AU2005227380A1 - Nociceptin Analogs - Google Patents

Description

P/00/011 28/5/91 Regulation 3.2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Name of Applicant: Actual Inventor Address for service is: Euro-Celtique, S.A.S.

Sun, Qun Goehring, Richard R Kyle, Donald Chen, Zhengming Victory, Sam Whitehead, John WRAY ASSOCIATES Level 4, The Quadrant 1 William Street Perth, WA 6000 Attorney code: WR Invention Title: "Nociceptin Analogs" The following statement is a full description of this invention, including the best method of performing it known to me:-

O

O

NOCICEPTIN ANALOGS This application claims priority from U.S. Provisional Application Serial Nos.

60/284,666; 60/284,667; 60/284,668; 60/284,669 all filed April 18, 2001, the O disclosures of which are hereby incorporated by reference.

00 BACKGROUND OF THE INVENTION C Chronic pain is a major contributor to disability and is the cause of an untold amount of suffering. The successful treatment of severe and chronic pain is a primary goal of the physician with opioid analgesics being preferred drugs.

Until recently, there was evidence of three major classes of opioid receptors in the central nervous system (CNS), with each class having subtype receptors. These receptor classes were designated as g, 8 and K. As opiates had a high affinity to these receptors while not being endogenous to the body, research followed in order, to identify and isolate the endogenous ligands to these receptors. These ligands were identified as enkephalins, endorphins and dynorphins.

Recent experimentation has led to the identification of a cDNA encoding an opioid receptor-like (ORL1) receptor with a high degree of homology to the known receptor classes. This newly discovered receptor was classified as an opioid receptor based only on structural grounds, as the receptor did not exhibit pharmacological homology. It was initially demdnstrated that non-selective ligands having a high affinity for it, 6 and c receptors had low affinity for the ORL1. This characteristic, along with the fact that an endogenous ligand had not yet been discovered, led to the term "orphan receptor".

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

The discovery of the ORL1 receptor presents an opportunity in drug discovery for novel compounds which can be administered for pain management or other syndromes modulated by this receptor.

All documents cited herein, including the foregoing, are incorporated by reference in their entireties for all purposes.

O

O

OBJECTS AND SUMMARY OF THE INVENTION

O

It is accordingly an object of certain embodiments of the present invention to provide new compounds which exhibit affinity for the ORL1 receptor.

It is an object of certain embodiments of the.present invention tb provide new C compounds which exhibit affinity for the ORL1 receptor and one or more of the g, 5 or Ki receptors.

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

It is an object of certain embodiments of the present invention to provide new compounds which have agonist activity at the p, 8 and ic receptors which is greater than compounds currently available e.g. morphine.

It is an object of certain embodiments of the present invention to provide methods of treating chronic and acute pain by administering compounds which have agonist activity at the 5 and Ki receptors which is greater than compounds currently available.

It is an object of certain embodiments of the present invention to provide methods of treating chronic and acute pain by administering non-opioid compounds which have agonist activity at the p, 8 and i receptors and which produce less side effects than compounds currently available.

It is an object of certain embodiments of the present invention to provide compounds useful as analgesics, anti-inflammatories, diuretics, anesthetics and neuroprotective agents, anti-hypertensives, anti-anxioltics; agents for appetite control; hearing regulators; anti-tussives, anti-asthmatics, modulators of locomotor activity, modulators of learning and memory, regulators of neurotransmitter and hormone release, kidney function modulators, anti-depressants, agents to treat memory loss due to Alzheimer's disease or other dementias, anti-epileptics, anti-convulsants, agents to treat withdrawal from alcohol and drugs of addiction, agents to control water balance, agents to control sodium excretion and agents to control arterial blood.pressure disorders and methods for administering said compounds.

The compounds of the present invention are useful for modulating a pharmacodynamic response from one or more opioid receptors (ORL-1, g, 8 and K) centrally and/or peripherally. The response can be attributed to the compound stimulating (agonist) or inhibiting (antagonist) the one or more receptors. Certain compounds can 0 stimulate one receptor a Vi agonist) and inhibit a different receptor an ORL-1I antagonist).

Other objects and advantages of the present invention Will become apparent from the following detailed description thereof. The present invention in certain embodiments 00 M comprises compounds having the general formula c-i R 2 (n) Dn 0 AN B wherein D is a 5-8 membered cycloalkyl, 5-8 mem'bered heterocyclic or a 6 membered aromatic or heteroaromatic group; n is an integer from 0 to 3; A. B and Q are independently hydrogen, alkyl, C34.2 cycloalkyl, C 1 1 0 alkoxy,

C

3 4.

2 cycloalkoxy, -0112011, -NHSO 2 hydroxyC 1 10 alkyl-, aminocarbonyl-, C 1 4 allcylaminocarbonyl-, diC 1 4 alkylamninocarbonyl-, acylamino-, aqylaninoalkyl-, anmide, sulfonylaminoC.

10 alcyl-, or A-B can together form a C2- bridge, or B-Q can together form a C 3 7 bridge, or A-Q can together form a C1.5 bridge; Z is selected from the group consisting of a bond, straight or branched CI14 alkylene, -CH 2

-CH

2

-CH

2

N(CH

3

-NHCH

2

-CH

2 CONH-, -NHCH 2

CO-,

-CH

2 C0-, -COCH 2

-CH

2 COCH-,C(H), and -HC=CH-, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with one or more lower o alkyl, hydroxy, halo or alkoxy group; R, is selected from the group consisting of hydrogen, CI- 10 alkyl, C 312 cycloalkyl,

C

2 .1 0 allcenyl, amino, 10 alkYlaMino-, C 3 4icycloa~kylamino-, -COOVI, -CI, 4 COOiVI, cyano, cyanoC, 0 alkyl-, cyanoC3- 10 cycloalkyl-, NH 2

SO

2

NH

2

SO

2 C,-alkyI-, NH 2

SQC,..

00 4 alkyl-, aminocarbonyl-, C,..4akylaminocarbony1-, dliC, 4 alkylaminocarbonyl-, benzyl, C 3 12 cycloalkenyl-, a monocyclic, bicYclic or tricyclic aryl or heteroaryl ring, a heteromonocyclic ring, a hetero-bicyclic ring system, and a spiro ring system of the formula

X

2

(V)

wherein X, and X 2 are independently selected from the, group consisting of NHl, 0, S and CH.; and wherein said alkyl, cycloalkyl, alkenyl, C 1 0 allylamino-, C 3 12 cycloalkylamino-, or benzyl of R, is optionally substituted with 1-3 substituents selected.

from the group consisting of halogen, hydroxy, CI-1 0 alkyl, C,- 40 ailcoxy, nitro, frifluoromethyl-, cyano, -COOVI, -C1 4 C00V 1 cyanoC 1 0 alkyl-, -C 1 SNHS(=O0) 2 WI, 5 NHS(=O)W,, a 5-membered heteroaromaticCoalkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, CI 10 alkyl-, 0 alkcoxy-, and cyano; and wherein said C 34 2 cycloalkyl, C 3 12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, or spiro ring system of the formula is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1 0 alkyl, C,, 0 o alkoxy, nitro, trifluorornethyl-, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogen,

C

1 0 alkyl, CI 10 alkoxy, and cyano; o WI is hydrogen, C 10 alkyl, C 31 2 cycloalkyl, C 1 1 0 alkoXY, C 3 1 2 cycloalkoxy,- 0 CH 2 OH, amino, C 1 -4allcylamino-, diC 1 4 alkylarnino-, or a*5-membered heteroaromatic ring optionally substituted with 1-3 lower alkyl; V, is H, C 1 Alkyl, C34 cycloallcyl, benzyl or phienyl;

R

2 is selected from the group consisting of hydrogen, C 1 1 0 alkyl, C3.12 cycloalkyl- 00 M and halogen, said alkyl or cycloalkyl optionally substituted with an oxo, amino, alkylamino or dialkylamino group;' and pharmaceutically acceptable salts thereof and solvates thereof.

The present invention in certain embodiments comprises compounds having the (1 general formula (IA) as follows:

R

2 (n)

K~

0 0

N,

N

(IA)

wherein n is an integer from 0 to 3; Z is selected from the group consisting of a bond, -CH 2

-CH

2

-CH

2

CH

2

-CH

2 NH-, -CH 2

N(CH

3

-NHCH

2

-CH

2 CONH-, -NHCH 2 CO-, -CH 2 CO-, -GOGH 2

CH

2

COCH

2

-CH(CH

3 and -HC=CH-, wherein the carbo~n and/or nitrogen atoms are unsubstituted. or substituted with a lower alkyl, halogen, hydroicy or alkoxy group; R, is selected from the group consisting of hydrogen, CI- 10 alkyl, 2 cycloalkyl, C 2 1 0 alkenyl, amino, C 110 alkYlarnino, C3- 12 Cycloalkylamino, benzyl, C 3 12 cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a hetero-monocyclic ring, a hetero- O bicyclic ring system, and a spiro ring system of the formula 00 X2 (v) wherein-X and X 2 are independently selected from the group consisting of NH, O, S and CHz; wherein said monocyclic aryl is preferably phenyl; wherein said bicyclic aryl is preferably naphthyl; wherein said alkyl, cycloalkyl, alkenyl, C.-oalkylamino, C 3 1 2 cycloalkylamino, or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halpgen, Cl-10 alkyl, C 11 o alkoxy, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, C 1 1 0 alkyl, CI-10 alkoxy, and cyano; wherein said C3.12 cycloalkyl, C3.12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, and spiro ring system of the formula are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1.0 alkyl, C1.10 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 of halogen, C1,10 alkyl, CI-1 alkoxy, and cyano;

R

2 is selected from the group consisting of hydrogen, CI-10 alkyl, C3.12 cycloallyl and halogen, said alkyl optionally substituted with an oxo group; and pharmaceutically acceptable salts thereof and solvates thereof.

In certain preferred embodiments of formula D is phenyl or a 6 membered heteroaromatic group containing 1-3 nitrogen atoms.

In certain preferred embodiments of formula or the R, alkyl is methyl, ethyl, propyl, butyl, pentyl, or hexyl.

In certain preferred embodiments of formula or the R cycloallcyl is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, or norbomyl.

0In other prefdrredembodiments of formula or the R, bicyclic ring system is naphthyl. In other preferred embodiments of formula or the R, bicyclic ring system is tetrahydronaphthyi, or decahydronaphthyl and the R, tricyclic ring system js dibenzocycloheptyl. In other preferred embodiments R, is phenyl or benzyl.

00 In other preferred embodiments of formula or the R, bicyclic aromatic ring is a lO-membered ring, preferably quinoline or naphthyl.

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

(N In certain embodiments of formula or Z is a bond, methyl, or ethyl.

In certain embodiments of formula or the Z group is maximally substituted.

as not to have any hydrogen substitution on the base Z group. For example, if the base Z group is -CE 2 substitution with two miethyl groups would remove hydrogens from the base Z group..

In other preferred embodiments of formula or n is 0.

In certain embodiments of formula or X, and X2 are both 0.

In certain embodiments of formula ZR 1 is cyclohexylethyl-, cyclohexylmrethyl-, cyclopentyimethyl-, diniethylcyclohexylmethyl-, phenylethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl-, pyridylethyl', cyclopentyl-, cyclohexyl-, mithoxycyclohexyl-, tetrahydropyranyl-, propylpiperidinyl-, indolyimethyl-, pyrazoylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl-, or oxocanyipropyl-.

In certain embodiments of formula ZRI is -CH 2

COOV

1 tetrazolylmethlyl-, cyanoMethyl-, NH 2

SQ

2 methyl-, NH 2 SOmethyl-, aminocarbonylmethyl-, C 1 4 allcylaminocarbonylmethyl-, or diC 1 ~akylaminocarbonyhnethy-.

In certain embodiments of formula ZR 1 is 3,3 diphenylpropyl optionally substituted at the 3 carbon of the propyl with -COOVI, tetrazolylC,,_alkyl-, cyano-, aminocarbonyl-, CI-4alkylarninocarbonyl-, or diCj 4 alkylamiaocarbonyl-.

The present invention in certain embodiments comprises compounds having the general formula (II):

C.)R

2

R

0]N 00

MQ

AN

B

wherein the dotted line represents an optional double bond; R is hydrogen, 0C.-10 alkyl C 3 12 cycloaicyl, C3-12 4CyloalcylC 1 4 alkyl-, CI-1 alkoxy, C3-12 CYCloalkoxy-, CI- 1 0 alkenyl, CI-.

1 0 alkylidene, oxo, CI1 alkyl substituted with 1-3 halogen, 03.12 cycloallcyl substituted with 1-3 halogen, C 3 4 12 cycloalkylC-4alkyl- substituted with 1-3 halogen, 01-10 alkoxy substituted with 1-3 halogen, C3-12 CYCloallCOXY- siibstituted with 1-3 halogen, -C00V 1

-CI

1 4COOV 1

-CH

2 OH, -SO 2

N(V

1 2 I hydroXYC 1 10 alkyl-, hydroXYC 310 cycloalcyl-, cyanoC 1 10 allcyl-', cyanoC 3 10 cycloalkyl-, -CON(V 1 2

NH

2 S0 2

CI,

4 allcyl-, NI{ 2

SOC

14 a'kYl-, SUlfonylaxninoC 1 1 0 allcYl-, diamninoakyl-, -sulfonylC 1 4 alcyl, a 6membered heterocyclic ring, a 6-membered heteroaromatic ring, a 6-membered heterocycicC,,alcyl-, a 6-membered heteroaromaticC 1 4 alcyl-, a 6-membered aromatic ring, a 6-membered aromaticCA alkyl-, a 5-membered heterocyclic ring optionally substituted with an oxo or thio, a 5-membered heteroaromatic ring, a heterocyclicC, 4 alkyl- optionally substituted with an oxo or thio, a heteroaromaticC.~allcyl-,

-C

1 5 (=O0)WI 1

-C

1 5 5 NHC(=0)W 1

-CI-.

NHS(=0) 2

W

1 -0 1 5 NHS(=-o)w 1 Wherein W, is hydrogen, CI-1 alkyl, 0312 cycloalkyl, C 1 alcoxy, C312 cycloalkoxy, -CH 2 OH, amino, C 1 4 alkylaxnino-, diC 14 alkylamino-, or a membered heteroarornatic ring optionally substituted with 1-3 lower ailcyl; o wherein each V, is independently selected from H, ailkyl, CM~ cycloalkyl, benzyl.

and phenyl; n is an integer from 0 to 3; D is a 5-8 membered cycloalkyl, 5-8 membered heterocyclic or a 6 membered 00 aromatic or heteroaromatic group; n is an integer from 0 to 3; A, B and Q are independently hydrogen, C 1 1 0 alkyl, C 3 1 2 CYCloalkyl, C alkoxy,

C

3 4.

2 cycloalkoxy, CI- 1 0 alkenyl, C 1 0 alkylidene, oxo, -CH 2 OH, -NHSQ 2 hYdroXYC..

c1 10 alkyl-, arniocarbonyl-, C 14 alkylaminocarbonyl-, diC 14 alkylaminocarbonyl-, acylarnino-, acylaminoalkyl-, amide, sulfonylaminoC..

10 alkyl-, or A-B can together form a C2- bridge, or B-Q can together form a C3-, bridge, or A-Q can together form a C 14 5 bridge; Z is selected from the group consisting of a bond, straight or branched C 1 6 alkylene, -CH 2

-CH

2 NH-, -CH 2

N(CH

3

-NHCH

2

-CH

2 CONH-, -NIICH 2 00-,

-CH

2

-COCI{

2

-CH

2

COCH

2

-CH(CH

3 and -HC=CH-, wherein te carbon and/or nitrogen atoms are unsubstituted or substituted with one or more lower alkyl, hydroxy, halo or alkoxy group; R, is selected from the group consisting of hydrogen, C11 alkyl, C3.

12 cyclOalkyl,

C

2 10 alkenYl, amino, C- 1 0 alkylamino-, C 3 2 cycloalkylamino-, -COOV 1

-C

1 -4C00V 1 cyano, cyanoC 1 1 0 alkyl-, cyanoC 3 10 cycloalicyl-, NH 2

SO

2 N H 2

SO

2

C

1 lalkY1-, NH 2

SOCI-

4 alkyl-, aminocarbonyl-, C 1 4aklaminocarbonyl-, diC, 4 alkylamninocarbonyl-, benzyl, C 3 12 cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a heteromonocyclic ring, a hetero-bicyclic. ring system, and a spiro ring system of the formula'(V):

X,

X

2

(V)

wherein X 1 and X2 are independently selected from the group consisting of NHT, 0, S and CH 2 and wherein said alkyl, cycloalkyl, alkenyl, 1 alkylamino-, C 3 12 cycloalkylamiino-, or benzyl. of R, is optionally substituted with 1-3 substituents selected 0 from the group consisting of halogen, hydroxy, C 1 1 0 alkyl, CI1 alkoxy, nitro, trifluoromethyl-, cyano, -COOV 1

-C

14 C00V 1 cyanoC 1 1 0 allcyl-, -C 1 5 1 -Cl.

NHS(=O)

2 Wj, -Cj- 5 NHS(=O)Wj, a 5-membered heteroaromaticCO-alky1-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with :1-3 00 substituents selected from the group consisting of halogen, C 1 1 0 ailkyl-, C 10 alkoxy-, and cyano; and wherein said C 342 cycloalkyl, C 3 .1 2 cycloallcenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ri ng, hetero-bicyclic ring syst'em,: or spiro ring system of the formula is optionally substituted with 1-3 substituents selected from c-i the group consisting of halogen, CI-.

1 0 alkyl, C 1 1 0 ailkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogen,

C

1 10 alkyl, CI-.

1 0 alkoxy, and cyano;.

R. is selected from the group consisting of hydrogen, 1 0 alkyl, C 3 2 cycloalcyland halogen, paid ailkyl or cycloalkcyl optionally substituted with an oxo, amino, alkylamino or dialkcylainino group; and pharmaceutically acceptable salts thereof and solvates thereof.

The present invention in certain embodiments comprises cornpounds having the formula (RA): 1

(IIA)

o the dotted line represents an optional double bond; Z sselected from the group consisting of a bond, -OH 2 -NHl-, -CH 2 -0112012c-i

,-CH

2 NH-, -CH- 2 N(CH3)-, -NHCH 2 -CH1 2 C0NH -NHCH1 2 00-,-H 2 -000112-,

CH

2

COCH

2

-CH(CH

3 -CH1=, and -HC=CH-, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with a lower aIkyl, halogen, hydroxy or alkoxy 00 M group; c- R and Q are the same or different and are each selected from the group. consisting c-i of hydrogen, halogen, 01..10 alkyl, 0 1 1 0 alkenyl, 01.10 alkylidene, C3. cycloalkyl, 01.10 alkoxy, and oxo; c-i R, is selected from the group consisting of hydrogen, C 1 10 allC 3 12 cycloalkyl, 02.

l 0 alkenyl, amino, C 1 10 alkylamino, C 3 12 cycloalkylamino, benzyl, 0312 cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a heteromonocyclic ring, a bicyclic ring system, and a spiro ring system of the formula

X

2 (X1) wherein X, and X 2 are independently selected from the group consisting of NH, 0, S and OH 2 wherein said monocyclic aryl is preferably phenyl; wherein said bicyclic aryl is preferably naphthyl; wherein said alkyl, cycloalcyl, alkenyl, C 1 10 alkylarnino, C3- 12 CYCloallcylaniino, or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, 01.10 alkyl, 01.10 alkoxy, nitro, trifluoromethayl, cyano, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, C0~ ailkyl, C1.10 alkoxy, and cyano; wherein said C 3 4 12 cycloalkyl, C342 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system, and spiro ring system of the formula are optionally substituted with 1-3 substituents selected from the group consisting of haogen, 0110O alkyl 01.10 alkoxy, nitro, trifluoromethyl, p henyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy

I_

are optionally substituted with 1-3 substituents selected from the group consisting of O halogen, C,-1o alkyl, Ci.,o alkoxy, and cyano;

R

2 is selected from the group consisting of hydrogen, C1.10 alkyl, C 3 1 2 cycloalkyl and halogen, said alkyl optionally substituted with an oxo group; and pharmaceutically acceptable salts thereof.

00 In certain preferred embodiments Q of formula (II) or is hydrogen or methyl.

In certain preferred embodiments, R of formula (II) or is hydrogen, methyl, C ethyl, or ethylidene.

n In certain preferred embodiments of formula D is phenyl or a 6 membered heteroaromatic group containing 1-3 nitrogen atoms.

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

In certain preferred embodiments of formula or (IIA), the R, cycloalkyl is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, or norbomyl.

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

In other preferred embodiments of formula (11) or the R, bicyclic aromatic ring is a 10-membered ring, preferably quinoline or naphthyl.

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

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

In certain embodiments of formula or (IIA), the Z group is maximally substituted as not to have any hydrogen substitution on the base Z group. For example, if the base Z group is -CH 2 substitution with two methyl groups would remove hydrogens from the -CH 2 base Z group.

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

In certain embodiments of formula (II) or (IIA), X, and X. are both O.

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

In certain embodiments of formula 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)CH3, -S02CH 3

CH

2

CH

2

NHSO

2

CH

3 furanylcarbonyl-, methylpyrrolylcarbonyl-, diazoleearbonyl-, azolemethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxo-oxazolemethyl-, or diazolemethyl-.

In certain embodiments of formula ZR is cyclohexylethyl-, cyclohexylmethyl-, cyclopentylmethyl-, dimethylcyclohexylmethyl-, phenylethyl-, pyrrolyltrifluoroethyl-, thienyltritluoroethyl-, pyridylethiyl-, cyclopentyl-, cyclohexyl-, methoxycyclohexyl-, o tetrahydropyranyl-, propylpiperidinyl-, indolylniethyl-, pyrazoylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhdxyl-, isopropoxybutyl-, hexyl-, or oxocanyipropyl-.

In certain embodiments of formula at least one of ZR 1 or R is -CH 2

CQOV

1 00 tetrazolylmethyl-, cyanomethyl-, NH 2

SO

2 methyl-, NH 2 SOmethyl-, aminocarbonylmethyl-, M C 1 4 alkylaminocarbonylmethyl-, or diC,4alkylarninocarbonylmethyl..

c-i In certain embodiments of formula ZR, is 3,3 diphenylpropyl optionally c-i substituted at the 3 carbon of the propyl with -COOVI, tetrazolylC 0 4 alkyl-, cyano-, an-ilnocarbonyl-, C 1 4 alkylarinocarbonyl-, or diC 1 4 allclaninocarbonyl-.

c-i The present invention in certain embodiments comprises compounds having the general formula (Il:

R

2 (n) D0

N

I

wherein R is hydrogen, C 1 1 0 alkyl, C 3 1 2 cyclIoalkyl, C 3 1 2 cycloa4lkl 4 alkYl-, C 11 0 alkoxy, C,- 1 2 cycloalkoxy-, CI1 alkyl substituted with 1-3 halogen, C 3 1 2 cycloalkcyl substituted with 1-3 halogen, C 3 4.

2 cycloalcylC 1 4 alcyI- substituted with 1-3 halogen, C 1 1 0 alkoxy substituted with 1 -3 haogen, C4 cycloalkoxy- substituted with 1-3 halogen,

-COOV

1 -C14C0OV 1

-CH

2 OH, -SO 2

N(V

1 2 hydroxyC..

10 alkyl-, hydroXYC 3 10 cycloalkyl- ,cyanoC 1 10 alkyl-, cyanoC 3 10 cycloalkyl-, -CON(V 1 2

NH

2 SQ2CI.

4 alkyl-, NH 2 SOC14akYl-, sulfonylaminoC,- 1 0 alkyl-, diaminoalkyl-, -sulfonylC..

4 alkyl, a 6-niembered heterocyclic ring, a 6-membered heteroaromatic ring, a 6-membered heterocycliC 1 A4alkyl-, a 6-membered heteroaromatic C.

4 allcyl-, a 6-membered aromatic ring, a 6-membered aromaticC14 alkyl-, a 5-membered heterocyclic ring optionally substituted with an oxo or thio, a o heteroaromatic ring, a 5-membered heterocyclicC 1 ~alkyl- optionally substituted withi an oxo or thio, a 5-membered heteroaromatiC 4 alcyl-, -C 1 5

(=O)W

1

-CI

1 5 NH)W,, -C 1 INHC(=O)Wl, -C 1 5

NHS(=)

2 WI, -C 1 5

NHS(=Q)W

1 wherein W, is hydrogen, C 140 o alkyl, 3.12 cycloalkyl, C1.10 alcoXY, C3-12 cycloalkoxcy, -CH 2 OH, amino, C M4alkcylamino-, diCj.

00 4 alcylamuno-, or a 5-membered heteroaromatic ring optionally substituted with 1-3 lower ailkyl; C1 wherein each V, is independently selected from H, C,-6 alkyl, C3.6 CYClOalkyl, benzyl and phenyl; n is aninteger from 0to 3; (71 D is a 5-8 membered cycloallcyl, 5-8 membered heterocyclic or a 6 membered aromatic or heteroaromatic group; Z is selected from the group consisting of a bond, straight or branched C1.6 alkylene, -(2120-, -CH 2 NH-, -CH 2

N(CH

3

-NHCH

2

-CH

2 CONH-, -NHCH 2

CO-,

-CH

2 CO-, -COCH 2

-CH

2 00CH 2 -C(211013)-, and -HC=CH-, wlierein the carbon and/or nitrogen atoms are unsubstituted or substituted with one or more lower alkyl, hydroxy, halo or alkoxy group; or Z is a cycloalkylamino system of the formula (VI):

(VI)

wherein A, B and Q are independently hydrogen, C 1 1 0 alkyl, C3- 12 cycloalcyl, C -1 alkoxy, 312 cycloalcoxy, -(212011, -NHS 02, hydroxyC 1 1 0 alkyl-, aminocarbonyl-, C 1 4 alkylaminocarbonyl-, diG 14 allcylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide, sulfonlylarninoC 1 1 0 alkyl-, or A-B can together form a 2.6 bridge, or B-Q can together form a (23.7 bridge, or A-Q can together form a CI- bridge; R, is selected from the group consisting of hydrogen, CI- 1 0 alkyl, C 312 cycloalkyl, C-2 10 alkenyl, amino, C 1 1 0 alkylaniino-, C 3 4 2 cycloalkylamino-, -COOVI, -CI- 4 C00V 1 cyano, cyanoC 11 oallcyl-, cyanoC3 10 cycloalcyl-, NH 2

SO

2

NH

2 S0 2 C,4alkyl-, NH 2

SOC,.

4 alkyl-, aminocarbonyl-, C 1 4a~kylaminocarbonyl-, diCl~alkylaminocarbonyl-, benzyl, C 34 2 cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a heteroo monocyclic ring, a hetero-bicyclic ring system,4 and a spiro ring system of the formula

X,

00

(V)

c-i wherein X, and X 2 are independently selected from the group consisting of NH, 0, S and CH 2 and wherein said alkyl, cycloalkyl, alkenyl, C 1 10 alcylarnino-, 03.

12 CYCloalkylamino-, or benzyl of R, is optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C 1 1 0 alkyl, t01-10* alkoxy, itrq, trifluoromethyl-, cyano, -COOV 1 -COM4OOYI, cyanoC.

10 alkyl-, -Ci.

5 -Ci..

NHS(=O)

2

-C

1 5 NHS(=O)W,, a 5-membered heteroarornaticCO-alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being'substituted with 1-3 substituents selected from the group consisting of halogen, C 1 1 0 alkyl-, CI-.10 alkoxy-, and cyano; and wherein said C3.12 cycloalkyl, 0342 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, or spiro ring system of the formula is optionally substituted with 1-3 substituents selected from the group consisting of halogen, t 1 _1 alkyl, C 1 1 0 alkoxy; nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogen,

C

1 1 0 alkyl, Cl-, ailcoxy, and cyano; is selected from the group consisting of hydrogen, Cl1 alkyl, C3-,2 cycloalcyland halogen, said alkcyl or cycloaicl optionally substituted with an oxo, amino, alkylamino or dialkylamino group; and pharmaceutically acceptable salts thereof and solvates thereof.

The present invention in certain embodiments comprises compounds having the formula (MA):

R

2 (n) (iaA) wherein nI is an integer from 0 to 3; Z is selected from the group consisting of a bond, -Gil 2

-CH

2

-CH

2

CH

2

-CH

2 NH-, -CH 2

N(CH

3

-NHCH

2

-CH

2 CONH-, -NI{CH 2 CO-, -CH 2 CO-, -GOGH 2

CH

2

COCH

2

-CH(CH

3 -HC=CH-, and a cycloalkylamino system of the formula

(VI):

(VI)

wherein the carbon and/or nitro gen atoms are unsubstititted. or substituted with a lower ailkyl, halogen, hydroxy, phenyl, benzyl, or alkoxy group; R is selected from the group consisting of hydrogen, C 110 ailkyl, CI1 alkoxy, and

C

3 12 cycloa lky R, is selected from the group consisting of hydrogen, C 1 .1(alkyl, C 3 12 cycloallcyl C 2 j 0 allcenyl, amino, C 1 1 aklamino, C 3 12 cycloalkylamino, benzyl, C 3 1 2 cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a heteromonocyclic ring, a heterobicyclic ring system, and a spiro ring system of the formula

O

O

r, 2 00

C,

n(V) C- wherein X, and X 2 are independently selected from the group consisting of NH, 0, S and CH,; wherein said monocyclic aryl is preferably phenyl; wherein said bicyclic aryl is preferably naphthyl; wherein said alkyl, cycloalkyl, alkenyl, CI- 1 alkylamino, C 3 2 cycloalkylamino, or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, Cio10 alkyl, C-o10 alkoxy, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected'from the group consisting of halogen, C.t-o alkyl, Ci-o alkoxy, and cyano; wherein said C 3 12 cycloalkyl, C3.12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system, and spiro ring system of the formula are optionally substituted with 1-3 substituents selected from the group consisting of halogen, CIo10 alkyl, Ci-1o 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 of halogen, alkyl, CI-io alkoxy, and cyano; R, is selected from the group consisting of hydrogen, C1.1o alkyl, C3-12 cycloalkyl and halogen, said alkyl optionally substituted with an oxo group; and pharmaceutically acceptable salts thereof.

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

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

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

In other preferred embodiments of formula (III) or (mIA), the R, bicyclic ring.

system is naphthyl. In other preferred embodiments of formula (MI) or (MiA), the R, o bicyclic ring system is tetrahydronaphthyl, or decahydronaphthyl and the R, tricyclic ring systemn is dibenzocycloheptyl. In other preferred embodiments R, is phenyl or benzyl.

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

00In other preferred embodiments of formula (IMl or (lIlA), the R, bicyclic aromatic ringis a 9-membered ring, preferably indenyl.

CI In certain embodiments of formula (Ml) or (111A), Z is a bond, methyl, or ethyl.

In certai emb~odiments of formula (IM) or (DIlA), the Z group is maximally substituted as not to have any hydrogen substitution on the base Z group. For example, if CI the base Z group is substitution with two methyl groups would remove hydrogens from the -CH- base Z group.

In certain embodiments of formula (l)or (flEA), Z is a cycloallcylaniino system of the formula (VI):

-N-

H

(VI)

wherein the nitrogen atom is optionally substituted with a C 1 ,.alkyl, phenyl, or beuzyl.

In other preferred embodiments of formula (MI) or (HIA), n is 0.

In certain embodiments of formula (I)or (HIA), X, and X 2 are both 0.

In certain embodiments of formula R is -CH 2

C(=O)NH

2

-C(NH)NH

2 *pyridyirnethyl, cyclopentyl, cyclohexyl, furanylmethlyl, -C(0-)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-, azolemethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxo-oxazoleinethyl-, or diazolemethyl-.

In certain embodiments of formula MDii, ZR 1 is cyclohexylethyl-, cyclohexylmethylcyclopentylmethyl-, dimethylcyclohexylmethyl-, phenylethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl-, pyridylethyl-, cyclopentyl-, cyclohexyl-, methoxycyclohexyl-, tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyrazoylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-,1 hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl-, or o oxocanyipropyl-.

In certain embodiments of formula at least one of ZR 1 or R is -CH 2

COOV

1 Cl tetrazolylmethyl-, cyanomethyl-, NH 2

SQ

2 methyl-, NH 2 S~methyl-, aminocarbonylmethyl-, Cl-4allcylaminocarbonyhmethyl-, or diCJ-4allylaminocarbonylmethy-.

In certain embodiments of formula ZR;* is 3,3 diphenyipropyl optionally M ~substituted at the 3 carbon of the propyl with -COOV 1 tetrazolylC 0 4 alkyl-, cyano-, aminocarbonyl:, C 1 .4alkylaxinocarbonyl-,.or diCt-4allcylaminocarbonyl-.

The present invention in certain embodiments comprises. c ompounds having the general formula (MV:

R

2

I

N

DN

K ~N -LC N

Q

A' N B z

R,

wherein R is hydrogen, CI1 alkyl, C 3 12 cycloalkyl, C 3 1 2 cycloallcylC 1 4alkyl-, CI-1 alkoxy, C 3 -12 cycloalkoxy-, 1 alk substituted with 1-3 halogen, C3-1 cyoloalkyl substituted with 1-3 halogen, C 3 1 2 cycloalcylC.-4alky1- substituted with 1-3 halogen, C 1 1 0 alkoxy substituted with 1-3 halogen, C: 3 .12 cycloalkoxy- substituted with 1-3 halogen, -COOV, -C 14 000V 1

-CH

2 OH, -SO 2

N(V

1 2 hydroxyC 1 10 alkyl-, hydroxyC 3 1 0 cycloalkylcyanoC 1 0 alkyl-, cyanOC.

0 cycloall-, -CON(VI) 2

NH

2

SO

2

C

1 4 alkyI-, NH 2

SOC

1 alkyl-, sulfonylaxninoC 1 10 alkyl-, diaminoalkyl-, -suLfonYlC 14 alkyl, a 6-membered heterocyclic ring, a 6-membered heteroaromatic ring, a 6-memibered heterocyclicC,4alkyl-, a 6-membered heteroaromaticC..

4 allcyl-, a 6-membered aromatic ring, a 6-membered aromaticCI- 4 alkyl-, a -membered heterocyclic ring optionally substituted with an oxo or tbio, a 5 -membered o heteroaromatic ring, a'5-membered heterocyclicC-4alky1- optionally substituted with an oxo or thio, a 5-membered heteroaromaticCalkyl-,

-C

1

-C

1

(NH)W

1

-C

2

NHIC(=O)W

1

-C

1 5

NHS(=O)

2

W

1 -Cl..

5 NHS(=O)W,, whereinW, is hydrogen, C 1 1 0 alkyl,

C

3 12 cycloalkyl, C11 alkoxy, C3- 12 cycloalkoxy, -CH 2 OH, amino, C,- 4 alkylamino-, diC 1 0C) 4 alkylamino-, or a 5-membered heteroaromatic ring optionally substituted with 1-3 lower alkyl; wherein each V, is independently selected from H, C1. alkyl, C3_ cycloallcyl, benzyl.

and phenyl; D is a 5-8 membered cycioalkyl, 5-8 membered heterocyclic or a 6 membered aromatic or heteroaromatic group; .n is an integer from 0 to 3; A, B and Q are independently hydrogen, C 1 10 alkyl, C 3 12 cycloalkyl, CI1 alkoxy,

C

3 4 12 cycloalkoxy, 7CH- 2 0H, -NHSO 2 hydroxyC 1 10 alkyl-, aminocarbonyl-, C 1 4 allcylaminocarbonyl-, diG 1 4alkylaxinocarbonyl-, acylarnino-, acylaminoalcyl-, amide, sulfonyaminoC.

10 alkyl-, or A-B can together form a C2- bridge, or B-Q cM n together form a C 3 7 bridge, or A-Q can together form a C 1 5 bridge; .Z is selected from the group consisting of a bond, straight or branched CIalkylene, -CH 2

-CH

2

-CH

2

N(CH

3

-NHCH-

2

-CH

2 CONH-, -NHCH 2

CO-,

-CH

2 CO-, -GOCH 2

-CH

2

GOGH

2

-CH(CH

3 -CH1=, and -HG=CH-, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with one or more lower alkyl, hydroxy, halo or alkoxy group; is selected from the group consisting of hydrogen, C 2 0 alkyl, C 3 1 2 cycloalkyl,

G

2 0 alkenyl. amino, C 11 0 a klmn-, C 3 2 cycloalkylaniino-, -GOOVI, -C 1 4

CQOV

1

I

cyano, cyanoG 110 alklcyl, CYanoGC.., 0 CYCloalkY1-, NH 2 SO2 2

,NH

2

SO

2

G

1 ~alkyl-, NH 2

SOC

1 4 alkyl-, aminocarbonyl-, G,4alkylaminocarbonyl-, diC, 4 alkylaminocarbonyl-, benzyl, C-3.1 2 cycloalkenyl-, a monocyclic, bicydlic or tricyclic aryl. or heteroaryl. ring, a heteromonocydlic ring, a hetero-bicyclic ring system, and a spiro ring system of the formula X1.

X

2

D

(V)

wherein X, and X 2 are independently selected from the group consisting of NH, 0, 0 S and CH 2 and wherein said alkcyl, cycloalkyl, alkenyl, C 1 1 alkylamino-, C 3 12 cycloalkylamino-, or benzyl of R, is optionally substituted with 1-3 substituents selected from the jroup consisting of halogen, hydroxy, CI- 0 alkyl, C 1 1 0 alkoxy, nitro., trifluoromethyl-, cyano, -COOV 1

-C

1 4 C00V 1 cyanoC 1 10 alkyl-, -C 1 5 (0)WI, -C 1 00 SNHS(=0) 2 WI, -C 1 5 NHS(=0)Wj, a 5-membered heteroaromaticCoalkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, CI-, 1 0 alkyl-, C 1 1 0 alkcoxy-, and cyano; and wherein -said C34 2 cycloalkyl, C34.2 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, or spiro ring system of the formula is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1 1 0 alkyl, C 1 1 0 alkoxy, nitro, trifluoromethyl-, phenyl, benzyl. phenyloxy and benzylgxy, wherein said phenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogen,

C

1 10 alkyl, C 1 1 0 alkoxy, and cyano;

R

2 is selected from the group consisting of hydrogen, C 1 1 .all,l C 3 1 2 cycloalkyland halogen, said ailkyl or cycloalkyl optionally substituted with an oxo,.amino, alkylamnio or dialkylanino group; atnd pharmaceutically acceptable salts thereof and solvates thereof.

The present invention in certain embodiments comprises compounds having the formula (IVA):

R

R

2 (n)I

N

(1 N I CN

N

(IVA)

wherein 0 nis aninteger from.0 to 3; Z is selected from the group consisting of a bond, -0112-, -CH 2 -0H 2

CH

2

-CH

2 NH-, -011 2 N(C11 3

-NHCH

2 -0H 2 00NH-, -NHCH 2 C0-, -CH 2 -CO0H2,-1

CH

2 C00H 2

-CH(CH

3 and -HC=CH-, wherein the carbon and/or nitrogen atoms are unsubksituted. or substituted with a lower alkcyl, halogen, hydroxy or alkoxy M group; R is selected from the group consisting of hydrogen,'C 1 10 alkyl, CI-1ilcoxy, and

C

3 12 cycloalkcyl; R, is selected from the group consisting of hydrogen, C 1 1 0 alkyl, C3- 12 CYClOalkyl, (71 0 2 10 akenyl, aminio, 0 1 .0allcylaMino, C 3 1 2 CYCloallCYlaMino, benzyl, 0312 CYCloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a heteromonocyclic, ring, a heterobicyclic ring system, and aspiro ring system of the formula X1

X'

2

(V)

wherein X, and X 2 are independently selected from the group consisting of NH, 0, S and 0112; wherein said monkocyclic aryl is preferably phenyl; wherein said bicyclic aryl is preferably naphthyl; wherein said alkyl, cycloalkyl, alkenyl, CI- 0 alcylarnino, C 3 12 CYCloalkylamino, or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, 01.10 alkcyl, C0~ ailcoxy, nitro, trifluorornethyl, cyano, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-.3 substituents selected from the group consisting of halogen, C11 alkyl, 01.10 aloxy, and cyano; wherein said C3412 cycloalkyl, C3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicydic ring system, and spiro ring system of the formula are optionally substituted with 1-3 substituents selected from the group consisting of halogen, 01-10 alkyl, C0 alkoxy, nitro, trifluorornethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy Sare optionally substituted with 1-3 substituents selected from the group consisting of O .halogen, C.

1 o alkyl, C1.

1 0 alkoxy, and cyano;

R

2 is selected from the group consisting of hydrogen, CI- 1 0 alkyl, C 3 -12 cycloalkyl and halogen, said alkyl optionally substituted with an oxo group; and pharmaceutically acceptable salts thereof.

In certain preferred embodiments of formula D is phenyl or a 6 membered heteroaromatic group containing 1-3 nitrogen atoms.

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

In certain preferred embodiments of formula (IV) or (IVA), the R, cycloalkyl is c1 cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, or norbornyl.

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

In other preferred embodiments of formula or (IVA), the R, bicyclic aromatic ring is a l0-membered ring, preferably quinoline or naphthyl.

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

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

In certain embodiments of formula (IV)or (IVA), the Z group is maximally substituted as not to have any hydrogen substitution on the base Z group. For example, if the base Z group is -CH 2 substitution with two methyl groups would remove hydrogens from the -CH 2 base Z group.

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

In certain embodiments of formula (IV) or (IVA), X, and X 2 are both O.

In certain embodiments of formula R is -CH 2

-C(NH)NH,

pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl, -C(=0)CH 3

CH

2

CH

2 NHC(=0)CH 3

-SO

2 CH, CH 2

CH

2

NHSO

2

CH

3 furanylcarbonyl-, methylpyrrolylcarbonyl-, diazolecarbonyl-, azolemethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxo-oxazolemethyl-, or diazolemethyl-.

.In certain embodiments of formula ZR, is cyclohexylethyl-, cyclohexylmethylcyclopentylmethyl-, dimethylcyclohexylmethyl-, phenylethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl-, p'ridylethyl-, cyclopentyl-, cyclohexyl-, methoxycyclohexyl-, tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyrazoylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl-, or o oxocanyipropyl-.

o In certain emb~odimnents of formula (MV, at least one of ZR, or R is -CH 2

COOV,

tetrazolylmethyl-, cyanomethyl-, NH 2

SO

2 methyl-, NII 2 S~methyl-, aminocarbonylmethyl-,

C,

4 allclaminocarbonylmethyl-, or diC,.4allcylaminocarbonytmethy1-.

In certain embodiments of formula MIV, ZRI is 3,3 diphenyipropyl optionally 00 substituted at the 3 carbon of the propyl with -COOVI, tetrazolyC 0 4akl-, cyano-, aminocarbonyl-, C,.

4 allylaminocarbonyl-, or diCl 4 alkylaminocarbonyl-.

C1 In alternate embodiments, of formulae (IIA), (fIlA), (IV, and (IVA), ZRI can be the following Y2 wherein YI is R 3 2 )alkYl, R 4 -arYl, R- 5 -heteroaryl, R 6

-(C

3

-C,

2 )cyclo-alkyl, R 7

-(C

3

C

7 )heterocycloalcyl, -C0 2

(CI-C

6 )alkyl, CN or -C(O)NR.R 9

Y

2 is hydrogen or YI; Y 3 is hydrogen or (C,-C 6 )alk-yl; or Y 2 and Y 3 together with the carbon to which they are attached, form one of the following structures: RIO E(CHRIO)u

EE

00 (CHRia)w r C-I

Y

3

RIO

E- E11 RIO )d-i.

C

S

RI, R1 or wherein r is 0 to 3; w and u are each 0-3, provided that the sum of w and u is 1-3; c and d are independently I or 2; s is 1 to 5; and ring E is a fused R 4 -phenyl orRsheteroaryl. ring; RIO is 1 to 3 substituents independently selected from the group consisting of H,

(C

1

-C

6 )allcyl, -OR 2

(C

1

-C

6 )alkyl-OR8, -NR9R 9 and -(C 1

-C

6 )alkYl-Nk 2 R2; I is I to 3 substituents independently selected from the group consisting of RIO,

CF

3

-OCE

3

NO

2 and halo, or R 1 1 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring; R. and R 9 are independently selected from the group consisting of hydrogen, (CI-

C

6 aill,~ (C 3

-C

12 )cycloalkYl, aryl and aryl(C 1

-C

6 )alkyl;

R

3 is 1 to 3 substituents independently selected from the group consisting of HR 4 arYl, R 6

-(C

3

-C

12 )CYCloallcyl, R 5 -hetefoarYl, R 7

-(C

3

-C

7 )heterocycloalkyl, -NRs R 9 1

R

2 and

R

6 is 1 -to 3 substituents independently selected from the group consisting of H, 0 (CI -C 6 )alkYl, R 4 -arYl, -NRSR1%, -OR 12 and -SR, 2

R

4 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C 1

C

6 )alkyl, R 13 -aryl, (C 3

C

12 )cycloalkYl, -CN, -CF 3

-OR

8

-(CI-

C

6 )alkyl-0R., -OCF 3

-NR

8

R

9 -(CI C 6 )alkYl -NR 8

R

9

-NHSO

2

R

8

-SO

2

N(R

4 2 -S0 2 Rs, 00 SOR 8

-SR

8

-NO

2

-CONRSR

9

-NR

9 00Rj, -CORs, -COCF 3 -OCORS, -0C0 2

R,-

COORS' -(Cl-C 6 )alkyl-NHCOOC(CH 3 3

-(C

1

-C

6 )alkyl-NHCOCF 3

-C

6 )alky-NHSO 2

(C

1

-C

6 )alkYl, -(Cl-C 6 )alkYl-NHCONH-(Cl-C 6 )-alkyl and

-(CH

2 f _N-R 8 wherein f is 0 to 6; or R.

4 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring; is 1 to 3 substitaents independently selected from the group consisting of hydrogen, halo, (C 1

-C

6 )alkyl, R 1 3 -aryl, (C 3

-C

12 )cycloallcyl -CN, -CF 3 -ORB, -(C 1

-C

6 )allcyl-

OR

8 -0CF 3

,-NR

8

R

9

-(CI-C

6 )alkyl-NR 8

R

9

-NHSO

2 R9, -SO 2

N(R

4 2

-NO

2

-CONRBR

9 NR9CORS, -CORO, -OCOR 8 -0C0 2

R

8 and -COORS 8

R.

7 is HL (C,-C 6 )alkyl, 6 )alkyl-0Rg, -N RgR 9 or -(C 1

-C

6 )allcyl-NRgR 9

R

1 2 is H, (CI-C 6 )alkyl, R 4 -aryl, -(C 1

-C

6 )alkyl-0R 8

-(CI-C

6 )alkyl-NR 8

R

9

-(CI-

C

6 )alkyl-SRs, or aryl (Cl-C 6 )alkyl;

R

13 is 1-3 substituents independently selected from the group consisting of H, (C 1

C

6 )alkyl, (C 1

-C

6 )alkoxy and halo;

R

14 is independently selected from the group consisting of 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 a single radical and 1-10 carbon atoms. Examples of alkyl *groups include methyl, propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and pentyl. A branched alkyl means that one or more alkyl groups such as methyl, ethyl or propyl, replace one or both hydrogens in a -CH 2 group of a linear alkyl chain. The term "lower alkyl" means an alkyl of 1-3 carbon atoms.

The term "alkoxy" means an "alkyl" as defined above connected to an oxygen radical.

The term "cycloalkyl" means a non-aromatic mono- or multicyclic hydrocarbon ring system having 6 single radical and 3-12 carbon atoms. Exemplary monocyclic 26

O

O

Scycioaulcy rmgs include cyclopropyl, cyclopentyl, and cyclohexyl. Exemplary multicyclic O cycloalkyl rings include adamantyl and norboryl.

The term "alkenyl" means a linear or branched aliphatic hydrocarbon group CI containing a carbon-carbon double bond having a single radical and 2-10 carbon atoms.

A "branched" alkenyl means that one or more alkyl groups such as methyl, ethyl or O propyl replace one or both hydrogens in a -CH 2 or -CH= linear alkenyl chain. Exemplary M alkenyl groups include ethenyl, 1- and 2- propenyl, 2- and 3- butenyl, 3-methylbut-2- C enyl, 2-propenyl, heptenyl, octenyl and decenyl.

The term "cycloalkenyl" means a non-aromatic monocyclic or multicyclic hydrocarbon ring system containing a carbon-carbon double bond having a single radical and 3 to 12 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopropenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. An exemplary multicyclic cycloalkenyl ring is norbornenyl.

The term "aryl" means a carbocyclic aromatic ring system containing one, two or three rings which may be attached together in a pendent manner or fused, and containing a single radical. Exemplary aryl groups include phenyl, naphthyl and acenaphthyl.

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

Examples of partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran, and dihydrofuran. Other heterocyclic groups can be 7 to 10 carbon rings substituted with heteroatoms such as oxocanyl and thiocanyl. When the heteroatom is sulfur, the sulfur can be a sulfur dioxide such as thiocanyldioxide.

The term "heteroaryl" means unsaturated heterocyclic radicals, wherein "heterocyclic" is as previously described. Exemplary heteroaryl groups include unsaturated 3 to 6 membered hetero-monocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, pyridyl, pyrimidyl, and pyrazinyl; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen itoms, such as indolyl, quinolyl and isoquinolyl;

O

O

unsaturated 3 to 6- membered hetero-monocyclic groups containing an oxygen atom, such O as furyl; unsaturated 3 to 6 membered hetero-monocyclic groups containing a sulfur atom, O such as thienyl; unsaturated 3 to 6 membered hetero-monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl; unsaturated condensed 0 heterocyclic groups containing 1 to 2 oxygen atoms.and 1 to 3 nitrogen atoms, such as 00 C benzoxazolyl; unsaturated 3 to 6 membered hetero-monocyclic groups containing 1 to 2 C sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl; and unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl. The term "heteroaryl" also includes unsaturated heterocyclic radicals, C wherein "heterocyclic" is as previously described, in which the heterocyclic group is fused with an aryl group, in which aryl is as previously described. Exemplary fused radicals include benzofuran, benzdioxole and benzothiophene.

As used herein, the term "heterocyclicCI.alkyl", "heteroaromaticC,4alkyl" and the like refer to the ring structure bonded to a C, 4 alkyl radical.

All of the cyclic ring structures disclosed herein can be attached at any point where such connection is possible, as recognized by one skilled in the art.

As used herein, the term "patient" includes a human or an animal such as a companion animal or livestock.

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

The invention disclosed herein is meant to encompass all pharmaceutically acceptable salts thereof of the disclosed compounds. The pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals 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, ptoluenesulfonate, and the like; amino acid salts such as arginate, asparginate, glutamate and the like.

The invention disclosed herein is also meant to encompass all prodrugs of the disclosed compounds. Prodrugs are considered to be any covalently bonded carriers which release the active parent drug in vivo.

The invention disclosed herein is also meant to encompass the in vivo metabolic 28- Sproducts of the disclosed compounds. Such products may result for example from the 0 oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such 0 products typically are identified by preparing a radiolabelled compound of the invention, M administering it parenterally in a detectable dose to an animal such as rat, mouse, guinea C pig, monkey, or to man, allowing sufficient time for metabolism to occur and isolating its conversion products from the urine, blood or other biological samples.

SThe invention disclosed herein is also meant to encompass the disclosed NC- compounds being isotopically-labelled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, H, 3 C, 14 1 5 N, 180, 17 31

P,

32 P, as, S 1 F, and 36 Cl, respectively. Some of the compounds disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present invention is also meant to encompass all such possible forms as well as their racemic and resolved forms and mixtures thereof. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended to include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present invention.

as well As used herein, the term "stereoisomers" is a general term for all isomers of individualmolecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (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 that is nonsuperimposeable on its mirror image and hence optically active wherein 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 "resolution" refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.

The term "modulate" as used herein with respect to the QRL-1 receptor means the 0 mediation of a pharmacodynamic response analgesia) in a 'subject from inhibiting or activating the receptor, or (ii) directly or indirectly affecting the normal regulation of the receptor activity. Compounds which modulate the receptor activity include agonists, antagonists, mixed agonists/antagonists and compounds which directly or indirecitly affect 0C) regulation of the receptor activity.

Certain preferred compounds of formula and (LA) include: -(naphth-2-yl-methyl)A4-piperidinyl2Hbezoxazol.2-one; tt~ 3-[l -(naphth- 1-yl-methyl)-4-piperidinyl]-2H-benzoxazol-2one; 3-[1 -(.p-phenylbenzyl)-4-piperidinyl]-2Hbenzoxazol2one; 3-[l1-(p-benzyloxybenzy)4-piperidiny]2Hbenzoxazol2one; 3-[1 pca~ezy)4pprdiy]2-eitxzl2oe 3-[1 3 3 -diphenylpropyl)-4-piperidinyl]-2H-benzoxazol.2one; 3-[1 4 4 -Bis-( 4 -fluorophenyl)buty]-4-piperidinyl]-2H-benzoxazol.2.one;.

3-[l 2 -phenylethyl)-4-piperidinyl]-2H-benzoxazol2one; 3-[1 ccocymeal--ieidnl-Hbnzxzl2oe 3-[l 2 3 4 -tetrahydro- 2 -naphthyl)-4-piperidinyl]-2H-benzoxazo[2-one; 3-[l -methylhex-2-yl)-4-piperidinyl]j2Hbenzoxazol-2.one; 3-[l -(10,1 l-Dihydro-5H-dibenzo[ad]-cyclohepten5yl)-4pipedinylp-2Hbenzoxazol-2-one; 3-[1 4 -propyl-cyclohexyl)A4-piperidinyl]-2Hbenzoxazol2one; 3 -[l-(norbornan-2-yl)-4-piperidinyl]-2H-benzoxzolp2one; 3-l(eayr--ahhl--~leiiy]2-ezxzl2oe 3-[l1-(3,3-dimnethyl-l ,5-dioxaspiro[5.5]undeca-9-yl)-4-pijperidinyl]-211-benzoxazol- 2-one; -methylethyl)-cylohexyl]4piperidinyl2Hbeoxazol-2one; 1-(l -iyride--l--ierdnl-Hbnzxzl2oe 3 -[l-(cyclooctyl)-4-piperidinyl]-2H-benzoxazol-2one; and *pharmaceutically acceptable salts thereof and solvates thereof.

Certain preferred compounds of formula (ID) and (HIA) include: *3-ethylidene-l-[l -(S-methylhex-2-y)-4-piperidinyl]-1 ,3-dihydro-211-indole-2-one; 3-ethylidene-l-[l 4 -propylcyclohexyl)-4-piperidinyl]-1 ,3-dihydro-2H-indole-2one; 3-ethylidene-1-[1 ,2,3 ,4-tetrahydro-2-niaphthyl)-4-piperidinyl]-l ,3-.dihydro-2Hindole-2-one; 3-ethylidene- 1-[l ,3-dihydroinden-2-yl)-4-piperidinyly 1 ,3-dihydro-2H-indole-2one; o 3 -ethyiidene-i-[1-(naphth-2-yl-methyl).4-piperidinyl].1 ,3-dihydro-2H-indole-2one; 3-ethylidene-i-[i p-benzyloxybenzyl)-4-piperidinyl]-1 ,3-dihydro-2H-indole-2one; 00 3-ethylidene-i-[i -(benzyl)-4-piperidinyl]-1 ,3-dihydro-2H-indole-2-one; M 3-ethylidene-l--[i-(cyciooctylmnethyl)-4-piperidinyl]-i ,3-dihydro-2H-indole-2-one; C1 3-ethylidene-i-[i -(norbornan-2-yl)-4-piperidinyl]-i ,3-dihydro-2H-indole-2-one; In 3-ethylidene- 1-[i 3 3 -dciphenylpropyl)-4-piperidinyl]-i ,3-dihydro-2H-indole-2one; C1 3-ethylidene- i-[i -(p-cyanobenzyl)-4-piperidinyl]-i ,3-dihydro-2H-indoie-2-one; 3-ethyl-I -[1-(5-methylhexc-2-yl)-4-piperidinyi]- 1,3-dihydro-2H-indole-2-one; 3-ethyl-i -metkiylethyl)-cyoiohexyl]-4-piperidiny]-1 ,3-dihydro-211-indoie- 2-one; 3-ethyl-i -(4-propyicyclohexyl)-4-piperidinyl]-i ,3-dihydro-2H-indole-2-one; 3-ethLyi-i-[1 ,4-tetrahydro-2-naphthyl)-4-piperidinyl]-i ,3-dihydro-211-indole- 2-one; 3-ethyl-i -[1-(decahydro-2-naphthyl)-4-piperidinyl]-1 ,3-dihydro-2H-indoie-2-one; 3-ethyl-i-[1 ,3-dihydroinden-2-yi)-4-piperidinyl]-i ,3-dihydro-2H-indole-2-one; 3-ethyl-I -(cyolooctylmethyl)-4:-piperidinyl]- 1,3-dihyclro-2H-indole-2-one; 3-ethyl- 1-ri-(norbornan-2 yl)-4-piperidinyi]- 1,3-dihydro-2H-indole-2-one; 1-ri -(naphth-i -yl-methyl)-4-piperidinyl]- 1,3-dihydro-2H-indole-2-one; 1-ri -(naphth-2-yl-methyl)-4-piperidinyl]-1 ,3-dihydro-2H-indole-2-one; 1 -(p-phenylb'enzyl)-4-piperidinyi]-i ,3-dihydro-2H-indole-2-one; i-[i -(3,3-Bis(phenyi)propyl)-4-piperidinyl]-l ,3-dihydro-2H-indole-2-one; i-[i -(p-cyanobenzyi)-4-piperidinyl]-1i,3-dihydro-2H-indole-2-one; i-ri -(p-benzyloxybenzyl)-4-piperidinyi]-i ,3-dihydro-2H-indole-2-one; i-ri ,2,3,4-tetrahydronaphth-2-yi)-4-piperidin~yl]-i ,3-dihydro-2H-indole-2-one; 1-[i-(5-methylhex-2-y)-4-piperiliny]-1 ,3-dihydro-2H-indoie-2-one; 1 -(norbornan-2-yi)-4-piperidinyi]-i ,3-dihydro-2H-indole-2-one; i-ri ,3-dihydroinden-2-y)-4-piperidiny]-1 ,3-dihydro-2H-indole-2-one; 1-[i-(cycooctyimethyl)-4-piperidinyi]- 1,3-dihydro-2H-indoie-2-one; i-ri -(benzyi)-3-(methyl)-4-piperidinyi]-i ,3-dihydro-2H-indole-2 -one; 1 4 -propyl-cyclohexy)-3-(methyl)-4-piperidinyl]-1 ,3-dihydro-2H-indole-2-one; i-ri -(S-methyihex-2-yi)-3-(methyl)A4-piperidinyl]- 1,3-dihydro-21{-indoie-2-one; i-ri -(decahaydro-2-naphthyl)-3-(methy)-4-piperidiny]]i ,3-dihydro-2H-indole-2o one; o 1-[i 4 -(l-rnethYlethyl)-cyclohexyl)- 3 -(methyl)-4-piperidiny}.1 ,3-dihydr o-2Hindoie-2-one; 1 -[i-(cycooctynethy)-3-(methyl)A..piperidijnylyi ,3-dihydro-2H-indole-2 -one; 00 one; M3-ethyl-i 3 3 -Bis(phenyl)propyl)-3-(methyl) .4..piperidinyl].1 ,3-dihydro-2Hindole-2-one-, tn3-ethyl-1-ri 4 -propylcyclohexy)-3-(methy)A4piperid-iny11,3-dihydro-2Hindoie-2-one; 3-ethyl-1-ri 5 -methylhex-2-yl)-3 -(methyl)-4-piperidinyl] .1 ,3-dihydro-2H-indole- 2-one; 3-ethyl-i -methylethyl)cyclohexyl]3methyl-4piperidinyl].1 ,3-dihydro- 2H-indole-2-one; 3 -ethyl- I-[I -(decahydro-2-naphthy)-3 (methyl)-4-piperidinyl]-. 1,3 -dihydro-2Hindole-2-one;.and pharmaceutically acceptable salts thereof and solvates thereo -f.

Certain preferred compounds of formula (111) and (MiA) include: 3-ethyl-i -(p-phenylbenzyl)-1 3 -dihydro-2H-benzimidazol-2.one; 3-ethyl-i -(5-methylhex-2-yl)-1,ihyr-Hbnimdzl2oe 3-ethyl-i 4 -propylcyclohexyi)-13ihyr-Hbnimdzl2oe 3-ethyl- i-(decahydro-2-naphthyl).1,3dhdo2Hbniiazl2o 3-ethyl- I -(naphth-2-yl-methyl)- 1, 3 -dihydro-2H-benzimidazol.2-one; 1 (-ezlxbny)3-ty-,-iyr-H-ezmdzl2o 1-benzyi-3 -ethyl-1,ihyr-Hbnimdzl2oe l-[ 4 -(benzylainuno)-cyciohexyl]-3ethy1 1, 3 -dihydro-2H-benzirnjdazol2one; 3-ethyl- 1-(naphthylmethyl)-1,ihyr-Hbnimdzl2oe 3-ethyl- i-[ 5 3 -fluoropheny)-5-(4-fluorophenyl)-hexyl]1 ,3-dihydro-2H-.

benzixnidazol-2-one; 1-[ 4 (naphth-2-yl-methyl)ethylamino]-cyclohexyl].1 ,3-dihydro-2H-benzimidazol- *2-one; l-[ 4 -(norbonan-2-ylamino)cyclohexl]..1,3 -dihydro-2.H-benzimidazo-2.one; I -methylethayl)-cyclohexyl]amino]pcyclohexyl]..i,3-dihydro-21{benzimidazol-2-one; 1 4 -[(decahydro-2-naphthyl)amino]-cycloliexyl] 1 ,3-dibiydro-2H-benzirnidazol-2.

one; o l41-4-(ethYlamino)cyclohexy11,3-dihydro-2F1-benzjmnidazol.2.one; o 1 4 -(benzylamino)-cyclohexyl} 1 ,3-dihydro-2H-benzimjdazol-2-one; 1-4[idn2y~ezla-io-ylhxl- -ehl,3 -dihydro-2H-benzimidazol- 2-one;I l-[ 4 -[(cyclooctlmethyl)amino] cycohexyl].3 -ethyl-.11,3 -dihydro-211-benzimidazol- 00 2-one; M l-[ 4 -[(naphth-2-yl)amino]-cyclohexyl]3 -ethyl- ,3-dihydro-2H-benzimidazol-2one; l-[ 4 -[(P-benzyloxybenzy)amino]-cyclohexyl]-3ethy11,3-dihydro-2Hbenzimidazol-2-one; I- 4 -[(cYclooctYlmethyl)aminocycohexy]3 ethy13dihyo2-eniidao.

2-one; 1 4 -[(decahydro-2-naphthyl)amino]-cyolohexyl3.efyl-1I,3-dihydro-2Hbenzimidazol-2-one;.

l-[ 4 -(benzylaino)-cyclohexy]-5-carbamoy1 1,3-dihydro-2H-benzimidazol-2-one; 1 -I 4 -(dibenzylamino)-cyclohexyl]-5-carbamoy1I,3-dihydro-2H-benzimidazol-2one; l-[ 4 -[(p-phenylbenzy1)amino]-rcyclohexy1]-s-carbamoy1,3-dihydro-21benzimidazol-2-one; 2 3 4 -tetrahydronaphthyl)amino]-cyclohexyl]-5-carbamoyl..1,3-dihydro- 2H-benzimidazol-2-one;

I

1 4 4 -propyl-cyclohexyl)aminoycyclohexyl}.5-carbamnoyl-.1 ,3-dihydro-2L1benzimidazol-2-one; 1 4 -[(5-met-hylhex-2-yl)amino] -cyclohex 1l]-5-carbamoyl.1 ,3-dihydro-2Hbenzimidazol-2-one; l-[ 4 -[(decahydro-2-naphthy1)aminoI-cyclohexy]5carbmoy1,3-dihydro-2Hbenzirinidazol-2-one; 1 4 -(cyclooctylamino)-cyclohexy]-5-carbamoy1,3-dihydro-2H-benziniidazol-2one; 1 -[4-[(indan- 2 -yl)an-ino]-cyclohexyl]-5-carbamoyl-1 ,3-dihydro-2H-benzimidazol- 2-one; 1 4

-[R

4 -phenyl-cyc-lohexyl)amino]cyclohexyli5-carbamoyl.1 ,3-dihydro-21{benzimidazol-2-one; 1 [-(-etyhx2-lanno-yIhey]7cabmy-,3-dihyclro-2Hbenzimidazol-2-one; and pharmaceutically acceptable salts thereof and solvates thereof.

33 Other preferred compounds formula (MV and (IVA) include: o 2 -cyanoimino-3-ethyl-l-[l-(p-phenylbenzyl)A..piperidjnyll 3-dihydro-2Hbenzinaidazole; 2-cyanoirniino-3 -ethyl-1-[Il-(p-benzyloxybenzyl)-4-piperidinyl] 1 ,3-dihydro-2H.berizimidazole; 00 2-cyanoimino-3-ethyl-1-[1-(naphth-2-yl-methyl)-4-piperidinyl] 1 ,3-dihydro-2Hbenzimidazole; 2-cyanoimino-3-ethyl-l -(4-propylcyclohexyl)-4-piperidinyl]-1 ,3-dihydro-21{in benzimidazole; 2 -cyanioimino-3-ethyl-l-[1-[4-(2-propyl)-cyclohexyl]p4-piperidinyl]j4 ,3-dihydro- CI 2H-benzimidazole; 2-cyanoimino-3 -ethyl-i -[1-(decahydro-2-naphthyl)-4-piperidinyl]-1 ,3-dihydro- 2H-benzimidazole; 2-cyanoimino-3 -ethyl-i -[l-(cyclooctyrl)-4-piperid inyl]- 1,3-dihydro-2Hbenzimidazole; 2-cyanoimino-3-ethyl-1-[1 -(10,1 1-dihydro-511-cibenazo~ad)-cyclohepten-5-yl)-4piperidinyl]- 1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-l -(3,3-Bis(phenyl)propyl)-4-piperidinyl]- 1,3-dihydro- 2H-benzimidazole; 2-cyanoimino-3-ethyl-1-[1 ,2,3,4-tetrahydronaphthyl)-4-piperidinyl]-1 ,3dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-l -(5-methylhex-2-yl)-4-piperidinyl]-1 ,3-dihydro-2Hbenzimidazole; 2-cyanoimino-3-ethyl-1 -(norbornan-2-yl)-4-piperidinyl]- 1,3-dihydro-2Hbenzimidazole; 2-cyanoimino-3-ethyl-1.{1-(1 ,3-dihydroinden-2-yI)-4-piperidinyl]-1 ,3-dihydro- 2H-benzimidazole; 2 -cyanoinmino-3-ethy1-1-[1-(cyclooctymethyl)-4-piperidinyl] 1 ,3-dihydro-2Hbenzimidazole; and pharmaceutically acceptable salts thereof and solvates thereof.

Other preferred compounds of formula (IV) include 2-cyanoimino-3-(2-hydroxy)ethyl-1 -(cyclooctyl)-4-piperidinyl]- 1,3-dihydro-2Hbenzimidazole; 2-cyanoimino-3-rnethoxycarbonylmethyl-l [-(cyclooctyl)-4-piperidinyl]- 1,3dihydro-2H-benzixnidazole; 2-cyanoimino-3-cyanomethyl-1 -[1-(cyclooctyl)-4-piperidinyl]- 1,3-dihydro-21{- 34 benzimidazole; O 2-cyanoimino-3-butyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2Hbenzimidazole; 2 -cyanoimino-3-(2-methanesulfonamido)ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3dihydro-2H-benzimidazole; 00 2-cyanoimino-3-acetomido-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2Hbenzimidazole; 2 -cyanoimino-3-carboxymethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2Hbenzimidazole; O 2 -cyanoimino-3-(2-dimethylamino)ethyl--[1-(cyclootyl)-4-piperidinyl]- ,3dihydro-2H-benzimidazole; 2-cyanoimino-1-[l-(cyclooctyl)-3-hydroxymethyl-4-piperidinyl]-l ,3-dihydro-2Hbenzimidazole; 2-cyanoimino-1 -[l1-(cyclooctyl)-4-piperidinyl]- ,3-dihydro-2H-7azabenzimidazole; 2-cyanoimino-1-[l-(cyclooctyl)-2,6-ethano-4-one-4-piperidinyl-1,3-dihydro-2Hbenzimidazole; and pharmaceutically acceptable salts thereof and solvates thereof.

The present invention also provides use of any of the disclosed compounds in the preparation of a medicament for treating pain and'other disease states modulated by an opioid receptor, the ORL-1 receptor.

DETAILED DESCRIPTION OF THE INVENTION The corhpounds of the present invention can be administered to anyone requiring modulation of the opioid and ORLI receptors. Administration may be orally, topically, by suppository, inhalation, or parenterally.

The present invention also encompasses all pharmaceutically acceptable salts of the foregoing compounds. One skilled in the art will recognize that acid addition salts of the presently claimed compounds may be prepared by reaction of the compounds with the appropriate acid via a variety of known methods.

Various oral dosage forms can be used, including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders and liquid forms such as emulsions, solution and suspensions. The compounds of the present invention can be administered alone or can be combined with various pharmaceutically acceptable carriers and excipients known to those skilled in the art, including but not limited to diluents, suspending agents, solubilizers, binders, disintegrants, preservatives, coloring agents,

O

O

Slubricants and the like.

O When the compounds of the present invention are incorporated into oral tablets, such tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, multiply compressed or multiply layered. Liquid oral dosage forms include aqueous and nonaqueous solutions, emulsions, suspensions, and solutions and/or suspensions OC reconstituted from non-effervescent granules, containing suitable solvents, preservatives, c emulsifying agents, suspending agents, diluents, sweeteners, coloring agents, and flavoring agents. When the compounds of the present invention are to be injected parenterally, they l may be, in the form of an isotonic sterile solution. Alternatively, when the compounds of the present invention are to be inhaled, they may be formulated into a dry C1 aerosol or may be formulated into an aqueous or partially aqueous solution.

In addition, when the compounds of the present invention are incorporated into oral dosage forms, it is contemplated that such dosage forms may provide an immediate release of the compound in the gastrointestinal tract, or alternatively may provide a controlled and/or sustained release through the gastrointestinal tract. A wide variety of controlled and/or sustained release formulations are well known to those skilled in the art, and are contemplated for use in connection with the formulations of the present invention.

The controlled and/or sustained release may be provided by, a coating on the oral dosage form or by incorporating the compound(s) of the invention into a controlled and/or sustained release matrix.

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

When the compounds of the present invention are incorporated for parenteral administration by injection continuous infusion or bolus injection), the formulation for parenteral administration may be in the form of suspensions, solutions, emulsions in oily or aqueous vehicles, and such formulations may further comprise pharmaceutically necessary additives such as stabilizing agents, suspending agents, dispersing agents, and the like. The compounds of the invention may also be in the form of a powder for reconstitution as an injectable formulation.

O In certain embodiments, the compounds of the present invention can be used in combination with at least one other therapeutic agent. Therapeutic agents include, but are not limited to, p-opioid agonists; non-opioid analgesics; non-steroid antiinflammatory agents; Cox-II inhibitors; antiemetics; |-adrenergic blockers; anticonvulsants; 0O 0 antidepressants; Ca2+-channel blockers; anticancer agent and mixtures thereof.

In certain embodiments, the compounds of the present invention can be formulated in a pharmaceutical dosage form in combination with a g-opioid agonist pi-ojpioid agonists, which may be included in the formulations of the present-invention include but C are not limited to include alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene; dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof.

In certain preferred embodiments, the p-opioid agonist is selected from codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, morphine, tramadol, oxymorphone, pharmaceutically acceptable salts thereof, and mixtures thereof.

In another embodiment of the invention, the medicament comprises a mixture of a Cox-II inhibitor and an inhibitor of 5-lipoxygenase for the treatment of pain and/or inflammation. Suitable Cox-II inhibitors and 5-lipoxygenase inhibitors, as well as combinations thereof are described in U.S. Patent No. 6,136,839, which is hereby incorporated by reference in its entirety. Cox-II inhibitors include, but are not limited to rofecoxib (Vioxx), celecoxib (Celebrex), DUP-697, flosulide, meloxicam, 6-1INA, L- 745337, nabumetone, 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 pharmaceutically acceptable O salts, enantiomers or tautomers thereof.

The compounds of the present invention can also be combined in dosage forms with non-opioid analgesics, non-steroidal anti-inflammatory agents, including aspiin, ibuprofen, diclofenac, liaproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, 00 ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, O clidanac, oxpinac, niefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid C tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicarn or isoxicam, pharmaceutically acceptable salts thereof, and mixtures thereof. Other suitable non-opioid analgesics which may be included in the dosage forms of the present invention include the following, nonlimiting, chemical classes of analgesic, antipyretic, nonsteroidal antifinflammatory drugs: salicylic acid derivatives, including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; paraaminophennol derivatives including acetaminophen; indole and indene acetic acids, including indomethacin, sulindac, and etodolac; heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates), including mefenamic acid, and meclofenamic acid; enolic acids, including oxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone); and alkanones, including nabumetone. For a more detailed description of the NSAIDs that may be included within the medicaments employed in the present invention, see Paul A. Insel Analgesic- Antipyretic and Antiinflammatory Agents and Drugs Employed in the treatment of Gout in Goodman Gilman's The Pharmacological Basis of Therapeutics, 617-57 (Perry B.

Molinhoff and Raymond W. Ruddon, Eds., Ninth Edition, 1996), and Glen R. Hanson Analgesic, Antipyretic and Ainit-Inflammatory Drugs in Remington: The Science and Practice of Pharmacy Vol II, 1196-1221 R. Gennaro, Ed. 19th Ed. 1995) which are hereby incorporated by reference in their entireties.

In certain embodiments, the compounds of the present invention can be formulated in a pharmaceutical dosage form in combination with antimigraine agents. Antimigraine agents include, but are not limited to, alpiropride, dihydroergotamine, dolasetron, ergocornine, ergocorninine, ergocryptine, ergot, ergotamine, flumedroxone acetate,fonazine,lisuride, lomerizine, methysergide oxetorone, pizotyline, and mixtures 38 thereof 0 The other therapeutic agent can also be an adjuvant to reduce any potential side effects such as, for example, an antieinetic agent. Suitable antiemnetic; agents include, but are not limited to, metoclopromide, domperidone, prochiorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acethylleucine 00 monoethanolamine, alizapride, azasern, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxypemndyl, pipamazine, scopolamine, siilpiride, tetrahydrocannabinols, thiethylperazine, thioproperazine, tropisetron, and mixtures thereof.

c-i In certain embodiments, the compounds of the present invention can be formulated in a pharmaceutical dosage form in combination with f-adrenergic blockers. Suitable 3 adrenergic blockers include, but are not limited to, acebutolol, aiprenolol, arnosulabol, arotiniolol, atenolol, befimolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol, practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol, tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

In certain embodiments, the compounds of the present invention can be formulated in a pharmaceutical dosage form in combination with anticonvulsa-nts. Suitable anticonvulsants include, but are not limited to, acetylpheneturide, albutoin, aloxidone, aminoglutethimnide, 4 -amino-3-hydroxybutyric acid, atrolactamide,beclamide, buramate, calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam, decimemide, diethadione, dimethadione, doxenitroin, eterobarb, ethadione, ethosuximide, ethotoin, felbamnate, fluoresone, gabapentin, 5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesi .um sulfate, mephenytoin, mephobarbital, me'tharbital, methetoin, methsuximide, methyl-5-(3-phenantbry)-hydantoin, 3 -methyl-5-phenyuhydantoin, narcobarbital, nimetazepamn, nitrazepamn, oxcarbazepine, paramethadione, phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide, phenylmethylbarbituric acid, phenytoin, phethenylate sodium, potassium bromide, pregabaline, primidone, progabide, sodium bromide, solanum, strontium bromide, suclofenide, suithiame, tetrantoin, tiagabine, topiramate, trimethadione, vaiproic acid, vaipromide, vigabatrin, and zonisamide.

39 ln certain embodiments, the compounds of the present invention can be formulated 0 in a pharmaceutical dosage 'form in combination with antidepressants. Suitable antidepressants include, but are not limited to, binedaline, caroxazone, citaloprani, dimethazan, fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine, oxitriptan, oxypertine, paroxetine, sertraline, thiazesini, trazodone, benoxine, 00 iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin, pheneizine, cotini .ne, rolicyprine, rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide, amnoxapine, butriptyline, clornipramine, dem~xiptiline, desipramine, dibdinzepin, dirnetacrine, dothiepin, doxepin, fluacizine, irnipranine, (1 imiprainine N-oxide, iprindole, lofepramine, melitracen, metapramine, riortriptyline, noxiptilin, opipramol, pizotyline, propizepine, protriptyline, quinuprainine, tianeptine, trimipramine, adrafinil, benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxanaine, hematoporphyrin, hypericin, levophacetoperane, medifoxamine, milnacipran, minaprine, rnoclobemide, nefazodone, oxaflozane, piberaline, prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium. chloride, sulpiride, tandospirone, thozalinone, tofenacin, toloxatone, tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.

In certain embodiments, the compounds of the present invention can be form ulated in a pharmaceutical dosage form in combination with Ca2+-channel blockers. Suitable Ca2+-channel blockers include, but are not limited to, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylarnine, semotiadil, terodiline, verapanil, axnlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, fantofarone, and perhexiline.

In certain embodiments, the compounds of the present invention can be formulated in a pharmaceutical dosage form in combination with anticancer agents. Suitable anticancer agents include, but are not limited to, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleuk-in;, altretamine; ambomycin; ametantrone acetate; aniinoglutethimide; anasacrine; anastrozole; anthramycin; aspar'aginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chioramnbucil; cirolemycin; 0 cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplaiin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; 00 eflornithine hydrochloride; elsaniitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate;* etoprine; fadro zole hydfochloride; fazarabine; fenretinide; floxuridine;'fludarabine phosphate; fluoroukacil; flurocitabine; C1 fosquidone; fostriecin sodium; gemcitabine; gemacitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin HI (including recombinant interleukin HI, or rIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-ni interferon alfa-n3; interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamnre hydrochloride; megestrol acetate; melengestrol acetate; meiphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; raitocromin; zuitogillin; mitomalcin; niitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate;'perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; ternoporfmn; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazam-ine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; *vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride. Other anti-cancer drugs include, but are not limited to: 20-epi- 1,25 dihydroxyvitamin D3; etnynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; o ALL-TK antagonists; altretamine; ambamustine; aniidox; amifostine; aminolevulinic acid; armbicin; arasacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist 0; antarelix; anti-dorsalizing morphogenetic protein-i; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense 00 oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atainestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; az~tyro sine; baccatin MI derivatives; balanol; batimastat; BCRIABL antagonists; benzochlorins; benzoyistaurosporine; beta lactamn derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutarnide; bisantrene; bisaziridinyispermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoxirnine; calcipotriol; caiphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-aminotriazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;' chiorlns; chioroquinoxaline sulfonarnide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretast 'atin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin

B;

deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; diderunin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomiab; eflornitbine; elemene; emitefur; epirubicin; epristeride; estramnustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride;. forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor- I receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; 42 iododoxorubicin; ipomeanol, iroplact; irsogladine; isobengazole; isohomohalicondrin. B; 0 itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; larireotide; leinamycin; lenograstlin; lentinan sulfate; leptoistatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide-Iestrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; 00 M lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium. texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin. A; marirnastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MNF inhibitor; inifepristone; niitefosine; mirimostim; mismatched double stranded RNA; n-itoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; moigramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl. lipid A-Imyobacterium. cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin.; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron, oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin. paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panoniifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perfiubron; perfosfanaide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triarnine complex; porfinier sodium; porfiromycin; prednisone; propyl bisacridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras famnesyl. protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium. Re 186 etidronate; rhizoxin; ribozymes; R.II retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B ruboxyl; O safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; 00 M sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors;,stipiamide; stromelysin y inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; t C tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

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

In another embodiment, a composition comprising the compounds of the present invention is administered prior to or subsequent to administration of another therapeutic agent.

The compounds of the present invention when administered, via the oral, parenteral or topical routes to mammals, can be in a dosage in the range of about 0.01 mg/kg to about 3000 mg/kg body weight of the patient per day, preferably about 0.01 mg/kg to about 1000 mg/kg body weight per day administered singly or as a divided dose.

However, variations will necessarily occur depending upon the weight and physical condition hepatic and renal function) of the subject being treated, the affliction to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the presence of any deleterious side-effects, and the particular compound utilized, among other things.

The compounds of the present invention preferably have a binding affinity K for the human ORL-1 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 KI can be measured by one skilled in the art by an assay utilizing membranes from recombinant HEK-293 cells expressing the human opioid receptor-like receptor (ORL-1) as described below.

The following examples illustrate various aspects of the present invention, and are not to be construed to limit the claims in any manner whatsoever.

EXAMPLE 1 SYNTHESIS OF BENZOXAZOLONE HEAD GROUPS.

The head groups of the present invention were synthesized according to the following procedure:

OH

N11 0

BOC

2 Na(AcO) 3

BH

DCE

Acetic Acid 0 CISCO -OCC 3 DIEA THF 0°C to RT

BOC

RT

NO

H

Procedure:

O

To a mixture of 1 1 .09 g, 10 mmol), 2 (1.99 g, 10 mmol) and acetic acid (0.60 g, 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 o0 through Celite and 1 N 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 vacuum to give crude 3 as Sa brown solid (2.75 g, yield: 94%).

S'HNMR (CDC 3 d 1.

2 0-1.60.(m, 11H), 2,00.(dd, 2H), 2.9 2H), 3.40 1H), 4.00 (m,

C

NI 2H), 6.60-6.85 4H).

To an ice cooled solution of crude 3 (12.0 g, 40 mmol) and DIEA (20.8 mL, 120 mmol) in 200 mL of THF, was added a solution oftriphosgene (4.32 g, 14.4 mmol) in 200 mL of THF. After the addition was complete the ice bath was removed and the mixture stirred at room temperature overnight. The solids were filtered off and the filtrate evaporated in vacuum. The residual 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 vacuum to give a red oil which was filtered through a column of silica gel eluting with a mixture of Et 3 N, 25% EtOAc and 70% hexane. The selected fractions were combined and the solvent evaporated in vacuum to give a brown solid which was crystallized from EtOAc to give pure 4 (10.0 g, 78% yield).

'H NMR (CDC1 3 d 1.50 9H), 1.85 2H), 2.25 2H), 2.85 2H); 4.20-4.45 (m, 3H), 7.00-7.25 4H).

A solution of 4 (4.0 g, 17.2 mmol) in 30% TFA/dichloromethane (25 mL) was stirred at room temperature for 3 h. The solvent was evaporated in vacuum and saturated aqueous

KCO

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 vacuum to give the crude product. Chromatography on silica gel eluting with a mixture of 10% Et 3 N, 60% EtOAc and 30% hexane gave 5 as a yellow solid (1.82 g, 66% yield).

MS: m/z 450 'H NMR (CDC13): d 1.75-2.10 3H), 2.30 2H), 2.80 2H), 3.20 2H), 4.25 (m, 1H), 7.00-7.25 4H).

i, S. EXAMPLE 2 O ATTACHMENT OF TAIL GROUPS Tail groups were attached to the head groups according to the following procedures: 0 R-Br, EtN

DMF

NN

H R 1

R

2 NaCN 3 BH, HOAc mol. sieves, MeOH

RI

1

R

2 General procedure for alkylation: To a solution of the amine (1 eq) and triethylamine (1 eq) in dimethylformamide, was added 1 eq of alkyl bromide or chloride in one portion. The mixture was stirred and heated at 80 0 C over night TLC indicated the reaction was complete. The reaction was quenched by the addition of water followed by 1 N NaOH to pH 10. The mixture was extracted 2x with Et 2 O. The combined organic extracts were dried over potassium carbonate and the solvent evaporated, followed by chromatography to give the pure product.

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

The following compounds were prepared by attaching the tail groups using the general 0 procedures described: 341 -(naphth-Z-yl-methyl)A4-piperidinyl]-211-benzoxazol.2-one 00 3-[1 -(naphth-1 -yl-methyl)- 4 -piperidinyl]-2H-benzoxazol-2-one 3-[1 -(p-phenylbenzy1)-4-piperidinyl]-2H-benzoxazol2.one 3 -[l-p-benzyloxybenzyl)-4-piperidinyl]-2Hbenzoxazol2-one 34 l-(p-cynobenzyl-4-piperidiny]-2H-benzoxazo1.2-one MS: nIz 334.4 (M+1) 3 3 3 -diphenylpropy1)-4-piperidinyl]-2H-benzo~xazol-2-one 3 4 4 -Bis-( 4 -fluorophenyl)butyl]-4-piperidinyl]-2H.benzoxaol.2one MS: m/z 463.6 (N4+1).

3-[1 2 -phenylethyl)-4-piperidinyl]-2H-benzoxazol.2-one 3 -[l-(cyclooctylmethyl)-4-piperidiny1]-2H-benzoxazo12-one LC: 100% MS: m/z 343.6 '11 Pvfl (CDCL 3 d 1.25 (in, 1.40-1.7 (in, 17ff), 2. 10 3. 10 (in, 2H), 4.20 (in, 7.10-7.20 (4H).

1 3C-NMR (CDCl3): 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.

341 2 3 4 -trahydro-2-naphthyl)A4-piperidinyl]-2H-benzoxazo1.2-one LC: 100% MS: 349.6 (M+1) 1I{-N4R (CDC13): d 1.70 (mn, 1H1), 2.00 211), 2.10 1H1), 2.40 (in, 4H1), 2.90 (mn, 511), 3. 10 (in, 211), 4.20 (in, 111), 7.10-7.3 0 (in, 8H1).

3 i-(5-methylhex-2-y1)-4-piperidiny1]-2H-benzoxazo1.2.one 48 LC: 100% o MS: 317.4 (M+l) r-'H-NMR (CDC1 3 d 0.90 (di, 6M1, 1.00 311, 1.20 (mn, 311), 1.50-1.60 (mn, 4H1), 1.80 (in, 2H), 2.20-2.60 5H), 2.90 211'), 4.2 (mn, 1H), 6.90-7.30 (mn, 4H1).

00 3[-1, LC: 96.4% 'H-NMR (CDCI 3 d 1.80 (cid, 2M1, 2.00 (dt, 2H), 2.30 (dq, 211), 2.80-2.95 (mn, 411), 4.01 (s, 1IM, 4.05-4.22 7.05-7.25 (mn, 12H-).

CI 3-[l1-( 4 -propyl-cyckohexyl)-4-piperidiny1]-2H-benzoxazo12.one MS: m/z 343.0 -(norbornan-2-yl)-4-piperidiny1]-211-benzoxazo12-one LC: 97% MS: m/z 313.41 (M+1) 'H-NMR (CDC1 3 di 0.90 (in,11), 1.30-2.50 (in,17H), 3.20 (in,211), 4.3 (in, 111), 6.90-7.30 (n,4 411).

-(decalhydro-2-naphthy)-4-piperdny]2Hbenoxao.2one MS: m/z 355.4 3-[1 -(3,3-diinethyl- 1 ,-dioxaspiro[5.5]undeca-9-yl)A-piperidinyl..2H.benzoxazo..2one MS: m/z 401.3 3-[1 4 -(l-inethylethy)-cycohexy]4piperdiny-2Hbezoxzo12-one MS: m/z343.0 31 ,3-dihydr oinden-2-y)-4-piperidiny].2H-.bep.zoxazolp2one LC: 100% MS: in/z 335.4*(M+1) 'H-NMR (CDCL 3 d 1.90 (in, 111), 2.40 (in, 211), 2.50 (in, 211), 2.90 211), 3.10-3.40 (mn, 611, 4.20 (mn, 1H1), 7.10-7.30 (in, 8M1.

3-[1 -(cyclooctyl)- 4 -piperidinyl]-2H-benzoxazol.2one LC: 100% MS: m/z 329.2 (M+1) O 'H-NMR (CDCl 3 d 1.40-2.00 16H), 2.40-2.65 4H), 2.80 1H), 3.05 2H), M 4.25 1H), 7.10-7.40 4H).

Other compounds within the scope of formula or (IA) of the present invention can 00 be synthesized by analogous techniques.

J EXAMPLE 3 In *Nociceptin affinity at the ORL 1 receptor for preferred compounds was obtained using the following assay: Membranes from recombinant HEK-293 cells expressing the human opioid receptorlike receptor (ORL-1) (Receptor Biology) were prepared by lysing cells in ice-cold hypotonic buffer (2.5 mM MgCl 2 50 mM HEPES, pH 7.4) (10 ml/10 cm dish) followed by homogenization with a tissue grinder/teflon pestle. Membranes were collected by centrifugation at 30,000 x g for 15 min at 4 0 C and pellets resuspended in hypotonic buffer to a final concentration of 1-3 mg/ml. Protein concentrations were determined using the BioRad protein assay reagent with bovine serum albumen as standard. Aliquots of the ORL-1 receptor membranes were stored at Functional SGTPgS binding assays were conducted as follows. ORL-1 membrane solution was prepared by sequentially adding final concentrations of 0.066 mg/ml ORL-1 membrane protein, 10 mg/ml saponin, 3 mM GDP and 0.20 nM ["S]GTPgS to binding buffer (100 mMNaCI, 10 mM MgCI 2 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 ml/well) was transferred to 96-shallow well polypropylene plates containing ml of 20x concentrated stock solutions of agonist prepared in DMSO. Plates were incubated for 30 min at room temperature with shaking. Reactions were terminated by rapid filtration onto 96-well Unifilter GF/B filter plates (Packard) using a 96-well tissue harvester (Brandel) and followed by three filtration washes with 200 ml ice-cold binding buffer (10 mM NaH 2

PO

4 mM Na 2 HPO4, pH Filter plates were subsequently dried at 50 0 C for 2-3 hours. Fifty ml/well scintillation cocktail (BetaScint; Wallac) was added and plates were counted in a Packard Top-Count for 1 min/well.

Data was analyzed using the curve fitting functions in GraphPad PRISM6, v. 3.0 and the results are set forth in table 1 below: TABLE 1 Nociceptin Affinity Compound caic K(M 3-[1 -(naPhth- 2 -Y-me thy)4pipernyI2Hbenzoxao.2one '3030 3-[1 '{naPhth- l-yI-methy)-4-piperidinyl-2Hbenzoxao2-one 370 l-(-phenylbenzyl)-4-piperidjnyl]-2H-benoxazol.2-one >10,000 -Pbnyoy5nyl--ieiiy]2Hbnoao--n 2173 3-[1 peaoezy)4pprdiyl2-ezoao--n >10,000 3-[l 33q y)4-ieiiy]2-bnoao--n 726 3 4[l-[ 4 4 -Bis-( 4 -fluorophenyl)buty1]A..piperidinyl].2H.. 3070 benzoxazolb2-one 1-( 2 -phen ylethy)-4-piperidiny1I-2Hbezoxao12-one 7087 -c~lotfelyl--ie!uyl2Hbnoao--n 64 3-[1 2 3 ,4-tetrahydro-2-naphthyl}4-piperidinyl]}2H.. 93 benzoxazol-2-one 3-[l 5rehle--l--ierdnl-Hbnoao--n 3-[l1-(10,1 1-Dihydro-5H-dibenzo[a,d].cyclohepten.5-y).4 >10,000 piperi nfyl]-2H-benzoxazol.2-one 3-fl ,3-dimethyl-1 ,5-dioxaspiro[5 .5]undeca-9-yl)-4- >10,000 piperidiry1]-2H-benzoxazo12-one 3-[l1-(1,3dhdone- l--ierdnl-Hbrzxzl2 512 one 3-[l ccoq-l+Pprdnl-H-ezxzl2 16 EXAMPLE 4 SYNTHESIS OF SUBSTITUTED IND OLE HEAD GROUPS 0

NH

2 2 Na(OjAc),BH

ONNH

0 AId 3 j

H

2

-BOC

2

O

Ny 0

NO

base

CH

3

CHO

B'O

acid N0

H

9 E/Z isomers 8 EIZ isomers Procedure: To a mixture of 2 (23.3 g, 0.25 mol), 1 (47.3 g,"0.25 mol), acetic acid (15 g, 0.25 mol) and molecular sieves (15 g) in 500 mL of dichioroethane, sodium triacetoxyborohydride (74.2 g, 0.35 mol) was added in one portion and the mixture stirred overnight. The molecular sieves were filtered off and 1 N NaOH-(500 mL) was added to quench the reaction. The o organic layer was separated and the aqueous layer extracted with EtOAc (2 x 300 mL). The 0 combined organic extracts were dried over K 2

CO

3 filtered and the solvent evaporated under vacuum to give crude 3 as a brown solid which was directly used in next step.

0 Compound 3 00 S'H-NMR (CDC1 3 d 1.50 2H), 2.05 2H), 2.20 (bt, 2H), 2.85 2H), 3.30 1H), C\1 3.52 2H), 6.60 2H), 6.70 1H), 7.20 2H), 7.25-7.40 To an ice cooled solution of crude 3 (0.25 mol, 100% yield assumed) and DIEA (48.4 g, 0.38 mol) in 500 mL of dichloromethane, was added dropwise chloroacetyl chloride (42.4 g, 0.375 mol). After the addition was complete the ice bath was removed and the reaction mixture stirred overnight. The solvent was removed in vacuum and the residue 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 removed in vaccum to give a brown gum which was filtered through a column of silica gel eluting with a mixture of 10% Et 3 N, 40% EtOAc and hexane. The selected fractions were combined and the solvent evaporated in vacuum to give a brown solid which was further crystallized from EtOAc to give 42.2 g of 4 2 steps).

Compound 4 'H NMR (DMSO): d 1.22 2H), 1.70 2H), 2.00 2H), 2.80 2H), 3.40 2H), 3.80 2H), 4.40 1H), 7.15-7.30 7H), 7.45 3H).

A mixture of 4 (42.2 g, 0.12 mol) and AIC1 3 (49.2 g, 0.369 mol) was mixed in a flask by rapid stirrihg. The mixture was then heated in an oil bath at 130 OC. Within a few minutes the solids melted and became a dark liquid with concomitant gas evolution. After heating for 1 h the reaction mixture was cooled somewhat and while still mobile poured into a beaker containing 500 mL of ice water. The solution was basified and extracted with dichloromethane. The organic layer was dried over Na 2

SO

4 filtered and the solvent evaporated in vacuum to give a dark oil which was filtered through a column of silica gel eluting with a mixture of 10% Et 3 N, 40% EtOAc and 50% hexane. The selected fractions were combined and the solvent evaporated in vacuum to give 5 as a red oil which set to a pale solid (22.0 g, 58.5%).

53

O

0 Compound O 'H NMR (CDC1 3 d 1.70 2H), 2.17 (m 2H), 2.50 2H), 3.05 2H), 3.55 2H), C 3.60 2H), 4.33 1H), 7.00-7.40 9H).

O To a solution of 5 (16.0 g, 0.052 mol) in 35 mL of methanol was added Pd(OH) 2 00 C The resulting suspension was hydrogenated at 50 psi for 12 h at room temperature. The CMi solution was filtered through a pad of Celite and the pad washed with methanol (2 x 20 mL).

t Evaporation of the solvent in vacuum gave 6 as a pale solid (11.2 g, 100%).

SCompound 6 LC: 100% MS: m/z 217 'H NMR (CDC1 3 d 1.75 3H), 2.35 (m 2H), 2.75 2H), 3.25 2H), 3.50 2H), 4.33 1H), 7.00-7.30 4H) To a solution of 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 h saturated aqueous K 2

CO

3 was added and the layers 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 vacuum to give a brown oil which was filtered through a column of silica gel eluting with a mixture of 10% EtN, 40% EtOAc and 50% hexane. The selected fractions were combined and the solvent evaporated in vacuum to give 7 as an off white solid (8.50 g, 73%).

Compound 7 'H NMR (CDCl 3 d 1.50 9H), 1.70 (m 2H), 2.20-2.50 2H), 2.80-3.00 2H), 3.50 2H), 4.20-4.50 3H), 6.90-7.60 To a mixture of 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, 38.0 mmol). The mixture was refluxed for 2 h. The solvent was evaporated in vacuum to give a dark oil which was filtered through a column of silica gel eluting with a mixture of 10% Et 3 N, 40% EtOAc and 50% hexane. The 54

O

O

selected fractions were combined and the solvent evaporated in vacuum to give 8 as a red oil O (5.90 g, 91%).

Compound 8 O LC: 2 isomers in aratio of2:1.

C) 'H NMR (CDC13): (mixture of 2 isomers) d 1.50 9H), 1.70 (m 2H), 2.20-2.50 6H), 2.60-3.00 2H), 4.20-4.50 3H), 6.90-7.60 SA solution of 8 (5.90 g, 17.2 mmol) in 30% TFA/dichloromethane (100 mL) was cstirred at room temperature for 3 h. The solvent was evaporated in vacuum and saturated aqueous K 2 CO 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,

filtered and evaporated in vacuum to give the crude product. Chromatography on silica gel eluting with a mixture of 10% Et 3 N, 50% EtOAc and 40% hexane gave 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 'H NMR (CDC 3 (mixture of 2 isomers) d 0.85 1H), 1.50 -2.00 4H), 2.20-2.50 (m, 2.60 1H), 3.10-3.50 2H), 4,30 1H), 6.90-7.60 in LS EXAMPLE 00 CH 3

CHO

N

N

0 01 To a mixture of 5 (5.50 g, 1.8 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 h.

The solvent was evaporated in vacuum to give a dark oil which was filtered through a column of silica gel eluting with a mixture of 10% Et 3 N, 40% EtOAc and 50% hexane. The selected fractions were combined and the solvent evaporated in vacuum to give 10 as a red oil (5.90 g, 98%).

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

MS: m/z 333.2 'H NMR (CDC13): d 1.70 (mn, 2H), 2.17 (m 2H), 2.30 3H11), 2.50 2H), 3.05 2H), 3.55 2H), 4.33 1H), 7.00-7.40 9H), 7.6 1H).

To a solution of 10 (5.90 g, .17.7 mmol) in 30 mL of methanol was added Pd(OH) 2 The resulting suspension was hydrogenated at 50 psi for 12 h at room temperature.

The solution was filtered through a pad of Celite and the pad washed with methanol (2 x mL). Evaporation of the solvent in vacuum gave a pale solid which was purified by chromatography on silica gel eluting with a mixture of 10% methanol and 90% EtOAc to give 11 as an off white solid (2.02 g, Compound 11 LC: 97% MS: m/z 245.2 (M+l) ti mVIu (CDC 3 d 0.85 3H), 1.26 2H), 2.00 211), 2.43 2H), 2.90 211H), 3.3 2H), 3.4 4.4 1H11), 7.05 1H), 7.15-7.30 31H).

EXAMPLE 6

NH

2 2 Na(OAc)BH Na(OAc)3BH N 0

NICIYCI

N

N,

14

AIC

3

H

2

O>O"

H

16 Procedure: In a manner similar to the preparation of 6, compound 16 was prepared.

Compound 13 LC: 89.4% MS: m/z 281.2 (M+1) 'H-NMNR (mixture of trans and cis) (CDC 3 d 0.95 3H), 1.50-2.75 5H), 2.80-3.20 (m, 1H), 3.50 2H), 3.60 (minor)+3.70 (major) (two 8, 2H), 6.55-6.80 2H), 7.05-7.45 8H).

Compound 14 MS: m/z 357.2 (M+l) DJVLK. (mixture f trans and cis) (CDC1 3 d 1.10 3H), 1.40-4.20 (mn, 111), 4.40 1H), O 7.05-7.50 Compound LC: 90.0% 00 MS: m/z 321.2 (M+1) 'H-NMR (CDC1 3 d 1.20 3H), 1.75 (nm, 1H), 2.10 (dt, 1H), 2.25 1H1), 2.30 (dd, 2.75 S(dd, 1H11), 3.05 1H), 3.20 1H), 3.50 4H), 4.10 1H), 6.99 2H), 7.23 3H), 7.37 4H).

Compound 16 LC: 92.5% MS: m/z 231.2 (M+1) 1H-NMR (CDC13): dd 1.20 3H), 1.75 11H), 2.10 (dt, 1H), 2.25 1H), 2.30 (dd, 1H), 2.75 (dd, 1H), 3.05 1H), 3.20 (mn, 1H), 3.50 2H), 4.10 1H), 6.99 2H), 7.23 (nm, 3H), 7.37 4H).

EXAMPLE 7 Sbase H2 0 N 0O base N 0

CH

3 CHO N3 17

H

18 17 58 Procedure: In a manner similar to the preparation of 11, compound 18 was prepared.

Compound 17 00 MS: m/z 347.3 (h4+1) Compound 18 LC: 82.6% c-IMS-. mhz 259.3 (M+1) '11 NMvR (CDC1 3 d 0.80 311), 1.20 311), 2.00 (in, 21-1, 2.3.0 (mn, 2.65 (in, 1M1', 2.82 (mn, 111), 3.15-3.25 (in, 111), 3.32 (mn, 111), 3.45 (in, 1H1), 3.65 (in, 1H1), 3.75 (mn, 111), 4.25 (mn, 1H1), 6.90 7.05 1M1, 7.25 (in, 211).

EXAMPLE 8 ATTACHMENT OF TAIL GROUPS Tail groups were attached to the head groups according to the following procedures: DMF f H0

R

1

R

NaCN 3 BH, HOAc mol. sieves, MeOH

Q

R

1 -1R 2 o General procedure for alkylation: o To a solution of the amine (1 eq) and triethylamine (1 eq) in dimethylformamide, was added 1 eq of alkyl bromide or chloride in one portion. The mixture was stirred and heated at 0 C over night. TLC indicated the reaction was complete. The reaction was quenched by the 0 addition of water followed by 1 NNaOH to pH 10. The mixture was extracted 2x with EtO. The 00 M combined organic extracts were dried over potassium carbonate and the solvent evaporated, followed by chromatography to give the pure product.

SGeneral procedure for reductive amination: To a mixture of ketone or aldehyde (1 eq), amine (1 eq); and acetic acid (1 eq) in methanol, was added sodium cyanoborohydride (1.4 eq) in one portion. The mixture was stirred over night at room temperature. TLC indicated the reaction was complete. The reaction was quenched by the addition of water followed by 1 N NaOH to pH 10. The mixture was extracted 2x with Et 2 O. The combined organic extracts were dried over potassium carbonate and the solvent evaporated, followed by chromatography to give the pure product.

The following compounds were prepared by attaching the tail groups using the general procedures described: 1-[1-(naphth-1-yl-methyl)-4-piperidinyl]-1, 3 -dihydro-2H-indole-2-one MS: m/z 357.2 -(naphth-2-yl-methyl)-4-piperidinyl]-1, 3 -dihydro-2H-indole-2-one MS: m/z 357.3 1-[1-(p-phenylbenzyl)-4-piperidinyl]-1, 3 -dihydro-2H-indole-2-one MS: m/z 383.2 1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-1, 3 -dihydro-2H-indole-2-one LC: 98.7% MS: m/z 411.2 (M+1) 'H-N[R (CDCI 3 d 1.65 (bd, 2F), 2.05 ft, 2H), 2.30 4H), 2.45 2F), 3.02 (bd, 2F), 3.50 2H), 4.01 1F), 4.30 (i 1F),,7.00 1F), 7.15-7.35 (in, 13H).

l-[l-(p-cyanobenzyl).4-piperidinylyl ,3-dihydro-2H-indole-2-one MS: ni/z 332.2 00 1 -[1-(p-benzy oxybenzyl)-4-piperidinyl]- MS: m/z 413.3 (M+1) 2 ,3, 4 -tetrahydronaphth-2-yl)-4-pipeidinyl]1 ,3-dihydro-2H-indole-2-one LC: 100% MS: r/z 347.5 'H NMR (CDCL 3 d 1.70 (in, 3Ff), 2,10 1f), 2.40 4H), 2.90 3.OOQ i, 5F), 3.10 (m, 2Ff), 3.60 2F), 4.3 1F), 7.00-7.30 8F).

1-[1 -(S-methylhex-2-yl)A4-piperiinyl].1,3-dihydro-2H-indole-2-one LC: 100% MS: r/z 315.4 'HNMR(CDC1 3 d 0.90 6Ff), 1.00 (in, 311), 1.20 3F), 1.5-1.8 2F), 2.2-2.6 2.90 2f), 3.60 2F), 4.2 11), 6.90-7.30 4f).

1-[1 -(norboman-2-yI)-4-piperidinyl]. 1 ,3-dihydro-2H-indole-2-one LC: 97% MS: rn/z 311.41 'H NMR (CDC1 3 d 0.90 1.

3 0- 2 .00(m, 7F), 2.10-2.30 5H), 3.20 2F), 3.60 (s, 2H), 4.3 1F), 6.90-7.30 4H).

1-[1-(1,3-dihydroinden-2-yl)-4-pipeidinyl].1,3-dihydro-2H-indole-2-one LC: 100% MS: n/z 332.4(M+1).

-,ri ±N!VJ.K (UuUJL1 3 CL 1.80 (in, 2H), 2,40 (in, 2M1, 2.50 (in, 211), 2.90 (in, 211), 3.10-3,40 (mn, 5H1), o 3.60 2H), 4.20 111), 7.10-7.30 (in, 811).

1 -[l-(c-ycooctylinethy1)..4-piperidinyl]i 3 -dihydro-211-jndole.2-.one LC: 97% 00 MS: m/z 341.50 'H NUR (CDC1 3 d 1.25 (mn, 3H), 1-4-1.7 (mn, 14H), 2. 10 (in, 411), 2.50(m, 211), 3.10 (mn, 211), c-I 3.60 211), 4.3 (mn, 7.10-7.20 (nm, 4H).

1 C-NIVMR (CDC1 3 d 23.07,26.04,26.89,27.56,28.63,31.27, 32.00,35.30,36.33,46.63,50.65, c-I 54.06, 66.47, 110.90, 12217, 124.90, 125.26, 127.94, 144.25, 175.3 1.

3-ethyl-i i-(1 2 3 4 -tetrahydro-2-naphthyl)..4.piperidiny1] 1 3 -dihydro-2H-indole-2one MS: rnlz 375.3 3-ethyl- -4poyccoey)--ieiiy]13diyr-Hidl--n MS: rn/z 369.2 3-ethyl- l-[l-(S-iethylhex-2-y)-4-pipeidiny1].1, 3 -dihydro-211-indole.2.one LC: 100% MS: m/z 342.4 NMR (CDC1 3 d 0.80 3H1), 0.90 (mn, 1.00 (mn, 311), 1.20 (mn, 3H), 1.5-1.8 (in, 211), 2.2-2.6 (mn, SIR), 2.90 (in, 211), 3.40 (mi, 11M, 4.3 (in4 11), 6.90-7.30 (mn, 411).

3-ethyl-i-[i -(norboinan-2-y1)..4.piperidinyl].1 3 -dihydro-211-indole.2.one LC: 100% MS: ni/z 339.41 'H1NM.(CDC1 3 0.80 (in,311,0.90 11), 1.30-1.45(in, 511,1.50-2.05(in, 8H), 2.10 (n, 111), 2.20 (n,4 211), 2.50 (mn, 211, 3.10 (in, 211), 3.40 (rn,1H), 4.3 (mn, 1H1), 6.90-7.30 (mn,4H).

3 -ethyl-1 l-(decahydro-2-naphthyl)4piperidiny1.l,3-dihydro-2H-jndole-2one MVS: nilz 381.3 3-ethyl- 1-L1-L4-(l -riethylethyl)-cyc~lohexyy4-piperidinyl}.1 ,3-dihydro-2H-indole-2-one o MS: m/z 369.3 (M+1) '1{-NMR (CDC1 3 d 0.88 3R), 0.92 6H), 1.17 (mn, 111), 1.40 (mn, 2H), 1.50-1.70 (in, 9H), 2.05 (mn, 2H), 2.25 (mn, 2H), 2.32-2.55 (mn, 31K), 3.15 2H), 3.43 1K), 4.35 (in, 1H), 7.05 (t, 1K), 7.22 7.28 (in, 2H).

00 3-ethyl-i 1-(1 3 -dihydroinden-2-yl)-4-pipericjilyl].1 ,3-dihydro-2H-indole-2-one MS: m/z 361.2 LC: 97% MS: rn/z 369.50 'H NMR (CDCL 3 d 0.80 3H), 1.25 (in, 3K), 1-4-1.7 (in, 14K), 2.10 (mn, 6K), 2.50(m, 2H),- 3. 10 (in, 2K), 3.40 (in, 1H), 4.3 (1n 1K, 710-7.20 (in, 4H).

3-ethylidene-1-[ l-(benzyl)-4-piperidinyl]l ,3-dihydro-2H-indole-2-one MS: rnlz 333.2 (M+1) 'I--NM.R (CDGI 3 d 1.70 (mn, 21K), 2.15 (dt, 2K), 2.28 3K), 2.47 (mn, 2K), 3.05 2k), 3.57 2K), 4.34 (mn, 1IM, 7.02 1K), 7.08-7.40 (in, SK), 7.58 1K).

3-ethylidene-1 npt--lmty)--ieiiy]13diyr-Hidl--n MS:ni/z 405.2 3-ethylidene-lI-[ l-( 3 3 -diphenylpropyl).4piperidinyl].1 ,3-dihydro-2H-jndole-2-one LC: >97% (2 isomers combined).

MS: in/z 437.5 111 NMR (CDC1 3 d 1.70 -1.80 2,10(rn, 2K), 2.20 -2.40(in, 3.10 (inl,2), 4.10 1K), 4.3 (mn, 1H), 7.00-7.30 (mn, 3-ethylidene-1-[ l.(p-cyanobenzyl).4-piperjdinyl.1 3 -dihydro-2H-indole-2-one LC: >97% (2 isomers combined).

0 ~'HNMR (CDC1 3 d 1.80 (in, 10-2.60 3.10~m, 2H), 3.70 2H), 4.3 ti,lIB), 6.90-7.60 (mn, 8B).

3-ethylidene- l-[l-(p-benzyoxybenzy)-4-piperidiny].1 ,3-dihydro-211-indole-2-one 00 MS: ni/z 405.2.

CI 3-ethylidene- 1l-El-(L, 2 ,3,4-tetrhydro-2-naphthyl)-4-piperidiuiyl]l ,3-dihydro-2H-indole-2-one LC: >97% (2 isomers combined).

MS: mlz 373.5 'H NMR (CDCI 3 d 1.70 -3.10 (mn, 18ff), 4.3 (mn, 7.00-7.30 (mn, 911).

3-ethylidene-1-[1 4 -propylcyclohexyl)-4jiperilinyl].1 ,3-dihydro-211-indole-2-one LC: >97% (2 isomers combined).

MS: m/z 367.5 'H NVR (CDC1 3 d 0.90 (in,4 1.

30 -2.00(m, 7ff), 2.10-2.30 (mn, 51-1), 3.20 (mn, 2H), 3.60 (s, 2ff), 4.3 (mn, 111), 6.90-7.30 (in, 3-ethylidene-1-[ 1-(S-methylhex-2-yI)-4-piperidinyl].1 ,3-dihydro-2H-indole-2-one LC: >97% (2 isomers combined).

MS: rn/z 341.4 'H NMR (0D01 3 d 0.90 -2.6 (nm, 24ff), 2.90 (n,4 2H1), 4.2 (in, 111), 6.90-7.30 (mn, 5H1).

3 -ethylidene-1-[1-(norbornan.2..y).4.pipeidinyl]-1, 3 -dihydro-2H-indole-2-one LC: >97% (2 isomers combined).

MS: in/z 337.41 'H NMR (CDC 3 dO0.90 (mn, 1H), 1.

3 0-2.50(mn, 17H1), 3.10 (in, 2H1), 4.3 (in, IHI), 6.90-7.30 (Mi, 3-ethylidene-1-[1-(1, 3 -dihydroinden-2-y)-4-piperidiny1]. ,3-dihydro-2H-indole-2-one LC: >97% (2 isomers comhbined).

c, MS: M/z :3 i.4 o 'H NMR (CDCL 3 d 1.80 3.10 17H), 4.20 (in, 1H), 7.10-7.30 9H).

3-ehbyihyl)-4 p, 3 -dihydro-21-indole-2.one LC: >97% (2 isomers combined).

00 MS: mlz 367.50 'HNMR (CDC1 3 d 1.25 31), 1.4-1.7 21H1), 2.10- 2 .50(m, 2M), 3.10 2H),4.3 (in, 11), 6.90-7.60 1-[1-(3,3-Bis(phny ropyl)-3-(methyl)-4 LC: 100% MS: mhz 425.3 (M+1) 'H-NMR (CDC1 3 d 1.20 3H), 1.69 (bd, 1H), 1.95 (dt, 1H), 2.13-2.30 5H), 2.72 (bd, 111), 2.98 (bd, 11), 3.15 (dq, 1H), 3.50 211), 4.03 (dt, 1H), 4.12 11), 6.94 7.00 11), 7.10-7.30 12H).

1-1: 1-0benzyl)-3-(methyl)-4-piperidinyl]- 1,3 -dihydro-2H-indole-2-one LC: 100% MS: mlz 321.2 (M+1) 'H-NMR (CDC 3 d 1.20 31), 1.70 11), 2. 10 (dt, 1H), 2.23 1H), 2.35 (cd, 11), 2.78 1H), 3.05 1H), 3.20 (dq, 111), 3.51'(m, 4H), 4.10 (dt, 11), 7.00 2H), 7.25 3H), 7.38 4H).

1-[l-(4-proyl-cyclohex methyl)-4-ieiiy]13dhyr-Hidl--n LC: 96.2% MS: r/z 355.2 (M+1) 'H-NMR (CDC1 3 d 0.85 1.15 1.22-1.85 131), 2.05-2.90 6M), 2.95- 3.20 2f), 3.50 211), 4.05 1H), 7.00 211), 7.22 21).

1-[0-(5-methylhex-2-yl)-3-(methyl)-4-pip LC: 100% r MS: m/z 329.2 (M+1) o H-NMR(CrDC1 3 d 0.85 9H), 1.15 3H), 1.20-1.75 6H), 2.25 11), 2.45-2.75 (in, 411), 2.88 3.10 1H1), 3.50 2Mi, 4.05 1M), 6.98 (in, 2R), 7.25 211).

S1-[l-(decahydro-2-naphthyl)-3-(methyl)-4-perdnl1,-iyo2Hnoe2oe 00 LC: 95.3% MS: mlz 367.2 (M+1) rI 'H-NMR(CDC1 3 1.11 3H), 1.16-1.85 1611), 2.20 2.35 2m), 2.52 (in, 2), 2.75 1H), 3.02 211), 3.50 21), 4.05 11), 6.96 21), 7.20 (in, 211).

-methylethyl)-cyclohexyl)-3-(methy)-4-p iyl,3-dihydro-2H-indole-2-one LC: 96.1 MS: m/z 355.2 (M+1) 1 1-NMR (GDC1 3 d 0.80 1.15 31), 1.22-1.48 (im, 31), 1.50-1.90 (ni, 61), 2.15- 2.90 41), 2.95-3.25 211), 3.50 211), 4.10 111), 6.95 (in, 7.22 21).

1-[1-(cyclooctyethy)-3-(methyl)-4-pipeidiny1,3-dihydro-2H-indole-2-one LC: 100% MS: m./z 355.2 (M+l) 'H-NMR (CDC1 3 d .1.2 3H), 1.15-1.75 16H), 1.92-2.10 31), 2.20 21), 2.73 (n, 1H), 3.00 (rn, 11), 3.12 (dq, 111), 3.50 2H), 4.05 (dt, 11), 6.99 211), 7.20 21).

3 -ethyl- 3 ,3 -Bis(phenyl)propyl)-3-(methyl)-4-piperidiny1-1,3-dihydro-2H-indole-2-one LC: 96.3% MS: m/z 453.3 (M+1) 'H-NMR (CDC1 3 d (two t, 31), 1.18 31), 1.70 111), 1.90-2.05 31), 2.12-2.30 (in, 51), 7.73 (in, 11), 2.97 (bd, 11), 3.10-3.30 3.38 11), 3.90-4.05 1H), 4.12 (q, 11), 6.90-7.00 (two d, 7.02 (t 11), 7.12-7.32 (m,'12H).

3-ethyl- 1-[I 4 -propylcyclohexyl)-3 -(methyl)-4-pipeidinyl]- ,3-dihydro-2H-indole-2-one LC: 93.2% cIvIO: 1W z Z5 i.-i(VI+ 1) o 'H-NMR (CDC1 3 d 0.75-0.95 6H), 1.05-1.20 5H), 1.20-1.35 4H), 1.35-1.75 (m, 61H), 1.75-1.90 (nm, 2H), 1.95-2.05 2H), 2.15-2.45 3H), 2.55 0.5H), 2.75 2.95-3.15 2H), 3.38 1H), 3.90-4.10 1H), 6.90-7.05 7.20-7.25 211).

003-ethyl-1-[ i-(5-methylhex- 2 -yl)-3-(methyl)-4-piperidinyl]-1, 3 -dihydro-2H-indole-2-one; LC: 92.3% MS: m/z 357.4 (M+1) 'H-NMR (CDCl 3 d 0.75-0.95 10H11), 1.10 3H), 1.15-1.40 3H), 1.40-1.75 4H11), 1.97-2.10 2H), 2.20 1H), 2.43-2.75 (nm, 4H), 2.80-2.95 1H), 3.00-3.25 (nm, 1H), 3.40 1H), 3.90-4.10 1H), 6.90-7.05 21H), 7.25 2H).

3-ethyl-1-[1-[4-(1-methylethylcylohexyl]-3-methyl-4-piperidinyl]-1,3-dihydro-2H-indole-2-one LC: 94.7% MS: m/z 383.4 (M+1) 'H-NMR (CDC1 3 d 0.75-1.05 8H), 1.10-1.50 7H), 1.50-1.90 7H), 1.90-2.10 (m, 2H), 2.15-2.43 3H11), 2.55 0.5H11), 2.75 0.5H), 2.90-3.25 3H), 3.40 1H), 3.90-4.10 1H11), 6.90-7.01 (mn, 2H), 7.25 (nm, 2H).

3-ethyl-1-[ -(decahydro-2-naphthyl)-3-(methyl)-4-piperidiny) -1, 3 -dihydro-2H-indole-2-one LC: 94.3% MS: m/z 395.3 (M+1) 'H-NMR

(CDC

3 d 1.75-1.90 (two t, 3H), 1.10 3H), 1.15-1.90 (nm, 15H), 2.00 2H), 2.20 (bs, 1H), 2.40 2H), 2.45-2.60 2H), 2.75 1H), 2.90-3.20 2H), 3.40 (bs, 11), 3.90- 4.15 1H11), 6.90-7.05 2H), 7.25 2H).

Other compounds within the scope of formula (II) or (IIA) of the present invention can be synthesized by analogous techniques.

SEXAMPLE 9 O Nociceptin affinity at the ORL1 receptor forpreferred compounds was obtained using the following assay: Membranes from recombinant HEK-293 cells expressing the human opioid receptor-like Sreceptor (ORL-) (Receptor Biology) were prepared by lysing cells in ice-cold hypotonic buffer 0 (2.5 mM MgCl 2 50 mM HEPES, pH 7.4) (10 ml/10 cm dish) followed by homogenization with a tissue grinder/teflon pestle. Membranes were collected by centrifugation at 30,000 x g for rC min at 4 0 C and pellets resuspended in hypotonic buffer to a final concentration of 1-3 mg/ml.

Protein concentrations were determined using the BioRad protein assay reagent with bovine Sserum albumen as standard. Aliquots of the ORL-1 receptor membranes were stored at-80 0

C.

Functional SGTPgS binding assays were conducted as follows. ORL-1 membrane solution was prepared by sequentially adding final concentrations of 0.066 mg/ml ORL-1 membrane protein, 10 mg/ml saponin, 3 mM GDP and 0.20 nM 3 5 S]GTPgS to binding buffer (100 mM NaC1, 10 mM MgC1, 20 mM HEPES, pH on ice. The prepared membrane solution (190 ml/well) was transferred to 96-shallow well polypropylene plates containing 10 ml of 20x concentrated stock solutions of agonist prepared in DMSO. Plates were incubated for min at room temperature with shaking. Reactions were terminated by rapid filtration onto 96well Unifilter GF/B filter plates (Packard) using a 96-well tissue harvester (Brandel) and followed by three filtration washes with 200 ml ice-cold binding buffer (10 mM NaH 2

PO

4 mM Na 2

HPO

4 pH Filter plates were subsequently dried at 50°C for 2-3 hours. Fifty ml/well scintillation cocktail (BetaScint; Wallac) was added andplates were counted in aPackard Top-Count for 1 min/well.

Data was analyzed using the curve fitting functions in GraphPad PRISMO, v. 3.0 and the results are set forth in table 2 below: TABLE 2 Nbeiceptin Affinity Compound caic XK 1 (nMl 3-ethylidene-1-[ l-(S.-methylhex-2-yl)-4-piperidinyl]..1,3- .11.1 dihYdro-2H-indole-2-one 3 -ethylidene-l-[l-(4-Propylcyciohexyl)4pipeiinyi}.i 19 dihydro-2R-indole-2-one 3-ethylidene-1-[ 1-(1 2 ,3,4-tetrahydro-2-naphthyl)-4- 16.7 piperidinyl]- 1,3-dihydro-2H-indole-2-one 3-ethylidene-l-[ i-cl,3 -dihydroinden-2-yl)-4-piperjd inyl}.1 20.7 dihydro-2H-indole-2-one 3-et-hylidene-i l-(naphth-2-yl-methyl)-4-piperid inyl}. 1,3- 630 dihydro-2H-indole-2-one 3-ethylidene-1 -[l-(P-benzyloxybenzyl).4-piperidinyl].1 516 dihydro-2H1-indole-2-one 3-ethiylidene-i-[ i-(benzyl)-4-piperidinyl]-1,3.dihydro2H. 1854 indole-2-one 3-etliylidene-] -(cyclooctylmethyl)-4-piperidiny]-. 22.3 dihydro-2H-indole-2-one 3-ethylidene-1-[ i-( 3 3 -diphenylpropyl)-4-pipericlinyly 1,3- 100.7 dihydro-2H-indole-2-one 3 -ethylidene-l14i-(norboman.2y)A..pipeidiny11,3-clihydro- 922 2H-indole-2-one 3-ethylidene-1-[i-(p-cyanobenzy1)-4-piperidiny1]..i,3..dihydo 7652 2H-indole-2-one 3-ethyl-i -(5-methylhex-2-yl)-4piperidinyq..i,3-dihydro- 4 2H-indole-2-one 3-ethyl-i l-[ 4 -(-methyethy)-cyclohexyl]..-piperidinyl]-li,3- .86 diydro-2H-indole-2-one 3-ethyl- i-r 4 -~propylcyclohexy1)..4.piperidinyl].1,3-dihydro- 2H-indg1e-2-one 3-ethyl-1-[l-(i 2 3 4 -tetrahydro-2-naphthyl)..4.piperidiny}.1 124 dihydro-2H-indole-2..one 3-ethyl- 1-[1 -(decahydro-2-naphthy)4pipeidiny].1,3- 3.6 dihydro-2H-indole-2-one 3-ethyl- -[1-Cl 1 3 -dihydroinden-2-yi)..4.pipericiinyl]-1,3- 43 dihydro-2H-indole-2-one 3-ethyl-i ccocymtyl--ieiiy]-,-iyr-H 9 indole-2-one 3-ethyl-i -r -(norbornan-2-yl)-4-piperidinyl].1,3-dihydro-2H- 82.7 indole-2-one 1 [-npt--hehl-tiprkyl13!kyr-H 92 indole-2-one l-[l-(naphth-2-Yl-methyl)-4piperidinyl} 1 ,3-dihydro-2H indole-2-one

H

1 -hnlezy)4.ieiinl-,-i~ro2-noe2 one 3 3 -Bis(phenyl)propyl)A..pipeidinyl]-1,3-dihydro-2H- .indole-2-one 1-ri -(p-cyanobenzyl)-4-piperidinyl.1 ,3-dihydro-2H-indole.2one 1-[l-p-benzYloxybenzyl)-4piperidinyl]-1 ,3-dihydro-2Iindole-2-one 1-ri 2 3 4-terahydronaphth2-4).4-piperidinyl] 1,3diii dro-2H-mndole-2..one 1-4 -methiylhex-2-y1)-4pipein-y1]. -l,3-dihydro-2H-ind o-e.

2-one 1-ri -(norbomain- 2 -yl)-4--piperidiny1].~,3-dihydro-2H-indole.2.

one 1-(1,3dhdonen2y)4pperd l-,3-dihydro-2Hindole-2-one l-[I-(cycooctylmethYl)-4-PiPelridinyi-1 ,3-dihydro-2H-indole- 2-one *1 -(bernzy)-3-(methiyl) 4-piperidinyl]..1 ,-dihydro-2H.

indole-2-one 1 l-( 4 -propYl-cYc~lohexyl)-3-(methy)4-piperidinyl]..l,3dihydro-2H-indole.2..one 1 -(5-mehyhhex-2-yl)-3-4methyl..4-piperidinyl] 1 ,3-dihydro- 2 H-indole-2-one 1 dchdo2-ahhl--Mehl--ierdnl-13 dihYdro-2H-indole4..one 1 -methylethyi)-cyclohexyl) .3 -(methyl)-4-piperidinyl]p 1 3 -dihydro-2indole.2.one 141 4(cyclooctylmethyl).3.(methyl..4-piperidinyl] 1 ,3-diydo- 2H-indole-2-one 107 1362 12.5 1267 32 28.7 215 18.7 54.3 10,000 2435 4335 366 167 189 EXAMPLE SYNTHESIS OF CERTAIN HEAD GROUPS.

SCHEME 1:

NH

2

NH

2 0 Na(OAc) 3

BH

acetic acid, DCE ecyNH2

I

CDI

H

P=

0 7 I H 2 /Pd(OH) 2 MeOH NHt _0

H

Na(OAc) 3 BH aN>=o acetic acid, DCE

N

H N 9 8 I H 2 /Pd(OH) 2 MeOH

NH

HN

2 Na(OAc) 3 BH N acetaldehyde, DCE NH2 11 4;

NH

2

I

Procedure: To a mixture of 4 (21.6 g, 0.2 mole), 5 (15.6 g, 0.1 mole), acetic acid (6 g, 0.lmole) in 500 ml of dichloroethane, 29.7 g of sodium triacetoxyborohydride (0.14 mol, 1.4 eq) was added in one portion. Gas evolves between 30 min and 1 hr. The mixture was stirred overniht.

TLC

indicated the reaction is complete. 1 N NaOH (500 ml) was added to quench the reaction. The 0 organic layer was separated and the aqueous, layer was extracted by EtOAC (300 ml x2). The r" combined organics were dried over potassium carbonate and the solvent evaporated to give a red oil which was column filtrated (5%Et3N, 25%EtOAc and 70%Hexane) to givel4 g of product 6 as a white solid 00 Compound 6 MS: m/z 249.3 i 'H NMR (CDC1 3 d 1.50 1.90 6H), 2.05 2H), 3.30 4H), 3.95 4H), 6.60 -6.80 0 4H).

To a solution of 13.5 g of 6 (54.4 mmol) in 50 ml of acetonitrile, 11.02 g of carbonyldiimidazole was added in one portion. The mixture was stirred over night. Solid precipitated out of solution which was filtered and washed by H 2 0 and TBMI to give 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 solid with a pink color which was column filtrated (10%Et3N, 40%EtOAc and 50%Hexane) to give another 4.5 g of product 7 (81 combined).

Compound 7 MS: m/z 274.7 'H NMR (CDCl 3 d 1.50 1.9.0 7H), 2.50 2H), 4.00 4H), 4.50 1H), 7.10 (m, 3H), 7.25 1H).

A mixture of 7 (7.5 g, 27.4 mmole) and 8.26 g of PPTS in 50 ml of acetone and H 2 0 (10:1) was stirred in refluxed over night. The mixture was cooled to room temperature, and acetone was evaporated. Addition of water to the mixture initiated crystalization to give 3 g of product 8 Compound 8 MS: m/z 231

'H.NMR(CDC

3 d 2.20 2H), 2.60 2H), 4.50 1H), 7.10 4H), 9.5 (br, 1H).

STo a mixture of8 (7.75 g, 3 3 6 5 mmole), benzylamine (3.61 g, 33.65 mmole), acetic acid 0 (2.0 g, 33.65 mmole) in 150 ml of dichloroethane, 10.3 g of sodium triacetoxyborohydride (47.1 mmol, 1.4 eq) was added in one portion. Gas evolves between 30 niin and 1 hr. The mixture.

was stirred over night. TLC indicated the reaction was complete. 1 N NaOH (500 ml) was added Sto quench the reaction. The organic layer was separated and the aqueous layer was extracted with 00 EtOAc (300 ml x2). The combined organics were dried over potassium carbonate and the solvent was evaporated to give a brown solid, which was column filtrated (5oEt3N, and 70%Hexane to 10%Et3N, 40%EtOAc and 50%Hexane) to give 4.7 g of product 10 as a Swhite solid and 3.01 g of product 9 as a white solid N Compound 9 MS: m/z 322 'HNMR (CDC1 3 d 1.40 2H), 1.80-2.35 6H), 2.70 1H), 3.86 2H), 4.30 1H), 7.10 -7.50 9H), 9.6 (br, 1H).

Compound MS: m/z 322 'H NMR (CDC1 3 d 1.60 4H), 1.90 2H), 2.60 2H), 3,10 1H), 3.84 2H), 4.50 1H), 7.10 -7.50 9H), 9.6 (br, 1H).

2 g of Pd(OH)2 was added into a solution of 30 ml of methanol containing 4.7 g of compound 10. The resulting suspension was hydrogenated at 50 psi for 12 hrs at room temperature. TLC indicated the reaction was complete over night. The solution was filtered through a pad of celite to remove the catalyst. The celite was washed with methanol twice ml). The organics were combined and 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 'HNMR(CDCl 3 d 1.50-1.85 8H), 2.60 2H), 4.30 1H), 7.10 3H), 7.30 1H).

To a mixture of 11 (1.7 g, 7.4 mmole), acetaldehyde (0.33 g, 7.4 .mmole) in 50 ml of O dichloroethane, 2.2 g of sodium triacetoxyborohydride (10.36 mmol, 1.4 eq) was added in one portion. Gas evolves between 30 min and 1 hr. The mixture was stirred over night. TLC indicated the reaction was complete. 1 NNaOH (500 ml) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc(300 ml x2). The 00 M combined organics were dried over potassium carbonate and the solvent was evaporated to give a brown oil which was chromatographed (10%Et3N, 40%EtOAc and 50%Hexane).to give Sg of product 2 as a sticky oil which recrystalized from TBME to give a white solid Compound 2 cN MS:. m/z 259 7 'H NMR (CDC1 3 d 1.15 3H), 1.50 -1.95 6H), 2.40 2.75 4H), 2.95 1H), 4.35 1H), 7.10 3H), 7.35 1H)..

g ofPd(OH), was added into a solution of 30 ml ofmethanol containing 3.01 g of compound 9. The resulting suspension was hydrogenated at 50 psi for 12 hrs at room temperature.

TLC

indicated the reaction.was complete over night. The solution was filtered through a pad ofcelite to remove the catalyst. The celite was washed with methanol twice (20 ml). The organics were combined and solvent was removed to give a pale solid which was purified by chromatography MeOH, 90% EtOAc) to give an off white product 1 (1.68 g, 77.4%).

Compound 1 MS: m/z 232 'H NMR(CDCl 3 d 1.50 2H), 1.90-2.35 6H), 3.00 1H), 4.30 1H), 7.10-7.30 (m, 4H).

SCHEME 2:

H

"r Eti

SDMF

xOO

N

PPTS

acetone/H20 reflux

N

.O 13 Na(OAc) 3

BH

acetic acid, DCE

S

2 H2N 0

H

2 /Pd(OH) 2 MeOH

HN

6 0

S.

HN

6 Procedure: g of NaH was washed byTHF twice, suspended in 100 ml of DMF, then 8.15 g of 7 (38 mmole) was added to the mixture: Gas evolves, and after 5 minutes, 7.13 g of ethyl iodide (45.7 mmole) was added. The mixture was stirred over night. LC/MS indicated that the starting material was completely consumed. The reaction was cooled down and H.O was added to the mixture. The product started to precipitated out of solution. The crystals was collected by filtration to give 9.7 g of 12 C6mpound 12 MS: m/z 303.3 'HNMR (CDC1 3 d 1.30 3H), 1.70 1.90 6H), 2.50 2H), 3.85-4.00 6H), 4.50 (m, 1H), 7.05 3H), 7.25 1H).

A mixture of 12 (9.7 g, 32.2 mmole) and 9.72 g of PPTS in 50 ml of acetone and was refluxed over night. The mixture was cooled to room temperature and acetone was 0 evaporated. Addition of water to the mixture initiated crystalization to give 6.85 g ofproduct 13 N Compound 13 MS: m/z 259 00 C 'H NMR (CDCl 3 d 1.35 3H), 2.20 2H), 2.60 6H), 3.95 2H), 4.85 1H), 7.10 C 4H).

To a mixture of 13 (6.85 g, 26.5 mmole), benzylamine (2.84 g, 26.5 mmole), acetic acid -(1.59 g, 26.5 mmole) in 150 ml of dichloroethane, 7.86 g of sodium triacetoxyborohydride (37.1 I mmol, 1.4'eq) was added in one portion. Gas evolves between 30 min and 1 hr. Th6 mixture was stirred over night. TLC idicated the reaction was complete. 1 N NaOH (500 ml) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (300 ml x2). The combined organics were dried over potassium carbonate and the solvent was evaporated to give a brown solid, which was column filtrated.(5%Et3N; and 70%Hexane to 10%Et3N, 4 0%EtOAc and 50%Hexane) to give 1.52g 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).

'H NMR (CDC1 3 d1.35 3H), 1.50 2H), 1.65 4H), 1.95.(m, 2H), 2.60 2H), 3,02 1H), 3.83 2H), 3.95 (ddd, 2H), 4.45 1H), 7.00 -7.50 9H).

Compound MS: m/z 350 'H NMR (CDC13): d 1.35 1.90 2H), 2.10-2.35 4H), 2.70 1H), 3.83 2H), 3.95 (ddd, 2H), 4.40 1H), 7.00 -7.50 9H).

0.3 g of Pd(OH)2 was.added into a solution of 20 ml of methanol containing 0.5 g of compound 14. The.resulting suspension was hydrogenated at 50 psi for 12 hr at room temperature. TLC indicated the reaction was complete over night: The solution was filtered Sthrough a pad of celite to remove the catalyst. The celite was washed with methanol twice ml). The organics were combined and solvent was removed to give a pale solid which was purified by chromatography (10% MeOR, 90% EtOAc) to give an off white product 3 (300 mg, 0 'Compound 3 MS: m/z 232 'H NMR (CDC 3 d 1.35 3H), 1.50-i1.85 81H); 2.69 (in, 211), 3.20 (in, 1H), 3.9*5 (ddd, 00 2H1), 4.3 0 (in, I 7 .l1O.(n4 311), 7.3 0 (n4 111).

EXAMPLE 11 ATTACHMENT OF TAIL

GROUPS

Tail groups were attached to the head groups according to the following procedures: R Et N

DMF

R

NaCN 3 BH, HOAc mol. seives, MeOH C N

R

1

R

2 General procedure for alkylation: To a solution of the amine (1 eq) and triethylarnine ecq) in diinethylforn-Amide was added 1 eq of alkyl bromide or chloride in one portion. The mixture was stirred and heated at over night. TLC indicated the reaction was complete. Th ecinwsqeced by the addition of water followed by 11'INaO11 to pH 10. The mixture was extracted 2x with Et.O. The combined organic extracts were dried over potassium carbonate and the solvent evaporated, followed by chromatography to give the pure product.

General procedure for reductive amination: O To a mixture of ketone or aldehyde (1 eq), amine (1 eq),'and acetic acid (1 eq) in methanol, was added sodium cyanoborohydride (1 .4.eq) in one portion.. The mixture was stirred -over night at room temperature. TLC indicated the'reaction was complete. The reaction was quenched by the addition of water followed byl1 N NaOH to pH 10. The mixture was extracted 00 2x with Et 2 O. The combined organic extracts were dried over potasgium. carbonate and the solvent evaporated,'followed by chromatography to' give the pure product.

The following; compounds were prepared by attaching the tail groups using the general CI procedures described: 1-[ 4 -(benzylamihio)-cyclohexyl]..3.ethyl1, 3 -dihydro-2H-benzinmidazo1.2-one 1 4 -(benzylamino)-cyclohexyl]..3.ethyl-1, 3 -dihydro-2H-bezimidazol-2one 4 -t(naplh2-yl-methiyl)ethylamino]-cyclohexyll-1l, 3 -diliydro-2H-benzimidazo1.2-one MS: m/z 400.2 (MA+l) l-[ 4 -(norbornan-2-ylanio)..cyclohexyl]-1, 3 -dihydro-2H-benzimidazol.2one MS: m/z 326.3 (M+1) -methylethyl)-cyclohexylI]aminoI..cyclohexyl] I ,3-dihydro2Hbenzriidao12.

0 ne MS: m/z 356.4 (M+l) [-(eahdo2npthlaio-ccoey]1 ,3-dihydro-2H-bbnzil-iidazol.2..

0 n MS:.m/z 368.2 (M+l) 1-[ 4 (ethylamino)..cyclohexyl]1 ,-iyro2-ezmiao--n l-[ 4 -(benzylamino).cyclohexyl.1 3 -dihydro-72H-benzimnidazol-2-.one l-[4-(benzYlalinfo>.cyclohexyl]l,3-dihdro 2-benimiazo12o l-[ 4 -[(indfan-2-y)benzylamino}cyclohexyl] 3 ethl-13l yro2-ezmiao--n MS: rn/z 466.3 (M+l) 'H-NMR

(CDCL

3 d 1.30 310),1.50-1.75 (mi, 211), 1.90 211), 2.02 211), 2.20 211, 00 2.80 (in, 111), 2.99 (mn, 4M1, 3.75 211), 3.90 (mn, 311), 4.2:5 (mn, .IH),.6.95-7.45 (mn, 13.1).

l- 4 -[(cyclooctylmethyl)amino]..cyolohexy]3-efyl-13dhdo2-ezxiao--n LC: 99% C1 MS:n i/z 384.5 'HNMR'(CDC1 3 ):dl.40 -l.

9 O(m,241),230(m 2 H 2 .0(in4211), 2 .90(in, 11), 3.90(ddd,211), 4 2 0(mn, 10(m, 3H1), 7 .30(mn, 111).

l-[ 4 -[(naphth-2-y)amino1.cycfohxy]3eyl-13dhdo Hbniiiao--n LC:97 MS: m/z 399 'HNNM(CDC1 3 1.50 31), 1.80 (rn,511), 2.0 (i,2H1), 2 .70(m, 21), 3 .10(m,4 11-1), 3 4.0( n,4 211), 4 4 0(mn, 1H1), 7 1 O(r, 311), 7 .5 0(r, 41-1), 7.90(m, 411).

1-1-(~ezlxbnylaio-ylhxl- -ehl, 3 -dihydro.2-beiilzoI2-one *LC: 97% MVS: in/z 455 'HNlvl (CDC1 3 d 1.40 1.70 1.90 (mn, 311), 2.60(r., 411), 3 .10(in, 111), 3.80(s, 2M1, 4.0(in, 2H1), 4 -50(rn 1M1, 5.10(s, 211), 7.10(mn, 61-1), 7 .50(mn, 6H1), 7.90(mn, 111).

1-[ 4 -[(cycoocty~ethy)a]nocycohexyl 3 thyl-, 3 dihydro--2H-benzinidazo1.2one tC: 99% *MS: mlz 369 'H NMR (CDC1 3 dl.4O 311), 1.70(mn, 511), 1.90(mn, 1211), 2. 10(im,) 2 4 0(mn, 2H1), 2.50(d, 2H1), 3 .30(in, 1H1), 3 9 0(mn,2H1), 4 2 0(mn, 1H1), 7 10(m, 111), 7 .30(in, 311).

1 -[4-(decafydro-2-naphthyl)amino]-cyclohexyl]-3 -ethyl- ,3-dihydro-2H-benzimidaz d-2-one o LO: 99% MS: m/z 395 'HNMR(CC1 3 dl.40 311), 1.70(m, 31), 1.80(m, 3H), 1.90(m, 12H), 2.20(m, 2H), 2.30(m, 311'), 2.50(q, 2H), 3.10(m, 1H), 3.90(ni, 21), 4.20(m, 1H),.4.30m, 1M1, 7.0(m; 1H), 7,30(m, 3H).

00 l-[ 4 -[(p-phenylbenzy)anhmo]-cyclohexyl]-5-carbamoyl- 1,3-dihydro-2H-benzimidazol-2-one LC: 100% MS: m-/z 440.8 (M+1) 'H-NMR(MeOH-d 4 d 1.75 2) 2.00 2H1), 2.40-2.55 3.35-3.52 211), 4.35 21), 7.40 21), 7.59 21), 7.607.72 61), 7.78 21).

,3, 4 -tetrahydronaphthyl)amino] -cyclohexyl] carbaminoyl- 1,3 -dihydro-2Hbenziridazol-2-one LC: 93.9% MS: i/z 405.7 (M+1) 'IH-NMR (MeOH-d 4 d 1.70 21), 1.85 11), 2.02 2H), 2.39 311), 2.50 211), 2.90 11), 3.00 21), 3.35 111), 3.60 11), 3.72 4.35 (in, 1H), 7.15 (b, 4H), 7.40 1Hj, 7.60 1H), 7.65 11).

1-[[(4-ppyl-loxyl,3-dihydro-2H-benziidazol-2one LC: 100% MS: mlz 399.6 (M+1) 'H-NMR (MeOH-d 4 d 0.95 31), 1.10 1H), 1.20-1.60 61), 1.70 511), 1.80-2.00 411), 2.10 11), 2.30 21), 2.45 21), 3.25 1H), 3.50 1H), 4.40 11), 7.40 1H), 7.60 11), 7.65 11).

1 -[4-[(-methex-2-yl)aminol-cyclohexy -carbainoyl-1, 3 -dihydro-2H-benziiidazol-2-one LC: 100% MS: r/z 373.5 (M+1) 'H-NMAR (MeOH-dj): d 0.95 611), 1.25-1.40 (in, 51-1), 1.50-1.75 411), 1.$5 (mn, 1H1), 1.95 0 2.30 (mn, 2H1), 2.40-2.55 (in, 2H), 3.35-3.55 (mn, 2%1) 4.38 (ra, 111), 7.40 111), 7.60 (s, I:-1IN), 7.70 111).

00 one *LC: 100% MS: m/z4113 1 H-NMR (MeOH-d 4 0.90-2.10 iSH), 2.10-2.50 (in, 2.82 IH, 3.50(in,211), 4.35 (mn, 1H1), 7.42 111), 7.60 111), 7.70 111).- I 4 -(cyclooctylai o)-cyclohexyl]-5-carbamoyl1,3-dihycio-21-benziinidazol-2-one; .LC: 95.4% MS: in/z 385.7 'H-NMVR(MeOH-d 4 d 1.50-2.10 (in, 1311), 2.30.(mn, 2ff), 2.40-2.52 (mn, 311M, 2.8 0-2 .95,(in, 3H1), 3.45(in, 211),3.70(in, 111, 4.38 (in, 7.40 11-1), 7.63 1H), 7.70 111).

1- 4 -[(indan-2-y)anino]cyeohexy]5cboyl,3-dihydro.-211-benzimidazol-2.one *LC: 100% MS: m/z 391.6 (M+1) 'H-NMR (MoOH-d 4 d 1.70 (mn, 211'), 2.00 (rA, 211), 2.40-2.60 (mn, 411), 3.10-3-.20 211), 3.50 (Mn, 311), 4.30-4.45 (in, 211, 7.25 (in, 211, 7.35 (mn, 2ff), 7.42 111), 7.60 111), 7.72 111).

1 -[4-(benz~1amino)-cyclohexyl]s..carbanoyl.1 3 -dihydro-211-benziinidazol-2-.one LC: 100% _MS: in/z 399.5 (M+1) 'H-NMR (MeO11-d 4 d 1.40-1.85 (in, 1511), 2.00 (mn, 411), 2.25-2.50 (in, 411), 2.93 211), 3.30 (in, 111), 4.30 (in, 111), 7.36 111), 7.60 lIH), 7.65 111).

l-[ 4 4 -phenyl-cycohexy')amin6]cycohexy]5caboyl-1,3-dihydro-2H-benziinidazol-2one, o LC: 100% o *MS: in/z 433.7 (M+1) 'H-NMAR(MeOH-d 4 di 1.65'(n4 2H), 1.85-2.20 (n,4 8H1), 2.25-2.50 (mn, 5H), 3.90 (rn, 111), 3.50 (mn, 2H1), 3.58 (mi, 4.30 (mn, 1H1), 7.15-7.40 (in, 6H1), 7.60 111), 7.65 1H).

00 rn1-[4-(dibenzylarnino)-cyclohexyl]-5-carbanoyl.1 ,3-dihydro-2H-benzixnidazol-2-one LC: 100% MS: rn/Z 455.6 'H-NMR (MdOH-d 4 di 2.00-2.25 (mn, 4H1), 2.40 (mn, 4H), 3.52 (in, 211), 4.25-4.65 (in, 411), 7.30 1H1), 7.45-7.58 (in, 10H), 7.60 1H1), 7.65 (di, 111).

l-[ 4 -[(5-inethylhex-2-yI)amino] -cyclohexy13-7-carbamoy1,3-dihydro-21{-beriziinidazol-2-one LC: 99.1%.

*MS: m/z 373.3 (M+1) '1-NMR (MeOH-4): di 0.95 (di, 611), 1.30 311), 1.45-1.68 (mn, 511), 1.75 (mn, 1H1), 2.00 (in, 211), 2.18-2.32 (mn, 3k1), 2.60 21H), 3.20-3.40 (in, 21-1), 4.30 (in, 111), 7.05-7.20 (in, 3H).

Other compounds within the scope of formula (DEE) or (ifA) of the present invention- can be synthesized by analogous techniques.

EXAMIPLIE 12 Nociceptin affinity at the ORLI receptor for preferred compounds was obtained using the following assay:.

Membranes frorffrecombinant 132K-293 cells expressing the human opioid, receptor-like receptor (ORL-1) (Receptor Biology) were prepared by lysing cells in ice-cold hypotonic buffer mM MgCl 2 50 mM HEPES, prH 7.4) (10 mi/lO0 cm dish) followed by homogenization with a tissue grinder/teflon pestle.. Membranes were collected by centrifugation at 30j000 x g for min at 4*C and pellets resuspended in hypotonic buffer to a final concentration of 1-3 mg/mi.

Protein concentrations were determined using the BioRad protein assay reagent with bovine o serum albumen as standard. Aliquots of the ORL-lI receptor membranes were stored at o Functional SGTPgS binding assays were conducted as*follows. ORL-l membrane solution was prepared by sequentially adding final concentrations of 0.066- mg/mi ORL-1 membrane protein, 10 mg/mI saponin, 3 mM GDP and 0.20DrM 35 S]GT~gS to binding buffer (100 mM NaCI, 10 mM MgC 2 20 mM HEPES, pRf on ice. The prepared. membrane 00 M solution (190 mi/well) was transferred to 96-shallow well polypropylene plates containing 10 ml of 20x concentrated stock solutions of agonist prepared in DMSO. Plates were incubated for min at room temperature with shaking. Reactions were terminated by rapid filtration onto 96-.

well -Unifilter GF/B filter pla'tes (Packard) using a 96-well tissue harvester (Brandel) and followed by three filtration washes with 200. ml ice-cold binding buffer (10 mM NaH 2

PO

4 mM Na 2 H:P0 4 pH Filter plates were subsequently dried at 50*C for 2-3 hours.. Fifty mi/well scintillation cocktail (BetaS cint; Wallac) was added and plates were counted in a Packard Top-Count for I min/well.

Data was analyzed using the curve fitting functions in GraphPad PRism6, V. 3.0 and the results are set forth in table 3 below: TABLE 3 Nociceptin Affinity ICompound calc K,(nM) 3-ethy1- l-(p-phenylbenzyl)-1 ,3-dihydro-2H-benzjxnidazoi-2-..509 one 3 -ethyl-l(5-methylhex.2.yl) 1 ,3-dihydro-2H-benzimidazol.2- 23 one 3 -ethyl-l-( 4 -propylcyclohexyl) 1 ,3-dihydro-2H-benzimidazo.. 68 2-one 3-ethyl-i -(decahydro-2-naphthyl).1 ,3-dihydro-2H- 1.6 benzimidazol-2-one* 3 3-ethyl-i -(naphth-2-yl-methfyl)-1, 3 -dihydro-2H-benzimidazol. 198 2-one 1 -(p-benzyloxybenzyl)-3-ethyll ,3-dihiydro-2H-benzimidazol- 438 2-one 1 -enzl-3etyl-1 3 -dihydro-2H-benzimidazo1.2-one29 1 4 -(bie~nzylamino)-cycloliexy1-3-ethy1,3-dihydro-2H- trans: 112 bdnzimidazol-2-one cis: >10,000 3-ethyl-l-(naphthylmetliyl)..1,3-dihydro-2H-benziiniidao.2. 39 one 3 -ethyl- 1-[5 3 -fluoropheny1)-5-(4-fluoroplieny1)-hexyl] -1,3 148 dihydro-2H-benzimidazol-2-one l-[ 4 -[(naphth-2-y-methyl)ethylan-ino]-cyclohexyl]-1,3- 3598 -dihiydro-2H-benzimidazol.2.one 1 4 -(norbona-2-ylamino)-cyclohexy1i.1,3-dihydro-2H- >10000 benziinjdazol-2-one -methylethyl)-cycldhexy1]affino]..cyclohexyl] 1,3- >10000 dihydro-2H-benzimdazo..2-.one l-[ 4 -[(decahydro-2-naphthyl)aminol..cyclohexyl]-l ,3-dihydro- >10000 2H-benzimidazol-2-one I 4 -(ethylamino)-cycloiexyl].1 ,3-dihydro-2H-benzimidazol 9179.

2-on e I -[4-cbenzylamino)-cyclohexylp I 3 -dihydror.2H-benzimidazo1-- -trans: 273 2-one cis: >10000 l-[ 4 -[(indan-2-yl)benzyamino-bycohexy]3ethyl,3- >10000 dihydro-2H-benzjnmidazo12-one l-[ 4 -[(cyclooctylmeth.yl)amino-cycloexyl3ethyl1,3- 115 dihydro-2H-benzimidazol-2-one 1 4 -[(naphth-2-yl)an inb]-cyclohexyl]-3-ethyl-1 ,3-dihydro- 961 l-[ 4 -[(p-benzyloxybenzyl)aminop-cyclohexyl].3-ethyl 1,3- 2935 dilhydro-2H-be'nzimiidazol2one l-[ 4 -(enzeyl thyo)aryc yohexscbmyl1 3-ihyr-H- >1000 diyHbenzimidazol-2-one I"l[(decayro-inapt lincyclohexyl]5c my. 3 -dihydro,- >1000 d H -be nz dzol.o 1-4(ezlaio-yloey]5cabmy-33dhdo2- >10000 diy-Hbenzimidazol-2one I 2 2 3 4 -ttamih-yrlnahyl--arbanopyl-13heydro >10000 carbanml- 1 ,3-ydo-2-nido1o l-[ 4 4 -propyl-cyclohexyl)amno]-cyclohexyl}..$cabamoyl- >1 0000 1 3 -dihydro-2H-benzinifida2zo1.2onet 1 [-(-ehlix2-laio-ylhxy]5cra l13- 10000 dihydrQ-2H-benzimidazo1-2-one -4[dchdo2np~y~lio-ccoey]5craol >10000 1,3-dihydro-2H-benzimidazol.2..one l-[ 4 -(cyclooctylamino)-cyclohexyl]-5-cabam.oy1,3-dihydro- >10000 2H-benzimidazol-2-one.

I-[

4 -[(indai1-2-y)amino]cyclohexy1)-5cbaoyl-.1,3- >10000 dihydro-2H-benzimidazol-2one 1-4[4pey--coey~mn]ccoey)5craol >10000 1,3-dihydro-2H-bienzimidazo..2.oiae l-[ 4 -[(Snethylhex-2yl)ainocyclohexy]7cboyl-1,3- >10000 dhdo-2H-benzimidazol.2..one EXAMPLE 13 SYNTHESIS OF SUBSTITUTED BENZIMIDAZOLE HEAD GROUPS.

C

2 :N 'CN 1. NaH, THF, 0 0 ->50 0 C 2 N 'CN HCI EtOAc f 2 N NCN 2. EtBr (iS B0c Boc;

H

.1 2 Procedure: Sodium hydride 60% dispersion in mineral oil (0.67 g, 16.7 rnmol) was washed with dry pentane .and then suspended in 80 ml, of dry THE under N 2 Compound 1 (European patent 0029707) (3.80 g, 11. 1 mrnol) was added, the mixture stirred at room temperature for 15 muin and' -then warmed to 50*C. tthyl bromide (1.06 mL, 13.3 rumol) was added and the resulting mixture stirred at 50*C for 18 hrn TLC (Si0 2

CH

2 Cl 2 :MeOH 96:4) showed -that the reaction was ca Complete. Additional so'dium. hydride (0.67 g) and ethyl bromide (1.06 mL) were added. *After heating at 50*C for an additional-24 hr the reaction mixture was cooled to room temperature and quenched with water. The layers were separated and the aqueous layer extracted with ethyl

O

O

acetate The combined organic extracts were washed with aqueous sodium bicarbonate 0 solution dried over MgSO 4 and the solvent was evaporated to give-the crude product as a F yellow solid. Trituration with diethyl ether gave pure 2 as a white solid (3.38 g, 82%).

'H-NMR (CDC1 3 d 1.45-1.55 12H), 1.82 (bs, 2H), 2.30 2H), 2.87 2H), 4.30 (bs, S 2H), 4.41 2H), 4.82 1H), 7.10-7.30 4H).

00 To a solution of 2 (3.60 g, 9.74 mmol) in 100 mL of ethyl acetate was added a 25 mL of a 1:1 mixture of ethyl acetate and concentrated HCI. The mixture was stirred vigorously at room.

temperature for 2hr. and evaporated to dryness. The residue was neutralized with 50 mL of C1 methanolic ammonia 10:1 and again evaporated to dryness. The residue was suspended in 100 mL a 1:1 mixture ofMeOH and CH 2 C1 2 filtered and the filtrate evaporated to dryness to leave an off-white solid. Flash chromatography on silica gel, eluting with CH 2

C!

2 :MeOH:NH 3 (300:10:1) gave pure 3 as a white crystalline solid (1.98 g, 76%).

'H-NMR (CDC1 3 d .1.45 3H), 1.82 (bs, 2H), 2.33 2H), 2.80 2H), 4.40 2H), 4.80 1H), 7.10-7.30 3H), 7.45 1H).

EXAMPLE 14 ATTACHMENT OF TAIL GROUPS Tail groups were attached to the head groups according to the following procedures: R-Br, Et 3

N

DMF

N

NR

R

H R< 1R 2 NaCN 3 BH, HOAc mol. selves, MeOH

RN

RI

R

2

O

0 General procedure for alkylation: To a solution of the amine (1 eq) and triethylamine (1 eq) in dimethylformamide, was added 1 eq of alkyl bromide or chloride in one portion. The mixture was stirred and heated at O 80C over night. TLC indicated the reaction was coniplete. The reaction was quenched by the 00 Maddition of water followed by 1 NNaOH to pH 10. The mixture was extracted 2x with Et 2 O. The combined organic extracts were dried over potassium carbonate and the solvent evaporated, followed by chromat6graphy to give the pure product.

General procedure for reductive amination: To a mixture of ketone -or aldehyde (1 eq), amine (1 eq), and acetic acid (1 eq) in methanol, was added sodium cyanoborohydride (1.4 eq) in one portion. The mixture was stirred over night at room temperature. TLC indicated the reaction was complete. The reaction was quenched by the addition of water followed.by 1 N NaOH to pH 10. The mixture was extracted 2x with Et 2 O. The combined organic extracts were dried over potassium carbonate and the solvent evaporated, followed by chromatography to give the pure product.

The following compounds were prepared by attaching the tail groups using the general procedures described: 2 -cyanoimino-3-ethyl-1-[ 1-(p-phenylbenzyl)-4-piperidinyl]- 1,3-dihydro-2H-benzimidazole 'H-NMR (CDC1 3 d 150 3H), 1.88 2H), 2.28 2H), 2.62 2H), 3.12 2H), 3.65 2H), 4.48 4.80 1H), 7,15-7.70 (nm, 13H).

2-cyanoimino-3-ethyl--[ l-(p-benzyloxybenzyl)-4-piperidinyl] 1,3-dihydro-2Hbenzimidazole LC: 96.5% MS: m/z 466.5 (M+1) 'H-NMR (CDCl 3 1.55 3H), 1.82 2H), 2.25 2H), 2.50 2H), 3.10 2H), 3.55 2H), 4.48 2H), 4.78 1H), 5.20 2H), 7.00 2H), 7.15-7.65 (in, 11H).

u 2-cyanoiniino-3-ethyl-1-[1 -(naphth-2-yl-methyl)-4-piperidinyl]I ,3-dihydro-2H-benzim'idazole- 0 LC: 93.9% MS:nilz 'H-NIV[R (CDCl 3 d 1.55 311), 1.80 (mn, 2H), 2.30 2H), 2.52 (in, 2H), 3.18 (bd, 2H); 3.78.

2H), 4.50 2H), 4.80 (in, 11i), 7.20-7.90 (mn, 11H)..

00 2-cyanoiinino-3-ethyI- l-(4-propylcyclohexyl)-4-piperidinyl]-1 ,3-dihydro-2Hbenzintidazole MS: mlz 394.4 (M+1) 'H-NMR (CDC1 3 d 0.90-2.28 (in, 2 1H), 3.10 (mn, 4M1, 3.62 (in, 211), 4.42 2H1), .5.15 (in, 111, 7.20 1H1), 7.30 (in, 111, 7.50.(t, 1H1), 7.80 1H1).

2-cyanoimino-3 -ethyl-I -[l-[4-(2-Propyl)-cyclohexyfl-4- piperidinyl)-1I,3-dihydro-2Hbenziinidazole LC: 100% MS; m/z 394.5(M+1)' 'H-NMR (CDC1 3 d 0.90 3M1, 0.98 3H1), 1.15-2.35 (mn, 14H1), 3.10 (mn, 5H), 3.70 (mn, 2H1), 3.92 (bs, 111), 4.40 211), 5.20 (in, 111), 7.20 111), 7.38 111), 7.52 1H1), 7.80 (m,I1H).

'2-cyanoiniino-3-ethyl-l-[l-(decahydro-2-naphthyl)A4-piperidinyl]l ,3-dihydro-211- *benzinidazole LC: 93.9% MS: im/z 406.6 (M+1) 'H-NMR (CDC1 3 d 1.25-2.35 (in, 2411), 1. 15 (in, 4H1), 3.60 (in, 211, 4.40 (mn, 211, 4.20 (mn, *1),7.20-7.80 (in, 4M1.

*2-cyanoiinino-3-ethyl-1-[1 -(cyc-looctyl)-4-piperidinyl]-1 ,3-dihydro-211-benziinidazole LQ: 100% MS: in/z 380.3 (M+1) 'H-NMR (CDC1 3 d 1.50-1.80 .13H), 1.90 2M), 2.10 4H), 3.05 3i1), 3.30 0 11), 3.45 (in. 2H), 3.90 1H), 4.42 2H), 5.15 (in, 111), 7.20 11), 7.35 1H), 7.50 1H), 7.78 11).

2-cyanoiniino-3-ethyl-1-[ 1-(10,1 l-dihydro-5H-dibenb[asd)-cyclohepten5yl)-4-piperidinyl}.

00 M1 ,3-dihydro-2H-benziidazole LC: 94.5% MS: m/z 462.2 'H-NMR (CDC1 3 d 1.40 3H), 1.70 (bs, 21), 2.01 (ni, 21), 2.2$ 2H, 2.80 4H), 3.95 11), 4.02 21), 4.32 21), 4.65 IH), 7.00-7.32 12H).

2-cyanoilnino-3-ethyl-l-[l-(3, 3 -Bis(pheny1)propy1)-4-piperidinyl].1,3-dihydro-2Hbenziinidazole MS: n/z 464.2 (M+l) 'H-NMR (CDC 3 d 1.40 311), 173 (bs, 2H), 2.09 21), 2.18-2.45 611), 2.98 (b, 2 3.93 11), 4.35 2Mh, 4.63 11), 7.10-7.30 13h, 7.40 IH).

2-cyanoimino-3-ethyl-1-[ 2 3 ,4-tetrahydronaphthyl)-4-piperidinyll ,3-dihydro-2Hbenzimidazole LC: 94.0% MS: m/z 400.2 (M+1) 'H-NMR (CDC1 3 d 1.30-1.70 6H), 1.85 211), 2.05 11), 2.45 3H), 2.85 (m, 4H), 3.10 21), 4.35 21), 4.71 1H), 7.00-7.60 8H).

2- yanoimino-3-ethyl-l-[l-(j-methylhex-2-yl)-4-piperidinyl]- ,3-dihydro-2H-benziiidazole LC: 94.9% MS: r/z 368.3 (M+1) 'I-NMR (CDC1 3 d 0.85 61), 0.95 3H, 1.12-1.65 8H), 1.80 21), 2.27-2.60 5H), 2.85 21), 4.38 2H), 4.62 11), 7.0877.30 31), 7.45 11).

2-cyanoirnino-3-ethyl-l-[l -(norbornan-2-yl)-4-piperidinyl]. 1,3-dihydro-2H-benzimidazole LC: 99.2% 0 MS: in/z 364.7 (M+1) IH-NMR (CDC1 3 d 1.10-2.10 (rr4 13H), 2.35 (n4 1H), 2.50-2.70 (mn 3H), 2.70-2.90 (mn, 3H), 3.50 (mn, 2H), 4.50 211), 4.80 (in, 111), 7.35 (mn, 2H1), 7.48 (in, 1H1), 7.75 (n4 111).

00 M* 2-cyanoimiino-3-ethyl-l-[1-(1 ,3-diliydroinden-2-yl)-4-pi;peridinyl]-1 ,3-dihydro-2Hbenziiiazole LC: 92.1 MS: m/z 386.2 (M+1) 'H-NMR (CDC1 3 d 1.42 3H), 1.82 2H1), 2.21 (mn, 2H), 2.43 (mn, 211), 2.88 (in, 2H), 3.02-3.19 (mn, 4H1), 3.23 (mn, 1H1), 4.38 211), 4.80 (mn, IH), 7.08-7.30 (mn, 711), 7.45 111).

2-cyanoimino-3-ethy1-1 -[1-(cyclooctyinethyl)-4-piperidinyl]-1 ,3-dihydro-2H-benzimidazole LC: 100%.

MS: m/z 394.7 (M+1) 'H-NMR (MeOH-): d 1.35-2.00 (mn, 2011), 2.60-2.$5 (mn, 611), 3.40 (in, 211),.2.52 2H1), 4.90 (rr, 111), 7.35 (in, 211), 7.48 (in, 1H1), 7.70 (mn, 111).

2- cyanoiinino -3 (2 -hydroxy) ethyl- I -(cyclo octyl) -4-p ip eri dinyl] 3 -dihydro -211benzirnidazole LC: 100%.- MS: rn/z 396.3 (M+1) 'H-NMR (DMSO). 7.52 (dt, 111), 7.45 (dt, 1H1), 7.21 (mn, 21H), 4.97 1H1), 4.55 (mn, 111), 4.38 211), 3.76 211), 2.88 (in, 211), 2.61 (bt, 111), 2.33 (in, 4H1), 1.76-1.37 (in, 1611).

*2-cyanoixino-3-inethoxycarbonylmethyl-1 -(cyclooctyl)-4-piperidinyl]- 1,3-dihydro-2Hbenziinidazole LC: 98.3% MS: in/z 424.2 (M+1) 'H-NMR (DMSO): 7.56 (ad, 111), 7.51 (dd, 1H1), 7.25 (mn, 211), 5.26 211), 4.56 (in, 111), 3.72 3H1), 3.34.(m, 211), 2.78 (mn, 211), 2.62 (bt, 111), 2.32.(m, 411), 1.80-1.35 (mn, 16H1).

2 -eyanoimino-3-cyanomethyl-1-[ 1-(cyclooctyl)-4pipeidinyl].1 ,3-dihydro-2H-benziinidazole LC: 100% MS: xn/z 391.2 (M+1) 00 'H-NMR (DMS0): 7.60 2H), 7.31 (mi, 21-1), 5.48 2H1), 4.77 9m, IH), 3.33 2H), 2.88 (in, 2H1), 2.62 (bt, 111), 2.33 (mn, 411), 1.86-1.37 2-cyanoimino-3-butyl-1-[ 1-(cyclooctyl)-4-piperidinyl].1 ,3-dihydro-2H-benziinidazole Cl LC: 95.4% MS: in/z 352.2 (M+l) 'H-NMR (DMSO): 7.58 (dd, 111), 7.49 (dd, 111), 7.24 (in, 211), 6.55 211), 4.59 (rn,11), 4.34 211), 2:.97 211, 2.80 (in, 11H), 2.55 (mn, 211), 2.38 (in, 2H1), 1.80-1.30 (in, 1811), 0.90 3m1.

2-yni-io3(-ehnsloaioehll[-ccocy)4pprdnl-,-iyr-H benziinidazole LC: 100% MS: In/z 473.2 (M+1) !H-NMR (DMSO0): 7.53 (dd, 111), 7.44 (dd, 111), 7.23 (in, 211), 4.60 (in, 111), 4.35 3.37 2H1), 2.87 (mn, 21-1), 2.82 311), 2.60 (bt, 114), 2.31 41), 1.76-1.37- (mn, 1511).

2-cyanoimino-3-acetomido-1-[ l-(cyclooctyl)-4-piperidinyl].1 ,3-dihydro-2H-benziinidazole LC: 100% MS: in/z 409.2 (M+1) 'H-NMR (DMSQ): 7.75 Cs, 111), 7.52 (dd, 111), 7.37 113), 7.30 (dd, 111), 7.20 (mn, 211), 4.96 (s,211), 4.55 (in, 11), 3.33 211), 2.88(n, 211), 2.62 (bt,l11), 2.30 (in,411), 1.80-1..37 Cm,.

15H1).

2-cyanoimino-3-carboxyrnethyM.{1..-(cycloocty')A..piperidinl 1 ,3-dihydro-2H-benziinidazole LC: 97.5% MS: in/z 409.9 (M+1) 'H-NMv.R (DMSO): 7.45 (dd, 111), 7.14 (mn, 3H), 4.57 2H), 4.50 (in, 1H), 2.87 (mn, 2H), 2.61 0 (bt, 1H), 2.33 (in, 4H), 1.7514.37 (in, 2-cyanoimino-3-(2-dimethylamino)ethyl.4-[1 -(cyclooctyl)-4-piperidinyl]- 1,3-dihydro-2Hbenzimidazole 00 LC:-100% m/z 423.3 (M+1) 'H-NlMR (DMSO): 7.60-6.96 (mn, 4H), 6.54 (2H, 4.65 (mn, LH), 4.40 2H1), 3.90 2H), 3.05 (in, 4H1), 2.90 (in, 11D', 2.63 (n4 3H1), 2.56-2.37 (mn, 4M), 1.85-1.35 (mn, 1511).

2 -cyanoimino-l-[l-(cycootyl)-3-hydroxymthyl.4pipeidiny1).1,3-dihydro-2H -benzimnidazole 2 -cyanoiinino-l-[l-(cyootyl)-4-piperidiny].1 ,3-dihydro-2H-7-azabenzimidazole; 2 -cyanoimnino-l-[l-(cycloocty1)-2,6-ethano-4one4pip'eidinyl..1, -dihydro-2H-benzimidazole Other compounds within the scope of formula (IV) or (IVA) of the present invention can be synthesized by analogous techniques.

EXAMPLE Nociceptin affinity at the ORLi receptor for preferred compounds was obtained using the following assiay: Membranes from recombinant HEK-293 cells expressing the hurnin opioid receptorlike receptor (ORL-1) (Receptor Biology) were prepared by lysing cells in ice-cold hypotonic buffer (2.5 mM MgC1 2 50 mM HEPES, pH 7.4) (10 ini/lO cm dish) followed by homogenization with a tissue grinder/teflon pestle. Membranes were collected by centrifugation at 30,000 x g for 15 min at 4 0 C and pellets resuspended in hypotonic buffer to a final concentration of 1-3 mg/mi. Protein concentrations were determined using the BioRad protein assay reagent with bovine serum albumen as standard. Aliquots of the ORL-1 receptor i~ieinbranes were stored at Functional SGTPgS binding assays we~e conducted as follows. ORL-1 membrane solution was prepared by sequentially adding *final concentrations of 0.066 mg/mi ORL-I membrane protein, 1.0 mg/ml saponin, 3 mM GDP and 0.20 riM 35 S]GTPgS to binding buffer (100 mM NaCI, 10 mM MgC1 2 20 tuM HEPES, pH 7.4) on ice. The prepared membrane solution (190 mI/well) was transferred to 96-shiallow well-polypropylene plates containing 10 mil of 20x concentrated stock solutions of agonist prepared in DMSO. Plates were incubated for min at room temperature with shaking. Reactions were terminated by rapid filtration onto 96well Unifilter GFIB filter plates (Packard) using a 96-well tissue harvester (Branidel) and followed by three filtration washes with 200 ml ice-cold binding buffr (10 mM.NSaH 2

PO

4 mM Na 2

HPO

4 pH Filter plates were subsequlently dried at 50*C for 2-3 hours. Fifty mi/well scintillation cocktail (BetaScint; Wallac) was added and plates were counted in a Packard -Top-Count for 1 min/well.

Data was analyzed using the curve fitting functions in GraphPad PRISM6~, v. 3.0 and the results are set forth in table 4 below: TABLE Nociceptin Affinity_______ Compound caic K, (nM) 2-cyanoimino-3-ethyl-1-[ l-(p-phenylbenizyl)-4-piperidinyl]- 5558S I ,3-dihydro-2H..benzimidazole 2-cyanoimino-3 -ethyl-i -(p-benzyloxybenzyl)-4-piperidinyl) 1660 1 ,3-dihydro-2H-benzixnidazole 2-cyanoimino-3-ethyl-I-[l -(naphth-2-ylmthl-4-piperidinyl]82 1 ,3-dihydro-2H-benzimidazole________ 2-cyanoimino-3-ethyl-1-[l -(4-propylcyclohexyl)4- 241 pip eridinyl]-1 ,3-dihydro-2H-benzirnidazoleI 2-cyanoimino-3 -ethyl- l-[l-[4-(2-propyl)-cyclohexyl]-4- 6.9 piperidinyl]-1,3-dihydro-2H-benzimi.dazole________ 2-cyanoimino-3-ethyl-1 -(decahydro-2-naphtliyl)-4- 6.6 piperidinyl]-1,3-dihydro-2H-benzirnjdazole.________ 2-cyanoimino-3-ethyl-l-[1 -(cyclooctyl)-4-piperidinyl]-1,3- 5.57 dihydro-2H-benzimidazole 2-cyanoirnino-3-ethyl-l-[ 1-(1 0,11 -Dihydro-5H-dibenzo[adj- 10,000 cyclohepten-5-yl)-4-piperidinyl]-.1 ,3-diliydro-2H-' benzimidazole; 2-yniio3ehll[-(,-i~hnlpoy)4 8b pip eridinyl]-1 ,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-1-[1 2 ,3,4-tetrahydronaphthyl)-4- 157 pip eridinyl]-1 3 -dihydro-2H-benzimidazole; 2-cyanoimino-3-.ethyl-1 -iethylhex-2-yl)-4-piperidinyl]- 76 1 ,3-dihydro-2H-benzimidazole;________ 2-cyanoimino-3'ethyl-1 -[li-(nprbornan-2-y)-4-piperidiny]- 323 I ,3-dihydro-2H-benzimidazole; 2-cyanoimixio-3-ethyl-1-[1 ,3-dihydroinden-2-yl)-4- 89 piperidinyl)-1 3 -dihydro-2H-benizimidazole; and 2-cyanoimino-3-ethyl-1-[1 -(cyclooctylniethyl)-4-piperidinyl]. 7.1 '1,3-dihydro-2H-benzimjdazole.

2 -Cyanoimino-3-(2-hydroxy)ethyl....{1-(cyclooctyl)-4'- 6.4 pip eridinyl]-1 ,3-dihydro-2H-benzimidazole 2 cyanoimino-3-methoxycarbonylmethyll...[ 1-(cyclooctyl)-4- 3.3 piperiin_______________nziidaol 2 -cyanoinino-3-cyanomethyl-l.{ I-(cyclooctyl)-4..piperidinyl]- .97 -1,3-dihydro-2H-benzimidazole 2-cyanoimmno-3-butyl-1 -(cyclooctyl)-4-piperidinyl].1 1.36 dihydro-2H-benzimidazole 2 -cyanoimino-3-(2-methanesulfonamido)ethyl...[ 1- 78 (cyclooctyl)-4- iperidinyl.1 3 -dihydro-2H-benzimidazole 2-cyanoinino-3-acetomidobl[ l-(cycloocty)-4-piperidinyl]- 11 1,3 -dihydro-2H-benzimidazole 2 -cyanoihino-3-carboxymethyb1.{1..(cyclooctl).4 201 pip eridinyl]-1 3 -dihydro-2H-benzimjdazole 2 -cyanoimino-:3-(2-dimethylamno)ethyl.1 -J11-(cyclooctyl)-4- 18 piperidinyl]-_ ,3-dihydro-2H-benzjmjidazole 2-cyanoiniino-1-[ l-(cyclooctyl)-3-hydroxymethyl-4 473 piperidinyl]-1 3 -dihydro-2H-benzimidazole 2 -cyanoimino-1-rl-(cyclooctyl)4piperidinyl.1 ,3-dihiydro-2H- 3743 7-azabenzimidazole 2-cyanoirnino- l-(cyclooctyl)-2,6-ethano-4.one.4 19 pip eridinyl-1 ,3-dihydro-2}{-benziridazole Example 16 Affinity at the receptor for compounds was obtained according to the following assay: Mu opioid receptor membrane solution was prepared by sequentially adding final concentrations of 0.075 .Lg/pVl of the desired membrane protein, 10 pVg/ml saponin, 3 IiM GDP and 0.20 nM 35 SIGTPyS to binding buffer (lO0'mM NaCi, 10 MM MgC 2 20mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 pl/well) was transferred to 96-shallow well polypropylene plates containing 10 111 of 20x concentrated stock solutions of agonist prepared in DMSO. Plates were incubated for 30 min at room temperature with shakcing.. Reactions were terminated by rapid filtration onto 96-well tiniflter GFIB filter plates (Packard) using a 96-well tissue harvester (Brandel) and followed by three filtration washes with 200 p1 ice-cold binding buffer (1.0 mM Na}1 2 P0 4 10 MM Na 2 H:P0 4 pH Filter plates were subsequently dried at 500 C. for 2-3 hours. Fifty p1l/well scintillation cocktail (lVeiroScint20,. Packard) was added and plates were counted in a Packard Top-Count for 1 min/well.

Data were analyzed using the curve fitting functions in GrapbPad, PRISM Tm, v. 3.0 and the results for several compounds are set forth in table 5 below: CompundcalcK 3-[l -(naphth-1 y-ehl--ieiiyl-Hbnoao--n 340 3-[l3,-ihnprpI4 1 rdny]2-enoaof2oe 726 3-[1 -(1,234ttayr 2-ahhl--ieiinl-Hbno'zl 343 2-one 3-l(-rplccohxl .prd.y]-Hbnoao--n 145 3-ethylidene- 2 3 4 -terahydro2naphthyl)4.piperidinyl}. 23.3 1 ,3-dihydro-2H-indole-2-one 3-tyieel[-npt--y-ehl -ieiiy)1 ,3-dihydro- 137 2H-indole-2-oh 3-tildn--I(-ezloyezl -ieiiy)1 ,3-dihydro- 1150 214-ifidole-2-one 3-ethylidene-l 3 3 -diphenylpropyl).4-.piperidinylj..l,3-dihydro- 24 2H-indole-2-onc 1-4[npt--laio-ylhxl--ty-,-iyr-H 2.1 benzjmidazol-2-one 2-yniio3ehll-l(-rplylhxy)4pprdnl 46 dihydro-2H-benzimidazole- 2-cyanoixnino-3-ethyl-l41 2 3 4 -tetrahydronaphthyl)-4 piperidinyl]-l 3 -dihydro-2H-benzimidazole I J imcuiyifex-i.y)..4piperjdiny -1,3dihydro-2H-benziidazole 2-cyanoimino-3-ethyl-l -(norbornan-2-yl)4piperidinyl}.1 ,3dihydro-2H-benzinmjdazole 1653 951 8 Throughout the specification, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising", will be understood to o imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

00 o..

95/2

Claims (27)

1. A *compound of the formula R 2 (n) wherein D is a 5-8 membered cycloalicyl, 5-8 membered heferocyclicora 6 membered aromatic or heteroaromatic group; n is an integer from 0 to 3; A, B arid Q are independently hydrogen, CI- 0 alkyl, C34 2 cycloalcyl, CI-. 1 0 alkQxy, C3- 2 *cycloalkoxy, -CH 2 OH, -NMSO 2 hydroxyC 1 10 alkyl-, aminocarbonyl-, Cl. 4 alkcylaminocarbonyl-, diC 1 4alkylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide, sulfonylaninoC. 10 ,alkyl-, or A- B can together form a bridge, or B-Q can together form a C 3 .7 bridge, or A-Q can together form a C,- 5 bridge; is selected ffmte group consisting of a bond, straight or branched CI.6 8lkylene, NH-, -CH 2 -CI' 2 NH-, -CH 2 N(CH 3 -NHCH 2 -CH 2 CONH-, -NHCH 2 CO-, -CH 2 CO-, COGH 2 -CH 2 00CH 2 -CH(CH 3 and -HC=CH-, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with one 'or more lower alkyl, hydroxy, halo or o alkoxy group; R, is selected from the group consisting of hydrogen, CI1 alkyl, C 3 12 CYCloalkyl, C2. Q 9 alkenyl, amino, C 1 10 alkcylamino-, 0 3 12 cycloallcylamino-, -C00VI, -Cl4COOVI, cyano, cyanoC 1 10 alkyl-, cyanoC 310 cycloalk~l-, NH 2 SO 2 -1 NH 2 SO 2 CI.4alkYl-, NH 2 SOC14alkyl-, 00 mncroy, 1akamncroy- i roy, eal arincaboy-,C 1 4 alylmiocronl- dG 1 4 alkylaminocabny- Cezl 312 *cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a hetero-monocyclic ring, a hetero-bicyclic ring system, and a spiro ring system of the formula X, X 2 (V) wherein X, and X 2 are independently selected from the group consisting of NH, 0, S and OH 2 and wherein said alkyl, cycloalkyl, alkenyl, C 110 atkylamnio-, C 3 12 cycloalkylamino-, or benzyl of R, is optionally substituted with 1-3 substituents selected fro m the group consisting of halogen, hydro xy, C1.1. ailkyl, C1.10 alkoxy, nitro, trifluoromethyl-, cyano, COO V 1 -C1COOV 1 cyanoC 1 10 alkyl-, Cl. 5 (-O)W 1 -C 1 5 NlS(=O) 2 WI, -C 1 5 NHSc=-O)W 1 a heteroaromaticC 0 4alkyl-, phenyl, benzyl, benzyloxy,- said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituients selected from the group consisting of halogen, 01.10 alkyl-, C 1 1 0 alkoxy-, and cyano; and wherein said C312 cycloalkyl, C3412 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl,'heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, or spiro ring system of the formula is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1.10 alkyl, Ci.- 1 0 alkoxy, nitro, tifluoromethyl-, phienyl, benzyl,, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogen, 01.10 alkyl, CI- 1 0 alkoxy, and cyano; W, is hydrogen, CI-. 1 0 alkyl, C3- 2 cycloallyl, C 1 1 0 alkoxy, C 3 12 cycloalkoxy, -CH 2 OI{, 0amino CI-4alkylamino-, diG 1 .alkcylamino-, or a 5-membered heteroaromatic ring optionally ri substituted with 1-3 lower alkyl; V, is H, CI-6 alkCyl, C 3 -6 cycloalkcyl, benzyl or phenyl; R. is selected from the group consisting of hydrogen, C 1 1 0 ailcyl, C 3 12 cycloalkyl- and 00 M ~halogen, said alkcyl or cycloallcyl optionally substituted with an oxo, amino, alkylamino or Ci dialklamino group; V) or a pharmaceutically acceptable salt thereof or a solvate thereof.

2. A compound of claim 1, wherein D is phenyl or a 6 membered heteroaromatic group containing 1-3 nitrogen atoms.

3. A compound of claim 1, wherein ZR, is cyclohexylethyl-, cyclohexylmethyl-, cyclopentylmethyl-, dimethylcyclohexylmethyl-, pheriylethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl-, pyridylethyl-, cyclopent~l-, cyclohexyl-, methoxycyclohexyl-, tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyrazoylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl-, or oxocanyipropyl-.

4. A compound of claim 1, wherein ZR 1 is -CH 2 COOV 1 tetrazolylmethyl-, cyanomethyl-, NH 2 SO 2 methyl-, NH 2 SOmethyl-, aminocarbonylmethyl-, C 1 4allkylaminocarbonylinethyl-, or *diC,. 4 alkylaminocarbonylmethyl-. A compound -of claim 1, wherein ZR 1 is 3,3 diphenyipropyl optionally substituted at the 3 carbon of the propyl with -COOV 1 tetrazolylC 0 4 alkyl-i cyano-, aminocarbonyl-, C 1 4 alkylaminocarbonyl-, or diC,.4alkylaminocarboriyl-.

6. A compound of the formula (IA): R 2 (n) (LA) wherein n is an integer f6om. 0 to 3; Z is selected from the grq'up consisting of a bond, -CH 2 -CH 2 -CH 2 CH 2 CH 2 NH-, -CH 2 N(CH 3 -NHCH 2 -CH 2 CONH-, -NHCH 2 C0-, -CH 2 CO-, -COCH 2 CH 2 0CI-1 2 -Ck(CH 3 and -H4C=CH-, wherein the carbon and/or nitrogen atoms are .unsubstituted or substituted with a lower alkcyl, halogen, hy droxy or alkoxy group; R, is selected from the group consisting of hydrogen, CI- 10 alkYl, C34 2 CYcloalky1, C2. 10 alkenyl, amino, C 1 1 0 allylaxnino, C 3 -1cycloalkylamino, benzyl, C 3 .12 cycloalkcenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a hetero-monocyclic ring, a hetero- bicyclic ring system.'and a spiro ring system of the formula C xi X 2 (V) wherein X, and X, are independently selected from the group consisting of NH, O, S O and CH,; wherein said alkyl, cycloalkyl, alkenyl, C.- 1 alkylamino, C 3 .,2cycloalkylamino, or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1.10 alkyl, C-.10 alkoxy, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, said phenyl, 00 M. benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, alkyl, alkoxy, and cyano; wherein said C3-12 cycloalkyl, C3.12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, and spiro ring system of the formula are optionally substituted with 1-3 substituents selected from the group consisting of halogen, CI- 1 0 alkyl, CI-1o 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 of halogen, alkyl, C1. o 1 0 alkoxy, and cyano; R 2 is selected from the group consisting of hydrogen, CI-1 0 alkyl, C 31 cycloalkyl and halogen, said alkyl optionally substituted with an oxo group; or a pharmaceutically acceptable salt thereof.

7. A compound of claim 6, wherein R, is alkyl selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl.

8. A compound of claim 6, wherein R, is cycloallcyl selected from the group consisting of cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and norbornyl.

9. A compound of claim 6, wherein R, is tetrahydronaphthyl, decahydronaphthyl or dibenzocycloheptyl. A compound of claim 6, wherein R, is phenyl or benzyl.

11.. A compound of claim 6, wherein R, is a bicyclic aromatic ring. A L. .WIFWUA UL i -L wnlerein saia Dicycuic aromatic ring is indenyl, quinoline or o naphthyl.

13. A compound of claim 6, wherein Z is a bond, methyl, or ethyl. 00 14.. A compound of claim 6, wherein n is 0. A compound of claim~ 6, wherein X, and X 2 are both 0.

16. *A compound selected from the group consisting of: 3-[l npt--lmtyl--~prdnl-2-ezxzl2oe 3-[1-(naphth- 1-yi-methyl)-4-piperdinyl2Hbenzoxazol2-one;~ 3-[1 ppeybn~y)4pprdiyl2-ezoao-2oe 3-[l -(-ezlxbny)4ppriiy]2-ezxzl2oe -(p-cyanobenzyl)-4piperidny]2Hbenoxezol12-one; 3-[1-(3,3dp ypoy)4pprdiy]2-ezxzl2oe 3-[l 44Bs(-loo~ny~uy]4pprdnl]Z-ezxzl2oe 3-[l 2peyehl-4pprdnl-H-ezxzl2oe -ccocymtyl--ieifil]2-ezxzl2one; ,2,3 4 -tetrahydro-2naphthyl)4piperidinylp2Hbenzoxazo12-one; 3 -[l,-(5-methylhzx 2-y) 4pipericiny12Hbenzoxazol12-one; 1-(10, ll-Dihydro-5Hdibenzo[adcyclohepten5yl)-4-piperidinyl]-2H- benzoxazol-2-one; 3-I(-rplccoey)4ppeiiy]2-ezxzl2oe 3-[l1-(norbornan-2-y)-4-piperidinyl] -2H-benzoxazol-2-one; 3 -[l-(dechydro-2-naphthyl)-4.piperidinylI.2N.bezoxazol12-one; 3-[l1-(3 ,3-dimethyl- l,S-dioxaspiro[5.5]undeca.9-yl)..4.piperidirlyl].2Hbenzoxazol-2 one; -methylethyl)-cyclohexy]4piperidiny]2Hbezoxazo12-one; 3-[1 ,3-dihydroi~den-2-yl)-4-piperidinyl]p2H..benzoxazol12-one; 3-[1 -(cyclooctyl)-4-piperidinyl]-2H-benzoxazol-2-one; and I O St La"',anuui;uliy acceptaole salts thereof. O

17. A pharmaceutical composition comprising a compound of claim 1 and at least one pharmaceutically acceptable excipient. 00

18. A method of treating pain comprising administering to a patient in'need thereof, an t. effective amount of an analgesic compound according to claim 1.

19. A method of modulating a pharmacological response from the ORL1 receptor comprising administering to a patient in need thereof an effective amount of a compound according to claim 1. A pharmaceutical composition comprising a cormpound of claim 6 and at least one pharmaceutically acceptable excipient.

21. A method of treating pain comprisiig administering to a patient in need thereof, an effective amount of an analgesic compound according to claim 6.

22. A method of modulating a pharmacological response from the ORL1 receptor comprising administering an effective amount of a compound according to claim 6.

23. A compound of the formula (IA): R 2 (n) (IA) wherein R 2 is selected from the group consisting of hydrogen, C.10, alkyl, C34 2 cycloalkyl and halogen, said alkyl optionally substituted with an oxo group; n is an integer from 0 to 3; SZR, is the following Y Y3 Y 2 wherein 0 Y, is R 3 -(Cl-C, 2 )alkyl, R 4 -aryl, R 5 -heteroaryl, R 6 -(C 3 -C, 2 )cyclo-alkYl, R 7 -(C 3 C7)heterocycloaky1, -CO 2 (C,-Cs~alkyl, CN or -C(O)NR 8 Y 2 is -hydrogen or Y 1 Y 3 is hydrogen or (C I-C 6 )allcyl; or Y 2 and Y 3 together with the carbon to which they are attached, form one of the following structures: 00 (CHRIa)u EI E (CHR 1 r Y 3 /RIO RR 1 O or h wherein risO0 to 3; w and u are each 0-3, provided that the sum of w and u is 1-3; c o and d are independently 1 or 2; s is 1 to 5; and ring E is a fused.R 4 -phenyl'or R 5 -heteroaryl ring;, RIO is 1 to 3.substituents independently selected from the group consisting of H, (C 1 C 6 )alkyl. (CI-C 6 )alkyl-0Rs, -NRgR 9 and 1 -C 6 )alkyl-NR 8 R.; 00 R, I is. I to 3 substituents independently selected from the group consisting of RIO, -CF 3 -OCF 3 N02 and halo, or R, 1 substituents on adjacent ring carbon atoms may together form a *methylenedioxy or ethylenedioxy ring; R. and R, are independently selected from the group consisting of hydrogen, (C 1 -C 6 alkyl, (C 3 -C 12 )cycloal'kyl, aryl and aryl(CI-C 6 )allcyl; R 3 is 1 to 3'substituents independently selected from the group consisting of FHL R 4 aryl, R 6 -(C 3 -C 12 )cycloalkyi, Rs-heteroarYl. R 7 -(C 3 -C 7 )heterocycloalkyl, -NR, R 9 -OR 12 and R. 6 is 1 to 3 substituents independently selected from the group consisting. of H, (Cl- C 6 )alkyi, R 4 -aryl, -NR 8 R OR 1 2 and -SR 1 2 R 4 is 1 to 3 substituents independently selected from the group con isting of hydrogen, halo, (C 1 C 6 )allcyl, RU 3 -aryl, (C 3 C 12 )cycloalkyl, -CN, -CF 3 -OR 8 -(Cl-C 6 )allcyl-0 R 8 OCF 3 -NRSR,, -(C1 C 6 )alkyl -NR 8 R 9 -NHSQ 2 Rg, -SO 2 N(R 4 2 -S0 2 R2, -SORs, -SRs, -NO 2 _CONR 8 Rq, -NR 9 COR 8 -C0Rg, -COCF 3 -OCORS, -0C0 2 R 8 -COOP., 1 -C,)alkyl- NHCOOC(CH 3 3 -(Cl-C 6 )alkyl-NHCOCF 3 -(Cl-C 6 )alkyl-NHSO 2 -(Cl-C 6 )alcyl, -(C 1 -C 6 )alkcyl- NHCONH-(CI-C 6 )-alkyl and -(CH 2 )r-N N-P. 8 wherein f is 0 to 6; or R 4 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring; R, is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C 1 -C 6 )alcyl, R 13 -aaYl, (C 3 -C 12 )cycloallcYl, -CN, -CF 3 -ORS, -(C 1 -C 6 )alkyl-OP. 8 -OCF 3 NR 8 R9, -(C1-C 6 )alkYl-NRXR,:_NHS0 2 R 8 -SO 2 N(P. 1 4 2 -NO 2 -CONP. 8 R 9 -NR 9 CORg,. -CORB, ._OCOP. 8 -0C0 2 P 8 and -CO OR 8 SR, is H, (C,-C 6 )alkyl, -ORs, 6 )alkyl-OR,, -NRR 9 or -(C-C 6 )alkyl-NRR 0 is H, (C,-C 6 )alkyl, R 4 -aryl, 6 )alkyl-ORS, 6 )alkyl-NRR,, 6 )alkyl- SR,, or aryl (C,-C 6 )alkyl; R i3 is 1-3 substituents independently selected from the group consisting of H, O C 6 )alkyl, (Ci-C 6 )alkoxy and halo; 00 c R 1 4 is independently.selected from the group consisting of H, (C,-C 6 )alkyl and R 13 SC6H-CH,-; l/ or a pharmaceutically acceptable salt thereof. .24. A pharmaceutical composition comprising a compound of claim 23 and at least one pharmaceutically acceptable excipient. A method of treating pain comprising administering to a patient in need thereof, an effective amount of an analgesic compound according to claim 23.

26. A method of modulating a pharmacological response from the ORL1 receptor- comprising administering to a patient in need thereof, an effective amount of a compound according to claim 23.

27. A method of modulating a pharmacological response from an opioid receptor comprising administering to a patient in need thereof, an effective amount of a compound according to claim 1.

28. A method of modulating a pharmacological response from an opioid receptor comprising administering to a patient in need thereof, an effective amount of a compound according to claim 6.

29. A method of modulating a pharmacological response from an opioid receptor comprising administering to a patient in need thereof, an effective amount of a compound according to claim 23. A compound of the formula (II): R 2 (n) A wherein the dotted line represents an .optional double bond; R is hydrogen, CI- 1 0 ailcl, C3.12 cycloalkyl, C 3 12 cycloalkcylC 1 4alkyb, CI1 alk(oxy, C3-1 cycloalkoxy., CI1 aikenyl, C1-10 alkylidene, oxo, CI-1 alkyl substituted with 1-3 halogen, C 3 -12 cycloaly' substituted with 1-3 halogen, 0312 CYCloalkY1C 1 -4alkyl1 substituted with 1-3 halogen, alkcoxy substituted with 1-3 halogen, C3-1 cycloalkcoxy- substituted with 1-3 halogen,--- COOV,, -C, 4 COOVI, -CH 2 OH, -SQ 2 N(V 1 2 hydroxyC, 10 aUcyl, hydroxyC 3 10 ocycloalkyl. cyanoCI- 10 alkyl.., cyanoC 310 cycloalyl.. -CON(V 1 2 NH 2 SO 2 C 1 4 allcyl.. NU 2 SOC 14 allcy-, sulfbnyldminoC, 1 0 aly.. diaininoalkyl-, -SUlfonY1C 1 4aucyl, a 6 -membered heterocyclic ring, a 6-membered heteroaromatic ring, a 6 -mernberecl heterocycliC1alkyl, a 6-membered heteroaromaticC 1 4.alkyl., a 6 -menibered aromatic ring, a 6-membered aromaticC, 4 alkyl-, a membered heterocyclic ring optionally substituted with an oxo orthio, a heteroaromatic ring, a 5-membered heterocyclieC 1 4 alcyl- optionally substituted with an oxo or o thia, a 5-membered heteroaromatieC0. 4 alkcyl-, -C 1 5 1 -C 1 .S(=NJ{W 1 -C 1 5 NHC(--O)W 1 -C 1 -5NHS(=O) 2 W' 1 -C 1 5 NHS(=-O)Wj, whereinW, is hydrogen, alkyl, C3412 cycloalkcyl, C,. 1. alkoxy, C342 cycloalkoxy, -CH 2 OH, amino, C 1 4 alkylamnino-, diC. 4 allcylainino-, or a membered heteroaromatic ring optionally substituted with 1-3 lower alkyl; wherein each V, is independently selected fromt H, alkyl, 036cycloalkyl, benzyl 00 C- and phenyl; (71 n is an-integer from 0 to 3; D is a 5-8 membered cycloallcyl, 5-8 mfembered heterocyclic or a 6 membered aromatic or heteroaromatic group; n is an integer from 0 to 3; A, B and Q are independently hydrogen, C 1 1 0 alkyl, 0312 cycloalkyl, c 10 alkoxy, C312 cycloalkoxy, 01.10 alkenyl, .01.10 alkylidene, oxo, -CH 2 OH, -NHSO 2 hydroxyC 1 10 alkyl-, aminocarbonyl-, C 14 alkylarninocarbonyl-, diG 1 ~alkylaniinocarbonyl-, aceylamino-, acylaminoalkyl-, amnide, sulfonylamioC 1 10 alkyl-, or A-B can together form a C2.6 bridge, or *B-Q can together form a. 03.7 bridge, or A-Q can together form a C0- bridge; Z is selected from the group consisting of a bond, straight or branched 01.6 alkylene, NH-, -0H 2 -CH 2 NH-, -OH 2 N(0H 3 -NHCH 2 -CH 2 C0NT{-, -NHCH 2 C0-, -CH 2 C0-, COCH 2 -CH 2 000H 2 -CH(CH 3 and -HC=CH-, wherein the carbon and/er nitrogen atoms are unsubstituted. or substituted with one or more lower alkyl, hydroxy, halo or alkoxy group; R 1 is selected from the group consisting of hydrogen, 0I.10 alkyl, C 3 12 cycloalkyl, 02- joalkenyl, amino, Cl-lalkcylamino-, C 3 12 cycloalkyla~ino-, -C00VI, -C 1 4000V, cyano, cyanoC,.,6allcyl-, cyano 3 1 0 cycloalcyl-, NqH 2 SO 2 NH 2 S0 2 0 1 4 alkyl-, NH 2 SOC 1 4 alkyl-, aminocarbonyl-, 0 1 4 alkcylaminocarbonyl-, diO 1 ,alkcylaminocarbonyl-, benzyl, 312 cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl. or heteroaryl. ring, a hetero-monocyclic ring, a hetero-bicyclic ring system, and a spiro ring system of the formula (V: X, X 2 (V) wherein X, and X 2 are independently selected from the group consisting of NH, 0, S o and CH 2 and where in said alkcyl, cycloalkyl, alkenyl, C 1 1 alkylaMino-, C 3 1 2 cycoalkcylarnino-, or benzyl of R, is optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C1..1 ailcyl, C 1 .1 0 alkoxy, nitro, trifluoromethyl-, cyano; COOV 1 -C 1 4COOV 1 cyanoC.. 10 alkyl-, -C 1 5 -Cl- 5 NHS(--0) 2 5 NHS(=0)W,, a M0 5-rnembered heteroaromaticC 0 4 alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the gipup consistigof halogen, CI- 10 alkyl-, CI- 1 0 alkoxy-, and cyano; and wherein said C 3 -'1cycloalkyl, C34.2 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, or spiro ring system of the formula is optionally substituted with 1-3 substit uents s elected from the group consisting of halogen, CI1 alkyl, C 1 10 alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1 1 0 alkyl, CI-. 1 0 alkoxy, and dyano; R 2 is selected from the group consisting of hydrogen, C 1-10 alkyl, C3- 12 cycloalicyl-and halogen, said ailcyl. or cycloalkyl optionally substituted with an oxo, amino, alkylamino or dialkylamino group; or a pharmaceutically acceptable salt thereof or solvate thereof.

31. A compound of claim 30, wherein D is phenyl or a 6 membered heteroaromatic group containing 1-3 nitrogen atoms..

32.- A compound of claim 30, wherein R is selected from the group consisting of -CH 2 C=ONH 2 -C(NH)N1 2 pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl, -C=OCH 3 -CH 2 CH 2 NHC=OC-H 3 -SO 2 CH 3 CH 2 CH 2 NHS0 2 CH 3 fuiranylcarbonyl-, methylpyrrolylcarbonyl-, diazolecarbonyl-, azolemethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxo-oxazolemethyl-, and diazolemethyl-.

33. A compound of claim 30, wherein ZR 1 is selected from the group consisting of cyclohexylethyl-, cyclohexylmethyl., cyclopentylmethyl-, dimethylcyclohexylmethyl., phenylethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl., pyridylethyl-, cyclopentyl-, cyclohexyl-, methoxycyclohexyl., tetrahydropyrany[-, propylpiperidinyl-, indolylmethyl-, pyrazoylpentyl-, thiazolylethyl-, phenyltrifluoro ethyl., hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl-, and oxocanylpropyl.

34. A compound of claim 30, wIherein. at least one of ZR 1 or R is selected fromthgru consisting of CH 2 000V 1 tetrazolylmeth .y1l, c n meh l NH S meh .,NH S ethygrou aminocarbonylmethyl,2 CI.4allcylaminocrbonymetfiyl .and diCi- 4 alkylaminocarboylnethyl. A compound of claim 30, wherein ZRI is 3,3 diphenyipropyl optionally substituted at. the 3 carbon of the propyl with -C0OV,, ttaoyC.ak1,caoaioab'y- 3 4 alkylalmnocarbony[-, or diC,~alkylan-dnocarbony.

36. A com pound 'f the formula (IIA): (hIA) wherein the dott -ed line represents an optional double bond; Z is selected from the group consisting of a bond, -CH2-, -0112 -CH 2 CH 2 CH 2 NH-, -CH 2 N(C11 3 -NHCH 2 -CH 2 C0NI{.. -NHCH 2 C0.. -CH 2 C0-, -GOGH 2 -,r

011200012.., -CH(0H 3 1 and -110=CH- wherein the carbon and/or nitrogen atoms are unsubstituted. or substituted with a lower alkyl, halogen, hydroxy or alkoxy group; R and Q are the same or different and are each selected from the group consisting of hlydrogen, halogen, Ci., 0 alkyl, C 1 0 alkcenyl, C 1 0 alkylidene, C 3 4~ 2 cycloalkyl, ailkoxy, and o oxo; Ris selected from the group consisting of hydrogen, 0 alkYl, C 3 .1 2 CYCloalkyl, 02. j 0 alkenyl, amino, 0 1 0 alkylaMino, C 3 -1 2 cycloalkylan-ino, benzyl, C3.12 cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or het .eroaryl ring, a heteromonocyclic ring, a bicyclic ring system, and a spiro, ring system of the formula x 2 (V) wherein X, and X 2 are irndependently selected from the group consisting of NH, 0, S and CH 2 wherein saidalc-'l, cycloalkyl, alkenyl, CI- 10 alkylamino, C 3 1 2 ycloalkylamino,. or benzyl is optionAlly substituted with 1-3 substituents selected from the group consisting of halogen,' alkyl, 01.10 alkoxy, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of hMogen, CI-10 alkyl. CI-1,, alkoxy, and cyano; wherein said C3-12 cycloalkyl, C3-12 cycloalkenyl, monocyclic, bicyclic o r tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system, and spiro ring system of the formula are optionally substituted with 1-3 substituents selected fr6m the gr'oup consisting of halogen, .01.10 alkcyl, C 1-1, 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 of halogen, 01.10 alkyl, C1.10 alkoxy, and cyano; R 2 is selected from the group consisting of hydrogen, C1.10 alkyl1, 0-3.12cycloalkyl. and halogen, said alkyl. optionally substituted vWith an oxo group; or a pharmaceutically acceptable salt thereof. 37. A compound of claim 3 6, wherein Q is hydrogen or methyl. 38. A compound of claim 3 6, wherein R is- hydrogen, methyl, ethyl, or ethylidene. I> 9. A compo'und of claim 36, wherein R, is alkyl selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl. 0040. A compound of claim 36, wherein R, is cycloalkyl selected from the group consisting of cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and norbornyl. 41. A compound of claim 36, wherein R, is tetrahydronaphthyl, decahyclronaphthyl or dibenzocycloheptyl. 42. A compound of claim 36, wherein R, is phienyl. or benzyl. 43. A compound of claim 36, wherein R, is a bicyclic aromaatic ring. 44. A comp ound of claim 43, wherein said bicyclic aromatic ring is indenyl, quinoline or naphthyl. 'A compound of claim 36, wherein Z is a bond, methyl, or ethyl. 46. A compound of claim -36, wherein n is 0. 47. A compound of claim 3 6, wherein X, and X 2 are both 0. 48. A compound of claim 36, wherein the dotted line is a double bond. .49. A compound selected from the group consisting of: 3-ethylidene-1 -(S-methylhex-2-yl)-4-piperidinyl]-1 ,3-dihydro-2H-indole-2-one; 3-ethiylidene- 4 -propylcyclohexyl).4-piperidinyl]- 1,3-dihydro-2H-indole-2-.one; 3-ethylidene-1-[ 1-(1 2 3 4 -tetrahydro-2-naphthyl)-4-piperidinyl].1 ,3-dihydro-2H- indole-2-one; 3-ethylidene-l1-[1 3 -dihydroinden-2-yl).4-piperidinyl].1,3 -dihydro-2H-indole-2-one; 3-ethylidene-1-:[1-(naphth-2-yl-methyl)-4-piperidinyl].1 ,3-dihydro-2H-indole-2-one; 3-ethylidene-1 -(p-benzyloxybenzyl)-4-piperidinyl] 1 ,3-dihydro-2H-indole-2-one; 3-ethylidene-l1-[1 -(benzyl)-4-piperidinyl]-1 ,3-dihydro-2H-indole-2-one; 112 3 -ethylidene- 1I-[ Il-(cyclooctylmethy)A4piperidinylp- 1 ,3-dihydro-2H--indoie-2-on'e; o 3-ethylidene- i-[i-(norbornan-2-yi)-4-piperidinyly 1 ,3-dihydro-2H-indole-2-one; 3 ,3-diphenypropyi).4piperidinyl)..i,3-dihydro-2H-indoie-2-one; 3-ethylidene- i-[i-(p-cyanobenzyl)-4-piperidinyJ..i ,3-dihydro-2H-indole-2-one; 3-ethyl-i 5 -rnethyihex-2-yl)-4-piperidinyl]p 1 ,3-dihydro-2F1-indole-2-one; OC) 3-ethyl-i -methyiethyl)-cyciohexyl]-4piperidinylp1 ,3-dihydro-2H-indoie-2- M one; 3 -ethiyl-i-[1-(4-propylcycohexyy..4.pipeiinyl]- I,3-dihydro-2H-indole-2--one; 3-ethyl-i 2 3 4 -tetrahydro-2-naLphthyl).4-piperidiny]1.i,3 -dihydro-2H-indoie-2- one; C13-ethyl-i -[li -(eayr--ahhi--ieiiy]13dhdo2-noe2oe 3 -ethyl-i1 3 -dihydroinden-2-y).4-piperidiny11,3-dihydro-2H-indole-2-one; 3 -ethyl-i1 -[1i-(cyclooctylmethyl)-4-piperidiny]. 1 ,3-dihydro-2H-indole-2-one; 3 -ethyl-i1 -(norbornan-2-yi)..4-piperidinyi]..-1,3 -dihydro-211-indoie-2-one; 1 -(naphth-i -yl-methyl)-4..piperidinyl} 1 ,3-diliydro-2H-indole-2-one;. 1 -(naphth-2-yl-methyl)A4piperidinyl].1 ,3-dihydro-2H-indole-2-one; 11 -(p-phenylbenzy)-4-piperid inyl].1 ,3-dihydro-2H-indole-2.one; i-[i 3 -Bis(phenyl)propyl)-4-piperidiniyl].1 ,3-dihydro-2H-indole-2-one;* i-ri -(p-cyanobenzy1)-4-piperidinyl]..i,3-dihydro-2H-indole-2-one; i-[i -O,-benzyloxyben'zyi)-4-piperidinyl].1,3 -dihydro-2H-!indole-2-one; 1-[i 4 -tetrahiydronaphth-2-yl)-4piperidinyl..1 ,3-dihydro-2H-indole-2-onle; -ri 5 -methyihex-2-yl)-4-piperidinyi]4 ,3.dihydro-2H-indole-2-one; i-[i -(norbornan-2-yl)-4-plP'eridinyl]..1 ,3-dihydro-2H-indoe-2-one; 1 3 -dihydroinden-2-y1)-4piperidinyi} 1 ,3-dihydro-2H-indole-2-onle; 1-[i -(cycooctylmethyl)-4-piperidiny].1 ,3-dihydro-2H-jndole-2-one;, 141 -(benzyl)- 3 -4methy)-4-piperidiny].1 ,3-dihydro-2H-indole-2-one; i-[i 4 -propyl-cyclohexyl)-3-(methy)-4piperidiny1. ,3-dihydro-2H-indole-2-one; i-ri 5 -methylhex-2-yl)-3-(methyl)..4-piperidiny}.1 ,3-dihydro-2H-indole-2-one; i-[i -(decahydro-2-naphthyl)-3-(methyl)4-.piperidinylp 1 ,3-dihydro-2H-indole-2-one; i-[i -methylethyl)-cycohexyl)3(methyly4-piperidiny)..1 ,3-dihydro-2H-indole- 2-one; 1-ti -(cyclooctyhnethyl)-3 -(methyl)-4-piperidiny3.4 ,3-dilhydro-2H-indoie-2-one; i-[i -Bis(phenyl)propyl)-3-(methyl)-4piperidiyl].1,3 -dihydro-2H-indoie-2-one; 3-ethyl-i -ti-( 3 3 -Bis(pheny)propyl)-3.(methyl)>4.piperidinyl]-1,3-dihydro-2H-indole- 2-one; O U 3 -ethyl-1-[ 4 -propylcyclohexyl)-3-(methyl)-4-piperidinyl]-1;3-dihydro-2H-indole-2- O one; 3-ethyl-l-[1-(5-methylhex-2-yl)-3-(methyl)-4-piperidinyl]- 1,3-dihydro-2H-indole-2- one; 3-ethyl- l [-[4-(1-methylethyl)cyclohexyl]-3-methyl-4-piperidinyl]- ,3-dihydro-2H- 00 indole-2-one; r- 3-ethy-l--[ l -(decahydro-2-naphthyl)-3-(methyl)-4-piperidinyl]-1,3-dihydro-2H-indole- 2-one; t~ and pharmaceutically acceptable salts thereof. A pharmaceutical composition comprising a compound of claim 30 and at least one pharmaceutically acceptable excipient. 51. A method of treating pain comprising administering to a patient in need thereof, an effective amount of an analgesic compound according to claim 52. A method of modulating a pharmacological response from the ORL1 receptor comprising administering to a patient in need thereof an effective amount of a compound according to claim 53. A pharmaceutical composition comprising a compound of claim 36 and at least one pharmaceutically acceptable excipient. 54. A method of treating pain comprising administering to a patient in need thereof, an effective amount of an analgesic compound according to claim 36. A method of modulating a pharmacological response from the ORL1 receptor comprising administering an effective amount of a compound according to claim 36. 56. A compound of the formula (HA): Z R (HA) wherein the dotted line represents an optional double bond; R and Q are the same or different and are each selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, C 1 o 10 alkylidene, C3.1 cycloalkyl, alkoxy, and oxo; R 2 is selected from the group consisting of hydrogen, alkyl, C 3 1 2 cycloalkyl and halogen, said alkyl optionally substituted with an oxo group; ZR, is the following VII01 UeIu 0 Y, is R 3 -(C 1 -C, 2 )alkyl, R. 4 -aryl, Rs-heteroaryl, R 6 -(C 3 -C 12 )cyclo-alkYl, R 7 -(C 3 C 7 )heterocycloalkcyl, -CQ 2 (CI-Cs)alkYl, CN or -C(O)NRRg; Y 2 is hydrogen or Y 3 is hydrogen or (C 3 -C 6 )alkyl; or Y,,Y 2 and Y 3 together with the carbon to which they are attached, form one of the following structures: 00 R 11 3R S EB (CHR. 1 r Y 3 Rio R 11 R 11 R1 .or .whlerein r is 0 to 3; w and u are each 0-3, provided that the sum of w and u is 1-3; c C) ring; RIO is 1 to 3 substituents independently selected from the-group consisting of H, (CI- C 6 alkcyl. -OR 8 (CI-Cs)alkcyl-OR 8 -NR 8 R 9 and -(C,-C,,)alkyl-NRR 9 R, is 1 to'3 substituents independently selected from, the group consisting of RIO, -OF 3 00 M -OCF 3 NO 2 and halo, or RII substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring; R, Rand R. are independently selected from the group consisting of hydrogen, (01-C6) alkyl, (0 3 -C, 2 )cy'doalkYl, aryl and aryl(C 1 -C 6 )alkyl; R 3 is I to 3 substituents independently selected from the group consisting of H, R 4 aryl, RZ 6 -(C 3 -C 1 2 )cycloalkcyl, R.-heteroaryl, R 7 -(C 3 -C 7 )heterocycloalkyl, -NR 8 R 9 and R, is 1 to 3 substituents independently selected from the group consisting of H, 0 6 )alkyl, R 4 -aryl. -NRsR 9 ,.-0RI 2 and -SR 12 R 4 is 1 to 3. substituents independently selected from the group consisting of hydrogen, *halo, (CI- 06 )allkyl, R 13 -aryl, (03 O, 2 )cycloalkYl, -ON, -OF 3 6 )alkyl-0Rs, 00F 3 -NRsR 9 -(CI 0 6 )alkyl -NR 8 -NHS0 2 R 8 -SO 2 N(R 14 2 -S0 2 R 8 -SOR 8 -SR 8 -NO 2 -CONRaR 9 -NR 9 00R 8 -COR2, -000F 3 -000R 8 -000 2 Rs, -COOR 8 6 )alk-yl- NHCOOC(CH 3 3 -(Cl-C 6 )alkyl-NHCOCF 3 6 )allcyl-NHS 2 (C,-C 6 )aUcyl, 6 )alkyl- NHCONH-(C-C 6 )-alMy and -(CH 2 N-R 8 wherein f is 0 to 6; or R 4 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring; R 5 is 1 to 3 substituents. independently selected from the group consisting of hydrogen, halo, (CI-0 6 )alkyl. R1 3 -arYl- (C3-O 12 )cycloalkyl, -ON, -OF 3 1 -0 6 )alkyl-0R 8 -OCF 3 NR 8 6 )alkyl-NR 8 -NHSO 2 R 8 -SO 2 N(R 4 2 -NO 2 -CONRgR 9 -NR 9 00R 8 -00R 8 -OCOR 8 -000 2 R 8 and -000R.; R 7 is H, (C,-C 6 )alkyl, -OR 8 6 )alkyl-OR 8 -NR 8 R 9 or 6 )alkyl-NRgR 9 R1 2 is H, (C 1 -C 6 )allcl, R- 4 -aryl, 6 )alkyl-0R., 6 )alkyl-NRgR. 9 6 )alkyl- SRI, or arYl (C,-C 6 )alkyl; SR,3 is 1-3 substituents independently selected from the group consisting of H, O C 6 )alkyl, (Ci-C 6 )alkoxy and halo; R 1 4 is independently selected from the group consisting of H, (C,-C 6 )alkyl and R 13 C 6 H 4 -CH 2 O or a pharmaceutically acceptable salt thereof. 00 57. A pharmaceutical composition comprising a compound of claim 56 and at least one pharmaceutically acceptable excipient. 58. A method of treating pain comprising administering to a patient in need thereof, an effective amount of an analgesic compound according to claim 56. 59. A method of modulating a pharmacological response from the ORL1 receptor comprising administering to a patient in need thereof, an effective amount of a compound according to claim 56. A method of modulating a pharniacological response from an opioid receptor comprising administering to a patient in need thereof, an effective amount of a compound according to claim 61. A method of modulating a pharmacological response from an opioid receptor comprising administering to a patient in need thereof, an effective amount of a compound according to claim 36. 62. A method of modulating a pharmacological response from an opioid receptor comprising administering to a patient in need thereof, an effective amount of a compound according to claim 56. .63. A compound of the (MI): 0R R 2 (n) N 00 D wherein R is hydrogen, CIt alkyl, C3.12 cycloalkYl, 312 cycloalkylC 1 4.alkyl-, C1.10 alkoxy, 03.12 cycloalkoxy-, alkyl substituted with 1-3 halogen, C 3 1 2 CYCloalkyl substituted with 1-3 halogen, 03.12 cycloalkylC 1 4alkyl- substitutedf with 1-3 halogen, CI1 alkoxy substituted with 1-3 halogen, 342 Cycloalkoxy- substituted with 1-3 halogen, -CQOV 1 -C 1 .4COOVI, -CH 2 OH, -SO 2 N(V 1 2 hydroxyC. 10 alkyl-, hydroXYC 310 cycloallcyl-, cyanoC 1 l 0 allcyl-, cyarioC 310 cyclbalcYl.. -CON(V 1 2 NH 2 SO 2 CI. 4 alkYl-, NH 2 SOC 1 4 alkcYl-, sulfonylam-inoC 1 10 oalkyl-, diaminoalkcyl-, -sulfony1C 1 .4alkyl, a 6-membered heterocyclic ring, a 6-membered heteroaromatic ring, a 6-membered heterocyclicC 14 alkyl-, a 6-membered heteroaromatiC.-,alkyl-, a 6-membered aromatic ring, a 6-membefed aromaticCCl alky[-, a membered heterocyclic ring optionally substituted with an oxo or tlhio, a he iteroaromnatic ring, a 5-membered heterocyclicC, 1 4 alkyl- optionally substituted with an oxo or thio, a 5-membered heteroaromaticC 1 4 alkyl-, -C 1 5 Q=O)WI, 5 (=NH)W 1 -C 1 .sNHC(=-O)W 1 -Q 1 .sNHS(=O) 2 -0 2 5 NHS(=0O)W,, whereinW, is hydrogen, CI1 alkyl, 0312cycloalkyl, C1. alkoxy, C3.12 cycloalkoxy, -CH 2 QH, amino, C 14 alkylamino-, diC 1 4 allcylamiino-, or a membered-heteroaromatic ring optionally substituted with 1-3 lower alkyl; wherein each V, is independently selected from H, 01-6 alkyl, 034 CYCloalkyl, benzyl and phenyl; n is an integer from 0 to 3; D is. a 5-8 membered cycloalkyl, 5-8 ijembered heterocyclic or a 6 membered aromatic or heteroaromatic group; 0 Z is selected firm the group consisting of a bond, straight or branched C1-6 alkylene, r- NH-,.-CH 2 -CH 2 NH-, -CH 2 N(C11 3 -NHCH 2 -CH 2 00NH-, -NHCH 2 C0-, -CH 2 CO-,- COCH 2 -qH 2 C00H 2 -CH(0H 3 and -HC=CH-, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with one or more lower alkcyl, hydroxy, halo or 0C) alkoxy group; orZ is a cycloalkylamino system of the formula (VI): (VI) wherein A, B and Q are independently hydrogen, CI- 1 0 alkyl, 03-12 CYCloallcyl, CI1 alkoxy, C3-1 cycloalkoxy, -CH 2 OH, -NHS 02, hydroxyC 1 1 0 alkyl-, arninocarbonyl-, 01.. 4 allcylaminocarbonyl-, diC 1 aklamiocarbony-, acylamino-, acylaminoallcyl-, amide, sulfonylaminoC 110 oalkyl-, or A-B can together form a C 2 -6 bridge, or B-Q can together form a C 3 bridge, or A-Q can together form a C 1.5 bridge; R, is selected from the group consisting of hydrogen, CI- 10 alkyl,'C 3 2 cycloalkyl, 0t2. j 0 alkenyl, amino, 0 alkylaxnino-, C 3 12 cycloallcylamino-, -COQV,, -Cl 1 4 000V,, cyano, CYanoC,.. 10 alkYl-, CYanoC3-, 0 cycloalkyl-. NH 2 SQ 2 NH 2 S0 2 CI..~al1CYl-, NH 2 SOC1. 4 alkcyl-, amnocarbonyl-, C 1 4 kalkcylaminocarbonyl-, 'diC,.4alkylanlinocarbonyl-, benzyl, C312 cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryf ring, a hetero-monocyclic ring, a hetero-bicyclic* ring system, and a spiro ring system of the formula X1 X 2 wherein X, and X 2 are independently selected from the group consisting of NH, 0, S 0 and Gil 2 and wherein said alkyl, cycloalkyl, alkenyl, 0 alkylamino-, C 3 12 CYCloalkylamnino-, or benzyl of R, is optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, CI1 alkyl, CI 1 0 alkoxy, nitro, trifluoromethyl-, cyano, COOVI, -C,.4C0OV,, cyanoC,., 0 alkYl-, 5 NHS(=O0) 2 WI, 5 NHS(-70)W,, a 0C) 5-membered hete-roaromaticC 0 4alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being-sub stituted with 1-3 su1bstituents selected from the group. consisting of halogen, C 1 .1 0 alkyl-, alkoxy-, and qyano; and wherein said C3.12 ycloalkyl, C3.12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic *ring, hetero-bicyclic ring system, or spiro ring system of the formula is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1.1 0 alkyl, C 1 1 0 allcoxy, nitro, trifluoromethyl-; phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl. benzyl. phenyloxy or benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogen; CI- 1 0 alkyl, alkcoxy, and cyano; R. 2 is selected from. the group consisting of hydrogen, CI- 10 alkCyl, 03.12 cycloalkyl-and halogen, said alkyl or cycloalkyl optionally substituted with an oxo, amino, al kylamino or dialkylamino group; or a pharmaceutically acceptable salt thereof or solvate thereof. 64. A compound of claim 63, wherein D is phenyl or a 6 muembered heteroaromatic group containing 1-3 nitrogen atoms. A compound of claim 63, wherein R. is selected from the group consisting of -CH.,C=ONH, -C(NH)NH 2 ,.pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl, -C=0CH 3 CH 2 CH 2 Ni{C=QCH3. -SO 2 CH 3 CH 2 CH 2 NHSO 2 CH3, furanylcarbonyl-, methylpyrrolylcarbonyl-, diazolecarbonyl-, azolemethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxo-oxazolemethyl-, and diazolemethyl-. 66. A compound of claim 63, wherein ZR, is selected from the group consisting of cyclohexylethyl-, cyclohexylmethyl-, cyclopentylmethyl-, dimethylcyclohexylmethyl-, phenylethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl-, pyridylethyl-, cyclopentyl-, cyclohexyl-, methoxycyclohexylb, tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyrazoylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl-, and oxocanylpropyl-. 121 A, 'o1. a compounci ot claim 63, wherein at least one of ZRI or R is selected from the group o .consisting of CH 2 COOVI, tetrKazolylmethyl-, cyanomethyl-, NH 2 SO 2 methyl-, NH 2 SOmethyl-, aminocarbonylmethyl-, Ci.4alkylaminocarbonylmethy.., and diC 1 ~alkylaminocarbonylmethyl-. -68. A compound of claim 63, wherein ZR 1 is 3,3 d~iphenylpropyl optionally substituted at the 3 carbon of the propyl with -CQOVI, tetrazolYlC 0 ~akyl,, cyano-, aminQcarboflyl-, C1. 4 alkylaminocarbonyl-, or diC 1 4 alkylaminocarbonyl. 69. 'A compound of formula (IIJA): R 2 (n) N z (IfIA) wherein n is aninteger from 0to 3; Z is. selected from the group consisting of a bond, -CH 2 7, -CH 2 -CH 2 CH 2 NH-, -CH 2 N(CH 3 -NHCH 2 -CI{ 2 CONH-, -NI{CH 2 00-, -CH 2 CO-, -COCH 2 CH 2 COCH 2 7, -CH(CH 3 -HC=CH-, and a cycloalklamino system of the formula (VI): N-- H 00 (VI). wherein the carbon and/or nitrogen atoms .are unsubstituted or substituted with a lower alkl; aloenhydroxy, phenyl, benzyl, or allcoxy group; Ris selected from the group consisting of hydrogen. C a -1y, 0 alkoxy, and C 3 C1 1 2 cyrloalkYl; R, is selected from the group consisting of hydrogen, C 1 1 0 allcyl, C 3 12 cycloallcy1 CI 10 alkenyl, amino, 1 alkylamino, C 3 12 CYCloilkylanfrno, beazyl, C 3 12 cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a heteromonocydlic ring, a.. heterobicyclic ring system, and a spiro ring system of the formula X, X 2 (V) wherein X, and X 2 are independently selected from the group consisting of NH, 0, S and CH 2 wherein said alkyl, cycloalkyl, alkenyl, CI- 1 0 allcylamino, C 3 12 cycloallcylarrnJno, or benzyl is optionally substituted with 1-3 subitituents selected from the group consisting of halogen,. alkyl, C I-10 alkoxy, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group. consisting of halogen, alkyl, C1.10 alkoxy, and cyano; wherein said C 3 12 cycloalicyl, C 3 12 cycloalkcenyl, monocyclic, bicyclic or tricyclic aryl, *heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system, and spiro ring system of the formula are optionally substituted with 1-3 substituents selected from the group consisting of halogen, CI1 alkyl, CI- 1 0 ailcoxy, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and 123 0 M O O\ N benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1 alkyl, alkoxy, and cyano; R, is selected from the group consisting of hydrogen, C -o alkyl,.C. 2 cycloallcyl and halogen, said alkyl optionally substituted with an oxo group; or a pharmaceutically acceptable salt thereof. A compound of claim 69, wherein R, is alkyl selected from the group consisting pf methyl, ethyl, propyl, butyl, pentyl and hexyl. 71. A compound of claim 69, wherein R, is cycloalkyl selected from the group consisting of cyclohexyl, cydloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and norbornyl. 72.. A compound of claim 69, wherein R, is tetrahydronaphthyl, decahydronaphthyl or dibenzocycloheptyl. 73. A compound of claim 69, wherein R, is phenyl or benzyl.. S74. A compound of claim 69, wherein R, is a bicyclic aromatic ring.. A compound of claim 74, wherein said bicyclic aromatic ring is indenyl, quinoline or naphthyl. 76. A compound of claim 69, wherein Z is a bond, methyl, or ethyl. 77. A compound of claim 69, wherein n is 0. 78. A compound of claim 69, wherein X, and X 2 are both O. 79. A compound of claim 69, wherein Z is a cycloalkylamino system of the formula (VI). A compound of claim selected from the group consisting of 3-ethyl-1-(p-phenylbenzyl)-1 3 -dihydro-2H-benzimidazol-2-one; 3-ethyl-l -(S-methylhex-2-yl) -1,3-diydro-2H-benzimidazol-2-one; 3-ethyl- -(4-propylcyclohexyl)-1, 3 -dihydro-2H-benzimidazol-2-one.; 124 3-ethyl'-i -(decahydro-2-naphthyl)- 1,3 -dihydro-2H-benzinmidazol.2one; 3-ethyl-i1 -(naphth-2-yl-methyl). I, 3 -dihydro-2-benzimidazol.2one.. 1 -(p-benzyloxybenzy)-3-ethyl-.1 3 -dihiydro-2H-benzimidazol.2-one; 1 -benzyl-3 -ethyl-i 3 -dihydro-2H-benzindzoI2-one; i-[4-(benzylanino)-cyclohexyl]p3-ethyl-. 1,3d do2Hbniiazl2oe 00 3.-ethyl-i nptylehl-, 3 -dihydro-2H-benzimidazo12.one; 3-ethyl-1 ±±fuorophenyl)5(4fluorophe'ny)heyl]i ,3-dihydro-2H-benzi'idazol- 2-one; 1-4[npt--lmty ehlmn)ccoey]1 ,3-dihydro-2H-benzimidazo..2 one; C1 i-[ 4 -(norbonan-2-ylamino)-cyclohexy].1 3 -dihydro-2Hi-benzimdazol2one .1[-[-I:ehlty)c lhxlaio-ylhxl-,3-dihydro-2H-benzimidazol- 2-one; i-[ 4 -[(decahydro-2-naphthyl)amino]-ycyc1heXY1]71,3 -dihydro-2H-benzmidazo1-.2-one; 1 4 -(ethylamino)-cyclohexyl..1 3 -dihydro-21{-benzimidazol-2-one; 1 4 -(benzylamino)-cyclohexy1,-dihyr-Hbnimdzl2oe 1-4[*'dn2y~ezlmio ccoixl- ehl 1 ,3-dihydro-2H-benzimidazol-2. one; 1- [Ccocymty~mio-ylhxl -ty-,3-dihydro-2H-benzimidazo-2- one; 1*4[npt--laio-ylhxl- -ehl 1, 3 -dihydro-21-benhnidazoi2-one; l-[ 4 -[Rp-benzyioxybenzyl)aino]-cyclohexy].3-ety1,3-dihiydro-2H- benzimidazol-2- one; 1-4[ cocymehlaio-yloey]3e l1 ,3-dihydro-211-benzimjdazol-2- one; 1-4[dchdo2apihlamn]c oey]3ehl.,3-dihydro-2H- benzimidazol-2-one; 1- 4 -(benzyamino)cycohexy]5crbaoy1,3dhy1 H-ezmiao-2oe 1-[ 4 -(dibenzylamino)-cyclohexy]s5carbamoy 1 ,3-dihydro-2H-benzimidazol-2one; 1i 4 [(p-phenylbenzy)amino]cyclohexy11-5cbaoyl 1 ,3-dihiydro-2H-benzjmjdazoi- 2-one; 1 2 3 4 tetrahydronaphthyl)amino]-cyclohexyi}-5-carbam1 1,3-dihydro-2H- benzimidazol-2-one; 1-4[4poy-yloey~mn] cohxl--abmy-,3-dihydro-2H- benzimidazol-2-one; *125 1-[4-[(-methylhex-2-yl)amino-cyclohexyl-5-carbamoyl- ,3-dihydro-2H- O benzimidazol-2-one; 1-[ 4 -[(decahydro-2-naphthyl)amino]-cyclohexyl]-5-carbamoyl-1l,3-dihydro-2H- benzimidazol-2-one; 1-[ 4 -(cyclooctylamino)-cyclohexyl]--carbamoyl-1,3-dihydro-2H-benzimidazol-2-one; 00 indan- 2 -yl)aminol-cyclohexyl]-5-carbamoyl-l ,3-dihydro-2H-benzimidazol-2- one; 1-[4-[(4-phenyl-cyclohexyl)amino-cycloexyl]-5-carbamoyl -1,3-dihydre-2H- benzimidazol-2-one; 1-[ 4 5 -methylhex-2-yl)amino]-cyclohexyl]-7-carbamoyl-1 ,3-dihydro-2H- benzimidazol-2-one; and pharmaceutically acceptable salts thereof.. 81. A pharmaceutical composition comprising a compound of claim 63 and at least one pharmaceutically acceptable excipient. 82, A method of treating pain comprising administering to-a patient in need thereof, an effective amount of an analgesic compound according to claim 63. 83. A method of modulating a pharmacological redponse from the ORL1 receptor comprising administerinig to a patient in need thereof an effective amount of a compound according to claim 63. 84. A pharmaceutical composition comprising a compound of claim 69 and at least one pharmaceutically acceptable excipient A method of treating pain comprising administering to a patient in need thereof, art effective amount of an analgesic compound according to claim 69. 86. A method of modulating a pharmacological response from the ORL1 receptor comprising administering an effective amount of a compound according to claim 69. 87. A compound of claim (UIA): 0R 00 z wherein n is an integer from 0 to 3; R is selected from the group consisting of hydrogen, CI1 alkyl, C 1 1 0 alkoxy, and C 3 12 cycloalkyl; 1, 2 is selected from the group consisting of hydrogen,*C 1 10 alkyl, C 31 2 cycloalkcyl and halogen,said alkyl optionally substituted with an oxo group; ZR 1 is the following Y2 wherein Yj is R 3 -(C 1 -0 12 )alkyl, R 4 -aryl, R 5 -heteroaryl, R 6 -(C 3 -C, 2 )cyclo-alkyl, R 7 -(C 3 C-7)heterocycloalkyl, -C0 2 (C 1 -C 6 )alkYl, CN or -C(O)NR 8 Rg; Y 2 is hydrogen or Y 1 Y 3 is hydrogen or (Cl-C 6 )alkyl; or YI, Y 2 and Y 3 together with the carbon to which they are attached, form one of the following structures: 127 RioE (CHRIa)u 00 E r ori ring; RIO is 1 to 3 substituents independently selected from the group consisting of H, (C 1 C 6 allcyl, (C 1 _-C 6 )alkyl-0R., -NRg 8 R 9 and 6 )alkyl-NRR 9 RII is I to 3 substituents independently selected from the group consisting of R 10 ,.-CF 3 OCF 3 NO.. and halo, or RII substituents: on adjacent ring carbon atoms may together form a' methylenedioxyor ethylenedioxy ring; Rs~ and R. are independently selected from the 'group consisting of hydrogen, (C 1 -C 6 alkyl, (C 3 -C 12 cycloalkyl, aryl and aryl(C,-C,)alkyl; R 3 is 1 to 3 substituents indepenidently selected from the group consisting of H, R 4 aryl, R 6 -(C 3 -C I 2 )cycloalkCYl, R 5 -heteroaryf, R7-(C 3 -C 7 )heterocycloalkyl, -NRs R 9 -OR 1 2 and .128 AC0.) 2 o R, is. 1 to 3 substituents independently selected from the group consisting of H, (Ce- C 6 )alkyl, R 4 -aryl, -NRsR.- -OR 12 and -SR 12 R 4 is 1 to 3 substituents independently elected from the group consisting of hydrogen, halo, (CI- C. )alkyl, R 13 -aryl, (C 3 0 12 )cycloalkyl, -CN, -CF 3 6 )alkyl-0RB,- OCF 3 -NR 8 R.9, -(CI C 6 )alkyl -NR 8 -NIHSO 2 R 8 -S0 2 N(R 4 2 -S0 2 R 8 -SORR, SgRg, -NO 2 00 M -CONRaR 9 -NR 9 C0Rz, -00k 8 -COCF 3 -OCOR 8 -0C0 2 RO, -COOR. 8 -(C,-C,)alkyl-, NHCOOC(0H 3 3 -(C 1 -0 6 )alkyl-NFICOCF 3 -(Ci-C 6 )allcyl-NHSo 2 7(q..d 6 )alkyl, r(C 1 -C 6 )alkyl- NHCONH-(C 1 -C 6 )-alkyl and -(0H 2 )f-N N-RS wherein f is 0 to 6; or R 4 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring-, is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C 1 -C 6 )alkyl. R 13 -arYl, (C 3 -C 12 )cycloalkYl, -CN, -CF 3 -ORB, -C 6 )alyl-0Rs; -OCF 3 NRgR 9 -(Ct-C 6 )a'kYl-NRgR 9 -NHSO 2 R 8 -SO 2 N(R 4 2 -N0 2 ,.-CONRSR 9 -N1%C0R 8 I -CORR' -000k 8 -000 2 Rg and -COOk 8 R 7 is'H, (C,-C 6 )alkyl, -OR 8 6 )alkyl-OR 8 -NR& 8 R 9 or 6 ,)alkyl-NR 8 R 9 R, 2 is H, (C 1 -C 6 )alkyl, R 4 -aryl, 6 )alkyl-OR., 6 )alkyl-NR&R 9 6 )alkyl- SR 8 or aryl (C 1 -C 6 )allcYl; R 13 is 1-3 substituents independently selected from the group consisting of H, (CI- C,)ellkyl, (C 1 -C 6 )alkoxy and halo; R 14 s independently selected from dlie group consisting of H, (C,-C 6 )alkyl and R 13 C 6 H 4 -CH 2 or a pharmaceutically acceptable salt thereof. 88. A pharmaceutical composition comprising a compound of claim 87 and at least one pharmaceutically acceptable excipient. 89. A method of treating pain comprising administering to a patient in need thereof, an effective amount of an analgesic compound according to claim 87. 90. A method of modulating a pharmacological response from the ORL1 receptor O comprising administering to a patient in need thereof, an effective amount of a compound according to claim 87. O 91. A method of modulating a pharmacological response from'an opioid receptor 00 comprising administering to a patient in need thereof, an effective amount of a compound S• according to claim 63. 92. A method of modulating a pharmacological response from an opioid receptor comprising administering to a patient in need thereof, an effective amount of a compound according to claim 69. 93. A method of modulating a pharmacological response from an opioid receptor comprising administering to a patient in need thereof, an effective amount of a compound according to claim 87. 94. A compound of formula (IV): R R 2 (n) N N N CN Q. A" N B .Z R1. (IV) wherein R is hydrogen, alkyl, C312 cycloalkyl, C 3 12 cycloalkylC 1 -4alkylb alcoxy, C 3 12 cycloalkoxy-, CI-10 alkyl substituted with 1 3 halogen, C312 cycloalkyl'substituted with 1-3 halogen, C3-12. CYcloalkylC alkylLsubstituted with 1-3 halogen, C, 0 alkoxy sub tit te wit 1-V I halogen, C3.12 cycloalkoxy.. substituted w ith 1-3 halogen, -C O Q QV,-CH 2 OH, -O 2 N(V 1 2 hydroxyCl-l. 1 alkyl-, hydroXYC 3 .1iocycloalkyl, .cyanoC 1 00 loalkyl-,' CyanoC 3 10 cycloa -kyl.., lkl- CON(V 1 2 NH 2 S *C 1 allcyl-, NH 2 SOC14alkyl. sulfonylaminoC,_,.alkyI*l diaminoalkyl-, -sulfonlyl1alkYl, a 6 -membered heterocyclic ring, a *6-membereci heteroaron-atic ring; a 6 -membered. heterocyclicCi~tky.. a 6-meiribeped heteroaromnaticC 1 4 -alkyl-, a 6 -membered aromatic ring, a 6 -membered arornaticCri.., alkyl-, a *membered heterocyclic ring optionally substituted with an oxo or thio, a heer~omtc ig, a 5mmee troYC14ly optionally substitulted with an 6xo or thio, a 5-membered heteroaromaticC 14 alkyi-, -CL- 5 1 5 -CI. 5 NIC(=_O)w 1 C .NH(O) 2 WI, -C 1 .sNIIS(=O)W, whereinW I is hydrogen, C -1 alkyl, 0342 cycloalkyl, Cj_ Salkoxy; C 3 1 2 .cycloalkoxy, -CH- 2 0H-, amino, C 1 -4alamino-, diCi. 4 alkylamino-, or a *membered heteroaromratic ring optionally substituted with 1-3 lower alkyl; wherein each V, is independently selected from HI-I 1 6 alkyl, C 3 -,cycloalkyl, b~nzyl and phenyl; D is a 5-8 membered cycloalkyl, 5-8 membered heterocyclic or a 6 membered aromatic or heteroaromatic group; n is aninteger from0o 0 3; A, B and Q are independently hydrogen, alkyl, C3-1 cycloallcyl, CI-1 alrox-y, 0312 *cycloalkoxy, -CH 2 OH, -NHS0 2 hydroxyC, 10 alkyl. aminocarbonyl- C 1 4 alkylaminocarbonyl., diCj._allcylaminocarbonyl. acylamino-, acylaminoalkyl, amide, sulfonylaminoC 1 0 ly- rA B can together form a bridge, or B-Q can together form a-C 3 bridge, or A-Q can together form a C 1 .3 bridge; .Z is selected from the group consisting of a bond, straight or branched C 3 6 alkylene, -CI-12O-, -CH 2 NH-, -CH 2 N(CH 3 -NHCH 2 -CH 2 CONH-* -NHCI- 2 00-, -CH 2 C0-, COCH 2 -CH 2 C00H 2 ,1 -CH(CH 3 -Or and -HC=CH-, wherein the carbon and/or.' nitrogen atoms ate unsubstituted or substituted with one or more lower alkyl, hydroxcy, halo or alkcoxy group; R, is selected from the group consisting of hydrogen,;C 1 alkyl, C 3 12 cycloalkyl, C2_ joalkenyl, amino, C 1 1 alkylamino C3-1 2 cylaklmn -O 1 1 -C 1 .4COOV, cyno Iy C, 0 lyl-. cyano 310 cycloalkyl. NH 2 SO 2 NH 2 SO 2 C 1 .akl. amiiarb,-onl- Ci.alylalncaiboy NHSOCI-4alkyl-, amincarony-, 14akylmincaron1-, diCi. 4 alkylarninocarboflyl. benzyl, C3.12 ccloalkenyl-, a mohocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a hetero-monocyclic ring, A hetero-bicyclic ring system, and a Spiro ring system of the formula 00 X wherein X, and X 2 are independently selected from the group consisting of NH, 0, S and H.;andwheeinsaid alkl Clolkyl, -alkenyl, C ,ialkylamino-, C 3 12 ycloalkcylamino-, or enzl o R 1 is ptioal susittdwith 1-3 substituents selected from the group' cons istingj of halogen, hydroxy, C 11 0 alkcyl, CI-10 alkoxy, nitro,- trifluoromethyl-, cyano, COOV 1 -C14C00Vj, cyanoC 1 10 alkyl, -C4- 5 -CI.sNHS(=0)jW 1 -C 1 5 a 5-iembredheteroaromaticCC0all1. phenyl, benzyl, benzyloxy, said phenyl, benzyl, and enzyloxy optionally being substituted with 1-3 substituents selected from the group *consisting of halogen, CI1 alkcyl-. C,.0 alkoxy-, and cyano;'and wherein said C3-, cycloalkyl, C3- 12 cycloalkcenyl, monocyclic, bicyclic br tricyclic'aryl, heteroaryl ring, hetero-mono cyclic ring, hetera-bicyclic ring system, or Spiro 'ring system of the formula (11) is optionally substituted xyith 1-3 substituents selected from the group consisting of halogen, CI-1 alkyl, C 1 10 alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy ai-id benzyloxy, wherein said *phenyl, benzyl, phenyloxy or. benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogens CI1 alkyl, alkoxy, and cyano; R 2 is selected from the group coiisi~ting of hydrog.6n, CI1 alkyl, C3.12 cycloalicyl-and halogen, said alkyl or cycloalkyl optionally substituted with an oxo, amino, alkylarnino or 'dialkylamino group; or a pharmaceutically acceptable salt thereof or solvate thereof. A conipound of claim 94, wherein D is phenyl or a 6 membered heteroaromatic group containinig 1-3 nitrogen atoms. 96. A compound of claim 94, wherein R is selected from the group consisting of -CI-1 2 C=ONH- 2 -C(NI-T)NH 2 pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl, -C=0 C13, CH 2 CH 2 NHC=OCH 3 -sO 2 CH 3 CH 2 CH 2 NHSO 2 CH 3 furany larbonyl-, methylpyrrolylcarbonyl- diazolecarbon'yl. azolemetiiyl.., trifluoroethyl-, hydroxyethyl-, 132 cyanomethyl., oxo-.oxazolemefiyl-, and diazolenaethyl.' *97. A compound of claim 94, wherein ZR, is selected "from the group consisting of cyclohexylethyl-, cyclohexylmethyl.; cyclopentylmnethyl., dimethylcyclohexylmety... phenylethyl-, Pyrrolyltrifluoroeihyl., thienyltrifluoro~thyl.. pyridylethyl-, cyclopentyl-, 00 cyclohexyl-, methoxycyclohexyl. tetrahydropyranyl.. propylpiperidiil. indolylmepthyl-, I> pyrazoylpentyl-, thiazolylethyl.., Phenyltrifluoroethiyl., hydroxyhexyl., methoxyhexyl-, isopropoxybutyl., hexyl-, and oxocanyipropyb- 98. A compound of claim 94, wherein at least one of ZR, or R is selected from the group *consisting of CH 2 COOV 1 tetrazolylrnethyl cyanomethyl., NHi 2 SO 2 Methyl-, NI- 2 SOMethYlI anminocarbonyimethyl., C14.alkylaniinocarbonylnethyl.., and i.4kyanorbylell. 99. A compound of claim 94, wherein ZR, is .3 3 diphenylpropyl optionally substituted at the 3 carbon of the propyl with -COOV,, tetrazolylC 0 4~alyl-,'cyano-, aminocarb-onyl., C,. 4 alkylamrinocarboqnyl. or diC,.,alkylamrlnocarbonyl. 100.. A compound of the formula. (IVA): (IVA) wherein n is aninteger fromo0to 3; Z is selected from the group- consisting of a bond, -CH 2 -CF 2 C. -1 2 *CH 2 NH-, -CH 2 N(CH 3 -NHCH2-, -CH 2 CONH-, -NHCH 2 00-, -CH 2 CO-, -COCH 2 iCH 2 COCH 2 -CH(CH 3 and -HC=CH-, wherein the carbon and/or nitrogen atoms are *unsubstituted or substituted with a lower alkcyl, halogen, hydroxy or alkoxy group; R is selected-from the group consisting*of-hydrogen, q 110 .alkyl, C 1 1 0 alkoxy, and C 3 1 2 CYcloalkcyl; R, is selected fr6m the group consisting of hydrogen, C 1 1 alkyl, C 3 12 CYCloalkyl, *C 2 4.alkenyl, amino, Ci.. 1 0alkylarnino, C 3 4 2 CYCloalcylmino, benzyl, C 3 1 2 cycloalken~yl, a niono~yclic, bicyclic or tricyclic aryl or heteroaryl ring, a heteromonocyclic ring, a heterobicyclic ring system, a nd a spiro rmind system of the formula 00 X wherein X, ah 2 aeidpnetyslce rm the group consisting of NH, 0, S and CH 2 wherein said alkyl, cycloalkyl, alkenyl, C,~akrmn 3 1 ccolclrio or beinzyl is optionally substituted with 1-3 ubstituents selected from the group consisting of halogen, alkyl, alkoxy, nitro, trifluorome'thyl, cyano, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substjtuenjs -selected from the group consisting of halogen, C 1 alkyl, Cj 1 10 alicoxy, and cyano;- wherein said C 3 12 cycloalkyl, C 3 -l cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system, ana spiro ring system of the formula are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1 10 alky~l, C 11 0 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 of halogen$: C'_1 alkyl, CI 1 8 alkoxy, and cao R 2 is selected from the group consisting of hydrogen, C -1 alkyl, C3.12 cycloalkyl and halogen, said alkcyl optionally substituted with an oxo group;, or a. pharmaceutically acceptable salt thereof. 101. A compound of claim 100, wherein R, is alkyl. selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl.- 102. A compoundi of claim 100, wherein R, is dycloalkyl selected from the group consisting- of cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and norbornyl. 103. A compound of claim 100, wherein R, is tetrahydronaphthyl, decahydronaphthyl or dibenzocycloheptyl. 0104. A compound of claim 100, Wherein R, is phenyl or benzyl. J 05. A compound of claim 100, wherein R, is a bicyclic aromatic ring. 00 A compound of claim 105, wherein said bicyclicaotcrigiineyqnoner naphthyl. (N *107, A compound of claim 100, wherein Z is a bond, methyl, or ethyl.. .i108. A compound of claim 100, wherein n is 0. 109.' *A compound. of claim 100, wherein X, and X. are both 0. 110. A compound selected from the group consisting Of 2 -cyanoimino-3-etlhyl1 -(p-phenylbenzyl)-4..piperidiyl]. 1,3-dihdr-2H- benzimidazole; I 2yaomn--ty-[11-(p-benzyloxybenzyl)4.piperidinyl] 1 ,3-dihydro-2H- benzimidazofe; 2 -Cyanoimino-3 -ethyl- I-[1 (ahh2y-ehy)4pprdil 1 ,3-dihydro-2H- ben =midazole; 2 -cyanoimino.3.ethyl-l-f[I-( 4 -propyicyclohexyl)4piperidinyl] 1 ,3-dihydro-2-- benzimidazole; 2 -cyanoimino6-3-etlyl1 4 2 -propyly.cycohexy]4piperidinyl] I ,3-dihydro- 2 11 -benziniidazole; 2 -cyanoimino-3.etiy.. 1 [tl(decahydro-2naphthyl).4-piperidinyl] I ,3-dihiydro- 2H--benzimidazole; 2 -cyanoimino-3ethyl..1-[ l-(cyclooctyl)..4.piperidinyl).. ,3-dihydro-2H-. *benzimidazole; 2 -qyanoimino-3-ethyLl -(-10,11 -dihydroSH.dibenzo[ad)..cyclohepten5-y17 4 piperidinyl]-1,-iyro2-eziiaoe 2 -cyanoimino-3ethy11-[ l-( 3 3 -Bis(phenyl)propyl)A4piperidinyl] 1 ,3-dihydr6- 2 -benzimidazole;' 2 -eyanoimino.3ethyl I-(1I 3 4 -tefrahydronaphtliyl)..4-piperidinyl] -1,3 dihydro-2H-benzi.'idazole; 136 2 -cyanoimino3ethyl... 5 -methylhex2yl)A4piperidinylp .3-Ihyr-1 0benzirnidazole; 3d~yr-H 2 -c~a~imi0~3etyl....[ -(norbornan-2-Yl)-4piperidiny1]-i ,3-4ihydro-2H- benzimidazole; 2 -cyanoimino-3..ety....l-[1 -dihydroinden..'xyl)..4.piperidinyl]-,-lhdo 00 2 H-benzirnidazole; 2 -Cyanoimino3ethy1...1 1-(cYcloc~ctylmethy.)-4-piperidinyl) 1,3dhdr-H C1benzimidazole* arnd 7iyr- pharmaceutically acceptable ialts thereof; 111. A compound selected'from the group consisting of 2 -cYanoimino-3-(2-hydroxy)eiyl.l 1 (cYclooctYl)A4.iperidiIYl.1 ,3-dihydro-2H- benzimidazole; 2 -cyanq.oimino3.methoxyarbonyrethyl_1 O.tl)4-'priiy]13.dhd 2 H-benzimidazole; 2 -cyanoimino-3cyao.ethy.....-[ 1 -(cYclooetyl)-4piperidnl l3dihydr'o-2H- benzimidazole; nll13 2 -eyanoimino-3-but111I-(cYclooctyl)-4piperidinyl] l, 3 -dihydro-2Hf-benzirnidazole; 2 -cyanoimilo32meianesufonad)thyl -(cyclooctyl)-4piperidinyl]. 1 3.- dihydro-2H-beinzimidzole; -yanoimino-3acetondo.l -(cyclooctyl>4-piperidi ny].1 ,3-dihydro-2H- benzirnidazole; 2 -cyanoimino-3-carboxymethyil l-[1 (cycootyl)4.pipe'idinyl]-1,3-dihydro-2H- benzimidazole; 2 -cyanoimino3(2dimefliunno)ethyll-[l-(cyclooctyl)-4-piperidinyl]- ,3-dihydro- 2H-benzimidazole; 2 -cyanoimidno-1 (cylooctyly.3..yoxymethylj4-piperidi yl] ,3-dihydro-2H-. benzimidazole; 2-cyoinino..1{I.{cycool) 1Aipidil] 1, 3 -dihydro2H7azabenziidaole; 2 -cyanoimino-l1-[1 -(cyclooctyly.2 6 -ethaxno-4.one-4-pipeiidiflyl] 1 ,3-dihydro-21{- benzimidazole; and. pharmaceutically acceptable salts thereof and solvates thereof. 112. A phraetcjcompositiofi comnprising a compound of claim 94 and at least one pharmaceutically acceptable excipient.* 137 113. A method of treating pain comprising administering to a patient in need thereof, an 0 effective amount of an analgesic conpound according to claim 94. (N 114. A method of modulating a pharmacological response from the ORL1 receptor comprising administering to a patient in need thereof an effective amount of a compound 00 according to claim 94. f115. A pharmaceutical composition comprising a compound of claim 100 and-at least one O pharmaceutically acceptable excipient. 116. A method of treating pain comprising administering to a patient in need thereof, an effective amount of an analgesic compound according to claim 100. 117. A method of modulating a pharmacological response from the ORL1 receptor comprising administering an effective amount of a compound according to claim 100. 118. A compound of the formula (IVA): R 2 (n) N S N R 1 (IVA) *wherein 0 fis aninteger fromo0to 3; R is selected from the group consisting of hydrogen, C 1 10 ailcyl, CI1 alkoxy, and 0C3. 12 CYcloalkyl; R, is selected from the group consisting of hydrogen, CI-. 1 0 alkyl, 03.22 cycloalkcyl and 00 halogen.,ai alkyl optionally substituted with an oxo group; ZR, is the following Y 1 S '2. wherein Y, is R 3 -((CC 2 )aucYl, R 4 -aryl, Rs-hetero'aryl, R,-(C 3 -C 12 )*cylo..alkyl R 7 -(C 3 C 7 )heterocycloalkyl, -CO2(C I-C6)illCYI, ON or -C(O)NRPR 9 Y 2 is hydrogen or Y 3 -is hydrogen or (C,-C 6 )alk>; or Y 2 and Y 3 together with the cirbon to which they are attached, form one of the following structures: RIIY R1Y 00 Ro(HI~ E (CHRio)w orr I w h e r i n is t o 3; a n d u a r e a h 0 3 r o v d e d t h a t h e s u m o f a n U s 1 333 -OCF 3 NO nd hao, or R sSte. o ad cet RIcrOn t m a o ehrfr wehyenein r i80ty3le ndx rg;-; is I 8 and 3 9 arett indepeently selected from the grup consisting of yroe, (C 6 CO)ly, '-ORO -2 kUIyl, aryl-R, and j~ arlC- 6 ad -Cl;C)lyN R, I( is 1 to 3 substituents independently selected from the group consisting of i, R-C3 arylR 6 -(C 3 -O 12 )cycloalkyl, R 5 -heteroarYl, R 7 -(C 3 -O7)heterocycloall -NRg R9, -OR 12 and 0 S(O) 0 2 R 1 2 R6.is 1 to 3 substituents independently selected from the group consisting of H. (CI- C 6 )alkcyl, R 4 -aryl, -NR 8 R 9 -OR 1 2 and -SR 1 2 R 4 is I to 3 s'ubstituents indepenidently selected from the group consisting.of hydrogen, 00 ~halo, C6 )allY,- R 1 3 -aryl, (03 Ci 2 )cycloalkyl, -OF 3 -ORI, -(0 1 -C 6 )a lkyl-ORB OCF 3 -NRa 8 R 9 -(CI C 6 )alicyl -N4R.R 9 -NHSO 2 R 8 -SO 2 N(R 14 2 -:SO 2 R-,0 8 -S 8 -NO 2 1 CICONR 8 R 9 -NR 9 00Rg, -COR 8 -COCF 3 0OC0RB, 000 2 Rg, -COOR 8 6 )Eikyl- NHCOOC(CH 3 3 9 Cl-C6)alkyl.-HOF,7CC6a. qNHSo..{C6a~l (I)alkyl *NHCONH-(CI-Co)alkyl and -C- 6 akl -(CH2)r-N N-R 8 wherein f is 0 to 6; or R 4 substitunsoadcetrg carbon atoms may together for a methylenedioxy or ethylenedioxy ring; R 5 is 1 to 3 substituents independently selected from the group consistinj of hydrogen, halo, (C 1 -C 6 )alkyl, R 1 3 -aryl (C 3 -C 12 )CYCloalkyl, -ON, -OF 3 -(C 1 -C 6 ~alkcyl4JR. 0ocF 3 .NRgR 9 -(CI-C 6 )alkyl-NRgp.., -NHSO 2 -SO 2 N(R 14 2 -NO 2 -CONROR 9 -NR 9 COR 8 -COR2, -OCORS, 00C0 2 R. and -COOR 8 R 7 is H, (C 1 -O 6 ~alkyl, -OR 8 -(C 1 -C 6 )alkyl-0R, 8 -NRaR 9 or -(C 1 -0 6 )alkYl-NRR 9 R 12 is (Cl-C 6 )alkyl, R 4 -aryl, -(O 1 -C 6 )alkyl-OR 8 1 -C 6 )alkyl-NR~p, -(C 1 -0 6 )alkyl- SR., or aryl (C 1 -C 6 )alkyl; k1 3 is 1-3 substituents independently selected from the group consisting of H, (CI- C 6 )alkyl, (C 1 -C 6 )alkoxy and halo; R, 4 is independently selected from the group consisting of H, (CI-0 6 )alkyl and RW 3 CAH-0CH 2 and a Pharmaceutically acceptable salt thereof. *119. A.pharmaCeutical comnposition comprising a compound of claim 118 and at least one pharmaceutically -acceptable excipient. 120. A method 6f treating pain comprising administering to a patient in need thereof, an 0 .effective amount of an analgesic compound according to claim 118. O N 121. A method of modulating a pharmacological response from the ORL1 receptor comprising administering to a patient in need thereof, an effective amount of a compound S according to claim 118. 00 122. A method of modulating a pharmacological respbnse from an opioid redeptor comprising administering to a patient in need thereof,.an effective amount of a compound Saccording to claim 94. .123. A method of modulating a pharmacological resporise from an opioid receptor comprising administering to a patient in peed thereof, an effective amount of a compound according to claim 100. 124. A method of modulating a pharmacological response from an opioid receptor comprising administering to a patient.in need thereof, an effective amount of a compound according to. claim 118. Dated this TWENTY SEVENTH day of OCTOBER 2005. EURO-CELTIQUE, S.A. Wray Associates Perth, Western Australia Patent Attorneys for the Applicant