RU2426730C2 - Nociceptin analogues - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof

, where D denotes phenyl; n equals 0; A, B and Q denote hydrogen; Z is selected from a group comprising a bond, straight C_1-3alkylene; R₁ is selected from a group comprising hydrogen, C_1-10alkyl, C_3-8cycloalkyl, benzyl, a 6-member monocyclic, 9-10-member bicyclic aromatic carbon-containing ring system and a spiro-ring system of formula

(V): where X₁ and X₃ denote O; and where the said alkyl, cycloalkyl or benzyl from the R₁ group is optionally substituted with 1-3 substitutes selected from a group comprising C_1-3alkyl, cyano, phenyl, wherein the said phenyl is optionally substituted with 1-3 substitutes selected from halogen. The invention also relates to compounds of formulae

.

Values of radicals of the said compounds are given in the claim. The invention also relates to a pharmaceutical composition having ORL1 receptor or µ opioid receptor inhibiting properties, containing an effective amount of the disclosed compound, a method of curing pain and a method of modulating pharmacological response from the opioid receptor, including the ORL1 or µ opioid receptor.

EFFECT: improved method.

41 cl, 5 tbl, 16 ex

Description

BACKGROUND OF THE INVENTION

Chronic pain is the main cause that causes impotence and causes great suffering. Successful treatment of severe and chronic pain is the primary goal of the physician, using opioid analgesics as preferred drugs.

Until recently, it was obvious that the three main classes of opioid receptors exist in the central nervous system (CNS), with each class having receptor subtypes. These receptor classes were designated as µ, δ, and κ. Since opiates have high affinity for these receptors, while not being endogenous to the body, a further study was conducted to identify and isolate endogenous ligands for these receptors. These ligands were identified as enkephalins, endorphins and dinorphins.

Recent experiments have led to the identification of cDNA encoding an opioid receptor-like receptor (ORL1), with a high degree of homology with known classes of receptors. This newly discovered receptor was classified as an opioid receptor only on the basis of its structure, since the receptor did not exhibit pharmacological homology. It was initially shown that non-selective ligands having high affinity for µ, δ and κ receptors have low affinity for ORL1. This characteristic, along with the fact that the endogenous ligand has not yet been discovered, has led to the term “orphan receptor”.

Subsequent research led to the isolation and establishment of the structure of the endogenous ligand of the ORL1 receptor. This ligand is a peptide of seventeen amino acids structurally similar to members of the opioid peptide family.

The discovery of the ORL1 receptor provides the opportunity to discover new compounds for the development of drugs that can be introduced to control pain or other syndromes modulated by this receptor.

All documents cited in this description are included in their entirety by reference for all purposes.

Objectives and summary of the invention

Accordingly, it is an object of certain embodiments of the invention to provide novel compounds that exhibit affinity for the ORL1 receptor.

It is an object of certain embodiments of the invention to provide novel compounds that exhibit affinity for the ORL1 receptor and one or more of the µ, δ or κ receptors.

It is an object of certain embodiments of the invention to provide novel compounds for treating a patient suffering from chronic or acute pain by administering a compound having an affinity for the ORL1 receptor.

The aim of some embodiments of the present invention is the provision of new compounds with agonistic activity against µ, δ and κ receptors, which is greater than that of currently available compounds, for example morphine.

The aim of some embodiments of the present invention is to provide methods for treating chronic or acute pain by administering compounds having agonistic activity on µ, δ and κ receptors, which is greater than that of currently available compounds.

It is an object of certain embodiments of the present invention to provide methods for treating chronic or acute pain by administering non-opioid compounds having agonistic activity on µ, δ and κ receptors and causing fewer side effects than currently available compounds.

The aim of some embodiments of this invention is to provide compounds useful as analgesics, anti-inflammatory drugs, diuretics, anesthetics and neuroprotective agents, antihypertensive agents, sedatives; means for regulating appetite; hearing regulators; cough suppressants, anti-asthma drugs, locomotor modulators, cognitive and memory modulators, neurotransmitter and hormone release regulators, kidney function modulators, antidepressants, drugs for treating memory loss due to Alzheimer's disease or other dementia, anti-epilepsy drugs, anticonvulsants, funds for the treatment of alcohol and drug abstinence, funds for regulating the water balance, funds for regulating I sodium and means for regulating the arterial blood pressure disorders and methods for administering said compounds.

The compounds of this invention are useful for modulating the pharmacodynamic response from one or more opioid receptors (ORL1, µ, δ and κ) of the central and / or peripheral nervous system. The answer can be attributed to a compound that stimulates (agonist) or inhibits (antagonist) one or more receptors. Some compounds may stimulate one receptor (e.g., µ agonist) and inhibit another receptor (e.g., ORL1 antagonist).

Other objectives and advantages of this invention will become apparent from the following detailed description of the invention. The present invention, in some embodiments, includes compounds having the general formula (I):

(I)

Where

D represents a 5-8 membered cycloalkyl, 5-8 membered heterocyclic or 6 membered aromatic or heteroaromatic group;

n represents an integer from 0 to 3;

A, B and Q independently represent hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy, -CH ₂ OH, -NHSO ₂ , hydroxyC _1-10 alkyl- , aminocarbonyl-, C _1-4 alkylaminocarbonyl-, diC _1-4 alkylaminocarbonyl-, acylamino, acylaminoalkyl-, amide, sulfonylaminoC _1-10 alkyl-, or AB together can form a C _2-6 bridge, or BQ together can form a bridge C _3-7 , or AQ together can form a C _1-5 bridge;

Z is selected from the group consisting of a bond, straight or branched C _1-6 alkylene, —NH—, —CH ₂ O—, —CH ₂ NH—, —CH ₂ N (CH ₃ ) -, —NHCH ₂ -, - CH ₂ CONH-, -NHCH ₂ CO-, -CH ₂ CO-, -COCH ₂ -, -CH ₂ COCH ₂ -, -CH (CH ₃ ) -, -CH =, -O- and -HC = CH- in which the carbon and / or nitrogen atoms are unsubstituted or substituted by one or more lower alkyl, hydroxy, halogen or alkoxy groups;

R _{1 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _2-10 alkenyl, amino, C _1-10 alkylamino, C _3-12 cycloalkylamino, -COOV ₁ , -C _1-4 COOV ₁ , cyano, cyanoC _1-10 alkyl-, cyanoC _3-10 cycloalkyl-, NH ₂ SO ₂ -, NH ₂ SO ₂ C _1-4 alkyl-, NH ₂ SOC _1-4 alkyl-, aminocarbonyl- , C _1-4 alkylaminocarbonyl-, diC _1-4 alkylaminocarbonyl-, benzyl, C _3-12 cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system, and spiro-ring system of formula (V) :

(V)

where X ₁ and X _{2 are} independently selected from the group consisting of NH, O, S, and CH ₂ ; and wherein said alkyl, cycloalkyl, alkenyl, C _1-10 alkylamino, C _3-12 cycloalkylamino or benzyl from the group R _{1 is} optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C _1-10 alkyl, C _1-10 alkoxy, nitro, trifluoromethyl-, cyano, -COOV ₁ , -C _1-4 COOV ₁ , cyanoC _1-10 alkyl-, -C _1-5 (= O) W ₁ , -C _{1- 5} NHS (= O) ₂ W ₁ , -C _1-5 NHS (= O) W ₁ , 5-membered heteroaryl C _0-4 alkyl-, phenyl, benzyl, benzyloxy, with said phenyl, benzyl and benzyloxy optionally substituted 1 -3 substituents selected from the group consisting of halogen, C _1-10 alkyl-, C _1-10 alkoxy and cyan about; and wherein said C _3-12 cycloalkyl, C _3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system or spiro ring system of formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, where these phenyl, benzyl, phenyloxy or benzyloxy are optionally substituted with 1-3 substituents selected from the group comp consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy and cyano;

W ₁ represents hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy, -CH ₂ OH, amino, C _1-4 alkylamino, diC _1-4 alkylamino or A 5 membered heteroaromatic ring optionally substituted with 1 to 3 lower alkyls;

V ₁ represents H, C _1-6 alkyl, C _3-6 cycloalkyl, benzyl or phenyl;

R _{2 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl and halogen, wherein said alkyl or cycloalkyl is optionally substituted with oxo, amino, alkylamino or dialkylamino;

and their pharmaceutically acceptable salts and solvates.

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

(IA)

Where

n represents an integer from 0 to 3;

Z is selected from the group consisting of, —CH ₂ -, —NH—, —CH ₂ O—, —CH ₂ CH ₂ -, —CH ₂ NH—, —CH ₂ N (CH ₃ ) -, —NHCH ₂ -, -CH ₂ CONH-, -NHCH ₂ CO-, -CH ₂ CO-, -COCH ₂ -, -CH ₂ COCH ₂ -, -CH (CH ₃ ) -, -CH = and -HC = CH-, in which the carbon and / or nitrogen atoms are unsubstituted or substituted by lower alkyl, halogen, hydroxy or alkoxy;

R _{1 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _2-10 alkenyl, amino, C _1-10 alkylamino, C _3-12 cycloalkylamino, benzyl, C _3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro-ring system of formula (V):

(V)

where X ₁ and X _{2 are} independently selected from the group consisting of NH, O, S, and CH ₂ ;

wherein said monocyclic aryl is preferably phenyl;

wherein said bicyclic aryl is preferably naphthyl;

wherein said alkyl, cycloalkyl, alkenyl, C _1-10 alkylamino, C _3-12 cycloalkylamino or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro , trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, wherein said phenyl, benzyl and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy and cyano;

wherein said C _3-12 cycloalkyl, C _3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro ring system of formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting yaschey of halogen, C _1-10 alkyl, C _1-10 alkoxy, and cyano;

R _{2 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl and halogen, wherein said alkyl is optionally substituted with an oxo group;

and their pharmaceutically acceptable salts and solvates.

In some preferred embodiments of the embodiment of formula (I), D represents a phenyl or 6-membered heteroaromatic group containing 1 to 3 nitrogen atoms.

In some preferred embodiments of the formula (I) or (IA), R ₁ alkyl is methyl, ethyl, propyl, butyl, pentyl or hexyl.

In certain preferred embodiments of the formula (I) or (IA), R ₁ cycloalkyl is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl or norbornyl.

In other preferred embodiments of the formula (I) or (IA), the bicyclic ring system R ₁ is naphthyl. In other preferred embodiments of the formula (I) or (IA), the bicyclic ring system R ₁ is tetrahydronaphthyl or decahydronaphthyl and the tricyclic ring system R ₁ is dibenzocycloheptyl. In other preferred embodiments, R ₁ is phenyl or benzyl.

In other preferred embodiments of the formula (I) or (IA), the bicyclic aromatic ring R ₁ is a 10-membered ring, preferably quinoline or naphthyl.

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

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

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

In other preferred embodiments of the embodiment of formula (I) or (IA), n is 0.

In some embodiments of formula (I) or (IA), X ₁ and X ₂ both represent O.

In some embodiments of formula (I), ZR ₁ is cyclohexylethyl, cyclohexylmethyl, cyclopentylmethyl, dimethylcyclohexylmethyl, phenylethyl, pyrrolyl trifluoroethyl, thienyl trifluoroethyl, pyridylethyl, cyclopentyl, cyclohexyl, methoxyphenyl, cyclohexyl, propyl indolylmethyl-, pyrazolylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl- or oxocanylpropyl.

In some embodiments of formula (I), ZR ₁ is —CH ₂ COOV ₁ , tetrazolylmethyl, cyanomethyl, NH ₂ SO ₂ methyl, NH ₂ SOmethyl, aminocarbonylmethyl, C _1-4 alkylaminocarbonylmethyl, or diC _1-4 alkylaminocarbonylmethyl -.

In some embodiments of Formula (I), ZR ₁ is 3,3-diphenylpropyl optionally substituted at 3 carbon with a propyl group of —COOV ₁ , tetrazolyl C _0-4 alkyl, cyano, aminocarbonyl, C _1-4 alkylaminocarbonyl or diC _1-4- alkylaminocarbonyl-.

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

(Ii)

Where

the dotted line represents an optional double bond;

R represents hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _3-12 cycloalkyl C _1-4 alkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy, C _1-10 alkenyl, C _1-10 alkylidene, oxo, C _1-10 alkyl substituted with 1-3 halogens, C _3-12 cycloalkyl substituted with 1-3 halogens, C _3-12 cycloalkyl C _1-4 alkyl- substituted with 1-3 halogens, C _1-10 alkoxy substituted with 1-3 halogens, C _3-12 cycloalkoxy-, substituted with 1-3 halogens, -COOV ₁ , -C _1-4 COOV ₁ , -CH ₂ OH, -SO ₂ N (V ₁ ) ₂ , hydroxyC _{1- 10} alkyl, hydroxyC _3-10 cycloalkyl, cyanoC _1-10 alkyl, cyanoC _3-10 cycloalkyl, -CON (V ₁ ) ₂ , NH ₂ SO ₂ C _1-4 alkyl, NH ₂ SOC _1-4 alkyl, sulfonylamino C _1-10 alkyl, diaminoalkyl, sul phonyl C _1-4 alkyl, 6-membered heterocyclic ring, 6-membered heteroaromatic ring, 6-membered heterocyclyl C _1-4 alkyl, 6-membered heteroaryl C _1-4 alkyl, 6-membered aromatic ring, 6-membered aryl C _{1- 4} alkyl, 5-membered heterocyclic ring, optionally substituted oxo or thio, 5-membered heteroaromatic ring, 5-membered heterocyclyl C _1-4 alkyl-, optionally substituted oxo or thio, 5-membered heteroaryl C _1-4 alkyl, -C _1-5 (= O) W ₁ , -C _1-5 (= NH) W ₁ , -C _1-5 NHC (= O) W _l , -C _1-5 NHS (= O) ₂ W ₁ , - C _1-5 NHS (= O) W ₁ , where W ₁ represents hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy, -CH ₂ OH, amino, C _1-4 alkylamino, diC _1-4 alkylamino or 5-membered heteroaromatic ring, optionally substituted with 1-3 lower alkyls;

where each V _{1 is} independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, benzyl and phenyl;

n represents an integer from 0 to 3;

D represents a 5-8 membered cycloalkyl, 5-8 membered heterocyclic or 6 membered aromatic or heteroaromatic group;

A, B and Q independently represent hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy, C _1-10 alkenyl, C _1-10 alkylidene, oxo, - CH ₂ OH, -NHSO ₂ , hydroxyC _1-10 alkyl-, aminocarbonyl-, C _1-4 alkylaminocarbonyl-, diC _1-4 alkylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide, sulfonylaminoC _1-10 alkyl-, or AB together can form a C _2-6 bridge, or BQ together can form a C _3-7 bridge, or AQ together can form a C _1-5 bridge;

Z is selected from the group consisting of a bond, straight or branched C _1-6 alkylene, —NH—, —CH ₂ O—, —CH ₂ NH—, —CH ₂ N (CH ₃ ) -, —NHCH ₂ -, - CH ₂ CONH-, -NHCH ₂ CO-, -CH ₂ CO-, -COCH ₂ -, -CH ₂ COCH ₂ -, -CH (CH ₃ ) -, -CH =, -O- and -HC = CH- in which the carbon and / or nitrogen atoms are unsubstituted or substituted by one or more lower alkyl, hydroxy, halogen or alkoxy groups;

R _{1 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _2-10 alkenyl, amino, C _1-10 alkylamino, C _3-12 cycloalkylamino, -COOV ₁ , -C _1-4 COOV ₁ , cyano, cyanoC _1-10 alkyl-, cyanoC _3-10 cycloalkyl-, NH ₂ SO ₂ -, NH ₂ SO ₂ C _1-4 alkyl-, NH ₂ SOC _1-4 alkyl-, aminocarbonyl- , C _1-4 alkylaminocarbonyl, diC _1-4 alkylaminocarbonyl, benzyl, C _3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro ring system of formula (V):

(V)

where X ₁ and X _{2 are} independently selected from the group consisting of NH, O, S, and CH ₂ ; and wherein said alkyl, cycloalkyl, alkenyl, C _1-10 alkylamino, C _3-12 cycloalkylamino or benzyl from the group R _{1 is} optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C _1-10 alkyl, C _1-10 alkoxy, nitro, trifluoromethyl-, cyano, -COOV ₁ , -C _1-4 COOV ₁ , cyanoC _1-10 alkyl-, -C _1-5 (= O) W ₁ , -C _{1- 5} NHS (= O) ₂ W ₁ , -C _1-5 NHS (= O) W ₁ , 5-membered heteroaryl C _0-4 alkyl-, phenyl, benzyl, benzyloxy, with said phenyl, benzyl and benzyloxy optionally substituted 1 -3 substituents selected from the group consisting of halogen, C _1-10 alkyl-, C _1-10 alkoxy and cyan about; and wherein said C _3-12 cycloalkyl, C _3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system or spiro ring system of formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro, triftormetila-, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with 1-3 substituents selected from the groups Consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, and cyano;

R _{2 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl and halogen, wherein said alkyl or cycloalkyl is optionally substituted with oxo, amino, alkylamino or dialkylamino;

and their pharmaceutically acceptable salts and solvates.

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

(IIA)

Where

the dotted line represents an optional double bond;

Z is selected from the group consisting of, —CH ₂ -, —NH—, —CH ₂ O—, —CH ₂ CH ₂ -, —CH ₂ NH—, —CH ₂ N (CH ₃ ) -, —NHCH ₂ -, -CH ₂ CONH-, -NHCH ₂ CO-, -CH ₂ CO-, -COCH ₂ -, -CH ₂ COCH ₂ -, -CH (CH ₃ ) -, -CH = and -HC = CH-, where the carbon and / or nitrogen atoms are unsubstituted or substituted by lower alkyl, halogen, hydroxy or alkoxy;

R and Q are the same or different and each is selected from the group consisting of hydrogen, halogen, C _1-10 alkyl, C _1-10 alkenyl, C _1-10 alkylidene, C _3-12 cycloalkyl, C _1-10 alkoxy and oxo ;

R _{1 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _2-10 alkenyl, amino, C _1-10 alkylamino, C _3-12 cycloalkylamino, benzyl, C _3-12 cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, bicyclic ring system and spiro-ring system of formula (V):

(V)

in which X ₁ and X _{2 are} independently selected from the group consisting of NH, O, S and CH ₂ ;

wherein said monocyclic aryl is preferably phenyl;

wherein said bicyclic aryl is preferably naphthyl;

wherein said alkyl, cycloalkyl, alkenyl, C _1-10 alkylamino, C _3-12 cycloalkylamino or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro , trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, wherein said phenyl, benzyl and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy and cyano;

wherein said C _3-12 cycloalkyl, C _3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro ring system of formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting yaschey of halogen, C _1-10 alkyl, C _1-10 alkoxy, and cyano;

R _{2 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl and halogen, wherein said alkyl is optionally substituted with an oxo group;

and their pharmaceutically acceptable salts.

In some preferred embodiments, Q in formulas (II) or (IIA) is hydrogen or methyl.

In some preferred embodiments, R in formulas (II) or (IIA) is hydrogen, methyl, ethyl or ethylidene.

In some preferred embodiments of the embodiment of formula (II), D represents a phenyl or 6 membered heteroaromatic group containing 1 to 3 nitrogen atoms.

In some preferred embodiments of the formula (II) or (IIA), R ₁ alkyl is methyl, ethyl, propyl, butyl, pentyl or hexyl.

In some preferred embodiments of the formula (II) or (IIA), R ₁ cycloalkyl is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl or norbornyl.

In other preferred embodiments of the formula (II) or (II A) R _{1, the} bicyclic ring system is naphthyl. In other preferred embodiments of the formula (II) or (IIA), R _{1 the} bicyclic ring system is tetrahydronaphthyl or decahydronaphthyl and R _{1 the} tricyclic ring system is dibenzocycloheptyl. In other preferred embodiments, R ₁ is phenyl or benzyl.

In other preferred embodiments of the formula (II) or (IIA) R _{1, the} bicyclic aromatic ring is a 10-membered ring, preferably quinoline or naphthyl.

In other preferred embodiments of the formula (II) or (IIA) R _{1, the} bicyclic aromatic ring is a 9-membered ring, preferably indenyl.

In some embodiments of formula (II) or (IIA), Z is a bond, methyl or ethyl.

In some embodiments of formula (II) or (IIA), the Z group is maximally substituted, so that there is no hydrogen substitution on the main Z group. For example, if the main group Z is —CH ₂ -, when substituted with two methyl groups, the hydrogens of the main —CH ₂ group Z are removed.

In other preferred embodiments of the embodiment of formula (II) or (IIA), n is 0.

In some embodiments of the formula (II) or (IIA), X ₁ and X ₂ both represent O.

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

In some embodiments of formula (II), R is —CH ₂ C (═O) NH ₂ , —C (NH) NH ₂ , pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl, —C (= O) CH ₃ , —CH ₂ CH ₂ NHC (= O) CH ₃ , -SO ₂ CH ₃ , CH ₂ CH ₂ NHSO ₂ CH ₃ , furanylcarbonyl-, methylpyrrolylcarbonyl-, diazolecarbonyl-, azolmethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxoxazolmethyl- or diazolmethyl- .

In some embodiments of Formula (II), ZR ₁ is cyclohexylethyl, cyclohexylmethyl, cyclopentylmethyl, dimethylcyclohexylmethyl, phenylethyl, pyrrolyl trifluoroethyl, thienyl trifluoroethyl, pyridylethyl, cyclopentyl, cyclohexyl, methyryl-tetra-cycloheptyl indolylmethyl-, pyrazolylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl- or oxocanylpropyl.

In some embodiments of formula (II), at least one of ZR ₁ and R is —CH ₂ COOV ₁ , tetrazolylmethyl, cyanomethyl, NH ₂ SO ₂ methyl, NH ₂ SO methyl, aminocarbonylmethyl, C _1-4 alkylaminocarbonylmethyl - or diC _1-4 alkylaminocarbonylmethyl-.

In some embodiments of Formula (II), ZR ₁ is 3,3-diphenylpropyl optionally substituted at 3 carbon with a propyl group of —COOV ₁ , tetrazolyl C _0-4 alkyl, cyano, aminocarbonyl, C _1-4 alkylaminocarbonyl or diC _1-4 alkylaminocarbonyl.

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

(III)

where R is hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _3-12 cycloalkyl C _1-4 alkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy, C _1-10 alkyl, substituted 1- 3 halogens, C _3-12 cycloalkyl substituted with 1-3 halogens, C _3-12 cycloalkyl C _1-4 alkyl, substituted with 1-3 halogens, C _1-10 alkoxy, substituted with 1-3 halogens, C _3-12 cycloalkoxy substituted with 1-3 halogens, -COOV ₁ , -C _1-4 COOV ₁ , -CH ₂ OH, -SO ₂ N (V ₁ ) ₂ , hydroxyC _1-10 alkyl-, hydroxyC _3-10 cycloalkyl-, cyanoC _{1 -10} alkyl-, cyanoC _3-10 cycloalkyl-, -CON (V ₁ ) ₂ , NH ₂ SO ₂ C _1-4 alkyl-, NH ₂ SOC _1-4 alkyl-, sulfonylamino C _1-10 alkyl-, diaminoalkyl-, -sulfonyl C _1-4 alkyl, 6-membered gete a cyclic ring, a 6-membered heteroaromatic ring, a 6-membered heterocyclyl C _1-4 alkyl, a 6-membered heteroaryl C _1-4 alkyl, a 6-membered aromatic ring, a 6-membered _aryl C _1-4 alkyl, a 5-membered heterocyclic ring optionally substituted oxo or thio, 5-membered heteroaromatic ring, 5-membered heterocyclyl C _1-4 alkyl-, optionally substituted oxo or thio, 5-membered heteroaryl C _1-4 alkyl, -C _1-5 (= O) W ₁ , -C _1-5 (= NH) W ₁ , -C _1-5 NHC (= O) W _l , -C _1-5 NHS (= O) ₂ W ₁ , -C _1-5 NHS (= O) W ₁ , where W ₁ represents hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy, —CH ₂ OH, amino, A C _1-4 alkylamino, diC _1-4 alkylamino or 5 membered heteroaromatic ring optionally substituted with 1-3 lower alkyls;

where each V _{1 is} independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, benzyl and phenyl;

n represents an integer from 0 to 3;

D represents a 5-8 membered cycloalkyl, 5-8 membered heterocyclic or 6 membered aromatic or heteroaromatic group;

Z is selected from the group consisting of a bond, straight or branched C _1-6 alkylene, —NH—, —CH ₂ O—, —CH ₂ NH—, —CH ₂ N (CH ₃ ) -, —NHCH ₂ -, - CH ₂ CONH-, -NHCH ₂ CO-, -CH ₂ CO-, -COCH ₂ -, -CH ₂ COCH ₂ -, -CH (CH ₃ ) -, -CH =, -O- and -HC = CH- where the carbon and / or nitrogen atoms are unsubstituted or substituted by one or more lower alkyl, hydroxy, halogen or alkoxy groups; or Z represents a cycloalkylamino system of formula (VI):

(Vi)

where A, B and Q are independently hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy, -CH ₂ OH, -NHSO ₂ , hydroxyC _1-10 alkyl -, aminocarbonyl-, C _1-4 alkylaminocarbonyl-, diC _1-4 alkylaminocarbonyl-, acylamino, acylaminoalkyl-, amide, sulfonylamino C _1-10 alkyl-, or AB together can form a C _2-6 bridge, or BQ together can form bridge C _3-7 , or AQ together can form bridge C _1-5 ;

R _{1 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _2-10 alkenyl, amino, C _1-10 alkylamino, C _3-12 cycloalkylamino, -COOV ₁ , -C _1-4 COOV ₁ , cyano, cyanoC _1-10 alkyl-, cyanoC _3-10 cycloalkyl-, NH ₂ SO ₂ -, NH ₂ SO ₂ C _1-4 alkyl-, NH ₂ SOC _1-4 alkyl-, aminocarbonyl- , C _1-4 alkylaminocarbonyl, diC _1-4 alkylaminocarbonyl, benzyl, C _3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro ring system of formula (V):

(V)

where X ₁ and X _{2 are} independently selected from the group consisting of NH, O, S, and CH ₂ ; and wherein said alkyl, cycloalkyl, alkenyl, C _1-10 alkylamino, C _3-12 cycloalkylamino or benzyl from the group R _{1 is} optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C _1-10 alkyl , C _1-10 alkoxy, nitro, trifluoromethyl-, cyano, -COOV ₁ , -C _1-4 COOV ₁ , cyanoC _1-10 alkyl-, -C _1-5 (= O) W ₁ , -C _1-5 NHS (= O) ₂ W ₁ , -C _1-5 NHS (= O) W ₁ , 5-membered heteroaryl C _0-4 alkyl-, phenyl, benzyl, benzyloxy, wherein said phenyl, benzyl and benzyloxy are optionally substituted with 1- 3 substituents selected from the group consisting of halogen, C _1-10 alkyl-, C _1-10 alkoxy and cyano; and wherein said C _3-12 cycloalkyl, C _3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro ring system of formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, where these phenyl, benzyl, phenyloxy or benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy and cyano;

R _{2 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl and halogen, wherein said alkyl or cycloalkyl is optionally substituted with oxo, amino, alkylamino or dialkylamino;

and their pharmaceutically acceptable salts and solvates.

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

(IIIA)

Where

n represents an integer from 0 to 3;

Z is selected from the group consisting of, —CH ₂ -, —NH—, —CH ₂ O—, —CH ₂ CH ₂ -, —CH ₂ NH—, —CH ₂ N (CH ₃ ) -, —NHCH ₂ -, -CH ₂ CONH-, -NHCH ₂ CO-, -CH ₂ CO-, -COCH ₂ -, -CH ₂ COCH ₂ -, -CH (CH ₃ ) -, -CH =, -HC = CH- and cycloalkylamino systems of the formula (VI):

(Vi)

where the carbon and / or nitrogen atoms are unsubstituted or substituted by lower alkyl, halogen, hydroxy, phenyl, benzyl or alkoxy;

R is selected from the group consisting of hydrogen, C _1-10 alkyl, C _1-10 alkoxy and C _3-12 cycloalkyl;

R _{1 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _2-10 alkenyl, amino, C _1-10 alkylamino, C _3-12 cycloalkylamino, benzyl, C _3-12 cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro-ring system of formula (V):

(V)

in which X ₁ and X _{2 are} independently selected from the group consisting of NH, O, S and CH ₂ ;

wherein said monocyclic aryl is preferably phenyl;

wherein said bicyclic aryl is preferably naphthyl;

wherein said alkyl, cycloalkyl, alkenyl, C _1-10 alkylamino, C _3-12 cycloalkylamino or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro , trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, wherein said phenyl, benzyl and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy and cyano;

wherein said C _3-12 cycloalkyl, C _3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro ring system of formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting yaschey of halogen, C _1-10 alkyl, C _1-10 alkoxy, and cyano;

R _{2 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl and halogen, wherein said alkyl is optionally substituted with an oxo group;

and their pharmaceutically acceptable salts.

In some preferred embodiments of the embodiment of formula (III), D represents a phenyl or 6-membered heteroaromatic group containing 1 to 3 nitrogen atoms.

In certain preferred embodiments of the formula (III) or (IIIA), R ₁ alkyl is methyl, ethyl, propyl, butyl, pentyl or hexyl.

In certain preferred embodiments of the formula (III) or (IIIA), R ₁ cycloalkyl is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl or norbornyl.

In other preferred embodiments of the formula (III) or (IIIA), the bicyclic ring system R ₁ is naphthyl. In other preferred embodiments of formula (III) or (IIIA), the bicyclic ring system R ₁ is tetrahydronaphthyl or decahydronaphthyl and the tricyclic ring system R ₁ is dibenzocycloheptyl. In other preferred embodiments, R ₁ is phenyl or benzyl.

In other preferred embodiments of the embodiment of formula (III) or (IIIA), the bicyclic aromatic ring R ₁ is a 10-membered ring, preferably quinoline or naphthyl.

In other preferred embodiments of the formula (III) or (IIIA), the bicyclic aromatic ring R ₁ is a 9-membered ring, preferably indenyl.

In some embodiments of the formula (III) or (IIIA), Z is a bond, methyl or ethyl.

In some embodiments of formula (III) or (IIIA), the Z group is maximally substituted, so that there is no hydrogen substitution on the main Z group. For example, if the main group Z is —CH ₂ -, when substituted with two methyl groups, the hydrogens of the main —CH ₂ group Z are removed.

In some embodiments of the formula (III) or (IIIA), Z is a cycloalkylamino system of the formula (VI):

(Vi)

wherein the nitrogen atom is optionally substituted with C _1-3 alkyl, phenyl or benzyl.

In other preferred embodiments of the embodiment of formula (III) or (IIIA), n is 0.

In some embodiments of formula (III) or (IIIA), X ₁ and X ₂ both represent O.

In some embodiments of formula (III), R is —CH ₂ C (═O) NH ₂ , —C (NH) NH ₂ , pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl, —C (= O) CH ₃ , —CH ₂ CH ₂ NHC (= O) CH ₃ , -SO ₂ CH ₃ , CH ₂ CH ₂ NHSO ₂ CH ₃ , furanylcarbonyl-, methylpyrrolylcarbonyl-, diazolecarbonyl-, azolmethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxoxazolmethyl- or diazolmethyl- .

In some embodiments of Formula (III), ZR ₁ is cyclohexylethyl, cyclohexylmethyl, cyclopentylmethyl, dimethylcyclohexylmethyl, phenylethyl, pyrrolyl trifluoroethyl, thienyl trifluoroethyl, pyridylethyl, cyclopentyl, cyclohexyl, methoxyphenyl, cyclohexyl, propyl indolylmethyl-, pyrazolylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl- or oxocanylpropyl.

In some embodiments of Formula (III), at least one of ZR ₁ and R is —CH ₂ COOV ₁ , tetrazolylmethyl, cyanomethyl, NH ₂ SO ₂ methyl, NH ₂ SO methyl, aminocarbonylmethyl, C _1-4 alkylaminocarbonylmethyl - or diC _1-4 alkylaminocarbonylmethyl-.

In some embodiments of Formula (III), ZR ₁ is 3,3-diphenylpropyl optionally substituted at 3 carbon with a propyl group of —COOV ₁ , tetrazolyl C _0-4 alkyl, cyano, aminocarbonyl, C _1-4 alkylaminocarbonyl or diC _1-4 alkylaminocarbonyl.

The present invention, in some embodiments, includes compounds having the general formula (IV):

(Iv)

where R is hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _3-12 cycloalkyl C _1-4 alkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy, C _1-10 alkyl, substituted 1- 3 halogens, C _3-12 cycloalkyl substituted with 1-3 halogens, C _3-12 cycloalkyl C _1-4 alkyl, substituted with 1-3 halogens, C _1-10 alkoxy, substituted with 1-3 halogens, C _3-12 cycloalkoxy substituted with 1-3 halogens, -COOV ₁ , -C _1-4 COOV ₁ , -CH ₂ OH, -SO ₂ N (V ₁ ) ₂ , hydroxyC _1-10 alkyl-, hydroxyC _3-10 cycloalkyl-, cyanoC _{1 -10} alkyl-, cyanoC _3-10 cycloalkyl-, -CON (V ₁ ) ₂ , NH ₂ SO ₂ C _1-4 alkyl-, NH ₂ SOC _1-4 alkyl-, sulfonylamino C _1-10 alkyl-, diaminoalkyl-, -sulfonyl C _1-4 alkyl, 6-membered gete a cyclic ring, a 6-membered heteroaromatic ring, a 6-membered heterocyclyl C _1-4 alkyl, a 6-membered heteroaryl C _1-4 alkyl, a 6-membered aromatic ring, a 6-membered _aryl C _1-4 alkyl, a 5-membered heterocyclic ring optionally substituted oxo or thio, 5-membered heteroaromatic ring, 5-membered heterocyclyl C _1-4 alkyl-, optionally substituted oxo or thio, 5-membered heteroaryl C _1-4 alkyl, -C _1-5 (= O) W ₁ , -C _1-5 (= NH) W ₁ , -C _1-5 NHC (= O) W _l , -C _1-5 NHS (= O) ₂ W ₁ , -C _1-5 NHS (= O) W ₁ , where W ₁ represents hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy, —CH ₂ OH, amino, A C _1-4 alkylamino, diC _1-4 alkylamino or 5 membered heteroaromatic ring optionally substituted with 1-3 lower alkyls;

where each V _{1 is} independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, benzyl and phenyl;

D represents a 5-8 membered cycloalkyl, 5-8 membered heterocyclic or 6 membered aromatic or heteroaromatic group;

n represents an integer from 0 to 3;

A, B and Q independently represent hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy, -CH ₂ OH, -NHSO ₂ , hydroxyC _1-10 alkyl- , aminocarbonyl-, C _1-4 alkylaminocarbonyl-, diC _1-4 alkylaminocarbonyl-, acylamino, acylaminoalkyl-, amide, sulfonylaminoC _1-10 alkyl-, or AB together can form a C _2-6 bridge, or BQ together can form a bridge C _3-7 , or AQ together can form a C _1-5 bridge;

Z is selected from the group consisting of a bond, straight or branched C _1-6 alkylene, —NH—, —CH ₂ O—, —CH ₂ NH—, —CH ₂ N (CH ₃ ) -, —NHCH ₂ -, - CH ₂ CONH-, -NHCH ₂ CO-, -CH ₂ CO-, -COCH ₂ -, -CH ₂ COCH ₂ -, -CH (CH ₃ ) -, -CH =, -O- and -HC = CH- where the carbon and / or nitrogen atoms are unsubstituted or substituted by one or more lower alkyl, hydroxy, halogen or alkoxy groups;

R _{1 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _2-10 alkenyl, amino, C _1-10 alkylamino, C _3-12 cycloalkylamino, -COOV ₁ , -C _1-4 COOV ₁ , cyano, cyanoC _1-10 alkyl-, cyanoC _3-10 cycloalkyl-, NH ₂ SO ₂ -, NH ₂ SO ₂ C _1-4 alkyl-, NH ₂ SOC _1-4 alkyl-, aminocarbonyl- , C _1-4 alkylaminocarbonyl, diC _1-4 alkylaminocarbonyl, benzyl, C _3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro ring system of formula (V):

(V)

where X ₁ and X _{2 are} independently selected from the group consisting of NH, O, S, and CH ₂ ; and wherein said alkyl, cycloalkyl, alkenyl, C _1-10 alkylamino, C _3-12 cycloalkylamino or benzyl from the group R _{1 is} optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C _1-10 alkyl , C _1-10 alkoxy, nitro, trifluoromethyl-, cyano, -COOV ₁ , -C _1-4 COOV ₁ , cyanoC _1-10 alkyl-, -C _1-5 (= O) W ₁ , -C _1-5 NHS (= O) ₂ W ₁ , -C _1-5 NHS (= O) W ₁ , 5-membered heteroaryl C _0-4 alkyl-, phenyl, benzyl, benzyloxy, wherein said phenyl, benzyl and benzyloxy are optionally substituted with 1- 3 substituents selected from the group consisting of halogen, C _1-10 alkyl-, C _1-10 alkoxy and cyano; and wherein said C _3-12 cycloalkyl, C _3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro ring system of formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, where these phenyl, benzyl, phenyloxy or benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy and cyano;

R _{2 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl and halogen, wherein said alkyl or cycloalkyl is optionally substituted with oxo, amino, alkylamino or dialkylamino;

and their pharmaceutically acceptable salts and solvates.

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

Where

n represents an integer from 0 to 3;

Z is selected from the group consisting of, —CH ₂ -, —NH—, —CH ₂ O—, —CH ₂ CH ₂ -, —CH ₂ NH—, —CH ₂ N (CH ₃ ) -, —NHCH ₂ -, -CH ₂ CONH-, -NHCH ₂ CO-, -CH ₂ CO-, -COCH ₂ -, -CH ₂ COCH ₂ -, -CH (CH ₃ ) -, -CH = and -HC = CH-, where the carbon and / or nitrogen atoms are unsubstituted or substituted by lower alkyl, halogen, hydroxy or alkoxy;

R is selected from the group consisting of hydrogen, C _1-10 alkyl, C _1-10 alkoxy and C _3-12 cycloalkyl;

R _{1 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _2-10 alkenyl, amino, C _1-10 alkylamino, C _3-12 cycloalkylamino, benzyl, C _3-12 cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro-ring system of formula (V):

(V)

in which X ₁ and X _{2 are} independently selected from the group consisting of NH, O, S and CH ₂ ;

wherein said monocyclic aryl is preferably phenyl;

wherein said bicyclic aryl is preferably naphthyl;

wherein said alkyl, cycloalkyl, alkenyl, C _1-10 alkylamino, C _3-12 cycloalkylamino or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro , trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, wherein said phenyl, benzyl and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy and cyano;

wherein said C _3-12 cycloalkyl, C _3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro ring system of formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting yaschey of halogen, C _1-10 alkyl, C _1-10 alkoxy, and cyano;

R _{2 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl and halogen, wherein said alkyl is optionally substituted with an oxo group;

and their pharmaceutically acceptable salts.

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

In some preferred embodiments of the formula (IV) or (IVA), alkyl R ₁ is methyl, ethyl, propyl, butyl, pentyl or hexyl.

In certain preferred embodiments of the formula (IV) or (IVA), cycloalkyl R ₁ is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl or norbornyl.

In other preferred embodiments of the formula (IV) or (IVA), the bicyclic ring system R ₁ is naphthyl. In other preferred embodiments of the formula (IV) or (IVA), the bicyclic ring system R ₁ is tetrahydronaphthyl or decahydronaphthyl and the tricyclic ring system R ₁ is dibenzocycloheptyl. In other preferred embodiments, R ₁ is phenyl or benzyl.

In other preferred embodiments of the formula (IV) or (IVA), the bicyclic aromatic ring R ₁ is a 10-membered ring, preferably quinoline or naphthyl.

In other preferred embodiments of the formula (IV) or (IVA), the bicyclic aromatic ring R ₁ is a 9 membered ring, preferably indenyl.

In some embodiments of formula (IV) or (IVA), Z is a bond, methyl or ethyl.

In some embodiments of formula (IV) or (IVA), the Z group is maximally substituted, so that there is no hydrogen substitution on the main Z group. For example, if the main group Z is —CH ₂ -, when substituted with two methyl groups, the hydrogens of the main —CH ₂ group Z are removed.

In other preferred embodiments, the embodiments of formula (IV) or (IVA) n is 0.

In some embodiments of formula (IV) or (IVA), X ₁ and X ₂ both represent O.

In some embodiments of formula (IV), R is —CH ₂ C (= O) NH ₂ , —C (NH) NH ₂ , pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl, —C (= O) CH ₃ , —CH ₂ CH ₂ NHC (= O) CH ₃ , -SO ₂ CH ₃ , CH ₂ CH ₂ NHSO ₂ CH ₃ , furanylcarbonyl-, methylpyrrolylcarbonyl-, diazolecarbonyl-, azolmethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxoxazolmethyl- or diazolmethyl- .

In some embodiments of Formula (IV), ZR ₁ is cyclohexylethyl, cyclohexylmethyl, cyclopentylmethyl, dimethylcyclohexylmethyl, phenylethyl, pyrrolyl trifluoroethyl, thienyl trifluoroethyl, pyridylethyl, cyclopentyl, cyclohexyl, methoxyphenyl, cyclohexyl, propyl indolylmethyl-, pyrazolylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl- or oxocanylpropyl.

In some embodiments of formula (IV), at least one of ZR ₁ and R is —CH ₂ COOV ₁ , tetrazolylmethyl, cyanomethyl, NH ₂ SO ₂ methyl, NH ₂ SO methyl, aminocarbonylmethyl, C _1-4 alkylaminocarbonylmethyl - or diC _1-4 alkylaminocarbonylmethyl-.

In some embodiments of Formula (IV), ZR ₁ is 3,3-diphenylpropyl optionally substituted at 3 carbon with a propyl group of —COOV ₁ , tetrazolyl C _0-4 alkyl, cyano, aminocarbonyl, C _1-4 alkylaminocarbonyl or diC _1-4 alkylaminocarbonyl.

In alternative embodiments of formulas (I), (IA), (II), (IIA), (III), (IIIA), (IV) and (IVA) ZR ₁ may be as follows

Where

Y ₁ represents R ₃ - (C ₁ -C ₁₂ ) alkyl, R ₄ aryl, R ₅ heteroaryl, R ₆ - (C ₃ -C ₁₂ ) cycloalkyl, R ₇ - (C ₃ -C ₇ ) heterocycloalkyl, - CO ₂ (C ₁ -C ₆ ) alkyl, CN or —C (O) NR ₈ R ₉ ; Y ₂ represents hydrogen or Y ₁ ; Y ₃ represents hydrogen or (C ₁ -C ₆ ) alkyl; or Y ₁ , Y ₂ and Y ₃ together with the carbon atom to which they are bonded form one of the following structures:

,

,

or

where r is 0-3; w and u each is 0-3, provided that the sum of w and u is 1-3; c and d are each independently 1 or 2; s is 1-5; and ring E is a fused R ₄ phenyl or R ₅ heteroaryl ring;

R ₁₀ represents 1-3 substituents independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, -OR ₈ , - (C ₁ -C ₆ ) alkyl-OR ₈ , -NR ₈ R ₉ and - (C ₁ -C ₆ ) alkyl-NR ₈ R ₉ ;

R ₁₁ represents 1-3 substituents independently selected from the group consisting of R ₁₀ , —CF ₃ , —OCF ₃ , NO ₂ and halogen, or R ₁₁ substituents on adjacent ring carbon atoms together can form a methylenedioxy or ethylenedioxy ring;

R ₈ and R _{9 are} independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₁₂ ) cycloalkyl, aryl and aryl (C ₁ -C ₆ ) alkyl;

R ₃ represents 1-3 substituents independently selected from the group consisting of H, R ₄ aryl, R ₆ - (C ₃ -C ₁₂ ) cycloalkyl, R ₅ -heteroaryl, R ₇ - (C ₃ -C ₇ ) heterocycloalkyl , -NR ₈ R ₉ , -OR ₁₂ and -S (O) _0-2 R ₁₂ ;

R ₆ represents 1-3 substituents independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, R ₄ aryl, —NR ₈ R ₉ , —OR ₁₂ and —SR ₁₂ ;

R ₄ represents 1-3 substituents independently selected from the group consisting of hydrogen, halogen, (C ₁ -C ₆ ) alkyl, R ₁₃ aryl, (C ₃ -C ₁₂ ) cycloalkyl, —CN, —CF ₃ , - OR ₈ , - (C ₁ -C ₆ ) alkyl-OR ₈ , -OCF ₃ , -NR ₈ R ₉ , - (C ₁ -C ₆ ) alkyl-NR ₈ R ₉ , -NHSO ₂ R ₈ , -SO ₂ N (R ₁₄ ) ₂ , -SO ₂ R ₈ , -SOR ₈ , -SR ₈ , -NO ₂ , -CONR ₈ R ₉ , -NR ₉ COR ₈ , -COR ₈ , -COCF ₃ , -OCOR ₈ , - OCO ₂ R ₈ , -COOR ₈ , - (C ₁ -C ₆ ) alkyl-NHCOOC (CH ₃ ) ₃ , - (C ₁ -C ₆ ) alkyl-NHCOCF ₃ , - (C ₁ -C ₆ ) alkyl-NHSO ₂ - (C ₁ -C ₆ ) alkyl, - (C ₁ -C ₆ ) alkyl-NHCONH- (C ₁ -C ₆ ) -alkyl and

where f is 0-6; or R ₄ substituents on adjacent ring carbon atoms together may form a methylenedioxy or ethylenedioxy ring;

R ₅ represents 1-3 substituents independently selected from the group consisting of hydrogen, halogen, (C ₁ -C ₆ ) alkyl, R ₁₃ aryl, (C ₃ -C ₁₂ ) cycloalkyl, —CN, —CF ₃ , - OR ₈ , - (C ₁ -C ₆ ) alkyl-OR ₈ , -OCF ₃ , -NR ₈ R ₉ , - (C ₁ -C ₆ ) alkyl-NR ₈ R ₉ , -NHSO ₂ R ₈ , -SO ₂ N (R ₁₄ ) ₂ , —NO ₂ , —CONR ₈ R ₉ , —NR ₉ COR ₈ , —COR ₈ , —OCOR ₈ , —OCO ₂ R _8, and —COOR ₈ ;

R ₇ represents H, (C ₁ -C ₆ ) alkyl, -OR ₈ , - (C ₁ -C ₆ ) alkyl-OR ₈ , -NR ₈ R ₉ or - (C ₁ -C ₆ ) alkyl-NR ₈ R ₉ ;

R ₁₂ represents H, (C ₁ -C ₆ ) alkyl, R ₄ -aryl, - (C ₁ -C ₆ ) alkyl-OR ₈ , - (C ₁ -C ₆ ) alkyl-NR ₈ R ₉ , - (C ₁ -C ₆ ) alkyl-SR ₈ or aryl (C ₁ -C ₆ ) alkyl;

R ₁₃ represents 1-3 substituents independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy and halogen;

R _{14 is} independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl and R ₁₃ -C ₆ H ₄ -CH ₂ -.

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 of the hydrogen in the —CH ₂ - linear alkyl chain group. The term "lower alkyl" means an alkyl consisting of 1-3 carbon atoms.

The term “alkoxy” means “alkyl,” as defined above, bound 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.

The term "alkenyl" means a linear or branched aliphatic hydrocarbon group containing a double carbon-carbon 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 of the hydrogen in the —CH ₂ - 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 that can be attached to each other or condensed, and containing one radical. Examples of aryl groups include phenyl, naphthyl and acenaphthyl.

The term “heterocyclic” means cyclic compounds having one or more heteroatoms (atoms other than carbon) in the ring and having one radical. The ring may be saturated, partially saturated or unsaturated, and 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 3-6 membered 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. Other heterocyclic groups may be rings of 7-10 carbon atoms substituted with heteroatoms, such as oxocanil and thiocanil. If the heteroatom is sulfur, then the sulfur may be sulfur dioxide, such as thiocanyl dioxide.

The term “heteroaryl” means 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; 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 3-6 membered heteromonocyclic groups containing a sulfur atom, such as thienyl;

unsaturated 3-6 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 fused 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 fused radicals include benzofuran, benzodioxol and benzothiophene.

As used herein, the term “heterocyclylC _1-4 alkyl”, “heteroarylC _1-4 alkyl” and the like refers to a ring structure associated with a C _1-4 alkyl radical.

All cyclic ring structures disclosed herein can be attached at any position where such attachment is possible, as is obvious to a person skilled in the art.

As used herein, the term “patient” includes a human or animal, such as a pet or livestock.

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

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

The invention disclosed herein also encompasses all prodrugs of the disclosed compounds. Prodrugs are any covalently bound carriers that release the active parent drug in vivo .

The invention disclosed herein also encompasses in vivo metabolism products of the disclosed compounds. 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. Accordingly, the invention includes compounds prepared by a process comprising contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof. Such products are usually identified by preparing a radiolabeled compound of the invention, by administering it parenterally in a detectable dose to an animal, such as a rat, mouse, guinea pig, monkey, or human, after a period of time sufficient to undergo metabolism and isolate its conversion products from urine, blood or other biological samples.

The invention disclosed herein also covers 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 isotopes that may be included in the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ² N, ³ N, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl, respectively. Some compounds disclosed in this description may contain one or more asymmetric centers, which leads to the formation of enantiomers, diastereomers and other stereoisomeric forms. The invention also encompasses all such possible forms, as well as their racemic and separated forms and mixtures thereof. If the compounds described in this invention contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise indicated, it is understood that both E and Z geometric isomers are included. It is also understood that all tautomers are encompassed by this invention.

As used herein, the term “stereoisomers” 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 molecule on which its mirror image cannot be superimposed and therefore optically active, in which the enantiomer rotates the plane of polarized light in one 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.

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

The term “modulate”, as used herein, with respect to the ORL1 receptor means mediating the pharmacodynamic response (eg, analgesia) in a subject (i) due to inhibition or activation of the receptor, or (ii) directly or indirectly, due to exposure on the normal regulation of receptor activity. Compounds that modulate receptor activity include agonists, antagonists, mixed agonists / antagonists, and compounds that directly or indirectly influence the regulation of receptor activity.

Specific preferred compounds of formula (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- [1- (p-phenylbenzyl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (p-benzyloxybenzyl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (p-cyanobenzyl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (3,3-diphenylpropyl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- [4,4-bis- (4-fluorophenyl) butyl] -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (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- [1- (5-methylhex-2-yl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (4-propylcyclohexyl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (norbornan-2-yl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (decahydro-2-naphthyl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (3,3-dimethyl-1,5-dioxaspiro [5.5] undeca-9-yl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- [4- (1-methylethyl) cyclohexyl] -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (cyclooctyl) -4-piperidinyl] -2H-benzoxazol-2-one; and

their pharmaceutically acceptable salts and solvates.

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

3-ethylidene-1- [1- (5-methylhex-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethylidene-1- [1- (4-propylcyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

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;

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;

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- [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;

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

1- [1- (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- [1- (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- [1- (5-methylhex-2-yl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

1- [1- (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- [1- (cyclooctylmethyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

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- [4- (1-methylethyl) cyclohexyl] -3-methyl-4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (decahydro-2-naphthyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one; and

their pharmaceutically acceptable salts and solvates.

Specific preferred compounds of formula (III) and (IIIA) include:

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

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;

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

3-ethyl-1- [5- (3-fluorophenyl) -5- (4-fluorophenyl) hexyl] -1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(naphth-2-ylmethyl) ethylamino] cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one;

1- [4- (norbornan-2-ylamino) cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [[4- (1-methylethyl) cyclohexyl] amino] cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(decahydro-2-naphthyl) amino] cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one;

1- [4- (ethylamino) cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one;

1- [4- (benzylamino) cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(indan-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 - [(naphth-2-yl) amino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(p-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;

1- [4 - [(decahydro-2-naphthyl) amino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;

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;

1- [4 - [(p-phenylbenzyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(1,2,3,4-tetrahydronaphthyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(4-propylcyclohexyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(5-methylhex-2-yl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(decahydro-2-naphthyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4- (cyclooctylamino) cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(indan-2-yl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(4-phenylcyclohexyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(5-methylhex-2-yl) amino] cyclohexyl] -7-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one; and

their pharmaceutically acceptable salts and solvates.

Other preferred compounds of formula (IV) and (IVA) 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;

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;

2-cyanoimino-3-ethyl-1- [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 (IV) include:

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;

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;

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;

2-cyanoimino-1- [1- (cyclooctyl) -2,6-ethan-4-one-4-piperidinyl] -1,3-dihydro-2H-benzimidazole; and

and their pharmaceutically acceptable salts and solvates.

The present invention also provides the use of any of the disclosed compounds in the manufacture of a medicament for the treatment of pain and another disease condition modulated by an opioid receptor, for example, the ORL-1 receptor.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention can be administered to any subject in need of modulation of opioid and ORL1 receptors. The introduction can be carried out orally, topically, using a suppository, inhalation or parenteral.

The invention also encompasses all pharmaceutically acceptable salts of the compounds described above. One of skill in the art will recognize that acid addition salts of the compounds of this invention can be prepared by reacting the compounds with suitable acids using a variety of known methods.

Various oral dosage forms may be used, including solid forms such as tablets, gel capsules, capsules, caplets, granules, lozenges and loose powders, and liquid forms such as emulsions, solutions and suspensions. The compounds of this invention may be administered alone or may be combined with various pharmaceutically acceptable carriers and excipients known to one skilled in the art, including, but not limited to, diluents, suspending agents, solubilizers, binders, disintegrants, preservatives, colorants, lubricants and etc.

If the compounds of this invention are included in tablets for oral use, such tablets can be compressed, processed by a tabletting machine, enteric coated, sugar coated, film coated, repeatedly compressed or coated in 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 containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, colorants and perfumes. 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 in a dry aerosol or may be formulated in an aqueous or partially aqueous solution.

In addition, if the compounds of this invention are administered in oral dosage forms, it is understood that such dosage forms can provide immediate release of the compound in the gastrointestinal tract or, alternatively, can provide a controlled and / or delayed release throughout the gastrointestinal tract. intestinal tract. A wide variety 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 delayed release can be achieved, for example, by coating the dosage form for oral administration or by introducing the compound (s) of the invention into a controlled and / or delayed release matrix.

Specific examples of pharmaceutically acceptable carriers and excipients that can be used to prepare dosage forms for oral administration are described in Handbook of Pharmaceutical Excipients , American Pharmaceutical Association (1986). Technologies and compositions for preparing solid dosage forms for oral administration are described in Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) 2nd Edition, published by Marcel Dekker, Inc. Technologies and compositions for the production of tablets (compressed and molded), capsules (hard and soft gelatin) and pills are also described in Remington ^, Pharmaceutical Sciences (Arthur Osol, editor), 1553B1593 (1980). Technologies and compositions for preparing liquid dosage forms for oral administration are described in Pharmaceutical Dosage Forms: Disperse Systems , (Lieberman, Rieger and Banker, editors), published by Marcel Dekker, Inc.

If the compounds of this invention are included in the composition for parenteral administration by injection (for example, continuous infusion or bolus injection), the composition for parenteral administration may be in the form of suspensions, solutions, emulsions in oily or aqueous vehicles, and such compositions may also contain pharmaceutically necessary additives such as stabilizers, suspending agents, dispersing agents, and the like. The compounds of the invention may also be in the form of a powder to be reconstituted in an injection composition.

In specific embodiments, the compounds of this invention can be used in combination with at least one other therapeutic agent. Therapeutic agents include, but are not limited to, µ-opioid agonists; non-opioid analgesics; non-steroidal anti-inflammatory drugs; Cox-II inhibitors; antiemetics; β-adrenergic blockers; anticonvulsants; antidepressants; Ca2 + channel blockers; antitumor agents and mixtures thereof.

In specific embodiments, the compounds of this invention may be formulated into a pharmaceutical dosage form in combination with a µ-opioid agonist. µ-Opioid agonists that may be included in the compositions of this invention include, but are not limited to, alfentanil, allylprodin, alfaprodin, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocin, diamorphon, dihydrocodeine, dihydromorphine, dimenoxadol, dimeheptanol, dimethylthiambutene, dioxafetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazenfentanil, gidroinodiforodinodin, gidroinodin tadone, ketobemidone, levorfanol, levofenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, methopon, morphine, myrofin, nalbuphine, narcein, nicomorphine, norlevorfanol, normetadone, nalorfinporzemporonfin, papormenfon, paporformin, normorphin, papormenfon, papormenfon, poroformin, paporfonormon, porfonormon, porfonormon, porfonormon, papillonin phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, pyritramide, proheptazine, promedol, properidine, propyram, propoxyphene, sufentanil, tilidine, tramadol, their pharmaceutically acceptable salts and mixtures.

In specific preferred embodiments, the µ-opioid agonists are selected from codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, morphine, tramadol, oxymorphone, their pharmaceutically acceptable salts and mixtures thereof.

In another embodiment, the medicament comprises a mixture of a Cox-II inhibitor and a 5-lipoxygenase inhibitor for the treatment of pain and / or inflammation. Suitable Cox-II inhibitors and 5-lipoxygenase inhibitors, as well as combinations thereof, are described in US Patent No. 6136839, which is incorporated herein by reference in its entirety. Cox-II inhibitors include, but are not limited to, rofecoxib (Vioxx), celecoxib (Celebrex), DUP-697, flosulide, meloxicam, 6-MNA, L-745337, nubumeton, nimesulide, NS-398, SC-5766, T -614, L-768277, GR-253035, JTE-522, RS-57067-000, SC-58125, SC-078, PD-138387, NS-398, flosulide, D-1367, SC-5766, PD-164387 , etoricoxib, valdecoxib and parecoxib or their pharmaceutically acceptable salts, enantiomers or tautomers.

The compounds of the present invention can also be combined in dosage forms with non-opioid analgesics, for example, non-steroidal anti-inflammatory drugs, including aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, phenoprofen, flufufen, ketrofrofen, carotenoprofen, phenoprofen, piroprofen, piroprofen, piroprofen, fenrofen, muroprofen, trioxaprofen, suprofen, aminoprofen, thiaprofenic acid, fluprofen, bucloxanic acid, indomethacin, sulindac, tolmetin, zomepirac, thiopinac, zidomethacin, acemet zinc, fentiazac, clidanac, oxspinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenizal, pyroxicam, sudoxic or isoxicam, their pharmaceutically acceptable salts and mixtures thereof. Other suitable non-opioid analgesics that may be included in the dosage forms of the present invention include, but are not limited to, the chemical classes of analgesic, antipyretic, non-steroidal anti-inflammatory drugs: salicylic acid derivatives, including aspirin, sodium salicylate, cholinomagnesium trisalicyl dialsalicylate, salisalicylate acid, sulfasalazine and olsalazine; para-aminophenol derivatives, including acetaminophen; indole and indene acetic acids, including indomethacin, sulindac and etodolac; heteroaryl acetic acids, including tolmetin, diclofenac and ketorolac; Anthranilic acids (phenamates), including mefenamic acid and meclofenamic acid; enolic acids, including oxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone, oxyfentartazone); and alkanones, including nabumeton. For a more detailed description of NSAIDs that can be included in drugs used in accordance with this invention, see Paul A. Insel Analgesic-Antipyretic and Anti-Inflammatory Agents and Drugs Employed in the treatment of Gout in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 617-57 (Perry B. Molinhoffand Raymond W. Ruddon, Eds., Ninth Edition, 1996), and Glen R. Hanson Analgesic, Antipyretic and Anti-Inflammatory Drugs in Remington: The Science and Practice of Pharmacy Vol II, 1196-1221 (AR Gennaro, Ed. 19th Ed. 1995), which are incorporated herein by reference in their entirety.

In some embodiments, the compounds of this invention may be formulated in pharmaceutical dosage form in combination with anti-migraine drugs. Migraine medications include, but are not limited to, alpiroprid, dihydroergotamine, dolasetron, ergocornin, ergocorninin, ergocriptine, ergot, ergotamine, flumedroxone acetate, phonazine, lysuride, lomerizine, metisergide oxetorone, and pisotiline and pisotiline.

Another therapeutic agent may also be an adjuvant to reduce potential side effects, such as an antiemetic. Suitable antiemetic agents include, but are not limited to, metoklopromid, domperidon, prohlorperazin, prometazin, hlorpromazin, trimeobenzamid, ondansetron, granisetron, gidroksizin, atsetilleytsinmonoetanolamin, alizaprid, azasetron, benzhinamid, bietanautin, bromoprid, buklizin, kleboprid, cyclizine, dimengidrinat, difenidol, dolasetron, meklizin, metal, metopimazine, nabilon, hydroxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocananopyrol, thiazopyr,

In some embodiments, the compounds of this invention may be formulated in a pharmaceutical dosage form in combination with β-adrenergic blockers. Suitable β-adrenergic blockers include, but are not limited to, atsebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol, betaksolol, bevantolol, bisoprolol, bopindolol, bukumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butidrina gidrohlorid, butofilolol, karazolol, karteolol , karvedilol, tseliprolol, tsetamolol, kloranolol, dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoksolol, nebivalol, nifenalol, nipradilol, oksprenolol, penbutolol, pindolol, praktolol, pronetalol, propranolol , sotalol, s ulfinolol, talinolol, tertatolol, tilisolol, timolol, toliprolol and xibenolol.

In some embodiments, the compounds of this invention may be formulated in pharmaceutical dosage form in combination with anticonvulsants. Suitable anticonvulsants include, but are not limited to, atsetilfeneturid, albutoin, aloksidon, aminoglutetimid, 4-amino-3-gidroksimaslyanuyu acid atrolaktamid, beklamid, buramat, calcium bromid, karbamazepin, tsinromid, klometiazol, klonazepam, detsimemid, dietadion, dimetadion, doksenitroin, eterobarb, etadion, etosuksimid, etotoin, felbamat, fluorezon, gabapentin, 5-gidroksitriptofan, lamotrigin, magnesium bromid, magniya sulfat, mefenitoin, mefobarbital, metarbital, metetoin, metsuksimid, 5-methyl-5- (3-fenantril) gidantoin , 3-methyl-5-phenylhydantoin, narcobarbital, nimetazepam, nitrazepa m okskarbazepin, parametadion, fenatsemid, fenetarbital, feneturid, fenobarbital, fensuksimid, fenilmetilbarbiturovuyu acid fenitoin sodium fetenilat, potassium bromid, pregabalin, primidon, progabid sodium bromid, solanum, strontium bromid, suklofenid, sultiam, tetrantoin, tiagabin, topiramat , trimethadione, valproic acid, valpromide, vigabatrin and zonisamide.

In some embodiments, the compounds of this invention may be formulated in a pharmaceutical dosage form in combination with anti-depressants. Suitable antidipressanty include, but are not limited to, binedalin, karoksazon, tsitalopram, dimetazan, fenkamin, indalpin, indeloksazina gidroholorid, nefopam, nomifenzin, oksitriptan, oksipertin, paroksetin, sertralin, tiazesim, trazodon, benmoksin, iproklozid, iproniazid, izotsarboksazid, nialamid, oktamoksin, fenelzin, kotinin, rolitsiprin, rolipram, maprotilin, metralindol, mianserin, mirtazepin, adinazolam, amitriptilin, amitriptilinoksid, amoksapin, butriptilin, klomipramin, demeksiptilin, dezipramin, dibenzepin, dimetakrin, dotiepin, doksepin, fluatsizin, imipramin, imipramin N-ca. id, iprindol, lofepramin, melitratsen, metapramin, nortriptilin, noksiptilin, opipramol, pizotilin, propizepin, protriptilin, hinupramin, tianeptin, trimipramin, adrafinil, benaktizin, bupropion, butatsetin, dioksadrol, duloksetin, etoperidon, febarbamat, femoksetin, fenpentadiol, fluoksetin, fluvoksamin, gematoporfirin, giperitsin, levofatsetoperan, medifoksamin, milnatsipran, minaprin, moklobemid, nefazodon, oksaflozan, piberalin, prolintan, pirisuktsideanol, ritanserin, roksindol, rubidium chloride, sulpirid, tandospiron, tozalinon, tofenatsin, toloksaton, traniltsipromin, L-triptofan, venlafaksin , viloxazine and wintering.

In some embodiments, the compounds of this invention may be formulated in pharmaceutical dosage form in combination with Ca2 + channel blockers. Suitable blockers Ca2 + channels include, but are not limited to, bepridil, klentiazem, diltiazem, fendilin, gallopamil, mibefradil, prenilamin, semotiadil, terodilin, verapamil, amlodipin, aranidipin, barnidipin, benidipin, cilnidipine, efonidipin, elgodipin, felodipin, isradipin, lacidipine, lercanidipine, manidipine, nikardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazin, lomerizin, benzofinfinzin

In some embodiments, the compounds of this invention may be formulated in pharmaceutical dosage form in combination with antitumor agents. Suitable antitumor agents include, but are not limited to, acivicin; aclarubicin; acodazole hydrochloride; acronine; azodelesin; aldeleykin; altretamine; ambomycin; amethronet acetate; aminoglutetimide; amsacrin; anastrozole; antramycin; asparaginase; asperlin; azacitidine; technician; azotomycin; batimastat; benzenedep; bicalutamide; bisanthrene hydrochloride; bisnaphide dimethylate; biselesin; bleomycin sulfate; brequinar sodium; bropyrimine; busulfan; actinomycin; calusteron; carocemide; carbimeter; carboplatin; karmustin; carubicin hydrochloride; carleselin; decodingol; chlorobambyl; cirolemicin; cisplatin; cladribine; cresnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanin; dezaguanina mesylate; diazikhon; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; the propeller is proprietary; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enterprise; epipropidine; epirubicin hydrochloride; erbulosol; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; ethanidazole; etoposide; etoposide phosphate; etoprin; fadrozole hydrochloride; phazarabin; phenretinide; phoxuridine; fludarabine phosphate; fluorouracil; fluorocytabin; phoschidon; sodium frusticin; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosin; interleukin II (including recombinant interleukin II or rIL2), alpha-2a interferon; alpha-2b interferon; interfer alpha-n1; interfer alpha-n3; beta-Ia interferon; gamma-Ib interferon; iproplatin; irinotecan hydrochloride; lanreotide acetate; lethrosol; leuprolide acetate; lyarosol hydrochloride; sodium lomethrexol; lomustine; losoxantrone hydrochloride; masoprotsol; maytansine; mechlortamine hydrochloride; megestrol acetate; melangestrol acetate; Melfalan; menogar; mercaptopurine; metrexate; sodium metrexate; metoprin; methodology; mitindomide; mitocarcin; mitocromine; mitogillin; mitomalcin; mitomycin; mitosper; Mitotan; Mitoxantrone hydrochloride; mycophenolate acid; Nokodazole; namalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipomania; piposulfan; pyroxanthrone hydrochloride; plicamycin; place; sodium porphymer; porphyromycin; prednimustin; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprin; roglimate; saffolol; safingola hydrochloride; semustine; simtrazen; sodium sparfosate; sparsomycin; spirogermania hydrochloride; spiramustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talizomycin; tecogalan sodium; tegafur; teloxanthron hydrochloride; temporfin; teniposide; Teroxiron; testosterone; thiamiprine; thioguanine; thiotepa; thiazofurin; tirapazamine; toremifene citrate; trust aceton; tricyribine phosphate; trimetrexate; trimetrexate glucuronate; tryptorelin; tubulose hydrochloride; uracil mustard; uredepa; varotoid; vertoporfin; vinblastine sulfate; vincristine sulfate; vincine; vincine sulfate; vinpidine sulfate; Winglicinate Sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidene sulfate; vinzolidine sulfate; plume; zeniplatin; zinostatin; zorubicin hydrochloride. Other antitumor agents include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethinyluracyl; an aboneron; aclarubicin; acyl fulven; acipenecene; azodelesin; aldeleykin; antagonists of ALL-TK; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrin; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; Antarelix; anti-dorsalizing morphogenetic protein-1; anti-androgen, anti-carcinoma agent; antiestrogen; anti-plastion; antisense oligonucleotides; apidicoline glycinate; gene modulators of aptosis; apoptosis regulators; apuric acid; ara-CDP-DL-PTBA; arginine deaminaminase; asulacrine; atamestan; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; asacetron; azatoxin; azathyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorins; benzoyl staurosporine; beta-lactam derivatives; beta-alethine; Beta-Clamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantren; bisaziridinylspermin; bisnaphide; Bistran A; biselesin; breflat; bropyrimine; awakened; butyonin sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canaripox IL-2; capecitabine; carboxamidaminotriazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage inhibitor; carleselin; casein kinase inhibitors (ICOS); castanospermine; Cecropin B; centrelix; chlorins; chloroquinoxaline sulfonamide; cycloprost; cis-porphyrin; cladribine; analogues of clomiphene; clotrimazole; collismicin A; collismicin B; combretastatin A4; analogues of combretastatin; konagenin; krambescidin 816; credit card; cryptophycin 8; Cryptophycin A derivatives; Curecin A; cyclopentantraquinones; cycloplatam; cypemycin; cytarabine okfosfat; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; desorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; diazichion; didemnin B; didox; diethylnospermine; dihydro-5-azacitidine; dihydrotaxol, 9-; dioxamycin; diphenylspiramustine; docetaxel; proved; dolcetron; doxifluuridine; droloxifene; dronabinol; duocarmycin SA; ebselin; eco -ustin; edelphosin; edrecolomab; eflornithine; email; emitfur; epirubicin; episteride; estramustine analogue; estrogen agonists; estrogen antagonists; ethanidazole; etoposide phosphate; exemestane; fadrozol; phazarabin; phenretinide; filgrastim; finasteride; flavopyridol; fleselastine; fluoster; fludarabine; fluorodaunorunicin hydrochloride; Forimenimeks; formestan; frusticin; photemustine; gadolinia texafirin; gallium nitrate; halocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; Hepsulfam; geregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramanton; ilmofosin; slurry; imidazoaacridones; imichimod; immunostimulating peptides; an insulin-like factor-1 receptor inhibitor; agonists of the interferon; interferons; interleukins; Iobenguang; iodoxorubicin; ipomeanol, 4-; iroplact; irsogladin; isobenzazole; iso-homogalicindrin B; itetron; jasplacinolide; Kagalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; lethrosol; a factor inhibiting leukemia; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprorelin; levamisole; lyarozol; linear analogue of poliamine; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricin; lomethrexol; lonidamine; losoxanthron; lovastatin; loxoribine; lurotekan; lutetia texafirin; lysophylline; lytic peptides; maytansine; mannostatin A; marimastat; Maspropol; maspin; matrilysin inhibitors; matrix inhibitors of metalloproteinase; menogar; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepriston; miltefosine; myrimostim; mismatching double-stranded RNA; mitogauzone; mitolactol; mitomycin analogues; mitonafid; mitotoxin growth factor fibroblastov-saporin; mitoxanthron; mofaroten; lightweight; monoclonal antibody, human chorionic gonadotrophin; monophosphoril lipid A + myobacterial membrane cell preparation sk; mopidamol; multidrug resistance gene inhibitor; therapeutic agent for suppressing multiple tumors-1; mustard anti-cancer agent; micaperoxide B; mycobacterial cell membrane extract; Mirioporone; N-acetyldydalin; N-substituted benzamides; nafarelin; grease; naloxone + pentazocin; napavin; naphtherpin; sap; nedaplatin; nemorubicin; non-hydronic acid; neutral endopeptidase; nilutamide; nizamycin; modulators of nitric oxide; nitroxide antioxidant; nitrulline; O6-benzylguanine; octreotide; okitson; oligonucleotides; onion; unansetron; unansetron; oracin; oral cytokine inducer; ormaplatin; ozterone; oxaliplatin; oxaunamycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrizoxin; pamidrononic acid; panaxitriol; pan-mifen; parabactin; paselliptin; pegaspargase; peldesin; sodium polysulfate pentosan; pentostatin; pentrosol; perflubo; perfosfamide; peryl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; pitsibanil; pilocarpine hydrochloride; pyrarubicin; pyritexime; placentin A; placentin B; plasminogen activator inhibitor; complex platinum; plate connections; the complex of platin triamine; sodium permeer; porphyromycin; prednisone; propylbis acridone; prostaglandin J2; protease inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinucleoside phosphorylase inhibitors; purpurins; pyrazoloaacridine; pyridoxylated conjugate of hemoglobin-polyoxyethylene; antagonists raf; Raltitrexed; Ramsetron; inhibitors of pharnesyl protein transferase ras; ras inhibitors; ras-GAP inhibitor; demethylated retelliptin; ethene rhenium Re 186; rhizoxin; ribozymes; RII retinamide; roglimate; rohitukin; romurtide; Rochinimex; rubiginon B1; ruboxyl; saffolol; sayntopin; SarCNU; sarcophytol A; sargramostim; mimetics Sdi 1; semustine; derivative inhibitor 1 aging; semantic oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; sobuzoxan; sodium borobactate; sodium phenylacetate; solver; co-medomedin binding protein; sonmin; sparfosinic acid; spicamycin D; spiramustine; splenopentin; spongistatin 1; schialamine; stem cell inhibitor; stem cell division inhibitors; stypyamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonin; synthetic glycosaminoglycans; tallymustine; tamoxifena methiodide; tauromustine; tazaroten; tekogalannatry; tegafur; tellurium; telomerase inhibitors; temporfin; temozolomide; teniposide; tetrachloride decahoxide; tetrazamine; taliblastine; thiocoralin; thrombopoietin; mimetics of thrombopoietin; thymalfazine; thymopoietin receptor agonist; thymotrine; thyroid stimulating hormone; ethyltin ethiopurpurine; tirapazamine; titanocene bichloride; topsentin; toramifen; stem cell multipotential factor; translation inhibitors; tretinoin; triacetyluridine; tricyribine; trimetrexate; tryptorelin; chart recorder; tourasteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimeks; inhibitor of the urogenital sinus growth factor; urokinase receptor antagonists; varotoid; variolin B; vector system, erythrocytogenic therapy; Velarezol; veramine; verdes; vertoporfin; vinorelbine; winxaltin; Vitaxin; plume; zanoteron; zeniplatin; Zilaskorb and Zinostatin stimulamer.

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

In the case of administration of the compounds of this invention to mammals, for example, by the oral, parenteral or topical route, a dosage in the range of from about 0.01 mg / kg to about 3000 mg / kg of the patient’s body weight per day, preferably from about 0.01 mg, can be used. / kg to about 1000 mg / kg of body weight per day, which is administered in single or divided doses. However, the dosage must be changed depending on the weight and physical condition (for example, liver and kidney function) of the subject being treated, the suffering caused, the severity of the symptoms, route of administration, dose frequency, the presence of any harmful side effects and, inter alia, the particular compound used .

The compounds of this invention preferably have a K _i binding affinity for the human ORL1 receptor of about 500 nM or less; 100 nM or less; 50 nM or less; 20 nM or less or 5 nM or less. The binding affinity of K _i can be measured by a person skilled in the art by analysis using membranes from recombinant HEK-293 cells expressing a receptor similar to a human opioid receptor (ORL1), as described below.

The following examples illustrate various aspects of the present invention and in no way claim to be limiting.

Example 1

Synthesis of benzoxazolone head groups

The head groups in accordance with this invention were synthesized in accordance with the following procedure:

Methodology

To a mixture of compounds 1 (1.09 g, 10 mmol), 2 (1.99 g, 10 mmol) and acetic acid (0.60 g, 10 mmol) in 50 ml of dichloroethane was added sodium triacetoxyborohydride (2.97 g, 14 mmol). The mixture was stirred at room temperature overnight. The mixture was filtered through celite and 1N NaOH (50 ml) 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 over K ₂ CO ₃ , filtered and evaporated in vacuo to give compound 3 as a brown solid (2.75 g, yield: 94%).

¹ H-NMR (CDCl ₃ ): d 1.20-1.60 (m, 11H), 2.00 (dd, 2H), 2.9 (m, 2H), 3.40 (m, 1H), 4.00 (m, 2H); 6.60-6.85 (m, 4H).

To a ice-cooled solution of crude compound 3 (12.0 g, 40 mmol) and DIEA (20.8 ml, 120 mmol) in 200 ml of THF was added a solution of triphosgene (4.32 g, 14.4 mmol) in 200 ml of THF. After complete addition, the ice bath was removed and the mixture was stirred at room temperature overnight. The solids were filtered off and the filtrate was evaporated in vacuo. The remaining brown oil was dissolved in EtOAc and washed with saturated aqueous K ₂ CO ₃ . The organic phase was dried over K ₂ CO ₃ , filtered and evaporated in vacuo to give a red oil, which was filtered through a silica gel column, eluting with a mixture of 5% Et ₃ N, 25% EtOAc and 70% hexane. The selected fractions were combined and the solvent was evaporated in vacuo to give a brown solid, which was crystallized from EtOAc to give pure compound 4 (10.0 g, yield: 78%).

¹ H-NMR (CDCl ₃ ): d 1.50 (s, 9H), 1.85 (d, 2H), 2.25 (m, 2H), 2.85 (m, 2H), 4.20- 4.45 (m, 3H); 7.00-7.25 (m, 4H).

A solution of compound 4 (4.0 g, 17.2 mmol) in a mixture of 30% TFA / dichloromethane (25 ml) was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo and a saturated aqueous solution of K ₂ CO _{3 was} added to the oily residue. The resulting mixture was extracted with dichloromethane (3 x 50 ml). The combined organic extracts were dried over K ₂ CO ₃ , filtered and evaporated in vacuo to give a crude product. Silica gel chromatography eluting with a mixture of 10% Et ₃ N, 60% EtOAc and 30% hexane afforded compound 5 as a yellow solid (1.82 g, yield: 66%).

MS: m / z 450

¹ H-NMR (CDCl ₃ ): d 1.75-2.10 (m, 3H), 2.30 (d, 2H), 2.80 (m, 2H), 3.20 (m, 2H), 4.25 (m, 1H); 7.00-7.25 (m, 4H).

Example 2

End group attachment

End groups were attached to the head groups in accordance with the following methods:

Basic procedure for alkylation:

To a solution of amine (1 equivalent) and triethylamine (1 equivalent) in dimethylformamide, 1 equivalent was added in one portion. alkyl bromide or chloride. The mixture was stirred and heated at 80 ° C. overnight. TLC indicated completion of the reaction. The reaction was quenched by the addition of water, followed by adjusting the pH to 10 with 1N NaOH. The mixture was extracted twice with Et ₂ O. The combined organic extracts were dried over potassium carbonate and the solvent was evaporated, followed by chromatography to give a pure product.

Basic procedure for reductive amination:

To a mixture of ketone or aldehyde (1 equivalent), amine (1 equivalent) and acetic acid (1 equivalent) in methanol, sodium cyanoborohydride (1.4 equivalent) was added in one portion. The mixture was stirred at room temperature overnight. TLC indicated completion of the reaction. The reaction was quenched by the addition of water, followed by adjusting the pH to 10 with 1N NaOH. The mixture was extracted twice with Et ₂ O. The combined organic extracts were dried over potassium carbonate and the solvent was evaporated, followed by chromatography to give a pure product.

The following compounds were prepared by attachment of end groups using the described basic procedures:

3- [1- (naphth-2-ylmethyl) -4-piperidinyl] -2H-benzoxazol-2-one

3- [1- (naphth-1-ylmethyl) -4-piperidinyl] -2H-benzoxazol-2-one

3- [1- (p-phenylbenzyl) -4-piperidinyl] -2H-benzoxazol-2-one

3- [1- (p-benzyloxybenzyl) -4-piperidinyl] -2H-benzoxazol-2-one

3- [1- (p-cyanobenzyl) -4-piperidinyl] -2H-benzoxazol-2-one

MS: m / z 334.4 (M + 1)

3- [1- (3,3-diphenylpropyl) -4-piperidinyl] -2H-benzoxazol-2-one

3- [1- [4,4-bis- (4-fluorophenyl) butyl] -4-piperidinyl] -2H-benzoxazol-2-one

MS: m / z 463.6 (M + 1)

3- [1- (2-phenylethyl) -4-piperidinyl] -2H-benzoxazol-2-one

3- [1- (cyclooctylmethyl) -4-piperidinyl] -2H-benzoxazol-2-one

LC: 100%

MS: m / z 343.6 (M + 1)

¹ H-NMR (CDCl ₃ ): d 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).

¹³ C-NMR (CDCl ₃ ): d 26.02, 26.87, 27.55, 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.

3- [1- (1,2,3,4-tetrahydro-2-naphthyl) -4-piperidinyl] -2H-benzoxazol-2-one

LC: 100%

MS: m / z 349.6 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.70 (m, 1H), 2.00 (broad, 2H), 2.10 (broad, 1H), 2.40 (m, 4H), 2, 90 (m, 5H), 3.10 (m, 2H), 4.20 (m, 1H), 7.10-7.30 (m, 8H).

3- [1- (5-methylhex-2-yl) -4-piperidinyl] -2H-benzoxazol-2-one

LC: 100%

MS: m / z 317.4 (M + 1)

¹ H-NMR (CDCl ₃ ): d 0.90 (d, 6H), 1.00 (d, 3H), 1.20 (m, 3H), 1.50-1.60 (m, 4H), 1.80 (m, 2H), 2.20-2.60 (m, 5H), 2.90 (br., 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

LC: 96.4%

¹ H-NMR (CDCl ₃ ): d 1.80 (dd, 2H), 2.00 (dt, 2H), 2.30 (dq, 2H), 2.80-2.95 (m, 4H), 4.01 (s, 1H); 4.05-4.22 (m, 3H); 7.05-7.25 (m, 12H).

3- [1- (4-propylcyclohexyl) -4-piperidinyl] -2H-benzoxazol-2-one

MS: m / z 343.0

3- [1- (norbornan-2-yl) -4-piperidinyl] -2H-benzoxazol-2-one

LC: 97%

MS: m / z 313.41 (M + 1)

¹ H-NMR (CDCl ₃ ): d 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: m / z 355.4

3- [1- (3,3-dimethyl-1,5-dioxaspiro [5.5] undeca-9-yl) -4-piperidinyl] -2H-benzoxazol-2-one

MS: m / z 401.3

3- [1- [4- (1-methylethyl) cyclohexyl] -4-piperidinyl] -2H-benzoxazol-2-one

MS: m / z 343.0

3- [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -2H-benzoxazol-2-one

LC: 100%

MS: m / z 335.4 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.90 (m, 1H), 2.40 (m, 2H), 2.50 (m, 2H), 2.90 (m, 2H), 3.10- 3.40 (m, 6H); 4.20 (m, 1H); 7.10-7.30 (m, 8H).

3- [1- (cyclooctyl) -4-piperidinyl] -2H-benzoxazol-2-one

LC: 100%

MS: m / z 329.2 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.40-2.00 (m, 16H), 2.40-2.65 (m, 4H), 2.80 (m, 1H), 3.05 (m , 2H); 4.25 (m, 1H); 7.10-7.40 (m, 4H).

Other compounds encompassed by formula (I) or (IA) of the present invention can be synthesized by similar methods.

Example 3

The nociceptin affinity for the ORL1 receptor for the preferred compounds was determined using the following assay:

Membranes of recombinant HEK-293 cells expressing a receptor similar to a human opioid receptor (ORL1), (Receptor Biology), were obtained by lysing cells in ice-cold hypotonic buffer (2.5 mm MgCl ₂ , 50 mm HEPES, pH 7.4) (10 ml / 10 cm Petri dish) followed by homogenization using a tissue homogenizer / teflon pestle. Membranes were collected by centrifugation at 30,000 xg for 15 min at 4 ° C and the pellet after centrifugation was resuspended in hypotonic buffer to a final concentration of 1-3 mg / ml. Protein concentrations were determined using BioRad protein reagent with bovine serum albumin as standard. Aliquots of ORL1 receptor membranes were stored at -80 ° C.

Functional binding assays of SGTPgS were performed as follows. The ORL1 membrane solution was prepared by sequentially adding final concentrations of 0.066 mg / ml ORL1 membrane protein, 10 mg / ml saponin, 3 mM GDP and 0.20 nM [ ³⁵ S] GTPgS to binding buffer (100 mM NaCl, 10 mM MgCl ₂ , 20 mM HEPES, pH 7.4) on ice. The resulting membrane solution (190 ml / well) was transferred into 96-well polypropylene plates containing 10 ml of 20x concentrated stock solutions of agonist obtained in DMSO. The plates were incubated for 30 minutes at room temperature with shaking. The reactions were terminated by rapid filtration on 96-well Unifilter GF / B filter plates (Packard) using a 96-well tissue harvester (Brandel) followed by three filter washes with 200 ml of ice-cold binding buffer (10 mM NaH ₂ PO ₄ , 10 mM Na ₂ HPO ₄ , pH 7.4). The filter plates were then dried at 50 ° C for 2-3 hours. Fifty ml / well of scintillation count cocktail (BetaScint; Wallac) was added and the plates were read on a Packard Top-Count for 1 min / well.

Data was analyzed using an approximation of the functional dependence curve in GraphPad PRISMO, v.3.0, and the results are presented in table 1 below:

TABLE 1
Nociceptin Affinity Compound calculation K _i  (nM) 3- [1- (naphth-2-ylmethyl) -4-piperidinyl] -2H-benzoxazol-2-one 3030 3- [1- (naphth-1-ylmethyl) -4-piperidinyl] -2H-benzoxazol-2-one 370 3- [1- (p-phenylbenzyl) -4-piperidinyl] -2H-benzoxazol-2-one > 10,000 3- [1- (p-benzyloxybenzyl) -4-piperidinyl] -2H-benzoxazol-2-one 2173 3- [1- (p-cyanobenzyl) -4-piperidinyl] -2H-benzoxazol-2-one > 10,000 3- [1- (3,3-diphenylpropyl) -4-piperidinyl] -2H-benzoxazol-2-one 726 3- [1- [4,4-bis- (4-fluorophenyl) butyl] -4-piperidinyl] -2H-benzoxazol-2-one 3070 3- [1- (2-phenylethyl) -4-piperidinyl] -2H-benzoxazol-2-one 7087 3- [1- (cyclooctylmethyl) -4-piperidinyl] -2H-benzoxazol-2-one 64 3- [1- (1,2,3,4-tetrahydro-2-naphthyl) -4-piperidinyl] -2H-benzoxazol-2-one 93 3- [1- (5-methylhex-2-yl) -4-piperidinyl] -2H-benzoxazol-2-one 60 3- [1- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) -4-piperidinyl] -2H-benzoxazol-2-one > 10,000 3- [1- (3,3-dimethyl-1,5-dioxaspiro [5.5] undeca-9-yl) -4-piperidinyl] -2H-benzoxazol-2-one > 10,000 3- [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -2H-benzoxazol-2-one 512 3- [1- (cyclooctyl) -4-piperidinyl] -2H-benzoxazol-2-one 16

Example 4

SYNTHESIS OF SUBSTITUTED INDOLES HEAD GROUPS

Methodology

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 500 ml dichloroethane was added in one portion sodium triacetoxyborohydride (74.2 g, 0.35 mol) and the mixture was stirred overnight. The molecular sieves were filtered off and 1N NaOH (500 ml) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 300 ml). The combined organic extracts were dried over K ₂ CO ₃ , filtered and the solvent was evaporated in vacuo to give the crude compound 3 as a brown solid, which was used directly in the next step.

Compound 3

¹ H-NMR (CDCl ₃ ): d 1.50 (m, 2H), 2.05 (m, 2H), 2.20 (br t, 2H), 2.85 (m, 2H), 3, 30 (m, 1H), 3.52 (s, 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 3 (0.25 mol, estimated yield 100%) and DIEA (48.4 g, 0.38 mol) in 500 ml of dichloromethane was added dropwise a solution of chloroacetyl chloride (42.4 g, 0.375 mol). After complete addition, 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 K ₂ CO ₃ , dried over K ₂ CO ₃ , filtered and the solvent was removed in vacuo to give a brown gum, which was filtered through a silica gel column, eluting with a mixture of 10% Et ₃ N, 40% EtOAc and 50% hexane . The selected fractions were combined and the solvent was evaporated in vacuo to give a brown solid, which was crystallized from EtOAc to give 42.2 g of compound 4 (49.2%, 2 steps).

Compound 4

¹ H-NMR (DMSO): d 1.22 (m, 2H), 1.70 (broad, 2H), 2.00 (t, 2H), 2.80 (broad, 2H), 3.40 (s, 2H), 3.80 (s, 2H), 4.40 (m, 1H), 7.15-7.30 (m, 7H), 7.45 (m, 3H).

A mixture of compound 4 (42.2 g, 0.12 mol) and AlCl ₃ (49.2 g, 0.369 mol) was mixed in a flask with rapid stirring. The mixture was then heated in an oil bath at 130 ° C. Within a few minutes, the solids melted and became a dark liquid, which was accompanied by the evolution of gas. After heating for 1 hour, the reaction mixture was slightly cooled, and while it was still mobile, it was poured into a beaker containing 500 ml of ice water. The solution was made basic and extracted with dichloromethane. The organic layer was dried over Na ₂ SO ₄ , 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 10% Et ₃ N, 40% EtOAc and 50% hexane. The selected fractions were combined and the solvent was evaporated in vacuo to give compound 5 as a red oil, which upon solidification turned into a pale solid (22.0 g, 58.5%).

Compound 5

¹ H-NMR (CDCl ₃ ): d 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 Pd (OH) ₂ (4.0 g). The resulting suspension was hydrogenated at 50 psi for 12 hours at room temperature. The solution was filtered through a pad of celite and the pad was washed with methanol (2 x 20 ml). Evaporation of the solvent in vacuo afforded compound 6 as a pale solid (11.2 g, 100%).

Compound 6

LC: 100%

MS: m / z 217 (M + 1).

¹ H-NMR (CDCl ₃ ): d 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).

To a solution of compound 6 (8.0 g, 37.0 mmol) in 50 ml of dichloromethane was added Et ₃ N (4.07 g, 40.7 mmol) and BOC anhydride (8.87 g, 40.7 mmol). 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 50 ml). The combined organic phase was dried over K ₂ CO ₃ , filtered and evaporated in vacuo to give a brown oil, which was filtered through a silica gel column, eluting with a mixture of 10% Et ₃ N, 40% EtOAc and 50% hexane. The selected fractions were combined and the solvent was evaporated in vacuo to give compound 7 as an off-white solid (8.50 g, 73%).

Compound 7

¹ H-NMR (CDCl ₃ ): d 1.50 (m, 9H), 1.70 (m 2H), 2.20-2.50 (m, 2H), 2.80-3.00 (m, 2H), 3.50 (s, 2H), 4.20-4.50 (m, 3H), 6.90-7.60 (m, 5H).

To a mixture of compound 7 (6.0 g, 19.0 mmol) and sodium acetate (2.58 g, 19.0 mmol) in 150 ml of methanol was added acetaldehyde (1.67 g, 38 mmol). 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 10% Et ₃ N, 40% EtOAc and 50% hexane. The selected fractions were combined and the solvent was evaporated in vacuo to give compound 8 as a red oil (5.90 g, 91%).

Compound 8

LC: 2 isomers in a ratio of 2: 1.

¹ H-NMR (CDCl ₃ ): (mixture of 2 isomers) d 1.50 (m, 9H), 1.70 (m, 2H), 2.20-2.50 (m, 6H), 2.60- 3.00 (m, 2H); 4.20-4.50 (m, 3H); 6.90-7.60 (m, 5H).

A solution of compound 8 (5.90 g, 17.2 mmol) in a mixture of 30% TFA / dichloromethane (100 ml) was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo and saturated aqueous K ₂ CO _{3 was} added to the oily residue. The resulting mixture was extracted with dichloromethane (3 x 150 ml). The combined organic extracts were dried over K ₂ CO ₃ , filtered and evaporated in vacuo to give a crude product. Silica gel chromatography eluting with a mixture of 10% Et ₃ N, 50% EtOAc and 40% hexane gave compound 9 (E / Z isomers) as a yellow foam (3.60 g, 82%).

Compound 9

LC: 2 isomers in a ratio of 2: 1.

MS: m / z 243.1 (M + 1).

¹ H-NMR (CDCl ₃ ): (mixture of 2 isomers) d 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).

Example 5

To a mixture of compound 5 (5.50 g, 18 mmol) and sodium acetate (2.45 g, 18 mmol) in 150 ml of methanol was added acetaldehyde (1.58 g, 36 mmol). 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 10% Et ₃ N, 40% EtOAc and 50% hexane. The selected fractions were combined and the solvent was evaporated in vacuo to give compound 10 as a red oil (5.90 g, 98%).

Compound 10

LC: 2 isomers in a ratio of 2: 1.

MS: m / z 333.2 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.70 (m, 2H), 2.17 (m, 2H), 2.30 (d, 3H), 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, 17.7 mmol) in 30 ml of methanol was added Pd (OH) ₂ (3.0 g). The resulting suspension was hydrogenated at 50 psi for 12 hours at room temperature. The solution was filtered through a pad of celite and the pad 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 10% methanol and 90% EtOAc, to give compound 11 as an off-white solid (2.02 g, 50%).

Compound 11

LC: 97%

MS: m / z 245.2 (M + 1)

¹ H-NMR (CDCl ₃ ): d 0.85 (t, 3H), 1.26 (m, 2H), 2.00 (m, 2H), 2.43 (m, 2H), 2.90 ( m, 2H), 3.3 (m, 2H), 3.4 (m, 1H), 4.4 (m, 1H), 7.05 (m, 1H), 7.15-7.30 (m , 3H).

Example 6

Methodology

Compound 16 was obtained in a manner analogous to the preparation of compound 6 .

Compound 13

LC: 89.4%

MS: m / z 281.2 (M + 1)

¹ H-NMR (mixture of trans and cis) (CDCl ₃ ): d 0.95 (m, 3H), 1.50-2.75 (m, 5H), 2.80-3.20 (m, 1H) 3.50 (m, 2H), 3.60 (minor) +3.70 (major) (two s, 2H), 6.55-6.80 (m, 2H), 7.05-7.45 (m, 8H).

Compound 14

MS: m / z 357.2 (M + 1)

¹ H-NMR (mixture of trans and cis) (CDCl ₃ ): d 1.10 (m, 3H), 1.40-4.20 (m, 11H), 4.40 (m, 1H), 7.05 7.50 (m, 10H).

Compound 15

LC: 90.0%

MS: m / z 321.2 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.20 (d, 3H), 1.75 (m, 1H), 2.10 (dt, 1H), 2.25 (broad, 1H), 2.30 (dd, 1H), 2.75 (dd, 1H), 3.05 (m, 1H), 3.20 (m, 1H), 3.50 (m, 4H), 4.10 (m, 1H) 6.99 (m, 2H); 7.23 (m, 3H); 7.37 (m, 4H).

Compound 16

LC: 92.5%

MS: m / z 231.2 (M + 1)

¹ H-NMR (CDCl ₃ ): dd 1.20 (d, 3H), 1.75 (m, 1H), 2.10 (dt, 1H), 2.25 (broad, 1H), 2.30 (dd, 1H), 2.75 (dd, 1H), 3.05 (m, 1H), 3.20 (m, 1H), 3.50 (m, 2H), 4.10 (m, 1H) 6.99 (m, 2H); 7.23 (m, 3H); 7.37 (m, 4H).

Example 7

Methodology

Compound 18 was obtained in a manner analogous to the preparation of compound 11 .

Compound 17

MS: m / z 347.3 (M + 1)

Compound 18

LC: 82.6%

MS: m / z 259.3 (M + 1)

¹ H-NMR (CDCl ₃ ): d 0.80 (t, 3H), 1.20 (d, 3H), 2.00 (m, 2H), 2.30 (m, 1H), 2.65 ( m, 1H), 2.82 (m, 1H), 3.15-3.25 (m, 1H), 3.32 (m, 1H), 3.45 (m, 1H), 3.65 (m , 1H), 3.75 (m, 1H), 4.25 (m, 1H), 6.90 (d, 1H), 7.05 (t, 1H), 7.25 (m, 2H).

Example 8

End group attachment

End groups were attached to the head groups in accordance with the following methods:

Basic procedure for alkylation:

To a solution of amine (1 equivalent) and triethylamine (1 equivalent) in dimethylformamide, 1 equivalent was added in one portion. alkyl bromide or chloride. The mixture was stirred and heated at 80 ° C. overnight. TLC indicated completion of the reaction. The reaction was quenched by the addition of water, followed by adjusting the pH to 10 with 1N NaOH. The mixture was extracted twice with Et ₂ O. The combined organic extracts were dried over potassium carbonate and the solvent was evaporated, followed by chromatography to give a pure product.

Basic procedure for reductive amination:

To a mixture of ketone or aldehyde (1 equivalent), amine (1 equivalent) and acetic acid (1 equivalent) in methanol, sodium cyanoborohydride (1.4 equivalent) was added in one portion. The mixture was stirred at room temperature overnight. TLC indicated completion of the reaction. The reaction was quenched by the addition of water, followed by adjusting the pH to 10 with 1N NaOH. The mixture was extracted twice with Et ₂ O. The combined organic extracts were dried over potassium carbonate and the solvent was evaporated, followed by chromatography to give a pure product.

The following compounds were prepared by attachment of end groups using the described basic procedures:

1- [1- (naphth-1-ylmethyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

MS: m / z 357.2 (M + 1)

1- [1- (naphth-2-ylmethyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

MS: m / z 357.3 (M + 1)

1- [1- (p-phenylbenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

MS: m / z 383.2 (M + 1)

1- [1- (3,3-bis (phenyl) propyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC: 98.7%

MS: m / z 411.2 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.65 (brd, 2H), 2.05 (br t, 2H), 2.30 (m, 4H), 2.45 (m, 2H), 3.02 (brd, 2H), 3.50 (s, 2H), 4.01 (t, 1H), 4.30 (m, 1H), 7.00 (t, 1H), 7.15 -7.35 (m, 13H).

1- [1- (p-cyanobenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

MS: m / z 332.2 (M + 1)

1- [1- (p-benzyloxybenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

MS: m / z 413.3 (M + 1)

1- [1- (1,2,3,4-tetrahydronaft-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC: 100%

MS: m / z 347.5 (M + 1).

¹ H-NMR (CDCl ₃ ): d 1.70 (m, 3H), 2.10 (m, 1H), 2.40 (m, 4H), 2.90-3.00 (m, 5H), 3.10 (m, 2H), 3.60 (s, 2H), 4.3 (m, 1H), 7.00-7.30 (m, 8H).

1- [1- (5-methylhex-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC: 100%

MS: m / z 315.4 (M + 1).

¹ H-NMR (CDCl ₃ ): d 0.90 (m, 6H), 1.00 (m, 3H), 1.20 (m, 3H), 1.5-1.8 (m, 2H), 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

LC: 97%

MS: m / z 311.41 (M + 1).

¹ H-NMR (CDCl ₃ ): d 0.90 (m, 1H), 1.30-2.00 (m, 7H), 2.10-2.30 (m, 5H), 3.20 (m , 2H); 3.60 (s, 2H); 4.3 (m, 1H); 6.90-7.30 (m, 4H).

1- [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC: 100%

MS: m / z 332.4 (M + 1).

¹ H-NMR (CDCl ₃ ): d 1.80 (m, 2H), 2.40 (m, 2H), 2.50 (m, 2H), 2.90 (m, 2H), 3.10- 3.40 (m, 5H); 3.60 (s, 2H); 4.20 (m, 1H); 7.10-7.30 (m, 8H).

1- [1- (cyclooctylmethyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC: 97%

MS: m / z 341.50 (M + 1).

¹ H-NMR (CDCl ₃ ): d 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).

¹³ C-NMR (CDCl ₃ ): d 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: m / z 375.3 (M + 1).

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

MS: m / z 369.2 (M + 1).

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

LC: 100%

MS: m / z 342.4 (M + 1).

¹ H-NMR (CDCl ₃ ): d 0.80 (t, 3H), 0.90 (m, 6H), 1.00 (m, 3H), 1.20 (m, 3H), 1.5- 1.8 (m, 2H), 2.2-2.6 (m, 5H), 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

LC: 100%

MS: m / z 339.41 (M + 1).

¹ H-NMR (CDCl ₃ ): d 0.80 (m, 3H), 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, 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: m / z 381.3 (M + 1).

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

MS: m / z 369.3 (M + 1)

¹ H-NMR (CDCl ₃ ): d 0.88 (t, 3H), 0.92 (d, 6H), 1.17 (m, 1H), 1.40 (m, 2H), 1.50- 1.70 (m, 9H), 2.05 (m, 2H), 2.25 (m, 2H), 2.32-2.55 (m, 3H), 3.15 (br., 2H), 3.43 (t, 1H); 4.35 (m, 1H); 7.05 (t, 1H); 7.22 (d, 1H); 7.28 (m, 2H).

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

MS: m / z 361.2 (M + 1)

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

LC: 97%

MS: m / z 369.50 (M + 1)

¹ H-NMR (CDCl ₃ ): d 0.80 (t, 3H), 1.25 (m, 3H), 1.4-1.7 (m, 14H), 2.10 (m, 6H), 2.50 (m, 2H), 3.10 (m, 2H), 3.40 (m, 1H), 4.3 (m, 1H), 7.10-7.20 (m, 4H).

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

MS: m / z 333.2 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.70 (m, 2H), 2.15 (dt, 2H), 2.28 (d, 3H), 2.47 (m, 2H), 3.05 ( broad., 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: m / z 405.2

3-ethylidene-1- [1- (3,3-diphenylpropyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC:> 97% (2 isomers together)

MS: m / z 437.5 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.70-1.80 (m, 3H), 2.10 (m, 2H), 2.20-2.40 (m, 8H), 3.10 (m , 2H); 4.10 (m, 1H); 4.3 (m, 1H); 7.00-7.30 (m, 15H).

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

LC:> 97% (2 isomers together)

MS: m / z 358.5 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.80 (m, 4H), 2.10-2.60 (m, 5H), 3.10 (m, 2H), 3.70 (s, 2H), 4.3 (m, 1H); 6.90-7.60 (m, 8H).

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

MS: m / z 405.2

3-ethylidene-1- [1- (1,2,3,4-tetrahydro-2-naphthyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC:> 97% (2 isomers together)

MS: m / z 373.5 (M + 1)

¹ H-NMR (CDCl ₃ ): d 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

LC:> 97% (2 isomers together)

MS: m / z 367.5 (M + 1)

¹ H-NMR (CDCl ₃ ): d 0.90 (m, 1H), 1.30-2.00 (m, 7H), 2.10-2.30 (m, 5H), 3.20 (m , 2H), 3.60 (s, 2H), 4.3 (m, 1H), 6.90-7.30 (m, 5H).

3-ethylidene-1- [1- (5-methylhex-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC:> 97% (2 isomers together)

MS: m / z 341.4 (M + 1)

¹ H-NMR (CDCl ₃ ): d 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

LC:> 97% (2 isomers together)

MS: m / z 337.41 (M + 1)

¹ H-NMR (CDCl ₃ ): d 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

LC:> 97% (2 isomers together)

MS: m / z 359.4 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.80-3.10 (m, 17H), 4.20 (m, 1H), 7.10-7.30 (m, 9H).

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

LC:> 97% (2 isomers together)

MS: m / z 367.50 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.25 (m, 3H), 1.4-1.7 (m, 21H), 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

LC: 100%

MS: m / z 425.3 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.20 (d, 3H), 1.69 (broad d, 1H), 1.95 (dt, 1H), 2.13-2.30 (m, 5H ), 2.72 (broad d, 1H), 2.98 (broad d, 1H), 3.15 (dq, 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

LC: 100%

MS: m / z 321.2 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.20 (d, 3H), 1.70 (m, 1H), 2.10 (dt, 1H), 2.23 (m, 1H), 2.35 ( dd, 1H), 2.78 (d, 1H), 3.05 (m, 1H), 3.20 (dq, 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

LC: 96.2%

MS: m / z 355.2 (M + 1)

¹ H-NMR (CDCl ₃ ): d 0.85 (m, 3H), 1.15 (m, 3H), 1.22-1.85 (m, 13H), 2.05-2.90 (m , 6H), 2.95-3.20 (m, 2H), 3.50 (s, 2H), 4.05 (m, 1H), 7.00 (m, 2H), 7.22 (m, 2H).

1- [1- (5-methylhex-2-yl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC: 100%

MS: m / z 329.2 (M + 1)

¹ H-NMR (CDCl ₃ ): d 0.85 (m, 9H), 1.15 (m, 3H), 1.20-1.75 (m, 6H), 2.25 (m, 1H), 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).

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

LC: 95.3%

MS: m / z 367.2 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.11 (d, 3H), 1.16-1.85 (m, 16H), 2.20 (m, 1H), 2.35 (m, 2H), 2.52 (m, 2H), 2.75 (m, 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

LC: 96.1%

MS: m / z 355.2 (M + 1)

¹ H-NMR (CDCl ₃ ): d 0.80 (m, 6H), 1.15 (m, 3H), 1.22-1.48 (m, 3H), 1.50-1.90 (m , 6H), 2.15-2.90 (m, 4H), 2.95-3.25 (m, 2H), 3.50 (s, 2H), 4.10 (m, 1H), 6, 95 (m, 2H); 7.22 (m, 2H).

1- [1- (cyclooctylmethyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC: 100%

MS: m / z 355.2 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.12 (d, 3H), 1.15-1.75 (m, 16H), 1.92-2.10 (m, 3H), 2.20 (m , 2H), 2.73 (m, 1H), 3.00 (m, 1H), 3.12 (dq, 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

LC: 96.3%

MS: m / z 453.3 (M + 1)

¹ H-NMR (CDCl ₃ ): d (two t, 3H), 1.18 (d, 3H), 1.70 (m, 1H), 1.90-2.05 (m, 3H), 2, 12-2.30 (m, 5H), 7.73 (m, 1H), 2.97 (brd, 1H), 3.10-3.30 (m, 1H), 3.38 (t, 1H), 3.90-4.05 (m, 1H), 4.12 (q, 1H), 6.90-7.00 (two 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

LC: 93.2%

MS: m / z 383.3 (M + 1)

¹ H-NMR (CDCl ₃ ): d 0.75-0.95 (m, 6H), 1.05-1.20 (m, 5H), 1.20-1.35 (m, 4H), 1 35-1.75 (m, 6H), 1.75-1.90 (m, 2H), 1.95-2.05 (m, 2H), 2.15-2.45 (m, 3H) 2.55 (d, 0.5H), 2.75 (d, 0.5H), 2.95-3.15 (m, 2H), 3.38 (t, 1H), 3.90-4 10 (m, 1H); 6.90-7.05 (2H); 7.20-7.25 (m, 2H).

3-ethyl-1- [1- (5-methylhex-2-yl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC: 92.3%

MS: m / z 357.4 (M + 1)

¹ H-NMR (CDCl ₃ ): d 0.75-0.95 (m, 10H), 1.10 (d, 3H), 1.15-1.40 (m, 3H), 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).

3-ethyl-1- [1- [4- (1-methylethyl) cyclohexyl] -3-methyl-4-piperidinyl] -1,3-dihydro-2H-indol-2-one

LC: 94.7%

MS: m / z 383.4 (M + 1)

¹ H-NMR (CDCl ₃ ): d 0.75-1.05 (m, 8H), 1.10-1.50 (m, 7H), 1.50-1.90 (m, 7H), 1 , 90-2.10 (m, 2H), 2.15-2.43 (m, 3H), 2.55 (d, 0.5H), 2.75 (d, 0.5H), 2.90 -3.25 (m, 3H), 3.40 (t, 1H), 3.90-4.10 (m, 1H), 6.90-7.01 (m, 2H), 7.25 (m , 2H).

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

LC: 94.3%

MS: m / z 395.3 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.75-1.90 (two t, 3H), 1.10 (d, 3H), 1.15-1.90 (m, 15H), 2.00 ( m, 2H), 2.20 (br s, 1H), 2.40 (m, 2H), 2.45-2.60 (m, 2H), 2.75 (m, 1H), 2.90 -3.20 (m, 2H), 3.40 (br s, 1H), 3.90-4.15 (m, 1H), 6.90-7.05 (m, 2H), 7.25 (m, 2H).

Other compounds encompassed by formulas (II) or (IIA) of the present invention can be synthesized by similar methods.

Example 9

The nociceptin affinity for the ORL1 receptor for the preferred compounds was determined using the following assay:

Membranes of recombinant HEK-293 cells expressing a receptor similar to a human opioid receptor (ORL1), (Receptor Biology), were obtained by lysing cells in ice-cold hypotonic buffer (2.5 mm MgCl ₂ , 50 mm HEPES, pH 7.4) (10 ml / 10 cm cup) followed by homogenization using a tissue homogenizer / teflon pestle. Membranes were collected by centrifugation at 30,000 xg for 15 min at 4 ° C and the pellet after centrifugation was resuspended in hypotonic buffer to a final concentration of 1-3 mg / ml. Protein concentrations were determined using BioRad protein reagent with bovine serum albumin as standard. Aliquots of ORL1 receptor membranes were stored at -80 ° C.

Functional binding assays of SGTPgS were performed as follows. An ORL1 membrane solution was prepared by sequentially adding final concentrations of 0.066 mg / ml ORL1 membrane protein, 10 mg / ml saponin, 3 mM GDP and 0.20 nM [ ³⁵ S] GTPgS to binding buffer (100 mM NaCl, 10 mM MgCl ₂ , 20 mM HEPES, pH 7.4) on ice. The resulting membrane solution (190 ml / well) was transferred to 96-well polypropylene plates containing 10 ml of 20x concentrated stock solutions of agonist obtained in DMSO. The plates were incubated for 30 minutes at room temperature with shaking. The reactions were terminated by rapid filtration on 96-well Unifilter GF / B filter plates (Packard) using a 96-well tissue harvester (Brandel) followed by three filter washes with 200 ml of ice-cold binding buffer (10 mM NaH ₂ PO ₄ , 10 mM Na ₂ HPO ₄ , pH 7.4). Filter plates were successively dried at 50 ° C for 2-3 hours. Fifty ml / well of scintillation count cocktail (BetaScint; Wallac) was added and the plates were read on a Packard Top-Count for 1 min / well.

Data was analyzed using an approximation of the functional dependence curve in GraphPad PRISMO, v.3.0, and the results are presented in table 2 below:

TABLE 2
Nociceptin Affinity Compound calculation K _i  (nM) 3-ethylidene-1- [1- (5-methylhex-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 11.1 3-ethylidene-1- [1- (4-propylcyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 19 3-ethylidene-1- [1- (1,2,3,4-tetrahydro-2-naphthyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 16.7 3-ethylidene-1- [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 20.7 3-ethylidene-1- [1- (naphth-2-ylmethyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 630 3-ethylidene-1- [1- (p-benzyloxybenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 516 3-ethylidene-1- [1- (benzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 1854 3-ethylidene-1- [1- (cyclooctylmethyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 22.3 3-ethylidene-1- [1- (3,3-diphenylpropyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 100.7 3-ethylidene-1- [1- (norbornan-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 922 3-ethylidene-1- [1- (p-cyanobenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 7652 3-ethyl-1- [1- (5-methylhex-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one four 3-ethyl-1- [1- [4- (1-methylethyl) cyclohexyl] -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 0.86 3-ethyl-1- [1- (4-propylcyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 40 3-ethyl-1- [1- (1,2,3,4-tetrahydro-2-naphthyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 124 3-ethyl-1- [1- (decahydro-2-naphthyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 3.6 3-ethyl-1- [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 43 3-ethyl-1- [1- (cyclooctylmethyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 9 3-ethyl-1- [1- (norbornan-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 82.7 1- [1- (naphth-1-ylmethyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 92 1- [1- (naphth-2-ylmethyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 107 1- [1- (p-phenylbenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 1362 1- [1- (3,3-bis (phenyl) propyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 12.5 1- [1- (p-cyanobenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 1267 1- [1- (p-benzyloxybenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 32 1- [1- (1,2,3,4-tetrahydronaft-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 28.7 1- [1- (5-methylhex-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 7.4 1- [1- (norbornan-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 215 1- [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 18.7 1- [1- (cyclooctylmethyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 54.3 1- [1- (benzyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one > 10,000 1- [1- (4-propylcyclohexyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 2435 1- [1- (5-methylhex-2-yl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 4335 1- [1- (decahydro-2-naphthyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 366 1- [1- (4- (1-methylethyl) cyclohexyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 167 1- [1- (cyclooctylmethyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 189

Example 10

Synthesis of some head groups

Scheme 1:

Methodology

To a mixture of compound 4 (21.6 g, 0.2 mol), compound 5 (15.6 g, 0.1 mol), acetic acid (6 g, 0.1 mol) in 500 ml of dichloromethane, 29 were added in one portion 7 g of sodium triacetoxyborohydride (0.14 mol, 1.4 equiv.). Gas evolution occurred between 30 minutes and 1 hour. The mixture was stirred overnight. TLC indicated completion of the reaction. 1N NaOH (500 ml) 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 red oil, which was filtered through a column (5% Et ₃ N, 25% EtOAc and 70% hexane) to give 14 g of product 6 as a white solid (54%).

Compound 6

MS: m / z 249.3 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.50-1.90 (m, 6H), 2.05 (m, 2H), 3.30 (m, 4H), 3.95 (s, 4H), 6.60-6.80 (m, 4H).

To a solution of 13.5 g of compound 6 (54.4 mmol) in 50 ml of acetonitrile, 11.02 g of carbonyldiimidazole was added in one portion. The mixture was stirred overnight. The solid precipitated from the solution, which was filtered and washed with H ₂ O and TBME, gave 7.5 g of product. The filtrate was evaporated and the crude material was dissolved in EtOAc, washed with water and saturated potassium carbonate solution. The organics were dried over potassium carbonate. The solvent was evaporated to give a second batch of pink solid, which was filtered through a column (10% Et ₃ N, 40% EtOAc and 50% hexane) to give another 4.5 g of product 7 (81%, combined).

Compound 7

MS: m / z 274.7 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.50-1.90 (m, 7H), 2.50 (m, 2H), 4.00 (m, 4H), 4.50 (m, 1H), 7.10 (m, 3H); 7.25 (m, 1H).

A mixture of compound 7 (7.5 g, 27.4 mmol) and 8.26 g of PPTS in 50 ml of acetone and H ₂ O (10: 1) was stirred at reflux overnight. The mixture was cooled to room temperature and the acetone was evaporated. Adding water to the mixture initiated crystallization to give 3 g of product 8 (47.4%).

Compound 8

MS: m / z 231 (M + 1)

¹ H-NMR (CDCl ₃ ): d 2.20 (m, 2H), 2.60 (m, 2H), 4.50 (m, 1H), 7.10 (m, 4H), 9.5 ( broad., 1H).

To a mixture of compound 8 (7.75 g, 33.65 mmol), benzylamine (3.61 g, 33.65 mmol), acetic acid (2.0 g, 33.65 mmol) in 150 ml of dichloromethane in one portion was added 10 3 g of sodium triacetoxyborohydride (47.1 mmol, 1.4 eq.). Gas is released between 30 minutes and 1 hour. The mixture was stirred overnight. TLC indicated completion of the reaction. 1N NaOH (500 ml) 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 solid, which was filtered through a column (from 5% Et ₃ N, 25% EtOAc and 70% hexane to 10% Et ₃ N, 40% EtOAc and 50% hexane ) to obtain 4.7 g of product 10 as a white solid (53.4%) and 3.01 g of product 9 as a white solid (34.2%).

Compound 9

MS: m / z 322 (M + 1)

¹ H-NMR (CDCl ₃ ): d 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 (br., 1H).

Compound 10

MS: m / z 322 (M + 1)

¹ H-NMR (CDCl ₃ ): d 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 (br, 1H).

To a solution of 30 ml of methanol containing 4.7 g of compound 10 , 2 g of Pd (OH) _{2 was} added. The resulting suspension was hydrogenated at 50 psi for 12 hours at room temperature. TLC indicated completion of the reaction. The solution was filtered through a pad of celite to remove the catalyst. Celite was washed twice with methanol (20 ml). The organics were combined and the solvent was removed to give a pale solid which was purified by chromatography (10% MeOH, 90% EtOAc) to give an off-white product 11 (1.79 g, 50.7%).

Compound 11

MS: m / z 232 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.50-1.85 (m, 8H), 2.60 (m, 2H), 4.30 (m, 1H), 7.10 (m, 3H), 7.30 (m, 1H).

To a mixture of compound 11 (1.7 g, 7.4 mmol), acetaldehyde (0.33 g, 7.4 mmol) in 50 ml of dichloroethane was added in one portion 2.2 g of sodium triacetoxyborohydride (10.36 mmol, 1.4 equiv.). Gas evolution occurred between 30 minutes and 1 hour. The mixture was stirred overnight. TLC indicated completion of the reaction. 1N NaOH (500 ml) 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 (10% Et ₃ N, 40% EtOAc and 50% hexane) to give 1.5 g of product 2 as a sticky oil, which was recrystallized from TBME with obtaining a white solid (78%).

Compound 2

MS: m / z 259.7 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.15 (t, 3H), 1.50-1.95 (m, 6H), 2.40-2.75 (m, 4H), 2.95 (m , 1H), 4.35 (m, 1H), 7.10 (m, 3H), 7.35 (m, 1H).

To a solution of 30 ml of methanol containing 3.01 g of compound 9 , 1.5 g of Pd (OH) _{2 was} added. The resulting suspension was hydrogenated at 50 psi 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). The organics were combined and the solvent was removed to give a pale solid which was purified by chromatography (10% MeOH, 90% EtOAc) to give an off-white product 1 (1.68 g, 77.4%).

Compound 1

MS: m / z 232 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.50 (m, 2H), 1.90-2.35 (m, 6H), 3.00 (m, 1H), 4.30 (m, 1H), 7.10-7.30 (m, 4H).

Scheme 2:

Methodology

About 2.5 g of NaH was washed twice with THF, suspended in 100 ml of DMF, then 8.15 g of compound 7 (38 mmol) was added to the mixture. Gas evolution occurred and after 5 minutes 7.13 g of ethyl iodide (45.7 mmol) was added. The mixture was stirred overnight. LC / MS indicated that the starting material was completely consumed. The reaction mixture was cooled and H ₂ O was added to the mixture. The product began to precipitate from the solution. The crystals were collected by filtration to obtain 9.7 g of compound 12 (84.7%).

Compound 12

MS: m / z 303.3 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.30 (t, 3H), 1.70-1.90 (m, 6H), 2.50 (m, 2H), 3.85-4.00 (m 6H); 4.50 (m, 1H); 7.05 (m, 3H); 7.25 (m, 1H).

A mixture of compound 12 (9.7 g, 32.2 mmol) and 9.72 g of PPTS in 50 ml of acetone and H ₂ O (10: 1) was refluxed overnight. The mixture was cooled to room temperature and the acetone was evaporated. Adding water to the mixture initiated crystallization to give 6.85 g of product 13 (82.3%).

Compound 13

MS: m / z 259 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.35 (t, 3H), 2.20 (m, 2H), 2.60 (m, 6H), 3.95 (q, 2H), 4.85 ( m, 1H), 7.10 (m, 4H).

To a mixture of compound 13 (6.85 g, 26.5 mmol), benzylamine (2.84 g, 26.5 mmol), acetic acid (1.59 g, 26.5 mmol) in 150 ml of dichloroethane was added in one portion 7 86 g of sodium triacetoxyborohydride (37.1 mmol, 1.4 eq.). Gas evolution occurred between 30 minutes and 1 hour. The mixture was stirred overnight. TLC indicated completion of the reaction. 1N NaOH (500 ml) 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 solid, which was filtered through a column (from 5% Et ₃ N, 25% EtOAc and 70% hexane to 10% Et ₃ N, 40% EtOAc and 50% hexane ) to obtain 1.52 g of product 14 as a white solid and 1.08 g of product 15 as a white solid.

Compound 14

MS: m / z 350 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.35 (t, 3H), 1.50 (m, 2H), 1.65 (m, 4H), 1.95 (m, 2H), 2.60 ( m, 2H), 3.02 (m, 1H), 3.83 (s, 2H), 3.95 (ddd, 2H), 4.45 (m, 1H), 7.00-7.50 (m , 9H).

Compound 15

MS: m / z 350 (M + 1)

¹ H-NMR (CDCl ₃ ): d 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).

0.3 g of Pd (OH) _{2 was} added to a solution of 20 ml of methanol containing 0.5 g of compound 14 . The resulting suspension was hydrogenated at 50 psi 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). The organics were combined and the solvent was removed to give a pale solid which was purified by chromatography (10% MeOH, 90% EtOAc) to give an off-white product 3 (300 mg, 50%).

Compound 3

MS: m / z 232 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.35 (t, 3H), 1.50-1.85 (m, 8H), 2.60 (m, 2H), 3.20 (m, 1H), 3.95 (ddd, 2H), 4.30 (m, 1H), 7.10, (m, 3H), 7.30 (m, 1H).

Example 11

End group attachment

End groups were attached to the head groups in accordance with the following methods:

Basic procedure for alkylation:

To a solution of amine (1 equivalent) and triethylamine (1 equivalent) in dimethylformamide, 1 equivalent was added in one portion. alkyl bromide or chloride. The mixture was stirred and heated at 80 ° C. overnight. TLC indicated completion of the reaction. The reaction was quenched by the addition of water, followed by adjusting the pH to 10 with 1N NaOH. The mixture was extracted twice with Et ₂ O. The combined organic extracts were dried over potassium carbonate and the solvent was evaporated, followed by chromatography to give a pure product.

Basic procedure for reductive amination:

To a mixture of ketone or aldehyde (1 equivalent), amine (1 equivalent) and acetic acid (1 equivalent) in methanol, sodium cyanoborohydride (1.4 equivalent) was added in one portion. The mixture was stirred at room temperature overnight. TLC indicated completion of the reaction. The reaction was quenched by the addition of water, followed by adjusting the pH to 10 with 1N NaOH. The mixture was extracted twice with Et ₂ O. The combined organic extracts were dried over potassium carbonate and the solvent was evaporated, followed by chromatography to give a pure product.

The following compounds were prepared by attachment of terminal groups using the described basic procedures:

1- [4- (benzylamino) cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one

1- [4 - [(naphth-2-ylmethyl) ethylamino] cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one

MS: m / z 400.2 (M + 1)

1- [4- (norbornan-2-ylamino) cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one

MS: m / z 326.3 (M + 1)

1- [4 - [[4- (1-methylethyl) cyclohexyl] amino] cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one

MS: m / z 356.4 (M + 1)

1- [4 - [(decahydro-2-naphthyl) amino] cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one

MS: m / z 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 - [(indan-2-yl) benzylamino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one

MS: m / z 466.3 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.30 (t, 3H), 1.50-1.75 (m, 2H), 1.90 (broad, 2H), 2.02 (broad, 2H ), 2.20 (m, 2H), 2.80 (m, 1H), 2.99 (m, 4H), 3.75 (s, 2H), 3.90 (m, 3H), 4.25 (m, 1H); 6.95-7.45 (m, 13H).

1- [4 - [(cyclooctylmethyl) amino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one

LC: 99%

MS: m / z 384.5

¹ H-NMR (CDCl ₃ ): d 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, 3H), 7.30 (m, 1H).

1- [4 - [(naphth-2-yl) amino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one

LC: 97%

MS: m / z 399

¹ H-NMR (CDCl ₃ ): d 1.50 (t, 3H), 1.80 (m, 5H), 2.0 (m, 2H), 2.70 (m, 2H), 3.10 ( m, 1H), 3.90 (m, 2H), 4.0 (m, 2H), 4.40 (m, 1H), 7.10 (m, 3H), 7.50 (m, 4H), 7.90 (m, 4H).

1- [4 - [(p-benzyloxybenzyl) amino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one

LC: 97%

MS: m / z 455

¹ H-NMR (CDCl ₃ ): d 1.40 (t, 3H), 1.70 (m, 2H), 1.90 (m, 3H), 2.60 (m, 4H), 3.10 ( m, 1H), 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

LC: 99%

MS: m / z 369

¹ H-NMR (CDCl ₃ ): d 1.40 (t, 3H), 1.70 (m, 5H), 1.90 (m, 12H), 2.10 (m, 3H), 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

LC: 99%

MS: m / z 395

¹ H-NMR (CDCl ₃ ): d 1.40 (t, 3H), 1.70 (m, 3H), 1.80 (m, 3H), 1.90 (m, 12H), 2.20 ( m, 2H), 2.30 (m, 3H), 2.50 (q, 2H), 3.10 (m, 1H), 3.90 (m, 2H), 4.20 (m, 1H), 4.30 (m, 1H), 7.0 (m, 1H), 7.30 (m, 3H).

1- [4 - [(p-phenylbenzyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one

LC: 100%

MS: m / z 440.8 (M + 1)

¹ H-NMR (MeOH-d ₄ ): d 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 - [(1,2,3,4-tetrahydronaphthyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one

LC: 93.9%

MS: m / z 405.7 (M + 1)

¹ H-NMR (MeOH-d ₄ ): d 1.70 (m, 2H), 1.85 (m, 1H), 2.02 (m, 2H), 2.39 (broad, 3H), 2 50 (m, 2H), 2.90 (m, 1H), 3.00 (br, 2H), 3.35 (m, 1H), 3.60 (m, 1H), 3.72 (br ., 1H), 4.35 (m, 1H), 7.15 (broad, 4H), 7.40 (d, 1H), 7.60 (s, 1H), 7.65 (d, 1H) .

1- [4 - [(4-propylcyclohexyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one

LC: 100%

MS: m / z 399.6 (M + 1)

¹ H-NMR (MeOH-d ₄ ): d 0.95 (t, 3H), 1.10 (m, 1H), 1.20-1.60 (m, 6H), 1.70 (broad, 5H), 1.80-2.00 (m, 4H), 2.10 (m, 1H), 2.30 (br., 2H), 2.45 (m, 2H), 3.25 (m, 1H), 3.50 (m, 1H), 4.40 (m, 1H), 7.40 (d, 1H), 7.60 (s, 1H), 7.65 (d, 1H).

1- [4 - [(5-methylhex-2-yl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one

LC: 100%

MS: m / z 373.5 (M + 1)

¹ H-NMR (MeOH-d ₄ ): d 0.95 (d, 6H), 1.25-1.40 (m, 5H), 1.50-1.75 (m, 4H), 1.85 (m, 1H), 1.95 (br, 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).

1- [4 - [(decahydro-2-naphthyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one

LC: 100%

MS: m / z 411.7 (M + 1)

¹ H-NMR (MeOH-d ₄ ): d 0.90-2.10 (m, 18H), 2.10-2.50 (m, 5H), 2.82 (m, 1H), 3.50 (m, 2H), 4.35 (m, 1H), 7.42 (d, 1H), 7.60 (s, 1H), 7.70 (d, 1H).

1- [4- (cyclooctylamino) cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one

LC: 95.4%

MS: m / z 385.7 (M + 1)

¹ H-NMR (MeOH-d ₄ ): d 1.50-2.10 (m, 13H), 2.30 (m, 2H), 2.40-2.52 (m, 3H), 2.80 -2.95 (m, 3H), 3.45 (m, 2H), 3.70 (m, 1H), 4.38 (m, 1H), 7.40 (d, 1H), 7.63 ( s, 1H); 7.70 (d, 1H).

1- [4 - [(indan-2-yl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one

LC: 100%

MS: m / z 391.6 (M + 1)

¹ H-NMR (MeOH-d ₄ ): d 1.70 (m, 2H), 2.00 (m, 2H), 2.40-2.60 (m, 4H), 3.10-3.20 (m, 2H), 3.50 (m, 3H), 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

LC: 100%

MS: m / z 399.5 (M + 1)

¹ H-NMR (MeOH-d ₄ ): d 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 (s, 1H), 7.65 (d, 1H) .

1- [4 - [(4-phenylcyclohexyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one

LC: 100%

MS: m / z 433.7 (M + 1)

¹ H-NMR (MeOH-d ₄ ): d 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

LC: 100%

MS: m / z 455.6 (M + 1)

¹ H-NMR (MeOH-d ₄ ): d 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, 10H), 7.60 (s, 1H), 7.65 (d, 1H).

1- [4 - [(5-methylhex-2-yl) amino] cyclohexyl] -7-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one

LC: 99.1%

MS: m / z 373.3 (M + 1)

¹ H-NMR (MeOH-d ₄ ): d 0.95 (d, 6H), 1.30 (d, 3H), 1.45-1.68 (m, 5H), 1.75 (m, 1H ), 2.00 (m, 2H), 2.18-2.32 (m, 3H), 2.60 (m, 2H), 3.20-3.40 (m, 2H), 4.30 ( m, 1H), 7.05-7.20 (m, 3H).

Other compounds encompassed by formulas (III) or (IIIA) of the present invention can be synthesized by similar methods.

Example 12

The nociceptin affinity for the ORL1 receptor for the preferred compounds was determined using the following assay:

Membranes of recombinant HEK-293 cells expressing a receptor similar to a human opioid receptor (ORL1), (Receptor Biology), were obtained by lysing cells in ice-cold hypotonic buffer (2.5 mm MgCl ₂ , 50 mm HEPES, pH 7.4) (10 ml / 10 cm cup) followed by homogenization using a tissue homogenizer / teflon pestle. Membranes were collected by centrifugation at 30,000 xg for 15 min at 4 ° C and the pellet after centrifugation was resuspended in hypotonic buffer to a final concentration of 1-3 mg / ml. Protein concentrations were determined using BioRad protein reagent with bovine serum albumin as standard. Aliquots of ORL1 receptor membranes were stored at -80 ° C.

Functional binding assays of SGTPgS were performed as follows. An ORL1 membrane solution was prepared by sequentially adding final concentrations of 0.066 mg / ml ORL1 membrane protein, 10 mg / ml saponin, 3 mM GDP and 0.20 nM [ ³⁵ S] GTPgS to binding buffer (100 mM NaCl, 10 mM MgCl ₂ , 20 mM HEPES, pH 7.4) on ice. The resulting membrane solution (190 ml / well) was transferred to 96-well polypropylene plates containing 10 ml of 20x concentrated stock solutions of agonist obtained in DMSO. The plates were incubated for 30 minutes at room temperature with shaking. The reactions were terminated by rapid filtration on 96-well Unifilter GF / B filter plates (Packard) using a 96-well tissue harvester (Brandel) followed by three filter washes with 200 ml of ice-cold binding buffer (10 mM NaH ₂ PO ₄ , 10 mM Na ₂ HPO ₄ , pH 7.4). Filter plates were successively dried at 50 ° C for 2-3 hours. Fifty ml / well of scintillation count cocktail (BetaScint; Wallac) was added and the plates were read on a Packard Top-Count for 1 min / well.

Data was analyzed using an approximation of the functional dependence curve in GraphPad PRISMO, v.3.0, and the results are presented in table 3 below:

TABLE 3
Nociceptin Affinity Compound calculation K _i  (nM) 3-ethyl-1- (p-phenylbenzyl) -1,3-dihydro-2H-benzimidazol-2-one 509 3-ethyl-1- (5-methylhex-2-yl) -1,3-dihydro-2H-benzimidazol-2-one 23 3-ethyl-1- (4-propylcyclohexyl) -1,3-dihydro-2H-benzimidazol-2-one 68 3-ethyl-1- (decahydro-2-naphthyl) -1,3-dihydro-2H-benzimidazol-2-one 1,6 3-ethyl-1- (naphth-2-ylmethyl) -1,3-dihydro-2H-benzimidazol-2-one 198 1- (p-benzyloxybenzyl) -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one 438 1-benzyl-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one 296 1- [4- (benzylamino) cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one trance: 112
cis:> 10000 3-ethyl-1- (naphthylmethyl) -1,3-dihydro-2H-benzimidazol-2-one 39 3-ethyl-1- [5- (3-fluorophenyl) -5- (4-fluorophenyl) hexyl] -1,3-dihydro-2H-benzimidazol-2-one 148 1- [4 - [(naphth-2-ylmethyl) ethylamino] cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one 3598 1- [4- (norbornan-2-ylamino) cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one > 10,000 1- [4 - [[4- (1-methylethyl) cyclohexyl] amino] cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one > 10,000 1- [4 - [(decahydro-2-naphthyl) amino] cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one > 10,000 1- [4- (ethylamino) cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one 9179 1- [4- (benzylamino) cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one trance: 273
cis:> 10000 1- [4 - [(indan-2-yl) benzylamino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one > 10,000 1- [4 - [(cyclooctylmethyl) amino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one 115 1- [4 - [(naphth-2-yl) amino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one 961 1- [4 - [(p-benzyloxybenzyl) amino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one 2935 1- [4 - [(cyclooctylmethyl) amino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one 286 1- [4 - [(decahydro-2-naphthyl) amino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one 288 1- [4- (benzylamino) cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one > 10,000 1- [4- (dibenzylamino) cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one > 10,000 1- [4 - [(p-phenylbenzyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one > 10,000 1- [4 - [(1,2,3,4-tetrahydronaphthyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one > 10,000 1- [4 - [(4-propylcyclohexyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one > 10,000 1- [4 - [(5-methylhex-2-yl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one > 10,000 1- [4 - [(decahydro-2-naphthyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one > 10,000 1- [4- (cyclooctylamino) cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one > 10,000 1- [4 - [(indan-2-yl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one > 10,000 1- [4 - [(4-phenylcyclohexyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one > 10,000 1- [4 - [(5-methylhex-2-yl) amino] cyclohexyl] -7-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one > 10,000

Example 13

Synthesis of substituted benzimidazole head groups

Methodology

A 60% dispersion of sodium hydride in mineral oil (0.67 g, 16.7 mmol) was washed with anhydrous pentane and then suspended in 80 ml of anhydrous THF under N ₂ . Compound 1 (European Patent 0029707) (3.80 g, 11.1 mmol) was added, the mixture was stirred at room temperature for 15 minutes and then heated to 50 ° C. Ethyl bromide (1.06 ml, 13.3 mmol) was added and the resulting mixture was stirred at 50 ° C for 18 hours. TLC (SiO ₂ , CH ₂ Cl ₂ : MeOH 96: 4) showed that the reaction was completed by approximately 40%. Additional amounts of sodium hydride (0.67 g) and ethyl bromide (1.06 ml) were added. After heating at 50 ° C. 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 aqueous sodium bicarbonate (1x), dried over MgSO ₄ 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 (3.38 g, 82%).

¹ H-NMR (CDCl ₃ ): d 1.45-1.55 (m, 12H), 1.82 (br s, 2H), 2.30 (m, 2H), 2.87 (m, 2H) ), 4.30 (br s, 2H), 4.41 (q, 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 was added 25 ml of a mixture of ethyl acetate and concentrated HCl (1: 1). The mixture was thoroughly stirred for 2 hours at room temperature and evaporated to dryness. The residue was neutralized with 50 ml of a 10: 1 methanol solution of ammonia and again evaporated to dryness. The residue was suspended in 100 ml of a mixture of MeOH and CH ₂ Cl ₂ 1: 1, filtered and the filtrate was evaporated to dryness to give an off-white solid. Flash chromatography on silica gel eluting with a mixture of CH ₂ Cl ₂ : MeOH: NH ₃ (300: 10: 1) gave pure compound 3 as a white crystalline solid (1.98 g, 76%).

¹ H-NMR (CDCl ₃ ): d 1.45 (t, 3H), 1.82 (br s, 2H), 2.33 (m, 2H), 2.80 (m, 2H), 4, 40 (q, 2H), 4.80 (m, 1H), 7.10-7.30 (m, 3H), 7.45 (d, 1H).

Example 14

End group attachment

End groups were attached to the head groups in accordance with the following methods:

Basic procedure for alkylation:

To a solution of amine (1 equivalent) and triethylamine (1 equivalent) in dimethylformamide, 1 equivalent was added in one portion. alkyl bromide or chloride. The mixture was stirred and heated at 80 ° C. overnight. TLC indicated completion of the reaction. The reaction was quenched by the addition of water, followed by adjusting the pH to 10 with 1N NaOH. The mixture was extracted twice with Et ₂ O. The combined organic extracts were dried over potassium carbonate and the solvent was evaporated, followed by chromatography to give a pure product.

Basic procedure for reductive amination:

To a mixture of ketone or aldehyde (1 equivalent), amine (1 equivalent) and acetic acid (1 equivalent) in methanol, sodium cyanoborohydride (1.4 equivalent) was added in one portion. The mixture was stirred at room temperature overnight. TLC indicated completion of the reaction. The reaction was quenched by the addition of water, followed by adjusting the pH to 10 with 1N NaOH. The mixture was extracted twice with Et ₂ O. The combined organic extracts were dried over potassium carbonate and the solvent was evaporated, followed by chromatography to give a pure product.

The following compounds were prepared by attachment of end groups using the described basic procedures:

2-cyanoimino-3-ethyl-1- [1- (p-phenylbenzyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

¹ H-NMR (CDCl ₃ ): d 1.50 (t, 3H), 1.88 (m, 2H), 2.28 (m, 2H), 2.62 (m, 2H), 3.12 (m, 2H), 3.65 (s, 2H), 4.48 (q, 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

LC: 96.5%

MS: m / z 466.5 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.55 (t, 3H), 1.82 (m, 2H), 2.25 (m, 2H), 2.50 (m, 2H), 3.10 ( m, 2H), 3.55 (s, 2H), 4.48 (q, 2H), 4.78 (m, 1H), 5.20 (s, 2H), 7.00 (d, 2H), 7.15-7.65 (m, 11H).

2-cyanoimino-3-ethyl-1- [1- (naphth-2-ylmethyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 93.9%

MS: m / z

¹ H-NMR (CDCl ₃ ): d 1.55 (t, 3H), 1.80 (m, 2H), 2.30 (t, 2H), 2.52 (m, 2H), 3.18 ( broad d, 2H), 3.78 (s, 2H), 4.50 (q, 2H), 4.80 (m, 1H), 7.20-7.90 (m, 11H).

2-cyanoimino-3-ethyl-1- [1- (4-propylcyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

MS: m / z 394.4 (M + 1)

¹ H-NMR (CDCl ₃ ): d 0.90-2.28 (m, 21H), 3.10 (m, 4H), 3.62 (m, 2H), 4.42 (q, 2H), 5.15 (m, 1H), 7.20 (d, 1H), 7.30 (m, 1H), 7.50 (t, 1H), 7.80 (br, 1H).

2-cyanoimino-3-ethyl-1- [1- [4- (2-propyl) cyclohexyl] -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 100%

MS: m / z 394.5 (M + 1)

¹ H-NMR (CDCl ₃ ): d 0.90 (d, 3H), 0.98 (d, 3H), 1.15-2.35 (m, 14H), 3.10 (m, 5H), 3.70 (m, 2H), 3.92 (br s, 1H), 4.40 (q, 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- [1- (decahydro-2-naphthyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 93.9%

MS: m / z 406.6 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.25-2.35 (m, 24H), 1.15 (m, 4H), 3.60 (m, 2H), 4.40 (m, 2H), 4.20 (m, 1H); 7.20-7.80 (m, 4H).

2-cyanoimino-3-ethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 100%

MS: m / z 380.3 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.50-1.80 (m, 13H), 1.90 (m, 2H), 2.10 (m, 4H), 3.05 (m, 3H), 3.30 (m, 1H), 3.45 (m, 2H), 3.90 (m, 1H), 4.42 (q, 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- [1- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 94.5%

MS: m / z 462.2 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.40 (t, 3H), 1.70 (br s, 2H), 2.01 (m, 2H), 2.28 (m, 2H), 2, 80 (m, 4H), 3.95 (s, 1H), 4.02 (m, 2H), 4.32 (q, 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: m / z 464.2 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.40 (t, 3H), 1.73 (br s, 2H), 2.09 (m, 2H), 2.18-2.45 (m, 6H) ), 2.98 (br, 2H), 3.93 (t, 1H), 4.35 (q, 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

LC: 94.0%

MS: m / z 400.2 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.30-1.70 (m, 6H), 1.85 (m, 2H), 2.05 (m, 1H), 2.45 (m, 3H), 2.85 (m, 4H), 3.10 (m, 2H), 4.35 (q, 2H), 4.71 (m, 1H), 7.00-7.60 (m, 8H).

2-cyanoimino-3-ethyl-1- [1- (5-methylhex-2-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 94.9%

MS: m / z 368.3 (M + 1)

¹ H-NMR (CDCl ₃ ): d 0.85 (d, 6H), 0.95 (d, 3H), 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- [1- (norbornan-2-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 99.2%

MS: m / z 364.7 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.10-2.10 (m, 13H), 2.35 (m, 1H), 2.50-2.70 (m, 3H), 2.70-2 90 (m, 3H), 3.50 (m, 2H), 4.50 (q, 2H), 4.80 (m, 1H), 7.35 (m, 2H), 7.48 (m, 1H), 7.75 (m, 1H).

2-cyanoimino-3-ethyl-1- [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 92.1%

MS: m / z 386.2 (M + 1)

¹ H-NMR (CDCl ₃ ): d 1.42 (t, 3H), 1.82 (m, 2H), 2.21 (m, 2H), 2.43 (m, 2H), 2.88 ( m, 2H), 3.02-3.19 (m, 4H), 3.23 (m, 1H), 4.38 (q, 2H), 4.80 (m, 1H), 7.08-7 30 (m, 7H); 7.45 (d, 1H).

2-cyanoimino-3-ethyl-1- [1- (cyclooctylmethyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 100%

MS: m / z 394.7 (M + 1)

¹ H-NMR (MeOH): d 1.35-2.00 (m, 20H), 2.60-2.85 (m, 6H), 3.40 (m, 2H), 2.52 (q, 2H), 4.90 (m, 1H), 7.35 (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

LC: 100%

MS: m / z 396.3 (M + 1)

¹ H-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 (q, 2H), 2.88 (m, 2H), 2.61 (br t, 1H), 2.33 (m, 4H), 1.76-1.37 (m, 16H).

2-cyanoimino-3-methoxycarbonylmethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 98.3%

MS: m / z 424.2 (M + 1)

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, 3H), 3.34 (m, 2H), 2.78 (m, 2H), 2.62 (br t, 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

LC: 100%

MS: m / z 391.2 (M + 1)

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 (br t, 1H), 2.33 (m, 4H), 1.86-1.37 (m, 16H).

2-cyanoimino-3-butyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 95.4%

MS: m / z 352.2 (M + 1)

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).

2-cyanoimino-3- (2-methanesulfonamido) ethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 100%

MS: m / z 473.2 (M + 1)

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 (s, 3H), 2.82 (s, 3H), 2.60 (br 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

LC: 100%

MS: m / z 409.2 (M + 1)

¹ H-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), 2.62 (br t, 1H), 2.30 (m, 4H); 1.80-1.37 (m, 15H).

2-cyanoimino-3-carboxymethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 97.5%

MS: m / z 409.9 (M + 1)

¹ H-NMR (DMSO): 7.45 (dd, 1H), 7.14 (m, 3H), 4.57 (s, 2H), 4.50 (m, 1H), 2.87 (m, 2H), 2.61 (br t, 1H), 2.33 (m, 4H), 1.75-1.37 (m, 15H).

2-cyanoimino-3- (2-dimethylamino) ethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole

LC: 100%

MS: m / z 423.3 (M + 1)

¹ H-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, 3H), 2.56-2.37 (m, 4H), 1.85 -1.35 (m, 15H).

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

2-cyanoimino-1- [1- (cyclooctyl) -2,6-ethan-4-one-4-piperidinyl] -1,3-dihydro-2H-benzimidazole

Other compounds encompassed by formula (IV) or (IVA) of the present invention can be synthesized by similar methods.

Example 15

The nociceptin affinity for the ORL1 receptor for the preferred compounds was determined using the following assay:

Membranes of recombinant HEK-293 cells expressing a receptor similar to a human opioid receptor (ORL1), (Receptor Biology), were obtained by lysing cells in ice-cold hypotonic buffer (2.5 mm MgCl ₂ , 50 mm HEPES, pH 7.4) (10 ml / 10 cm cup) followed by homogenization using a tissue homogenizer / teflon pestle. Membranes were collected by centrifugation at 30,000 xg for 15 min at 4 ° C and the pellet after centrifugation was resuspended in hypotonic buffer to a final concentration of 1-3 mg / ml. Protein concentrations were determined using BioRad protein reagent with bovine serum albumin as standard. Aliquots of ORL1 receptor membranes were stored at -80 ° C.

Functional binding assays of SGTPgS were performed as follows. An ORL1 membrane solution was prepared by sequentially adding final concentrations of 0.066 mg / ml ORL1 membrane protein, 10 mg / ml saponin, 3 mM GDP and 0.20 nM [ ³⁵ S] GTPgS to binding buffer (100 mM NaCl, 10 mM MgCl ₂ , 20 mM HEPES, pH 7.4) on ice. The resulting membrane solution (190 ml / well) was transferred to 96-well polypropylene plates containing 10 ml of 20x concentrated stock solutions of agonist obtained in DMSO. The plates were incubated for 30 minutes at room temperature with shaking. The reactions were terminated by rapid filtration on 96-well Unifilter GF / B filter plates (Packard) using a 96-well tissue harvester (Brandel) followed by three filter washes with 200 ml of ice-cold binding buffer (10 mM NaH ₂ PO ₄ , 10 mM Na ₂ HPO ₄ , pH 7.4). Filter plates were successively dried at 50 ° C for 2-3 hours. Fifty ml / well of scintillation count cocktail (BetaScint; Wallac) was added and the plates were read on a Packard Top-Count for 1 min / well.

Data was analyzed using an approximation of the functional dependence curve in GraphPad PRISMO, v.3.0, and the results are presented in table 4 below:

TABLE 4
Nociceptin Affinity Compound calculation K _i  (nM) 2-cyanoimino-3-ethyl-1- [1- (p-phenylbenzyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 5558 2-cyanoimino-3-ethyl-1- [1- (p-benzyloxybenzyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 1660 2-cyanoimino-3-ethyl-1- [1- (naphth-2-ylmethyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 882 2-cyanoimino-3-ethyl-1- [1- (4-propylcyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 241 2-cyanoimino-3-ethyl-1- [1- [4- (2-propyl) cyclohexyl] -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 6.9 2-cyanoimino-3-ethyl-1- [1- (decahydro-2-naphthyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 6.6 2-cyanoimino-3-ethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 5.57 2-cyanoimino-3-ethyl-1- [1- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole > 10,000 2-cyanoimino-3-ethyl-1- [1- (3,3-bis (phenyl) propyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 80 2-cyanoimino-3-ethyl-1- [1- (1,2,3,4-tetrahydronaphthyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 157 2-cyanoimino-3-ethyl-1- [1- (5-methylhex-2-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 76 2-cyanoimino-3-ethyl-1- [1- (norbornan-2-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 323 2-cyanoimino-3-ethyl-1- [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 89 2-cyanoimino-3-ethyl-1- [1- (cyclooctylmethyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 7.1 2-cyanoimino-3- (2-hydroxy) ethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 6.4 2-cyanoimino-3-methoxycarbonylmethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 3.3 2-cyanoimino-3-cyanomethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 0.97 2-cyanoimino-3-butyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 1.36 2-cyanoimino-3- (2-methanesulfonamido) ethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 78 2-cyanoimino-3-acetamido-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole eleven 2-cyanoimino-3-carboxymethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 201 2-cyanoimino-3- (2-dimethylamino) ethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole eighteen 2-cyanoimino-1- [1- (cyclooctyl) -3-hydroxymethyl-4-piperidinyl] -1,3-dihydro-2H-benzimidazole 473 2-cyanoimino-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-7-azabenzimidazole 3743 2-cyanoimino-1- [1- (cyclooctyl) -2,6-ethan-4-one-4-piperidinyl] -1,3-dihydro-2H-benzimidazole 19

Example 16

The μ receptor affinity for the compounds was determined in accordance with the following assay:

A membrane solution of a μ opioid receptor was prepared by sequentially adding final concentrations of 0.075 μg / μl of the desired membrane protein, 10 μg / ml saponin, 3 μM GDP and 0.20 nM [ ³⁵ S] GTPgS to the binding buffer (100 mM NaCl, 10 mM MgCl ₂ , 20 mM HEPES, pH 7.4) on ice. The resulting membrane solution (190 ml / well) was transferred to 96-well polypropylene plates containing 10 ml of 20x concentrated stock solutions of agonist obtained in DMSO. The plates were incubated for 30 minutes at room temperature with shaking. The reactions were terminated by rapid filtration on 96-well Unifilter GF / B filter plates (Packard) using a 96-well tissue harvester (Brandel) followed by three filter washes with 200 μl of ice-cold binding buffer (10 mM NaH ₂ PO ₄ , 10 mM Na ₂ HPO ₄ , pH 7.4). Filter plates were successively dried at 50 ° C for 2-3 hours. Fifty μl / well of scintillation count cocktail (MicroScint20; Packard) was added and the plates were read into a Packard Top-Count for 1 min / well.

The data were analyzed using an approximation of the functional dependence curve in GraphPad PRISMO, v.3.0, and the results for some compounds are presented in table 5 below:

TABLE 5
Μ receptor affinity Compound calculation K _i  (nM) 3- [1- (naphth-1-ylmethyl) -4-piperidinyl] -2H-benzoxazol-2-one 340 3- [l- (3,3-diphenylpropyl) -4-piperidinyl] -2H-benzoxazol-2-one 726 3- [1- (1,2,3,4-tetrahydro-2-naphthyl) -4-piperidinyl] -2H-benzoxazol-2-one 343 3- [1- (4-propylcyclohexyl) -4-piperidinyl] -2H-benzoxazol-2-one 145 3-ethylidene-1- [1- (1,2,3,4-tetrahydro-2-naphthyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 23.3 3-ethylidene-1- [1- (naphth-2-ylmethyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 137 3-ethylidene-1- [1- (p-benzyloxybenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 1150 3-ethylidene-1- [1- (3,3-diphenylpropyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one 24 1- [4 - [(naphth-2-yl) amino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one 2.1 2-cyanoimino-3-ethyl-1- [1- (4-propylcyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 46 2-cyanoimino-3-ethyl-1- [1- (1,2,3,4-tetrahydronaphthyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 458 2-cyanoimino-3-ethyl-1- [1- (5-methylhex-2-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole fifteen 2-cyanoimino-3-ethyl-1- [1- (norbornan-2-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole 1653

Claims (41)

1. The compound of formula (I)

where D is phenyl;
n represents 0;
A, B and Q represent hydrogen;
Z is selected from the group consisting of a bond, direct C _1-3 alkylene;
R _{1 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-8 cycloalkyl, benzyl, a 6-membered monocyclic, 9-10-membered bicyclic aromatic carbon-containing ring system and a spiro ring system of formula (V):

where X ₁ and X ₃ represent O;
and wherein said alkyl, cycloalkyl or benzyl from the group R _{1 is} optionally substituted with 1-3 substituents selected from the group consisting of C _1-3 alkyl, cyano, phenyl, wherein said phenyl is optionally substituted with 1-3 substituents selected from halogen;
or its pharmaceutically acceptable salts. 2. The compound according to claim 1, in which ZR ₁ is cyclohexylethyl, cyclohexylmethyl, cyclopentylmethyl, dimethylcyclohexylmethyl, phenylethyl, cyclopentyl, cyclohexyl or hexyl. 3. The compound according to claim 1, in which ZR ₁ is cyanomethyl. 4. The compound according to claim 1, in which ZR ₁ is 3,3-diphenylpropyl. 5. The compound of formula (IA):

where n represents 0;
Z is selected from the group consisting of a bond, —CH ₂ -;
R _{1 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-8 cycloalkyl, benzyl, a 6-membered monocyclic, 9-10-membered bicyclic aromatic carbon-containing ring system and a spiro ring system of formula (V):

in which X ₁ and X ₂ represent O;
wherein said alkyl, cycloalkyl or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of C _1-3 alkyl, cyano, phenyl, wherein said phenyl is optionally substituted with 1-3 substituents selected from halogen;
or its pharmaceutically acceptable salts. 6. The compound according to claim 5, in which R ₁ represents an alkyl selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl. 7. The compound according to claim 5, in which R ₁ represents cycloalkyl selected from the group consisting of cyclohexyl, cycloheptyl, cyclooctyl or norbornyl. 8. The compound according to claim 5, in which R ₁ represents tetrahydronaphthyl, decahydronaphthyl or dibenzocycloheptyl. 9. The compound according to claim 5, in which R ₁ represents phenyl or benzyl. 10. The compound according to claim 5, in which R ₁ represents a 9-10 membered bicyclic carbon-containing aromatic ring. 11. The compound of claim 10, wherein said bicyclic aromatic ring
represents indenyl or naphthyl. 12. The compound according to claim 5, in which Z represents a bond. 13. A compound selected from the group consisting of:
3- [1- (p-cyanobenzyl) -4-piperidinyl] -2H-benzoxazol-2-one;
3- [1- [4,4-bis- (4-fluorophenyl) butyl] -4-piperidinyl] -2H-benzoxazol-2-one;
3- [1- (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- [1- (5-methylhex-2-yl) -4-piperidinyl] -2H-benzoxazol-2-one;
3- [1- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) -4-piperidinyl] -2H-benzoxazol-2-one;
3- [1- (4-propylcyclohexyl) -4-piperidinyl] -2H-benzoxazol-2-one;
3- [1- (norbornan-2-yl) -4-piperidinyl] -2H-benzoxazol-2-one;
3- [1- (decahydro-2-naphthyl) -4-piperidinyl] -2H-benzoxazol-2-one;
3- [1- (3,3-dimethyl-1,5-dioxaspiro [5.5] undeca-9-yl) -4-piperidinyl] -2H-benzoxazol-2-one;
3- [1- [4- (1-methylethyl) cyclohexyl] -4-piperidinyl] -2H-benzoxazol-2-one;
3- [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -2H-benzoxazol-2-one;
3- [1- (cyclooctyl) -4-piperidinyl] -2H-benzoxazol-2-one;
and their pharmaceutically acceptable salts. 14. The compound of formula (II):

where the dotted line represents an optional double bond;
R represents C _1-3 alkyl;
n represents 0;
D represents a 6 membered aromatic group;
A, B and Q independently represent hydrogen, C _1-3 alkyl;
Z is selected from the group consisting of a bond, direct C _1-3 alkylene;
R _{1 is} selected from the group consisting of C _1-10 alkyl, C _3-12 cycloalkyl, benzyl, a monocyclic 6-membered aryl ring system;
where the specified alkyl, cycloalkyl or benzyl from the group R ₁ optionally substituted by 1-3 substituents selected from the group consisting of cyano, phenyl, benzyloxy;
or its pharmaceutically acceptable salts. 15. The compound of claim 14, wherein D is phenyl. 16. The compound of claim 14, wherein ZR _{1 is} selected from the group consisting of cyclohexyl ethyl, cyclohexyl methyl, cyclopentyl methyl, phenylethyl, cyclopentyl, cyclohexyl or hexyl. 17. The compound of claim 14, wherein ZR ₁ is cyanomethyl. 18. The compound of claim 14, wherein ZR ₁ is 3,3-diphenylpropyl. 19. The compound of formula (IIA):

where the dotted line represents an optional double bond;
Z is selected from the group consisting of bond, —CH ₂ -;
n represents 0;
R and Q are the same or different and each is selected from the group consisting of C _1-3 alkyl;
R ₁ selected from the group consisting of C _1-10 alkyl, C _3-12 cycloalkyl, benzyl, monocyclic 6-membered aryl ring system;
wherein said alkyl, cycloalkyl, benzyl is optionally substituted with 1-3 substituents selected from the group consisting of cyano, phenyl, benzyloxy;
or its pharmaceutically acceptable salts. 20. The compound according to claim 19, in which Q represents methyl. 21. The compound according to claim 19, in which R represents methyl, ethyl or ethylidene. 22. The compound according to claim 19, in which R ₁ represents an alkyl selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl or hexyl. 23. The compound of claim 19, wherein R ₁ is cycloalkyl selected from the group consisting of cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and norbornyl. 24. The compound according to claim 19, in which R ₁ represents phenyl or benzyl. 25. The compound according to claim 19, in which Z represents a bond. 26. The compound according to claim 19, in which the dashed line represents a double bond. 27. A compound selected from the group consisting of:
3-ethylidene-1- [1- (5-methylhex-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;
3-ethylidene-1- [1- (4-propylcyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;
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;
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;
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- [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- (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;
1- [1- (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- [1- (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- [1- (p-cyanobenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;
1- [1- (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- [1- (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- [1- (5-methylhex-2-yl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;
1- [1- (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- [1- (cyclooctylmethyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;
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- [4- (1-methylethyl) cyclohexyl] -3-methyl-4-piperidinyl] -1,3-dihydro-2H-indol-2-one;
3-ethyl-1- [1- (decahydro-2-naphthyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;
and its pharmaceutically acceptable salts. 28. The compound of formula (III):

where R represents C _1-3 alkyl;
n represents 0;
D represents a 6 membered aromatic group;
Z represents a cycloalkylamine system of formula (VI):

where A, B and Q are hydrogen;
R ₁ selected from the group consisting of C _1-3 alkyl, C _3-12 cycloalkyl, benzyl, 10-membered bicyclic aryl ring system;
wherein said cycloalkyl or benzyl from the group R _{1 is} optionally substituted with 1-3 substituents selected from the group consisting of C _1-10 alkyl, phenyl, benzyloxy;
or its pharmaceutically acceptable salts. 29. The compound of claim 28, wherein D is phenyl. 30. The compound of formula (IIIA):

where n represents 0;
Z represents a cycloalkylamine system of formula (VI):

R represents C _1-3 alkyl;
R ₁ selected from the group consisting of C _1-3 alkyl, C _3-12 cycloalkyl, benzyl, 10-membered bicyclic aryl ring system;
wherein said cycloalkyl or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of C _1-10 alkyl, phenyl, benzyloxy;
or its pharmaceutically acceptable salts. 31. The compound of claim 30, wherein R ₁ is alkyl selected from the group consisting of methyl, ethyl, and propyl. 32. The compound of claim 30, wherein R ₁ is cycloalkyl selected from the group consisting of cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and norbornyl. 33. The compound of claim 30, wherein R ₁ is tetrahydronaphthyl or decahydronaphthyl. 34. The compound of claim 30, wherein R ₁ is benzyl. 35. The compound of claim 30, wherein R ₁ is a 10-bicyclic aromatic ring. 36. The compound of claim 35, wherein said bicyclic aromatic ring is indenyl or naphthyl. 37. A compound selected from the group consisting of:
1- [4- (norbornan-2-ylamino) cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one;
1- [4 - [[4- (1-methylethyl) cyclohexyl] amino] cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one;
1- [4 - [(decahydro-2-naphthyl) amino] cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one;
1- [4 - [(cyclooctylmethyl) amino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;
1- [4 - [(naphth-2-yl) amino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;
1- [4 - [(p-benzyloxybenzyl) amino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;
1- [4 - [(decahydro-2-naphthyl) amino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;
1- [4- (dibenzylamino) cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;
1- [4 - [(p-phenylbenzyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;
1- [4 - [(1,2,3,4-tetrahydronaphthyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;
1- [4 - [(4-propylcyclohexyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;
1- [4 - [(5-methylhex-2-yl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;
1- [4 - [(decahydro-2-naphthyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;
1- [4- (cyclooctylamino) cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;
1- [4 - [(indan-2-yl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;
1- [4 - [(4-phenylcyclohexyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;
1- [4 - [(5-methylhex-2-yl) amino] cyclohexyl] -7-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one; and
its pharmaceutically acceptable salts. 38. A compound selected from
1- [4 - [(naphth-2-ylmethyl) ethylamino] cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one;
1- [4 - [(indan-2-yl) benzylamino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;
1- [4- (benzylamino) cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one. 39. A pharmaceutical composition having the property of an ORL1 or μ opioid receptor inhibitor, comprising an effective amount of a compound according to any one of claims 1, 5, 13, 14, 19, 27, 28, 30, 37 or 38, and at least one pharmaceutically acceptable excipient. 40. A method of treating pain, comprising administering to a patient in need thereof an effective amount of an analgesic compound according to any one of claims 1, 5, 13, 14, 19, 27, 28, 30, 37 or 38. 41. A method of modulating the pharmacological response from an opioid receptor, including an ORL1 receptor or μ opioid receptor, comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1, 5, 13, 14, 19, 27, 28, 30, 37 or 38.