments of the formula (IM) or (MA), alkyl K is methyl, ethyl, propyl, butyl, pentyl or hexyl.

In some preferred embodiments of formula (IM) or (MA), cycloalkyl K is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl or norbornyl.

In other preferred embodiments of the formula (IM) or (MA), the bicyclic ring system K. is naphthyl. In other preferred embodiments of the formula (IM) or (IMA), the bicyclic ring system K. is tetrahydronaphthyl or decahydronaphthyl and the tricyclic ring system KK; is c dibenzocycloheptyl. In other preferred embodiments, K/ is phenyl or benzyl.

In other preferred embodiments of the formula (IM) or (MA), the bicyclic aromatic ring Ki is i) a 10-membered ring, preferably quinoline or naphthyl.

In other preferred embodiments of the formula (IM) or (MA), the bicyclic aromatic ring K/ is a 9-membered ring, preferably indenyl. In some embodiments of the formula (IM) or (IMA) 7 represents a bond, methyl or ethyl.

In some embodiments of formula (IM) or (MA), group 7 is maximally substituted, so that there is no hydrogen substitution on the main 7th group. For example, if the main group 7 is -CH 2-, during (c) substitution with two methyl groups, hydrogens of the main -CH»o- group 7 are removed.

In other preferred versions of the embodiment of the formula (IM) or (MA), n is equal to 0. -

In some variants of the implementation of the formula (IM) or (IMA) Hu and Ho both represent 0. h-

In some variants of the embodiment of the formula (IM), K represents -CH 5С (-О)МН», -С(МН)МН», pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl, -С(5О0)СН3з, -СНХСНХМНО(-О) СН3, -505СН3, СНоОСНОМНЗО»СН», furanylcarbonyl-, methylpyrrolylcarbonyl-, diazolecarbonyl-, azolemethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxoxazolemethyl- or diazolemethyl-. "

In some variants of the embodiment of the formula (IM) 2K 3 is cyclohexylethyl-, cyclohexylmethylch-, sh

Gases cyclopentylmethyl-, dimethylcyclohexylmethyl-, phenylethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl-, pyridylethyl-, cyclopentyl-, cyclohexyl-, methoxycyclohexyl-, tetrahydropyranyl-, propylpiperidinyl-, )» indolylmethyl-, pyrazolylpentyl-, thiazolylethyl, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl- or oxocanylpropyl-.

In some variants of the embodiment of the formula (IM), at least one of 2K 3 and K is -CH COM, -and tetrazolylmethyl-, cyanomethyl-, MH.zoO»methyl-, MH»ZzO methyl, aminocarbonylmethyl,

Si lalkylaminocarbonylmethyl- or disC. dalkylaminocarbonylmethyl-. it. In some versions of the implementation of the formula (IM) 2K. is 3,3-diphenylpropyl, optionally substituted with Z

He) carbon atom of propyl group -sOooOmM., tetrazolylSo dalalkyl-, cyano-, aminocarbonyl-, / C. dalylaminocarbonyl- or dis dalylaminocarbonyl-. ini In alternative versions of the implementation of formulas (I), (IA), (1), (PA), (1), (ША), (IM) and (MA) 2Ku can be as follows

IR e) I live because I am 60 years old

U represents K 3-(C1-C12)alkyl, K/-aryl, Co-heteroaryl, Ke-(C3-C12)cycloalkyl, K7-(C3-C7)heterocycloalkyl, -b05(C1-C)alkyl, CM or -С(О)МКаКо; U" represents hydrogen or U); Uz is hydrogen or (C.-C.)alkyl; or U. M" and U3, together with the carbon atom with which they are connected, form one of the following structures:

From her h and k re a. vocal le ; in sia with in her basket 2 (I o z where g is equal to 0-3; m/ and i are each equal to 0-3, provided that the sum of m and i is equal to 1-3; c and i are each independently equal to 1 or 2; 8 is equal to 1-55 and ring E is a condensed K /-phenyl or that)

Kb-heteroaryl ring; b

Clio is 1-3 substituents independently selected from the group consisting of H, (C4-Cv)alkyl, -OKv, -(C1-Cv)alkyl-OKa, -MKaKeo and -"C4-Cv)alkyl- MKaCo; -

Kii represents 1-3 substituents independently selected from the group consisting of K 10, -SEz, -OSEz, MO" and B. halogen, or K.4 substituents on adjacent ring carbon atoms can together form a ring of methylenedioxy or ethylenedioxy;

Ka and Ko are independently selected from the group consisting of hydrogen, (C 4-C) alkyl, (C 3-C 42 ) cycloalkyl, aryl and aryl(C 1-C ) alkyl; "

Kz represents 1-3 substituents, independently selected from the group consisting of H, K D-aryl, w c Ke-(C3-C12)cycloalkyl, Co-heteroaryl, K7-(C3-C7)heterocycloalkyl, -MKaCo, -OK 1" and -X0)0.2K42,-

Ke represents 1-3 substituents independently selected from the group consisting of H, (C 4 -C 4 )alkyl, C 1 -aryl, )" -MAvVo, "OB" and 542;

K; represents 1-3 substituents independently selected from the group consisting of hydrogen, halogen, (C1-C6)alkyl, C1-aryl, (C33-C2)cycloalkyl, -CM, -CE3, -OCv, -( C4-Cv)alkyl-OKa, -OSEz, -MEaCo»e, -I -(C4 -Cv)alkyl-MCaCo, -MNZO»Kva, -502МЩ(КИ14)2, -502Kv, -ЗОКv, -ЗКv, - MO», -SOMEaKoa, -MKeSOGK»v, -СооКв, -СОСЕ», - -OSOG,B, -OSOVv, -СОокК»v, -(-С4-Св)alkyl-МНСООС(СН»З)з, - -C1-Cv)alkyl-MZNHSOSE with, -(C1-Cv)alkyl-"MNZO"-(C1-Cv)alkyl, -(C4-Cv)alkyl-MNSOMN-(C-Cv)-alkyl and as Art. y i "hi ge p o k x - yh where i is equal to 0-6; or Ku substituents on adjacent ring carbon atoms together can form a Methylenedioxy or Ethylenedioxy ring;

Kb represents 1-3 substituents, independently selected from the group consisting of hydrogen, halogen, (F, (Ci-Cv)alkyl, C.is-aryl, (C33-C12)cycloalkyl, -CM, -CE3, - OKv, -(C4-Cv)alkyl-OKv, -OSEz, -MEaK»e, ke -(C4 -Cv)alkyl-MKaKo, -MNZO»Ka, -302М(К14)2, -MO», -SOMEKaKoa, -MKeSOK in, -SOKv, -OSOK", -OSOKv8 and -SOOg in;

KU is H, (C4-Cv)alkyl, -OKa, -(C4-Cv)alkyl-OKa, -MCaK»o or -(C4-Cv)alkyl-MKaCo; in Ki" represents H, (C 4-Cv)alkyl, C/-aryl, -(C4-Cv)alkyl-OKa, -(C1-Cv)alkyl-MKaCo, -(C41-Cv)alkyl-ZKa or aryl(C4-C8)alkyl;

Kiz represents 1-3 substituents, independently selected from the group consisting of H, (Co /4-Cv)alkyl, (C4-Cv)alkoxy and halogen;

Kia is independently selected from the group consisting of H, (C.4-C)alkyl, and K.sub.13-SeH-CH»-. 65 As used herein, the term "alkyl" means a linear or branched saturated aliphatic hydrocarbon group having one radical and 1-10 carbon atoms. Examples of alkyl groups include methyl,

propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, tert-butyl and pentyl. Branched alkyl means that one or more alkyl groups, such as methyl, ethyl or propyl, replace one or both hydrogens in the -CH 5- group of the linear alkyl chain. The term "lower alkyl" means an alkyl consisting of 1-3 carbon atoms.

"Alkoxy" means "alkyl", as defined above, linked to an oxygen radical.

The term "cycloalkyl" means a non-aromatic mono- or polycyclic hydrocarbon ring system having one radical and 3-12 carbon atoms.

Examples of monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl and cyclohexyl. Examples of polycyclic cycloalkyl rings include adamantyl and norbornyl. 70 The term "alkenyl" means a linear or branched aliphatic hydrocarbon group containing a carbon-carbon double bond having one radical and 2-10 carbon atoms. "Branched alkenyl" means that one or more alkyl groups, such as methyl, ethyl or propyl, replace one or both hydrogens in the -CH 5 - or -CH- group of a linear alkenyl chain. Examples of alkenyl groups include ethenyl, 1- and 2-propenyl, 1-, 2- and 3-butenyl, 3-methylbut-2-enyl, 2-propenyl, heptenyl, octenyl and decenyl.

The term "cycloalkenyl" means a non-aromatic monocyclic or polycyclic hydrocarbon ring system containing a carbon-carbon double bond having one radical and 3-12 carbon atoms. Examples of monocyclic cycloalkenyl rings include cyclopropenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. Examples of polycyclic cycloalkenyl rings include norbornenyl.

The term "aryl" means a carbocyclic aromatic ring system containing one, two or three rings, which may be attached to each other or fused, and which contains one radical. Examples of aryl groups include phenyl, naphthyl and acenaphthyl.

The term "heterocyclic" refers to cyclic compounds having one or more heteroatoms (atoms other than carbon) in the ring and having a single radical. The ring may be saturated, partially saturated, or unsaturated, and the heteroatoms may be selected from the group consisting of nitrogen, sulfur, and oxygen. Examples of saturated heterocyclic radicals include saturated 3-6-membered heteromonocyclic groups containing 1-4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl; saturated 3-6b-membered io) heteromonocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms, such as morpholinyl; saturated 3-6-membered heteromonocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms, such as thiazolidinyl.

Examples of partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran, and dihydrofuran. oz z Other heterocyclic groups can be rings consisting of 7-10 carbon atoms substituted with heteroatoms, such as oxocanyl and thioxanyl. If the heteroatom is sulfur, then the sulfur may be a sulfur dioxide such as thioxanyl dioxide. Gee!

The term "heteroaryl" refers to unsaturated heterocyclic radicals, where the term "heterocyclic" is as defined above. Examples of heteroaryl groups include unsaturated 3-6-membered heteromonocyclic groups containing 1-4 nitrogen atoms, such as pyrrolyl, pyridyl, pyrimidyl, and pyrazinyl; and unsaturated fused heterocyclic groups containing 1-5 nitrogen atoms, such as indolyl, quinolyl and isoquinolyl; unsaturated 3-6-membered heteromonocyclic groups containing an oxygen atom, such as furyl; unsaturated 3-6b-membered heteromonocyclic groups containing a sulfur atom, such as thienyl; unsaturated 3-6b-membered heteromonocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms, such as oxazolyl; unsaturated condensed heterocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms, such as benzoxazolyl; unsaturated 3-6-membered heteromonocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms, such as thiazolyl; and unsaturated condensed heterocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms, such as )» benzothiazolyl. The term "heteroaryl" also includes unsaturated heterocyclic radicals, where the term "heterocyclic" is as defined above, in which the heterocyclic group is fused to an aryl group, in

Which aryl is as defined above. Examples of condensed radicals include benzofuran, benzdioxol, and -I benzothiophene.

As used herein, the term "heterocyclylC4-alkyl", "heteroarylC4-alkyl" and the like

Sh- refers to the ring structure associated with the Su alkyl radical.

Ge) All of the cyclic ring structures disclosed herein may be attached in any position where such attachment is possible, as will be apparent to those skilled in the art. o As used herein, the term "patient" includes a human or an animal such as a pet or livestock.

As used herein, the term "halogen" includes fluoride, bromide, chloride, iodide, or alabamide.

The invention disclosed in this description is intended to cover all pharmaceutically acceptable salts of the compounds disclosed. Pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt, and the like; salts of alkaline earth metals, such as calcium salt, magnesium salt, etc.; iF, organic amine salts, such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, M,M'-dibenzylethylenediamine salt, etc.; salts of inorganic acids, such as hydrochloride, hydrobromide, sulfate, phosphate, etc.; salts of organic acids, such as formate, acetate, trifluoroacetate, maleate, fumarate, tartrate, etc.; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; salts of amino acids, such as arginate, asparaginate, glutamate, etc.

The invention disclosed herein also encompasses all prodrugs of the disclosed compounds. Prodrugs are considered to be any covalently linked carriers that release the active parent drug ip mimo.

The invention disclosed herein also encompasses the products of metabolism of the disclosed compounds. 65 Such products can be formed, for example, as a result of oxidation, reduction, hydrolysis, amidation, esterification, and the like of the introduced compound, primarily due to enzymatic processes. In accordance,

the invention includes compounds obtained by a method comprising contacting a compound of this invention with a mammal for a period of time sufficient to obtain its metabolic product. Such products are usually identified by obtaining a radiolabeled compound of the invention, administering it parenterally in a dose that

It appears in an animal, such as a rat, mouse, guinea pig, monkey, or human, after a period of time sufficient for metabolism and excretion of its transformation products from urine, blood, or other biological samples.

The invention disclosed herein also encompasses disclosed compounds that are isotopically labeled by replacing one or more atoms with an atom having a different atomic mass or mass number. Examples of 7/0 isotopes that may be included in the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2H, ЗН, 13c, 14, 15M, 180, 170, p, 32p, 358, 18E | Z6C, respectively. Some of the compounds disclosed herein may contain one or more asymmetric centers, resulting in the formation of enantiomers, diastereomers, and other stereoisomeric forms. The present invention also encompasses all such possible forms, as well as their racemic and resolved forms and mixtures thereof. If the compounds described in this 75 invention contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise indicated, it is understood that both E and 7 geometric isomers are included. It is also intended that all tautomers are encompassed by the present invention.

As used herein, the term "stereoisomerism" is a general term for all isomers of individual molecules that differ only in the spatial orientation of their atoms. It includes enantiomers and isomers of compounds with more than one chiral center, and which are not mirror images of each other (diastereomers). .

The term "chiral center" refers to a carbon atom to which four different groups are attached.

The term "enantiomer" or "enantiomeric" refers to a non-mirror, and therefore optically active, molecule in which the enantiomer rotates the plane of polarized light in one c direction and its mirror image rotates the plane of polarized light in the opposite direction .

The term "racemic" refers to a mixture of equal parts of enantiomers, and which is optically inactive. i9)

The term "separation" refers to the separation or concentration or depletion of one or two enantiomeric forms of a molecule.

The term "modulate", as used herein, with respect to the OKI1 receptor means (ee) mediating a pharmacodynamic response (eg, analgesia) in a subject (s) through inhibition or activation of the receptor, or (ii) directly or indirectly, through the influence of on the normal regulation of receptor activity. i am

Compounds that modulate receptor activity include agonists, antagonists, mixed agonists/antagonists, and He! compounds that directly or indirectly affect the regulation of receptor activity.

Specific preferred compounds of formulas (I) and (IA) include: - 3-(1-(naphth-2-ylmethyl)-4-piperidinyl|-2H-benzoxazol-2-one; - 3-(1-(naphth-1-ylmethyl)-4-piperidinyl|-2H-benzoxazol-2-one; 3-11-(p-phenylbenzyl)-4-piperidinyl|-2H-benzoxazol-2-one; 3-11-(p-benzyloxybenzyl)-4-piperidinyl|-2H-benzoxazol-2-one; 3-11-(p-cyanobenzyl)-4-piperidinyl|-2H-benzoxazol-2-one; « 3-(11--3,3-diphenylpropyl)-4-piperidinyl|-2H-benzoxazol-2-one; what

Gani 3-(1-I4,4-bis-(4-fluorophenyl)butyl1|-4-piperidinyl|-2H-benzoxazol-2-one; 3-(11-(2-phenylethyl)-4-piperidinyl|-2H -benzoxazol-2-one; )» 3-(1-(cyclooctylmethyl)-4-piperidinyl|-2H-benzoxazol-2-one; 3-(1-(1,2,3,4-tetrahydro-2-naphthyl) )-4-piperidinyl)|-2H-benzoxazol-2-one; 3-11-(5-methylhex-2-yl)-4-piperidinyl|-2H-benzoxazol-2-one; -I 3-(11- (10,11-dihydro-5H-dibenzo(a,4|cyclohepten-5-yl)-4-piperidinyl|-2H-benzoxazol-2-one; 3-(11-(4-propylcyclohexyl)-4-piperidinyl| -2H-benzoxazol-2-one; 7 3-/1-(norbornan-2-yl)-4-piperidinyl|-2H-benzoxazol-2-one; (Ce) 3-/1-(decahydro-2-naphthyl )-4-piperidinyl|-2H-benzoxazol-2-one; 3-(11-(3,3-dimethyl-1,5-dioxaspiro|5,5)undeca-9-yl)-4-piperidinyl|-2H -benzoxazol-2-one; i-th 3-(11-4--1-methylethyl)cyclohexyl|)|-4-piperidinyl|-2H-benzoxazol-2-one; (Che 3-(11-(1, 3-dihydroinden-2-yl)-4-piperidinyl|-2H-benzoxazol-2-one; 3-11-(cyclooctyl)-4-piperidinyl|-2H-benzoxazol-2-one; and their pharmaceutically acceptable salts and solvates .

Specific preferred compounds of formula (II) and (PA) include:

3-ethylidene-1-(1-(5-methylhex-2-yl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one; o 3-ethylidene-1-(1-(4 -propylcyclohexyl)-4-piperidinyl/|-1,3-dihydro-2H-indol-2-one; co 3-ethylidene-1-(1-(1,2,3,4-tetrahydro-2-naphthyl)- 4-piperidinyl|-1,3-dihydro-2H-indol-2-one;

3-ethylidene-1-(1-(1,3-dihydroinden-2-yl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one; in 3-ethylidene-1-(1- (naphth-2-ylmethyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one;

3-ethylidene-1-(1-(p-benzyloxybenzyl)-4-piperidinyl)-1,3-dihydro-2H-indol-2-one;

3-ethylidene-1-(1-(benzyl)-4-piperidinyl-1,3-dihydro-2H-indol-2-one;

3-ethylidene-1-(1-(cyclooctylmethyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one;

3-ethylidene-1-(1-(norbornan-2-yl)-4-piperidinyl-1,3-dihydro-2H-indol-2-one; 65 3-ethylidene-1-(1-(3,3- diphenylpropyl)-4-piperidinyl/|-1,3-dihydro-2H-indol-2-one;

3-ethylidene-1-(1-(p-cyanobenzyl)-4-piperidinyl)|-1,3-dihydro-2H-indol-2-one;

3-ethyl-1-(1-(5-methylhex-2-yl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one;

3-ethyl-1-(1-I(4--1-methylethyl)cyclohexyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one;

3-ethyl-1-(1-(4-propylcyclohexyl)-4-piperidinyl)-1,3-dihydro-2H-indol-2-one;

3-ethyl-1-(1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one;

3-ethyl-1-(1-(decahydro-2-naphthyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one;

3-ethyl-1-(1-(1,3-dihydroinden-2-yl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one;

3-ethyl-1-(1-(cyclooctylmethyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one;

3-ethyl-1-(1-(norbornan-2-yl)-4-piperidinyl)-1,3-dihydro-2H-indol-2-one; 70 1-11-(naphth-1-ylmethyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one; 1-1-(naphth-2-ylmethyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one; 1-11-(p-phenylbenzyl)-4-piperidinyl-1,3-dihydro-2H-indol-2-one; 1-(1-(3,3-bis(phenyl)propyl)-4-piperidinyl)-1,3-dihydro-2H-indol-2-one; 1-11-(p-cyanobenzyl)-4-piperidinyl/|-1,3-dihydro-2H-indol-2-one; 1-11-(p-benzyloxybenzyl)-4-piperidinyl/|-1,3-dihydro-2H-indol-2-one; 1-(1-(1,2,3,4-tetrahydronaphth-2-yl)-4-piperidinyl/|-1,3-dihydro-2H-indol-2-one; 1-(1-(5-methylhex) -2-yl)-4-piperidinyl (1,3-dihydro-2H-indol-2-one; 1-1-(norbornan-2-yl)-4-piperidinyl)-1,3-dihydro-2H -indol-2-one; 1-(1-«1,3-dihydroinden-2-yl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one; 1-11-(cyclooctylmethyl) -4-piperidinyl|)|-1,3-dihydro-2H-indol-2-one; 1-1-(benzyl)-3-(methyl)-4-piperidinyl)-1,3-dihydro-2H-indol-2-one; 1-(1-4-propylcyclohexyl)-3-(methyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one; 1-11-"(5-methylhex-2-yl)-3-(methyl)-4-piperidinyl/|-1,3-dihydro-2H-indol-2-one; 1-11-(decahydro-2-naphthyl)-3-(methyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one; 1-(1-(4-(1-methylethyl)cyclohexyl)-3-(methyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one; 1-11-(cyclooctylmethyl)- 3-(methyl)-4-piperidinyl ()-1,3-dihydro-2H-indol-2-one; at); 1-(1-(3,3-bis(phenyl)propyl)-3-(methyl)-4-piperidinyl/|-1,3-dihydro-2H-indol-2-one;

3-ethyl-1-(1-(3,3-bis(phenyl)propyl)-3-(methyl)-4-piperidinyl/|-1,3-dihydro-2H-indol-2-one;

3-ethyl-1-(1-(4-propylcyclohexyl)-3-(methyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one; 3-ethyl-1-(1 -(5-methylhex-2-yl)-3-(methyl)-4-piperidinyl)-1,3-dihydro-2H-indol-2-one;

3-ethyl-1-(1-I(4--1-methylethyl)cyclohexyl/|-3-methyl-4-piperidinyl|-1,3-dihydro-2H-indol-2-one; o

3-ethyl-1-(11-(decahydro-2-naphthyl)-3-(methyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one; and their pharmaceutically acceptable salts and to solve

Specific preferred compounds of formula (I) and (PA) include:

3-ethyl-1-(p-phenylbenzyl)-1,3-dihydro-2H-benzimidazol-2-one; uh-

3-ethyl-1-(5-methylhex-2-yl)-1,3-dihydro-2H-benzimidazol-2-one;

3-ethyl-1-(4-propylcyclohexyl)-1,3-dihydro-2H-benzimidazol-2-one;

3-ethyl-1-(decahydro-2-naphthyl)-1,3-dihydro-2H-benzimidazol-2-one;

3-ethyl-1-(naphth-2-ylmethyl)-1,3-dihydro-2H-benzimidazol-2-one; « 1-(p-benzyloxybenzyl)-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one; sho c 1-benzyl-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one; 1-(4-(benzylamino)cyclohexyl|-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one; 3»3-ethyl-1-(naphthylmethyl)-1,3-dihydro-2H-benzimidazole -2-one;

3-ethyl-1-(5-(3-fluorophenyl)-5-(4-fluorophenyl)hexyl)-1,3-dihydro-2H-benzimidazol-2-one; 1-4-Knaphth-2-ylmethyl)ethylamino|cyclohexyl|d-1,3-dihydro-2H-benzimidazol-2-one; -I 1-(4-(norbornan-2-ylamino)cyclohexyl)-1,3-dihydro-2H-benzimidazol-2-one; 1--4-C4-(1-methylethyl)cyclohexyl)amino)cyclohexyl |-1,3-dihydro-2H- - benzimidazol-2-one;

Ge) 1-(4-Kdecahydro-2-naphthyl)amino|cyclohexyl|d-1,3-dihydro-2H-benzimidazol-2-one; 1-(4-(ethylamino)cyclohexyl)-1,3-dihydro-2H-benzimidazol-2-one; o 1-(4-(benzylamino)cyclohexyl-1,3-dihydro-2H-benzimidazol-2-one; c 1-4-Kindan-2-yl)benzylamino|cyclohexyl|-3-ethyl-1,3-dihydro -2H-benzimidazol-2-one; 1-4-(cyclooctylmethyl)amino|cyclohexyl|-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one; 1-(4-Knaphth-2-yl)amino|cyclohexyl|-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one; 1-(4-Kp-benzyloxybenzyl)amino)| cyclohexyl) -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one; 1-4-(cyclooctylmethyl)amino|cyclohexyl|/|-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one; iF, 1-(4-Kdecahydro-2-naphthyl)amino|cyclohexyl|-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one; ka 1-(4-(benzylamino)cyclohexyl|-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one; 1-(4-(dibenzylamino)cyclohexyl)-5-carbamoyl-1,3-dihydro -2H-benzimidazol-2-one; in 1-(4-N-phenylbenzyl)amino|cyclohexyl)-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one; 1-4-K1,2,3,4-tetrahydronaphthyl)amino|cyclohexyl)-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one; 1-4-K4-propylcyclohexyl)amino|cyclohexyl|-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one; 1-44-K5-methylhex-2-yl)amino|cyclohexyl|-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one; 1-(4-Kdecahydro-2-naphthyl)amino|cyclohexyl|-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one; 65 1-(4-(cyclooctylamino)cyclohexyl)-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one; 1-(4-Kindan-2-yl)amino|cyclohexyl)-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;

1-4-K4-phenylcyclohexyl)amino|cyclohexyl)-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one; 1-4-K5-methylhex-2-yl)amino|cyclohexyl|)|-7-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one; and pharmaceutically acceptable salts and solvates thereof.

Other preferred compounds of formula (IM) and (IMA) include: 2-cyanoimino-3-ethyl-1-(1-(p-phenylbenzyl)-4-piperidinyl/|-1,3-dihydro-2H-benzimidazole; 2- cyanoimino-3-ethyl-1-1-(p-benzyloxybenzyl)-4-piperidinyl-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-1-(1-(naphth-2-ylmethyl) -4-piperidinyl)-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-1-(1-(4-propylcyclohexyl)-4-piperidinyl)-1,3-dihydro-2H-benzimidazole; 70 2-cyanoimino-3-ethyl-1-(1-14-(2-propyl)ucyclohexyl)-4-piperidinyl)-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-1-(1-(decahydro-2-naphthyl)-4-piperidinyl|-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-1-I1-(cyclooctyl )-4-piperidinyl-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-1-I(1-(10,11-dihydro-5H-dibenzo(a, d|cyclohepten-5-yl )-4-piperidinyl|-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-1-(1-(3,3-bis(phenyl)propyl)-4-piperidinyl|-1, 3-dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-1-(1-(1,2,3,4-tetrahydronaphthyl)-4-piperidinyl/|-1,3-dihydro-2H-benzimidazole; 2 -cyanoimino-3-ethyl-1-(1-(5-methylhex-2-yl)-4-piperidinyl-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-1-(/1- (norbornan-2-yl)-4-piperidinyl-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-1-(1-(1,3-dihydroinden-2-yl)-4-piperidinyl) -1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-1-(1-(cyclooctylmethyl)-4-piperidinyl|-1,3-dihydro-2H-benzimidazole; and their pharmaceutically acceptable salts and solvates .

Other preferred compounds of formula (IM) include: 2-cyanoimino-3-(2-hydroxy)ethyl-1-(1-(cyclooctyl)-4-pseridinyl)-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-methoxycarbonylmethyl-1-(1-(cyclooctyl)-4-piperidinyl)|-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-cyanomethyl-1-(11-(cyclooctyl)-4-piperidinyl-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-butyl-1-(1-(cyclooctyl)-4 -piperidinyl|-1,3-dihydro-2H-benzimidazole; o); 2-cyanoimino-3-(2-methanesulfonamido)ethyl-1-(1-(cyclooctyl)-4-piperidinyl-1,3-dihydro-2H -benzimidazole; 2-cyanoimino-3-acetamido-1-(1-(cyclooctyl)-4-piperidinyl-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-carboxymethyl-1-(1-(cyclooctyl) -4-piperidinyl) -1,3- dihydro-2H-benzimidazole; 2-cyanoimino-3-(2-dimethylamino)ethyl-1-(1-(cyclooctyl)-4-piperidinyl)|-1,3- dihydro-2H-benzimidazole; 2-cyanoimino-1-(/1-(cyclooctyl)-3-hydroxymethyl-4-piperidinyl)-1,3-dihydro-2H-benzimidazole; o 2-cyanoimino-1-(/1- (cyclooctyl)-4-piperidinyl-1,3-dihydro-2H-7-azabenzimidazole; 2-cyanoimino-1-((1-(cyclooctyl)-2,6-ethan-4-one-4-pseridinyl) |-1,3-dihydro-2H-benzimidazole and their pharmaceutically acceptable salts and solvates.

The present invention also provides the use of any of the disclosed compounds in the preparation of medicinal product M for the treatment of pain and other painful conditions modulated by an opioid receptor, for example, the OKI-1 receptor.

The compounds of this invention can be administered to any subject requiring modulation of opioid and OKI 1 receptors. The introduction can be carried out orally, locally, with the help of a suppository, inhalation or parenterally. The present invention also encompasses all pharmaceutically acceptable salts of the compounds listed above. It will be clear to a person skilled in the art that the acid addition salts of the compounds of the present invention can be obtained by reacting the compounds with the corresponding acids using a variety of known methods.

A variety of oral dosage forms may be used, including solid forms such as

AS tablets, gel capsules, capsules, caplets, granules, cakes and loose powders, and liquid forms such as -And emulsions, solutions and suspensions. The compounds of this invention may be administered alone or may be combined with a variety of pharmaceutically acceptable carriers and excipients known to those skilled in the art, including,

Including, but not limited to, diluents, suspending agents, solubilizers, binders, co-disintegrants, preservatives, dyes, lubricants, etc.

If the compounds of this invention are included in tablets for oral administration, then such tablets may be compressed, processed on a tableting machine, coated with an enteric coating, coated with sugar, coated with a film, compressed multiple times or coated with several layers. Liquid dosage forms for oral administration include aqueous and non-aqueous solutions, emulsions, suspensions and solutions and/or suspensions reconstituted from non-effervescent granules, which contain suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, colors and fragrances. If the compounds of this invention are administered parenterally, they can be, for example, in the form of an isotonic sterile solution. Alternatively, if the compounds of this invention are an inhalation agent, they may be formulated into a dry aerosol or may be formulated into an aqueous or partially aqueous solution.

Furthermore, when the compounds of the present invention are administered in dosage forms for oral administration, it is intended that such dosage forms may provide immediate release of the compound in the gastrointestinal tract or, alternatively, may provide and/or delayed controlled release in the gastrointestinal tract. intestinal tract. A wide range of controlled and/or sustained release compositions that can be used in connection with the compositions of this invention are well known to those skilled in the art.

Controlled and/or sustained release can be provided, for example, by coating the oral dosage form or by incorporating the compound(s) of the invention into a controlled and/or sustained release matrix.

Specific examples of pharmaceutically acceptable carriers and excipients that can be used to prepare dosage forms for oral administration are described in

Ategisap Rpagtaseciisa| Azzosiaiop (1986)). Technologies and compositions for obtaining solid dosage forms for oral administration are described in (Rpagtaseciisai YuOozade ERogtve: Tabrieev (I iereptap, I asptap apa 5spmagiya, ediyugv) 2nd edition, published by Magse! YuOekKeg, Ips.)1. Technologies and compositions for obtaining tablets (pressed and molded), capsules (hard and soft gelatin) and pills are also described in (Ketipdiop'v

Rpagtaseciisa! Zsiepsez (Agiyig Ozvoi, eayog), 155381593 (1980)). Technologies and compositions for obtaining liquid dosage forms for oral administration are described in |РНагтасециис! Juozade Rogte: Oizregwe buvietv, 7/0 ""MCereptap, Kiedeg apa Wapkeg, eaogv), published by Magse! Oekkeg, Ips.1.

When the compounds of this invention are included in a composition for parenteral administration by injection (eg, continuous infusion or bolus injection), the composition for parenteral administration may be in the form of suspensions, solutions, emulsions in oily or aqueous carriers, and such compositions may also contain pharmaceutically necessary impurities, such as stabilizers, suspending agents, dispersing agents, etc. Compounds /5 according to the invention can also be in the form of a powder that can be reconstituted in a composition for injections.

In specific embodiments, the compounds of this invention may be used in combination with at least one other therapeutic agent. Therapeutic agents include, but are not limited to, opioid agonists; non-opioid analgesics; nonsteroidal anti-inflammatory drugs; Soh-11 inhibitors; antiemetics; p-adrenergic blockers; anticonvulsants; antidepressants; Sag channel blockers; anticancer agents and their mixtures.

In specific embodiments, the compounds of this invention can be formulated into a pharmaceutical dosage form in combination with an RD-opioid agonist. d-opioid agonists that may be included in the compositions of the present invention include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, se diampromide . metazocine, methadone, metopone, morphine, myrofine, nalbuphine, narcein, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, 99 papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, yu proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, their pharmaceutical common salts and mixtures. b"

In specific preferred embodiments, d-opioid agonists are selected from codeine, hydromorphone, chn hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, morphine, tramadol, oxymorphone, their 32 pharmaceutically acceptable salts and mixtures. uh-

In another variant of the embodiment of the invention, the medicinal product includes a mixture of the Sox-II inhibitor and the inhibitor

BB-lipoxygenase for the treatment of pain and/or inflammation. Suitable Cox inhibitors and 5-lipoxygenase inhibitors, as well as combinations thereof, are described in US Patent No. 136839, which is incorporated herein by reference in its entirety. Cox II inhibitors include, but are not limited to, rofecoxib (Miokh), celecoxib (SeIebgeh), FOR-697, flosulid, meloxicam, 6-MMA, I-745337, nabumeton, nimesulide, M5-398, Z c 5O-5766, T-614, I-768277, K-253035 , UTE-522, K5-57067-000, 50S-58125, 560-078, RO-138387, M5-398, flosulide,

I» p-1367, 50-5766, RO-164387, etoricoxib, valdecoxib and parecoxib or their pharmaceutically acceptable salts, enantiomers or tautomers.

The compounds of this invention can also be combined in dosage forms with non-opioid analgesics, for example, non-steroidal anti-inflammatory drugs, including aspirin, ibuprofen, diclofenac, s-naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, pyroprofen, -I carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxanic acid, indomethacin, sulindac, tolmetin, zomepirac, thiopinac, zidomethacin, and acemethacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, rlufenam acid, with 20 niflumic acid, tolfenamic acid, diflurizal, flufenizal, piroxicam, sudoxicam or isoxicam, their pharmaceutically acceptable salts and mixtures. Other suitable non-opioid analgesics that may be included in the sodium dosage forms of the present invention include, but are not limited to, the following chemical classes of analgesic, antipyretic, nonsteroidal anti-inflammatory drugs: salicylic acid derivatives, including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid, 22 sulfasalazine and olsalazine; derivatives of para-aminophenol, including acetaminophen; indole and indene vinegars

F! acids, including indomethacin, sulindac, and etodolac; heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates), including mefenamic acid and meclofenamic acid; enolic acids, including oxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone, oxyfentartazone); and alkanones, including nabumetone. For a more detailed description of NSAIDs, which can be included in the medicinal products used in accordance with this invention, see Ratsi A. Ipsei

ApaiIdesis-Apiirugeis apa Apii-IpYaiattaiyogu Adepiv apa Ogydv Etriowayd ip (SHTte i(geaitepi oi botsi ip boodtap "

Sitapz Te RIagtasoiiodisa! Vasiv oi Tpegaretsiisv, 617-57 (Retpu V. MoippoPyapa Kautopa MU. Kyadop, Eadv.,

Mip(y Eaiiop, 1996), apa Siep K. Napsop ApaiYidevis, Apiirugeis apa Apii-Ipattayogu Ogydv ip Ketipdiop: Te

Zsiepse apa Rgasiise oi Rpagtasu Moi II, 1196-1221 (AK Seppago, Ea. 19(th Ed. 1995)), which are included in this description in their entirety by reference.

In some embodiments, the compounds of this invention may be formulated into a pharmaceutical dosage form in combination with anti-migraine medications. Anti-migraine drugs include, but are not limited to, alpiropride, dihydroergotamine, dolasetron, ergocornine, ergocorninine, ergocriptine, ergot, ergotamine, flumedroxone acetate, phonazine, lisuride, lomerizine, methysergide oxeterone, pisotilin, and mixtures thereof.

Another therapeutic agent can also be an adjuvant to reduce potential side effects, for example, an antiemetic. Suitable antiemetics include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimeobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, 70 bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol .

In some embodiments, the compounds of this invention may be formulated into a pharmaceutical dosage form in combination with β-adrenergic blockers.

Suitable β-adrenergic blocking agents include, but are not limited to, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butydrine hydrochloride, butofilolol, carazolol, carteolol , carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivalol, niphenalol, nipradilol, oxprenolol, penbutolol, pindolol, practolol, pronetalol, propranolol , sotalol, sulfinalol, talinolol, tertatolol, tilisolol, timolol, toliprolol and xibenolol.

In some embodiments, the compounds of this invention may be formulated into a pharmaceutical dosage form in combination with anticonvulsants. Suitable anticonvulsants include, but are not limited to, acetylfeneturide, albutoin, aloxidone, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atrolactamide, hebeclamide, buramate, calcium bromide, carbamazepine, zinromide, clomethiazole, clonazepam, decimide, dietadione, dimethadione . phenanthryl)hydantoin, 3-methyl-5-phenylhydantoin, narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione, phenacemide, fenetarbital, feneturide, phenobarbital, o phensuximide, phenylmethylbarbituric acid, phenytoin, sodium fetenylate, potassium bromide, pregabalin, primidone, progabid, sodium bromide, solanum, strontium bromide, suclofenide, sulthiam, tetrantoin, tiagabine, topiramate, juju trimethadione, valproic acid, valpromide, vigabatrin, and zonisamide. Ge")

In some embodiments, the compounds of this invention can be formulated into a pharmaceutical dosage form in combination with antidepressants. Suitable antidepressants include, but are not limited to, binedalin, t caroxazone, citalopram, dimethasan, phencamine, indalpine, indeloxazin hydrochloride, nefopam, nomifenzine, che oxytriptan, oxypertin, paroxetine, sertraline, thiazesime, trazodone, benmoxin, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxine, phenelzine, cotinine, roliciprin, rolipram, maprotiline, metrolindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptyline oxide, amoxapine, butryptyline, clomipramine, « demexyptiline, desipramine, dibenzepine, dimethacrine, dothiepine, doxepin, fluacizin, imipramine, imipramine M-oxide, iprindole, lofepramine, melitracene, metapramine, nortriptyline, noxyptyline, opipramol, pisotyline, - with propyzepine, protriptyline, quinupramine, tianeptine, trimipramine, adrafinil, benactysine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine, and" hematoporphyrin, hypericin, levofacetoperan, medifoxamine, milnacipran, minaprine, moc lobemide, nefazodone, oxaflozan, piperalin, prolintan, pyrisuccidanol, ritanserin, roxindole, rubidium chloride, sulpiride, tandospirone, tozalinone, tofenacin, toloxatone, tranylcypromine, I-tryptophan, venlafaxine, viloxazine and -I zimeldine.

In some embodiments, the compounds of this invention can be formulated into a pharmaceutical dosage form and in combination with Ca?g channel blockers. Suitable Ca2 channel blockers include, but are not limited to, bepridil, clentiazem, diltiazem, fendiline, halopamil, mibefradil, prenilamine, semotiadil, terodiline, sl 50 verapamil, amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine,

IR f) nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, benzizlan, etafenone, fantofaron and perhexilin.

In some embodiments, the compounds of this invention may be formulated into a pharmaceutical dosage form in combination with anticancer agents. Suitable antitumor agents include, but are not limited to, acivicin; aclarubicin; acodazole hydrochloride; acronin; adozelesin; aldesleukin; altretamine; ambomycin; amethantrone acetate; aminoglutethimide; amsacrine; anastrozole; Anthramycin; asparaginase; asperlin; azacitidine; iF) azetep; azotomycin; batimastat; Benzodepa; bicalutamide; bisantrene hydrochloride; bisnafid dimesylate; ko bizelesin; bleomycin sulfate; brequinar sodium; bropyrimine; busulfan; cactinomycin; calusterone; caracemid; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; 60 cirolemicin; cisplatin; cladribine; chrysnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; desaguanine mesylate; diazychone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; Dromostanolone propionate; Duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromat; epipropidine; epirubicin hydrochloride; erbulozol; esorubicin hydrochloride; estramustine; Estramustine sodium phosphate; etanidazole; 65 etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fasarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabic; foschidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin I! (including recombinant interleukin II or II/2), interferon alpha-2a; interferon alpha-2p; interferon alpha-p1; interferon alpha-p3; interferon beta-1ia; interferon gamma-1r; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozol hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlortamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaryl; mercaptopurine; methotrexate; sodium methotrexate; methoprine; meturedepa; mithindomide; mitocarcinoma; mitocromin; mitogyline; mitomalcin; mitomycin; mitospore; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxysuran; paclitaxel; pegaspargase; /o peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; pyroxantrone hydrochloride; plicamycin; plomestan; sodium porfimer; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; Riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazen; sodium sparphosate; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; Thalizomycin; tekogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprin; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribin phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulosol hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesyn; vindesine sulfate; vinpidine sulfate; Vinglycinate sulfate; vinylurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidin sulfate; vorozol; Zeniplatin; zinostatin; zorubicin hydrochloride. Other anticancer agents include, but are not limited to: 20-epi-1,25 dihydroxyvitamin 03; B-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; antagonists of AIHI-TC; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist O; antagonist about; Antarelix; anti-dorsalizing morphogenetic protein-1; anti-androgen, anti-carcinoma of the prostate; sch about anti-estrogen; antinoplaston; antisense oligonucleotides; aphidicolin glycinate; gene modulators of apoptosis; regulators of apoptosis; apuric acid; aga-SOR-PI -RTVA; arginine deaminase; asulacrine; atamestan; atrimustine; at); Axinastatin 1; axinastatin 2; Axinastatin Z; azasetron; azatoxin; azatyrosine; derivatives of bacatin PI; balanol; batimastat; VSK/AVI antagonists; benzochlorins; benzoylstaurosporine; beta-lactam derivatives; beta-alletin; betaclamycin B; betulinic acid; BES inhibitor; bicalutamide; bisanthrene; co zo bisaziridinylspermine; bisnafid; Bistraten A; Bizelesin; breflat; bropyrimine; budotitan; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox I1II/-2; capecitabine; carboxamidaminotriazole; o carboxyamidotriazole; SaKezi M3; SAKM 700; an inhibitor derived from cartilage; carzelesin; casein kinase inhibitors Ge! (ISO5); castanospermine; cecropin B; cetrorelix; chlorine; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; analogues of clomiphene; clotrimazole; colismycin A; colismycin B; combretastatin A4; uh-

Zv analogues of combretastatin; conagenin; crambescidin 816; chrysnathol; cryptophycin 8; cryptophycin A derivatives; i- curatsin A; cyclopentantraquinones; cycloplatam; cypemycin; cytarabine oxphosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; diazichion; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxyfluridine; droloxifene; dronabinol; « duocarmycin ZA; ebselen; ecomustin; edelfosine; edrecolomab; eflornithine; element; emitefur; epirubicin; (/- c epristeride; analogue of estramustine; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastin; )» fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; halocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; - I idoxifen; hydramanton; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulating peptides; insulin-like factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguan; - iododoxorubicin; ipomeanol, 4-; iroplakt; irsogladin; isobenzazole; isohomohalichondrin B; itasetron; so jasplakinolide; kagalalide E; lamellarin-M triacetate; lanreotide; Leinamycin; lenograstim; lentinan sulfate; br leptolestatin; letrozole; factor that inhibits leukemia; leukocyte alpha interferon; o leuprolidtestosteroneprogesterone; leuprorelin; levamisole; liarozol; linear analogue of polyamine; lipophilic c disaccharide peptide; lipophilic platinum compounds; lisoclinamide 7; lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysophyllin; lytic peptides; maytansine; manostatin A; marimastat; mass puncture; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaryl; merbaron; meterelin; methioninase; metoclopramide; MIE inhibitor; mifepristone; miltefosine; measurable; mismatched double-stranded RNA; mitohuason; mitolactol; mitomycin analogues; iF, mitonafid; mitotoxin growth factor of fibroblasts-saporin; mitoxantrone; mofarotene; thunderous; ka monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid Azh myobacterial membrane cell preparation 85K; mopidamol; multidrug resistance gene inhibitor; because a therapeutic agent for suppressing multiple tumors-1; mustard anticancer agent; micaperoxide B; extract of mycobacterial cell membranes; myriaporon; M-acetyldinalin; M-substituted benzamides; nafarelin; nagrestype; naloxonepentazocine; Napavin naphtherpine; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nizamycin; nitric oxide modulators; nitroxide antioxidant; nitrulin;

Ob-benzylguanine; octreotide; oxycenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; 65 oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidrononic acid; panoxytriol;

panomifen; parabactin; pazeliptin; pegaspargase; peldesin; sodium pentosan polysulfate; pentostatin; Pentrozol; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; pizzabanil; pilocarpine hydrochloride; pirarubicin; pyritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; sodium porfimer; porfiromycin; prednisone; propylbis-acridone; prostaglandin .2; proteasome inhibitors; immune modulator based on protein A; protein kinase C inhibitor; inhibitors of protein kinase C, microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurin; pyrazoloacridine; pyridoxylated hemoglobin-polyoxyethylene conjugate; antagonists of the grove; raltitrexed; ramosetron; inhibitors of farnesyl protein transferase in/o Taz; HAV inhibitors; gas-SAP inhibitor; demethylated retelliptin; Rhenium etidronate Ke 186; rhizoxin; ribozymes; WHO! retinamide; rogletimide; rohitukin; romurtide; Rohinimex; rubiginone W; ruboxyl; safingol; saintopin; orders; Sarcophytol A; sarliterate; mimetics Zai 1; semustine; derivative inhibitor of aging 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single-chain antigen-binding protein; Sizofiran; sobuzoxan; sodium borocaptate; sodium phenylacetate; solverol; protein /5 Binding of somatomedin; sonermin; sparfosic acid; spicamycin O; spiromustine; splenopentin; spongistatin 1; schialamine; stem cell inhibitor; stem cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradist; suramin; swainsonine; synthetic glycosaminoglycans; talismustine; tamoxifen methiodide; tauromustine; tazarotene; thecogallan sodium; tegafur; tellurapyryllium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; taliblastin; thiocoralin; thrombopoietin; thrombopoietin mimetics; thymalfazin; thymopoietin receptor agonist; timotrynan; thyroid stimulating hormone; ethyl tin ethiopurpurine; tirapazamine; titanocene bichloride; topsentin; toremifene; polypotential factor of stem cells; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosterid; tyrosine kinase inhibitors; tyrphostin; inhibitors of VS; ubenimex; urogenital sinus growth factor inhibitor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte therapy; velarezol; veramin; Verdins; verteporfin; vinorelbine; Vinxaltine; vitaxin; at); vorozol; zanoterone; Zeniplatin; zilascorb and zinostatin stimalamer.

The compounds of this invention and other therapeutic agents may act additively or, more preferably, synergistically. In a preferred embodiment, the composition containing the compounds of this invention is administered simultaneously with the administration of another therapeutic agent, which may be part of the same composition or a composition different from the one containing the compounds of this invention. In another embodiment, the composition containing the compounds of this invention is administered before or after the administration of another therapeutic agent. b

In the case of administration of the compounds of this invention to a mammal, for example, by oral, parenteral or topical routes, dosages ranging from about 0.01mg/kg to about 3000mg/kg of patient body weight can be used. zv per day, preferably, from about 0.01 mg/kg to about 100 Ω/kg of body weight per day, which is administered once or in divided doses. However, the dosage must be varied depending on the weight and physical condition (e.g., liver and kidney function) of the subject being treated, the suffering caused, the severity of symptoms, the route of administration, the frequency of dosing, the presence of any harmful side effects, and, among other things, , of the specific compound used. "

The compounds of this invention preferably have binding affinity K; relative to the receptor OK! human (/(/-) s approximately 5O0NM or less; T00NM or less; 5ONM or less; 20nM or less, or 3NM or less.

Binding affinity K; can be measured by a person skilled in the art using an assay using membranes from recombinant HEK-293 cells expressing a human opioid receptor-like receptor (OKI 1) as described below.

The following examples illustrate various aspects of the present invention and are in no way intended to limit it.

Example 1 - Synthesis of the main groups of bexoxazolone. The main groups according to this invention were synthesized according to the following method:

ИЧ e) and I chagiachnymchni shn, netnkyai sa (F) pishshnnny. - name) n i

Method 60 Sodium triacetoxyborohydride (2.97 g, 14 mmol) was added to a mixture of compounds 1 (1.09 g, 1 mmol), 2 (1.99 g, TO mmol) and acetic acid (0.6 bOg, TO mmol) in 5 O ml of dichloroethane. The mixture was stirred at room temperature overnight. The mixture was filtered through celite and 1M Mahon (50ml) was added to quench the reaction.

The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic layers were dried at 65 °C, filtered and evaporated in vacuo to give compound C as a brown solid (2.75 g, yield: 94905).

TN-NMR (SOCI3): a 1.20-1.60 (m, 11Н), 2.00 (dd, 2Н), 2.9 (m, 2Н), 3.40 (m, 1Н), 4, 00 (m, 2H), 6.60-6.85 (m, 4H).

To an ice-cooled solution of crude compound C (12.0 g, 4 AOmmol) and OIEA (20.vml, 120 mmol) in 200 ml

A solution of triphosgene (4.32 g, 14.4 mmol) in 200 ml of THF was added to THF. After the addition was complete, the ice bath was removed and the mixture was stirred at room temperature overnight. The solids were filtered off and the filtrate was evaporated under vacuum. The remaining brown oil was dissolved in EtOAc and washed with saturated aqueous K 2 CO 3 . The organic phase was dried over K»CO»z, filtered and evaporated in a vacuum to obtain a red oil, which was filtered through a column with silica gel, eluting with a mixture of 595 E(z33M, 2590 EtOAc and 7090 hexane.

The selected fractions were combined and the solvent was evaporated in vacuo to give a brown solid 70, which was crystallized from E(OAc) to give pure compound 4 (10.0 g, yield: 78905). 7"H-NMR (SOCI"):a 1 .50 (s, 9H), 1.85 (d, 2H), 2.25 (m, 2H), 2.85 (m, 2H), 4.20-4.45 (m, ЗН), 7, 00-7.25 (m, 4H).

A solution of compound 4 (4.0 g, 17.2 mmol) in a mixture of 3096 TFO/dichloromethane (25 ml) was stirred at room temperature for 3 hours. The solvent was evaporated under vacuum and a saturated aqueous solution of K»CO3 was added to the oily residue. The resulting mixture was extracted with dichloromethane (3x50ml). The combined organic extracts were dried over CO2, filtered and evaporated in vacuo to give the crude product. Chromatography on silica gel eluting with a mixture of 1095 EEzM, 6090 EtOAc and 3095 hexane gave compound 5 as a yellow solid (1.82g, yield: 66905).

MS:ti/:2 450 "H-NMR (SOCI3):α 1.75-2.10 (m, ЗН), 2.30 (d, 2Н), 2.80 (m, 2Н), 3.20 (m, 2H), 4.25 (m, 1H), 7.00-7.25 (m, 4H).

Example 2

Joining finite groups

The final groups were joined to the main groups according to the following methods:

I t she sh | oh

Kk Y u l V: Leo and shepherd

Basic technique for alkylation:

Equiv. was added to a solution of amine (Eq.) and triethylamine (Eq.) in dimethylformamide in one portion. alkyl bromide or chloride. The mixture was stirred and heated at 802C overnight. TLC showed the completion of the reaction. The reaction was quenched by adding water, followed by adjusting the pH to 10 using 1M Mahon. The mixture was extracted twice with EBO. The combined organic extracts were dried over potassium carbonate and the solvent was evaporated, followed by chromatography to give a pure product.

Basic technique for reductive amination: )" Sodium cyanoborohydride (1.4 eq.) was added in one portion to a mixture of ketone or aldehyde (Eq.), amine (Eq.) and acetic acid (Eq.) in methanol. The mixture was stirred at room temperature overnight. TLC indicated the completion of the reaction. The reaction was quenched by adding water, followed by bringing the pH to 10 using 1M Mahon. The mixture was extracted twice with EBO. The combined organic extracts were dried over potassium carbonate -1 and the solvent was evaporated, followed by chromatography to obtain a pure product.

The following compounds were obtained by addition of end groups using the described basic techniques: -ylmethyl)-4-piperidinyl|-2H-benzoxazol-2-one 3-11-(p-phenylbenzyl)-4-piperidinyl|-2H-benzoxazol-2-one and 42) 3-/1-(p-benzyloxybenzyl) -4-piperidinyl|-2H-benzoxazol-2-one 3-11-(p-cyanobenzyl)-4-piperidinyl|-2H-benzoxazol-2-one

MS: m/2 334.4 (Ma-1) 3-(11-(3,3-diphenylpropyl)-4-piperidinyl|-2H-benzoxazol-2-one o 3-(1-I4,4-bis- (4-fluorophenyl)butyl 1|-4-piperidinyl|-2H-benzoxazol-2-one

MS: t/ 463.6 (M--1) co 3-(11-(-2-phenylethyl)-4-piperidinyl|-2H-benzoxazol-2-one 3-/1-(cyclooctylmethyl)-4-piperidinyl |-2H-benzoxazol-2-one 60 РХ: 100905

MS: t/:2 343.6 (M--1) "H-NMR SOCI3):a 1.25 (m, 2H), 1.40-1.7 (m, 17H), 2.10 (m , 4H), 3.10 (m, 2H), 4.20 (m, 1H), 7.10–7.20 (4H). .55, 29.27, 31.23, 35.31, 53.39, 53.70, 66.28, 110.45, 110.51, 122.45, 123.96, 130.45, 143.08 , 154.51. bo 3-(1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl|-2H-benzoxazol-2-one

РХ: 10090

MS: t/2 349.6 (M--1)

TN-NMR (SOSIV): I 1.70 (m, 1H), 2.00 (width, 2H), 2.10 (width, 1H), 2.40 (m, 4H), 2.90 ( m, 5H), 3.10 (m, ?2H), 4.20 (m, 1H), 7.10-7.30 (m, 8H). 3-11 -(5-methylhex-2-yl)-4-piperidinyl|-2H-benzoxazol-2-one

РХ: 10090

MS: t/h 317.4 (Ma-1) 7TN-NMR (SOSIS)a 0.90 (d, 6H), 1.00 (d, ZN), 1.20 (m, ZN), 1.50 -1.60 (m, 4H), 1.80 (m, 2H), 2.20-2.60 70. (m, BN), 2.90 (width, 2H), 4.2 (m, 1H), 6.90-7.30 (m, 4H). 3-(1-(10,11-dihydro-5H-dibenzo(a, d|cyclohepten-5-yl)-4-piperidinyl|-2H-benzoxazol-2-one)

RH: 96.49

TN-NMR (SOSIZ)a 1.80 (dd, 2H), 2.00 (dt, 2H), 2.30 (dkw, 2H), 2.80-2.95 (m, 4H), 4.01 (c, МН), 4.05-4.22 (m, ЗН), 7.05-7.25 (m, 12Н). 3-(11-(4-propylcyclohexyl)-4-piperidinyl|-2H-benzoxazol-2-one

MS: t/2 343.0 3-1-(norbornan-2-yl)-4-piperidinyl|-2H-benzoxazol-2-one

РХ: 9790

MS:t/2 313.41 (Mn)

TN-NMR (SOSIS): a 0.90 (m, 1H), 1.30-2.50 (m, 17H), 3.20 (m, 2H), 4.3 (m, 1H), 6, 90-7.30 (m, 4H). 3-/1-(decahydro-2-naphthyl)-4-piperidinyl|-2H-benzoxazol-2-one

MS:t/2 355.4 3-(11-(3,3-dimethyl-1,5-dioxaspiro|5,5)undeca-9-yl)-4-piperidinyl|-2H-benzoxazol-2-one

MS: t/» 401.3 s 3-(11--4--1-methylethyl)cyclohexyl|)|-4-piperidinyl|-2H-benzoxazol-2-one o

MS: t/2 343.0 3-(1-(1,3-dihydroinden-2-yl)-4-piperidinyl|-2H-benzoxazol-2-one

РХ: 10090

MO: t/x 335.4 (Ma) so "H-NMR (SOSIV): a 1.90 (m, 1H), 2.40 (m, 2H), 2.50 (m, 2H), 2, 90 (m, 2H), 3.10-3.40 (m, 6H), 420 (m, 1H), 7.10-7.30 (m, 8H). 3-/1-(cyclooctyl)- 4-piperidinyl|-2H-benzoxazol-2-one o

РХ: 10090 h-

MS: t/:2 329.2 (Ma-1) "H-NMR (SOCI3): a 1.40-2.00 (m, 16Н), 2.40-2.65 (m, 4Н), 2 .80 (m, 1H), 3.05 (m, 2H), 4.25 (m, 1H), 7.10-7.40 (m, 4H).

Other compounds covered by formula (I) or (IA) of this invention can be synthesized by similar methods.

Example C "du Affinity for nociceptin at the OKI1 receptor for the preferred compounds was determined using the following assay: c Membranes of recombinant HEK-293 cells expressing a human opioid receptor-like receptor 1" (OK), (Caseriog Vioisdu), were obtained by lysing cells in ice-cooled hypotonic buffer (2.5mM MoSi, 50MM NEREB, pH7.4) (10ml/10cm Petri dish) followed by homogenization using a tissue homogenizer/Teflon pestle. Membranes were collected by centrifugation at 30,000 rpm for -1 every 15 minutes. at 42C and the precipitate after centrifugation was resuspended in a hypotonic buffer to a final concentration of 1-Zmg/ml. Protein concentrations were determined using VioKai protein assay reagent with bovine serum albumin as a standard. Aliquots of OKI 1 receptor membranes were stored at -809C.

Ge) Analyzes of the functional binding of ZOTRaz were carried out as follows.

OKI membrane solution 1 was obtained by successive addition of final concentrations of 0.0b6bmg/ml membrane

Mn of OBBI 1 protein, 10 mg/ml saponin, ZMM COP and 0.20 nM IZ5)5TRoZ to the binding buffer (100 mM Masi, 10 mM

IR e) Massi", 20MM NEREB, pH7.4) on ice. The resulting membrane solution (190ml/well) was transferred to 96-well polypropylene tablets containing 10ml of 20x concentrated agonist stock solutions prepared in DMSO.

Tablets were incubated for ZOhv. at room temperature with shaking. Reactions were terminated by rapid filtration on 96-well filter plates OpiinNeg SR/B (RaskKaga) using a 96-well tissue harvester (Vgapaei)) followed by three filter washes with 200 ml of ice-cooled binding buffer (10 mM Man»RO;, 10 mM Ma»HRO, pH7.4). The filter tablets were then dried (Imo) at 5022 for 2-3 hours. Fifty ml/well of cocktail for scintillation counting (Veyazsipii;

UMaiIas) and tablets were read in RasKaga Tor-Soshpa for 1 min./well. 60 The data were analyzed using the approximation of the functional dependence curve in sharpRai RKIZMO, M.3.0, and the results are presented in Table 1 below: b5

TAELITSYA 1

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Methodology of the Swiss

To a mixture of compounds 2 (23.3 g, 0.25 mol), 1 (43.7 g, 0.25 mol), acetic acid (15 g, 0.25 mol) and molecular sieves (15 g) in 5X000 ml of dichloroethane, sodium triacetoxyborohydride ( 74.2g, 0.ZBmol) and the mixture was stirred overnight. Molecular sieves were filtered and 1M Mahon (500ml) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EAs (2 x 30 mL). The combined organic extracts were dried over CO2, filtered, and the solvent was evaporated in vacuo to give the crude compound C in -I form as a brown solid, which was directly used in the next step. - Compound Z

TN-NMR (SOSIV)a 1.50 (m, 2H), 2.05 (m, 2H), 2.20 (width, 2H), 2.85 (m, 2H), 3.30 (m , IN), 3.52 (s, (Ce) 2H), 6.60 (d, 2H), 6.70 (t, 1H), 7.20 (m, 2H), 7.25-7.40 (m, 5H).

To an ice-cooled solution of crude compound C (0.25 mol, expected yield 100905) and OIEA (48.4 g, 1 .

A solution of chloroacetyl chloride (42.4 g, 0.375 mol) was added dropwise to 500 ml of dichloromethane. After the addition was complete, the ice bath was removed and the reaction mixture was stirred overnight. The solvent was removed in vacuo and the residue was dissolved in dichloromethane. The organic phase was washed with saturated aqueous CoSoO, dried over KSO, filtered, and the solvent was removed in vacuo to give a brown resin, which was filtered

Through a silica gel column, eluting with a mixture of 1095 EtOAc, 4095 EtOAc, and 5095 Hexane. The selected fractions were combined and the solvent was evaporated in vacuo to give a brown solid, which was crystallized from

EtOAc to obtain 42.2 g of compound 4 (49.2905, 2 stages). ime) Compound 4 "'NA-NMR (DMSO): a 1.22 (m, 2H), 1.70 (lat., 2H), 2.00 (t, 2H), 2.80 (lat., 2H ), 3.40 (s, 2H), 3.80 (s, 60 2H), 4.40 (m, 1H), 7.15-7.30 (m, 7H), 7.45 (m, ЗН ).

A mixture of compound 4 (42.2 g, 0.12 mol) and AICl3 (49.2 g, 0.369 mol) was mixed in a flask with rapid stirring.

The mixture was then heated in an oil bath at 1302C. Within a few minutes, the solids melted and became a dark liquid, which was accompanied by the release of gas. After heating for 1 hour, the reaction mixture was cooled slightly and, while it was still mobile, poured into a beaker containing 500 ml of ice water. The solution was alkalized and extracted with dichloromethane. The organic layer was dried over NaCl, filtered, and the solvent was evaporated in vacuo to give a dark oil, which was filtered through a silica gel column, eluting with a mixture of 1095 EM, 4095 EtOAc, and 5095 hexane. The selected fractions were combined and the solvent was evaporated in vacuo to give compound 5 as a red oil, which turned into a pale solid upon solidification (22.0g, 58.5905).

Compound 5

IGN-NMR (SOCI3): a 1.70 (m, 2H), 2.17 (m, 2H), 2.50 (m, 2H), 3.05 (m, 2H), 3.55 (s, 2H), 3.60 (s, 2H), 4.33 (m, 1H), 7.00-7.40 (m, 9H).

To a solution of compound 5 (16.0 g, 0.052 mol) in 35 ml of methanol was added PaY(OH)" (4.0 g). The resulting suspension was hydrogenated at 5O0f/sq.in. for 12 hours at room temperature. The solution was filtered through a layer of celite and the 7/0 layer was washed with methanol (2x20ml). Evaporation of the solvent in vacuo afforded compound 6 as a pale solid (11.2 g, 100905).

Compound 6

РХ: 10090

MS:t/2217(M-1). 15 7H-NMR (SOCI3): a 1.75 (m, 3H), 2.35 (m, 2H), 2.75 (m, 2H), 3.25 (m, 2H), 3.50 (s , 2H), 4.33 (m, 1H), 7.00-7.30 (m, 4H).

EBM (4.07g, 40./mmol) and BOC anhydride (8.87g, 40.7mmol) were added to a solution of compound b (8.0g, 37.0mmol) in 500ml dichloromethane. After stirring for 3 hours, saturated aqueous K 2 CO 3 was added and the layers were separated. The aqueous phase was extracted with dichloromethane (2 x 5 Oml). The combined organic phase was dried over CO2, filtered and evaporated in vacuo to give a brown oil which was filtered through a column of 20 silica gel eluting with a mixture of 1095 EM, 4095 EtOAc and 5095 hexane. The selected fractions were combined and the solvent was evaporated in vacuo to give compound 7 as an off-white solid (8.50g, 7390).

Compound 7

TN-NMR (SOSIZ)a 1.50 (m, 9H), 1.70 (m 2H), 2.20-2.50 (m, 2H), 2.80-3.00 (m, 2H), 3.50 (c, 2H), 4.20-4.50 (m, ЗН), 6.90-7.60 (m, 5H). c 25 Acetaldehyde (1.67g, Zvmmol) was added to a mixture of compound 7 (6b, 0g, 19, 0mmol) and sodium acetate (2.58g, 19, 00mmol) in 150ml of methanol. The mixture was refluxed for 2 hours. The solvent was evaporated in vacuo to give a dark oil, which was filtered through a silica gel column, eluting with a mixture of 1095 EM, 4095 EtOAc, and 5095 hexane. The selected fractions were combined and the solvent was evaporated in vacuo to give compound 8 as a red oil (5.90 g, 91965). so 30 Compound 8 ju

MOTION: 2 isomers in a ratio of 2:1. "H-NMR (SOCI5): (mixture of 2 isomers) 4 1.50 (m, 9H), 1.70 (m, 2H), 2.20-2.50 (m, 6H), 2.60-3 ,00 (m, 2H), o 4.20-4.50 (m, ЗН), 6.90-7.60 (m, 5H).

A solution of compound 8 (5.90 g, 17.2 mmol) in a mixture of 3096 TFO/dichloromethane (100 ml) was stirred at room temperature for 3 hours. The solvent was evaporated under vacuum and saturated aqueous K»CO3 was added to the oily residue. The resulting mixture was extracted with dichloromethane (3x150ml). The combined organic extracts were dried over K»CO»z, filtered and evaporated in vacuo to give the crude product. Chromatography on silica gel eluting with a mixture of 10956 E6/;,ugM, 5096 EtOAc and 4095 hexane gave compound 9 (E/7 isomer) as a yellow foam (3.60 g, 82905). what

Compound 9 with MOTION: 2 isomers in a ratio of 2:1. y» MS:t/2 243.1 (M--1). "H-NMR (SOS15): (mixture of 2 isomers) 4 0.85 (m, 1H), 1.50-2.00 (m, 4H), 2.20-2.50 (m, 5H), 2 .60 (m, 1H), 3.10-3.50 (m, 2H), 4.30 (m, 1H), 6.90-7.60 (m, 5H). - and with Zo 7 of the Customs To a mixture of compound 5 (5.50 g, 1 mmol) and sodium acetate (2.45 g, 18 mmol) in 150 ml of methanol was added acetaldehyde (1.58 g, 5 mmol). The mixture boiled was refluxed for 2 hours. The solvent was evaporated in vacuo to give a dark oil, which was filtered through a column of silica gel, eluting with a mixture of 1095 EM, 4095 EtOAc, and 5095 hexane. The selected fractions were combined and the solvent was evaporated in vacuo to give the compound 10 in the form of red oil (5.90 g, 98965) with Compound 10

MOTION: 2 isomers in a ratio of 2:1. in MS:t/2 333.2 (M--1) "H-NMR (SOSIS)a 1.70 (m, 2H), 2.17 (m, 2H), 2.30 (d, ЗН), 2.50 (m, 2H), 3.05 (m, 2H), 3.55 (s, 2H), 4.33 (m, 1H), 7.00-7.40 (m, 9H), 7 ,6 (d, 1H).

To a solution of compound 10 (5.90 g, 17./mmol) in 300 ml of methanol was added RY(OH)" (3.0 g). The resulting suspension was hydrogenated at 5O0f/sq.in. for 12 hours at room temperature. The solution was filtered through a layer of celite and the second layer was washed with methanol (2 x 20 ml). Evaporation of the solvent in vacuo gave a pale solid, which was purified by silica gel chromatography, eluting with a mixture of 1095 methanol and 9090 EtOAc, to give compound 11 as an off-white solid (2.02g, 50905).

Compound 11

РХ: 9790

MS: t/g 245.2 (M--1) "H-NMR (SOSIV): I 0.85 (t, ЗН), 1.26 (m, 2Н), 2.00 (m, 2Н), 2.43 (m, 2H), 2.90 (m, 2H), 3.3 (m, 2H), 34 (m, 1H), 4.4 (m, 1H), 7.05 (m, 1H ), 7.15-7.30 (m, ZN).

Example 6 " bu b Z la Fu ge MI ia i "KV zhu shield: Ve: y l: z

Method

Compound 16 was obtained by a method similar to the preparation of compound 6.

Compound 13

RH: 89.49

MS: t/g 281.2 (M--1) "H-NMR (mixture of trans and cis) (SOCI3): a 0.95 (m, ЗН), 1.50-2.75 (m, 5Н) , 2.80-3.20 (m, 1H), 3.50 (m, 2H), 3.60 (tipog) 3.70 (taiog) (two s, 2H), 6.55-6.80 ( m, 2H), 7.05-7.45 (m, 8H).

Compound 14

MS: t/» 357.2 (Ma) s 29 H-NMR (mixture of trans and cis) (SOCI3): a 1.10 (m, ЗН), 1.40-4.20 (m, 1Н), 4 .40 (m, 1H), 7.05-7.50 (m, TON). heh)

Compound 15

РХ: 90,090

MS:t/2 321.2 (М-А1)

TN-NMR (SOSIZ)a 1.20 (d, ZH), 1.75 (m, 1H), 2.10 (dt, 1H), 2.25 (lat., 1H), 2.30 (dd, Sh), 2.75 (dd, so 1H), 3.05 (m, 1H), 3.20 (m, 1H), 3.50 (m, 4H), 4.10 (m, 1H), 6 .99 (m, 2H), 7.23 (m, ЗН), 7.37 (m, 4H). iv)

Compound 16

RH: 92.590 F

MS: t/2 231.2 (М-А1) - "H-NMR (SOCI3): а а 1.20 (d, ЗН), 1.75 (m, 1Н), 2.10 (dt, 1Н) , 2.25 (width, 1H), 2.30 (dd, 1H), 2.75 (dd, M 1H), 3.05 (m, 1H), 3.20 (m, 1H), 3, 50 (m, 2H), 4.10 (m, 1H), 6.99 (m, 2H), 7.23 (m, ЗН), 7.37 (m, 4H).

Example 7. nick shlya kt ny Z y pinni m i nn a Stv )» and - t

Method

Compound 18 was obtained by a method similar to the preparation of compound 11.

Compound 17 and MS: pU» 347.3 (Ma) -I Compound 18

PH: 82.690 and MS: t/z 259.3 (M-1) 1 20 7TN-NMR (SOSIZ)a 0.80 (t, ZN), 1.20 (d, ZN), 2.00 (m, 2H), 2.30 (m, 1H), 2.65 (m, 1H), 2.82 (m, 1H), so 3.15-3.25 (m, 1H), 3.32 (m, 1H), 3.45 (m, 1H), 3.65 (m, 1H), 3.75 (m, 71H), 4.25 (m, 1H), 6.90 (d, 1H), 7, 05 (t, 1H), 7.25 (m, 2H).

Example 8

Attachment of end groups 59 End groups were attached to main groups according to the following methods:

F) name) 60 b5 then Mesvovn:noko,

Basic technique for alkylation:

Equiv. was added to a solution of amine (Eq.) and triethylamine (Eq.) in dimethylformamide in one portion. alkyl bromide or chloride. The mixture was stirred and heated at 802C overnight. TLC indicated the completion of the reaction. The reaction was quenched by adding water, followed by adjusting the pH to 10 using 1M Mahon. The mixture was extracted twice with EBO. The combined organic extracts were dried over potassium carbonate and the solvent was evaporated, followed by chromatography to obtain a pure product.

Basic technique for reductive amination:

Sodium cyanoborohydride (1.4 eq.) was added in one portion to a mixture of ketone or aldehyde (Eq.), amine (Eq.) and acetic acid (Eq.) in methanol. The mixture was stirred at room temperature overnight. TLC indicated the completion of the reaction. The reaction was quenched by adding water, followed by bringing the pH to 10 with He using 1M Mahon. The mixture was extracted twice with EBO. The combined organic extracts were dried over potassium carbonate and the solvent was evaporated, followed by chromatography to obtain a pure product.

The following compounds were obtained by addition of end groups using the described basic techniques: 1-1-(naphth-1-ylmethyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one

MS:t/2 357.2 (M--1) s 1-1-(naphth-2-ylmethyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one

MS: m/2 357.3 (M--1) 1-11-(p-phenylbenzyl)-4-piperidinyl-1,3-dihydro-2H-indol-2-one (22)

MS: t/2 383.2 (M-1) M 1-(1-(3,3-bis(phenyl)propyl)-4-piperidinyl)-1,3-dihydro-2H-indol-2-one

РХ: 98,790 -

MS: t/ 411.2 (Mat)

TN-NMR (SOCI3): a 1.65 (width, 2H), 2.05 (width, t, 2H), 2.30 (m, 4H), 2.45 (m, 2H), 3.02 ( shird, 2H), 3.50 (s, 2H), 4.01 (t, 1H), 4.30 (m, 1H), 7.00 (t, 1H), 7.15-7.35 (m , 13H). « 1-11-(p-cyanobenzyl)-4-piperidinyl)|-1,3-dihydro-2H-indol-2-one

MS: t/2 332.2 (Ma-1) With c 1-(1-(p-benzyloxybenzyl)-4-piperidinyl/|-1,3-dihydro-2H-indol-2-one y» MS: t / 413.3 (М--1) 1-(1-(1,2,3,4-tetrahydronaphth-2-yl)-4-piperidinyl/)-1,3-dihydro-2H-indol-2-one

РХ: 10090

MS: t/h 347.5 (M--1). 7 TN-NMR (SOSIZ)a 1.70 (m, ЗН), 2.10 (m, 71Н), 2.40 (m, 4Н), 2.90-3.00 (m, 5Н), 3, 10 (m, 2H), 3.60 (s, -and 2H), 4.3 (m, 1H), 7.00-7.30 (m, 8H). 1-11 -(b-methylhex-2-yl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one pH: 10095 sia 70 MS: t/» 315.4 (M-а1 ). co TN-NMR (SOSIZ)a 0.90 (m, 6H), 1.00 (m, ЗН), 1.20 (m, ЗН), 1.5-1.8 (m, 2Н), 2, 2-2.6 (m, 5H), 2.90 (m, 2H), 3.60 (s, 2H), 4.2 (m, 1H), 6.90-7.30 (m, 4H) . 1-1-(norbornan-2-yl)-4-piperidinyl)-1,3-dihydro-2H-indol-2-one

RH: 9790 59 MS: t/x 311.41 (Ma). gF) 1H-NMR (SOCI3): a 0.90 (m, 1H), 1.30-2.00 (m, 7H), 2.10-2.30 (m, 5H), 3.20 (m , 2H), 3.60 (s, 2H), 43 t (m, 1H), 6.90-7.30 (m, 4H). 1-(1-41,3-dihydroinden-2-yl)-4-piperidinyl/|-1,3-dihydro-2H-indol-2-one

RH: 10090 bo MS: tu 332.4 (Ma). "NA-NMR (SOSIv)a 1.80 (m, 2H), 2.40 (m, 2H), 2.50 (m, 2H), 2.90 (m, 2H), 3.10-3, 40 (m, 5H), 3.60 (c, 2H), 4.20 (m, 1H), 7.10-7.30 (m, 8H). 1-11-(cyclooctylmethyl)-4-piperidinyl| -1,3-dihydro-2H-indol-2-one v5 РХ: 9790

MS:t/2 341.50 (M-H1).

1H-NMR (SOSISMa 1.25 (m, 3H), 1.4-1.7 (m, 14H), 2.10-(m, 4H), 2.50 (m, 2H), 3.10 ( m, 2H), 3.60 (s, 2H), 4.3 (m, 1H), 7.10-7.20 (m, 4H). 1ZS-NMR (SOSIZ)a 23.07, 26.04 , 26.89, 27.56, 28.63, 31.27, 32.00, 35.30, 36.33, 46.63, 50.65, 54.06, 66.47, 110.90, 122 ,17, 124.90, 125.26, 127.94, 144.25, 175.31.

3-ethyl-1-(1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one

MS:t/2 375.3 (M--1).

3-ethyl-1-(1-(4-propylcyclohexyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one

MS: t/: 369.2 (M-n1). 70 3-ethyl-1-I(1-(5-methylhex-2-yl)-4-piperidinyl)|-1,3-dihydro-2H-indol-2-one

РХ: 10090

MS: t/h 342.4 (M-n1).

TN-NMR (SOSIS): a 0.80 (t, ЗН), 0.90 (m, 6Н), 1.00 (m, ЗН), 1.20 (m, ЗН), 1.5-1, 8 (m, 2H), 2.2-2.6 (m,

BN), 2.90 (m, 2H), 3.40 (m, 1H), 4.3 (m, 1H), 6.90-7.30 (m, 4H).

3-ethyl-1-(1-(norbornan-2-yl)-4-piperidinyl)-1,3-dihydro-2H-indol-2-one

РХ: 10090

MS: t/2 339.41 (Mn1). 1H-NMR (SOCI3): a 0.80 (m, ЗН), 0.90 (m, 1H), 1.30-1.45 (m, 5H), 1.50-2.05 (m, 8H ), 2.10 (m, 1H), 2.20 (m, 2H), 2.50 (m, 92 2H), 3.10 (m, 2H), 3.40 (m, 1H), 4, 3 (m, 1H), 6.90-7.30 (m, 4H).

3-ethyl-1-(1-(decahydro-2-naphthyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one

MS: t/: 381.3 (M-n1).

3-ethyl-1-(1-I4--1-methylethyl)cyclohexyl|)|-4-piperidinyl|-1,3-dihydro-2H-indol-2-one

MS: t/:2 369.3 (M--1) "NA-NMR (SOCI3)a 0.88 (t, ЗН), 0.92 (d, 6Н), 1.17 (m, 1Н), 1.40 (m, 2H), 1.50-1.70 (m, 9H), 2.05 (m, with 2H), 2.25 (m, 2H), 2.32-2.55 (m , ZH), 3.15 (width, 2H), 3.43 (t, 1H), 4.35 (m, 1H), 7.05 (t, 1H), 7.22 (d, 1H), 7.28 (m, 2H). o

3-ethyl-1-(1-(1,3-dihydroinden-2-yl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one

MS: t/ 361.2 (M--1)

3-ethyl-1-(1--(cyclooctylmethyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one

РХ: 9790 p

MS: t/:2 369.50 (M--1) yu

TN-NMR (SOCI3): Yaa 0.80 (t, ЗН), 1.25 (m, ЗН), 1.4-1.7 (m, 14Н), 2.10 (m, 6Н), 2, 50 (m, 2H), 310 (m, 2H), 3.40 (m, 1H), 4.3 (m, 1H), 7.10-7.20 (m, 4H). Me

3-ethylidene-1-(1-(benzyl)-4-piperidinyl-1,3-dihydro-2H-indol-2-one M

MS: t/2 333.2 (M-1)

TN-NMR (SOCI3)U:Ya 1.70 (m, 2H), 2.15 (dt, 2H), 2.28 (d, ЗН), 2.47 (m, 2H), 3.05 (s ., 2H), 3.57 (s, - 2H), 4.34 (m, 1H), 7.02 (t, 1H), 7.08-7.40 (m, 8H), 7.58 ( d, 1H).

3-ethylidene-1-(1-(naphth-2-ylmethyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one

MS: t/" 405.2 "

3-ethylidene-1-(1-(3,3-diphenylpropyl)-4-piperidinyl)|-1,3-dihydro-2H-indol-2-one C t0 PH: 29796 (2 isomers together) s MS: t /x 437.5 (Ma) 1" TN-NMR (SOSIS): a 1.70-1.80 (m, ЗН), 2.10 (m, 2Н), 2.20-2.40 (m, 8H), 3.10 (m, 2H), 4.10 (m, tn), 43 (m, 1H), 7.00-7.30 (m, 15H).

Z-ethylidene-1-(1-(p-cyanobenzyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one - 15 РХ: 29796 (2 isomers together)

MS: t/:2 358.5 (M--1) - TN-NMR (SOSIS): a 1.80 (m, 4Н), 2.10-2.60 (m, 5Н), 3.10 ( m, 2H), 3.70 (s, 2H), 4.3 (m, 1H), 6.90-7.60 (m, 8H). o 3-ethylidene-1-(1-(p-benzyloxybenzyl)-4-piperidinyl)-1,3-dihydro-2H-indol-2-one

MS: t/2 405.2 1 3-ethylidene-1-(1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl|-1,3-dihydro-2H-indole-2 -on «so РХ: 29796 (2 isomers together)

MS: t/2 373.5 (M--1) "H-NMR (SOCI3): a 1.70-3.10 (m, 18H), 4.3 (m, 1H), 7.00-7 ,30 (m, 9H).

3-ethylidene-1-(1-(4-propylcyclohexyl)-4-piperidinyl)|-1,3-dihydro-2H-indol-2-one

PH: 29796 (2 isomers together) iF, MS: ti/» 367.5 (Ma) ime) TNA-NMR (SOCI3): a 0.90 (m, 1), 1.30-2.00 (m, 7H), 2.10-2.30 (m, 5H), 3.20 (m, 2H), 3.60 (s, 2H), 43 (m, 1H), 6.90-7.30 (m , 5H). in 3-ethylidene-1-(1-(5-methylhex-2-yl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one

РХ: 29796 (2 isomers together)

MS: t/h 341.4 (M--1)

TN-NMR (SOSI»z): a 0.90-2.6 (m, 24H), 2.90 (m, 2H), 4.2 (m, 1H), 6.90-7.30 (m , 5H).

3-ethylidene-1-(1-(norbornan-2-yl)-4-piperidinyl)|-1,3-dihydro-2H-indol-2-one bB РХ: 29796 (2 isomers together)

MS: t/2 337.41 (M--1)

TN-NMR (SOSI»z): a 0.90 (m, 1H), 1.30-2.50 (m, 17H), 3.10 (m, 2H), 4.3 (m, 1H), 6.90-7.30 (m, 5H).

3-ethylidene-1-(1-(1,3-dihydroinden-2-yl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one

РХ: 29796 (2 isomers together)

MS: t/2 359.4 (M-1) "H-NMR (SOSIS): a 1.80-3.10 (m, 17Н), 4.20 (m, 1Н), 7.10-7, 30 (m, 9H).

3-ethylidene-1-(1-(cyclooctylmethyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one

РХ: 29796 (2 isomers together)

MS: t/g2 367.50 (M--1) "H-NMR (SOCI3): a 1.25 (m, ЗН), 1.4-1.7 (m, 21Н), 2.10-2 .50 (m, 2H), 3.10 (m, 2H), 4.3 (m, 1H), 6.90-7.60 (m, 5H). 1-(1-(3,3-bis) (phenyl)propyl)-3-(methyl)-4-piperidinyl/|-1,3-dihydro-2H-indol-2-one

РХ: 10090

MS: t/ 425.3 (M-1)

TN-NMR (SOSIZ)a 1.20 (d, ZN), 1.69 (shrd, 1H), 1.95 (dt, 1H), 2.13-2.30 (m, 5H), 2.72 (width, 1H), 729 2.98 (width, 1H), 3.15 (dkv, 1H), 3.50 (s, 2H), 4.03 (dt, 1H), 4.12 (t , 1H), 6.94 (d, 1H), 7.00 (t, 1H), 7.10-7.30 (m, 12H). 1-1-(benzyl)-3-(methyl)-4-piperidinyl)-1,3-dihydro-2H-indol-2-one

РХ: 10090

MS: t/g2 321.2 (MAT), "H-NMR (SOSIV): Yaa 1.20 (d, ЗН), 1.70 (m, 1Н), 2.10 (dt, 1Н), 2, 23 (m, 1H), 2.35 (dd, IN), 2.78 (d, 1H), 3.05 (m, 1H), 3.20 (dkv, 1H), 3.51 (m, 4H ), 4.10 (dt, 1H), 7.00 (m, 2H), 7.25 (m, 3H), 7.38 (m, 4H). 1-(1-4-propylcyclohexyl)-3 -(methyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one

РХ: 96,290

MS:t/2 355.2 (M--1)

TN-NMR (SOSIZ): a 0.85 (m, ЗН), 1.15 (m, ЗН), 1.22-1.85 (m, 1З3Н), 2.05-2.90 (m, 6Н ), 2.95-3.20 (m, 2H), sc 3.50 (s, 2H), 4.05 (m, 1H), 7.00 (m, 2H), 7.22 (m, 2H ). (o) 1-11-(5-methylhex-2-yl)-3-(methyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one

РХ: 10090

MS: t/:2 329.2 (Ma-1) so 7TN-NMR (SOSIS): a 0.85 (m, 9H), 1.15 (m, ZN), 1.20-1.75 (m , 6H), 2.25 (m, 1), 2.45-2.75 (m, 4H), 2.88 (m, 1H), 3.10 (m, 1H), 3.50 (s, 2H), 4.05 (m, 1H), 6.98 (m, 2H), 7.25 (m, 2H). it) 1-11-(decahydro-2-naphthyl)-3-(methyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one Fo

RH: 95.39

MS: t/: 367.2 (Ma-1) -

TN-NMR (SOSISUa 1.11 (d, ЗН), 1.16-1.85 (m, 16Н), 2.20 (m, 1), 2.35 (m, 2Н), 2.52 (m , 2H), 2.75 (m, cha 1H), 3.02 (m, 2H), 3.50 (s, 2H), 4.05 (m, 1H), 6.96 (m, 2H), 7.20 (m, 2H). 1-(1-(4-(1-methylethyl)cyclohexyl)-3-(methyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one

РХ:96,190

MS: t/2 355.2 (M--1) « "NA-NMR (SOSIv): a 0.80 (m, 6H), 1.15 (m, ЗН), 1.22-1.48 ( m, ZN), 1.50-1.90 (m, 6H), 2.15-2.90 (m, 43), Z

Gani 2.95-3.25 (m, 2H), 3.50 (s, 2H), 4.10 (m, 1H), 6.95 (m, 2H), 7.22 (m, 2H). 1-11-(cyclooctylmethyl)-3-(methyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one)» РХ: 10095

MS: t/2 355.2 (M--1) "H-NMR (SOCI3): a 1.12 (d, ЗН), 1.15-1.75 (m, 16Н), 1.92-2 ,10 (m, ZN), 2.20 (m, 2H), 2.73 (m, 1H), 3.00 (m, 1H), 3.12 (dkv, 1H), 3.50 ( s, 2H), 4.05 (dt, 1H), 6.99 (m, 2H), 7.20 (m, 2H).

3-ethyl-1-(1-(3,3-bis(phenyl)propyl)-3-(methyl)-4-piperidinyl/|-1,3-dihydro-2H-indol-2-one

Sh-.

RH: 96.390 se) MS:ti/: 453.3 (Mt) sl 50 "NA-NMR (SOSIz):a (two t, ЗН), 1.18 (d, ЗН), 1.70 (m, 1Н ), 1.90-2.05 (m, ZN), 2.12-2.30 (m, 5H), 7.73 (m, 7H), 2.97 (lat, 71H), 3, 10-3.30 (m, 1H), 3.38 (t, 1H), 3.90-4.05 (m, 1H), 4.12 (sq., 1H), 6.90-7.00 ( two so d, 1H), 7.02 (t, 1H), 7.12-7.32 (m, 12H).

3-ethyl-1-(1-(4-propylcyclohexyl)-3-(methyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one

РХ: 93,290

MS:t/2 383.3 (M--1)

F! TN-NMR (SOSIS): a 0.75-0.95 (m, 6Н), 1.05-1.20 (m, 5Н), 1.20-1.35 (m, 4Н), 1.35 -1.75 (m, 6H), 1.75-1.90 (m, 2H), 1.95-2.05 (m, 2H), 2.15-2.45 (m, ЗН), 2 .55 (d, 0.5 N), 2.75 (d, 0.5 N), 2.95-3.15 (m, 2H), 3.38 (t, di 1H), 3.90- 4.10 (m, 1H), 6.90-7.05 (2H), 7.20-7.25 (m, 2H).

3-ethyl-1-I(1-(5-methylhex-2-yl)-3-(methyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one 60 PH: 92.390

MS:t/2 357.4 (M--1)

TN-NMR (SOSIZ) U:a 0.75-0.95 (m, TON), 1.10 (d, ZN), 1.15-1.40 (m, ZN), 1.40-1, 75 (m, 4H), 1.97-2.10 (m, 2H), 2.20 (m, 1H), 2.43-2.75 (m, 4H), 2.80-2.95 ( m, 1H), 3.00-3.25 (m, 1H), 3.40 (t, 1H), 3.90-4.10 (m, 1H), 6.90-7.05 (m, 2H), 7.25 (m, 2H). bo 3-ethyl-1-(1-(4--1-methylethyl)cyclohexyl|-3-methyl-4-piperidinyl|-1,3-dihydro-2H-indol-2-one

РХ: 94,790

MS:t/2 383.4 (M--1)

TN-NMR (SOSIV): a 0.75-1.05 (m, 8Н), 1.10-1.50 (m, 7Н), 1.50-1.90 (m, 7Н), 1.90 -2.10 (m, 2N), 2.15-2.43 (m, ЗН), 2.55 (d, 0.5 N), 2.75 (d, 0.5 N), 2.90 -3.25 (m, ЗН), 3.40 (t, 1Н), 3.90-4.10 (m, 1Н), 6.90-7.01 (m, 2Н), 7.25 (m , 2H).

3-ethyl-1-(1-(decahydro-2-naphthyl)-3-(methyl)-4-piperidinyl|-1,3-dihydro-2H-indol-2-one

RH: 94.39

MS:t/2 395.3 (M--1) "NA-NMR (SOSIvz)a 1.75-1.90 (two t, ZN), 1.10 (d, ZN), 1.15-1 .90 (m, 15H), 2.00 (m, 2H), 2.20 (width, 1H), 2.40 (m, 2H), 2.45-2.60 (m, 2H), 2.75 (m, 1H), 2.90-3.20 (m, 2H), 3.40 (width, 1H), 3.90-4.15 (m, 1H), 6.90- 7.05 (m, 2H), 7.25 (m, 2H).

Other compounds covered by formulas (II) or (PA) of this invention can be synthesized by similar methods.

Example 9

Affinity for nociceptin at the OKI1 receptor for preferred compounds was determined using the following assay:

Membranes of recombinant HEK-293 cells, which express a receptor similar to the human opioid receptor (OC), (Caseriog Vioisdu), were obtained by lysing the cells in an ice-cooled hypotonic buffer (2.5 mM MoCl, 50 mM NERB5, pH 7.4) (10 ml /lOsm cup) followed by homogenization using a tissue homogenizer/Teflon pestle. Membranes were collected by centrifugation at 30,000 rpm for 15 minutes. at 42C and the precipitate after centrifugation was resuspended in a hypotonic buffer to a final concentration of 1-Zmg/ml. Protein concentrations were determined using VioKai protein assay reagent with bovine serum albumin as a standard. Aliquots of OKI 1 receptor membranes were stored at -809C. p 29 Analyzes of the functional binding of ZOTRaz were carried out as follows. Gee)

The OKI1 membrane solution was obtained by successive addition of final concentrations of 0.06 bbmg/ml membrane protein OBI 1, 1Omg/ml saponin, ZMM COP and 0.20 nM (8|STROS) to the binding buffer (100 MM mass, 10 MM Maosi", 20 MM NEREZ, pH ?7.4) on ice. The resulting membrane solution (190ml/well) was transferred to 96-well polypropylene plates containing 10ml of 20x concentrated stock solutions of the agonist prepared in DMSO. The plates were incubated for 30 minutes at room temperature with shaking. Reactions was cut off by rapid filtration on 9-well filter plates Opiyeg OR/B (RasKaga) using a 9-well tissue harvester (VagapaeI) with subsequent three filter washes with 200 ml of ice-cooled binding buffer (10 mM Man»oRO, 10 mM (Ma»HRO, pH7.4). The filter tablets /-|h« were successively dried at 502 for 2-3 hours. Fifty ml/well of the scintillation cocktail was added

SHO , m. account (Veiazsipi; UuaImas) and tablets were read in RasKaga Tor-Soshpa for 1 min./well.

The data were analyzed using the approximation of the functional dependence curve in SgarpRad RKIZMO, u.3.0, and the results are presented in Table 2 below:

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Example 10

Synthesis of some main groups

Scheme 1: b5 mine. ; aso s v ro 4 - yiv y , s what y y

S, R. Xia. : and their x. high school

The methodology of

29.7 g of sodium triacetoxyborohydride (0.14 mol) was added in one portion to a mixture of compound 4 (21.6 g, 0.2 mol), compound 5 (15.6 g, 0.1 mol), acetic acid (bg, 0.1 mol) in 500 ml of dichloromethane , 1 4 eq.). The release of gas occurred in the interval between ЗОохв. and hours The mixture was stirred overnight. TLC indicated the completion of the reaction.

1M Mahon (500ml) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (30 mLx2). The combined organics were dried over potassium carbonate and the solvent was evaporated to give a red oil, which was filtered through a column (595 ЕЖИЗМ, 2590 ЕУдАс and 7095 hexane) to give 14 g of product 6 as a white solid (54965). (22)

Compound 6 them

MS:t/2 249.3 (M--1)

2 H-NMR (SOCI3): a 1.50-1.90 (m, 6H), 2.05 (m, 2H), 3.30 (m, 4H), 3.95 (s, 4H), 6.60-6.80 (m, 4H). -

11.02 g of carbonyldiimidazole was added in one portion to a solution of 13.5 g of compound b (544 mmol) in 5 mL of acetonitrile. The mixture was stirred overnight. A solid precipitated from the solution, which was filtered and washed with NaOH and TVME, yielded 7.5 g of product. The filtrate was evaporated and the crude substance was dissolved in EtOAc, washed with water and a saturated solution of potassium carbonate. Organic substances were dried over potassium carbonate.

The solvent was evaporated to give a second batch of pink solid, which was filtered through a -c column (1095 EIZM, 4095 EtOAc and 5095 hexane) to give another 4.5 g of product 7 (8195, combined). )" Compound 7

MS: t/2 274.7 (Ma1) "H-NMR (SOCI3): a 1.50-1.90 (m, 7H), 2.50 (m, 2H), 4.00 (m, 4H) , 4.50 (m, 1H), 7.10 (m, ЗН), 7.25 (m, 1H).

A mixture of compound 7 (7.5g, 27.4mmol) and 8.26bg of PPT5 in 50ml of acetone and H2O (10:1) was stirred at reflux overnight. The mixture was cooled to room temperature and the acetone was evaporated. -I Addition of water to the mixture initiated crystallization to give Zg product 8 (47.4905).

Compound 8 o MS:t/g231 (Ma) 1 20 "H-NMR (SOCI3):a 2.20 (m, 2H), 2.60 (m, 2H), 4.50 (m, 1H), 7 ,10 (m, 4H), 9.5 (width, 1H).

To a mixture of compound 8 (7.75g, 33.6bMmol), benzylamine (3.61g, 33.5mmol), acetic acid (2.0g,

IR e). . : . 33.65 mmol) in 150 ml of dichloromethane was added in one portion to 10.3 g of sodium triacetoxyborohydride (47.1 mmol, 1.4 equiv.). Gas is released between ЗОхв. and 1 hour. The mixture was stirred overnight. TLC indicated the completion of the reaction. 1M Mahon (500µL) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with 59 EtOAc (300mlx2). The combined organics were dried over potassium carbonate and the solvent was evaporated to give (F) a brown solid which was filtered through a column (from 595 EM, 2590 EtOAc and 7095 g of hexane to 1095 EM, 4095 EtOAc and 5095 hexane) to give 4 .7g of product 10 as a solid white substance (53.490) and 3.01g of product 9 as a solid white substance (34.2905). in Compound 9

MS: pt/h 322 (Math)

TN-NMR (SOSIZ)a 1.40 (m, 2H), 1.80-2.35 (m, 6H), 2.70 (m, 1H), 3.86 (s, 2H), 4.30 (m, 1H), 7.10-7.50 (m, 9H), 9.6 (width, 1H).

Compound 10 v5 MS:t/2322(M 1)

TN-NMR (SOSIZ)a 1.60 (m, 4H), 1.90 (m, 2H), 2.60 (m, 2H), 3.10 (m, 1H), 3.84 (s, 2H ), 4.50 (m, 1H),

7.10-7.50 (m, 9H), 9.6 (width, 1H).

To a solution of 30 ml of methanol containing 4.7 g of compound 10, 2 g of RY(OH) was added. The resulting suspension was hydrogenated at

BOf/sq.in for 12 hours at room temperature by TLC indicated completion of the reaction. Solution

It was filtered through a celite pad to remove the catalyst. Celite was washed twice with methanol (20 ml). The organics were combined and the solvent removed to give a pale solid, which was purified by chromatography (1095 Meon, 9095 EtOAc) to give the off-white product 11 (1.79g, 50.7 905).

Compound 11

MS:t/2232(M1) 70 7"H-NMR (SOSIS):a 1.50-1.85 (m, 8H), 2.60 (m, 2H), 4.30 (m, 1H), 7.10 (m, ЗН), 7.30 (m, 1H).

To a mixture of compound 11 (1.7 g, 7 Ammol), acetaldehyde (0.33 g, 7 Ammol) in 500 ml of dichloroethane, 2.2 g of sodium triacetoxyborohydride (10.3 mmol, 1.4 equiv.) was added in one portion. Gas release occurred in the interval between

REFERENCE and 1 hour The mixture was stirred overnight. TLC indicated the completion of the reaction. 1M Mammon (500ml) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (300 ml x 2). The combined organics were dried over potassium carbonate and the solvent was evaporated to give a brown oil which was chromatographed (1095 E33M, 4095 EOAc and 5095 hexane) to give 1.5 g of product 2 as a gummy oil, which was recrystallized from TVME to give a white solid (7895).

Compound 2

MS: t/h 259.7 (Ma-1)

TN-NMR (SOSISUa 1.15 (t, ЗН), 1.50-1.р95 (m, 6Н), 2.40-2.75 (m, 4Н), 2.95 (m, 1Н), 4 .35 (m, 1H), 7.10 (m, ЗН), 7.35 (m, 1H).

1.5 g of RY(OH) was added to a solution of 30 ml of methanol containing 3.01 g of compound 9. The obtained suspension was hydrogenated at 5Of/sq.in. for 12 hours at room temperature. TLC indicated completion of the reaction overnight.

The solution was filtered through a pad of celite to remove the catalyst. Celite was washed twice with methanol (20 ml). everything

The organics were combined and the solvent removed to give a pale solid, which was purified by chromatography (1095 Meon, 9095 EtOAc) to give off-white product 1 (1.68g, 77.490).

Compound 1

MS:t/2232(M1) "H-NMR (SOCIz):a 1.50 (m, 2H), 1.90-2.35 (m, 6H), 3.00 (m, 1H), 4, 30 (m, 1H), 7.10-7.30 (m, 4H). so

Scheme 2: yu

St o i-o0 0O- sh

S ve du nena: So and so. 1 life | - i z: za: she x y "nin svi that "A r S - z y z -I Methodology

About 2.5 g of Man was washed twice with THF, suspended in 100 ml of DMF, then 8.15 g of compound 7 se) was added to the mixture. and I am (Zvmmol). Gas evolution occurred, and after 5 minutes, 7.13 g of ethyl iodide (45./7 mmol) was added. The mixture (9) 50 was stirred overnight. LC/MS indicated that the starting material was completely consumed. The reaction mixture was cooled and H2O was added to the mixture. The product began to settle out of the solution. Crystals were collected

IR e). by filtration to obtain 9.7 g of compound 12 (84.7 905).

Compound 12

MS: t/2 303.3 (M--1) 25 TN-NMR (SOSISUa 1.30 (t, ЗН), 1.70-1.90 (m, 6Н), 2.50 (m, 2Н) , 3.85-4.00 (m, 6H), 4.50 (m, 1H), 7.05 (F) (m, ЗН), 7.25 (m, 1H). g Mixture of compounds 12 (9 .7g, 32.2mmol) and 9.72g of RRTZ in 50ml of acetone and HNO (10:1) were refluxed overnight. The mixture was cooled to room temperature and the acetone was evaporated. Addition of boron Water to the mixture initiated crystallization to give 6 .85 g of product 13 (82.390).

Compound 13

MS: t/2 259 (Ma-1) 7H-NMR (SOCI3): a 1.35 (t, ЗН), 2.20 (m, 2H), 2.60 (m, EN), 3.95 ( sq, 2H), 4.85 (m, 1H), 7.10 (m, 4H).

7.86 g of sodium triacetoxyborohydride (37 ,1 mmol, 1.4 eq.). Gas release occurred in the interval between ЗОхв. etc. The mixture was stirred overnight. TLC indicated the completion of the reaction. 1 Mahon (500 mL) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with E(Ac (300 ml x 2 ). The combined organics were dried over potassium carbonate and the solvent was evaporated to give a brown solid which was filtered through a column (from

From EM, 2595 EAc and 7095 hexane to 10906 EBM, 4090 E(Ac and 5095 hexane) to give 1.52g of product 14 as a white solid and 1.08g of product 15 as a white solid.

Compound 14

MS: pt/2 350 (M-1) "H-NMR (SOSIS): a 1.35 (t, ЗН), 1.50 (m, 2Н), 1.65 (m, 4Н), 1.95 (m, 2H), 2.60 (m, 2H), 3.02 (m, 1H), 70. 3.83 (s, 2H), 3.95 (ddd, 2H), 4.45 (m, 1H), 7.00-7.50 (m, 9H).

Compound 15

MS: pt/2 350 (M-1) "H-NMR (SOSIS): Yaa 1.35 (m, 5H), 1.90 (m, 2H), 2.10-2.35 (m, 4H) , 2.70 (m, 1H), 3.83 (s, 2H), 3.95 (ddd, 2H), 4.40 (m, 1H), 7.00-7.50 (m, 9H).

To a solution of 20 ml of methanol containing 0.5 g of compound 14, 0.3 g of РЯ(OH) was added. The obtained suspension was hydrogenated at 5Of/sq.in. for 12 hours at room temperature. TLC indicated completion of the reaction overnight.

The solution was filtered through a pad of celite to remove the catalyst. Celite was washed twice with methanol (2 Oml).

The organics were combined and the solvent was removed to give a pale solid, which was purified by chromatography (1095 Meon, 9095 EAs) to give the off-white product C (300mg, 50905).

Compound Z

MS: pt/2 232 (Mat) "NA-NMR (SOSIz): a 1.35 (t, ЗН), 1.50-1.85 (m, 8Н), 2.60 (m, 2Н), 3 ,20 (m, 1H), 3.95 (ddd, 2H), 4.30 (m, 1H), 7.10, (m, ЗН), 7.30 (m, 1H).

Example 11 p

Joining finite groups about

The final groups were joined to the main groups according to the following methods: "VVIV ey « ke e Ya: (ee) sha vo her yu her Y t F "nina pinni nik p - dyn che. sche dich "

Basic technique for alkylation: C c To a solution of amine (Eq.) and triethylamine (1 eq.) in dimethylformamide, Eq. was added in one portion. alkyl )» bromide or chloride. The mixture was stirred and heated at 8092 overnight. TLC indicated the completion of the reaction. The reaction was quenched by adding water, followed by adjusting the pH to 10 using 1M Mahon. The mixture was extracted twice with EBO. The combined organic extracts were dried over potassium carbonate and the solvent was evaporated, followed by chromatography to give the pure product. - The basic technique for reductive amination: -I Sodium cyanoborohydride (1.4 eq.) was added in one portion to a mixture of ketone or aldehyde (Eq.), amine (Eq.) and acetic acid (Eq.) in methanol. The mixture was stirred at room temperature overnight. TLC is indicated the completion of the reaction. The reaction was quenched by adding water, followed by bringing the pH to 10 using 20 s of 1 mM mMon. The mixture was extracted twice with EBO. The combined organic extracts were dried over potassium carbonate and the solvent was evaporated, followed by chromatography to obtain a pure product. The following compounds were prepared by end-group attachment using the basic procedures described: 1-(4-(benzylamino)cyclohexyld|-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one 1-4-Knaphth-2-ylmethyl )ethylamino|cyclohexyl/d-1,3-dihydro-2H-benzimidazol-2-one 29 MS:t/ 400.2 (M-1)

HF) 1-(4-(norbornan-2-ylamino)cyclohexyl/)-1,3-dihydro-2H-benzimidazol-2-one

MS:t/2 326.3 (M--1) o 1-(4-(4-(1-methylethyl)cyclohexyl|amino|cyclohexyl|d-1,3-dihydro-2H-benzimidazol-2-one

MS:t/2 356.4 (M--1) bo 1-(4-((decahydro-2-naphthyl)amino|cyclohexyl|)-1,3-dihydro-2H-benzimidazol-2-one

MS:t/2 368.2 (M--1) 1-(4-(ethylamino)cyclohexyl)-1,3-dihydro-2H-benzimidazol-2-one 1-(4-(benzylamino)cyclohexyl-1 ,3-dihydro-2H-benzimidazol-2-one 1-(4-Quindan-2-yl)benzylamino|cyclohexyl|-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one bo MS:t/ 466.3 (M-1)

"NA-NMR (SOSIV): a 1.30 (t, ZN), 1.50-1.75 (m, 2H), 1.90 (width, 2H), 2.02 (width, 2H) , 2.20 (m, 2H), 2.80 (m, 1H), 2.99 (m, 4H), 3.75 (s, 2H), 3.90 (m, ЗН), 4.25 ( m, 1H), 6.95-7.45 (m, 13H). 1-4-(cyclooctylmethyl)amino|cyclohexyl|-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one

РХ: 9990

MS: p/ 384.5 "H-NMR (SOSIV): I 1.40-1.90 (m, 24H), 2.30 (m, 2H), 2.50 (m, 2H), 2.90 (m, 1H), 3.90 (ddd, 2H), 4.20 (m, 1H), 7.10 (m, ЗН), 7.30 (m, 1H). 1-(4-Knaft-2 -yl)amino|cyclohexyl|-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one

РХ: 9790

MS: t/2 399 "H-NMR (SOSIV): a 1.50 (t, ЗН), 1.80 (m, 5Н), 2.0 (m, 2Н), 2.70 (m, 2Н) , 310 (m, 1H), 3.90 (m, 2H), 4.0 (m, 2H), 4.40 (m, 1H), 7.10 (m, ЗН), 7.50 (m, 4H), 7.90 (m, 4H). 1-(4-Kp-benzyloxybenzyl)amino|cyclohexyl|-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one

РХ: 9790

MS: t/:2 455

TN-NMR (SOSIZ)a 1.40 (t, ЗН), 1.70 (m, 2Н), 1.90 (m, ЗН), 2.60 (m, 4Н), 3.10 (m, 1Н ), 3.80 (s, 2H), 4.0 (m, 2H), 4.50 (m, 1H), 5.10 (s, 2H), 7.10 (m, 6H), 7.50 (m, 6H), 7.90 (m, 1H). 1-4-(cyclooctylmethyl)amino|cyclohexyl|-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one

РХ: 9990

MS: t/:2 369 "H-NMR (SOSIV): Yaa 1.40 (t, ЗН), 1.70 (m, 5Н), 1.90 (m, 12Н), 2.10 (m, ЗН ), 2.40 (m, 2H), 2.50 (d, 2H), 3.30 (m, 1H), 3.90 (m, 2H), 4.20 (m, 1H), 7.10 (m, 1H), 7.30 (m, 3H). 1-(4-(decahydro-2-naphthyl)amino|cyclohexyl|-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one c 29 RH: 9996 o

MS: t/2 395

TN-NMR (SOCIz): a 1.40 (t, ЗН), 1.70 (m, ЗН), 1.80 (m, ЗН), 1.90 (m, 12Н), 2.20 (m, 2H), 2.30 (m, ЗН), 2.50 (kv, 2H), 3.10 (m, 1H), 3.90 (m, 2H), 4.20 (m, 1H), 4, 30 (m, 1H), 7.0 (m, 1H), 7.30 (m, ЗН). so 1-(4-N-phenylbenzyl)amino|cyclohexyl)|-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one

РХ: 10095 yu

MS:t/2 440.8 (M--1) o "H-NMR (meOH-4yd):a 1.75 (m, 2H), 2.00 (m, 2H), 2.40-2, 55 (m, 4H), 3.35-3.52 (m, 2H), 4.35 (s, 2H), 7.40 (m, 2H), 7.59 (t, 2H), 7.60 -7.72 (m, 6H), 7.78 (d, 2H). - 1-4-K1,2,3,4-tetrahydronaphthyl)amino|cyclohexyl)|-5-carbamoyl-1,3-dihydro- 2H-benzimidazol-2-one

РХ: 93,990

MS:t/2 405.7 (M--1) "H-NMR (MeOH-ada 1.70 (m, 2H), 1.85 (m, 1H), 2.02 (m, 2H), 2 .39 (width, ZN), 2.50 (m, 2H), 2.90 (m, 1H), 3.00 (width, 2H), 3.35 (m, 1H), 3.60 ( m, 1H), 3.72 (width, 1H), 4.35 (m, 1H), 7.15 (width, 4H), 7.40 (d, « 420. 1H), 7.60 ( c, 1H), 7.65 (d, 1H). 1-4-K4-propylcyclohexyl)amino|cyclohexyl|-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one

PH: 10090 )» MO: t/x 399.6 (M) "H-NMR (MeOH-4a)): I 0.95 (t, ЗН), 1.10 (m, 1Н), 1.20- 1.60 (m, 6H), 1.70 (width, 5H), 1.80-2.00 (m, 4H), 4350210 (m, 1H), 2.30 (width, 2H), 2 .45 (m, 2H), 3.25 (m, 1H), 3.50 (m, 1H), 4.40 (m, 1H), 7.40 (d, 1), 7.60 (s, -I 1H), 7.65 (d, 1Hn). 1-4-K5-methylhex-2-yl)amino|cyclohexyl/|-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one - pH: 10095 (Ce) MS: t/2 373.5 (M--1) sl 50 "NA-NMR (meOH-a)):a 0.95 (d, 6H), 1.25-1.40 (m, 5H), 1.50-1.75 (m, 4H), 1.85 (m, 1H), 1.95 (width, 2H), 2.30 (m, 2H), 2.40 -2.55 (m, 2H), 3.35-3.55 (m, 2H), 4.38 (m, 1H), 7.40 (d, 1H), 7.60 (s, 1H), 7.70 (d, 1H).

IR e) 1-4-((decahydro-2-naphthyl)amino|cyclohexyl)|-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one

РХ: 10090

MS: t/ 411.7 (Mat) "NA-NMR (MeOH-4/): I 0.90-2.10 (m, 18H), 2.10-2.50 (m, 5H), 2, 82 (m, 1H), 3.50 (m, 2H), 4.35 (m, 1H),

He) 7.42 (d, 1H), 7.60 (c, 1H), 7.70 (d, 1H). 1-(4-(cyclooctylamino)cyclohexyl)|-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one o PH: 95.495

MS:t/2 385.7 (M--1) 60 TN-NMR (MeOH-y)):a 1.50-2.10 (m, 13Н), 2.30 (m, 2Н), 2, 40-2.52 (m, ЗН), 2.80-2.95 (m, ЗН), 3.45 (m, 2Н), 3.70 (m, 1Н), 4.38 (m, 1Н) , 7.40 (d, 1H), 7.63 (c, 1H), 7.70 (d, 1H). 1-(4-Quindan-2-yl)amino|cyclohexyl)|-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one

РХ: 10090

MS:t/2 391.6 (M--1) bo TN-NMR (MeOH-y)a 1.70 (m, 2H), 2.00 (m, 2H), 2.40-2.60 ( m, 4H), 3.10-3.20 (m, 2H), 3.50 (m, ZN),

4.30-4.45 (m, 2H), 7.25 (m, 2H), 7.35 (m, 2H), 7.42 (d, 1H), 7.60 (s, 1H), 7 ,72 (d, 1H). 1-(4-(benzylamino)cyclohexyl|-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one

РХ: 10090

MS:t/2 399.5 (M--1) "NA-NMR (MeOH-4/): Jaa 1.40-1.85 (m, 15H), 2.00 (m, 4H), 2, 25-2.50 (m, 4H), 2.93 (d, 2H), 3.30 (m, 1H), 4.30 (m, 1H), 7.36 (d, 1H), 7.60 (c, 1H), 7.65 (d, 1H). 1-4-K4-phenylcyclohexyl)amino|cyclohexyl)-5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one

РХ: 10090

MS:t/2 433.7 (M--1) "H-NMR (MeOH-ad:a 1.65 (m, 2H), 1.85-2.20 (m, 8H), 2.25- 2.50 (m, 5H), 3.90 (m, 1H), 3.50 (m, 2H), 3.58 (m, 1H), 4.30 (m, 1H), 7.15-7 .40 (m, 6H), 7.60 (s, 1H), 7.65 (d, 1H). 1-(4-(dibenzylamino)cyclohexyl/|-5-carbamoyl-1,3-dihydro-2H- benzimidazol-2-one

РХ: 10090

MS: ti/: 455.6 (M'-1) "NA-NMR (MeOH-y/): I 2.00-2.25 (m, 4H), 2.40 (m, 4H), 3, 52 (m, 2H), 4.25-4.65 (m, 4H), 7.30 (d, 1H), 7.45-7.58 (m, 10OH), 7.60 (s, 1H) , 7.65 (d, 1H). 1-4-K5-methylhex-2-yl)amino|cyclohexyl)-7-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one

RH: 99.19

MS:t/2 373.3 (M--1) 7TH-NMR (meOH-4d): aY 0.95 (d, 6H), 1.30 (d, ЗН), 1.45-1.68 ( m, 5H), 1.75 (m, 1H), 2.00 (m, 2H), 2.18-2.32 (m, ЗН), 2.60 (m, 2H), 3.20-3 .40 (m, 2H), 4.30 (m, 1H), 7.05-7.20 (m, ЗН).

Other compounds covered by formulas (II) or (ША) of this invention can be synthesized by similar methods. at

Example 12

Affinity for nociceptin at the OKI1 receptor for preferred compounds was determined using the following assay:

Membranes of recombinant HEK-293 cells, which express a receptor similar to the human opioid receptor, co (OVI), (Beseriog Viodou) were obtained by lysing cells in ice-cooled hypotonic buffer (2.5 mM MaCl, 50 mM NEREZ, pH 7.4 ) (10ml/1Osm cup) followed by homogenization using a tissue homogenizer/teflon pestle. Membranes were collected by centrifugation at 30,000 rpm for 15 minutes. at 42C and the sediment after centrifugation was resuspended in a hypotonic buffer to a final concentration of 1-Zmg/ml. Protein concentrations were determined using the bovine VioKai protein assay reagent

With serum albumin as standard. Aliquots of OKI 1 receptor membranes were stored at -809C. -

Analyzes of the functional binding of ZOTRaz were performed as follows.

The OKI1 membrane solution was obtained by sequentially adding final concentrations of 0.06 bbmg/ml membrane protein OBI 1, 10mg/ml saponin, ZMM COP and 0.20nM (3951cTRose) to the binding buffer (100MM "20 mass, 10MM Maosi", 20MM NEREZ, pH ?7.4) on ice. The resulting membrane solution (190ml/well) was transferred to 96-well polypropylene plates containing 10ml of 20x concentrated agonist stock solutions prepared in DMSO. The plates were incubated for 30 minutes at room temperature with shaking. Reactions were stopped by rapid filtration on 9-well filter plates Opiyeg OR/B (RasKaga) using a 9-well tissue harvester (Vgapde)) followed by three filter washes with 20 Oml of ice-cold binding buffer (10 mM ManH»PO, 10 mM ManrPo, pH7.4). Filter tablets -1 were successively dried at 502 for 2-3 hours. Fifty ml/well of scintillation counting cocktail (Veiazsipi; UuaImas) was added and plates were read in a RasKaga Tor-Soshpi for 1 min/well. - The data were analyzed using the approximation of the functional dependence curve in sharpRai RKIZMO, M.3.0,

Ge) and the results are presented in table C below: p. 50

IR e)

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Ф) Example 13 ka Synthesis of substituted benzimidazole main groups 60 miles, M. n J ' . .

Methodology 65 60905 dispersion of sodium hydride in mineral oil (0.67 g, 16.7 mmol) was washed with anhydrous pentane and then suspended in 800 ml of anhydrous THF under Mo atmosphere. Compound 1 was added (European patent 0029707)

(3.80 g, 11.1 mmol), the mixture was stirred at room temperature for 15 min. and then heated to 50 2C.

Ethyl bromide (1.0 bml, 13.mmol) was added and the resulting mixture was stirred at 502 for 18 hours. TLC (5iO", SNCl:Meon 96:4) showed that the reaction was complete at about 4095. Additional amounts of sodium hydride (0.67g) and ethyl bromide (1.0bml) were added. After heating at 502C for an additional 24 hours, the reaction mixture was cooled to room temperature and quenched with water. The layers were separated and the aqueous layer was extracted with ethyl acetate (1x). The combined organic extracts were washed with an aqueous solution of sodium bicarbonate (1x), dried over Moa53O), and the solvent was evaporated to give the crude product as a yellow solid.

Trituration with diethyl ether gave pure compound 2 as a white solid (3.38g, 82905).

TN-NMR (SOSIS): a 1.45-1.55 (m, 12H), 1.82 (b.c, 2H), 2.30 (m, 2H), 2.87 (m, 2H), 4.30 (width, 2H), 4.41 (sq., 2H), 4.82 (m, 1H), 7.10-7.30 (m, 4H).

To a solution of compound 2 (3.60 g, 9.74 mmol) in 100 ml of ethyl acetate, 25 ml of a mixture of ethyl acetate and concentrated HC (1:11) was added. The mixture was thoroughly stirred for 2 hours at room temperature and evaporated to dryness. The residue was neutralized with 5 bOml of a 10:11 methanol solution of ammonia and evaporated again to dryness for 75 minutes. The residue was suspended in 100 ml of a 1:1 mixture of MeOH and СНоСи», filtered and the filtrate was evaporated to dryness to obtain a not quite white solid. Flash chromatography on silica gel with mixture elution

СНоСИ:Меон:МнН» (300:10:1) gave pure compound C as a white crystalline solid (1.98g, 7695). "NA-NMR (SOSIv)a 1.45 (t, ZN), 1.82 (lat, 2H), 2.33 (m, 2H), 2.80 (m, 2H), 4.40 ( sq, 2H), 4.80 (m, 1H), 7.10-7.30 (m, ЗН), 7.45 (d, 1H).

Example 14

Joining finite groups

The end groups were joined to the main groups according to the following methods: z. ko chk (so) shchi "a i-

Basic technique for alkylation:

Equiv. was added to a solution of amine (Eq.) and triethylamine (Eq.) in dimethylformamide in one portion. alkyl bromide or chloride. The mixture was stirred and heated at 8023 overnight. TLC indicated the completion of « 70 reactions. The reaction was quenched by adding water, followed by adjusting the pH to 10 using 1M Mahon. The mixture was extracted with EBO twice. The combined organic extracts were dried over potassium carbonate and the solvent was evaporated, followed by chromatography to obtain a pure product. )» The basic technique for reductive amination:

Sodium cyanoborohydride (1.4 eq.) was added in one portion to a mixture of ketone or aldehyde (Eq.), amine (Eq.) and acetic acid (Eq.) in methanol. The mixture was stirred at room temperature overnight. TLC -I indicated the completion of the reaction. The reaction was quenched by adding water, followed by bringing the pH to 10 with 1M NaOH. The mixture was extracted twice with EBO. The combined organic extracts were dried over potassium carbonate and ate. the solvent was evaporated, and the pure product was obtained by subsequent chromatography. (Ce) The following compounds were obtained by addition of end groups using the described basic techniques: cl 50 2-cyanoimino-3-ethyl-1-11-(p-phenylbenzyl)-4-piperidinyl/|-1,3-dihydro-2H-benzimidazole "NA-NMR (SOSIV): I 1.50 (t, ZN), 1.88 (m, 2H), 2.28 (m, 2H), 2.62 (m, 2H), 3.12 (m , 2H), 3.65 (s, 2H), so 4.48 (sq, 2H), 4.80 (m, 1H), 7.15-7.70 (m, 13H). 2-cyanoimino-3 -ethyl-1-(1-(p-benzyloxybenzyl)-4-piperidinyl)-1,3-dihydro-2H-benzimidazole

РХ: 96,590

MS:t/2 466.5 (M--1)

GF! "NA-NMR (SOSIv): I 1.55 (t, ZN), 1.82 (m, 2H), 2.25 (m, 2H), 2.50 (m, 2H), 310 (m, 2H ), 3.55 (s, 2H), 4.48 (sq, 2H), 4.78 (m, 1H), 5.20 (s, 2H), 7.00 (d, 2H), 7.15 -7.65 (m, 11H). o 2-Cyanoimino-3-ethyl-1-(1-(naphth-2-ylmethyl)-4-piperidinyl)-1,3-dihydro-2H-benzimidazole

PH: 93.990 bo MS: t/g "NA-NMR (SOSIS): a 1.55 (t, ЗН), 1.80 (m, 2Н), 2.30 (t, 2Н), 2.52 (m , 2H), 318 (sheard, 2H), 3.78 (s, 2H), 4.50 (square, 2H), 4.80 (m, 1H), 7.20-7.90 (m, 11H) 2-cyanoimino-3-ethyl-1-I(1-(4-propylcyclohexyl)-4-piperidinyl)-1,3-dihydro-2H-benzimidazole

MS: t/2 394.4 (M--1) bo TN-NMR (SOSIvs): Yaa 0.90-2.28 (m, 21Н), 3.10 (m, 4Н), 3.62 (m , 2H), 4.42 (sq., 2H), 5.15 (m, 1H), 7.20 (d,

1H), 7.30 (m, 1H), 7.50 (t, 1H), 7.80 (width, 1H). 2-Cyanoimino-3-ethyl-1-(1-I4-(2-propyl)ucyclohexyl|)-4-piperidinyl)-1,3-dihydro-2H-benzimidazole

РХ: 10090

MS: t/: 394.5 (M--1)

TNA-NMR (SOSIvZ): I 0.90 (d, ЗН), 0.98 (d, ЗН), 1.15-2.35 (m, 14Н), 310 (m, 5Н), 3.70 ( m, 2H), 3.92 (width, 1H), 4.40 (sq., 2H), 5.20 (m, 1H), 7.20 (d, 1H), 7.38 (d, 1H ), 7.52 (t, 1H), 7.80 (m, 1H). 2-Cyanoimino-3-ethyl-1-I(1-(decahydro-2-naphthyl)-4-piperidinyl|-1,3-dihydro-2H-benzimidazole

РХ: 93,990

MS: t/ 406.6 (M--1) "H-NMR (SOCI»z): a 1.25-2.35 (m, 24Н), 1.15 (m, 4Н), 3.60 ( m, 2H), 4.40 (m, 2H), 4.20 (m, 1H), 7.20-7.80 (m, 4H). 2-Cyanoimino-3-ethyl-1-(11-( cyclooctyl)-4-piperidinyl|-1,3-dihydro-2H-benzimidazole

РХ: 10090

MS:t/2 380.3 (M--1) "H-NMR (SOSIv):a 1.50-1.80 (m, 13Н), 1.90 (m, 2Н), 2.10 (m , 4H), 3.05 (m, ЗН), 3.30 (m, 1H), 3.45 (m, 2H), 3.90 (m, 1H), 4.42 (kv, 2H), 5 .15 (m, 1H), 7.20 (d, 1H), 7.35 (d, 1H), 7.50 (m, 1H), 7.78 (m, 1H). 2-cyanoimino-3- ethyl-1-I(1-(10,11-dihydro-5H-dibenzo(a, d|cyclohepten-5-yl)-4-piperidinyl|-1,3-dihydro-2H-benzimidazole

RH: 94.59

MS:ti/2 462.2 (M-A1) "NA-NMR (SOSIv)a 1.40 (t, ЗН), 1.70 (sh.s, 2H), 2.01 (m, 2H), 2.28 (m, 2H), 2.80 (m, 4H), 3.95 (s, 1H), 4.02 (m, 2H), 4.32 (sq, 2H), 4.65 (m , 1H), 7.00-7.32 (m, 12H). 2-Cyanoimino-3-ethyl-1-(1-(3,3-bis(phenyl)propyl)-4-piperidinyl|-1,3 -dihydro-2H-benzimidazole

MS: t/» 464.2 (Ma) s 29 "H-NMR (SOSIV): I 1.40 (t, ЗН), 1.73 (sh.s, 2H), 2.09 (m, 2H) , 2.18-2.45 (m, 6H), 2.98 (width, 2H), 3.93 g) (t, 1H), 4.35 (sq., 2H), 4.63 (m, 1H), 7.10-7.30 (m, 13H), 7.40 (d, 1H). 2-Cyanoimino-3-ethyl-1-(1-(1,2,3,4-tetrahydronaphthyl)- 4-piperidinyl/|-1,3-dihydro-2H-benzimidazole

РХ: 94,090

MS:tu/» 400.2 (Ma) 09 "NA-NMR (SOSIV): I 1.30-1.70 (m, 6H), 1.85 (m, 2H), 2.05 (m, 1H ), 2.45 (m, ЗН), 2.85 (m, 4H), 310 (m, yuyu 2H), 4.35 (kv, 2H), 4.71 (m, 1H), 7.00- 7.60 (m, 8H). b» 2-cyanoimino-3-ethyl-1-(1-(5-methylhex-2-yl)-4-piperidinyl-1,3-dihydro-2H-benzimidazole

RH: 94.99 -

MS:t/2 368.3 (M--1) m "NA-NMR (SOSIv): I 0.85 (d, 6H), 0.95 (d, ЗН), 1.12-1.65 ( m, 8H), 1.80 (m, 2H), 2.27-2.60 (m, 5H), 2.85 (m, 2H), 4.38 (m, 2H), 4.62 (m , 1H), 7.08-7.30 (m, 3H), 7.45 (m, 1H). 2-Cyanoimino-3-ethyl-1-(11-(norbornan-2-yl)-4-piperidinyl) -1,3-dihydro-2H-benzimidazole

PH: 99.295 « 20 MS: t/ 364.7 (M-1) with s "NA-NMR (SOSIV): I 1.10-2.10 (m, 13Н), 2.35 (m, 1Н), 2.50-2.70 (m, ЗН), 2.70-2.90 (m, ЗН), 3.50 (m, 2Н), 4.50 (кв, 2Н), 4.80 (m, 1H), 7.35 (m, 2H), 7.48 (m, 1H), 7.75 (m, 1H). 3 » 2-cyanoimino-3-ethyl-1-I(1-(1,3 -dihydroinden-2-yl)-4-piperidinyl-1,3-dihydro-2H-benzimidazole

РХ:92,190

MS: t/2 386.2 (M--1) -I "H-NMR (SOSIS)a 1.42 (t, ЗН), 1.82 (m, 2Н), 2.21 (m, 2Н) , 2.43 (m, 2H), 2.88 (m, 2H), 3.02-3.19 (m,

AN), 3.23 (m, 1H), 4.38 (q, 2H), 4.80 (m, 1H), 7.08-7.30 (m, 7H), 7.45 (d, 1H ). 7 2-Cyanoimino-3-ethyl-1-(1-(cyclooctylmethyl)-4-piperidinyl|-1,3-dihydro-2H-benzimidazole (Ce) РХ: 10090

MS: t/ 394.7 (Ma-1) n TN-NMR (meOH): a 1.35-2.00 (m, 20Н), 2.60-2.85 (m, 6Н), 3.40 (m, 2H), 2.52 (sq, 2H), 4.90 (m, 1H), 7.35

IR e) (m, 2H), 7.48 (m, 1H), 7.70 (m, 1H). 2-Cyanoimino-3-(2-hydroxy)ethyl-1-(1-(cyclooctyl)-4-piperidinyl)|-1,3-dihydro-2H-benzimidazole

РХ: 10090

MS: t/2 396.3 (M--1)

He) TN-NMR (DMSO): 7.52 (dt, 1H), 7.45 (dt, 1H), 7.21 (m, 2H), 4.97 (t, 1H), 4.55 (m , 1H), 4.38 (t, 2H), 3.76 (sq., 2H), 2.88 (m, 2H), 2.61 (width, t, 1H), 2.33 (m, 4H) , 1.76-1.37 (m, 16Н). where 2-cyanoimino-3-methoxycarbonylmethyl-1-(1-(cyclooctyl)-4-piperidinyl)|-1,3-dihydro-2H-benzimidazole

PH: 98.39 b MS: t/ 424.2 (Ma-1) "H-NMR (DMSO): 7.56 (dd, 1H), 7.51 (dd, 1H), 7.25 (m, 2H), 5.26 (s, 2H), 4.56 (m, 1H), 3.72 (s, ЗН), 3.34 (m, 2H), 2.78 (m, 2H), 2, 62 (width, 1H), 2.32 (m, 4H), 1.80-1.35 (m, 16H). 2-cyanoimino-3-cyanomethyl-1-(1-(cyclooctyl)-4- piperidinyl|-1,3-dihydro-2H- benzimidazole b5 PH: 10090

MS:t/2 391.2 (M--1) "H-NMR (DMSO): 7.60 (m, 2H), 7.31 (m, 2H), 5.48 (s, 2H), 4 .77 (m, 1H), 3.33 (d, 2H), 2.88 (m, 2H), 2.62 (width, 1H), 2.33 (m, 4H), 1.66- 1.37 (m, 16H). 2-Cyanoimino-3-butyl-1-(/1-(cyclooctyl)-4-piperidinyl)|-1,3-dihydro-2H-benzimidazole

RH: 95.49

MS: t/g 352.2 (M-1) "H-NMR (DMSO): 7.58 (dd, 1H), 7.49 (dd, 1H), 7.24 (m, 2H), 6, 55 (s, 2H), 4.59 (m, 1H), 4.34 (t, 2H), 2.97 (m, 2H), 2.80 (m, 1H), 2.55 (m, 2H ), 2.38 (m, 2H), 1.80-1.30 (m, 18H), 0.90 (t, 3H). 70 2-cyanoimino-3-(2-methanesulfonamido)ethyl-1-( 1-(cyclooctyl)-4-piperidinyl-1,3-dihydro-2H-benzimidazole

РХ: 10090

MS: t/ 473.2 (M--1) "H-NMR (DMSO): 7.53 (dd, 1H), 7.44 (dd, 1H), 7.23 (m, 2H), 4, 60 (m, 1H), 4.35 (t, 2H), 3.37 (t, 2H), 2.87 (m, 2H), 2.82 (s, ЗН), 2.60 (width t , 1H), 2.31 (m, 4H), 1.76-1.37 (m, 15H). 2-Cyanoimino-3-acetamido-1-(1-(cyclooctyl)-4-piperidinyl/|-1 ,3-dihydro-2H-benzimidazole

РХ: 10090

MS: t/ 409.2 (Ma-1) "TN-NMR (DMSO): 7.75 (s, 1H), 7.52 (dd, 1H), 7.37 (s, 1H), 7.30 (dd, 1H), 7.20 (m, 2H), 4.96 (s, 2H), 4.55 (m, 1H), 3.33 (d, 2H), 2.88 (m, 2H) . -4-piperidinyl)-1,3-dihydro-2H-benzimidazole

РХ: 97,590

MS: t/: 409.9 (M--1)

TN-NMR (DMSO): 7.45 (dd, 1H), 7.14 (m, 3H), 4.57 (s, 2H), 4.50 (m, 1H), 2.87 (m, 2H ), 2.61 (width, 1H), 2.33 (m, 4H), 1.75-1.37 (m, 15H). c 2-cyanoimino-3-(2-dimethylamino)ethyl-1-(1-(cyclooctyl)-4-piperidinyl/|-1,3-dihydro-2H-benzimidazole)

РХ: 10090

MS:t/2 423.3 (M--1)

TN-NMR (DMSO): 7.60-6.96 (m, 4H), 6.54 (2H, s), 4.65 (m, 1H), 4.40 (t, 2H), 3.90 (t, 2H), 3.05 (m, 4H), 2.90 (m, 1H), 2.63 (m, ЗН), 2.56-2.37 (m, 4H), 1.85- 1.35 (m, 15N). so 3o 2-cyanoimino-1-(/1-(cyclooctyl)-3-hydroxymethyl-4-piperidinyl)|-1,3-dihydro-2H-benzimidazole IS o) 2-cyanoimino-1-(1-(cyclooctyl) -4-piperidinyl-1,3-dihydro-2H-7-azabenzimidazole 2-cyanoimino-1-(/1-(cyclooctyl)-2,6-ethan-4-one-4-piperidinyl-1,3-dihydro- 2H-benzimidazole F

Other compounds covered by the formula (IM) or (MA) of this invention can be synthesized by similar methods.

Example 15 -

Affinity for nociceptin at the OKI1 receptor for preferred compounds was determined using the following assay:

Membranes of recombinant HEK-293 cells, which express a receptor similar to the human opioid receptor, du (OK), (Caseriog Vioisdu), were obtained by lysing cells in ice-cooled hypotonic buffer 7 (2.5 mM MosiI2, 50 mM HERE5, pH7.4) (1O0ml/lOsm cup) followed by homogenization using a tissue homogenizer/teflon pestle. Membranes were collected by centrifugation at 30,000 rpm for 1" 15 min. at 42C and the precipitate after centrifugation was resuspended in a hypotonic buffer to a final concentration of 1-Zmg/ml. Protein concentrations were determined using VioKai protein assay reagent with bovine serum albumin as a standard. Aliquots of OKI 1 receptor membranes were stored at -802C. -I Analyzes of the functional binding of ZOTRaz were carried out as follows.

OKI1 membrane solution was obtained by successive addition of final concentrations of 0.06 bbmg/ml - membrane protein OBI 1, 10 mg/ml saponin, ZMM SOR and 0.20 nM (3951 cTRose) to the binding buffer (100 MM (Se) mass, 10 MM Maosi, 20 MM NEREZ , pH?7.4) on ice. The resulting membrane solution (190 ml/well) was transferred to 50-well polypropylene tablets containing 1 Oml of 20x concentrated stock solutions of the agonist obtained in DMSO. The tablets were incubated for 30 minutes at room temperature at Reactions were interrupted

Che) by rapid filtration on 9b-well filter plates Opijeg OR/B (RasKaga) using a 9b-well tissue harvester (Vgapde)) followed by three filter washes with 20 Oml of ice-cooled binding buffer (10mM ManH»oRO,, 10mM Ma »NHO, pH7.4). Filter tablets were successively dried at 502C for 2-3 hours. Fifty ml/well of scintillation counter cocktail (Veiazsipi; UuaImas) was added and plates were read in a RasKaga Tor-Soshpi for 1 min/well.

The data were analyzed using the approximation of the functional dependence curve in sgappRai RKETZMO. M.3 0. ime) and the results are presented in table 4 below: 60 b5 pe cnetno z tet -sinfevia ven i pred i Z anidin Bo!

He p peny ktnyannitya GI 1 liti NA bBe vni p... . . g. Still, NI: Y X siklyashchya I I t i po t TN-I t yan Kk tn still GIA p p 70 Tyn benzinet. y po- shSH 7. - y v MAN en y V - Vypidi YAN Pe ly Y "Y VANYASHYU-Z y shchi 1--(e a i ПИЛНИЙ perett zli t nya y sya yiv y T3- B! "Where gi din Ne KT PdyaZOo and "podenvvZ evi-O- insty roya dna ope. Bash! p) pli! per DILI S: shchi yar EE nor to settle - nich . And oo pienomine Z elite TV Ssfenidiyuropilu and taperedanil with her-

And shnhydro-levenya named after and sowntuko he i ethno PS C 5 4 tetriti failure) I pipendat sia | 5

20,000,000 per day in the bath.

Hook achnyaya (o) : ZA voimino-Zevtikh1413-0 3 vyt doc 1ya) I pierilyniyu 1 di

Ly Iz yar IN BO IAZ, anion Z cho KI bikini inn her " Z«tsivnopntvinZ- o stlyarovet etnleY-P Sdykikyuvtnia) 4 siperidenstt 1 A" o "Zopivyaoinanyu with methoxykarbo neme tyt 1 (ohnlodktiveue 3 " klin s Z-dinichya sia Nevada them- 35 | nin ON Pen vadnIot, . ch- koni be duvoektniau 4-piperyadinyli Mokh tiky I: lipervidnnili-1. yahydrnu with v. " hapdnidimno- Z ecetekt up to 151 inclookte m a pileridnni 1 25- 40: kigipr t NN hyda : -sh s za«pivnoimino I karbyukonm sny TP fate yuyutn fpipernyayanil-T,55 I " yaigtyarooeE Penzapla, . . - ped pani zeangiluriue and bBenziminesol: : z«tsnknsivyeyuyu1 Z raklyyuyutiya Z pzdrokenietii a peridiniya GI 3- - : digiyar 2 - benti mi dao Y y 7 - "dentin 1 papoyyuyutyp I pisheridnni pisi, Z-dnhydro- ZNI-

Ge) di hydr entry Tai. k Kt vch) YES . pg 50 Example 16

Affinity for the |, receptor for the compounds was determined according to the following analysis: co The solution of the nd opioid receptor membranes was obtained by sequentially adding the final concentrations of 0.075 μg/μl of the desired membrane protein, 1 μg/ml saponin, 3 μM COP and 0.20 nM I3551cTRozZ to the binding buffer ( 100mM Mad, 10MM Masi", 20MM STAINLESS STEEL, pH7.4) on ice. The resulting membrane solution (190 ml/well) was transferred to 96-well polypropylene tablets containing 10 ml of 20x concentrated stock solutions

GF) of the agonist obtained in DMSO. Tablets were incubated for ZOhv. at room temperature with shaking. Reactions were stopped by rapid filtration on 96-well filter plates Opieneg SR/V (RaskKaga) using a 96-well tissue harvester (Vagapaeyi) followed by three filter washes with 200 μl of ice-cooled binding buffer (10 mM Man»PO,;X, 10 mM NaCl, pH 7.4). 60 filter tablets were successively dried at 502C for 2-3 hours.

Fifty µl/well of scintillation counting cocktail (Misgozsipi20; RasKaga) was added and plates were read in a RasKaga Tor-Soshpa for 1 min/well.

The data were analyzed using the approximation of the functional dependence curve in SgarpRad RKIZMO, u.3.0, ve and the results for some compounds are presented in Table 5 below: -БО0-

Claims (31)

The formula of the invention 1. The compound of the formula (IM): y v (M Rep) M Х cm r A y B s v io) 1 where LC is hydrogen, C 4.zralalkyl, C.zocycloalkyl, C.z.42cycloalkylC. alkyl-, C..ralkoxy, C3-2cycloalkyl-, C. alkyl, substituted by 1-3 halogens, C. zocycloalkyl, substituted by 1-3 halogens, 09. C. zocycloalkylSi dalalkyl-, substituted by 1-3 halogens, C. oalkoxy, substituted by 1-3 halogens, oh C3.12cycloalkoxy-, substituted by 1-3 halogens, -"СООМ., -С4.АСООМ., -СННОН, -502М(М1)", hydroxyС. zoalkyl-, hydroxyC3-ocycloalkyl-, cyanoC3-ocycloalkyl-, -CoOM(M1)», МН»ЗО»С. dalkil-, F» MN»ZOsS. dalalkyl-, sulfonylaminoC)..4ralkyl-, diaminoalkyl-, -sulfonyl. lalkyl, b-membered heterocyclic ring, b6-membered heteroaromatic ring, b-membered heterocyclylC. alkyl-, b--len heteroaryls). dalalkyl-, b-membered aromatic ring, b--linen aryls. dalalkyl, 5-membered heterocyclic ring, optionally substituted with oxo or thio, 5-membered heteroaromatic ring, 5-membered heterocyclylC. alkyl-, optionally substituted oxo or thio, 5-ene heteroarylC. dalkil-, -C4 5B(O)MM, -C3. (МН, -С4.5МНОС(OMMI, -С4 BMNOZ(O)2MU, -С415МНБ(-О)МУХ, where MU1 is hydrogen, С4. oralalkyl, C3.1o2cycloalkyl, C3.oalkyl, C3.12cycloalkyl, "- SNON, amino, Su . dalalkylamino-, dis-alkylamino- or 5-membered heteroaromatic ring, optionally substituted by 1-3 lower alkyls; With c where each MU is independently selected from H, C. alkyl, C3-cycloalkyl, benzyl and phenyl; y"O is a 5-8-ene cycloalkyl, 5-8-ene heterocyclic or b-ene aromatic or heteroaromatic group; n is an integer from 0 to 3; A, B and 0 are independently hydrogen, C 4.zoralkyl, C 12 cycloalkyl, C 12 cycloalkyl, C 12 cycloalkoxy, C 12 cycloalkoxy, and -CHNON, -MNBZO», hydroxyC zralalkyl-, aminocarbonyl-, C) lalkylaminocarbonyl-, disC. lalkylaminocarbonyl-, -I acylamino-, acylaminoalkyl- , amide, sulfonylamino, dialkyl-, or A-B together can form a bridge Сов, or B-О together can form a bridge C3.7, or A-О together can form a bridge Су.в; d) 7 selected from the group that consists of connection, direct or branched C 4. alkylene, -МН-, -СНХО-, sl 50. -сСНоМнН-, -СН.М(СнНЗ)-, -«МНеН»-, -СНСОМнН-, -«ЧТНСНННСО-, -СННСО- , -СОСН»-, -СНСОСН»-, -СН(СН»У)-, -СНе, -0- ии-НС-СНУ.-, where the carbon and/or nitrogen atoms are unsubstituted or substituted by one or more groups lower co alkyl, hydroxy, halogen or alkoxy; Ki is selected from the group consisting of hydrogen, C4-zoalkyl, C3-1ocycloalkyl, C3-zoalkenyl, amino, Si. loalkylamino-, C3.12cycloalkylamino-, -СООМ, -С4.АСООМ., cyano, cyanos. zralkylu-, cyanoC3 zocycloalkyl-, 22 МН»ЗО»-, МН»ЗО»С. dalkilu-, МН»ьЖЗОС. dalalkyl-, aminocarbonyl-, C.alkylaminocarbonyl-, HF) diC.alkylaminocarbonyl-, benzyl, C3.42cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and de spiro ring system of formula (M): . ; (M) I СХ x; 65 where Hu and Ho are independently selected from the group consisting of MH, 0, 5 and CH"; and where the specified alkyl, cycloalkyl, alkenyl, C. zoalkylamino-, C. 12-cycloalkylamino-, or benzyl from group Ki is optionally substituted with 1-3 substituents, selected from the group consisting of halogen, hydroxy, C..4alkyl, C.alkyloxy, nitro, trifluoromethyl-, cyano, -COOM. , -b41 SOM, cyanosSu.oralkilu-, -S. (ОМ , -б4.5МНЗ(-О)2ММ 1, -б41.5МНБ(-ОММ, 5-membered heteroarylCo dalalkyl-, phenyl, benzyl, benzyloxy, while the specified phenyl, benzyl and benzyloxy are Optionally substituted 1 -3 substituents selected from the group consisting of halogen, C 4-alkyl-, C 1-zoalkoxy- and cyano; and where indicated are C3-102cycloalkyl, C3-42cycloalkyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and the spiro ring system of formula (M) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C. alkyl, C. zoalkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy, and benzyloxy, where 7 are indicated /0 phenyl, benzyl, phenyloxy or benzyloxy optionally substituted with 1-3 substituents selected from the group consisting of halogen, C. zralkyl, C. zraloxy and cyano; EK" selected from the group consisting of hydrogen, C . 4.zralalkyl, C3.12cycloalkyl- and halogen, while the specified alkyl or cycloalkyl is not necessarily substituted substituted with an oxo, amino, alkylamino or dialkylamino group; and pharmaceutically acceptable salts and solvates thereof. 2. The compound according to claim 1, in which O is a phenyl or b-ch-len heteroaromatic group containing 1-3 nitrogen atoms. 3. The compound according to claim 1, in which K is selected from the group consisting of -СН 5С-ОМН», -С(МН)МН», pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl, -С-ОСН3, -СНоСНОМНОо-ЗОосСНнз, -502СН3, CHНСНоМНЗО»СН», furanylcarbonyl-, methylpyrrolylcarbonyl-, diazolecarbonyl-, azolemethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxoxazolemethyl- or diazolemethyl-. 4. The compound according to claim 1, in which 7K 4 is selected from the group consisting of cyclohexylethyl-, cyclohexylmethyl-, cyclopentylmethyl-, dimethylcyclohexylmethyl-, phenylethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl-, pyridylethyl-, cyclopentyl-, cyclohexyl-, methoxycyclohexyl- , tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyrazolylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl- and oxocanylpropyl-. 5. Compound according to claim 1, in which at least one of 2K. and K is selected from the group consisting of -СНСООМ), о tetrazolylmethyl-, cyanomethyl-, МН»ЗзО»метилю-, МН.зОметилю-, aminocarbonylmethyl-, Сі dalkylaminocarbonylmethyl-, and diСсі lаlkylaminocarbonylmethyl-. 6. The compound according to claim 1, in which AK is 3,3-diphenylpropyl, optionally substituted at the carbon atom with a propyl group -COOM., tetrazolylSoalkyl-, cyano-, aminocarbonyl-, C..alkylaminocarbonyl- or diSi dalkylaminocarbonyl-. at 7. Compound of the formula (MA): Ge») in ; (MA) cha (n) | and - heh M and M - no Gani! SM and" ate - Shchi M o s 20 2 so Kk, where gF) p is an integer from 0 to 3; 7 7 is selected from the group consisting of the bond, -CH 5-, -MH-, -CHNO-, -CHNH»-, -CHNHMH-, -CHNoM(ChNH3)-, -MHneH»e-, -CHNHSOmH -, -МНОНХСО-, -СНХСО-, -СОСНо-, -СНХСОСН»-, -СН(СНУ)-, -СН: and -НС-СН-, where carbon and/or nitrogen atoms are unsubstituted or substituted by lower alkyl, a halogen, hydroxy or alkoxy group; because K is selected from the group consisting of hydrogen, C-4 alkyl, C-4 alkyl, and C3-42 cycloalkyl; Ki is selected from the group consisting of hydrogen, C 4 -alkyl, C 3-10 cycloalkyl, C 1-10 cycloalkyl, C 1-10 -zoalkenyl, amino, C 1-10 alkylamino-, C 1-10 cycloalkylamino-, benzyl, C 34-ocycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, heterobicyclic in ring system and spiro ring system of the formula (M): x that (xx B, x; in which X. and Xo are independently selected from the group consisting of MH, O, 5 and CH"; and in which the indicated alkyl, cycloalkyl, alkenyl, C ..alkylamino, C3.41o2cIykCloalkylamino or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 4-1 alkyl, C 1-10 alkyl, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, and phenyl, benzyl, and benzyloxy are optionally indicated optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-4 alkyl, C1-4 aryloxy and cyano, and in which C3-42 cycloalkyl, C3-42 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring are indicated , the heterobicyclic ring system and the spiro ring system of the formula (M) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1-1 alkyl, C 1-4 alkyl, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, where the specified phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C. zralkilu, C. zralcox and cyano; Co is selected from the group consisting of hydrogen, C 1.4 alkyl, C 1-2 cycloalkyl and halogen, and the specified alkyl is optionally substituted with an oxo group; or pharmaceutically acceptable salts thereof. 8. The compound according to claim 7, in which K/ is alkyl selected from the group consisting of methyl, ethyl, propyl, butyl, peptide and hexyl. 9. The compound according to claim 7, in which Ki is cycloalkyl selected from the group consisting of cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and norbornyl. p. 29 10. The compound according to claim 7, in which K/ represents tetrahydronaphthyl, decahydronaphthyl or dibenzocycloheptyl. heh) 11. The compound according to claim 7, in which Ki is phenyl or benzyl. 12. The compound according to claim 7, in which K/ is a bicyclic aromatic ring. 13. The compound according to claim 12, in which the indicated bicyclic aromatic ring is indenyl, quinoline or naphthyl. 14. The compound according to claim 7, in which 7 is a bond, methyl or ethyl. Sat 30 15. Compound according to claim 7, in which n is equal to 0. yuyu 16. The compound according to claim 7, in which Hu and Ho both represent 0. 17. A compound selected from the group consisting of: b 2-cyanoimino-3-ethyl-1-I(1-(p-phenylbenzyl)-4-piperidinyl/|-1,3-dihydro-2H-benzimidazole; h - 2-cyanoimino-3-ethyl-1-(1-(p-benzyloxybenzyl)-4-piperidinyl-1,3-dihydro-2H-benzimidazole; 35 2-cyanoimino-3-ethyl-1-I1-(naphth- 2-ylmethyl)-4-piperidinyl/|-1,3-dihydro-2H-benzimidazole; - 2-cyanoimino-3-ethyl-1-I(1-(4-propylcyclohexyl)-4-piperidinyl|-1,3 -dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-1-(1-(4-(2-propyl)cyclohexyl|-4-piperidinyl-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3 -ethyl-1-(1-(decahydro-2-naphthyl)-4-piperidinyl-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-1-1-(cyclooctyl)-4-piperidinyl) -1,3-dihydro-2H-benzimidazole; Z t0 2-cyanoimino-3-ethyl-1-I(1-(10,11-dihydro-5H-dibenzo(a,d|cyclohepten-5-yl)-4 2-cyanoimino-3-ethyl-1-(1-(3,3-bis(phenyl)propyl)-4-piperidinyl-1,3 -dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-1-(1-(1,2,3,4-tetrahydronaphthyl)-4-piperidinyl/|-1,3-dihydro -2H-benzimidazole; 2-cyanoimino-3-ethyl-1-1-(5-methylhex-2-yl)-4-piperidinyl)-1,3-dihydro-2H-benzimidazole; 45 2-cyanoimino-3-ethyl-1-(1-(norbornan-2-yl)-4-piperidinyl-1,3-dihydro-2H-benzimidazole; 7 2-cyanoimino-3-ethyl-1-(1- (1,3-dihydroinden-2-yl)-4-piperidinyl|-1,3-dihydro-2H-benzimidazole;-1 2-cyanoimino-3-ethyl-1-1-(cyclooctylmethyl)-4-piperidinyl-1 ,3-dihydro-2H-benzimidazole and its pharmaceutically acceptable salts. 18. A compound selected from the group consisting of: c 20 2-cyanoimino-3-(2-hydroxy)ethyl-1-(1-(cyclooctyl)-4-piperidinyl)-1,3-dihydro-2H- benzimidazole; 2-cyanoimino-3-methoxycarbonylmethyl-1-(1-(cyclooctyl)-4-piperidinyl|-1,3-dihydro-2H-benzimidazole; so 2-cyanoimino-3-cyanomethyl-1-(1-(cyclooctyl)- 4-piperidinyl-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-butyl-1-(1-(cyclooctyl)-4-piperidinyl|-1,3-dihydro-2H-benzimidazole; 2-cyanoimino- 3-(2-methanesulfonamido)ethyl-1-(1-(cyclooctyl)-4-piperidinyl-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-acetamido-1-(1-(cyclooctyl)-4 -piperidinyl/|-1,3-dihydro-2H-benzimidazole; gF) 2-cyanoimino-3-carboxymethyl-1-(1-(cyclooctyl)-4-piperidinyl/|-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-(2-dimethylamino)ethyl-1-|(1-(cyclooctyl)-4-piperidinyl/|-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-1-(/1- (cyclooctyl)-3-hydroxymethyl-4-piperidinyl/|-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-1-(/1-(cyclooctyl)-4-piperidinyl|-1,3-dihydro-2H -7-azabenzimidazole; 60 2-cyanoimino-1-(/1-(cyclooctyl)-2,6-ethan-4-one-4-piperidinyl-1,3-dihydro-2H-benzimidazole; and its pharmaceutically acceptable salts and to solve 19. Pharmaceutical composition containing the compound according to claim 1 and at least one pharmaceutically acceptable excipient. 20. A method of treating pain, comprising administering to a patient in need thereof an effective amount of an analgesic compound according to claim 1. 21. A method of modulating the pharmacological response of the OKI 1 receptor, comprising administering to a patient in need thereof an effective amount of the compound of claim 1. 22. Pharmaceutical composition containing the compound according to claim 7 and at least one pharmaceutically acceptable excipient. 23. A method of treating pain, comprising administering to a patient in need thereof an effective amount of the analgesic compound of claim 7. 24. A method of modulating the pharmacological response of the OKI 1 receptor, comprising administering to a patient in need thereof an effective amount of the compound according to claim 7. 70 25. Compound of the formula (MA): ve ; (MA) hop) he M -M SM i s MI (o) 2 so yu Kk, o» where - p is an integer from 0 to 3; K is selected from the group consisting of hydrogen, C-4 alkyl, C-4 alkyl, and C3-42 cycloalkyl; - Ko is selected from the group consisting of hydrogen, C..alkyl, C.sub.12cycloalkyl and halogen, while the specified alkyl is optionally substituted by an oxo group; 781 represents "no c 1" mi yo 1 h z 2 -i de -I U represents K 3-(C1-C12)alkyl, K/-aryl, Co-heteroaryl, Ke-(C3-C12)cycloalkyl . and Mo is hydrogen or U/; U3 is hydrogen or (C 4 -C 4 )alkyl; or U, Mo and M3, together with the C 20 carbon atom to which they are connected, form one of the following structures: | Kk. 1 F) does not have) 60 b5 -B4- cha or ,; Kv'E 5 i Ky Ko i i Y Sho where g is equal to 0-3; m/ and i are each equal to 0-3, provided that the sum of m and i is equal to 1-3; c and i are each independently equal to 1 or 2; 85 equals 1-5; and ring E is a condensed C)-phenyl or Cb-heteroaryl ring; Ko represents 1-3 substituents independently selected from the group consisting of H, (Cy 4-Cv)alkyl, -OKv, -(C4 -Cv)alkyl-OKav, -MKaKao and -(C4 -Cv)alkyl- MKaCo; Kii represents 1-3 substituents independently selected from the group consisting of K 10, -SEz, -OSEz, MO" and halogen, or K.4 substituents on adjacent ring carbon atoms can together form a ring of methylenedioxy or ethylenedioxy; Ka and Ko are independently selected from the group consisting of hydrogen, (C4-C8)alkyl, (C3-C42)cycloalkyl, aryl and aryl(C4-C8)alkyl; Kz represents 1-3 substituents independently selected from the group consisting of H, Kk 4-aryl, Ke-(C3-C12)cycloalkyl, Co-heteroaryl, K7-(C3-C7)heterocycloalkyl, -MKaCo, -OK 1" and -5X0)0.2Kch12; Ke represents 1-3 substituents independently selected from the group consisting of H, (C 4-C )alkyl, C/-aryl, -MEvKao, "OB" and -8Bch42; with K; represents 1-3 substituents independently selected from the group consisting of hydrogen, halogen, (Ci-Ci)alkyl, C-C-aryl, (C3-C12)cycloalkyl, -CM, -CE3, -OCv, - (C4-Cv)alkyl-OKv, -OSEz, -MEaK»e, -(C4-Cv)alkyl-MKaCo, -МНЗО»Ква, -502МЩ(КИ14)2, -502Кв, -ЗОКв, -ЗКв, -MO », -SOMEaKoa, -MKeSOGK»v, -СооКv, -СОСЕ», -OSOG,B, -OSOVv, -СОокК»v, -(-С4-Св)alkyl-МНСООС(СН»З)з, --С1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -- ' iv) Kk ze Zo where i is equal to 0-6; or Ku substituents on adjacent ring carbon atoms can together form a ring - methylenedioxy or ethylenedioxy; Co is 1-3 substituents independently selected from the group consisting of hydrogen, halogen, (Ci-Ci)alkyl, C-C-aryl, (C3-C12)cycloalkyl, -CM, -CE3, -OCv, - (C4-Cv)alkyl-OKv, -OSEz, -MEaK»e, « 20 -(C4-Cv)alkyl-MKaCo, -MNZO»Ka, -302M(K14)2, -MO», -SOMEKaCoa, -MKeSOK in, -SOKv, -OSOK", -OSOKv8 and -SOOg in; sv KU represents H, (C4-Cv)alkyl, -OKa, -(C4-Cv)alkyl-OKa, -MKaK»o or -(C4-Cv)alkyl-MKaKo; c Ki" represents H, (C 4-Cv)alkyl, C/-aryl, -(C4-Cv)alkyl-OKa, -(C1-Cv)alkyl-MKaCo, -(C41-Cv)alkyl-ZKa or 1" aryl(C.-C.)alkyl; Kiz represents 1-3 substituents independently selected from the group consisting of H, (C.4-C)alkyl, (Ci-C)alkyl, and halogen; - 15 Kia independently selected from the group consisting of H, (C.4-Cv)alkyl and K13-SeH.-CH»n-; or pharmaceutically acceptable salts thereof. -and 26. Pharmaceutical composition containing the compound according to claim 25 and at least one pharmaceutically acceptable co-excipient. 27. A method of treating pain, comprising administering to a patient in need thereof an effective amount of 1 50 of the analgesic compound of claim 25. 28. A method of modulating the pharmacological response of the OKI 1 receptor, comprising administering to a patient in need thereof an effective amount of the compound of claim 25. 29. A method of modulating the pharmacological response of an opioid receptor, comprising administering to a patient in need thereof an effective amount of the compound of claim 1. 30. A method of modulating the pharmacological response of an opioid receptor, comprising administering to a patient in need thereof an effective amount of the compound according to claim 7. 7 31. A method of modulating the pharmacological response of an opioid receptor, comprising administering to a patient in need thereof an effective amount of the compound according to claim 25. 60 b5