Title of Invention

"A PIPERIDINYL CYANOIMINO-BENZIMIDAZOLE COMPOUND OF FORMULA (IV)"

Abstract

The present invention relates to a piperidinyl cyanoimino-benzimidazole compound of formula (IV): wherein R is C1-10alkyl, C3-12 cycloalkyl, C3-12cycloalkylC1-4alkyl-, CMO alkoxy, C3-12cycloalkoxy-, C1-10 alkyl substituted with 1-3 halogen, C3-12 cycloalkyl substituted with 1-3 halogen, C3-12 cycloalkylC1-4alkyl-substituted with 1-3 halogen, Cuo alkoxy substituted with 1-3 halogen, C3-12cycloalkoxy- substituted with 1-3 halogen, -COOV1, -C1-4COOV1, -CH2OH, -SO2N(V1)2, hydroxyC1-10alkyl-, hydroxyC3-10cycloalkyl-, cyanoC1-10alkyl-, cyanoC3-10cycloalkyl-, -CON(V1)2, NH2SO2C1-4alkyl-, NH2SOC1-4alkyl-, sulfonylaminoC1-10alkyl-, diaminoalkyl-, sulfonylC1-4alkyl, a 6-membered heterocyclic ring, a 6-membered heteroaromatic ring, a 6-membered heterocyclicC1-4alkyl-, a 6-membered heteroaromaticC1-4alkyl-, a 6-membered aromatic ring, a 6-membered aromaticC1-4alkyl-, a 5- membered heterocyclic ring optionally substituted with an oxo or thio, a 5-membered heteroaromatic ring, a 5-membered heterocyclicC1-4alkyl-optionally substituted with an oxo or thio, a 5-membered heteroaromaticC1-4alkyl-, -C1-5(=O)W1, -C1-5(=NH)W1, -C1-5NHC(=O)W1, -C1-5NHS(=O)2W1, -C1-5NHS(=O)W1, wherein W1 is hydrogen, C1-10 alkyl, C3-12 cycloalkyl, C1-10alkoxy, C3-12 cycloalkoxy, -CH2OH, amino, C1-4alkylamino-, diC1-4alkylamino-, or a 5- membered heteroaromatic ring optionally substituted with 1-3 lower alkyl; wherein each V1 is independently selected from H, C1-6 alkyl, C3-6 cycloalky, benzyl and phenyl; D is a 5-8 membered cycloalkyl, 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, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, -CH2OH, -NHSO2, hydroxyC1-10alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, diC1-4alkylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide, sulfonylaminoC1-10alkyl-; or A- B can together form a C2-6 bridge, or B-Q can together form a C3-7 bridge, or A-Q can together form a C1-5 bridge; Z is selected from the group consisting of a bond, straight or branehed C1-6alkylene, -NH-, -CH2O-, -CH2NH-, -CH2N(CH3)-, -NHCH2-, -CH2CONH-, -NHCH2CO-, -CH2CO,, -CH2OCH2-, -CH(CH3)-, -CH=, -O- and-HC=CH-, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with one or more lower alKyl, hydroxy, halo or alkoxy group; R1 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-10alkylamino-, C3-12cycloalkylamino-, -COOV1, -C1-4COOV1, cyano, cyanoC1-10alkyl-, cyanoC3-10cycloalkyl-, NH2SO2-, NH2SO2C1-4alkyl-, NH2SOC1-4alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, diC1-4alkylaminocarbonyl-, benzyl, C3-12 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): wherein X1 and X2 are independently selected from the group consisting of NH, 0, S and CH2; and wherein said alkyl, cycloalkyl, alkenyl, C1-10alkylamino, C3-12cycloalkylamino-, or benzyl of R1 is optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, CMO alkyl, C1-10 alkoxy, nitro, trifluoromethyl-, cyano, -COOV1, -C1-4COOV1, cyanoC1-10alkyl-, -C4-5(=O)W1, -C1-5NHS(=O)2W1, -C1-5NHS(=O)W1, a 5-membered heteroaromaticC0-4alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, CMO alkyl-, CMO alkoxy-, and cyano; and wherein said C3-i2cycloalkyl, C3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, or spiro ring system of the formula (II) is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10alkyl, C1-10alkoxy, 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, C1-10 alkyl, C1-10 alkoxy, and cyano; R2 is selected from the group consisting of hydrogen, C1-10alkyl, C3-12 cycloalkyl-and halogen, said alkyl or cycloalkyl optionally substituted with an oxo, amino, alkylamino or dialkylamino group; or a pharmaceutically acceptable salt thereof or solvate thereof.

Full Text

NOCICEPTIN ANALOGS 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 disclosures of which are hereby incorporated by BACKGROUND OF THE INVENTION 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 µ, and K. As opiates had a high affinity to these receptors while not being endogenous to the body, research followed in order to identify andjisolate the endogenous ligands to these receptors. These ligands were identified as cnkcphalins, 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 homi|)logy. It was initially demonstrated that non-selective ligands having a high affinity for µ, 8 and K 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 ld to the isolation and structure of the endogenous ligand of the ORL1 receptor. This ligand is a seventeen ajmino acid peptide structurally similar to members of the opioid peptide family. The discovery of the PRLl receptor presents an opportunity in drug discovery for novel compounds which can be administered fcjr pain management or other syndromes modulated by this receptor. All documents cited Iferein, including the foregoing, are incorporated by reference in their entireties for all purposes. OBJECTS AND SUMMARY OF THE INVENTION It is accordingly an object of certain embodiments of the present invention to provide new compounds which exhibit affinity for thejORLl receptor. It is an object of certain embodiments of the present invention to provide new compounds which exhibit affinity for the ORL1 teceptor and one or more of the \i, 8 and K receptors. It is an object of certain embodiments of the present invention to provide new compounds for treating a patient suffering from chronics or acute pain by administering a 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 u, 8 and! K receptors which is greater than compounds currently available e. g. morphine. It is an object of certjain embodiments of the present invention to provide methods of treating chronic and acute pain by administering compounds which have agonist activity at the and K receptors which is greater than compounds currently available. It is an object of certjain 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 8 and K 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 autiy. modulators qf 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, 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 stimulate one receptorj(e. g., a u, agonist) and inhibit a different receptor (e. g., an ORL-1 antagonist). Other objects and advantages of the present invention will become apparent from the following detailed description thereof. The present invention in certain embodiments comprises compounds having the general formula (I (Formula Removed) wherein 1) is a 5-8: membered cycloalkyl, 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, C1-10 alkyl, C3-12 cycloalkyl, CC1-10alkoxy,C3-12 cycloalkoxy,-CH2OH, -NI1SO2 hydroxyC1-10alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, diC1-4alkylaminocarbonyl-, acylamino-, acylamincpalkyk amide, sulfonylaminoC1-10alkyl-, or A-B can together form a €3-6 bridge, or B-Q can together form a C 1-7 bridge, or A-Q can together form a C1-5 bridge; / is selected from the (group consisting of a bond, straight or branched Q.6 alkylene, -NH-, -CH2O-, -CH2NH-, -CH2N(CH3)-, -NHCFfc-, -CH2CONH-, -NHCH2CO-, -CH2CO-, -COCH2-, -CH2COCH2-, -CH(CH3)-, -CH=, -O- and -HOCH-, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with one or more lower alkyl, hydroxy, halo or alkoxy group; R1 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C|. loalkylamino-, C3-12cycloalkylamino-, -COOVi, -C1-4COOV1, cyano, cyanoCi.ioalkyl-, cyanoCs-iocycIoalkyl-, NH2SO2-, NH2SO2C1-4aIkyl-, NH2SOC1-44alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, diC1 lalkylaminocarbonyl-Jbenzyl, C3-12cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a )- monocyclic rinjg, a hetero-bicyclic ring system, and a spiro ring system of the formula (V): (Formula Removed) wherein Xi and X1 are: independently selected from the group consisting of NH, O, S and CH2; and wherein said alkyl, cycloalkyj, alkenyl, C1-10alkylamino-, C3-12cycloalkylamino-, or benzyl of RI is optionally substituted with 1-3 siubstituents selected from the group consisting of halogen, hydroxy, CMO alkyl, C|.|0 alkoxy, nitro, trifluoromethyl-, cyano, -COOV,, -C1-4COOV,, cyanoC1-4alkyl-,-C1-5(:=O)W1, -C,.5NHS ( O)2W1. -C1-5NHS(-0)W|, a 5-membered heteroaromaticCo-4alkyl-, phenyl, benzyl, benzyloxy, said phenyl, ben/yl, and ben/yloxyj optionally being substituted with 1-3 substituents selected from the group consisting of halogen. C1-10 alkyl-,!C1-10 alkoxy-, and cyano ; and wherein said C3-12 cycloalkyl, C3-12 cycloalkenyl, monocyclic, bicyclic cjr tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, or spiro ring system of tjie formula (V) is optionally substituted with 1-3 substituents selected from the group consisting of halogenj, CMO alkyl, CMO alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and ben/yloxy, wherein laid phenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with 1-3 substituents selected ftjom the group consisting of halogen, CMO alkyl, CMO alkoxy, and cyano; Wi is hydrogen, C1-10 alkyl, C3-12 cycloalkyl, CMO alkoxy, C3-12cycloalkoxy, - CH2OH, amino, C|. ialkylamino-, diC|.4all|ylamino-, or a 5-membered heteroaromatic ring optionally substituted with 1-3 lower alkyl ; " V1is 11, C1-6, alkyl, C3-6icycloalkyl, benzyl or phenyl; R2 is selected from thtt group consisting of hydrogen, CMO alkyl, C3-12 cycloalkyl- and halogen, said alkyl or cycloalkyl optionally substituted with an oxo, amino, alkylamino or dialkylamino group; and pharmaceutical ly Acceptable salts thereof and solvates thereof. The present invention! in certain embodiments comprises compounds having the general formula (1A) as follows: (Formula Removed) wherein n is an integer from 0 tc 3; /"is selected from the. group consisting of a bond,-CH2-,-NH-,-CH2O-,-CH2CH2- ,-CH2NH-, -CH2N(CH3)-, -NllCll,-, -CH2CONHh -NHCH2CO-, -CH2CO-, -COCH2-, - CH2COCH2-,-CH(CH3)-,-CH=, and-HC=CH-, wherein the carbon anl/or nitrogen atoms are unsubstituted or substituted with a lower alkyl, halogen, hydroxy or alkoxy group; RI is selected from the group consisting of hydrogen, C1-10alkyl, C3-12cycloalkyl, CMO alkenyl, amino, C|. loalkylamino, C3-12cycjloalkylamino, benzyl, C3-12 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): (Formula Removed) wherein X|, and X2 art? independently selected from the group consisting of NH, O, S and CH2; wherein said monocyclic aryl is preferably phenyl; wherein said bicyclic aryl is preferably naphthyl; wherein said alkyl, Cycloalkyl, alkenyl, C1-10alkylamino, C3-12cycloalkylamino, or benzyl is optionally substituted with 1-3 sijbstituents selected from the group consisting of halogen, CMO alkyl, CMO alkoxy, nitro, trifluoromethyl, cyan4, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, CMO alkyl, CMO alkoxy, and cyano ; wherein saidC3-12 cyclbalkyl, C3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetfro-bicyclic ring system, and spiro ring system of the formula (V) are optionally substituted with 1-3 sijibstituents selected from the group consisting of halogen, C1-10alkyl, C1-10alkoxy, nitro, trilluoromethyl, phenol, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and ben/vloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, CMO alkyl, CMO alkoxy, ancl cyano; R2 is selected from the group consisting of hydrogen, CMO alkyl, C3-12 cycloalkyl and halogen, said alkyl optionally substituted with an oxo group; and pharmaceutical ly acceptable salts thereof and solvates thereof. In certain preferred embodiments of formula (I), D is phenyl or a 6 membered heteroaromatic group containing 1-3 nitrogefi atoms. In certain preferred embodiments of formula (1) or (1A), the R1alkyl is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In certain preferred embodiments of formula (1) or (1A), the RI cycloalkyl is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyj, cyclodecyl, or norbornyl. In other preferred embodiments of formula (I) or (IA), the R1 bicyclic ring system is naphthyl. In other preferred embodiments of formula (I) or (IA), the R1 bicyclic ring system is tetrahydronaphthyl, or decahydronaphthyl and the R1 tricyclic ring system is dibenzocycloheptyl. In other preferred embodiments R1 is phcnyl or benxyl. m other preferred embodiments of formula (I) or (IA), the R] bicyclic aromatic ring is a 10-membered ring, preferably quinoline ot naphthyl. In other preferred embodiments of formula (I) or (IA), the RI bicyclic aromatic ring is a 9-membered ring, preferably indenyl. In certain embodiment^ of formula (I) or (IA), Z is a bond, methyl, or ethyl. In certain embodiments of formula (I) or (IA), the Z group is maximally substituted as not to have any hydrogen substitution Jon the base Z group. For example, if the base Z group is-CH2-, substitution with two methyl groups would remove hydrogens from the- CH2-base Z group. In other preferred embodiments of formula (I) or (IA), n is 0. In certain embodiments of formula (I) or (I A), X1, and X2 are both O. In certain embodiments of formula (I), ZR] is cyclohexylethyl-, cyclohexylmethyl-, cyclopentylmethyl-, dimethylcyclohexylmtjthyl-, phenylethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl-, pyridylethyl-, cyclopentyl-, cycloht^xyl-, methoxycyclohexyl-, tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyra/oylpentyl-, thiaifolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl-, or oxocanytprapyl-. In certain embodiments of formula (I), ZR| is-CH2COOVi, tetrazolylmethyl-, cyanomethyl-, NHjSChmethyl-, NHiSOmcthyl-, amincicarbonylmethyl-, Ci^alkylaminocarbonylmethyl-, or diCualkylaminocarbonylmethyl-. In certain embodiments of formula (I), ZR| is 3,3 diphenylpropyl optionally substituted at the 3 carbon of the propyl with-COOV|, tetraxolylCo^alkyl-, cyano-, aminocarbonyl-, C|.4alkylaminocarbonyl-, or diC]. lalkylaminocarbonyl-. The present invention in certain embodiments comprises compounds having the general formula (II): (Formula Removed) wherein the dotted line represents an optional double bond; R j*hydrogen, C1-10 aflkyl, C3-12 cycloalkyl, C3-12 cycloalkylC1-4alkyl-, CMO alkoxy, C3-12 cycloalkoxy-, CMO rffkenyl. C1-10 alkylideijie, oxo, C1-10 alkyl substituted with 1-3 halogen, C3-12 cycloalkyl substituted with 1-3 halogen. (Yi2 cycloaHiylC1-4alkyl- substituted with 1-3 halogen, Ci-ioalkoxy substituted with 1-3 halogen, €3. pcycloalkoxy-substitubd with 1-3 halogen, -COOVi,-C1-10C1-4COOV|, -CH2OH, -SO2N(V,)2, hydroxyCMOalkyl-, hydroxyCYiocycloalkyll-, cyanoCMOalkyl-, cyanoC3.|0cycloalkyl-, -CON(Vi)2, NH2SO2C,.4alkyl-, NH2SOC|. ialkyl-. sulfonyiamindC1-10alkyl-, diaminoalkyl-, -sulfonyIC1-10alkyl, a 6- membered heterocyclic ring, a 6-membered heteroaromjatic ring, a 6-membered heterocyclicC1-10alkyl-, a 6-membered heteroaromaticC|.4alkyl-, a 6-membered aromatjic ring, a 6-membered aromaticC1-10 alkyl-, a 5-membered heterocyclic ring optionally substituted with an OKO or thio, a 5-membered heteroaromatic ring, a 5-membered heterocyclicC|.4alkyl-optionally substituted with an oxo or thio, a 5-membered heteroaromaticC1-4alkyl-, -C1-5(=O)W|, -C|.S(=NH) W,, -C,.sNHC(=O)Wj, -C,.5NHS (=O)2W,,-C,.5NHS (=O)WU wherein W,, is hydrogen, C,.10alkyl, C3.,2 cycloalkyl, C1-10alkox|y, C3-12 cycloalkoxy, -CH2OH, amino, C1-4alkylamino-, diC|.4alkylamino-, or a 5-membered heteroaromiatic ring optionally substituted with 1-3 lower alkyl; wherein each V1, is independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, benzyl and phenyl; n is an integer from 0 |o 3 ; I) is a 5-8 membered; cycloalkyl, 5-8 membered heterocyclic or a 6 membered aromatic or heteroaromatic group: n is an integer from 0 lo 3; A. B and Q are independently hydrogen, C1-10 alkyl, C3-12 cycloalkyl, CMO alkoxy, C3-12cycloalkoxy, C\.\o alkenyl, CMO alkylidefte, oxo,-CH2OH,-NHSO2, hydroxyCi.ioalkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-. diCi-talkylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide, sulfonylaminoC1-10alkyl-, or A-B can together form a C2-6 bridge, or B-Q can together form a €3.7 bridge, or A-Q can together form a C\.$ bridge ; / is selected from the^group consisting of a bond, straight or branched C1-6 alkylene,-NH-,-CH2O-,-CH2NH-,-Cl 12N C3-12-,-NHCH2-,-CH2CONH-,-NHCH2CO-, -CH2CO-,-COCH2-,-CH2COCH2-,-CH (CH3)-,-CH=,-O-and-IIC' CH-, whereiin the carbon and/or nitrogen atoms are unsubstituted or substituted with one or more lower alkyl, hydroxy. halo or alkoxy group; RI is selected from the group consisting of hydrogen, C1-10alkyl, C3-12cycloalkyl, C2_1oalkenyl, amino, C|. malkylamino-, C3-12cycloalkylamino-, -COOV1, -C1-4COOV], cyano, cyanoCMoalkyl-, cyanoCs-iocycloalkyl-, Nll,S()r. NH2SO2alkyl, NH2SOC|.4alkyl-, aminocarbonyl-, C].4alkylaminocarbonyl-, did. (alkylaminocarbonyl-, benzyl, C3-12 cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a hetero- monocyclic rirjg, a hetero-bicyclic ring system, and a spiro ring system of the formula (V): (Formula Removed) wherein X| and X2 art independently selected from the group consisting of NH, O, S and CH2; and wherein said alkyl, cycloalkyp, alkenyl, C1-10alkylamino-, C3-12cycloalkylamino-, or benzyl of RI is optionally substituted with I-3 sjubstituents selected from the group consisting of halogen, hydroxy, CHO alkyl, CMO alkoxy. nilro, triflupromethyl-, cyano, -COOV,, -CMCOOV|, cyanoCMoalkyl-, -C1-5(=O)W|, -C|. ,NHS( O)2W|,-C|-5NF|S(=O)W|, a 5-membered heteroaromaticCo-4alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and ben/yloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl-, C1-10 alkoxy-, and cyano; and wherein said C3-12 cycloalkyl, C3.|2 cycloalkenyl, monocyelic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, or spiro ifing system of the formula (V) is optionally substituted with 1-3 substituents selected from the group consisting of halogen, CMO alkyl, C1-10 alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, (tidnyloxy and benzy!0xy, wherein said phenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, CMO alkoxy, and cyano ; R2 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12 cycloalkyl- and halogen, said alkyl or cycloalkyl optionally substituted with an oxo, amino, alkylamino or dialkylamino group; and pharmaceutically acceptable salts thereof and solvates thereof. 1 he present invention in certain embodiments comprises compounds having the formula (IIA) (Formula Removed) : wherein the dotted line represents an optional double bond; /. is selected from theigroup consisting of a bond, -CH2-, -NH-, -CH2O-, -CH2CH2-,-CH2NH-,-CH2N (CH3)-,-NHCH2 -CH2CONH-rNHCH2CO-,-CH2CO-,-COCH2-,- CH2COCH2-,-CH(CH3)-,-CH=, and-HC=CH-, wherein the carbon anil/or nitrogen atoms are unsubstituted or substituted with a lower alkyl, halogen, hydroxy or alkoxy group; R and Q are the same»r different and are each selected from the group consisting of hydrogen, halogen, CMO alkyl, CMO alkenyl, CMO alkylidene, C3-12 cycloalkyl, CMO alkoxy, and oxo; Rj is selected from the group consisting of hydrogen, C1-10alkyl, C3-12cycloalkyl,C2-10alkenyl, amino, C|. malkylamino, C3-12cyaloalkylamino, benzyl, C3-12 cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a hetefomonocyclic ring, a bicyclic ring system, and a spiro ring system of the formula (V): (Formula Removed) (V) wherein X| and XT areiindependently selected from the group consisting of NH, O, S and CH2; wherein said monocycjic aryl is preferably phenyl; wherein said bicyclic aryl is preferably naphthyl; wherein said alkyl, ipycloalkyl, alkenyl, C1-10alkylamino, C3-12cycloalkylamino, or benzyl is optionally substituted with 1-3 sijbstituents selected from the group consisting of halogen, CMO alkyl, C1-10alkoxy, nitro, irifluoromethyl, cyano, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 siibstituents selected from the group consisting of halogen, CMO alkyl, CMO alkoxy, and cyano ; wherein said C3-12 cycloalkyl,C3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system, and spiro ring system of the formula (V) are optionally substituted with 1-3 siibstituents selected from the group consisting of halogen, CMO alkyl, CMO alkoxy, nitro, trifluoromethyi, phenfl, ben/.yl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and bcn/yloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, CMO alkyl. C1-10alkoxy, andscyano ; R:> is selected from the group consisting of hydrogen, CMO alkyl, C3-12cycloalkyl and halogen, said alkyl optionally substituted with an oxo group ; and pharmaceutically acceptable salts thereof. In certain preferred erribodiments Q of formula (II) or (I1A), is hydrogen or methyl. In certain preferred erribodiments, R of formula (II) or (IIA), is hydrogen, methyl, ethyl, or ethylidene. In certain preferred Embodiments of formula (11), D is phenyl or a 6 membered heteroaromatic group containing 1-3 nitrogen atoms. In certain preferred embodiments of formula (II) or (IIA), the RI alkyl is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In certain preferred ambodirnents of formula (II) or (IIA), the RI cycloalkyl is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, or norbornyl. In other preferred embodiments of formula (II) or (IIA), the RI bicyclic ring system is naphthyl. In other preferred embodimenis of formula (II) or (IIA), the RI bicyclic ring system is tetrahydronaphthyl, or decahydronaphthyl and the RI tricyclic ring system is dibenzocycloheptyl. In other preferred embodiments R] is phenyl or ben/yl. In other preferred embodiments of formula (II) or (IIA), the RI bicyclic aromatic ring is a 10-membered ring, preferably quinoline or naphthyl. In other preferred embodiments of formula (II) or (IIA), the RI bicyclic aromatic ring is a 9-membered ring, preferably indenyl. In certain embodiments of formula (II) or (IIA), Z is a bond, methyl, or ethyl. In certain embodiments of formula (II) or (IIA), the Z group is maximally substituted as not to have any hydrogen substitution bn the base Z group. For example, if the base Z group is-CH2-, substitution with two fltet^l groups would remove hydrogens from the-CH2-base Z group. In other preferred embodiments of formula (II) or (IIA), n is 0. In certain embodiments of formula (II) or (IIA), X| and X2 are both O. In other preferred embodiments, the dotted line is a double bond. In certain embodiments of formula (II), R is-CH2C(=O)NH2,-C(NH)NH2, pyridylmethyl, cyclopentyl, cyclohexyl, fuifanyImethyl,-C(O))CH3,- CH2CH2NHC(=O)CH3,-SO2CH3,CH2CH2NHS02CH3, furanylcarbonyl-. methylpyrrolylcarbonyl-, diazolecarbonyl-, azolemethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxo-oxq/olemethyl-, or diazolemethyl-. In certain embodiments of formula (II), ZRi is cyclohexylethyl-, cyclohexylmethyl-, cyclopentylmethyl-, dimethyicyclohexylmejthyl-, phenylethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl-, pyridylethyl-, cyclopentyl-, cyclohejxyl-, methoxycyclohexyl-, tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyra/.oylpentyl-, thiaZolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl-. or oxocanylprojpyl-. In certain embodiments of formula (II), at least one of ZRi or R is-CH2COOV|, tetrazolylmethyl-, cyanomethyl-, NH2SO2 methyl-, NH2SOmethyl-, aminocarbonylmethyl-, C1-4|.4alkylaminocarbonylmethyl-, or diCYialkylaminocarbohylmethyl-. In certain embodiment of formula (II), ZR] is 3,3 diphenylpropyl optionally substituted at the 3 carbon of the propyl with-COOVi,; tetrazolylCo-4alkyI-, cyano-, aminocarbonyl-, C1-4alkylaminocarbonyl-, or diC|. lalkylaminocarbonyk The present invention (n certain embodiments comprises compounds having the general formula (III): (Formula Removed) wherein R is hydrogefl, C1-10 alkyl, C3.l2 cycloalkyl, C3.l2 cycloalkylC1-4alkyl-,C1-10 alkoxy, C3.l2 cycloalkoxy-alkyl substituted with 1-3 halogen, C3.l2 cycloalkyl substituted with 1-3 halogen, C3.l2 cycloalkylCu iaikyl- substituted with 1-3 halogen, CMO alkoxy substituted with 1-3 halogen, C3.l2 cycloalkoxy-substituted with 1-3 halogen, -COOV,1-C,.4COOV|, -CH2OH, -SO2N(V|)2, hydroxyCM0alkyl-, hydroxyC3-iocycloalkyl-, cyanoC1-10|.u,alkyl-, cyanC3.1ocycloalkyl-, -CON(V|)2, NH2SO2C,.4alkyl, NH2SOC1-4alkyl-, sulfonylaminoCi-io alkyl-. diaminoalkyl-,-sjulfonylC|-4aIkyl, a 6-membered heterocyclic ring, a 6-membered heteroaromatic ring, a 6-mJhibered heterocycjicC1-4alkyl-, a 6-membered heteroaromaticC1-4alkyl-, a 6-membered aromatic ring, a 6-pfewDered aromaticCi4t alkyl-, a 5-membered heterocyclic ring optionally substituted with an oxo or thio, a 5-mcmbered heteroaromatic ring, a 5-membered heterocyclicC1-4alkyl-optionally substituted with an oxo or thio, a 5-membered heteroatk)maticC1-4aIkyl-, -C,.5(=O)W,, -C1-5(=NH)W|, -CMNHC(=O)W,, -C1-5NHS(-O)2W1, -C1-5NHS( O)W|, wherein Wi is hydrogen, CMO alkyl, C3-12 cycloalkyl, CMO alkoxy, C3-12 cycloalkoxy, -CH2Oll, amino, C1-4|ilkylamino-, diC1-4alkylamino-, or a 5-membered heteroaromatic ring optionally substituted with 1-3 lower alkyl ; wherein each V|, is independently selected from H, C1-6alkyl, C3-6cycloalkyl, benzyl and phenyl; n is an integer from 0 to 3; 1) is a 5-8 membered cycloalkyl, 5-8 membered heterocyclic or a 6 membered aromatic or heteroaromatic group: / is selected from the group consisting of a bond, straight or branched Q.6 alkylene,-NH-,-CH2O-,-CH2NH-,-CII2N(CH3)-,-NHCH21,-CH2CONH-,-NHCH2CO-, -CH2CO-,-COCH2-,-CH2COCH2-,-CH(CH3)-,-CH-,-O-and-HC CH-, whereir) 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): (Formula Removed) wherein A, B and Q arte independently hydrogen, CMO alkyl, C3-12cycloalkyl, CMO alkoxy, C3.]2 cycloalkoxy, -CH2OH, -NHSO2, hydroxyC1-10alkyl-, aminocarbonyl-, C1-.4alkylaminocarbonyl-, diC1-.4alkylaminocarbonyl-, acylamino-, acylaminqalkyl-, amide, sulfonylaminoC1-10alkyl-, or A-B can together form a C2.& bridge, or B-Q can together form a C3,7 bridge, or A-Q can together form a CM bridge ; K| is selected from the group consisting of hydrogen, CMO alkyl, C3-12cycloalkyl, C2_ioalkenyl, amino, C|. loalkylamino-, C3-12cyeloalkylamino, -COOVi, -C1-.4COOVi, cyano, cyanoC1-10alkyl-, cyanoC3.|0cycloalkyl-, NlhSC):-, NM2SO2C1-.4alkyl-, NH2SOC1-.4alkyl-, aminocarbonyl-, C1-.4alkylaminocarbonyl-, diC|_ lalkylaminocarbonyl-, benzyl, C3.|2 cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a hctcro monocyclic rinig, a hetero-bicyclic ring system, and a spiro ring system of the formula (V): (Formula Removed) wherein X| and XT are independently selected from the group consisting of NH, O, S and CH2 ; and wherein said alkyl. cycloalkyj, alkenyl, C1-10alkylamino-, C3-12cycloalkylamino-, or benzyl of R, is optionally substituted with 1-3 spbstituents selected from the group consisting of halogen, hydroxy, CMC alkyl, CMO nitro, triflu$romethyl-, cyano, -COOV,, -C|.4COOVi, cyanoC1-10alkyl-, -C1-5(=O)W|, -C|. O)?Wu -C1-5N!HS(=O)W|, a 5-membered heteroaromaticCo-4alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and bienzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen), CHO alkyl-, C1-10 alkoxy-, and cyano; and wherein said C3-12 cycloalkyl, €3.12 cycloalkenyl, monocyiflic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, or spiro ring system of the formula (V) is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10alkoxy, 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, CMO alkyl, CMO alkoxy, and cyano; R:> is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12 cycloalkyl- 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 formula (IIIA): (Formula Removed) wherein n is an integer from 0 to 3; wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with a lower alkyl, halogen, hydroxy, phenyl, benzyl, or alkoxy group; /. is selected from the group consisting of a bond,-CH2-,-NH-,-CH2O-,-CH2CH2-,-CH2NH-,-CH2N (CH3)-,-Nl 1C1h-X:i I2CONHi-NHCH2CO-,-CH2CO-,-COCH2-,- CH2COCH2-,-CH(CH3)-,-CH=,-HC=CH-, and a cycloalkylamino system of the formula (VI): (Fourmla Removed) RI is selected from the:group consisting of hydrogen, CMO alkyl, CMO alkoxy, and C3-12cycloalkyl; RI is selected from the group consisting of hydrogen, C3-12alkyl, C3-12cycloalkyl, C3-12alkenyl, amino, C|. H.allkyiamino, C3-12cycloalkylamino, benzyl, C3-12 cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or ffeteroaryl ring, a heteifomonocyclic ring, a heterobicyclic ring system, and a spiro ring system of the formula (V): (Formula Removed) (V) wherein X| and X2 are (independently selected from the group consisting of NH, O, S and CH2; wherein said monocyciic aryl is preferably phenyl; wherein said bicyclic aryl is preferably naphthyl; wherein said alkyl, fycloalkyl, alkenyl, Ci-ioalkylamino, Cs.^cycloalkylamino, or benzyl is optionally substituted with 1-3 sujbstituents selected from the group consisting of halogen, CMO alkyl, CMO 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, CMO alkyl, CMO alkoxy, and cyano; wherein said ("3-12 cycloalkyl, C3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic rin^, heterobicyclic ring system, and spiro ring system of the formula (V) are optionally substituted with 1-3 sijbstituents selected from the group consisting of halogen, CMO alkyl, C1-10alkoxy, nitro, trifluorornethyl. phenyl, ben/yl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, CMO alkyl. C1-10 alkoxy, and cyano; R: is selected from the group consisting of hydrogen, CMO 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 (111), D is phenyl or a 6 membered heteroaromatic group containing 1-3 nitrogen atoms. In certain preferred embodiments of formula (111) or (IIIA), the R] alkyl is methyl, ethyl, propyl, butyl, pentyl, or hexy I. In certain preferred embodiments of formula (III) or (IIIA), the R1 cycloalkyl is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyi, cyclodecyl, or norbornyl. In other preferred embodiments of formula (III) or (IIIA), the R1 bicyclic ring system is naphthyl. In other preferred embodiments of formula (III) or (IIIA), the R1 bicyclic ring system is tetrahydronaphthyl, or decahydronaphthyl anil the R1 tricyclic ring system is dibenzocycloheptyl. In other preferred embodiments RI is phenyl or benzyl. In other preferred embodiments of formula (III) or (IIIA), the RI bicyclic aromatic ring is a 10-membered ring, preferably quinoline or naphthyl. In other preferred embodiments of formula (III) or (IIIA), the RI bicyclic aromatic ring is a 9-membered ring, preferably indenyl. S*a, 1^Br In certain embodiments of formula (III) or (IIIA), Z is a bond, methyl, or ethyl. In certain embodiments of formula (HI) or (IIIA), the Z group is maximally substituted as not to have any hydrogen substitution bn the base Z group. For example, if the base Z group is-CH2-, substitution with two methyl groups would remove hydrogens from the-CH2: base Z group. In certain embodiments of formula (III) or (IIIA), Z is a cycloalkylamino system of the formula (VI): (Formula Removed) (VI) wherein the nitrogen atom is optionally substituted with a C1-3alkyl, phenyl, or benzyl. In other preferred embodiments of formula (III) or (IIIA), n is 0. In certain embodiments of formula (III) or (IIIA), Xi and X2 are both O. In certain embodiments of formula (III), R is-CH2C(=O)NH2 -C(NH)NH2, pyridylmethyl, cyclopentyl, cyclohexyl, fu*anylmethyl,-C(=O)CH3,-CH2CH2NHC(=O)CH3,-S02CH3, CH2CH2NHSO2CH3, t'uranylcarbonyl-, met|hylpyrrolylcarbonyl-, diazolecarbonyl-, azolemethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxo-oxttzolemethyl-, or diazolemethyl-. In certain embodimenjls of formula (III), ZR1 is cyclohexylethyl-, cyclohexylmethyl- , cyclopentylmethyl-, dimethvlcyclohexylmejthyl-, phenylethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl-, pyridylethyl-, cyclopentyl-, cyclohexyl-, methoxycyclohexyl-, tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyra/.oylpentyl-, thiaijolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl-, or oxocanylprojpyl-. In certain embodiments of formula (III), at least one of ZRi or R is-CH2COOVi, tetrazolylmethyl-, cyanomethyl-, NH2S02methyl-, NH2SOmethyl-, aminocarbonylmethyl-, C|.4alkylaminocarbonylmethyl-, or diCVialkylaminocarbofiylmethyl-. In certain embodiments of formula (III), ZR, is 3,3 diphenylpropyl optionally substituted at the 3 carbon of the propyl with-COOVi, tetrazolylCo-4alkyl-, cyano-, aminocarbonyl-, C1-4alkylaminocarbonyl-, or diC|. talkylaminocarbonyl-. The present invention in certain embodiments comprises, compounds having the general formula (IV): (Formula Removed) wherein R is hydrogen, C1-10 alkyl, C3-12 cycloalkyl, C3-12 cycloalkylC3-12alkyl-, CMO alkoxy, C3-12 cycloalkoxy-. C,1-10 alkyl substituted with 1-3 halogen, C3-12cycloalkyl substituted with 1-3 halogen, C3-12 cycloalkylC]. talkyl- substituted wit| 1-3 halogen, CMO alkoxy substituted with 1-3 halogen, C3-12 cycloalkoxy- substituted with 1-3 halogen, -COpV,, -CMCOOV,, -CH2OH, -SO2N(V,)2, hydroxyC,1-10alkyl-, hydroxyC3-12cycloalkyl- , cyanoC,1-10alkyl-, cyanjoC3-iocycloalkyl-, -CON(V,)2, NH2SO2CMalkyl-, NH2SOCi.4alkyl-, sulfonylaminoCi. loalkyl-, diaminoalkyU, -sulfonylC1-4alkyl, a 6-membered heterocyclic ring, a 6-membered heteroaromatic ring, a 6-membered heterocyclicC1-4alkyl-, a 6-membered heteroaromaticC|_4alkyl-, a 6-membered aromatic ring, a 6-membered ar0maticC1-4 alkyl-, a 5-membered heterocyclic ring optionally substituted with an oxo or thio, a 5-membered heteroaromatic ring, a 5-membered heterocyclicC1-4C1-4alkyl-optionally substituted with an oxo or thio, a 5-membered heteroaromaticC1-4alkyl-, -C1-4(=O)W|, -C|.5(=NH)W,, -C,. 5NHC (=O) W|,-Q. ,NUS ( ()):Wi,-C|.5NjHS(=O)W|, whereinW, is hydrogen, CMO alkyl, C3-12 cycloalkyl, C3-12 alkoxy, C3-12 cycloalkoxy, -CH2OHj, amino, C1-4alkylamino-, diC1-4alkylamino-, or a 5-membered heteroaromatic ring optionally substituted with 1-3 lower alkyl ; wherein each V| is independently selected from H, C1-6 alkyl, C3.& cycloalkyl, benzyl and phenyl ; 1) is a 5-8 membered cycloalkyl, 5-8 membered heterocyclic or a 6 membered aromatic or heteroaromatic group; n is an integer from 0 lo 3; A, B and Q are independently hydrogen, CMO alkyl, C3-12 cycloalkyl, CMO alkoxy, C3-12 cycloalkoxy,-ClhOH.-NHSOT, hydjroxyC|. loalkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, diC1-4alkylaminocarbonyl-, acylamino-, acylaminoalkyi-, amide, sulfonylaminoC1-10alkyl-, or A-B can together form a C2-6 bridge, or B-Q can together form a C3-7 bridge, or A-Q can together form a C\.$ bridge; / is selected from the group consisting of a bond, straight or branched C1-6 alkylene, -NH-, -CFbO-, -CH2NH-, -CM b(C'H3)-, -N11CH2% -CH2CONH-, -NHCH2CO-, -CH2CO-,-COCH2-,-CH2COCH2-,-CH (CH3)-,-CH=,-O-and-HC' CH-, whereih the carbon and/or nitrogen atoms are unsubstituted or substituted with one or more lower alkyl, hydroxy, fialo or alkoxy group; RI is selected from t|e group consisting of hydrogen, CMO alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C|. ,alkylamino-, C3-12cyt;loalkylamino-, -COOVi, -C1-4COOVi, cyano, cyanoC1-10alkyl-, cyanoC3.]ocycloalkyl-, NH2SOC1-4alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, diC|. .lalkylaminocarbonyl-, benzyl, C3-12 cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a hctero- monocyclic ring, a hetero-bicyclic ring system, and a spiro ring system of the formula (V): (Formula Removed) wherein X; and X? are independently selected from the group consisting of NH, O, S and Chb; and wherein said alkyl, cycloalkyl, alkenyl, C1-10alkylamino-, C3-12cycloalkylamino-, or benzyl of RI is optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, CMO alkyl, CMO alkoxy, nitro, trifluoromethyl-, cyano, -COOVh -C1-4COOV,, cyanoCMOalkyl-, -C|.S(=O)W|, -C,.5NHS(=O) iW|,-C|sNHS(=O)W|, a 5-membered heteroaromaticCo-4alkyl-, phenyl, benzyl, benzyloxy, said phenyl, ben/yl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl-,• C1-10alkoxy-, and cyano ; and wherein said C3-12 cycloalkyl, C3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, or spiro ring system of t|e formula (V) is optionally substituted with 1-3 substituents selected from the group consisting of halogeni, CMO alkyl, CMO alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and ben/.yloxy, wherein said phenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogen, CMO alkyl, CMO alkoxy, and cyano ; K2 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12 cycloalkyl- and halogen, said alkyl or cycloalkyl optionally substituted with an oxo,. amino, alkylamino or dialkylamino group ; and pharmaceutically acceptable salts thereof and solvates thereof. (IVA)The present invention in certain embodiments comprpounds having the formula (1VA): (Formula Removed) n is an integer from 0 to 3; / is selected from thtj group consisting of a bond,-CH2-,-NH-,-CH2O-,-CH2CH2-,-CH2NH-,-CH2N (CH3)-,- NIICll2-,-CH2CONH-rNHCH2CO-,-CH2CO-,-COCH2-,-CH2COCH2-,-CH(CH3)-,-CH=, and-HC=CH-, wherein the carbon anc)/or nitrogen atoms are unsubstituted or substituted with a lower alkyl, halogen, hydroxy CJrIrmoxy group; R is selected from the group consisting of hydrogen, CMO alkyl, CMO alkoxy, and C3-12cycloalkyl; RI is selected from tlie group consisting of hydrogen, C1-10alkyl, C3-12cycloalkyl, C3-12alkenyl, amino, C|. loalkylamino, C3-12cycj|oalkylamino, benzyl, C3-12 cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a hetetomonocyclic ring, a heterobicyclic ring system, and a spiro ring system of the formula (V): (Formula Removed) wherein X] and X2 are independently selected from the group consisting of NH, O, S and CH2; wherein said monocyc|ic aryl is preferably phenyl; wherein said bicyclic aryl is preferably naphthyl; wherein said alkyl, cycloalkyl, alkenyl, Ci-ioalkylamino, Cs-ncycloalkylamino, or benzyl is optionally substituted with 1-3 sijbstituents selected from the group consisting of halogen, CMO alkyl, CMO alkoxy, nitro, trifluoromethyl, cyanc|, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 sijibstituents selected from the group consisting of halogen, CMO alkyl, CMO alkoxy, and cyano: wherein said C3-12 cycloalkyl, C3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring., heterobicyclic ring system, and spiro ring system of the formula (V) are optionally substituted with 1-3 sijbstituents selected from the group consisting of halogen, CMO alkyl, CMO alkoxy, nitro, trilluoromcthyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and ben/yloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, CMO alkyl, CMO alkoxy, and cyano ; R2 is selected from the group consisting of hydrogen, CMO alkyl, C3-12 cycloalkyl and halogen, said alkyl optionally substituted With an oxo group; and pharmaceutically acceptable salts thereof. In certain preferred irmbodiments of formula (IV), D is phenyl or a 6 membered heteroaromatic group containing 1-3 nitrogen atoms. In certain preferred enfibodiments of formula (IV) or (IVA), the RI alkyl is methyl, ethyl, propyl, butyl, pentyl, orhexyl. In certain preferred embodiments of formula (IV) or (IVA), the RI, cycloalkyl is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyi, cyclodecyl, or norbornyl. In other preferred embodiments of formula (IV) or (IVA), the R1 bicyclic ring system is naphthyl. In other preferred embodiments of formula (IV) or (IVA), the R1 bicyclic ring system is tetrahydronaphthyl, or decahydronaphthyl and the RI tricyclic ring system is dibenzocycloheptyl. In other preferred embodiments RI, is phenyl or benzyl. In other preferred embodiments of formula (IV) or (IVA), the R1 bicyclic aromatic ring is a 10-membered ring, preferably quinoline or naphthyl. In other preferred embodiments of formula (IV) or (IVA), the R1 bicyclic aromatic ring is a 9-membered ring, preferably indenyl. In certain embodiment! 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 pn the base Z group. For example, if the base Z group is-CH2-, substitution with two methyl groups would remove hydrogens from the-CH2-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 X2 are both O. In certain embodiments of formula (IV), R is-CH2C(=O)NH2,-C(NH)NH2, pyridylmethyl, cyclopentyl, cyclohexyl, futanylmethyl,-C(=O)CH3,-CH2CH2NHC(=O)CH3,-SO2CH3 CH2CH2NHSO2CH3, furanylcarbonyl-, methylpyrrolylcarbonyl-, diazolecarbonyl-, azolemethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxo-oxaizolemethyl-, or diazolemethyl-. In certain embodiments of formula (IV), ZR| is cyclohexylethyl-, cyclohexylmethyl- , cyclopentylmethyl-, dimethyleyclohexylmelhyl-, phenylethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl-, pyridylethyl-, cyclopentyl-, cyclohepcyl-, methoxycyclohexyl-, tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyra/oylpentyl-, thiazjolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hcxyl-, or oxocanylpropyl-. In certain embodiments of formula (IV), at least one of ZR| or R is -CH2COOVi, tetrazolylmethyl-, cyanomethyl-, NH2SQ2methyl-, NH2SOmethyl-, aminocarbonylmethyl-, C1-4alkylaminocarbonylmethyl-, or diC|..(alkylaminocarbonylmethyl-. In certain embodiments of formula (IV), ZRi is 3,3 diphenylpropyl optionally substituted at the 3 carbon of the propyl with-COOVi, tetrazolylCo-4alkyl-, cyano-, aminocarbonyl-, C1-4alkylaminocarbonyl-, or diC|. lalkylarninocarbonyl-In alternate embodiments of formulae (1), (IA), (II), (I1A), (III), (IIIA), (IV), and (IVA), ZR, can be thefollowing wherein Yi is Rr(C1-C12) alkyji, R4-aryl, R5-heteroaryl, R6 (C3-C12) cyclo-alkyl, R7- (C3- C7) heterocycloalkyl, -CO2 (C1-C6) alkyl, CN or-(j (O) NR8R9; Y2 is hydrogen or Y,; Y3 is hydrogen or(C1-C6) alkyl ; or Y,, Y2 and Y3, together with the carbdn to which they are attached, form one of the following structures: (Figure Removed) wherein r is 0 to 3; w and u are each 0-3, provided that the sum of w and u is I-3; c and d are independently I or 2; s is I to 5 ; and rifig E is a fused R4-phenyl or Rs- heteroaryl ring; RIO is I to 3 substitueijits independently selected from the group consisting of H, (C1-C6) alkyl,-OR8,-((C1-C6) alkyl-OR8,-NR8R9 andl (C1-C6) alkyl-NR8R9; RH is 1 to 3 substituents independently selected from the group consisting of RIO,- CF3,-OCF3, NO2 and halo, or RI i, substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring; RS and R9 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (Cs-Cjj) cycloalkyl, aryl and aryl ((C1-C6) alkyl; R.i is I to 3 substitjuents independently selected from the group consisting of H, R4- aryl, C12)cycloalkyl, R5-hettfroaryl, R7-(C3-C7)heterocycloalkyl, -NR8R9,-OR,2 and -S(O)0.2R12; I R.) is 1 to 3 substituerjts independently selected from the group consisting of hydrogen, halo, (C\-C(,) alkyl, Ru-aryl, (C3-C12) cyciloalkyl,-CN,-CF3,-OR8,-(C1-C6)alkyl-OR8, -OCF3, -NR8R9, -(C1-C6)alkyl -NR8R9, -NHSO3Rg, -SO2N(R|4(2, -SO2R8, - SOR8, -SR8, -NO2, -CONR8R9, -NR9COR8, -COR8, -COCF3, -OCOR8, -OCO?RK. - COORg, -(C1-C6)alkyl-NHCOOC(CH3)3, -(C1-C6)aIkyl-NHCOCF3, -(C1-C6)alkyl-NHSO2- (C,-C6) alkyl,-(C1-C6) alkyl-N|lCONH-(C,-C6)-alkyl and wherein f is 0 to 6; or R4 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring; Rs is 1 to 3 substituenjts independently selected from the group consisting of hydrogen, halo, (C\-C(>) alkyl, Rn-aryl. (C3-C,2)cyclqalkyl, -CM, -CF3, -OR8, -(C1-C6) alkyl- ORg, -OCF3,-NR8R9, -(Ci-C6)alkyl-NRgR9, -ti, -S02N(R,4, -NO2, -CONR8R9, - NR9COR8,-COR8,.-OCOR8,-OCO2R8and-CC>OR8; R7 is H, (C1-C6) alkyl, ^OR8-, -(C1-C6)alkyl-OR8, -NR8R9 or -(C1-C6)alkyl-NR8R9; R,2 is H. (C1-C6) alkyl, R4-aryl,-(C1-C6) alkyl-OR8,-(C,-C6) alkyl-NR8R9,(C1-C6) alkyl-SR8, or aryl (C,-C6) alkyl : RH is 1-3 substituents independently selected from the group consisting of H, (C1-C6) alkyl, (CpCa) alkoxy and halo; RI.I is independently seilected from the group consisting of H, (C1-C6)alkyl and RB- C6H4-CH2 As used herein, the tejrm"alkyl"means a linear or branched saturated aliphatic hydrocarbon group having a single radical and 1-1 (j) carbon atoms. Examples of alkyl groups include methyl, propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butjyl, 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-CH2-group of a linear alkyl chain. The term "lower alkyl"means an alkyl oif 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 a single radical and 3-12 carboh atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, and cyclohexyl. Exemplary, multicyclic cycloalkyl rings include adamantyl and norbornyl. The term"alkenyl"meafis a linear or branched aliphatic hydrocarbon group containing a carbon-carbon double bond having a single radical and 2-10 carbon atoms. A"branehed"alkenyl rrjeans that one or more alkyl groups such as methyl, ethyl or propyl replace one or both hydrogens in a-CH2-or-CH= linear alkenyl chain. Exemplary alkenyl groups include ethenyl, 1-and 2-propenyl. 1-, 2-and 3-butenyl, 3-methylbut-2- enyl, 2-propenyl, heptenyl, octenyl and decenyl. The term"eycloalkeny|"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 cycloalkemyl 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 ajcenaphthyl. The term"heterocyclic!'means cyclic compounds having one or more heteroatoms (atoms other than carbon) in the ring, and having a single radical. The ring may be saturated, partially saturated or unsaturated, and the heteroatoms may be selected from the group consisting of nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered hetero-monocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrojlidinyl, 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 hetefo-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 terrn"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 atoms, such as indolyl, quinolyl and isoquinolyl ; unsaturated 3 to-membered hetero-monocyclic groups containing an oxygen atom, such as furyl; unsaturated 3 to 6 membered hetero-monbcyclic groups containing a sulfur atom, 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 heterocyclic groups containing 1 to 2 oxygen atoms, and 1 to 3 nitrogen atoms, such as ben/oxa/olyl; unsaturated 3 to 6 membered hetero-monocyclic groups containing 1 to 2 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 nitfogen atoms, such as benzothiazolyl. The term"heteroaryl"also includes unsaturated heterocyclic radicals, "wherein "heterocyclic"is as previously described, in which the heterocyclic group is fused with an aryl gfoup, in which aryl is as previously described. Exemplary fused radicals include ben/ofuran, benzdioxoile and benzothiophene. As used herein, the term "heterocyclicC1-4alkyl", "heteroaromaticC1-4alkyl"and the like refer to the ring structure bonded to a C1-4alkl 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 terfm"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, ben/enesulfonate, p- tpluenesulfonate, 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 arty covalently bonded carriers which release the active parent drug in vivo. The invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esteritkation 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 products typically are identified by preparin| a radiolabelled compound of the invention, administering it parenterally in a detectable dose to an animal such as rat, mouse, guinea 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. The invention disclosed herein is also meant to encompass the disclosed compounds being isotopically-labelled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Kxamples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H,I3C,14C,15N,I8O,17O, 31P, 32P, 35S, IXF. and 16C1, 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 tautomersjare intended to be encompassed by the present invention, as well As used herein, the teiim "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientatiomof 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 centeK" 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 thje 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 ORL-1 receptor means the mediation of a pharmacodynamic response (e.g;, analgesia) in a subject from (i) 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 indirectly affect regulation of the receptor activity. Certain preferred compounds of formula (I) and (IA) include: 3-1 l-(naphth-2-yI-met|iyl)-4-piperidinyl]-2H-benzoxazol-2-one ; 3-11- (naphth-l-yl-me|hyl)-4-piperidinyl]-2H-benzoxazol-2-one ; 3-11- (p-phenylbenzyl)-4-piperidinyl]-2H-benzoxazol-2-one ; 3-11- (p-ben/.yloxyberjzyl)-4-piperidinyl]-2H-benzoxazol-2-one ; 3-11- (p-cyanobenzyl)s-4-piperidinyl]-2H-benzoxazol-2-one ; 3- [1- (3, 3-diphenylpr4pyl)-4-piperidinyl]-2H-benzoxazol-2-one ; 3- [ 1- |4,4-Bis- (4-fluojrophenyl) butyl]-4-piperidinyl]-2H-benzoxazol-2-one; 3-1 l-(2-phenylethyl)-4-piperidinyl]-2H-benzoxazol-2-one ; 3-1 l-(cyelooctylmeth)|l)-4-piperidinyl]-2H-benzoxazol-2-one ; 3-| 1 -(1. 2,3,4-tetrahydj-o-2-naphthyl)-4-piperidinyl]-2H-benzoxazol-2-one; 3-11- (5-rnethylhex-2-yl)-4-piperidinyl]-2H-benzoxazol-2-one ; 3-11- (10, 1 l-Dihydroi-5 H-dibenzo [a, d]-cyclohepten-5-yl)-4-piperidinyl]-2H- benzoxazol-2-one; 3- [1- (4-propyl-cyclohpxyl)-4-piperidinyl]-2H-benzoxazol-2-one ; 3-1 l-(norbornan-2-yi)J4-piperidinyl]-2H-benzoxazol-2-one ; 3-11- (decahydro-2-najphthyl)-4-piperidinyl]-2H-benzoxazol-2-one ; 3-| l-(3,3-dimethyl-l, |-dioxaspiro [5.5] undeca-9-yl)-4-piperidinyl]-2H-benzoxazol- 2-one; 3-11- |4-(l-methyleth|l)-cyclohexyl]-4-piperidinyl]-2H-benzoxazol-2-one ; 3-11- ( !, 3-dihydroind]en-2-yl)-4-piperidinyl]-2H-benzoxazol-2-one ; 3-11- (cyclooctyl)-4-pijperidinyl]-2H-benzoxazol-2-one ; and pharmaceutically acceptable salts thereof and solvates thereof. Certain preferred compounds of formula (II) and (IIA) include: 3-ethylidene-l-|l-(5-mbthylhex-2-yl)-4-piperidinyI]-l,3-dihydro-2H-indole-2-one; 3-ethylidene-l- [ 1- (4-jpropylcyclohexyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2- one; 3-ethylidene-l- [ 1- (l,i2,3,4-tetrahydro-2-naphthyl)-4-piperidinyI]-l,3-dihydro-2H- indole-2-one; 3-ethylidene-l-11- (l,B-dihydroinden-2-yl)-4-piperidinyl]-l,3-dihydro-2H-indole-2- one; 3-ethylidene-1 -[ 1 -(narjhth-2-yt-methyl)-4-piperidinyl]-1,3-dihydro-2H-indole-2- one; 3-cthylidene-l- [I- (p-benzyloxybenzyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2- one; 3-ethylidene-l- [1- (be|izyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one ; 3-ethylidene-l- [1- (cyclooctylmethyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one ; 3-ethylidene-l-11- (n4rbornan-2-yl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one; 3-ethylidene-l- [ 1- (3,(3-diphenyIpropyl)-4-piperidinyl]-l,3-dihydro-2H-indole-2- one; 3-ethylidene-l- [1- (p-cyanobenzyl)-4-piperidinyl]-l, 3,-dihydro-2H-indole-2-one; 3-cthyl-3-cthyl- 3-cthyl-3-clhyl- 1- (5-methyIhex-2-yl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one ; 1-14- (l-methylethyl)-cyclohexyl]-4-piperidinyl]-l, 3-dihydro-2H-indole- 2-one; 1- (4-propy!cyclohexyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one; 1- (1, 2,3, 4-tetrahydro-2-naphthyl)-4-piperidinyl]-l,3-dihydro-2H-indole- 2-one; 1- (decahydro-2-naphthyI)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one; 3-cthyl-3-ethyl-3-ethyl- 1- (1, 3-dihydroinden-2-yl)-4-piperidinyl]-l,3-dihydro-2H-indole-2-one; I-(cycloocyjmethyl)-4-piperidinyl]-l,3-dihydro-2H-indole-2-one; 1 -(norbornan-2-y l)-4-piperidinyl]-1,3-dihydro-2H-indole-2-one; - [ I- (naphth-l-yl-methyl)-4-piperidinyl]-l,3-dihydro-2H-indole-2-one; -11- (naphth-2-yl-mefhyl)-4-piperidinyl]-l,3-dihydro-2H-indole-2-one; 1-1 l-(p-phenylbenzyl|-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one; -11- (3, 3-Bis (phenyj) propyl)-4-piperidinyl]-l,3-dihydro-2H-indole-2-one; -11- (p-cyanobenzyl)f4-piperidinyl]-l,3-dihydro-2H-indole-2-one; -11- (p-benzyloxybenzyl)-4-piperidinyl]-l,3-dihydro-2H-indole-2-one; -11- (1. 2,3,4-tetrahy(|ronaphth-2-yl)-4-piperidinyl]-l,3-dihydro-2H-indole-2-one; -1 i- (5-methylhex-2-yl)-4-piperidinyl|-l, 3-dihydro-2H-indole-2-one; - (1- (norbornan-2-yl)H-piperidinyl]-l,3-dihydro-2H-indole-2-one; -11- (1. 3-dihydroinddn-2-yl)-4-piperidinyl]-l,3-dihydro-2H-indole-2-one; -11- (cycooctylmethyiH-piperidinyl]-!, 3-dihydro-2H-indole-2-one ; -11- (bcn/yl)-3- (methyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one; -11- (4-propyl-cyclohexyl)-3- (methyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one; -11- (5~methyIhex-2-)fl)-3- (methyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one; -11- (decahydro-2-najphthyl)-3- (methyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2- one; - (I- (4- (l-methylethyi)-cyclohexyl)-3- (methyl)-4-piperidinyl]-l, 3-dihydro-2H- indole-2-one; -11- (eycIooctyImethyl)-3- (methyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one ; -11- (3. 3-Bis (phenyl| propyl)-3- (methyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2- one; 3-cthyl-l-11- (3, 3-Bis(phenyl) propyl)-3- (methyl)-4-piperidinyl]-l, 3-dihydro-2H- indole-2-one; 3-cthyl-l-11- (4-propylcyclohexyl)-3- (methyl)-4-piperidinyl]-l, 3-dihydro-2H- indole-2-one; 3-cthyl-l-11- (5-methjlhex-2-yl)-3- (methyl)-4-piperidinyl]-l, 3-dihydro-2H-indole- 2-one; 3-cthyl-l-11-14- (1-mfcthylethyl) cyclohexyI]-3-methyl-4-piperidinyl]-l, 3-dihydro- 2H-indole-2-one; 3-cthyl-l-1 l-(decahydro2-naphthyl)-3-(methyl)-4-piperidinyl]-l, 3-dihydro-2H- indole-2-one; and pharmaccutically acceptable salts thereof and solvates thereof. Certain preferred compounds of formula (III) and (IIIA) include: 3-cthyl-3-ethyl-3-ethyl-3-cthyl-3-ethyl- - (p-phenylbeh/yl)-U-dihydro-2H-benzimidazol-2-one; - (5-methylhetx-2-yl)-1,3-dihydro-2H-benzimidazol-2-one; - (4-propylcytlohexyl)-l, 3-dihydro-2H-benzimidazol-2-one; - (decahydro-2-naphthyl)-l, 3-dihydro-2H-benzimidazol-2-one; -(naphth-2-ylMnethyl)-1, 3-dihydro-2H-benzimidazol-2-one 1 -(p-bcn/yloxybenzy l))-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one; l-ben/yl-3-ethyl-l,3-djihydro-2H-benzimidazol-2-one; 1-14- (bcn/ylamino)-cjyclohexyl]-3-ethyl-l, 3-dihydro-2H-benzimidazol-2-one; 3-cthyl-l- (naphthylm^thyl)-l, 3-dihydro-2H-benzimidazol-2-one; 3-cthyl-l-15- (3-fluorcjphenyl)-5- (4-fluorophenyl)-hexyl]-l, 3-dihydro-2H- benzimidazol-2-one; 1-14- [ (naphth-2-yl-rr|ethyl)ethylamino]-cyclohexyl]-l,3-dihydro-2H-benzimidazol-2-one; 1-14- (norbornan-2-ylamino)-cyclohexylJ-l, 3-dihydro-2H-benzimidazol-2-one ; l-|4-||4-(l-methylethyjl)-cyclohexyl] amino]-cyclohexyl]-l,3-dihydro-2H- benzimidazol-2-one; 1-14-| (decahydro-2-naphthyl) amino]-cyclohexylj-l, 3-dihydro-2H-benzimidazol-2- one; 1-14- (cihylamino)-cyclohexyl]-l, 3-dihydro-2H-benzimidazol-2-one; I-14- (bcn/ylamino)-cjyclohexyl]-l, 3-dihydro-2H-benzimidazol-2-one; 1-14- |(indan-2-yl) ben/ylaminoj-cyclohexyl]-3-ethyl-l, 3-dihydro-2H-benzimidazol- 2-one; I-14-1 (cyclooctylme^hyl) amino]-cyclohexyl]-3-ethyl-l,3-dihydro-2H-benzimidazol- 2-one; 1-14-1 (naphth-2-yl) 4minoj-cycIohexyl]-3-ethyl-l, 3-dihydro-2H-benzimidazol-2- one ; 1- [4- |(p-benzyloxyMnzyl)arnino]-cyclohexyl]-3-ethyl-l, 3-dihydro-2H- benzimidazol-2-one; 1-14- l(cyclooctylmethyl) aminoJ-cyclohexyl]-3-ethyl-l, 3-dihydro-2H-benzimidazol- 2-one; 1-14-1 (decahydro-2-naphthyI) amino]-cyclohexyl]-3-ethyl-l, 3-dihydro-2H- benzimidazol-2-one;. I-14- (ben/ylamino)-cyclohexyl]-5-carbamoyl-l, 3-dihydro-2H-benzimidazol-2-one; 1-14- (dibenzylamino)-cyclohexyl]-5-carbamoyl-l, 3-dihydro-2H-benzimidazol-2- one; 1- [4-1 (p-phenyIbenzy.l)amino]-cyclohexyl]-5-carbamoyl-l,3-dihydro-2H-benzimidazol-2-one; 1-|4-|(1. 2,3,4-tetrahycfronaphthyl) amino]-cyclohexyl]-5-carbamoyl-l, 3-dihydro- 2H-benzimidazol-2-one ; (4-propyl-cycl4hexyl) aminoJ-cyclohexyl]-5-carbamoyl-l, 3-dihydro-2H- benzimidazol-2-one; (5-methylhex-2-yl) amino]-cyclohexyI]-5-carbamoyl-l, 3-dihydro-2H- benzimidazol-2-one; I-14-1 (decahydro-2-njaphthyI) amino]-cyclohexyl]-5-carbamoyl-l, 3-dihydro-2H- benzimidazol-2-one; 1-14- (cyclooctylamino))-cyclohexyl]-5-carbamoyl-l, 3-dihydro-2H-benzimidazol-2- one ; 1-14- |(indan-2-yl)amiho|-cyclohexyl]-5-carbamoyl-l,3-dihydro-2H-benzimidazol- 2-one; 1-14-1 (4-phenyl-cyclohexyl) amino]-cyclohexyl]-5-carbamoyl-l, 3-dihydro-2H- benzimidazol-2-one ; 1-14-1 (5-methylhex-2-yl) amino]-cyclohexyl]-7-carbamoyl-l, 3-dihydro-2H- benzimidazol-2-one; and pharmaceutical ly acceptable salts thereof and solvates thereof. Other preferred compounds formula (IV) and (IVA) include: 2-cyanoimino-3-ethyl-l- [1- (p-phenylbenzyl)-4-piperidinyl]-l, 3-dihydro-2H- benzimidazole; 2-cyanoimino-3 ethyl-1i-11-(p-benzyloxybenzyl)-4-piperidinyl] l,3-dihydro-2H- benzimidazole; 2-cyanoimino-3-ethyl-l- [1- (naphth-2-yl-methyl)-4-piperidinyl] l,3-dihydro-2H- benzimidazole; 2-cyanoimino-3-ethyljl-11- (4-propylcyclohexyl)-4-piperidinyl]-l, 3-dihydro-2H- benzimidazole; 2-eyanoimino-3-ethyl-p- [ 1- [4- (2-propyl)-cyclohexyl]-4-piperidinyl]-l, 3-dihydro- 2H-benzimidazole; 2-cyanoimino-3-ethyl-l-11- (decahydro-2-naphthyl)-4-piperidinyl]-l, 3-dihydro- 2H-benzimidazole; 2-cyanoimino-3-ethyl-|-11- (cyclooctyl)-4-piperidinyl]-l, 3-dihydro-2H- benzimidazole; 2-cyanoimino-3-ethyl-l- [1- (10,1 l-dihydro-5H-dibenzo[a, d]-cyclohepten-5-yl)-4- piperidinyl]-!, 3-dihydro- 211-ben/imida/ole; 2-cyanoimino-3-ethyl-l-11- (3, 3-Bis (phenyl) propyl)-4-piperidinyl]-l, 3-dihydro- 2H-benzimidazole; 2-cyanoimino-3-ethyl-|-|l-(l, 2,3,4-tetrahydronaphthyl)-4-piperidinyl]-l,3- dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-il-[ l-(5-methylhex-2-yl)-4-piperidinyl]-l, 3-dihydro-2H- benzimidazole; 2-cyanoimino-3-ethyl-1- [1- (norbornan-2-yl)-4-piperidinyl]-l, 3-dihydro-2H- benzimidazole ; 2-cyanoimino-3-ethy1-1~ [1- (l,3-dihydroinden-2-yI)-4-piperidinyl]-l,3-dihydro- 2H-benzimidazole; 2-cyanoimino-3-ethyl-1-1 l-(cyclooctylmethyl)-4-piperidinyl]-l, 3-dihydro-2H- benzimidazole; and pharmaceutical ly acceptable salts thereof and solvates thereof. Other preferred compounds of formula (IV) include 2-cyanoimino-3-(2-hydroxy) ethyl-l-[l-(cyclooctyl)-4-piperidinyl]-l,3-dihydro-2H- benzimidazole ; 2-cyanoirnino-3-metha!xycarbonylmethyl-l- [1- (cyclooctyl)-4-piperidinyl]-l, 3- dihydro-2H-benzimidazole; 2-cyanoimino-3-cyano|nethyl-l- [1- (cyclooctyI)-4-piperidinyl]-l, 3-dihydro-2H- benzimidazole; 2-eyanoimino-3-buty1-1- [1- (cyclooctyl)-4-piperidinyl]-l, 3-dihydro-2H- benzimidazole; 2-cyanoimino-3-(2-me!thanesulfonamido)ethyl-l-[l-(cyclooctyl)-4-piperidinyl]-l,3-dihydro-2H- ben/imida/ole; 2-cyanoimino-3-acetoilnido-l- [1- (cyclooctyl)-4-piperidinyl]-l, 3-dihydro-2H- benzimidazole ; 2-cyanoimino-3-carboKymethyl-l- [1- (cyclooctyl)-4-piperidinyl]-l, 3-dihydro-2H- benzimidazole ; 2-cyanoimino-3-(2-dirjiethylamino) ethyl- l-[l-(cyc!ooctyl)-4-piperidinyl]-1,3- dihydro-2H-benzimidazole; 2-cyanoimino-l-11- (qyclooctyl)-3-hydroxymethyl-4-piperidinyl]-l, 3-dihydro-2H- benzimidazole; 2-cyanoimino-l- [ 1- (dyclooctyl)-4-piperidinyl]-l, 3-dihydro-2H-7- azabenzimidazole; 2-cyanoimino-l-11- (cyclooctyl)-2, 6-ethano-4-one-4-piperidinyl]-l, 3-dihydro-2H- benzimidazole; and pharmaceutically acceptable salts thereof and solvates thereof. The present invention piso 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, e. g., the ORL-1 receptor. DETAILED DESCRIPTION OF THE INVENTION The compounds of thes present invention can be administered to anyone requiring modulation of the opioid and OR1.1 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 pharmaccutically 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, lubricants like. 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 reconstituted from non-effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, coloring agents, and flavoring agents. When the compounds of the present invention are to be injected parenterally, they may be, e. g., 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 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, e. g., 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 pharmaceutical ly 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 Dosagp 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 gelatinj) and pills are also described in Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1 553B1593 (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 (e. g., continuous infusion OK 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. 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, u,-opioid agonists; non-opioid analgesics; non-steroijd anti inflammatory agents; Cox-Il inhibitors; antiemetics; p-adrenergic blockers; anticonvulsants; antid0pressants; Ca2+-channel blockers; anticancer agent and mixtures thereof. In certain embodiments, the compounds of the present invention can be formulated in a pharmaceutical dosage I'orm in combination with a u.-opioid agonist. u,-opioid agonists, which may be included in the formulations of the present invention include but are not limited to include alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, beK-itramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dim|thylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutenie, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isofnethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, mepta/.inol, metazocine. methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazipcine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramidc, proheptazjne, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, pharmaccutically acceptable salts thereof, and mixtures thereof. n preferred embodiments, the u.-opioid agonist is selected from codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, morphine, tramadol, oxymorphone, pharmaccutically 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-lipoxygejnase 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 (Cejlebrex), DUP-697, flosulide, meloxicam, 6-MNA, L- 745337, nabumetone, nimesulide, NS-398, SC-5766, T-6J14, L-768277, GR-253035, JTE- 522, RS-57067-000, SC-58125, SC-078, PD-1 38387, NS-398, flosulide, D-1.367, SC- 5766, PD-164387, etoricoxib, valdecoxib and parecoxib or pharmaceutically acceptable salts, enantijomers or tautomers thereof. The compounds of thejpresent invention can also be combined in dosage forms with non-opioid analgesics, e. g., non-steroidal anti-inlammatory agents, including aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, llurbiprofen, fenoprof^n, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zoftiepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic aeid, meclofenamic acid, flufenamic acid, niflumic acid tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or isoxicant, 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, non- limiting, chemicajl classes of analgesic, antipyretic, nonsteroidal antifinflammatory drugs: salicylic acid derivatives, including; aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salieylsalicylic acid, sulfasalazine, and olsalazin; para- aminophennol derivatives including acetaminophen; indole and indene acetic acids, including indomethacin, sulindac, and etodolac; heteroaryl acetic acids, including tolrnetin, diclofenac, and ketorolac ; anthranilic acids (fenamates), including mefenamic acid, and mecloienamic acid; fcnolic acids, including oxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone, oxypjhenthartazone); and alkanones, including nabumetone. For a more detailed description of the NSAlDs that may be included within the medicaments employed in the present invention, see Paul A. Insel Analgesic- Antipyretic and Anti inflammatory Agents and Drugs Employed in the treatment of Gout in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 617-57 (Perry B. Molinhoff and Raymond W. Ruddon, Eds., Ninth Edition, 1996), and Glen R. Hanson Analgesic, Antipyretic and An it-Inflammatory Drugs in Remington: '('he Science and Practice of Pharmacy Vol II, 1196-1221 (A. 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, tbna/ine, lisurjde, lomerizine, methysergide oxetorone, pizotyline, and mixtures thereof. 1 he other therapeutic agent can also be an adjuvant to reduce any potential side effects such as, for example, an antiemetic agent. Suitable antiemetic agents include, but are not limited to, metoclopromide, domperidone, prochiorpera/ine, proriiethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, aceihylleucine monoetjhanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyeli/ine, |imenhydrinate, diphenidot, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazihe, scopolamine, sulpiride, tetrahydrocannabinols, thiethylperazine, thioproperazine, tropisetron, and mixtures thereof. In certain embodiments, the compounds of the present invention can be formulated in a pharmaceutical dosage form in combination with P-adrenergic blockers. Suitable p-adrenergic blockers include, but are not limited to, acebulolol, alprenolo), amosulabol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol, cara/olol, carteolol, qarvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol, indenolol, labctalol. levobunololj, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol, practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol, tertatolol, tili$olol, timolol, toliprolol, and xibenolol. In certain embodiments, the compounds of the present invention can be formulated in a pharmaceutical dosage form in combination; with anticonvulsants. Suitable anticonvulsants include, but are not limited to, acetylpheneturide, albjjtoin, aloxidone, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate, ialcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam, decimemide, diethadione, dimethad|one, doxenitroin, eterobarb, ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin, 5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate, mephenytoin, mcphobarbital, methatrbital, methetoin, methsuximide, 5- methyl-5- (S-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin, narcjobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione, phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide, phenylmethylbarbituric acid, phenytoin, phethenylate sodium, | potassium bromide, pregabaline, primidone, progabide, sodium bromide, solanum, strontium bromide, sqclofenide, sulthiame, tetrantoin, tiagabine, topiramate, trimethadione, valproic acid, valpromide, vigabatrinj, and zonisamide. In certain embodiments, the compounds of the present invention can be formulated in a pharmaceutical dosage form in combination with antidepressants. Suitable antidepressants include, but are not limited to, binedaline, caroxa/.one, citaloprajm, dimethazan, fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine, oxitriptah, oxypertine, paroxetine, sertraline, thiazesim, trazodone, benmoxine, iproclozide, ipronia/id, isocarboxazid, nialamide, octamoxin, phenelzine, cotinine, rolicyprine, rolipram, maprotiline, melralindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide, amoxapine, butriptyline, clomipramine, demeiiptiline, desipramine, dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine, imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine, nortriptyline, noxiptilin, opipramol, pizotyline, propizepine, protriptyline, quinupramine, tianeptine, trimipramine, adrafmil, benacty/ine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate, femoxetine, fenpentadiol, fluoxetine. fluvoxamjne, hematoporphyrin, hypericin, levophacetoperane, medifoxamine, milnacipran, minaprine, moclobeniide, nefazodone, oxaflozane, piberaline, prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium cliloride, sulpiride, tandospirone, thozalinone, tofenacin, toloxatone, tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine. In certain embodiments, the compounds of the present invention can be formulated in a pharmaceutical dosage form in combination with Ca2+-channel blockers. Suitable Ca2+-channel blockers include, but are not limited to, bepridil, clentiazehn, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine, barnidipine, benidipine, cilnidiptne, 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; aldesleukin; altretamine; ambomycin; ametantrone acetate: aminoglutethijnide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; a/.otomycin; batimastait; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; Hrequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; dia/.iquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propjonate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromale; epipropidjine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydroehloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fbsquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamjide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl; interferon alfa-n3; interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan r|ydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride ; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestfol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; fnetoprine; meturedepa; mitindomide; mitocarcin; mitocromin ; mitogillin; mitomalcin; mitomycin; mitosper; jmitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide ; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prcdnimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tccogalan sodium; te^afur; teloxantrone hydrochloride; temoporfm; teniposide; teroxirone; testolactone; thiamiprine; thioguanijie; thiotepa; tiazofurin; tirapazamine ; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexa|e; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vfnglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vin/.olidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride. Other anti-cancer drugs include, but arc not limited to: 20-epi-l, 25 dihydroxyvitamin D3; 5- ethynyluracil; abiraterone; aclarubicin; acyllulvcne; adecypenpl; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevu|inic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; aritiestrogen; antineoplaston ; antisense oligonucleotides ; aphidicolin glycinate; apoptosis gent1 modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA ; arginine deaminase; asulacrine; atamcstane; atrimustinne; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin 111 derivatives; balano); batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutarnide; bisantrene; bisa/.iridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sullbximine; calcipotribl; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino- triazole; carboiyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinasc inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrjin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; qombretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine oclbsfaie: cytolytic fadtor; cylostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dcxifosfamide; dexrazi>xane ; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-a/.acytidine; dihydrotfaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxilluridine; droloxijene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; cflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazcjle; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; fmasteride; flavopiricjol; flezelastine ; fluasterone; fludarabine ; fluorodaunorunicin hydrochloride; Ibrfenimex; formestafie; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirciix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin ; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imida/.oacridones; imjquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; iinterferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengajrole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor: leukocyte alpha; interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear poiyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofyllinej; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix bietalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF; inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitogua/one; mitolacjtol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphory! lipid; A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1- based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myrfaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone t pentazocinei napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endeptidase; nilutajnide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06-ben/ylguanine; octreotjide; okicenone; oligonucleotides; onapristone ; ondansetron; ondansetron; oracin ; oral cytokine inducer; orm4platin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamjne; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl salcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydroehloride; piraruBicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis- acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; prbtein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphoryljase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron ; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; reUflliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukin£; romurtide; roquinimex; rubiginone Bl ; ruboxyl; safingol ; saintopin; SarCNU ; sareophytol A; sargrjamostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; si/.ofiran; sobjuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1 ; squalamine; stem cell inhibitor; stem-dell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal jseptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifeji methiodide; 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 ; topscntin; toremifene;stotipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelijn; 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; verteporfm; vinorelbine; vinxaltine; vitaxin; voifozole; 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 thtj present invention when administered, e. g., via the oral, parenteral or topical routes to mammals, can be in a jdosage 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. Howevr variations will necessarily occur depending upon the weight and physical condition (e. g., 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 thf present invention preferably have a binding affinity K, for the human ORL-1 receptor of about 500 nM or lejss; 100 nM or less; 50 nM or less; 20 nM or less or 5 nM or less. The binding affinity K, can be measured by ohe 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 followings procedure: (Figure Removed) Procedure: To a mixture of 1 (l.(j)9 g, 10 mmol), 2 (1.99 g, 10 mmol) and acetic acid (0.60 g, 10 mmol) in 50 mL of dichloroethane, was acjded sodium triacetoxyborohydride (2.97 g, 14 mmol). The mixture was stirred at room temperature overnight,; The mixture was filtered through Celite and 1 N NaOH (50 mL) was added to quench the reaction. The orgahic layer was separated and the aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic! layers were dried over K^COs, filtered and evaporated in vacuum to give crude 3 as a brown solid (2.75 g, yield: 94%). 'HNMK (CDC13): d 1.20-1.60.(m, 11H), 2,00 (dd, 2H), 2.9 (m, 2H), 3.40 (m, 1H), 4.00 (m, 2H), 6.60-6.85 (m, 411). To an iee cooled solutiion of crude 3 (12.0 g, 40 mmol) and DIEA (20.8 mL, 120 mmol) in 200 mL of THF, was added a solution of triphosgene (4.32 g, 14.4 mmol) in 200 mL of THF. After the addition was complete the iee 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 K2CO3. The organic phase was dried over K2CO3, filtered and evaporated in vacuum to give a red oil which was filtered through a column of silica gel eluting with a mixture of 5% EtsN, 25% EtOAc and 70% hexane. The selqcted 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 (CDC13): d 1.50 (s, 9H), 1.85 (d, 2H), 2.25 (m, 2H), 2.85 (m, 2H), 4.20-4.45 (m, 3H), 7.00-7.25 (m, 411). A solution of 4(4.0 g, 117.2 mmol) in 30% TFA/dichloromethane (25 mL) was stirred at room temperature for 3 h. The solvent was evaporated in vacuum and saturated aqueous K.2CO3 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/'CO3, filtered and evaporated in vacuum to give the crude product. Chromatography on silica gel eluting with a mixture of 10% Et3N, 60% EtOAc and 30% hexane gave 5 as a yellow solid (1.82 g, 66% yield). MS: m/y. 450 'll NMR(CDCI3): d 1.75-2.10 (m, 3H), 2.30 (d, 2H), 2.80 (m, 2H), 3.20 (m, 2H), 4.25 (m, 1H), 7*Jp*.25(m,4H). EXAMPLE 2 ATTACHMENT OF TAIL GROUPS Tail groups were attached to the head groups according to the following procedures: (Figure Removed) General procedure far alkylation: To a solution of the arnine (I 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°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 EtjO. 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 ketona 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 NaO11 to pH 10. The;mixture was extracted 2x with Et2O. The combined organic extracts were dried over potassium carbonate aiid 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: 3-| 1 -(naphth-2-yl-met|yl)-4-pipertdinyl]-2H-benzoxazol-2-one 3-| I -(naphth-1 -y l-met|yl)-4-piperidinyl]-2H-benzoxazol-2-one 3-11- (p-phenylbenzyl)i-4-piperidinyl]-2H-benzoxazol-2-one 3-| 1 - (p-benzyloxybenKyl)-4-piperidinyl]-2H-benzoxazoI-2-one 3- 1- (p-cyanobenzyl)-4-piperidinyl]-2H-benzoxazol-2-one MS: m 334.4 (M+l): 3-( I-(3.3-diphenylpro^yl)-4-piperidinyl]-2H-benzoxazol-2-one 3- 1 1- |4,4-Bis- (4-fluorophenyl) butyl]-4-piperidinyl]-2H-benzoxazol-2-one MS: m/ 463.6 (M+l). 3- 1 1- (2-phenylethyl)-f-piperidinyl]-2H-benzoxazol-2-one 3r 1 l-(cyclooctylmethyl)-4-piperidinyI]-2H-benzoxazol-2-one MS: m// 343. 6 (M+l). 'll-NMR (CDCb): d L25 (m, 2H), 1.40-1.7 (m, 17H), 2.10 (m, 4H), 3.10 (m, 2H), 4.20 (m, IH), 7.10-7.20 (411). 13C-NMR (CDCB): ds26.02, 26.87, 27.55, 29.27, 31.23, 35.31, 53.39, 53.70, 66.28, 1 10.45, 1 10.51, 122.45, 123.96, 130.45, 143.08J, 154.51. 3- 1 1-(1. 2,3,4-tetrahyd!ro-2-naphthyl)-4-piperidinyl]-2H-benzoxazol-2-one LC: 100% MS: 349.6 (M+l) 'll-NMR (CDCB): d lj.70 (m, IH), 2.00 (b, 2H), 2.10 (b, IH), 2.40 (m, 4H), 2.90 (m, 5H), 3.10 (m, 2H), 4.20 (m. Ill), 7. 10-7.30 (mJ8H). 3- 1 1- (5-methyIhex-2-yl)-4-piperidinyl]-2H-benzoxazol-2-one LC: 100% MS: 3 17.4 (M+l) 'll-NMR (CDC13): d 0.90 (d, 6H), 1.00 (d, 3H), 1.20 (m, 3H), 1.50-1.60 (m, 4H), 1.80 (m, 2H), 2.20-2.60 (m, 511), 2.90 (b, 2H), 4.2 3- 1 1- ( 10, 1 l-Dihydroi5H-dibenzo [a, d]-cyclohepten-5-yl)-4-piperidinyl]-2H-benzoxazol-2-one LC: 96.4% 'll-NMR (CDCb): d 1J80 (dd, 2H), 2.00 (dt, 2H), 2.30 (dq, 2H), 2.80-2.95 (m, 4H), 4.01 (s, IH), 4.05-4.22 (m, 311). 7.05-7.25 (m, 12$). 3- 1 1- (4-propyl-cycloh£xyl)-4-piperidinyl]-2H-benzoxazol-2-one MS: m//, 343.0 3-| I -(norbornan-2-yl)-4-piperidinyI]-2H-benzoxazol-2-one LC: 97% MS: ml/. 313.41 (M+l| ' ll-NMR (CDCb) :d 0.90 (m, IH), 1.30-2.50 (m, 17H), 3.20 (m, 2H), 4.3 (m, IH), 6.90-7.30 (m, 4H). 3- 1 1 -(dccahydro-2-na|>hthyl)-4-piperidinyl]-2H-benzoxazol-2-one MS: m// 355.4 3-| 1- (3. 3-dimethyl-l,5-dioxaspiro [5.5] undeca-9-yl)-4-piperidinyl]-2H-benzoxazol-2-one MS: m// 40 1.3 3- 1 1- 1 4- (l-methylethiyl)-cyclohexyl]-4-piperidinyl]-2H-benzoxazol-2-one MS: m// 343.0 3-| 1- ( 1, 3-dihydroinden-2-yl)-4-piperidinyl]-2H-benzoxazol-2-one LC: 100% MS: m// 335.4 (M+l) 'll-NMR (CDCb): d J.90 (m, IH), 2.40 (m, 2H), 2.50 (m, 2H), 2.90 (m, 2H), 3.10-3.40 (m, 6H), 4.20 (m, 111). 7. 10-7.30 (m, 8H). 3- | l-(cyclooctyl)-4-pijperidinyl]-2H-benzoxazol-2-one LC: 100% MS: m//329.2 (M+1) !11-NMR (CDC13): d 1.40-2.00 (m, 16H), 2.40-2.65 (m, 4H), 2.80 (m, 1H), 3.05 (m, 2H), 4.25 (m, 1H), 7.10- 7.40 (m. 411). compounds within the scope of formula (1) or (IA) of the present invention can be synthesized by ous techniques. EXAMPLE 3 Nociceplin affinity at the ORL1 receptor for preferred compounds was obtained using the following assay: Membranes from reco^nbinant HEK-293 cells expressing the human opioid receptor- like receptor (ORL-1) (Receptor Biology) wjere prepared by lysing cells in ice-cold hypotonic buffer (2.5 mM MgCl2, 50 mM 1IHPHS. 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°C and pellets resuspended in hypotonic buffer to a final concentration of 1-3 mg/ml. Protein concentrations were determined using the BioRad protein assayi reagent with bovine serurn albumen as standard. Aliquots of the ORL-1 receptor membranes were stored at-80°C. Functional SGTPgS binding assays were conducted as follows. ORL-1 membrane solution was prepared by sequentially adding firjal concentrations of 0.066 mg/ml ORL-1 membrane protein, 10 mg/ml saponin, 3 mM GDP and 0.20 nM [3Sfc] GTPgStobindingbuffer(100 mM NaCl, 10 mM MgCl2, 20 mM HEPES, pH 7.4) on ice. The prepared menibrane 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 30 min at room temperature with shaking. Reactions were terminated by rapid filtration onto 96-welI Unifilter G1-7B tiller plates (Packard) using a 96-well tissue harvester (Brandel) and followed by three filtration washes with 200 ml ice-cold! binding buffer (10 mM NaH2PO4, 10 mM Na2HPO4, pH 7.4). Filter plates were subsequently dried at 50°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 PRISMO, v. 3.0 and the results are set forth in table 1 below: TABJE1 (Table Removed)EXAMPLE 4 SYNTHESIS OF SUBSTITUTED INDOLE HEAD GROUPS (Figure Removed) 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 Idichloroethane, 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 organic layer was separated and the aqueous layer extracted with EtOAc (2 x 300 mL). The combined organic extracts were dried over K2CO3, filtered and the solvent evaporated under vacuum to give crude 8 as a brown solid which was directly used in next step. Compound 3 'll-NMR (CDC13): d 1.50 (m, 2H), 2.05 (m, 2H), 2.20 (bt, 2H), 2.85 (m, 2H), 3.30 (m, 1H), 3.52 (s, 2H), 6.60 (d. 211), 6.70 (t, 1H), 7.20 (m, 2H), 7.25-7.40 (m, 5H). I o 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 K2CO3 dried over K2CO3 filtered and the solvent removed in vaccum to give a brown gum which was filtered through a column of sjlica gel eluting with a mixture of 10% Et3N, 40% EtOAc and 50% 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 (49.2%, 2 steps). Compound 4 'H NMR (DMSO): d 1,22 (m, 2H), 1.70 (b, 2H), 2.00 (t, 2H), 2.80 (b, 2H), 3.40 (s, 2H), 3.80 (s, 2H), 4.40 (m, i 11), 7.15-7.30 (m, 7H), 7.45 (m, 3H). A mixture of 4 (42.2 g, 0.12 mol) and AIC13 (49.2 g, 0.369 mol) was mixed in a flask by rapid stirring. The mixture was then heated in an oil bath at 130 °C. Within a few minutes the solids melted and became a dark liquid 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 dichlordmethane. The organic layer was dried over Na2SO4, filtered and the solvent evaporated in vacuum to give a datk oil which was filtered through a column of silica gel eluting with a mixture of 10% Et3N, 40% EtOAc an$ 50% hexane. The selected fractions were combined and the solvent evaporated in vacuum to give 5 as a lied oil which set to a pale solid (22. 0 g, 58. 5%). Compound 5 'H NMR (CDC13): d 170 (m, 2H), 2.17 (m 2H), 2.50 (m, 2H), 3.05 (m, 2H), 3.55 (s, 2H), 3.60 (s, 2H), 4.33 (m. III), 7.00-7.40 (m,9H). lo a solution of 5 (If 0 g, 0.052 mol) in 35 mL of methanol was added Pd (OH)2 (4.0 g). The resulting suspension was hydrog^enated at 50 psi for 12 h at room temperature. The solution was filtered through a pad ot'Celite and the pad Washed with methanol (2 x 20 mL). Evaporation of the solvent in vacuum gave 6 as a pale solid (11.2 g, 100%). Compound 6 l.C: 100% MS:m//217(M+l). 'II NMR (CDCh): d 175 (m, 3H), 2.35 (m 2H), 2.75 (m, 2H), 3.25 (m, 2H), 3.50 (s, 2H), 4.33 (m, 1H), 7.00- 7.30 (m. 411) lo a solution of 6 (8. (I g, 37.0 mmol) in 50 mL of dichloromethane was added Et3N (4.07 g, 40.7 mmol) and BOC anhydride (8.87 $>, 40.7 mmol). After stirring for 3 h saturated aqueous K2CO3was added and the layers separated. The aqueous phase was extracted with dichloromethane (2 x 50 mL). The combined organic phase was dried over K2CO3 filtered and evaporated in vacuum to give a brown oil which was filtered through a column of silica gel elfiting with a mixture of 10% Et3N, 40% EtOAc and 50% hexane. The selected fractions were combined and thd solvent evaporated in vacuum to give 7 as an off white solid (8.50 g, 73%). Compound 7 'H NMR(CDC13): d 1.50 (m, 9H), 1.70 (m 2H), 2.20-2.50 (m, 2H), 2.80-3.00 (m, 2H), 3.50 (s, 2H), 4.20-4.50 (m, 311), 6.90-7.60 (m,:5H). 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 (167 g, 38. 0 mmol). The mixture was refluxed for 2 h. The solvent was evaporated in vacuum to give a darH oil which was filtered through a column of silica gel eluting with a mixture of 10% 1A(N, 40% EtOAc anil 50% hexane. The selected fractions were combined and the solvent evaporated in vacuum to give 8 as a red oil (5. 90 g, 91%). Compound 8 l.C: 2 isomers in a ratio of 2:1. !ll NMR (CDCI.3) (mixture of 2 isomers) d 1.50 (m, 9H), 1.70 (m 2H), 2.20-2.50 (m, 6H), 2.60-3.00 (m, 2H), 4.20-4.50 (m, 3H), 6.90-7. 60(m, 5H). A solution of 8 (5.90 $, 17.2 mmol) in 30% TFA/dichloromethane (100 mL) was stirred at room temperature for 3 h. The solvent Was evaporated in vacuum and saturated aqueous K2CO3 was added to the oily residue. The resulting mixture (was extracted with dichloromethane (3 x 150 mL). The combined organic extracts were dried over K2CO3, filtered and evaporated in vacuum to give the crude product. Chromatography on silica gel cluting with a mixture of 10% EtsN, 50% EtOAc and 40% hexane gave 9 (E/Z isomers) as a yellow foam (3.60g, 82%). Compound 9 IX': 2 isomers in a ratitji of 2:1, MS: m// 243.1 (M+l). 'H NMR (CDClj): (miKture of 2 isomers) d 0.85 (m, 1H), 1.50-2.00 (m, 4H), 2.20-2.50 (m, 5H), 2.60 (m, 1H), 3.10-3.50 (m, 2H), 4.30 (m, 1H), 6.90-7.60 (m, 5H). EXAMPLE 5 (Figure Removed) To a mixture of 5 (5.50 g, 18 mmol) and sodium acetate (2.45 g, 18 mmol) in 150 mL of methanol was added acetaldehyde (1.58 g, B6 mmol). The mixture was refluxed for 2 h. The solvent was evaporated in vacuum to give a dark oil which jwas filtered through a column of silica gel eluting with a mixture of 10% Et3N, 40% EtOAc and 50% hexaijie. The selected fractions were combined and the solvent evaporated in vacuum to give 10 as a red oil (5.90 g,-98%). Compound 10 LC : 2 isomers in a ratio of 2: 1. MS: m//. 333.2 (M-H).' 'II NMR (CDCI3): d 1.70 (m, 2H), 2.17 (m 2H), 2.30 (d, 3H), 2.50 (m, 2H), 3.05 (m, 2H), 3.55 (s, 2H), 4.33 (m. 111). 7.00-7.40 (m lo a solution of 10 (5.90 g, 17.7 mmol) in 30 mL of methanol was added Pd(OH)2(3.0 g). The resulting suspension was hydrofeenated 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 20 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 ail off white solid (2.02 g, 50%). Compound 11 LC:97% MS: m//245.2 (M+l) 'H NMR (CDC13): d 0.85 (t, 3H), 1.26 (m, 2H), 2.00 (m, 2H), 2.43 (m, 2H), 2.90 (m, 2H), 3.3 (m, 2H), 3. 4 (m. 111). 4.4 (m, lH)j7.05(m, 1H), 7.15-7.30 (m, 3H). EXAMPLE 6 (Figure Removed) Proccdiirc; In a manner similar to the preparation of 6, compound 16 was prepared. Compound 13 LC: 89.4% MS: m/z281.2 (M+l)' 'll-NMR (mixture of trans and cis) (CDC13): d 0.95 (m, 3H), 1.50-2.75 (m, 5H), 2.80-3.20 (m, IH), 3.50 (m, 211), 3.60 (minor) +3.7)0 (major) (two s, 2H), 6. 55-6. 80 (m, 2H), 7.05-7.45 (m, 8H). Compound 14 MS: m//357.2 (M+l). 'll-NMR (mixture of trans and cis) (CDC13): d 1.10 (m, 3H), 1.40-4.20 (m, 1 IH), 4.40 (m, IH), 7.05-7.50 (m, 1011). Compound 15 l.C: 90.0% MS: m//321.2 (M+l). !11-NMR (CDCh): d 1,20 (d, 3H), 1.75 (m, IH), 2.10 (dt, IH), 2.25 (b, IH), 2. 30 (dd, IH), 2.75 (dd, IH), 3.05 (m. III). 3.20 (m, 1 H), 3.50 (m, 4H), 4.10 (m, 1 H), 6.99 (m, 2H), 7. 23 (m, 3H), 7.37 (m, 4H). Compound 16 LC: 92.5% MS: m//231.2 (M+l). 'll-NMR (CDCI3): d d 1.20 (d, 3H), 1.75 (m, IH), 2.10 (dt, IH), 2.25 (b, IH), 2.30 (dd, IH), 2.75 (dd, IH), 3.05 (m, 111), 3.20 (m, 1 H), 3.50 (m, 2H), 4.10 (m, IH), 6.99 (m, 2H), 7.23 (m, 3H), 7.37 (m, 4H). EXAMPLE 7 (Figure Removed) Procedure: In a manner similar to fhe preparation of 11, compound 18 was prepared. Compound 17 MS:m//347.3(M+l) Compound 18 LC: 82.6% MS:Pm/z. 259.3 (M-HJ !I I-NMR (CDCIj): d Oi80 (t, 3H), 1.20 (d, 3H), 2.00 (m, 2H), 2.30 (m, 1H), 2.65 (m, 1H), 2.82 (m, 1H), 3.15- 3.25 (m. Ill), 3.32 (m,;lH), 3.45 (m, lH),3.65(m, 1H), 3.75 (m, lH),4.25(m, lH),6.90(d, lH),7.05(t, 1H), 7.25 (m, 211). EXAMPLE 8 ATTACHMENT OF TAIL GROUPS Tail groups were attached to the head groups according to the following procedures (Figure Removed) procedure fqr alkylation: To a solution of the alnine (I eq) and triethylamine (I eq) in dimethylformamide, was added I eq of alkyl bromide or chloride in one portion. The mixture was stirred and heated at 80°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 Et2O. The combined organic extracts were dried over potassium carbonate and the solvent evaporjited, 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 cyanohorohydride (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 I N NaOli to pH 10. The mixture was extracted 2x with Et2O. The combined organic extracts were dried over p4tajsJSum 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: 1-11- (naphth-l-yl-metfiyI)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one MS: m/z357.2 (M+l).; 1-11- (naphth-2-yl-met!hyl)-4-piperidinyI]-l, 3-dihydro-2H-indole-2-one MS: m/x 357.3 (MM). 1-11- (p-phenylbenzyl)f4-piperidinyl]-l, 3-dihydro-2H-indole-2-one MS: m/z383.2 (M+l). I - [ 1 - (3. 3-Bis (phenyl!) propyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one I .C: 98.7% MS: m//411.2 (M+l) 'll-NMR (CDC13) : d|l.65 (bd, 2H), 2.05 (bt, 2H), 2.30 (m, 4H), 2.45 (m, 2H), 3.02 (bd, 2H), 3.50 (s, 2H), 4.01 (t. 111), 4.30 (m, lJH),7.00(t, 1H), 7.15-7.35 (m, 13H). I -11 - (p-cyanoben/yl)-(4-piperidinyl]-1, 3-dihydro-2H-indole-2-one MS: m/z332.2 (M+l). 1 -| 1 -(p-benzyloxybenz!yl)-4-piperidinyl]-l ,3-dihydro-2H-indole-2-one MS: m/z 413.3 (M+l); l-|l-(1.2,3,4-tetrahydr LC: 100% MS: m/z. 347.5 (M+l). 'II NMR (CDCI3): d 1)70 (m, 3H), 2,10 (m, 1H), 2.40 (m, 4H), 2.90-3.00 (m, 5H), 3.10 (m, 2H), 3.60 (s, 2H), 4.3 (m. Ill), 7.00-7.30|(m, 8H). 1-11- (5-methylhex-2-yI)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one I.C: 100% MS: m//315.4 (M+l)., '11 NMR (CDC13): d O.J90 (m, 6H), 1.00 (m, 3H), 1.20 (m, 3H), 1.5-1.8 (m, 2H), 2.2-2.6 (m, 5H), 2.90 (m, 2H), 3.60 (s, 211), 4.2 (m, 1 lii). 6.90-7.30 (m, 4H). 1- 11- (norbornan-2-yl)j-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one I.C: 97% '. MS: m//.311.41 (M+l|. '11 NMR(CDCh): d Ol9() (m. 1H), 1.30-2.00 (m, 7H), 2.10-2.30 (m, 5H), 3.20 (m, 2H), 3.60 (s, 2H), 4. 3 (m, 111), 6,90-7.30 (m,4H). 1- [I- (1, 3-dihydroind0n-2-yl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one LC: 100% MS: m/z.332.4 (M + l), 'HNMR (CDCh): d l.BO (m, 2H), 2, 40 (m, 2H), 2.50 (m, 2H), 2.90 (m, 2H), 3.10-3,40 (m, 5H), 3.60 (s, 2H), 4.20 (m. Ill), 7.10-7.30 (m,8H). 1- 11- (cycooctylmethylj)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one LC: 97% ; MS:m//341.50 (M+lI). '11 NMR (CDCb): d 1,25 (m, 3H), 1-4-1.7 (m, 14H), 2.10 (m, 4H), 2.50 (m, 2H), 3.10 (m, 2H), 3.60 (s, 2H), 4.3 (m, IH), 7.10-7.20 jm,4H); "C-NMR (CDCI3): d S23.07, 26.04, 26.89, 27.56, 28.63, 31.27, 32.00, 35.30, 36.33, 46.63, 50.65, 54.06, 66.47. 110.90, 122.17,1124.90, 125.26, 127.94, 144.25, 175.31. - 1 -1 1 -( 1 , 2,3,4-ttrahydro-2-naphthyl)-4-piperidinyl]- 1 ,3-dihydro-2H-indole-2-one MS: m// 375.3 (M+l).- 3-cthyl- 1 -[ 1 -(4-propylqyclohexyl)-4-piperidinyl]-l ,3-dihydro-2H-indole-2-one MS: m// 369.2 (M+l). ' 3-ethyl-l- 1 1- (5-methyilhex-2-yl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one I.C: |'00% : MS : m// 342.4 (M+l).: '11 NMR (CDC13): d 080 (t, 3H), 0.90 (m, 6H), 1.00 (m, 3H), 1.20 (m, 3H), 1.5-1.8 (m, 2H), 2.2-2.6 (m, 5H), 2.90 (m. 2H), 3.40 (m, ;1 H), 4.3 (m, IH), 6.90-7.30 (m, 4H). 3-ethyl-l- 1 1- (norbornan-2-yI)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one LC: 100% MS: m/z 339.41 (M+l). 'HNMR (CDCb): d 0.^0 (m, 3H), 0.90 (m, IH), 1.30-1.45 (m, 5H), 1.50-2.05 (m, 8H), 2.10 (m, IH), 2.20 (m, 211), 2.50 (m, 2H). 3.1(1 (m, 2H), 3.40 (m, IH), 4.3 (m, IH), 6. 90-7.30 (m, 4H). 3-cthyl- 1 -| l-(decahydri)-2-naphthyl)-4-piperidinyl]-l,3-dihydro-2H-indole-2-one MS:m/z38l.3(M-H)J 3-cthyl- 1- 1 1- [4- ( l-mjethylethyl)-cyclohexyl]-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one MS: m/z 369.3 (M+l) 'll-NMR (CDC13) : d 0.88 (t, 3H), 0.92 (d, 6H), 1.17 (m, IH), 1.40 (m, 2H), 1.50-1.70 (m, 9H), 2.05 (m, 2H), 2.25 (m. 2H), 2.32-2.S& (m, 3H), 3.15 (b, 2H), 3.43 (t, IH), 4.35 (m, IH), 7.05 (t, IH), 7.22 (d, IH), 7.28 (m, 211). 3-ethyl-l- 11- (1, 3-dihydroinden-2-yI)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one MS: m/z 36 1.2 (M+l). 3-ethyl-l- 11- (cyclooctylmethyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one I.C : 97% MS: m//. 369.50 (M+l). 'II NMR (CDCb) : d (|.80 (t, 3H), 1.25 (m, 3H), 1-4-1.7 (m, 14H), 2.10 (m, 6H), 2.50 (m, 2H), 3.10 (m, 2H), 3.40 (m. 111), 4.3 (m, 1JH), 7. 10-7.20 (m,4H). 3-cthylidcne-l- 1 1- (befizyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one MS: m/z 333.2 (M t 1) 'll-NMR (CDCb) : d 1.70 (m. 2H), 2.15 (dt, 2H), 2.28 (d, 3H), 2.47 (m, 2H), 3.05 (b, 2H), 3.57 (s, 2H), 4.34 (m. 111). 7.02 (t, IH), 7.08-7.40 (m,8H), 7.58 (d, IH). 3-cthylidcne-l- 11- (naphth-2-yl-methyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one MS: m/z 405.2 3-cthylidcne-l- 1 1- (3, 3-diphenylpropyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one I.C: >97% (2 isomers aombined). MS: m/7 437.5 (M+l).: '11 NMR (CDC13): d 1|. 70-1.80 (m, 3H), 2,10 (m, 2H), 2,. 20-2.40 (m, 8H), 3.10 (m, 2H), 4.10 (M, IH), 4.3 (m. 111). 7.00-7.30 (m,15H). 3-ethylidcne-l- [ 1- (p-eyanobenzyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one LC: >97% (2 isomcrs combined). MS: m/z 358.5 (M+l). rt>: m, ' .-* 'HNMR (CDCb): d l.gO (m, 4H), 2.10-2.60 (m, 5H), 3.10 (m, 2H), 3.70 (s, 2H), 4.3 (m, IH), 6.90-7.60 (m, 811). 3-ethylidene-l- [I- (p-btenzyloxybenzyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one . MS:m/z. 405.2. 3-ethylidcne-l- [1- (1, 2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-l,3-dihydro-2H-indole-2-one IX': >97% (2 isomers combined). MS: m/z 373.5 (M+l). 'H NMR(CDCl3):d 1.70-3.10 (m, 18H),4.3(m, IH), 7.00-7.30 (m, 9H). 3-ethylidcne-l- [1- (4-propylcyclohexyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one I,C: >97% (2 isomers Combined). MS: m/z367.5 (M+l). 'II NMR (CDCb): d Oj90 (m, IH), 1.30-2.00 (m, 7H), 2.10-2.30 (m, 5H), 3.20 (m, 2H), 3.60 (s, 2H), 4. 3 (m, III). 6.90-7.30 (m, 5HJ. 3-cthylidene-l-11- (5-ijnethylhex-2-yl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one IX": >97% (2 isomers dombined). MS: m/z341.4 (M+l). '11 NMR (CDC13): d 0.90-2.6 (m, 24H), 2.90 (m, 2H), 4.2 (m, IH), 6. 90-7.30 (m, 5H). 3-ethylidcne-l- [1- (no|rboman-2-yl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one LC: >97% (2 isomers Combined). MS: m//337.41 (M+l). 'II NMR (CDCb) :d 0.90 (m, IH), 1.30-2.50 (m, 17H), 3.10 (m, 2H), 4.3 (m, IH), 6.90-7.30 (m, 5H). 3-ethylidcne-l-11- (1, 3-dihydroinden-2-yl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one LC: >97% (2 isomers combined). MS: m/z359.4 (MU), 'II NMR (CDCb): d U80-3.10(m, 17H),4.20(m, IH), 7.10-7.30 (m, 9H). 3-ethylidene-l-| l-(cyc|ooctylmethyl)-4-piperidinyl]-l,3-dihydro-2H-indole-2-one LC: >97% (2 isomers (Combined). MS: m/z. 367.50 (M-H). '11 NMR (CDCb): d 1125 (m, 3H), 1.4-1.7 (m, 21H), 2.10-2.50 (m, 2H), 3.10 (m, 2H), 4.3 (m, IH), 6.90-7.60 (m. 511), 1-| l-(3. 3-Bis (phenyl)jpropyl)-3- (methyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one l.C: 100% MS: m//425.3 (M+l) 'll-NMR (CDC13): d L20 (d, 3H), 1.69 (bd, 1H), 1. 95 (dt, 1H), 2.13-2.30 (m, 5H), 2.72 (bd, 1H), 2.98 (bd, lll),3.15(dq. lH),3.5JO(s,2H),4.03(dt, lH),4.12(t, lH),6.94(d, lH),7.00(t, 1H), 7.10-7.30 (m, 12H). I -1(benz.yl)-3-(methil)-4-piperidiny 1]-1,3-dihydro-2H-indole-2-one LC: 100% MS: m/z. 321.2 (M+l)' 'll-NMR (CDC13): d U20 (d, 3H), 1.70 (m, 1H), 2.10 (dt, 1H), 2.23 (m, 1H), 2.35 (dd, 1H), 2.78 (d, 1H), 3.05 (m, 111), 3.20 (dq, 1 H)| 3.51 (m, 4H), 4.10 (dt, 1H), 7.00 (m, 2H), 7.25 (m, 3H), 7.38 (m, 4H). I -| 1 -(4-propyl-cyclohe|xyl)-3-(methyl)-4-piperidinyl]-l,3-dihydro-2H-indole-2-one !.C:%.2% MS: m/z.355.2 (M+l) !ll-NMR (CDCb): d Oj.85 (m, 3H), 1.15 (m, 3H), 1.22-1.85 (m, 13H), 2.05-2.90 (m, 6H), 2.95- 3.20 (m, 2H), 3.50 (s, 211), 4.05 (m, JH), 7.00 (m, 2H), 7.22 (m, 2H). l-|l-(5-methylhex-2-y|)-3-(methyI)-4-piperidinyl]-l,3-dihydro-2H-indole-2-one LC: 100% MS: mlz 329.2 (M+l) 'll-NMR (CDC13): dO.$5 (m, 9H), 1.15 (m, 3H), 1.20-1.75 (m, 6H), 2.25 (m, 1H), 2.45-2.75 (m, 4H), 2.88 (m, IH). 3.10 (m, 1H), 3.50 (s, 2H), 4.05 (m, 1H), 6.98 (m, 2H), 7.25 (m, 2H). 1-11- (decahydro-2-naphthyl)-3- (methyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one l.C: 95.3% : MS: m//367.2 (M+l): 'll-NMR (CDCI3): d 1L11 (d, 3H), 1. 16-1.85 (m, 16H), 2.20 (m, 1H), 2.35 (m, 2H), 2.52 (m, 2H), 2.75 (m, 111). 3.02 (m, 2H), 3.50 (s, 2H), 4.05 (m, 1 H), 6.96 (m, 2H), 7.20 (m, 2H). 1-11- (4- ( l-methyletliyl)-cyclohexyl)-3- (methyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one I,C: 96.1% MS: m//355.2 (M+l) 'll-NMR (CDC13): d 01.80 (m, 6H), 1.15 (m, 3H), 1.22-1.48 (m, 3H), 1.50-1.90 (m, 6H), 2.15- 2.90 (m, 4H), 2.95-3.25 (m, 2H), 3.50 (s, 2H), 4.10 (m, 1H), 6.95 (m, 2H), 7.22 (m, 2H). 1-| l-(cyclooctylmethyl|)-3-(methyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one LC : 100% ' MS: m/z355.2 (M+l) 'll-NMR (CDCI3): d L12 (d, 3H), 1.15-1.75 (m, 16H), 1. 92-2.10 (m, 3H), 2.20 (m, 2H), 2.73 (m, 1H), 3.00 (m, 111). 3.12 (dq, 1 H)\ 3.50 (s, 2H), 4.05 (dt, 1H), 6.99 (m, 2H), 7.20 (m, 2H). 3-ethyl-l-11- (3, 3-Bis(phenyl) propyl)-3-(methyl)-4-piperidinyl]-l,3-dihydro-2H-indole-2-one LC: 96.3% ; MS: m/z453.3 (Mi 1) 'll-NMR (CDC 13) : d {two t, 3H), 1.18 (d, 3H), 1.70 (m, 1H), 1.90-2.05 (m, 3H), 2.12-2.30 (m, 5H), 7.73 (m, 111). 2.97 (bd, 1H), 3.10-3.30 (m, 1H), 3.38 (t, 1H), 3.90-4.05 (m, 1H), 4.. 12 (q, 1H), 6.90-7.00 (two d, 1H), 7.02(1, IH),7.12-7.32(jm, 12H). 3-ethyl-l-11- (4-propylpyclohexyl)-3- (methyl)-4-piperidinyl]-l, 3-dihydro-2H-indole-2-one LC: 93.2% MS: in/z383.3 (M+l) 'll-NMR (CDC 13) : d p.75-0.95 (m, 6H), 1.05-1.20 (m, 5H), 1.20-1.35 (m, 4H), 1.35-1.75 (m, 6H), 1.75-1.90 (m, 211), 1.95-2.05 (m,J2H), 2.15-2.45 (m, 3H), 2.55 (d, 0.5H), 2.75 (d, 0.5H), 2.95-3.15 (m, 2H), 3.38 (t, 1H), 3.90-4.10 (m, 111), 6.9^-7.05 (2H), 7.20-7.25 (m, 2H). 3-ethyl-l-11- (5-methylIhex-2-yl)-3- (methyl)-4-piperidinyl]-l,3-dihydro-2H-indole-2-one; LC: 92.3% MS: m//357.4 (Mi 1) 'll-NMR (CDC 13): d 0.75-0.95 (m, 10H), 1.10 (d, 3H), 1.15-1.40 (m, 3H), 1.40-1.75 (m, 4H), 1.97-2.10 (m, 211). 2.20 (m, 111). 2.4D-2.75 (m, 4H), 2.80-2.95 (m, 1H), 3.00-3.25 (m, 1H), 3.40 (t, 1H), 3.90-4.10 (m, 1H), 6.aff ;,05 (m, 211), 7.2$ (m, 211). 3-ethyl-l- 1- [4- (1-metjhylethyl) cyclohexyl]-3-methyl-4-piperidinyl]-l, 3-dihydro-2H-indoIe-2-one I.C: 94.7% MS: m//383.4(M+l): 'll-NMR (CDC !3): d 0.75-1.05 (m, 8H), 1.10-1.50 (m, 7H), 1.50-1.90 (m, 7H), 1.90-2.10 (m, 2H), 2.15-2.43 (m, 311), 2.55 (d, 0. 5H). 2.75 (d, 0. 5H), 2.90-3.25 (m, 3H), 3.40 (t, 1H), 3.90-4.10 (m, 1H), 6.90-7.01 (m, 211), 7.25 (m, 211). 3-ethyl-l-11- (decahydro-2-naphthyl)-3- (methyl)-4-piperidinyI]-l, 3-dihydro-2H-indole-2-one I.C: 94.3% MS: m//395.3 (M-H): 'll-NMR (CDC 1,) : d 1.75-1.90 (two t, 3H), 1.10 (d, 3H), 1.15-1.90 (m, 15H), 2.00 (m, 2H), 2.20 (bs, 1H), 2.40 (m, 2H), 2.45-2.^0 (m, 2H), 2.75 (m, 1H), 2. 90-3.20 (m, 2H), 3.40 (bs, 1H), 3.90- 4.15 (m, 1H), 6.90- 7.05 (m, 211), 7.25 (m,J2H). Other compounds wittjiin the scope of formula (II) or (IIA) of the present invention can be synthesized by analogous techniques. EXAMPLE 9 Nociceptin affinity at the ORL1 receptor for preferred compounds was obtained using the following assay: Membranes from recojmbinant HEK-293 cells expressing the human opioid receptor-like receptor (ORJL-1) (Receptor Biology) wjere prepared by lysing cells in ice-cold hypotonic buffer (2.5 mM MgCl2, 50 mM HKPES. pll 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°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 ORJL-1 receptor membranes were stored at-80°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 |35S] GTPgS to binding buffer (100 mM NaCI, 10 mM MgCl2, 20 mM HEPES, pH 7. 4) on ice. The prepared membrane solution (190 ml/well) was transferred to 96-shallow well polypropylene plates containing 10 ml of 20ix concentrated stock solutions of agonist prepared in DMSO. Plates were incubated for 30 min at room tempettature 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 NaH2PO4, 10 mM Na2HPO4, pH 7.4). Filter plates were subsequently dried at 50°C for 2-3 hours. Fifty ml/well scintillation cocktail (BetaScint; Wallac) was added and plates were counteid in aPackard Top-Count for 1 min/well. Data was analy/ed usihg the curve fitting functions in GraphPad PRISMO, v. 3.0 and the results are set forth in table 2 below: (Table Removed) EXAMPLE 10 SYNTHESIS OF CERTAIN HEAD GROUPS. SCHEME 1: (FigureRemoved) Procedure: To a mixture of 4 (21.6 g, 0.2 mole), 5 (15.6 g, 0.1 mole), acetic acid (6 g, O.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 rriin and 1 hr. The mixture was stirred over night. TLC indicated the reaction is complete. I N NaOH (500 ml) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted by EtOAC (300 ml x2). The 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 give 14 g of product 6 as a white solid (54%). Compound 6 MS: m/Z249.3 (M+l). 1U NMR(CDCI3): d 1 (50-1.90 (m, 6H), 2.05 (m, 2H), 3.30 (m, 4H), 3.95 (s, 4H), 6.60-6.80 (m, 4H). To a solution of 13.5 g of 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 H2O and TBME 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/Z274.7 (M+l). 'll NMR(CDC13): d 1 .50-1.90 (m, 7H), 2.50 (m, 2H), 4.00 (m, 4H), 4.50 (m, 1H), 7.10 (m, 3H), 7.25 (m, 1H) A mixture of 7 (7.5 g, 27.4 mmole) and 8.26 g of PPTS in 50 ml of acetone and H2O (10: 1) was stirred i refluxed over night. The mixture was cooled to room temperature and acetone was evaporated. Addition Compound 8 MS: m/z231 (M+l). 'H NMR(CDC13) : d 2,20 (m, 2H), 2.60 (m, 2H), 4.50 (m, 1H), 7.10 (m, 4H), 9.5 (br, 1H). To a mixture of 8 (7.75 g, 33.65 mmole), benzylamine (3.61 g, 33.65 mmole), acetic acid (2.0 g, 33.65 mmoli in 150 ml of dichlorofthane, 10.3 g of sodium triacetoxyborohydride (47.1 mmol, 1.4 eq) was added in or portion. Gas evolves between 30 min and 1 hr. The mixture was stirred over night. TLC indicated the reactic was complete. 1 N NaOH (500 ml) was added to quench the reaction. The organic layer was separated and tl aqueous layer was extracted with EtOAc (300 ml x2). The combined organics were dried over potassiui carbonate and the solvient was evaporated to give a brown solid, which was column filtrated (5% Et3N, 25' E-tOAc and 70% Hexa|ne to 10% Et3N, 40% EtOAc and 50% Hexane) to give 4.7 g of product 10 as a whi solid (53.4%) and 3.01! g of product 9 as a white solid (34.2%). Compound 9 MS: m/Z. 322 (M+l). !11 NMR(CDCb): d 1.40 (m, 2H), 1.80-2.35 (m, 6H), 2. 70 (m, 1H), 3.86 (s, 2H), 4.30 (m, 1H), 7.10-7.50 (r 911), 9.6 (br, 1H). Compound 10 MS :m/Z. 322 (M+l). 'H NMR(CDCl3):d 1.60 (m,4H), 1.90 (m, 2H), 2.60 (m, 2H), 3,10 (m, 1H), 3.84 (s, 2H), 4.50 (m, 1H), 7.1' 7.50 (m, 9H), 9.6 (br, Hi). 2 g of Pd (OH) 2 was added into a solution of 30 ml of methanol containing 4.7 g of compound 10. Tl resulting suspension was hydrogenated at 50 psi for 12 hrs at room temperature. TLC indicated the reactic was complete over night. The solution was filtered through a pad of celite to remove the catalyst. The celi was washed with methanol twice (20 ml). The organics were combined and solvent was removed to give pale solid which was purified by chromatography (10% MeOH, 90% EtOAc) to give an off white product (1.79g, 50.7%). Compound 11 MS :m/z 232 (M+l), 'l INMR(CDCI3): d 1 . 50-1 . 85 (m, 8H), 2.60 (m, 2H), 4.30 (m, 1H), 7.10 (m, 3H), 7.30 (m, 1H). To a mixture of 1 1 (1.7 g, 7.4 mmole), acetaldehyde (0.33 g, 7.4 mmole) in 50 ml of dichloroethane, 2.2 g sodium triacetoxyborohydride (10. 36 mmol, 1.4 eq) was added in one portion. Gas evolves between 30 m and 1 hr. The mixture was stirred over night. TLC indicated the reaction was complete. 1 N NaOH (500 rr was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted wi EtOAc (300 ml x2). The combined organics were dried over potassium carbonate and the solvent w evaporated to give a brown oil which was chromatographed (10% Et3N, 40% EtOAc and 50% Hexane) give 1 .5 g of product 2 as a sticky oil which recrystalized from TBME to give a white solid (78%). Compound 2 MS: m//. 259. 7 (M+l). '11 NMR(CDCb): d 1.15 (t, 3H), 1.50-1.95 (m, 6H), 2.40-2.75 (m, 4H), 2.95 (m, 1H), 4.35 (m ; 1H), 7.10 (m, 311), 7.35 (m, 111).. 1.5 g of Pd (OH)2 a was added into a solution of 30 ml of methanol 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 of celite 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 (10% MeOH, 90% EtOAc) to give an off white product 1 (1.68 g. 77.4%). Compound 1 MS:m/z232(M+l). '11NMR (CDCI3): d 1.50 (m, 2H), 1.90-2.35 (m, 6H), 3.00 (m, 1H), 4.30 (m, 1H), 7.10-7.30 (m, 4H). SCHEME 2: (Figure Removed) Procedure : Aboui 2.5 g of NaH vyas washed by THF 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 stirrejd over night. LC/MS indicated that the starting material was completely consumed. The reaction was cooled |own and H20 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 (84. 7%). Compound 12 MS: m/z303.3 (M+l), 'II NMR(CDC13): d 1,30 (t, 3H), 1.70-1.90 (m, 6H), 2.50 (m, 2H), 3.85-4.00 (m, 6H), 4.50 (m, 1H), 7.05 (m, 311). 7.25 (m, IN). A mixture of 12 (9.7 g, 32.2 mmole) and 9.72 g of PPTS in 50 ml of acetone and H2O (10: 1) was refluxed over night. The mixture was cooled to room temperature and acetone was evaporated. Addition of water to the mixture initiated crystttli/ation to give 6.85 g of product 13 (82.3%). Compound 13 MS:m/7. 259 (M+l). 'II NMR(CDCI3): d 1. 35 (t, 3H), 2.20 (m, 2H), 2.60 (m, 6H), 3.95 (q, 2H), 4.85 (m, 1H), 7.10 (m, 4H). To a mixture of 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 dichlorotthane, 7.86 g of sodium triacetoxyborohydride (37.1 mmol, 1.4 eq) was added in one portion Gas evolves between 30 min and 1 hr. The mixture was stirred over night. TLC tndicated the reaction was complete 1 N NaOH (500 ml) was added to quench the reaction. The organic layer was separated and the afeueous layer was extracted with EtOAc (300 ml x2). The combined organics were dried over potass.um carbonate and the solvent was evaporated to give a brown solid, which was column filtrated. (5/o Et3N ; 25/o HtOAc and 70% Hexane to 10% Et3N, 40% 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+l). '11 NMR(CDCb): d 1. 35 (t, 3H), 1.50 (m, 2H), 1.65 (m, 4H), 1.95, (m, 2H), 2.60 (m, 2H), 3,02 (m, 1H), 3.83 (s, 211). 3.95 (ddd, 2HJ, 4.45 (m, 1H), 7.00-7.50 (m, 9H). Compound 15 MS:m/z/350(M+l). 'H NMR(CDCh): d 1.35 (m, 5H), 1.90 (m, 2H), 2.10-2.35 (m, 4H), 2.70 (m, 1H), 3.83 (s, 2H), 3.95 (ddd, 2H), 4.40 (m. 1H), 7.00-7.50 (m,9H). 0 3 B of Pd (OH)2 was added into a solution of 20 ml of methanol containing 0.5 g of compound 14. The resulting suspension wias hydrogenated at 50 psi for 12 hr 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 cel.te 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 (10% MeOH, 90% EtOAc) to g.ve an off white product 3 (300 mg, 50%). Compound 3 MS:m//232(M+l). '11 NMR(CDCb): d 1135 (t, 3H), 1.50-1.85 (m, 8H) ; 2.60 (m, 2H), 3.20 (m, 1H), 3.95 (ddd, 2H), 4.30 (m, ill). 7.10. (m,3H). 7.30 (m, 1H). EXAMPLE 11 ATTACHMENT OF TAIL GROUPS Tail groups were attached to the head groups according to the following procedures: (Figure Removed) General procedure for aikylation: To a solution of the amine (1 eq) and triethylamine (1 eq) in dimethylformamide, was added I eq of alkyl bromide or chloride in one portion. The mixture was stirred and heated at 80°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. Thc mexture was extracted 2x with Et2O. 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 animation: To a mixture of keton4 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 Et2O. 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- |4-(ben/ylamino)-cyclohexyI]-3-ethyl-l, 3-dihydro-2H-benzimidazol-2-one 1 - |4-(ben/ylamino)-cyclohexyl]-3-ethyl-l, 3-dihydro-2H-benzimidazol-2-one I- |4-|(naphth-2-yl-mefhyI)ethylamino]-cyclohexyl]-l, 3-dihydro-2H-benzimidazol-2-one MS: m/z400.2 (M+l)' 1- |4-(norbornan-2-ylaimino)-cyclohexyl]-l, 3-dihydro-2H-benzimidazol-2-one MS: m/z/326.3 (M+l)| 1 -|4-| |4-( 1 -methylethyl)-cyclohexyl]amino]-cyclohexyl]-l, 3-dihydro-2H-benzimidazol-2-one MS : m//356.4 (M+l) 1 -14-|(decahydro-2-na;phthyl)amino]-cyclohexyl]-1, 3-diliydro-2H-benzimidazol-2-one MS :m//368.2 (M+l) 1- |4-(cthylamino)-cycilohexylj-l, 3-dihydro-2H-benzimidazol-2-one I - |4-(ben/ylamino)-cyclohexyl]-l, 3-diliydro-2H-benzimidazol-2-one I - |4-(ben/,ylamino)-cj/clohexyrj-l, 3-dihydro-2H-benzimidazol-2-one l-[4-|(indan-2-yl)benyjylamino|-cyclohexyl]-3-ethyl-l,3-dihydro-2H-benzimidazol-2-one MS: m/y 466.3 (M+l)' 'H-NMR(CDCb): dl.30 (t, 3H), 1. 50-1.75 (m, 2H), 1.90 (b, 2H), 2.02 (b, 2H), 2.20 (m, 2H), 2. 80 (m, 1H), 2.99 (m, 4H), 3.75 (s, 2H), 3.90 (m, 3H), 4.25 (m, 1H), 6.95-7.45 (m, 13H). l-|4-|(cyclooctylmethyl)amino]-cyclohexyl]-3-ethyl-l,3-dihydro-2H-benzimidazol-2-one 1,C: 99% MS: m/z/384.5 'HNMR(CDCI3): d 1.40-1.90 (m, 24H), 2. 30 (m,2H), 2.50 (m, 2H), 2.90 (m, 1H), 3.90 (ddd, 2H), 4.20 (m, III), 7. 10(m. 3H), 7.30 (m, 1 H). 1-14- |(naphth-2-yl) amino]-cyclohexyl]-3-ethyl-l, 3-dihydro-2H-benzimidazol-2-one l.C: 97% MS: m/y. 399 'II NMR(CDCb):. dl,50 (t, 3H), 1.80 (m, 5H), 2.0 (m, 2H), 2.70 (m, 2H), 3.10 (m, 1H), 3.90 (m, 2H), 4.0 (m, 211). 4. 40 (m, 1H), 7.10 (m, 3H), 7.50 (m, 4H), 7.90 (m, 4H). I-14-1 (p-benzyloxybjpn/yl)aminol-cyclohexyl]-3-ethyl-l, 3-dihydro-2H-benzimidazol-2-one LC: 97% MS:m/z/455 'I! NMR(CDCh): d 1.40 (t, 3H), 1.70 (m, 2H), 1.90 (m, 3H), 2.60 (m, 4H), 3.10 (m, IH), 3.80 (s, 2H), 4.0 (m, 211), 4.50 (m, IH), 5.10 (s, 2H), 7.10 (m, 6H), 7.50 (m, 6H), 7.90 (m, IH). I-t^-||tyelooctylrnethyl) amino]-cyclohexyl]-3-ethyl-l, 3-dihydro-2H-benzimidazol-2-one 1 .C : 99% MS: m/z/ 369 'HNMR (CDC13): dl|40 (t, 3H), 1.70 (m, 5H), 1.90 (m, 12H), 2.10 (m, 3H), 2.40 (m, 2H), 2.50 (d, 2H), 3.30 (m. 111), 3.90 (m,2H), 4.20 (m, lH),7.10(m, IH), 7.30 (m, 3H). !-14-1 (decallydro-2-r>aphthyl)amino]-cyclohexyl]-3-ethyl-l, 3-dihydro-2H-benzimidazol-2-one LC: 99% MS:m//395 '11-NMR(CDC13): dl. 40 (t, 3H), 1.70 (m, 3H), 1.80 (m, 3H), 1.90 (m, 12H), 2.20 (m, 2H), 2.30 (m, 3H), 2.50 (q, 211), 3.10 (m, IH), 3.90 (m, 2H), 4.20 (m, IH), 4.30 (m, IH), 7.0 (m, IH), 7.30 (m, 3H). 1-|4-1 (p-phenylbenzyl)amino]-cyclohexyl]-5-carbamoyl-l, 3-dihydro-2H-benzimidazol-2-one LC: 100% MS: m/z/440. 8 (M+1) 'H-NMR(MeOH-d4): cl 1.75 (m, 2H), 2.00 (m, 2H), 2.40-2.55 (m, 4H), 3.35-3.52 (m, 2H), 4.35 (s, 2H), 7.40 (m. 211), 7.59 (t, 2H), t. 60-7.72 (m, 6H), 7.78 (d, 2H). 1 -|4-|(1, 2,3,4-tetrahy I .C: 93.9% MS: m/z/. 405.7 (M+1) 'll-NMR(MeOH-d4): dl.70 (m, 2H), 1.85 (m, IH), 2.02 (m, 2H), 2.39 (b, 3H), 2.50 (m, 2H), 2.90 (m, IH), 3.00 (b, 2H), 3.35 (m,;lH), 3.60 (m, IH), 3.72 (b, IH), 4.35 (m, IH), 7.15 (b, 4H), 7.40 (d, IH), 7.60 (s, IH), 7.65 (d. IH). l-|4-|(4-propyl-cycloHexyl)amino]-cyclohexyl]-5-carbamoyl-l, 3-dihydro-2H-benzimidazol-2- one LC: 100% MS: m/x 399.6 (M+1)' 'H-NMR(MeOH-d4) : dO.95 (t, 3H), 1.10 (m, IH), 1.20-1.60 (m, 6H), 1.70 (b, 5H), 1.80-2.00 (m, 4H), 2.10 (m, HI). 2.30 (b, 2H), 2.45 (m, 2H), 3.25 (m, IH), 3. 50 (m, IH), 4.40 (m, IH), 7.40 (d, IH), 7. 60 (s, IH), 7.65 (d. 111). l-|4-|(5~methylhex-2-yl)amino]-cyclohexyl]-5-carbamoyl-l, 3-dihydro-2H-benzimidazol-2-one LC: 100% MS: m//373.5 (M+1); 'll-NMR(MeOH-d4): dO.95 (d, 6H), 1.25-1.40 (m, 5H), 1.50-1.75 (m, 4H), 1.85 (m, IH), 1.95 (b, 2H), 2.30 (m. 211), 2. 40-2.55 (m, 2H), 3.35-3.55 (m, 2H), 4.38 (m, IH), 7.40 (d, IH), 7.60 (s, IH), 7.70 (d, IH). l-|4-|(dccahydro-2-nabhthyl)amino]-cyclohexyl]-5-carbamoyl-l, 3-dihydro-2H-benzimidazol-2-one LC: 100% MS: m/z/ 411. 7 (M+1) 'H-NMR(MeOH-d4): |0. 90-2.10 (m, 18H), 2.10-2.50 (m, SH), 2.82 (m, IH), 3.50 (m, 2H), 4.35 (m, IH), 7.42 (d, IH), 7.60 (s, IH), 170 (d, IH). 1-14- (cyclooctylamint>)-cyclohexyl]-5-carbamoyl-l, 3-dihydro-2H-benzimidazol-2-one ; l.C:95.4% MS: m//385.7 (M+1) 'H-NMR(MeOH-d4): d 1.50-2.10 (m, 13H), 2.30 (m, 2H), 2.40-2.52 (m, 3H), 2.80-2.95 (m, 3H), 3.45 (m, 2H), 3.70 (m. III), 4.38 (m, IH), 7.40 (d, IH), 7.63 (s, IH), 7.70 (d, IH). I-|4-|(indan-2-yl)amirto|-cyclohexyl]-5-carbamoyl-l,3-dihydro-2H-benzimidazol2-one LC: 100% MS:m//391.6(M+l): 'M-NMR(MeOH-d4): dl.70 (m, 2H), 2.00 (m, 2H), 2.40-2.60 (m, 4H), 3.10-3.20 (m, 2H), 3.50 (m, 3H), 4.30- 4.45 (m, 2H), 7.25 (m, 2H), 7.35 (m, 2H), 7.42 (d, 1H), 7.60 (s, 1H), 7.72 (d, 1H). LC: 100% MS : m/z/399.5 (Mi-1) 'H-NMR(MeOH-d4):(p 1.40-1.85 (m, 15H), 2.00 (m, 4H), 2.25-2.50 (m, 4H), 2.93 (d, 2H), 3.30 (m, 1H),4.30 (m. III), 7.36 (d, IH), 17.60 (s, lH),7.65(d, 1H). l-|4-|(4-phenyl-cyclor|exyl) amino]-cyclohexyl]-5-carbamoyl-l, 3-dihydro-2H-benzimidazol-2- one I.C: 100% MS: m/z/433.7 (M+l)i 'H-NMR(MeOH-d4): |1.65 (m, 2H), 1.85-2.20 (m, 8H), 2.25-2.50 (m, 5H), 3.90 (m, 1H), 3.50 (m, 2H), 3.58 (m. Ill), 4.30 (m, 1 H),t7.15-7.40 (m, 6H), 7.60 (s, 1H), 7.65 (d, 1H). l-[4-(diben/ylamino)-tyclohexyl]-5-carbamoyl-l, 3-dihydro-2H-benzimidazol-2-one LC: 100% MS: m/z/455.6 (M+l). 'H-NMR(MeOH-d4): d 2.00-2.25 (m, 4H), 2.40 (m, 4H), 3.52 (m, 2H), 4.25-4.65 (m, 4H), 7.30 (d, 1H), 7.45- 7.58 (m. 1011), 7.60 (s, 1H), 7.65 (d, 1H). l-|4-|(5-methylhex~2-iT) amino|-cycIohexyl]-7-carbamoyl-l, 3-dihydro-2H-benzimidazol-2-one IX.": 99.1% MS: in/z/ 373.3 (M+l) 'll-NMR(MeOH-d4) : dO.95 (d, 6H), 1.30 (d, 3H), 1.45-1.68 (m, 5H), 1.75 (m, 1H), 2.00 (m, 2H), 2.18-2.32 (m, 311), 2.60 (m, 2H), 3.20-3.40 (m, 2H), 4.30 (m, 1H), 7.05-7.20 (m, 3H). Other compounds within the scope of formula (III) or (IIIA) of the present invention can be synthesized by analogous techniques. EXAMPLE 12 Nociceptin affinity at ttie ORL1 receptor forpreferred compounds was obtained using the following assay: Membranes from reccfmbinant HEK-293 cells expressing the human opioid receptor-like receptor (ORL-1) (Receptor Biology) vfere prepared by lysing cells in ice-cold hypotonic buffer (2.5 mM MgCl2, 50mM 1IKPHS, pH7.4) (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°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-80°C. Functional SGTPgS binding assays were conducted as follows. ORL-1 membrane solution was prepared by sequentially adding fiijal concentrations of 0. 066 mg/ml ORL-1 membrane protein, 10 mg/ml saponin, 3 mM GDP and 0.20 nM [35 Data was analyzed using the curve fitting functions in GraphPad PRISMO, v. 3.0 and the results are set forth in table- 3 below: (Table Removed) (Table Removed) EXAMPLE 13 SYNTHESIS OF SUBSTITUTED BENZIMIDAZOLE HEAD GROUPS. (TFigure Removed) Procedure: Sodium hydride 60% dispersion in mineral oil (0.67 g, 16.7 mmol) was washed with dry pentane and then suspended in 80 mL of dry THF under N2. Compound 1 (European patent 0029707) (3.80 g, 11.1 mmol) was added, the mixture stiijred at room temperature for 15 min and then warmed to 50°C. Ethyl bromide (1.06 mL, 13.3 mmol) was added and the resulting mixture stirred at 50°C for 18 hr. TLC (SiO2, CH2C12: MeOH 96: 4) showed that the reaction was ca 40% complete. Additional sodium 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 acetate (Ix). The combined organic extracts were washed with aqueous sodium bicarbonate solution (Ix), dried over MgSO4 and the; solvent was evaporated to give the crude product as a yellow solid. Trituration with dicthyl ether gave purf 2 as a white solid (3.38 g, 82%). '||-NMR(CDC13): d 1.45-1.55 (m, 12H), 1.82 (bs, 2H), 2.30 (m, 2H), 2.87 (m, 2H), 4.30 (bs, 2H), 4.41 (q, 211). 4.82 (m, 111), 7.10-7.30 (m, 4H). 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 methanolic ammonia 10:1 and again evaporated to dryness» The residue was suspended in 100 mL a 1: 1 mixture of MeOH and CH2C12, filtered and the filtrate evaporated to dryness to leave an off-white solid. Flash chromatography on silica gel, eluting with CH2CI2:MeOH:NH3 (300:10: 1) gave pure 3 as a white crystalline solid (1.98 g, 76%). 'M-NMR(CDC13): d 1145 (t, 3H), 1.82 (bs, 2H), 2.33 (m, 2H), 2.80 (m, 2H), 4.40 (q, 2H), 4.80 (m, 1H), 7.10-7.30 (m, 311), 7.45 (d, 1H). EXAMPLE 14 ATTACHMENT OF TAIL GROUPS Tail groups were attached to the head groups according to the following procedures: (Figure Removed) *\/\/^^4^W^ General procedure for alkylation: To a solution of the a]mine (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°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 Et2O. 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 ketomf 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. ILL 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 Et2O. 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-l- [1- (P-phenylbenzyl)-4-piperidinyl]-l, 3-dihydro-2H-benzimidazole 'll-NMR(CDC13): dl.fSO (t, 3H). 1.88 (m, 2H), 2.28 (m, 2H), 2.62 (m, 2H), 3.12 (m, ZH), 3.65 (s, 2H), 4.48 (q, 211). 4.80 (m, 1H), 7.15-7.70 (m, 13H). 2-cyanoimino-3-ethyl-|l- 1 1- (p-benzyloxybenzyD-4-piperidinyl] 1, 3-dihydro-2H- benzimidazole l.C: 96.5% dKSS (t, 3H), 1-82 (m, 2H), 2.25 (m, 2H), 2.50 (m, 2H), 3.10 (m, 2H), 3. 55 (s, 2H), 4.48 (q, 2H). 4.78 (m, 1 H), 5.20 (s, 2H), 7.00 (d, 2H), 7.15-7.65 (m, 1 1H). 2-cyanoimino-3-ethyI-l- [1- (naphth-2-yl-methylH-piperidinyl] 1, 3-dihydro-2H-benzimidazole l.C: 9.19% : dl.|5 (t, 3H), 1.80 (m, 2H), 2.30 (t, 2H), 2.52 (m, 2H), 3.18 (bd, 2H), 3.78 (s, 2H), 4.50 (q, 211), 4.80 (m, 1 H), 7.2D-7.90 (m, 1 1 H). 2-cyanoimino-3-ethyl- [ 1- (4-propylcyclohexyl)-4-piperidinyl]-l, 3-dihydro-2H- benzimidazole MS: m/z/ 394.4 (M+l); 'lI-NMR(CDCI3):d0.90-2.28(m, 21H), 3.10 (m, 4H), 3.62 (m, 2H), 4.42 (q. 2H), 5. 15 (m, lH),7.20(d, 1H), 7.30 (m, 1H). 7.50 (t, 1H), 7.80 (b, 1H). 2-cyanoimino-3-ethyl*l-11- [4- (2-propyl)-cyclohexyl]-4-piperidinyl]-l, 3-dihydro-2H- benzimidazole l.C: 100% MS:r0U 394.5 (M+l); 'II-NMR(CDCI3): d 0^90 (d, 3H), 0.98 (d, 3H), 1.15-2.35 (m, 14H), 3.10 (m, 5H), 3.70 (m, 2H), 3.92 (bs, 1H), 4.40 (q. 2H), 5.20 (m, 1H), 7.20 (d, 1H), 7.38 (d, 1H), 7.52 (t, 1H), 7.80 (m, 1H). 2-cyanoimino-3-ethyl-1-l- [1- (decahydro-2-naphthyl)-4-piperidinyl]-l, 3-dihydro-2H- benzimidazole l.C: 93.9% MS: m/z/406.6 (M+l) 'H-NMR(CDC13): d 1.25-2.35 (m, 24H), 1.15 (m, 4H), 3.60 (m, 2H), 4.40 (m, 2H), 4.20 (m, 1H), 7.20-7.80 (m, 411). 2-cyanoimino-3-ethyl-il- [1- (cyclooctyl)-4-piperidinyl]-l, 3-diliydro-2H-benzimidazole IX': 100% MS: m//380.3 (M+l) 'll-NMR(CDCI3): d 1,50-1.80 (m, 13H), 1.90 (m, 2H), 2.10 (m, 4H), 3.05 (m, 3H), 3.30 (m, 1H), 3.45 (m, 211). 3. 90 (m, 1 H), 4.42 (q,2H), 5.15 (m, lH),7.20(d, lH),7.35(d, lH),7.50(m, lH),7.78(m, 1H). 2-cyanoimino-3-ethyI-*l- |1- (10, 1 l-dihydro-5H-dibenzb [a,d]-cyclohepten-5-yl)-4-piperidinyl]- 1,3-dihydro- 211-benimidazole LC: 94.5% MS:m/z/462.2 (M+1.J 'I1-NMR(CDC13): d U40 (t, 3H), 1.70 (bs, 2H), 2.01 (m, 2H), 2.28 (m, 2H), 2.80 (m, 4H), 3.95 (s, 1H), 4.02 (m, 211). 4.32 (q, 2H),;4.65 (m, 1H), 7.00-7.32 (m, 12H). 2-cyanoimino-3-ethyl->l-11- (3, 3-Bis (phenyl) propyl)-4-piperidinyl]-l, 3-dihydro-2H- benzimidazole MS": ml/. 464.2 (M+l) 'll-NMR(CDC13): dl.40 (t, 3H), 1.73 (bs, 2H), 2.09 (m, 2H), 2.18-2.45 (m, 6H), 2.98 (b, 2H), 3.93 (t, 1H), 4.35 (q, 2H). 4.63 (m, I H), 7.10-7.30 (m, 13H), 7.40 (d, 1H). 2-cyanoimino-3-ethyl-1 - [ 1 - (1,2,3,4-tetrahydronaphthyl)-4-piperidinyl]-1,3-dihydro-2H- benzimidazole l.C: 94.0% MS: m/z/. 400.2 (M+l) 'l 1-NMR(CDC13): dl ..10-1.70 (m, 6H), 1.85 (m, 2H), 2.05 (m, 1H), 2. 45 (m, 3H), 2.85 (m, 4H), 3. 10 (m, 2H), 4.35 (q. 211), 4.71 (m, 1H), 7.00-7.60 (m, 8H). 2-cyanoimino-3-ethyl-il-11- (5-methylhex-2-yl)-4-piperidinyl]-l, 3-dihydro-2H-benzimidazole LC:94. 9% MS:m//368.3 (M+l) 'H-NMR(CDC13): dO.fcS (d, 6H), 0.95 (d, 3H), 1.12-1.65 (m, 8H), 1.80 (m, 2H), 2.27-2.60 (m, 5H), 2.85 (m, 211), 4.38 (m, 211), 4.6fe (m, 1 H), 7. 08-7. 30 (m, 3H), 7.45 (m, 1H). 2-cyanoimino-3-ethyl-l- [1- (norbornan-2-yl)-4-piperidinyl]-l, 3-dihydro-2H-benzimidazole I.C:99.2% MS: m//364.7 (M+l) !H-NMR(CDCI3): dl.10-2.10 (m, 13H), 2.35 (m, 1H), 2.50-2.70 (m, 3H), 2.70-2.90 (m, 3H), 3.50 (m, 2H), 4.50 (q, 211), 4.80 (m, lH), 7.35 (m, 2H), 7.48 (m, 1H), 7.75 (m, 1H). 2-cyanoimino-3-ethyl-*l- [1- (1, 3-dihydroinden-2-yl)-4-piperidinyl]-l, 3-dihydro-2H- benzimidazole LC:92.I% MS: m/z/ 386.2 (M+l); 'H-NMR(CDC13): dl.42 (t, 3H), 1.82 (m, 2H), 2.21 (m, 2H), 2.43 (m, 2H), 2.88 (m, 2H), 3.02-3.19 (m, 4H), 3.23 (m, 1H), 4.38 (q,2H), 4.80 (m, 1H), 7.08-7.30 (m, 7H), 7.45 (d, 1H). 2-cyanoirnino-3-ethylil- [1- (cyclooctylmethyl)-4-piperidinyl]-l, 3-dihydro-2H-benzimidazole. l.C: 100%. MS: m//394. 7(M+1) 'H-NMR(MeOH): d 1.35-2.00 (m, 20H), 2.60-2.85 (m, 6H), 3.40 (m, 2H), 2.52 (q, 2H), 4.90 (m, 1H), 7.35 (m, 211). p8(m, IH), 7.7)0 (m, 1 H). 2-cyanoimino-3- (2-hj|droxy)ethyl-l- [l-(cyclooctyl)-4-piperidinyl]-l,3-dihydro-2H-benzimidazole LC: 100% MS: m/z/396.3 (M+l)( 'H-NMR(DMSO): 7.5J2 (dt, 1H), 7.45 (dt, 1H), 7.21 (m, 2H), 4.97 (t, 1H), 4.55 (m, 1H), 4.38 (t, 2H), 3.76 (q, 211), 2.88 (m,2H),2.6Jl (bt, 1 H), 2.33 (m, 4H), 1.76-1.37 (m, 16H). 2-cyanoimino-3-meth0xycarbonylrnethyl-l- [1- (cyclooctyl)-4-piperidinyl]-l, 3-dihydro-2H- benzimidazole LC:98.3% MS: m/z/424.2 (M+l). 'II-NNIR(DMSO): 7.56 (dd, 1H), 7.51 (dd, 1H), 7. 25 (m, 2H), 5.26 (s, 2H), 4.56 (m, 1H), 3.72 (s, 3H), 3.34 (m. 211). 2.78 (m,2H)j 2.62 (bt, 1H), 2.32 (m, 4H), 1.80-1.35 (m, 16H). 2-cyanoimino-3-cyanqmethyl-l- [1- (cyclooctyl)-4-piperidinyl]-l, 3-dihydro-2H-benzimidazole l.C: 100% ; MS: m// 391.2 (M+l) 'H-NMR(DMSO): 7.60 (m, 2H), 7.31 (m, 2H), 5. 48 (s, 2H), 4.77 9m, 1H), 3.33 (d, 2H), 2.88 (m, 2H), 2.62 (bt, 111). 2.33 (m,4H), 1.86-1.37 (rn, 16H). 2-cyanoimino-3-butyl-i 1 - [ 1 -(cyclooctyl)-4-piperidinyl]-1, 3-dihydro-2H-benzimidazole LC: 95.4% MS: m/z/352.2 (M+l). 'll-NMR(DMSO): 7.518 (dd, 1H), 7.49 (dd, 1H), 7.24 (m, 2H), 6.55 (s, 2H), 4.59 (m, 1H), 4.34 (t, 2H), 2. 97 (m. 211), 2.80 (m, 1 H). 2.55 (m, 2H), 2.38 (m, 2H), 1.80-1.30 (m, 18H), 0.90 (t, 3H). 2-cyanc)imino-3-(2-methanesulfonamido)ethyl-l-ri-(cyclooctyl)-4-piperidinyl]-l,3-dihydro-2H-benzimidazole LC: 100% MS: m/z/ 473.2 (M + l) 'll-NMR(DMSO): 7.58 (dd, 1H), 7.44 (dd, 1H), 7.23 (m, 2H), 4.60 (m, 1H), 4.35 (t, 2H), 3.37 (t, 2H), 2.87 (m, 211), 2.82 (s, 3H), 2.60 (bt, 1 H), 2.31 (m, 4H), 1.76-1.37 (m, 15H). 2-cyanoimino-3-acetotjnido-l- [1- (cyclooctyl)-4-piperidinyl]-l, 3-dihydro-2H-benzimidazole LC: 100% MS: m/z 409.2 (M+l) 'H-NMR(DMSO): 7.75 (s, 1H), 7.52 (dd, 1H), 7.37 (s, 1H), 7.30 (dd, 1H), 7.20 (m, 2H), 4.96 (s, 2H), 4.55 (m, 111). 3.33 (d, 2H), 2.88 (m, 2H), 2.62 (bt, 1 H), 2.30 (m, 4H), 1.80-1.37 (m, 15H) 2-cyanoimino-3-carbokymethyl-l- [1- (cyclooctyl)-4-piperidinyl]-l, 3-dihydro-2H-benzimidazole l.C: 97.5% MS: m/z/409.9 (Ml 1) 'H-NMR(DMSO): 7.45 (dd, 111), 7.14 (m, 3H), 4.57 (s, 2H), 4.50 (m, 1H), 2.87 (m, 2H), 2.61 (bt, 1H), 2.33 (m. 411), 1.75-1.37 (m, 15H). 2-cyanoimino-3-(2-diitiethylamino) ethyl-l-[l-(cyclooctyl)-4-piperidinyl]-l,3-dihydro-2H- benzimidazole LC: 100% MS:m/z/. 423. 3 (M+l) 'l l-NMR(DMSO): 7.6D-6.96 (m, 4H), 6.54 (2H, s), 4.65 (m, 1H), 4.40 (t, 2H), 3.90 (t, 2H), 3.05 (m, 4H), 2.90 (m, I H), 2.63 (m, 3H)j 2.56-2.37 (m, 4H), 1.85-1.35 (m, 15H). 2-cyanoimino-l- [1- (cyclooctyl)-3-hydroxymethyl-4-piperidinyl]-l, 3-dihydro-2H-benzimidazole; 2-cyanoimino-l- [1- (eyclooctyl)-4-piperidinyI]-l, 3-dihydro-2H-7-azabenzimidazole; 2-cyanoimino-l-11- (cryclooctyl)-2, 6-ethano-4-one-4-piperidinyl]-l, 3-dihydro-2H-benzimidazole Other compounds within the scope of formula (IV) or (IVA) of the present invention can be synthesized by analogous techniques. EXAMPLE 15 Nociceptin affinity at the ORL1 receptor for preferred compounds was obtained using the following assay: Membranes from recqmbinant HEK-293 cells expressing the human opioid receptor- like receptor (ORL-1) (Receptor Biology) were prepared by lysing cells in ice-cold hypotonic buffer (2.5 mM MgCl2, 50 mM HF.PHS. 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°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 -80°C. Functional SGTPgS binding assays were conducted as follows. ORL-1 membrane solution was prepared by sequentially adding fiifial concentrations of 0.066 mg/ml ORL-1 membrane protein, 10 mg/ml saponin, 3 mM GDP and 0.20 nM [35$] GTPgS to binding buffer (100 mM NaCl, 10 mM MgCl2, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 ml/well) was transferred to 96-shallow well polypropylene plates containing 10 ml of 2(|x 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 NaH2PO4, 10 mM Na2HPO4, pH 7.4). Filter plates were subsequently dried at 50°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 PRISMO, v. 3.0 and the results are set forth in table 4 below: (Table Removed) Example 16 Affinity at the u. receptor for compounds was obtained according to the following assay: Mu opioid receptor niembrane solution was prepared by sequentially adding final concentrations of 0.075 u.g/ul of the desired membrane protein, 10 ug/ml saponin, 3 uM GDP and 0.20 nlVI [35S] GTPyS to binding buffer (100 mM NaCl; 10 mM MgCl2, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 ul/well) was transferred to 96-shallow well polypropylene plates containing 10 ul of 20x concentrated stock solutions of agonist pfepared in DMSO. Plates were incubated for 30 min at room temperature with shaking. Reactions were termirjated by rapid filtration onto 96-well Unifilter GF/B filter plates (Packard) using a 96-well tissue harvester (firandel) and followed by three filtration washes with 200 \i\ ice-cold binding buffer (10 mM NaH2PO4, 10 mM Na2HPO4, pH 7.4). Filter plates were subsequently dried at 50° C for 2-3 hours. Fifty |uil/well scintillation cocktail (MicroScint20, Packard) was added and plates were counted in a Packard Top-Count for 1 min/well. Data were analyzed u$ing the curve fitting functions in GraphPad PRISM™, v. 3.0 and the results for several compounds are set forth in table 5 below: TABLE 5 (Table Removed) WE CLAIM: 1. A piperidinyl cyanoimino-benzimidazole compound of formula (IV): (Formula Removed) wherein R is C1-10alkyl, C3-12 cycloalkyl, C3-12cycloalkylC1-4alkyl-, C1-10 alkoxy, C3-12cycloalkoxy-, C1-10 alkyl substituted with 1-3 halogen, C3-12 cycloalkyl substituted with 1-3 halogen, C3-12 cycloalkylC1-4alkyl-substituted with 1-3 halogen, C1-10 alkoxy substituted with 1-3 halogen, C3-12cycloalkoxy- substituted with 1-3 halogen, -COOV1, -C14COOV1, -CH2OH, -SO2N(V1)2, hydroxyC1-10alkyl-, hydroxyC3-10cycloalkyl-, cyanoC1-10alkyl-, cyanoC3-10cycloalkyl-, -CON(V1)2, NH2SO2C1-4alkyl-, NH2SOC1-4alkyl-, sulfonylaminoC1-10alkyl-, diaminoalkyl-, sulfonylC1-4alkyl, a 6-membered heterocyclic ring, a 6-membered heteroaromatic ring, a 6-membered heterocyclicC1-4alkyl-, a 6-membered heteroaromaticC1-4alkyl-, a 6-membered aromatic ring, a 6-membered aromaticC1-4alkyl-, a 5- membered heterocyclic ring optionally substituted with an oxo or thio, a 5-membered heteroaromatic ring, a 5-membered heterocyclicC1-4alkyl-optionally substituted with an oxo or thio, a 5-membered heteroaromaticC1-4alkyl-, -C1-5(=O)W1, -C1-5(=NH)W1, -C1-5NHC(=O)W1, -C1. 5NHS(=O)2W1, -C1-5NHS(=O)W1, wherein W1 is hydrogen, C1-10 alkyl, C3-12 cycloalkyl, C1-10alkoxy, C3-12 cycloalkoxy, -CH2OH, amino, C1-4alkylamino-, diC1-4alkylamino-, or a 5- membered heteroaromatic ring optionally substituted with 1-3 lower alkyl; wherein each V1 is independently selected from H, C1-6 alkyl, C3-6 cycloalky, benzyl and phenyl; D is a 5-8 membered cycloalkyl, 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, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, -CH2OH, -NHSO2, hydroxyCi-ioalkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, diC1-4alkylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide, sulfonylaminoC1-10alkyI-; or A- B can together form a C2-6 bridge, or B-Q can together form a C3-7 bridge, or A-Q can together form a C1-5 bridge; Z is selected from the group consisting of a bond, straight or branehed C1-6alkylene, -NH-, -CH2O-, -CH2NH-, -CH2N(CH3)-, -NHCH2-, -CH2CONH-, -NHCH2CO-, -CH2CO, , -CH2COCH2-, -CH(CH3)-, -CH=, -O- and-HC=CH-, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with one or more lower alKyl, hydroxy, halo or alkoxy group; R1 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-10alkylamino-, C3-12cycloalkylamino-, -COOV1, -C1-4COOV1, cyano, cyanoC1-10alkyl-, cyanoC3-10cycloalkyl-, NH2SO2-, NH2SO2C1-4alkyl-, NH2SOC1-4alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, diC1-4alkylaminocarbonyl-, benzyl, C3-12 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): (Formula Removed) wherein X1 and X2 are independently selected from the group consisting of NH, O, S and CH2; and wherein said alkyl, cycloalkyl, alkenyl, C1-10alkylamino, C3-12cycloalkylamino-, or benzyl of R1 is optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C1-10 alkyl, C1-10 alkoxy, nitro, trifluoromethyl-, cyano, -COOV1, -C1-4COOV1, cyanoC1-10alkyl-, -C4-5(=O)W1, -C1-5NHS(=O)2W1, -C1-5NHS(=O)W1, a 5-membered heteroaromaticC0-4alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl-, C1-10 alkoxy-, and cyano; and wherein said C3-12cycloalkyl, C3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, or spiro ring system of the formula (II) is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10alkyl, C1-10alkoxy, 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, C1-10 alkyl, C1-10 alkoxy, and cyano; R2 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12 cycloalkyl-and halogen, said alkyl or cycloalkyl optionally substituted with an oxo, amino, alkylamino or dialkylamino group; or a pharmaceutically acceptable salt thereof or solvate thereof. 2. A compound as claimed in claim 1, wherein D is phenyl or a 6 membered heteroaromatic group containing 1-3 nitrogen atoms. 3. A compound as claimed in claim 1, wherein R is selected from the group consisting of -CH2C=ONH2, -C(NH)NH2, pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl, -C=OCH3, -CH2CH2NHC=OCH3, -SO2CH3, CH2CH2NHSO2CH3, furanylcarbonyl-, methylpyrrolylcarbonyl-, diazolecarbonyl-, azolemethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxo-oxazolemetliyl-, and diazolemethyl- 4. A compound as claimed in claim 1, wherein ZR1 is selected from the group consisting of cyclohexylethyl-, cyclohexylmethyl-, cyclopentylmethyl-, dimethylcyclohexylmethyl-, phenylethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroetliyl-, pyridylethyl-, cyclopentyl-, cyclohexyl-, methoxycyclohexyl-, tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyrazoylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl-, and oxocanylpropyl-. 5. A compound as claimed in claim 1, wherein at least one of ZR1 or R is selected from the group consisting of CH2COOV1, tetrazolylmethy-, cyanomethyl-, NH2S02methyl-, NH2SOmethyl-, aminocarbonylmethyl-, C1-4allcylaminocarbonylmethyl-,and di C1-4alkylaminocarbonylmethyl-. 6. A compound as claimed in claim 1, wherein ZR1 is. 3,3 diphenylpropyl optionally substituted at the 3 carbon of the propyl with -COOV1, tetrazolylC0-4alkyl-, cyano-, aminocarbonyl-, C1-4alkylaminocarbonyl-, or diC1-4alkylaminocarbonyl-. 7. A piperidinyl cyanoimino-benzimidazole compound as claimed in claim 1 of the formula (IVA): (Formula Removed) wherein n is an integer from 0 to 3; Z is selected from the group consisting of a bond, -CH2-, -NH-, -CH2O-, -CH2CH2-, - CH2NH-, -CH2N(CH3)-, -NHCH2-, -CH2CONH-, -NHCH2CO-, -CH2CO-,, -CH2COCH2-, -CH(CH3)-, -CH=, and -HC=CH-, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with a lower alkyl, halogen, hydroxy or alkoxy group; R is selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, and C3-i2cycloalkyl; R1 is selected from the group consisting of hydrogen, C1-10alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-10alkylamino, C3-12cycloalkylamino, benzyl, C3-12 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 (V): (Formula Removed) wherein X1 and X2 are independently selected from the group consisting of NH, O, S and CH2; wherein said alkyl, cycloalkyl, alkenyl, C1-10alkylamino, C3-12cycloalkylamino, or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10allcyl, C1-10alkoxy, 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, C1-10 alkyl, C1-10 alkoxy, and cyano; wherein said C3-12 cycloalkyl, C3-12cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system, and spiro ring system of the formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkxoy, 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, C1-10 alkoxy, and cyano; R2 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12 cycloalkyl and halogen, said alkyl optionally substituted with an oxo group; or a pharmaceutically acceptable salt thereof. 8. A compound as claimed in claim 7, wherein R1 is alkyl selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl. 9. A compound as claimed in claim 7, wherein R1 is cycloalkyl selected from the group consisting of cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and norbomyl. 10. A compound as claimed in claim 7, wherein R1 is tetrahydronaphthyl, decahydronaphthyl or dibenzocycloheptyl. 11. A compound as claimed in claim 7, wherein R1 is phenyl or benzyl. 12. A compound as claimed in claim 7, wherein R1 is a bicyclic aromatic ring. 13. A compound as claimed in claim 12, wherein said bicyclic aromatic ring is indenyl, quinoline or naphthyl. 14. A compound as claimed in claim 7, wherein Z is a bond, methyl, or ethyl. 15. A compound as claimed in claim 7, wherein n is 0. 16. A compound as claimed in claim 7, wherein X1 and X2 are both 0. 17. A piperidinyl cyanoimino-benzimidazole compound as claimed in claim 1 selected from the group consisting of 2-cyanoimino-3-ethyl-1 -[1 -(p-phenylbenzyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-l- [1- (p-benzyloxybenzyl)-4-piperidinyl] 1,3-dihydro-2H- benzimidazole; 2-cyanoimino-3-ethyl-1- [1- (naphth-2-yl-methyl)-4-piperidinyl] 1,3-dihydro-2H- benzimidazole; 2-cyanoimino-3-ethyl-1-[l- (4-propylcyclohexyl)-4-piperidinyl]-1,3-dihydro-2H- benzimidazole; 2-cyanoimino-3-ethyl-l-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-1 -[1 -(decahydro-2-naphthyl)-4-piperidinyl]-1,3-dihydro- 2H-benzimidazole; 2-cyanoimino-3-ethyl-1 -[1 -(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H- benzimidazole; 2-cyanoimino-3-ethyl-1-[l-(10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)-4- piperidinyl]-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-1 -[1 -(3,3-Bis(phenyl)propyl)-4-piperidinyl]-1,3-dihydro- 2H-benzimidazole; 2-cyanoimino-3-ethyl-1-[1-(1,2,3,4-tetrahydronaphthyl)-4-piperidinyl]-1I3-dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-1-(1-(5-methylhex-2-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-l-[1 -(norbornan-2-yl)-4-piperidinyl]-1,3-dihydro-2H- benzimidazole; 2-cyanoimino-3-ethyl-1 -[1 -(1 3-dihydroinden-2-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-ethyl-1 -[1 -(cyclooctylmethyl)-4-piperidinyl]-1,3-dihydro-2H- benzimidazole; and pharmaceutically acceptable salts thereof. 18. A piperidinyl cyanoimino-benzimidazole compound as claimed in claim 1 selected from the group consisting of 2-cyanoimino-3-(2-hydroxy)ethyl-1-[1-(cyclooctyl)-4-piperidinyl]-l,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-methoxycarbonylmethyl-1-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-cyanomethyl-l-[1 (cycloocyl)-4-piperidinyl]-1,3-dihydro-2H- benzimidazole; 2-cyanoimino-3-butyl-1 -[1 -(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-(2-methanesulfonamido)ethyl-l-[1-(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazole; 2-cyanoimino-3-acetomido-1 -[1 -(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H- benzimidazole; 2-cyanoimino-3-carboxymethyl-l-[1 -(cyclooctyl)-4-piperidinyl]-1,3-dihydro-2H- benzimidazole; 2-cyanoimino-3-(2-dimethylamino)ethyl-1 -[1 -(cyclooctyl)-4-piperidinyl]-1,3-dihydro- 2H-benzimidazole; 2-cyanoimino-1-[1-(cyclooctyl)-3-hydroxymethyl-4-piperidinyl]-1,3-dihydro-2H- benzimidazole; 2-cyanoimino-1 -[1 -(cyclooctyl)-4piperidinyl]-1,3-dihydro-2H-7- azabenzimidazole; 2-cyanoimino-1-[l-(cyclooctyl)-2,6-ethano-4-one-4-piperidinyl]-1,3-dihydro-2H- benzimidazole; and pharmaceutically acceptable salts thereof and solvates thereof. 19. A piperidinyl cyanoimino-benzimidazole compound as claimed in claim 1 whenever used for the manufacture of a pharmaceutical composition useful as an analgesic.

Documents:

4136-DELNP-2007-Abstract-(15-05-2012).pdf

4136-delnp-2007-abstract.pdf

4136-DELNP-2007-Assignment-(27-02-2012).pdf

4136-delnp-2007-assignment.pdf

4136-DELNP-2007-Claims-(15-05-2012).pdf

4136-DELNP-2007-Claims-(27-02-2012).pdf

4136-DELNP-2007-Correspondence Others-(15-05-2012).pdf

4136-DELNP-2007-Correspondence Others-(16-01-2012).pdf

4136-DELNP-2007-Correspondence Others-(27-02-2012).pdf

4136-delnp-2007-Correspondence Others-(28-03-2012).pdf

4136-delnp-2007-correspondence others.pdf

4136-delnp-2007-correspondence-others 1.pdf

4136-DELNP-2007-Correspondence-Others-(17-01-2011).pdf

4136-delnp-2007-description (complete).pdf

4136-DELNP-2007-Form-1-(15-05-2012).pdf

4136-DELNP-2007-Form-1-(27-02-2012).pdf

4136-delnp-2007-form-1.pdf

4136-delnp-2007-form-18.pdf

4136-DELNP-2007-Form-2-(15-05-2012).pdf

4136-delnp-2007-form-2.pdf

4136-DELNP-2007-Form-3-(16-01-2012).pdf

4136-delnp-2007-form-3.pdf

4136-DELNP-2007-Form-5-(27-02-2012).pdf

4136-delnp-2007-form-5.pdf

4136-DELNP-2007-GPA-(17-01-2011).pdf

4136-delnp-2007-pct-101.pdf

4136-delnp-2007-pct-210.pdf

4136-delnp-2007-pct-220.pdf

4136-delnp-2007-pct-304.pdf

4136-delnp-2007-pct-409.pdf

4136-delnp-2007-pct-416.pdf

4136-delnp-2007-Petition-137-(28-03-2012).pdf

4146-delnp-2007-claims.pdf