AU2012251956A1 - Buprenorphine analogs - Google Patents

Buprenorphine analogs Download PDF

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Publication number
AU2012251956A1
AU2012251956A1 AU2012251956A AU2012251956A AU2012251956A1 AU 2012251956 A1 AU2012251956 A1 AU 2012251956A1 AU 2012251956 A AU2012251956 A AU 2012251956A AU 2012251956 A AU2012251956 A AU 2012251956A AU 2012251956 A1 AU2012251956 A1 AU 2012251956A1
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Australia
Prior art keywords
alkyl
halo
membered
compound according
cycloalkyl
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Abandoned
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AU2012251956A
Inventor
Marian E. Fundytus
R. Richard Goehring
Donald J. Kyle
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Purdue Pharma LP
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Purdue Pharma LP
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Priority claimed from AU2009277095A external-priority patent/AU2009277095B2/en
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Priority to AU2012251956A priority Critical patent/AU2012251956A1/en
Publication of AU2012251956A1 publication Critical patent/AU2012251956A1/en
Abandoned legal-status Critical Current

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Abstract

The present invention is directed to Buprenorphine Analog compounds of the 2 3 3a 3b Formula I, Formula II or Formula III shown below, wherein R1, R2 , R8, R3, Ra, R , X, Z and Y are as defined herein. &RZ H3CO O OCHa 5 (1) N "R R 3" &~~~R3b z0YR x O OCH3 (II) R' R3aa X0 OCHa (III) 10 Compounds of the Invention are useful for treating pain and other conditions modulated by activity of opioid and ORLI receptors. 1011995v1

Description

1 AUSTRALIA Patents Act 1990 PURDUE PHARMA L.P. COMPLETE SPECIFICATION STANDARD PATENT Invention Title: Buprenorphine analogs The following statement is a full description of this invention including the best method of performing it known to us:- BUPRENORPHINE ANALOGS FIELD OF THE INVENTION The invention is in the field of medicinal chemistry. It relates to novel buprenorphine 5 analogs having activity as opioid receptor agonists. In certain embodiments compounds of the invention have dual activity as opioid agonists and ORLI receptor antagonists. BACKGROUND OF THE INVENTION Pain is the most common symptom for which patients seek medical advice and 10 treatment. While acute pain is usually self-limited, chronic pain can persist for 3 months or longer and lead to significant changes in a patient's personality, lifestyle, functional ability and overall quality of life (K.M. Foley, Pain, in Cecil Textbook ofMedicine 100-107, J.C. Bennett and F. Plum eds., 20th ed. 1996). Pain has traditionally been managed by administering either a non-opioid analgesic 15 (such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, diflunisal or naproxen), or an opioid analgesic (such as morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone or oxymorphone). Although the term "narcotic" is often used to refer to opioids, the term is not specifically applicable to opioids. The term "narcotic", derived from the Greek word for 20 "stupor", originally referred to any drug that induced sleep, only later being associated with opioids (Gutstein Howard B., Akil Huda, "Chapter 21. Opioid Analgesics" (Chapter 21), Brunton LL, Lazo JS, Parker KI: Goodman & Gilman's The Pharmacological Basis of Therapeutics, I lPh Edition: http://www.accessmedicine.com/content.aspx?aID=940653). In the legal context, the term "narcotic" refers to a variety of mechanistically unrelated 25 substances with abuse or addictive potential (Gutstein Howard B., Akil Huda, "Chapter 21. Opioid Analgesics" (Chapter 21), Brunton LL, Lazo JS, Parker KI: Goodman & Gilman's Th6 Pharmacological Basis of Therapeutics, I l't Edition: http://www.accessmedicine.com/content.aspx?aID=940653). Thus, the term "narcotic" not only refers to opioids, but also refers to such drugs as cocaine, methamphetamine, ecstasy, 30 etc., which exert their pharmacological effects via different receptors than opioids. Furthermore, because the term "narcotic" refers to such a wide variety of unrelated drugs, many of which do not possess analgesic properties, it cannot be assumed that a drug that has "narcotic" properties is necessarily analgesic. For example, drugs such as ecstasy and methamphetamine are not analgesic, and are not used to treat pain.
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 are known as p, 5 and ic. As opiates have a high affinity to these receptors while not being endogenous to the body, research followed in order to identify and isolate the 5 endogenous ligands to these receptors. These ligands were identified as endorphins, enkephalins, and dynorphins, respectively. Additional experimentation has led to the identification of the opioid receptor-like (ORL-1) receptor, which has 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 10 pharmacological homology. It was initially demonstrated that non-selective ligands having a high affinity for p, S and ic receptors had low affinity for the ORL-1 receptor. This characteristic, along with the fact that an endogenous ligand had not yet been discovered, led to the ORL-1 receptor being designated as an "orphan receptor". Subsequent research led to the isolation and structure of the endogenous ligand of the 15 ORL-1 receptor. This ligand, nociceptin (also known as orphanin FQ (OFQ)), is a seventeen amino acid peptide structurally similar to members of the opioid peptide family. (C. Altier et al., "ORLI receptor-mediated internalization of N-type calcium channels." Nature Neuroscience, 2005, 9:31). The discovery of the ORL-1 receptor, and its endogenous agonist, presents an 20 opportunity for the discovery of novel compounds that can be administered for pain management or other syndromes influenced by this receptor. Many publications in the ORL-1/nociceptin field provide evidence that activation of ORL-1 receptors in the brain can inhibit opioid-mediated analgesia (e.g., D. Barlocco et al., "The opioid-receptor-like I (ORL-1) as a potential target for new analgesics." Eur. J. Med. 25 Chem., 2000, 35:275; J.S. Mogil et al., "Orphanin FQ is a functional anti-opioid peptide." Neurosci., 1996, 75:333; K. Lutfy et al., "Tolerance develops to the inhibitory effect of orphanin FQ on morphine-induced antinociception in the rat." NeuroReport, 1999, 10:103; M.M. Morgan et al., "Antinociception mediated by the periaqueductal gray is attenuated by orphanin FQ." NeuroReport, 1997, 8:3431; and J. Tian et al., "Involvement of endogenous 30 Orphanin FQ in electroacupuncture-induced analgesia." NeuroReport, 1997, 8:497). A growing body of evidence supports a more generalized regulatory role for ORL-I against the actions of the g receptor, possibly contributing to the development of p-agonist -2tolerance in patients being treated with classical opiates (e.g., J. Tian et al., "Functional studies using antibodies against orphanin FQ/nociceptin." Peptides, 2000, 21:1047; and H. Ueda et al., "Enhanced Spinal Nociceptin Receptor Expression Develops Morphine Tolerance and Dependence." J. Neurosci., 2000, 20:7640). Moreover, ORL-1 activation appears to 5 have an inhibitory effect on the rewarding properties of several drugs of abuse, including p agonists. Certain compounds have been described as at least partial agonists for ORL-I (e.g., buprenorphine (ICso of 8.4 nM), fentanyl (ICso of about 10,000 nM), 7-benzylidenenaltrexone (ICso about 10,000 nM) (S. Wnendt et al., "Agonistic effect of buprenorphine in a 10 nociceptin/OFQ receptor-triggered reporter gene assay." Molec. Pharmacol., 1999, 56:334 338), and etorphine (IC 50 of about 2000 nM) (Hawkinson et al., "Opioid activity profiles indicate similarities between the nociceptin/orphanin FQ and opioid receptors." Eur. J. Pharmacol, 2000, 389:107-114)). However, buprenorphine's s potency is disclosed to be much greater than its ORL- 1 potency. 15 Recent data have shown that the analgesic efficacy of buprenorphine is enhanced by pre-treatment with an ORL-1 receptor antagonist. Using the tail-flick test in mice, Lutfy et al. demonstrated that buprenorphine's typical bell-shaped dose-response curve (wherein low and high doses induce little analgesia, and mid-range doses produce maximal analgesia) is eliminated by pre-treatment with the ORL-I antagonist J-1 13397, and analgesic efficacy is 20 improved at the higher range of doses (K. Lutfy et al., "Buprenorphine-induced antinociception is mediated by mu-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors." J. Neurosci., 2003, 23:10331-10337). Recently, a multidisciplinary group of experts in the fields of pharmacology, toxicology, pain management, and anesthesia have recommended buprenorphine as the best 25 opioid for treating chronic severe pain in elderly patients (Pergolizzi, et al. (2008). Opioids and the Management of Chronic Severe Pain in the Elderly: Consensus Statement of an International Expert Panel with Focus on the Six Clinically Most Often Used World Health Organization step III Opioids (buprenorphine, Fentanyl, Hydromorphone, Methadone, Morphine, Oxycodone. Pain Practice 8(4): 287-313). It was found that of the opioids 30 studied, buprenorphine provided the best analgesic-to-side effect profile. Buprenorphine was the most effective opioid for treating neuropathic pain. Buprenorphine was the only opioid for which metabolism was not affected by impaired renal function. Buprenorphine was the only opioid demonstrating a ceiling effect for respiratory depression, indicating that higher -3 doses may be used. Also, buprenorphine was the least likely to induce immunosuppression. The panel of experts attributed the improved therapeutic efficacy of buprenorphine to its unique pharmacological profile. Buprenorphine has also been shown to have an improved side effect profile in animal 5 models. A review of recent data in animal models of reward and addiction has shown that buprenorphine has a low addictive and dependence-inducing profile compared to other opioids (Tzschentike (2002). Behavioral pharmacology of buprenorphine, with a focus on preclinical models of reward and addiction. Psychopharmacology 161: 1-16. 10 BRIEF SUMMARY OF THE INVENTION The present invention provides novel buprenorphine analog compounds useful for treating a variety of conditions, including pain, in particular chronic pain. More specifically, the present invention provides compounds of Formula I, Formula II or Formula III, below, and the pharmaceutically acceptable salts, prodrugs and solvates thereof that exhibit affinity 15 for one or more of the ORL-1, p, 8, and/or K opioid receptors. Such compounds are collectively referred to hereinafter as "Compounds of the Invention" (each is individually referred to hereinafter as a "Compound of the Invention"). The present invention provides novel compounds of Formula I: R1 R3 z Y
H
3 CO 0 OCH 3 20 (1) wherein -4- R' is selected from the group consisting of -(Ci-Cio)alkyl, -(C 2
-C
12 )alkenyl, -(C 2 C[ 2 )alkynyl, -(C 3
-C
12 )cycloalkyl, -(C 4 -C[2)cycloalkenyl, ((C 3
-CI
2 )cycloalkyl)-(CI-C 6 )alkyl-,
((C
4
-CI
2 )cycloalkenyl)-(CI-C 6 )alkyl-, -(5- to 12-membered)aryl, -(5- to 12 membered)heteroaryl, and -(3- to 12-membered)heterocycle; any of which is optionally 5 substituted with one to three substituents independently selected from the group consisting of
-(CI-C
6 )alkyl, OH, halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), NH 2 , -NH(Ci-C 6 )alkyl, CN and SH;
R
2 is selected from the group consisting of hydrogen, -(Ci-Cio)alkyl, -(C 2
-C
1 2 )alkenyl,
-(C
2
-C
2 )alkynyl, -(CrCi2)cycloalkyl, -(C 4
-C
1 2)cycloalkenyl, -(C 6 -Ci4)bicycloalkyl, -(C 8 . 10 C 2 o)tricycloalkyl, -(C7-CI4)bicycloalkenyl, -(Cs-C 20 )tricycloalkenyl, -(5- to 12 membered)aryl, -(5- to 12-membered) heteroaryl, -(3- to 12-membered)heterocycle, or -(7 to 12-membered)bicycloheterocycle; any of which is optionally substituted with one or two substituents independently selected from the group consisting of OH, halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(Ci-C 6 )alkyl, halo(Ci-C 6 )alkyl-, -(C 2
-C
6 )alkenyl, 15 (C-C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, C(=O), NH 2 , -NH(Ci-C 6 )alkyl, CN, SH and OR 4 ;
R
3 is selected from the group consisting of hydrogen, -- (C6-C 6 )alkyl, -(C 2
-C
6 )alkenyl,
-(C-C
6 )alkynyl, OH, hydroxy(CI-C 6 )alkyl-, C(=O), -(C(halo) 3 , -CH(halo) 2 , and -CH 2 (halo);
R
4 is selected from the group consisting of-(Ci-C 6 )alkyl, -(C 2
-C
6 )alkenyl, -(Cr
C
6 )alkynyl, OH, hydroxy(Ci-C 6 )alkyl-, -(C3-C 12 )cycloalkyl, -(C 6
-CI
4 )bicycloalkyl, -(C 8 20 C 2 0)tricycloalkyl, -(C 4 -C2)cycloalkenyl, -(C7-CI 4 )bicycloalkenyl, -(C8-C 2 0)tricycloalkenyl, (5- to 12-membered)aryl, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, and -(7- to 12-membered)bicycloheterocycle; Z is (CH 2 )m; Y is (CH 2 )n; 25 m is an integer 1, 2, 3, 4, 5, or 6; n is an integer 0, 1, 2, 3, 4, 5 or 6; and the pharmaceutically acceptable salts, prodrugs and solvates thereof. The present invention also provides compounds of Formula (II): 30 -5 - Ri N R3a .,..-R3b ZR O R 2 X O O CH3 (II) wherein R' is selected from -(CI-CIo)alkyl, -(C 2
-C
12 )alkenyl, -(C 2
-C
1 2 )alkynyl, -(C 3 5 C 12 )cycloalkyl, -(C4-Cu 2 )cycloalkenyl, ((C 3
-C
1 2)cycloalkyl)-(CI-C 6 )alkyl-, ((C 4 C12)cycloalkenyl)-(CI-C 6 )alkyl-, a (5- to 12-membered)aryl, a (5- to 12-membered)heteroaryl, a (3- to 12-membered)heterocycle, phenyl, and benzyl; any of which is optionally substituted with one to three substituents independently selected from the group consisting of -(C 1 C 6 )alkyl, OH, halo, -C(halo) 3 , -CH(halo) 2 , -CH2(halo), NH 2 , -NH(CI-C 6 )alkyl, CN, SH, -(5 10 to 12-membered)carbocyclic ring, -(5- to 12-membered)heterocycle, phenyl, and benzyl;
R
2 is selected from hydrogen, -(Ci-Cio)alkyl, -(C 2
-C
1 2 )alkenyl, -(C 2
-C
1 2 )alkynyl, (C 3 -Cu)cycloalkyl, -(C 4 -Cu)cycloalkenyl, -(C 6
-CI
4 )bicycloalkyl, -(CS.C 2 o)tricycloalkyl, -(C 7 C 14 )bicycloalkenyl, -(C8-C 2 0)tricycloalkenyl, :(5- to 12-membered)aryl, -(5- to 12 membered)heteroaryl, -(3- to 12-membered)heterocycle, -(7- to 12-membered) 15 bicycloheterocycle, phenyl and benzyl; any of which is optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(CI-C 6 )alkyl, halo(Ci-C 6 )alkyl-, -(C 2
-C
6 )alkenyl, (C2-C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, phenyl, benzyl, NH1 2 , -NH(Ci-C 6 )alkyl, CN, SH, OR 4 ,
CONRR
6 and COOR 7 ; 20 R 3 ' and R 3 b are each independently selected from hydrogen, -(Ci-C 6 )alkyl, -(C 2 C6)alkenyl, -(C 2
-C
6 )alkynyl, OH, hydroxy(C-C 6 )alkyl-, (=0), -C(halo) 3 , -CH(halo) 2 , and CH2(halo);
R
4 is selected from -(C-C 6 )alkyl, -(C2-C 6 )alkenyl, -(C-C 6 )alkynyl, hydroxy(Cl
C
6 )alkyl-, -(C3-C 12 )cycloalkyl, -(C 6 -C )bicycloalkyl, -(Cs-C 2 o)tricycloalkyl, -(C 4 -6-
C
12 )cycloalkenyl, -(C-Ci4)bicycloalkenyl, -(Cs-C 2 0 )tricycloalkenyl, -(5- to 12 membered)aryl, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, and (7- to 12-membered)bicycloheterocycle;
R
5 and R 6 are each independently -(C I-C 6 )alkyl, -(C 3 -Cs)cycloalkyl, ((C 3 5 Cs)cycloalkyl)-(Ci-C 6 )alkyl-, or together with the nitrogen atom to which they are attached form a (4- to 8- membered)heterocycle;
R
7 is selected from hydrogen, -(Ci-C 6 )alkyl, -(C-C 6 )alkenyl, -(C-C 6 )alkynyl, -(C 3 C 12 )cycloalkyl, -(C 4 -C )cycloalkenyl, ((C 3 -Cu 2 )cycloalkyl)-(CI-C 6 )alkyl-, and ((C 4 C 12 )cycloalkenyl)-(CI-C 6 )alkyl- ; 10 X is selected from (CI-C 6 )alkoxy and OH; Z is (CH 2 )m; Y is (CH 2 )n; m is an integer 1, 2, 3, 4, 5, or 6; n is an integer 0, 1, 2, 3, 4, 5 or 6; 15 and the pharmaceutically acceptable salts, prodrugs and solvates thereof. The present invention further provides compounds of Formula (III): Ri N R 3a .....- RR2 ZY R8 X O OCH3 (III) 20 wherein R' is selected from -(Ci-Cio)alkyl, -(C-C: 2 )alkenyl, -(C 2
-C
1 2 )alkynyl, -(C 3 C12)cycloalkyl, -(C 4 -C, )cycloalkenyl, ((C 3 -Clz)cycloalkyl)-(CI-C 6 )alkyl-, ((C 4 C12)cycloalkenyl)-(CI-C 6 )alkyl-, -(5- to 12-membered)aryl, ((5- tol2-membered)aryl)-(C,
C
6 )alkyl-, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, phenyl, and -7benzyl; any of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -(Ci-C 6 )alkyl, OH, halo, -C(halo) 3 , -CH(halo) 2 , CH 2 (halo), NH 2 , -NH(CI-C 6 )alkyl, CN, SH, -(5- to 12-membered)carbocyclic ring, -(5- to 12 membered)heterocycle, phenyl, and benzyl; 5 R 2 and R 8 are each independently hydrogen, -(C-Cio)alkyl, -(C 2
-C
1 2 )alkenyl, -(C 2 C 12 )alkynyl, -(C 3
-C
2 )cycloalkyl, -((C 3 -C,2)cycloalkyl)-(C-C 6 )alkyl, -(C 4
-C
2 )cycloalkenyl, (C 6 -Ci 4 )bicycloalkyl, -(Cs.C 2 0)tricycloalkyl, -(C 7
-CI
4 )bicycloalkcnyl, -(C 8 -C2o)tricycloalkenyl, -(5- to 12-membered)aryl, ((5- tol2-membered)aryl)-(C-C 6 )alkyl-, -(7- to 12 membered)bicyclic ring system, -(7- to 12-membered)bicyclic aryl, -(5- to 12 10 membered)heteroaryl, -(3- to 12-membered)heterocycle, -(7- to 12-membered) bicycloheterocycle, phenyl and benzyl; any of which is optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(C-C 6 )alkyl, halo(C-C 6 )alkyl-, -(C 2
-C
6 )alkenyl, 4
(C
2
-C
6 )alkynyl, hydroxy(C-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(C-C 6 )alkyl, CN, SH, OR , 15 CONRR 6 and COOR 7 ;
R
3 a and R 3 b are each independently selected from hydrogen, -(C-C 6 )alkyl, -(C 2 C 6 )alkenyl, -(C 2
-C
6 )alkynyl, OH, hydroxy(C-C 6 )alkyl-, (=0), -C(halo) 3 , -CH(halo) 2 , and CH 2 (halo);
R
4 is selected from -(CI-C6)alkyl, -(C-C 6 )alkenyl, -(C 2
C
6 )alkynyl, -C(halo) 3 , 20 hydroxy(C-C 6 )alkyl-, -(CrCI2)cycloalkyl, -(C 6
-CI
4 )bicycloalkyl, -(Cs-C2o)tricycloalkyl, (C 4 -Cu 2 )cycloalkenyl, -(C 7
-CI
4 )bicycloalkenyl, -(Cs-C 2 0)tricycloalkenyl, -(5- to 12 membered)aryl, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, and (7- to 12-membered)bicycloheterocycle;
R
5 and R 6 are each independently -(CI-C 6 )alkyl, -(C 3 -Cs)cycloalkyl, ((C 3 25 Cs)cycloalkyl)-(Ct-C 6 )alkyl-, or together with the nitrogen atom to which they are attached form a (4- to 8- membered)heterocycle;
R
7 is selected from hydrogen, -(C 1
-C
6 )alkyl, -(C-C 6 )alkenyl, -(C 2
-C
6 )alkynyl, -(C 3 C 1 2)cycloalkyl, -(C 4 -Cu)cycloalkenyl, ((C 3 -C z)cycloalkyl)-(C-C 6 )alkyl-, and ((C 4 C12)cycloalkenyl)-(CI-C 6 )alkyl-; 30 X is selected from (CI-C 6 )alkoxy and OH; Z is (CH2)n,; Y is (CH 2 )n-CH or a direct bond, provided that when Y is a direct bond then R8 is absent; m is an integer 1, 2, 3, 4, 5, or 6; -8n is an integer 0, 1, 2, 3, 4, 5 or 6; and the pharmaceutically acceptable salts, prodrugs and solvates thereof. It is an object of certain embodiments of the present invention to provide new 5 Compounds of the Invention that have antagonist activity at the ORL-1 receptor which is greater than compounds currently available, e.g., JTC-801 (described in WO 99/48492; and Shinkai et al., "4-aminoquinolines: Novel nociceptin antagonists with analgesic activity", J. Med. Chem., 2000, 43:4667-4677) and J-1 13397 (described in WO 98/54168; and Kawamoto et al., "Discovery of the first potent and selective small molecule opioid receptor-like (ORLI) 10 antagonist: 1-[(3R,4R)- I -cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl- 1,3 dihydro-2H-benzimidazol-2-one (J- 113397)", J. Med. Chem., 1999, 42:5061-6063). Certain Compounds of the Invention have agonist activity at the p, 8 and/or K receptors which is greater than currently available compounds, e.g., morphine. Certain Compounds of the Invention have both: (i) antagonist activity at the ORL-1 15 receptor; and (ii) agonist activity at one or more of the p, 8 and/or K receptors. Certain Compounds of the Invention have both: (i) antagonist activity at the ORL-1 receptor; and (ii) agonist activity at the p receptor. Compounds of the Invention may be useful as analgesics; anti-inflammatories; diuretics; anesthetics; neuroprotective agents; anti-hypertensives; anxiolytics; agents for 20 appetite control; hearing regulators; anti-tussives; anti-asthmatics; anti-epileptics; anti convulsants; modulators of locomotor activity; modulators of learning and memory; regulators of neurotransmitter release; modulators of hormone release; kidney function modulators; anti-depressants; agents to treat memory loss due to Alzheimer's disease or other dementias; agents to treat withdrawal from alcohol and/or drugs of addiction; or agents to 25 control water balance, sodium excretion, arterial blood pressure disorders, UI, ulcers, IBD, IBS, addictive disorders, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, pruritic conditions, psychosis, cognitive disorders, memory deficits, restricted brain function, Huntington's chorea, ALS, dementia, retinopathy, muscle spasms, migraines, vomiting, dyskinesia, and/or depression (each being a "Condition"). 30 The present invention further provides methods for treating a Condition, comprising administering to an animal in need thereof a therapeutically effective amount of a Compound of the Invention. In certain embodiments, the Condition is chronic or acute pain. The -9- Compounds of the Invention are particularly useful for treating chronic pain. In certain embodiments, the Compound of the Invention is an ORL-I receptor antagonist. In other embodiments, the Compound of the Invention is an agonist at one or more of the p, S and/or x receptor. In other embodiments, the Compound of the Invention is both an ORL-I receptor 5 antagonist and an agonist at one or more of the pL, S and/or K receptor. In other embodiments, the Compound of the Invention is both an ORL-l receptor antagonist and an agonist at the .t receptor. In certain non-limiting embodiments, the Compound of the Invention produces fewer side. effects and/or less severe side effects than currently available analgesic opioid compounds when administered at doses producing equivalent levels of analgesia and/or anti 10 hyperalgesia. In certain non-limiting embodiments, the Compound of the Invention exhibits a substantially linear dose response curve, such that the bell-shaped dose response curve observed for most opioid analgesics (i.e. low and high doses do not produce significant analgesia, whereas mid-range doses produce analgesia) is not observed for the Compound of 15 the Invention. It is expected, therefore, that it will be easier to titrate to an effective dose of the Compound of the Invention in a patient than it is for conventional opioid analgesics. It is further expected that the Compound of the Invention will produce effective analgesia and/or anti-hyperalgesia in a patient who has become tolerant to conventional opioids, and for whom a conventional opioid is no longer an effective treatment. It is further expected that a 20 Compound of the Invention will produce effective analgesia and/or anti-hyperalgesia at doses that do not induce side effects such as respiratory depression in patients for whom a dose of a conventional opioid that is high enough to be an effective treatment also induces significant side effects such as respiratory depression. The present invention further provides methods for preventing a Condition, 25 comprising administering to an animal in need thereof a Condition-preventing effective amount of a Compound of the Invention. The present invention further provides pharmaceutical compositions comprising a therapeutically effective amount of a Compound of the Invention admixed with a pharmaceutically acceptable carrier or excipient. Such compositions are useful for treating or 30 preventing a Condition in an animal. The pharmaceutical compositions of the present invention may be formulated as immediate release formulations, or as controlled release formulations. Pharmaceutical compositions of the present invention may be formulated for administration by any of a number of different routes known in the art, including but not -10limited to, oral, intradermal, intramuscular, intraperitoneal, parenteral, intravenous, subcutaneous, intranasal, epidural, sublingual, intracerebral, intravaginal, transdermal, transmucosal, rectal, by inhalation, or topical (particularly to the ears, nose, eyes, or skin). The present invention further provides methods for preparing a composition, 5 comprising the step of admixing a Compound of the Invention and a pharmaceutically acceptable carrier or excipient to form a pharmaceutical composition. The invention still further relates to a kit comprising a container containing an effective amount of a Compound of the Invention. DESCRIPTION OF THE DRAWINGS 10 Fig. I shows oxygen tension in collected blood samples as a measure of respiration in rats prior to drug administration (baseline), and 1, 3, 5 and 24 hours following administration of either water, 30 mg/kg of morphine, or 3, 10 or 30 mg/kg of compound 11. Fig. 2 shows oxygen saturation in collected blood samples as a measure of respiration in rats prior to drug administration (baseline), and 1, 3, 5 and 24 hours following 15 administration of either water, 30 mg/kg of morphine, or 3, 10 or 30 mg/kg of compound 11. Fig. 3 shows carbon dioxide tension in collected blood samples as a measure of respiration in rats prior to drug administration (baseline), and 1, 3, 5 and 24 hours following administration of either water, 30 mg/kg of morphine, or 3, 10 or 30 mg/kg of compound 11. Fig. 4 shows total carbon dioxide (including bicarbonate) in collected blood samples 20 as a measure of respiration in rats prior to drug administration (baseline), and 1, 3, 5 and 24 hours following administration of either water, 30 mg/kg of morphine, or 3, 10 or 30 mg/kg of compound 11. Fig. 5 shows blood pH in collected blood samples as a measure of respiration in rats prior to drug administration (baseline), and 1, 3, 5 and 24 hours following administration of 25 either water, 30 mg/kg of morphine, or 3, 10 or 30 mg/kg of compound 11. Fig. 6 shows oxygen tension in collected blood samples as a measure of respiration in rats prior to drug administration (baseline), and 1, 3, and 5 hours following administration of either water, 30 mg/kg of morphine, or 3, 10 or 200 mg/kg of compound 6. Fig. 7 shows oxygen saturation in collected blood samples as a measure of respiration 30 in rats prior to drug administration (baseline), and 1, 3, and 5 hours following administration of either water, 30 mg/kg of morphine, or 3, 10 or 30 mg/kg of compound 6. -Il1- Fig. 8 shows carbon dioxide tension in collected blood samples as a measure of respiration in rats prior to drug administration (baseline), and 1, 3, and 5 hours following administration of either water, 30 mg/kg of morphine, or 3, 10 or 30 mg/kg of compound 6. Fig. 9 shows total carbon dioxide (including bicarbonate) in collected blood samples 5 as a measure of respiration in rats prior to drug administration (baseline), and 1, 3, and 5 hours following administration of either water, 30 mg/kg of morphine, or 3, 10 or 30 mg/kg of compound 6. Fig. 10 shows blood pH in collected blood samples as a measure of respiration in rats prior to drug administration (baseline), and 1, 3, and 5 hours following administration of 10 either water, 30 mg/kg of morphine, or 3, 10 or 30 mg/kg of compound. Fig. 11 shows MPE (% reversal) of mechanical hyperalgesia, compared to pre-drug (pre-administration PWT), 1, 3 and 5 hours after administration of either 30 mg/kg indomethacin, or 1, 3 or 10 mg/kg compound 11, in rats given an intraplantar injection of FCA. 15 DETAILED DESCRIPTION OF THE INVENTION The Compounds of the Invention are novel buprenorphine analogs. They are useful for treating one or more Conditions, such as pain. Compounds of the Invention may provide a reduced liability for developing analgesic tolerance and physical dependence. 20 The Compounds of the Invention are useful for modulating a pharmacodynamic response from ORL-1 receptors either centrally or peripherally, or both. The Compounds of the Invention may also be useful for modulating a pharmacodynamic response from one or more opioid receptors (lp, 5, K) either centrally or peripherally, or both. The pharnacodynamic response may be attributed to the compound stimulating (agonizing) or 25 inhibiting (antagonizing) the one or more receptors. Certain Compounds of the Invention may inhibit (or antagonize) the ORL-1 receptor, while also stimulating (or agonizing) one or more other receptors (e.g. as a p, S and/or K agonist). Compounds of the Invention having agonist activity may be either full or partial agonists. In certain embodiments, Compounds of the Invention can be used in combination 30 with at least one other therapeutic agent. The other therapeutic agent can be, but is not limited to, a p-opioid agonist, a non-opioid analgesic, a non-steroidal anti-inflammatory agent, a Cox-II inhibitor, an anti-emetic, a 0-adrenergic blocker, an anticonvulsant, an antidepressant, a Ca 2 -channel blocker, an anticancer agent, or a mixture thereof. - 12 - Various objects and advantages of the present invention will become apparent from the following detailed description. The present invention provides compounds represented by Formula I: R1 R3 Z0 R2 H3CO O OCH3 5 (I) wherein R1 is selected from the group consisting of -(CI-Clo)alkyl, -(C 2
-C
12 )alkenyl, -(C 2 C 12 )alkynyl, -(C 3 -Cu)cycloalkyl, -(C 4 -Cu2)cycloalkenyl, ((C 3
-C
2 )cycloalkyl)-(CI-C 6 )alkyl-, 10 ((C 4
-C
1 )cycloalkenyl)-(CI-C 6 )alkyl-, -(5- to 12-membered)aryl, -(5- to 12 membered)heteroaryl, and -(3- to 12-membered) heterocycle; any of which is optionally substituted with one to three substituents independently selected from the group consisting of
-(CI-C
6 )alkyl, OH, halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), NH 2 , -NH(CI-C 6 )alkyl, CN and SH. 15 R2 is selected from the group consisting of hydrogen, -(Ci-Cio)alkyl, -(C 2
-C]
2 )alkenyl,
-(C
2 -CII)alkynyl, -(C 3 -C 2 )cycloalkyl, -(C 4 -C 2)cycloalkenyl, -(C 6
-C
1 4 )bicycloalkyl, -(C 8 .
C
2 0)tricycloalkyl, -(C 7
-CI
4 )bicycloalkenyl, -(Cs-C 2 0)tricycloalkenyl, -(5- to 12 membered)aryl, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, and (7- to 12-membered)bicycloheterocycle; any of which is optionally substituted with one or 20 two substituents independently selected from the group consisting of OH, halo, -C(halo)3, -CH(halo) 2 , -CH 2 (halo), -(C I-C 6 )alkyl, halo(CI-C 6 )alkyl-, -(CZ-C 6 )alkenyl, (C-C 6 )alkynyl, hydroxy(C-C 6 )alkyl-, C(=O), NH 2 , -NH(CI-C 6 )alkyl, CN, SH and OR 4 ;
R
3 is selected from the group consisting of hydrogen, -(Ci-C 6 )alkyl, -(C 2
-C
6 )alkenyl,
-(C-C
6 )alkynyl, OH, hydroxy(CI-C 6 )alkyl-, C(=O), -(C(halo) 3 , -CH(halo) 2 , and -CH 2 (halo); -13-
R
4 is selected from the group consisting of -(C 1
-C
6 )alkyl, -(C 2
-C
6 )alkenyl, -(C 2 C 6 )alkynyl, OH, hydroxy(CI-C 6 )alkyl-, -(C 3 -C)2)cycloalkyl, -(C 6
-CI
4 )bicycloalkyl, -(C 8 C 2 0)tricycloalkyl, -(C 4 -C2)cycloalkenyl, -(C7-CI 4 )bicycloalkenyl, -(Cs-C20)tricycloalkenyl, (5- to 12-membered)aryl, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, 5 and -(7- to 12-membered)bicycloheterocycle; Z is (CH2)m; Y is (CH 2 )n; m is an integer 1, 2, 3, 4, 5, or 6; n is an integer 0, l, 2, 3, 4, 5 or 6; 10 and the pharmaceutically acceptable salts, prodrugs and solvates thereof. In certain embodiments, the invention provides compounds represented by Formula (IA): R1 N
R
3 0R Z Y R2
H
3 CO O
OCH
3 (IA) 15 wherein R', R 2 , R 3 , Y and Z are as described above for Formula (I). In certain embodiments, the invention provides compounds represented by Formula (IB): - 14 - R1 N R3 H3CO O0 OCH3 (IB) wherein R', R 2 , R 3 , Y and Z are as described above for Formula (I). In one embodiment, R' is -(Ci-Cio)alkyl optionally substituted as set forth above. In a more specific embodiment, R' is selected from the group consisting of methyl, ethyl, and 5 isopropyl, each of which is optionally substituted. In another embodiment R' is a -(C 2
-C
1 2 )alkenyl optionally substituted as set forth above. In a more specific embodiment, R' is selected from the group consisting of ethenyl and propenyl, each of which is optionally substituted. In another embodiment, R' is a -(C 3 -C12)cycloalkyl optionally substituted as set forth 10 above. In another embodiment, R' is a -(C 4
-C
1 2 )cycloalkenyl optionally substituted as set forth above. In another embodiment, R' is a ((C 3
-C,
2 )cycloalkyl)-(CI-C 6 )alkyl-. In a more specific embodiment, R' is selected from the group consisting of cyclopropylmethyl, 15 cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl, each of which is optionally substituted. In another embodiment, R' is -(5- to 12-membered)aryl, -(5- to 12 membered)heteroaryl, or -(3- to 12-membered)heterocycle, each of which is optionally substituted as set forth above. 20 In one embodiment, R 2 is -(Ci-Cio)alkyl optionally substituted as set forth above. In a more specific embodiment, R 2 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pentyl and hexyl, each of which is optionally substituted. - 15 - In another embodiment, R 2 is -(C 2
-C
12 )alkenyl optionally substituted as set forth above. In a more specific embodiment, R 2 is selected from the group consisting of 2-methyl but-2-enyl and propenyl, each of which is optionally substituted. In another embodiment, R 2 is -(C 2
-C
1 2 )alkynyl optionally substituted as set forth 5 above. In a more specific embodiment, R 2 is optionally substituted propynyl. In another embodiment, R 2 is -(C 3
-C]
2 )cycloalkyl optionally substituted as set forth above. In another embodiment, R 2 is -(C4-Cu 2 )cycloalkenyl optionally substituted as set forth above. 10 In another embodiment, R 2 is selected from the group consisting of-(C 6 C 14 )bicycloalkyl, -(Cs-C 20 )tricycloalkyl, -(C 7
-C,
4 ) bicycloalkenyl, and -(Cs C2o)tricycloalkenyl, each of which is optionally substituted as set forth above. In another embodiment, R 2 is -(5- to 12-membered)aryl optionally substituted as set forth above. In a more specific embodiment, R 2 is phenyl optionally substituted with one or 15 two substituents independently selected from -(Ci-C 6 )alkyl, OH, halo, NH 2 , -NH(Ci-C 6 )alkyl, CN, and SH. In another embodiment, R 2 is -(5- to 12-membered)heteroaryl, -(3- to 12-membered) heterocycle, or -(7- to 12-membered) bicycloheterocycle, each of which is optionally substituted as set forth above. 20 In one embodiment, R 3 is hydrogen. In another embodiment, R 3 is OH. In another embodiment, R 3 is -(Ci-C 6 )alkyl. In a more specific embodiment, R 3 is selected from the group consisting of methyl, ethyl and isopropyl. In another embodiment, R 3 is -CH2(halo). In a more specific embodiment, R 3 is 25 selected from the group consisting of CH2F and CH 2 Cl. In one embodiment, Z is -CH 2 -. In another embodiment, Y is -CH 2 -. In a further embodiment, both Z and Y are -CH 2 -. In another embodiment, Y is absent. 30 In another embodiment, Z is -CH 2 - and Y is absent. In another embodiment, Y is -CH 2
-CH
2 -. In another embodiment, Z is -CH 2
-CH
2 -. In another embodiment, both Y and Z are -CH 2
-CH
2 -. In another embodiment, Z is -CH 2
-CH
2 - and Y is absent. -16- In another embodiment, Z is -CH 2 - and Y is -CH 2
-CH
2 -. In another embodiment, Z is -CH 2
-CH
2 and Y is -CH 2 -. In another embodiment, Y is -CH 2
-CH
2
-CH
2 - C In another embodiment, Z is -CH 2
-CH
2
-CH
2 -. 5 In another embodiment, Y is absent and Z is -CH 2
-CH
2
-CH
2 -. In another embodiment, Y is -CH 2
-CH
2
-CH
2 - and Z is -CH 2 -. In another embodiment, Y is -CH 2 - and Z is -CH 2
-CH
2
-CH
2 -. In another embodiment, Y is -CH 2
-CH
2
-CH
2 - and Z is -CH 2
-CH
2 -. In another embodiment, Y is -CH 2
-CH
2 - and Z is -CH 2
-CH
2
-CH
2 -. 10 In one embodiment, Z and Y are both -CH 2 -, R' is -(Ci-C 6 )alkyl, R 2 is -(Cr
C
6 )alkenyl, and R 3 is H. In one embodiment, Z and Y are both -CH 2 -, R' is -(Ci-C 6 )alkyl, R 2 is -(C 2 C 6 )alkynyl, and R 3 is H. In one embodiment, Z and Y are both -CH 2 -, R is -(CI-C 6 )alkyl, R 2 is -(5- to 12 15 membered)aryl, and R 3 is H. In one embodiment, Z and Y are both -CH 2 -, R' is ((C 3
-C
1 2 )cycloalkyl)-(CI-C 6 )alkyl-,
R
2 is -(C 2
-C
6 )alkenyl, and R 3 is H. In one embodiment, Z and Y are both -CH 2 -, R' is ((C 3
-C
1 )cycloalkyl)-(CI-C 6 )alkyl-,
R
2 is -(C2-C 6 )alkynyl, and R 3 is H. 20 In one embodiment, Z and Y are both -CH 2 -, R is ((C3-C 12 )cycloalkyl)-(CI-C 6 )alkyl-,
R
2 is -(5- 12-membered)aryl, and R 3 is H. In one embodiment, Z and Y are both -CH 2 -, R is -(Ci-C 6 )alkyl, R 2 is -(C 2 C 6 )alkenyl, and R 3 is OH. In one embodiment, Z and Y are both -CH 2 -, R' is -(Ci-C 6 )alkyl, R 2 is -(C 2 25 C 6 )alkynyl, and R 3 is OH. In one embodiment, Z and Y are both -CH 2 -, R' is -(Ci-C 6 )alkyl, R 2 is -(5- to 12 membered)aryl, and R 3 is OH. In one embodiment, Z and Y are both -CH 2 -, R' is ((C 3
-C
1 2 )cycloalkyl)-(CI-C 6 )alkyl-,
R
2 is -(C 2
-C
6 )alkenyl, and R 3 is OH. 30 In one embodiment, Z and Y are both -CH 2 -, R is ((C 3
-C
1 )cycloalkyl)-(Ci-C 6 )alkyl-,
R
2 is -(C 2
-C
6 )alkynyl, and R 3 is OH. In one embodiment, Z and Y are both -CH 2 -, R' is ((C3-C 12 )cycloalkyl)-(C 1
-C
6 )alkyl-,
R
2 is -(5- 12-membered)aryl, and R 3 is OH. -17- In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is -(CI-C 6 )alkyl, R 2 is -(C 2 C 6 )alkenyl, and R 3 is H. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R is -(Ci-C 6 )alkyl, R 2 is -(C 2 C 6 )alkynyl, and R 3 is H. 5 In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R is -(CI-C 6 )alkyl, R 2 is -(5- to 12 membered)aryl, and R 3 is H. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is ((C 3
-C]
2 )cycloalkyl)-(C
C
6 )alkyl-, R 2 is -(C 2
-C
6 )alkenyl, and R 3 is H. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is ((C 3
-C
1 2 )cycloalkyl)-(C 10 C 6 )alkyl-, R2 is -(C 2
-C
6 )alkynyl, and R 3 is H. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is ((C 3 -CI)cycloalkyl)-(CI
C
6 )alkyl-, R 2 is -(5- to 12-membered)aryl, and R 3 is H. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is -(Ci-C 6 )alkyl, R 2 is -(C 2 C 6 )alkenyl, and R 3 is OH. 15 In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is -(Ci-C 6 )alkyl, R 2 is -(C2 C6)alkynyl, and R 3 is OH. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is -(Ci-C6)alkyl, R 2 is -(5- to 12 membered)aryl, and R 3 is OH. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is ((C 3
-C
12 )cycloalkyl)-(C 20 C 6 )alkyl-, R 2 is -(C2-C 6 )alkenyl, and R 3 is OH. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is ((C 3
-C
1 2 )cycloalkyl)-(CI
C
6 )alkyl-, R 2 is -(C 2
-C
6 )alkynyl, and R 3 is OH. In one embodiment Z, is -CH 2 , Y is -CH 2
-CH
2 -, R' is ((C3-C 12 )cycloalkyl)-(C,
C
6 )alkyl-, R 2 is -(5- to 12-membered)aryl, and R 3 is OH. 25 In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is -(CI-C 6 )alkyl, R 2 is -(C2
C
6 )alkynyl, and R 3 is H. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is -(CI-C 6 )alkyl, R 2 is -(5- to 12 membered)aryl, and R 3 is H. In one embodiment, Z is -CH 2 , Y is absent, R' is ((C 3
-C)
2 )cycloalkyl)-(CI-C 6 )alkyl-, 30 R 2 is -(C2-C 6 )alkenyl, and R 3 is H. In one embodiment, Z is -CH 2 , Y is -CH 2 -CH2-, R' is ((C 3
-C
12 )cycloalkyl)-(C
C
6 )alkyl-, R 2 is -(C 2
-C
6 )alkynyl, and R 3 is H. In one embodiment, Z is -CH 2 , Y is absent, R' is ((C3-C1)cycloalkyl)-(CI-C 6 )alkyl-,
R
2 is (5- to 12-membered)aryl, and R 3 is H. -18- In one embodiment, Z is -CH 2 , Y absent, R' is -(CI-C 6 )alkyl, R 2 is -(C 2
-C
6 )alkenyl, and R 3 is OH. In one embodiment, Z is -CH 2 , Y is absent, R' is -(CI-C 6 )alkyl, R 2 is -(C 2
-C
6 )alkynyl, and R 3 is OH. 5 In one embodiment, Z is -CH 2 , Y is absent, R' is -(CI-C 6 )alkyl, R 2 is -(5- to 12 membered)aryl, and R 3 is OH. In one embodiment, Z is -CH 2 , Y is absent, R' is ((C 3
-C
12 )cycloalkyl)-(CI-C 6 )alkyl-,
R
2 is -(C 2
-C
6 )alkenyl, and R 3 is OH. In one embodiment, Z is -CH 2 , Y absent, R' is ((C-C 2 )cycloalkylHCi-C 6 )alkyl-, R 2 10 is -(C 2
-C
6 )alkynyl, and R 3 is OH. In one embodiment Z is -CH 2 , Y is absent, R 1 is ((C 3
-CI
2 )cycloalkyl)-(CI-C 6 )alkyl-,
R
2 is -(5- to 12-membered)aryl, and R 3 is OH. The present invention also provides compounds of Formula (II): 15 RI
R
3 b 0R2 z Y X 0
OCH
3 (II) wherein R' is selected from -(Ci-Cio)alkyl, -(C 2
-C
1 2 )alkenyl, -(C 2
-C
12 )alkynyl, -(C 3 20 C12)cycloalkyl, -(C 4 -C2)cycloalkenyl, ((C 3 -C2)cycloalkyl)-(CI-C 6 )alkyl-, ((C 4 C12)cycloalkenyl)-(Ci-C 6 )alkyl-, -(5- to 12-membered)aryl, (5- to 12-membered)heteroaryl, a (3- to 12-membered)heterocycle, phenyl, and benzyl; any of which is optionally substituted with one to three substituents independently selected from the group consisting of -(C 1 -19-
C
6 )alkyl, OH, halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), NH 2 , -NH(CI-C 6 )alkyl, CN, SH, -(5 to 12-membered)carbocyclic ring, -(5- to 12-membered)heterocycle, phenyl, and benzyl;
R
2 is selected from hydrogen, -(Ci-CIo)alkyl, -(C 2
-C
12 )alkenyl, -(C 2
-C
12 )alkynyl, -(C 3 C 12 )cycloalkyl, -(C 4 -C z)cycloalkenyl, -(C 6 -CI4)bicycloalkyl, -(Cs.C 2 0)tricycloalkyl, -(C 7 5 C 14 )bicycloalkenyl, -(Cs-C 2 o)tricycloalkenyl, -(5- to 12-membered)aryl, -(5- to 12 membered)heteroaryl, -(3- to 12-membered)heterocycle, -(7- to 12 membered)bicycloheterocycle, phenyl and benzyl; any of which is optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(CI-C 6 )alkyl, halo(CI-C 6 )alkyl-, -(C 2
-C
6 )alkenyl, 10 (C 2
-C
6 )alkynyl, hydroxy(CI-C 6 )alkyl-, phenyl, benzyl, NH 2 , -Ni(Ci-C 6 )alkyl, CN, SH, OR 4 ,
CONRR
6 and COOR 7 ;
R
3 ' and R 3 b are each independently hydrogen, -(CI-C 6 )alkyl, -(C 2
-C
6 )alkenyl, -(C 2 C 6 )alkynyl, OH, hydroxy(CI-C 6 )alkyl-, (=0), -(C(halo) 3 , -CH(halo) 2 , and -CH 2 (halo);
R
4 is selected from -(Ci-C 6 )alkyl, -(C-C 6 )alkenyl, -(C-C 6 )alkynyl, hydroxy(C, 15 C 6 )alkyl-, -(C 3 -Cu 2 )cycloalkyl, -(C6-C 14 )bicycloalkyl, -(Cs-C 2 0)tricycloalkyl, -(C 4 C 12 )cycloalkenyl, -(C 7 -CI4)bicycloalkenyl, -(Cs-C 2 0)tricycloalkenyl, -(5- to 12 membered)aryl, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, and (7- to 12-membered)bicycloheterocycle;
R
5 and R 6 are each independently -(Ci-C 6 )alkyl, -(C 3 -Cs)cycloalkyl, ((C 3 20 Cg)cycloalkyl)-(C 1
-C
6 )alkyl-, or together with the nitrogen atom to which they are attached form a (4- to 8- membered)heterocycle;
R
7 is selected from hydrogen, -(Ci-C 6 )alkyl, -(C-C 6 )alkenyl, -(C 2
-C
6 )alkynyl, -(C 3 C 1 2)cycloalkyl, -(C 4 -Cu 2 )cycloalkenyl, ((C 3 -C, )cycloalkyl)-(CI-C 6 )alkyl-, ((C 4 C 1 2)cycloalkenyl)-(CI-C 6 )alkyl- ; 25 X is selected from (Ci-C 6 )alkoxy and OH; Z is (CH 2 )m; Y is (CH 2 )n; m is an integer 1, 2, 3, 4, 5, or 6; n is an integer 0, 1, 2, 3, 4, 5 or 6; 30 and the pharmaceutically acceptable salts, prodrugs and solvates thereof. In certain embodiments, the invention provides compounds represented by Formula (1IA): - 20 - R1 N R3a R3b RaR 0 R2 z Y OCH3 (1IA) wherein R', R 2 R 3 3, R 3, X, Y and Z are as described above for Formula (II). 5 In certain embodiments, the inve n ti o n provides compounds represented by Formula (IIB): R' N R3a R3 - 21 2 z Y x OCH3 (IIB). wherein R', R2, Rsa R ,X Y and Z are as described above for Formula (II). 10 In one embodiment, R' is -(CI-Clo)alkyl optionally substituted as set forth above. In a more specific embodiment, R' is selected from the group consisting of methyl, ethyl, or isopropyl, each of which is optionally substituted. - 21 - In another embodiment, R' is -(C2-C 1 2 )alkenyl optionally substituted as set forth above. In a more specific embodiment, R' is selected from the group consisting of ethenyl and propenyl, each of which is optionally substituted. In another embodiment, R' is -(C 3 -CI2)cycloalkyl optionally substituted as set forth 5 above. In another embodiment, R 1 is-(C 4
-C
1 2 )cycloalkenyl optionally substituted as set forth above. In another embodiment, R' is ((C 3
-C
12 )cycloalkyl)-(CI-C 6 )alkyl-. In a more specific embodiment, R1 is selected from the group consisting of cyclopropylmethyl, 10 cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl, each of which is optionally substituted. In another embodiment, R' is -(5- to 12-membered)aryl, -(5- to 12 membered)heteroaryl, or -(3- to 12-membered)heterocycle, each of which is optionally substituted as set forth above. 15 In one embodiment, R 2 is -(Ci-CIo)alkyl optionally substituted as set forth above. In a more specific embodiment, R 2 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pentyl and hexyl, each of which is optionally substituted. In another embodiment, R 2 is -(C 2 -Cu 2 )alkenyl optionally substituted as set forth 20 above. In a more specific embodiment, R 2 is selected from the group consisting of 2-methyl but-2-enyl and propenyl, each of which is optionally substituted. In another embodiment, R 2 is -(C2-C 12 )alkynyl optionally substituted as set forth above. In a more specific embodiment, R 2 is optionally substituted propynyl. In another embodiment, R 2 is -(C3-C 1 2 )cycloalkyl optionally substituted as set forth 25 above. In another embodiment, R 2 is -(C4-C 1 2 )cycloalkenyl optionally substituted as set forth above. In another embodiment, R 2 is -(C6-C] 4 )bicycloalkyl, -(CS-C 2 0)tricycloalkyl, -(C 7
-C
1 4 ) bicycloalkenyl, or -(C 8
-C
2 0)tricycloalkenyl, each of which is optionally substituted as set 30 forth above. In another embodiment, R2 is -(5- to 12-membered)aryl optionally substituted as set forth above. In a more specific embodiment, R2 is phenyl optionally substituted with one or two substituents independently selected from -(Ci-C 6 )alkyl, OH, halo, NH 2 , -NH(C 1
-C
6 )alkyl, CN, (=0), and SH. - 22 - In another embodiment, Y is CH 2 and R2 is phenyl. In another embodiment, R 2 is benzyl. In another embodiment, R 2 is -(5- to 12-membered)heteroaryl, -(3- to 12 membered)heterocycle, or -(7- to 12-membered)bicycloheterocycle, each of which is 5 optionally substituted as set forth above. In one embodiment, at least one of R 3 " or R 3 b is hydrogen. In another embodiment, both R 3 and R 3 b are hydrogen. In another embodiment, at least one of R 3 a or R 3 1 is OH. In another embodiment, at least one of R 3 a or R 3 b is -(Ci-C 6 )alkyl. In a more specific 10 embodiment, at least one of R 3 a or R 3 A is selected from the group consisting of methyl, ethyl and isopropyl. In another embodiment, at least one of R 3 " or R 3 b is -CH 2 (halo). In a more specific embodiment, at least one of R 3 " or R 3 b is selected from the group consisting of CH 2 F and
CH
2 Cl. 15 In one embodiment, X is (CI-Cs)alkoxy. In another embodiment, X is methoxy. In another embodiment, X is OH. In one embodiment, Z is -CH 2 -. In another embodiment, Y is -CH 2 -. 20 In a further embodiment, both Z and Y are -CH 2 -. In another embodiment, Y is absent. In another embodiment, Z is -CH 2 - and Y is absent. In another embodiment, Y is -CH 2
-CH
2 -. In another embodiment, Z is -CH 2
-CH
2 -. 25 In another embodiment, both Y and Z are -CH 2
-CH
2 -. In another embodiment, Z is -CH 2
-CH
2 - and Y is absent. In another embodiment, Z is -CH 2 - and Y is -CH 2
-CH
2
-
In another embodiment, Z is -CH 2
-CH
2 - and Y is -CH 2 -. In another embodiment, Y is -CH 2
-CH
2
-CH
2 -. 30 In another embodiment, Z is -CH 2
-CH
2
-CH
2 -. In another embodiment, Y is absent and Z is -CH 2
-CH
2
-CH
2 -. In another embodiment, Y is -CH 2
-CH
2
-CH
2 - and Z is -CH 2 -. In another embodiment, Y is -CH 2 - and Z is -CH 2
-CH
2
-CH
2 -. In another embodiment, Y is -CH 2
-CH
2
-CH
2 - and Z is -CH 2
-CH
2 -. - 23 - In another embodiment, Y is -CH 2
-CH
2 - and Z is -CH 2
-CH
2
-CH
2 -. In one embodiment, Z and Y are both -CH 2 -, R 1 is -(Ci-C 6 )alkyl, R 2 is -(C 2 C 6 )alkenyl, and at least one of R 3 ' and R 3 b is H. In one embodiment, Z and Y are both -CH 2 -, R' is -(Ci-C 6 )alkyl, R 2 is -(C 2 5 C 6 )alkenyl, and both R 3 " and R 3 b are H. In one embodiment, Z and Y are both -CH 2 -, R' is -(C1i-C 6 )alkyl, R 2 is -(C 2 C 6 )alkynyl, and at least one of R 3 " and R 3 b is H. In one embodiment, Z and Y are both -CH 2 -, R' is -(Ci-C 6 )alkyl, R 2 is -(C 2 C 6 )alkynyl, and both R 3 " and R are H. 10 In one embodiment, Z and Y are both -CH 2 -, R' is -(CI-C 6 )alkyl, R 2 is -(5- to 12 membered)aryl, and at least one of R 3 ' and R 3 b is H. In one embodiment, Z and Y are both -CH 2 -, R' is -(Ci-C 6 )alkyl, R 2 is -(5- to 12 membered)aryl, and both R " and Rb are H. In one embodiment, Z and Y are both -CH 2 -, R' is ((C 3
-C
12 )cycloalkyl)-(C-C 6 )alkyl-, 15 R 2 is -(C-C 6 )alkenyl, and at least one of R 3 ' and R 3 b is H. In one embodiment, Z and Y are both -CH 2 -, R' is ((C-CI2)cycloalkyl)-(C-C 6 )alkyl-, R2 is -(C 2
-C
6 )alkenyl, and both R 3 ' and R 3 b are H. In one embodiment, Z and Y are both -CH 2 -, R' is ((C3-CI 2 )cycloalkyl)-(C-C 6 )alkyl-,
R
2 is -(C2-C 6 )alkynyl, and at least of R 3 a and R 3 b is H. 20 In one embodiment, Z and Y are both -CH 2 -, R' is ((C3-C 12 )cycloalkyl)-(CI-C 6 )alkyl-,
R
2 is -(C 2
-C
6 )alkynyl, and both R 3 ' and R 3 A are H. In one embodiment, Z and Y are both -CH 2 -, R' is ((C3-CI2)cycloalkyl)-(C-C 6 )alkyl-,
R
2 is -(5- 12-membered)aryl, and at least one of R 3 and R 3 b is H. In one embodiment, Z and Y are both -CH 2 -, R' is ((C 3
-C
12 )cycloalkyl)-(C-C 6 )alkyl-, 25 R 2 is -(5- 12-membered)aryl, and both R 3 " and R 3 b are H. In one embodiment, Z and Y are both -- CH 2 -, R' is -(C i-C 6 )alkyl, R 2 is -(C 2 C 6 )alkenyl, and at least one of R 3 ' and R 3 b are OH. In one embodiment, Z and Y are both -CH 2 -, R' is -(C -C 6 )alkyl, R 2 is -(C 2 C6)alkynyl, and at least one of R 3 ' and R 3 b are OH. 30 In one embodiment, Z and Y are both -CH 2 -, R' is -(C1-C 6 )alkyl, R 2 is a (5- to 12 membered)aryl, and at least one of R3a and R3b is OH. In one embodiment, Z and Y are both -CH 2 -, R' is ((C3-Cl)cycloalkyl)-(C-C 6 )alkyl-,
R
2 is -(C 2
-C
6 )alkenyl, and at least one of R 3 ' and R 3 b is OH. -24- In one embodiment, Z and Y are both -CH 2 -, R' is ((C 3
-CI
2 )cycloalkyl)-(CI-C 6 )alkyl-,
R
2 is -(C 2
-C
6 )alkynyl, and at least one of R 3 a and R 3 1 is OH. In one embodiment, Z and Y are both -CH 2 -, R' is ((C 3
-C
1 2 )cycloalkyl)-(CI-C 6 )alkyl-,
R
2 is -(5- 12-membered)aryl, and at least one of R 3 " and R3b is OH. 5 In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R 1 is -(Ci-C 6 )alkyl, R 2 is -(C 2 C 6 )alkenyl, and at least one of R 3 a and R 3 b is H. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is -(Ci-C 6 )alkyl, R 2 is -(C 2 C 6 )alkenyl, and both R 3 ' and R 3 b are H. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is -(Ci-C 6 )alkyl, R 2 is -(C 2 10 C 6 )alkynyl, and at least one of R3a and R 3 b is H. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is -(Ci-Cs)alkyl, R 2 is -(C 2 C 6 )alkynyl, and both R 3 a and R 3 b are H. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is -(Ci-C 6 )alkyl, R 2 is -(5- to 12 membered)aryl, and at least one of R a and R 3 b is H. 15 In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is -(Ci-C 6 )alkyl, R 2 is -(5- to 12 membered)aryl, and both R'a and Rlb are H. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is ((C 3
-CI
2 )cycloalkyl)-(C
C
6 )alkyl-, R 2 is -(C 2
-C
6 )alkenyl, and at least one of R 3 a and R 3 b is H. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R 1 is ((C 3 -C12)cycloalkyl)-(CI 20 C 6 )alkyl-, R 2 is -(C 2
-C
6 )alkenyl, and both R 3 ' and R 3 b are H. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is ((C 3
-C
12 )cycloalkyl)-(C
C
6 )alkyl-, R 2 is -(C 2
-C
6 )alkynyl, and at least one of R 3 a and R 3 b is H. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is ((C3-C) 2 )cycloalkyl)-(C:
C
6 )alkyl-, R 2 is -(C 2
-C
6 )alkynyl, and both R 3 " and R 3 b are H. 25 In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R 1 is ((C 3
-C
1 2 )cycloalkylHCI Cs)alkyl-, R 2 is -(5- to 12-membered)aryl, and at least one of R a and R 3 b is H. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is ((C 3
-C
2 )cycloalkylHC C 6 )alkyl-, R 2 is -(5- to 12-membered)aryl, and both R 3 ' and R 3 b are H. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is -(C i-C 6 )alkyl, R 2 is -(C 2 30 C 6 )alkenyl, and at least one of R 3 and R b is OH. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is -(Ci-C 6 )alkyl, R 2 is -(C 2 C 6 )alkynyl, and at least one of R 3 ' and R 3 b is OH. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is -(Ci-C 6 )alkyl, R 2 is -(5- to 12 membered)aryl, and at least one of R 3 ' and R"b is OH. - 25 - In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is ((C 3
-C
12 )cycloalkylMC
C
6 )alkyl-, R 2 is -(C 2
-C
6 )alkenyl, and at least one of R 3 e and R 3 b is OH. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is ((C 3
-C
12 )cycloalkyl)-(C
C
6 )alkyl-, R 2 is -(C 2
-C
6 )alkynyl, and at least one of R 3 " and R 3 b is OH. 5 In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is ((C 3
-C
1 2 )cycloalkyl)-(Ci
C
6 )alkyl-, R 2 is -(5- to 12-membered)aryl, and at least one of R 3 a and R 3 b is OH. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is -(Ci-C 6 )alkyl, R 2 is -(C 2 C 6 )alkynyl, and at least one of R 3 a and R 3 b is H. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R 1 is -(Ci-C 6 )alkyl, R 2 is -(C 2 10 C 6 )alkynyl, and both R 3 a and R 3 b are H. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is -(Ci-C 6 )alkyl, R 2 is -(5- to 12 membered)aryl, and at least one of R 3 ' and R A is H. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 , R' is -(Ci-C 6 )alkyl, R 2 is -(5- to 12 membered)aryl, and both R3a and R 3 b are H. 15 In one embodiment, Z is -CH 2 , Y is absent, R 1 is ((C 3
-C
2 )cycloalkyl)-(CI-C 6 )alkyl-,
R
2 is -(C 2
-C
6 )alkenyl, and at least one of R 3 ' and R 3 b is H. In one embodiment, Z is -CH 2 , Y is absent, R' is ((C 3
-C
2 )cycloalkyl)-(Ci-C 6 )alkyl-,
R
2 is -(C 2
-C
6 )alkenyl, and both R 3 ' and R 3 b are H. In one embodiment, Z is -CH 2 , Y is -CH 2
-CH
2 -, R' is ((C 3
-C
1 2 )cycloalkylH 20 C 6 )alkyl-, R 2 is -(C 2
-C
6 )alkynyl, and at least one of R3a and R 3 b is H. In one embodiment, Z is -CH 2 , Y is -CHr 2
-CH
2 -, R' is ((C 3
-C
12 )cycloalkyl)-(Ci
C
6 )alkyl-, R 2 is -(C 2
-C
6 )alkynyl, and both R 3 a and R 3 A are H. In one embodiment, Z is -CH 2 , Y is absent, R' is ((C 3 -Ci 2 )cycloalkyl)-(CI-C 6 )alkyl-,
R
2 is -(5- to 12-membered)aryl, and at least one of R 3 a and R 3 b is H. 25 In one embodiment, Z is -CH 2 , Y is absent, R' is ((C 3
-C
12 )cycloalkyl)-(CI-C 6 )alkyl-,
R
2 is -(5- to 12-membered)aryl, and both R 3 a and R"b are H. In one embodiment, Z is -CH 2 , Y absent, R' is -(CI-C 6 )alkyl, R 2 is -(C 2
-C
6 )alkenyl, and at least one of R 3 a and R 3 b is OH. In one embodiment, Z is -CH 2 , Y is absent, R' is -(CI-C 6 )alkyl, R 2 is -(C-C 6 )alkynyl, 30 and at least one of R 3 a and R 3 b is OH. In one embodiment, Z is -CH 2 , Y is absent, R' is -(CI-C 6 )alkyl, R 2 is -(5- to 12 membered)aryl, and at least one of R 3 a and R 3 b is OH. In one embodiment, Z.is -CH 2 , Y is absent, R' is ((C 3
-C
12 )cycloalkyl)-(CI-C 6 )alkyl-,
R
2 is -(C 2
-C
6 )alkenyl, and at least one of R 3 and R"' is OH. - 26 - In one embodiment, Z is -CH 2 , Y absent, R' is ((C 3
-C
1 )cycloalkyl)-(CI-C 6 )alkyl-, R 2 is -(C 2
-C
6 )alkynyl, and at least one of R 3 a and R 3 ' is OH. In one embodiment, Z is -CH 2 , Y is absent, R' is ((C 3
-C,
2 )cycloalkyl)-(C-C 6 )alkyl-,
R
2 is -(5- to 12-membered) aryl, and at least one of R 3 a and R 3 b is OH. 5 Specific compounds of the present invention include: 7a-(allyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 7a-(benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 7a-(propargyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 22-cyclopropyl-7a-(benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 10 22-cyclopropyl-7a-(allyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 22-cyclopropyl-7a-(propargyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; and the pharmaceutically acceptable salts, prodrugs and solvates thereof. Specific compounds of the present invention further include: 22-cyclopropyl-7a-(cyclohexylmethoxymethyl)-6,14-endo-ethanotetrahydrothebaine; 15 22-cyclopropyl-7a-(4-chlorobenzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 22-cyclopropyl-7a-((3,4-dichloro)benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 22-cyclopropyl-7a-((4-trifluoromethyl)benzyloxymethyl)-6,14-endo ethanotetrahydrothebaine; 7c-(cyclohexylmethoxymethyl)-6,14-endo-ethanotetrahydrothebaine; 20 7ax-((4-trifluoromethyl)benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 7a-((2-naphthyl)methoxymethyl)-6,14-endo-ethanotetrahydrothebaine; 7a-((3,4-dichloro)benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 7a-((3-methyl)benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 7a-((4-tert-butyl)benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 25 7a-((trans-3-phenylprop-2-enyl)oxymethyl)-6,14-endo-ethanotetrahydrothebaine; and the pharmaceutically acceptable salts, prodrugs and solvates thereof. The present invention further provides compounds of Formula (III): - 27 - RR N R 3a R3b 0 R2 R8 X 0 OCH3 (Ill) wherein R' is selected from -(CI-Cio)alkyl, -(C 2
-C
1 2 )alkenyl, -(C 2 -C1 2 )alkynyl, -(C 3 5 C 12 )cycloalkyl, -(C 4
-C
2 )cycloalkenyl, ((C 3
-C
2 )cycloalkyl)-(C-C 6 )alkyl-, ((C 4 C 1 2)cycloalkenyl)-(C-C 6 )alkyl-, -(5- to 12-membered)aryl, ((5- tol2-membered)aryl)-(C
C
6 )alkyl-, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, phenyl, and benzyl; any of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -(C-C 6 )alkyl, OH, halo, -C(halo) 3 , -CH(halo) 2 , 10 CH 2 (halo), NH 2 , -NH(CI-C 6 )alkyl, CN, SH, -(5- to 12-membered)carbocyclic ring, -(5- to 12 membered)heterocycle, phenyl, and benzyl;
R
2 and R 8 are each independently hydrogen, -(CI-CIo)alkyl, -(C2-C 12 )alkenyl, -(C 2 C 1 2)alkynyl, -(C 3 -C2)cycloalkyl, -((C 3 -C2)cycloalkyl)-(CI-C 6 )alkyl, -(C 4 -Cu2)cycloalkenyl, (C 6 -CI4)bicycloalkyl, -(CS.C20)tricycloalkyl, -(C 7
-CI
4 )bicycloalkenyl, -(Cs-C 2 0)tricycloalkenyl, 15 -(5- to 12-membered)aryl, ((5- tol2-membered)aryl)-(C-C 6 )alkyl-, -(7- to 12 membered)bicyclic ring system, -(7- to 12-membered)bicyclic aryl, -(5- to 12 membered)heteroaryl, -(3- to 12-membered)heterocycle, -(7- to 12-membered) bicycloheterocycle, phenyl and benzyl; any of which is optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), 20 halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(C-C 6 )alkyl, halo(C-C 6 )alkyl-, -(C 2
-C
6 )alkenyl, (C 2
-C
6 )alkynyl, hydroxy(C-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(CI-C 6 )alkyl, CN, SH, OR 4 ,
CONRR
6 and COOR'; - 28 -
R
3 ' and R 3 b are each independently selected from hydrogen, -(CI-C 6 )alkyl, -(C 2 C 6 )alkenyl, -(C 2
-C
6 )alkynyl, OH, hydroxy(Ci-C 6 )alkyl-, (=0), -C(halo) 3 , -CH(halo) 2 , and CH 2 (halo);
R
4 is selected from -(Ci-C 6 )alkyl, -(C-C 6 )alkenyl, -(C 2
-C
6 )alkynyl, -C(halo) 3 , 5 hydroxy(Ci-C 6 )alkyl-, -(C 3 -Cu 2 )cycloalkyl, -(C 6
-CI
4 )bicycloalkyl, -(CS-C 20 )tricycloalkyl, (C 4 -C 2 )cycloalkenyl, -(C 7 -CI4)bicycloalkenyl, -(C8-C20)tricycloalkenyl, -(5- to 12 membered)aryl, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, and (7- to 12-membered)bicycloheterocycle;
R
5 and R 6 are each independently -(C I-C 6 )alkyl, -(C 3 -Cs)cycloalkyl, ((C 3 10 Cs)cycloalkyl)-(C1-C 6 )alkyl-, or together with the nitrogen atom to which they are attached form a (4- to 8- membered)heterocycle; R' is selected from hydrogen, -(Ci-C 6 )alkyl, -(C 2
-C
6 )alkenyl, -(C2-C 6 )alkynyl, -(C 3 C 12 )cycloalkyl, -(C 4
-C,
2 )cycloalkenyl, ((C 3
-C
2 )cycloalkyl)-(CI-C 6 )alkyl-, and ((C 4 C 1 2 )cycloalkenyl)-(CI-C 6 )alkyl- ; 15 X is selected from (Ci-C 6 )alkoxy and OH; Z is (CH 2 )m; Y is (CH 2 )n-CH or a direct bond, provided that when Y is a direct bond then R 8 is absent; m is an integer 1, 2, 3, 4, 5, or 6; 20 n is an integer 0, 1, 2, 3, 4, 5 or 6; and the pharmaceutically acceptable salts, prodrugs and solvates thereof. In certain embodiments, the invention provides compounds represented by Formula (IIA): 25 -29- RR /N
R
3 b R2 Z Y Rea X 60
OCH
3 (IIIA) wherein R1, R 2 , R , R 3 a, R 3 b, X Y and Z are as described above for Formula (III). In certain embodiments, the invention provides compounds represented by Formula 5 (IIIB3): R1 N R3a -R 3b Z Y x O OCH3 R wherein R1, R2, R8, R3a, R3 b, X Y and Z are as described above for Formula (III). In one embodiment, R' is -(CI-CIO)alkyl optionally substituted as set forth above. In a 10 more specific embodiment, R' is selected from the group consisting of methyl, ethyl, or isopropyl, each of which is optionally substituted. In another embodiment, R' is -(C2-C12)alkenyl optionally substituted as set forth above. In a more specific embodiment, R' is selected from the group consisting of ethenyl and propenyl, each of which is optionally substituted. - 30 - In another embodiment, R' is -(C3-CIu)cycloalkyl optionally substituted as set forth above. In another embodiment, R' is-(C4-C 1 2 )cycloalkenyl optionally substituted as set forth above. 5 In another embodiment, R' is ((C3-CI2)cycloalkyl)-(Ci-C 6 )alkyl-. In a more specific embodiment, R' is selected from the group consisting of cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl, each of which is optionally substituted. In another embodiment, R' is -(5- to 12-membered)aryl, -(5- to 12 10 membered)heteroaryl, or -(3- to 12-membered)heterocycle, each of which is optionally substituted as set forth above. In one embodiment, at least one of R 2 or R 8 is -(Ci-Cio)alkyl optionally substituted as set forth above. In a more specific embodiment, at least one of R 2 or R 8 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pentyl and 15 hexyl, each of which is optionally substituted. In one embodiment, both R2 and R8 are -(Ci-Cio)alkyl optionally substituted as set forth above. In a more specific embodiment, both R2 are R are selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pentyl and hexyl, each of which is optionally substituted. 20 In another embodiment, at least one of R 2 or R 8 is -(C 2 -Cu 2 )alkenyl optionally substituted as set forth above. In a more specific embodiment, at least one of R 2 or R 8 is selected from the group consisting of 2-methyl-but-2-enyl and propenyl, each of which is optionally substituted. In another embodiment, at least one of R 2 or R 8 is -(C2-Cu2)alkynyl optionally 25 substituted as set forth above. In a more specific embodiment, at least one of R 2 or R 8 is optionally substituted propynyl. In another embodiment, at least one of R 2 or R 8 is -(C 3 -C,2)cycloalkyl optionally substituted as set forth above. In another embodiment, both R 2 and R 8 are -(C3-C)2)cycloalkyl optionally substituted 30 as set forth above. In another embodiment, at least one of R 2 or R 8 is -(C4-C12)cycloalkenyl optionally substituted as set forth above. -31 - In another embodiment, at least one of R 2 or R 8 is -(C 6
-CI
4 )bicycloalkyl, -(Cs
C
2 0)tricycloalkyl, -(C 7
-C
1 4 ) bicycloalkenyl, or -(Cs-C 2 0)tricycloalkenyl, each of which is optionally substituted as set forth above. In another embodiment, at least one of R 2 or R 8 is -(5- to 12-membered)aryl 5 optionally substituted as set forth above. In a more specific embodiment, at least one of R 2 or
R
8 is phenyl optionally substituted with one or two substituents independently selected from (Ci-C 6 )alkyl, OH, halo, NH 2 , -NH(Ci-C 6 )alkyl, CN, (=0), SH, phenyl, -C(halo) 3 , -OC(halo)3, and -O(CI-C 6 )alkyl. In another embodiment, both R 2 and R 8 are -(5- to 12-membered)aryl optionally 10 substituted as set forth above. In a more specific embodiment, both R 2 and R 8 are phenyl optionally substituted with one or two substituents independently selected from -(CI-Cs)alkyl, OH, halo, NH 2 , -NH(CI-C 6 )alkyl, CN, (=0), and SH. In another embodiment, at least one of R 2 or R 8 is -(5- to 12-membered)heteroaryl, (3- to 12-membered)heterocycle, or -(7- to 12-membered)bicycloheterocycle, each of which 15 is optionally substituted as set forth above. In one embodiment, at least one of R 3 , or R 3 b is hydrogen. In another embodiment, both R 3 a and R A are hydrogen. In another embodiment, at least one of R 3 a or R 3 b is OH. In another embodiment, at least one of R 3 , or R 3 b is -(Ci-C 6 )alkyl. In a more specific 20 embodiment, at least one of Raa or R 3 b is selected from the group consisting of methyl, ethyl and isopropyl. In another embodiment, both R 3 " and R 3 A are -(C i-C 6 )alkyl. In another embodiment, at least one of R 3 , or R 3 b is -CH2(halo). In a more specific embodiment, at least one of R3a or R 3 b is selected from the group consisting of CH 2 F and 25 CH 2 CL. In one embodiment, X is (Ci-C 6 )alkoxy. In another embodiment, X is methoxy. In another embodiment, X is OH. In one embodiment, Z is -CH 2 -. 30 In another embodiment, Y is -CH. In a further embodiment, Z is -CH 2 - and Y is -CH. In another embodiment, Y is a direct bond. In another embodiment, Z is -CH 2 - and Y is a direct bond. In another embodiment, Y is -CH 2 -CH. - 32 - In another embodiment, Z is -CH 2
-CH
2 -. In another embodiment, Y is -CH 2 -CH and Z is -CH 2
-CH
2 -. In another embodiment, Z is -CH 2
-CH
2 - and Y is a direct bond. In another embodiment, Z is -CH 2 - and Y is -CH 2 -CH. 5 In another embodiment, Z is -CH 2
-CH
2 - and Y is -CH. In another embodiment, Y is -CH 2
-CH
2 -CH. In another embodiment, Z is -CH 2
-CH
2
-CH
2 -. In another embodiment, Y is a direct bond and Z is -CH 2
-CH
2
-CH
2 -. In another embodiment, Y is -CH 2
-CH
2 -CH and Z is -CH 2 -. 10 In another embodiment, Y is -CH and Z is -CH 2
-CH
2
-CH
2 -. In another embodiment, Y is -CH 2
-CH
2 -CH and Z is -CH 2
-CH
2 -. In another embodiment, Y is -CH 2 -CH and Z is -CH 2
-CH
2
-CH
2 -. In one embodiment, Y is -CH and at least one of R 2 or Rg is phenyl. In another embodiment, Y is a direct bond and at least one of R 2 or Ra is benzyl. 15 In one embodiment, Y is -CH and both R 2 and Rg are phenyl. In another embodiment, Y is a direct bond and R 2 is benzyl. In one embodiment, X is -(C I-C 6 )alkoxy, Z -CH 2 -, Y is -CH, R' is -(CI-C 6 )alkyl, at least one of R 2 or R 8 is -(Ci-C 6 )alkyl, and at least one of R 3 a and R b is H. In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is -(CI-C 6 )alkyl, 20 at least one of R 2 or R 8 is -(C 3
-C
12 )cycloalkyl, and at least one of R 3 a and R 3 b is H. In one embodiment, X is OH, Z is -CHr 2 -, Y is -CH, R' is -(C-C 6 )alkyl, at least one of R 2 or R 8 is -(CI-C 6 )alkyl, and at least one of R 3 ' and R 3 b is H. In one embodiment, X is OH, Z is -CHr, Y is -CH, R' is -(Ci-C 6 )alkyl, at least one of R 2 or R 8 is -(C 3
-C
12 )cycloalkyl, and at least one of R 3 " and R 3 " is H. 25 In one embodiment, X is OH, Z is -CHr 2 -, Y is -CH, R' is -(CI-C 6 )alkyl, both R 2 and R8 are -(CI-C 6 )alkyl, and at least one of R 3 a and R 3 " is H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CHr 2 -, Y is --CH, R' is -(Ci-C 6 )alkyl, at least one of R 2 or R 8 is -(C 1-C 6 )alkyl, and both R 3 ' and R 3 b are H. In one embodiment, X is -(C-C 6 )alkoxy, Z is -CHR 2 -, Y is -CH, R' is -(CI-C 6 )alkyl, 30 at least one of R 2 or R8 is -(C 3
-CI
2 )cycloalkyl, and both R 3 " and R 3 b are H. In one embodiment, X is -(Cr.C 6 )alkoxy, Z is -CHR 2 -, Y is -CH, R' is -(C-C 6 )alkyl, both R 2 or R8 are -(C1-C 6 )alkyl, and both R 3 a and Rb3 are H. In one embodiment, X is OH, Z is -CHr 2 -, Y is -CH, R' is -(CI-C 6 )alkyl, at least one of R 2 or R 8 is -(C i-C 6 )alkyl, and both R 3 , and R 3 b are H. - 33 - WO 2010/014229 PCT/US2009/004391 In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is -(C-C 6 )alkyl, both R 2 and Rg are -(Ci-C 6 )alkyl, and both R 3 ' and R 3 b are H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is -(Ci-C 6 )alkyl, at least one of R 2 or R 8 is -(C-C 6 )alkenyl, and at least one of R 3 and R is H. 5 In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is -(Ci-C 6 )alkyl, at least one of R 2 or R 8 is -(C 2
-C
6 )alkenyl, and both R 3 ' and R 3 A are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is -(Ci-C 6 )alkyl, at least one of R 2 or R 8 is -(C2-C 6 )alkenyl, and at least one of R a and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y -CH, R' is -(Ci-C 6 )alkyl, at least one of 10 R 2 or R is -(C-C 6 )alkenyl, and both R 3 and R 3 b are H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is -(Ci-C 6 )alkyl, at least one of R 2 or R 8 is -(C 2
-C
6 )alkynyl, and at least one of R 3 ' and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is -(Ci-C 6 )alkyl, at least one of R 2 or R 8 is -(C 2
-C
6 )alkynyl, and at least one of R 3 and R 3 b is H. 15 In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is -(Ci-C 6 )alkyl, at least one of R 2 or R 8 is -(C 2
C
6 )alkynyl, and both R3' and R 3 b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is -(CI-C 6 )alkyl, at least one of R 2 or R 8 is -(C 2
-C
6 )alkynyl, and both R 3 a and R 3 b are H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is -(Ci-C 6 )alkyl, 20 at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and at least one of R 3 ' and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is -(Ci-C 6 )alkyl, at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and at least one of R3 and R 3 b is H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is -(Ci-C 6 )alkyl, at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and both R 3 l and R"b are H. 25 In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is -(C-C)alkyl, at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and both R3 and R3b are H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is -(Ci-C 6 )alkyl, at least one of R 2 or R 8 is ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and at least one of R 3 ' and R 3 is H. 30 In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is -(Ci-C 6 )alkyl, at least one of R 2 or R' is ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and both R 3 a and R b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is -(Ci-C 6 )alkyl, at least one of R 2 or R 8 is ((5- to 12-membered)aryl)-(C 1
-C
6 )alkyl-, and at least one of R 3 a and R31 is H. -34- In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is -(C I-C 6 )alkyl, at least one of R 2 or R 8 is ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and both R 3 and R 3 b are H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CHr 2 -, Y is -CH, R' is -(CI-C 6 )alkyl, both R2 and R8 are ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and at least one of R 3 S and R 3 b is 5 H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is -(CI-C 6 )alkyl, both R 2 and R 8 are ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and both R 3 " and R 3 b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R 1 is -(C 1
-C
6 )alkyl, both R 2 and
R
8 are ((5- to 12-membered)aryl)-(C 1
-C
6 )alkyl-, and at least one of R 3 ' and R 3 b is H. 10 In one embodiment, X is OH, Z is -CHr 2 -, Y -CH, R' is -(CI-C 6 )alkyl, both R 2 and R 8 are ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and both R 3 and R 3 b are H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CHR 2 -, Y is -CH, R' is ((Cr
C
12 )cycloalkyl)-CI-C 6 )alkyl-, at least one of R 2 or R 8 is -(C 1
-C
6 )alkyl, and at least one of R 3 and R 3 1 is H. 15 In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CHR 2 -, Y is -CH, R' is ((C 3 CI 2 )cycloalkyl)-(C 1
-C
6 )alkyl-, at least one of R 2 or R 8 is -(C 3 -Cu 2 )cycloalkyl, and at least one of R 3 a and R 3 b is H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CHr 2 -, Y is -CH, R' is ((C 3 CI 2 )cycloalkyl)-(C 1
-C
6 )alkyl-, both R 2 and R' are -(Ci-C 6 )alkyl, and at least one of R 3 ' and 20 R" is H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is ((C 3 C 12 )cycloalkyl)-(CI-C 6 )alkyl-, at least one of R 2 or R 8 is -(CI-C 6 )alkyl, and both R 3 and R 3 1 are H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CHr 2 -, Y is -CH, R' is ((C 3 25 Cu)cycloalkyl)-(CI-C 6 )alkyl-, at least one of R 2 or R 8 is -(C 3 -Cu 2 )cycloalkyl, and both R 3 " and R3b are H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is ((C 3 C 12 )cycloalkyl)-(CI-C 6 )alkyl-, both R 2 and R 8 are -(CI-C 6 )alkyl, and both R 3 ' and R 3 b are H. In one embodiment, X is OH, Z is -CHR 2 -, Y is -CH, R' is ((C 3 -C,2)cycloalkylHCI 30 C 6 )alkyl-, at least one of R 2 or Ra is -(CI-C 6 )alkyl, and at least one of R 3 ' and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is ((C 3
-C
12 )cycloalkyl)-(Ci
C
6 )alkyl-, at least one of R 2 or R 8 is -(C 3
-C
1 2 )cycloalkyl, and at least one of R 3 a and R 3 b is H. In one embodiment, X is OH, Z is -CHr 2 -, Y is -CH, R' is ((C 3
-C
1 2 )cycloalkyl)-(C
C
6 )alkyl-, both R 2 and R 8 are -(Ci-C 6 )alkyl, and at least one of R 3 ' and R 3 b is H. - 35 - In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is ((C 3
-C
12 )cycloalkyl)-(C
C
6 )alkyl-, at least one of R 2 or R 8 is -(C-C 6 )alkyl, and both R 3 a and R 3 b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is ((C 3
-C
1 )cycloalkyl)-(C
C
6 )alkyl-, at least one of R 2 or R 8 is -(C-C 2 )cycloalkyl, and both R 3 a and R 3 b are H. 5 In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is ((C 3
-C
12 )cycloalkyl)-(Cl
C
6 )alkyl-, both R 2 and R 8 are -(C 1
-C
6 )alkyl, and both R 3 ' and R 3 b are H. In one embodiment, X is -(C -C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is ((C 3 C,)cycloalkylHCI-C 6 )alkyl-, at least one of R 2 or R 8 is -(C-C 6 )alkenyl, and at least one of
R
3 a and R 3 1 is H. 10 In one embodiment, X is -(CrC 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is ((C 3 C1 2 )cycloalkyl)-(C-C 6 )alkyl-, at least one of R 2 or R 8 is -(C 2
-C
6 )alkenyl, and both R 3 ' and
R
3 1 are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is ((C 3
-C
1 2 )cycloalkyl)-(Cr
C
6 )alkyl-, at least one of R 2 or R 8 is -(C 2
-C
6 )alkenyl, and at least one of R 3 ' and R 3 b is H. 15 In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is ((C 3
-C
1 )cycloalkyl)-(C
C
6 )alkyl-, at least one of R 2 or R 8 is -(C-C 6 )alkenyl, and both R 3 ' and R 3 b are H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R1 is ((C 3 C 12 )cycloalkyl)-(C-C 6 )alkyl-, at least one of R 2 or R 8 is -(C 2 -CS)alkynyl, and at least of R 3 a and R 3 1 is H. 20 In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is ((Cr
C
1 )cycloalkyl)-(CrC 6 )alkyl-, at least one of R2 or R8 is -(C 2
-C
6 )alkynyl, and both R and
R
3 b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is ((C 3
-C
1 )cycloalkyl)-(C
C
6 )alkyl-, at least one of R 2 or R 8 is -(C-C 6 )alkynyl, and at least of R 3 a and R 3 b is H. 25 In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is ((C 3
-C
1 )cycloalkyl)-(C
C
6 )alkyl-, at least one of R 2 or R 8 is -(C 2
-C
6 )alkynyl, and both R 3 a and R 3 b are H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is ((C 3 C 12 )cycloalkyl)-(C-C 6 )alkyl-, at least one of R 2 or R 8 is -(5- 12-membered)aryl, and at least one of R 3 ' and R 3 b is H. 30 In one embodiment, X is -(C I-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is ((C 3 C, 2 )cycloalkyl)-(C-C 6 )alkyl-, at least one of R 2 or R 8 is -(5- 12-membered)aryl, and both
R
3 a and R 3 b are H. - 36 - In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is ((C 3
-C
12 )cycloalkyl)-(Cr
C
6 )alkyl-, at least one of R 2 or R 8 is -(5- 12-membered)aryl, and at least one of R 3 " and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is ((C 3
-C
12 )cycloalkyl)-(C 5 C 6 )alkyl-, at least one of R 2 or R 82 is -(5- 12-membered)aryl, and both R 3 a and R 3 b are H. In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is -(C-C 6 )alkyl, at least one of R 2 or Rg is -(C 2
-C
6 )alkenyl, and at least one of R 3 " and R 3 b are OH. In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is -(C-C 6 )alkyl, at least one of R 2 or R8 is -(C 2
-C
6 )alkynyl, and at least one of R ' and R 3 b are OH. 10 In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is -(C-C 6 )alkyl, at least one of R 2 or R 8 is -(C-C 6 )alkenyl, and at least one of R 3 ' and Rab are OH. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is -(C-C 6 )alkyl, at least one of R 2 or R 8 is -(C 2
-C
6 )alkynyl, and at least one of R 3 a and R 3 b are OH. In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is -(C-C 6 )alkyl, 15 at at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and at least one of R 3 ' and R A is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is -(C-C 6 )alkyl, at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and at least one of R 3 a and R 3 b is OH. In one embodiment, X is -(CI-C)alkoxy, Z is -CH 2 -, Y is -CH, R' is -(CI-C 6 )alkyl, at at least one of R 2 or R 8 is ((5- to 12-membered)aryl)-(C 1
-C
6 )alkyl-, and at least one of R 3 , 20 and R 3 b is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is -(CI-C 6 )alkyl, at least one of R 2 or R 8 is ((5- to 12-membered)aryl)-(C-C 6 )alkyl-, and at least one of R 3 a and R3b is OH. In one embodiment, X is -(CrC 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is -(C-C 6 )alkyl, both R 2 and R 8 are ((5- to 12-membered)aryl)-(C-C 6 )alkyl-, and at least one of R 3 a and R 3 b is 25 OH. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is -(CI-C 6 )alkyl, both R 2 and
R
8 are ((5- to 12-membered)aryl)-(C-C 6 )alkyl-, and at least one of R 3 ' and R 3 b is OH. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is ((C 3 C12)cycloalkyl)-(CI-C 6 )alkyl-, at least one of R 2 or R 8 is -(C 2
-C
6 )alkenyl, and at least one of 30 R 3 a and R 3 b is OH. In one embodiment, X is -(C I-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is ((C 3 C 1 2)cycloalkylHC-C 6 )alkyl-, at least one of R 2 or R 8 is -(C 2
-C
6 )alkynyl, and at least one of Raa and R 3 b is OH. - 37 - In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is ((C 3 C1 2 )cycloalkylHCi-C 6 )alkyl-, at least one of R 2 or R 8 is -(5- 12-membered)aryl, and at least one of R 3 ' and R 3 b is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is ((C 3
-CI
2 )cycloalkyl)-(CI 5 C 6 )alkyl-, at least one of R 2 or R 8 is -(C 2
-C
6 )alkenyl, and at least one of R3a and R 3 b is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is ((C 3
-C
12 )cycloalkylHCi
C
6 )alkyl-, at least one of R 2 or R 8 is -(C 2
-C
6 )alkynyl, and at least one of R 3 2 and R 3 b is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is ((C 3
-C
2 )cycloalkyl)-(CI
C
6 )alkyl-, at least one of R 2 or R 8 is -(5- 12-membered)aryl, and at least one of R 3 a and R 3 b is 10 OH. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is ((C 3 C1 2 )cycloalkyl)-(Ci-C 6 )alkyl-, at least one of R 2 or R 8 is ((5- to 12-membered)aryl)-(C 1 C 6 )alkyl-, and at least one of R 3 ' and R 3 b is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is ((C 3
-CI
2 )cycloalkyl)-(CI 15 C 6 )alkyl-, at least one of R 2 or R 8 is ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and at least one of R 3 8 and R 3 " is OH. In one embodiment, X is -(C 1
-C
6 )alkoxy, Z is -CH 2 -, Y is -CH, R' is ((C 3 C 12 )cycloalkyl)-(CI-C 6 )alkyl-, both R 2 and R 8 are ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and at least one of R'a and R 3 b is OH. 20 In one embodiment, X is OH, Z is -CH 2 -, Y is -CH, R' is ((C 3
-C
2 )cycloalkyl)-(Ci
C
6 )alkyl-, both R 2 and R 8 are ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and at least one of R 3 , and R 3 b is OH. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(CI C)alkyl, at least one of R 2 or R 8 is -(Ci-C 6 )alkyl, and at least one of R 3 " and R A is H. 25 In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(CI-C 6 )alkyl, at least one of R 2 or R 8 is -(C 1
-C
6 )alkyl, and both R 3 ' and R 3 b are H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C C)alkyl, at least one of R 2 or R 8 is -(C 3 -CI2)cycloalkyl, and at least one of R 3 a and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(Ci-C 6 )alkyl, at least 30 one of R 2 or R 8 is -(C3-CI2)cycloalkyl, and both R 3 . and R 3 b are H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C C)alkyl, both R 2 and R 8 are -(Ci-C 6 )alkyl, and at least one of R 3 " and R is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(Ci-C 6 )alkyl, both R 2 and R 8 are -(Ci-C 6 )alkyl, and both Ra and R 3 b are H. -38- In one embodiment, X is -{CrC 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C
C
6 )alkyl, at least one of R 2 or R 8 is -(C 2
-C
6 )alkenyl, and at least one of R 3 , and R b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C-C 6 )alkyl, at least one of R 2 or R 8 is -(C-C 6 )alkenyl, and both R 3 a and R 3 b are H. 5 In one embodiment, X is -(CrC 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(Cr
C
6 )alkyl, at least one of R2 or R is -(C 2
C
6 )alkynyl, and at least one of R 3 ' and R 3 b is H. In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C
C
6 )alkyl, at least one of R2 or R8 is -(C 2
-C
6 )alkynyl, and both R 3 8 and R 3 b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C-C 6 )alkyl, at least 10 one of R 2 or R 8 is -(C 2
-C
6 )alkynyl, and at least one of R 3 a and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C-C 6 )alkyl, at least one of R 2 or R 8 is -(C 2
-C
6 )alkynyl, and both R 3 " and R 3 b are H. In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R, is -(C
C
6 )alkyl, at least one of R2 or R is -(5- to 12-membered)aryl, and at least one of R and R3b 15 is H. In one embodiment, X is -{C-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C,
C
6 )alkyl, at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and both R 3 a and R 3 b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, Rl is -(C-C 6 )alkyl, at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and at least one of R3a and R 3 b is H. 20 In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C-C 6 )alkyl, at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and both R 3 ' and R 3 b are H. In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R1 is -(C
C
6 )alkyl, at least one of R 2 or Ra is ((5- to 12-membered)aryl)-(C-C 6 )alkyl-, and at least one of R 3 a and R 3 1 is H. 25 In one embodiment, X is -(CrC 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C
C
6 )alkyl, at least one of R2 or R8 is ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-and both R 3 ' and
R
3 b are H. In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C
C
6 )alkyl, both R 2 and R 8 are ((5- to 12-membered)aryl)-(C-C 6 )alkyl-, and at least one of R 3 a 30 and R 3 b is H. In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C
C
6 )alkyl, both R 2 and R 8 are ((5- to 12-membered)aryl)-(C-C 6 )alkyl-and both R3" and R 3 b are H. -39- In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(Cr-C 6 )alkyl, at least one of R 2 or R 8 is ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and at least one of R 3 ' and R3b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(CI-C 6 )alkyl, at least 5 one of R 2 or R 8 is ((5- to 12-membered)aryl)-(C-C 6 )alkyl-, and both R 3 ' and R3b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C-C 6 )alkyl, both R 2 and R 8 are ((5- to 12-membered)aryl)-(C-C 6 )alkyl-, and at least one of R 3 ' and R3b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C-C 6 )alkyl, both R 2 and Rg are ((5- to 12-membered)aryl)-(C-C 6 )alkyl-, and both R 3 " and R3b are H. 10 In one embodiment, X is -(CI.C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R, is ((C 3 C 12 )cycloalkyl)-(C-C 6 )alkyl-, at least one of R 2 or R 8 is -(CI-C 6 )alkyl, and at least one of Ri3 and R3b is H. In one embodiment, X is -(CIC 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 CI 2 )cycloalkyl)-(C-C 6 )alkyl-, at least one of R 2 or R 8 is -(C-C 6 )alkyl, and both R 3 ' and R3b 15 are H. In one embodiment, X is -(C I-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 C 12 )cycloalkyl)-(C-C 6 )alkyl-, both R 2 and R 8 are -(CI-C 6 )alkyl, and at least one of Ri3 and R3b is H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 20 C 12 )cycloalkyl)-(C-C 6 )alkyl-, both R 2 and R 8 are -(CI-C 6 )alkyl, and both Ria and Rib are H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 C12)cycloalkyl)-(CrC 6 )alkyl-, at least one of R 2 or R 8 is -(C-C 12 )cycloalkyl, and at least one of R 3 a and R3b is H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 25 C12)cycloalkyl)-(CrC 6 )alkyl-, at least one of R2 or R8 is -(C 3
-C,
2 )cycloalkyl, and both R3 and R3b are H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 Ci 2 )cycloalkyl)-(C-C 6 )alkyl-, at least one of R 2 or R 8 is -(C 2
-C
6 )alkenyl, and at least one of R3a and R31 is H. 30 In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R 1 is ((C 3 C 12 )cycloalkyl)-(C 1
-C
6 )alkyl-, at least one of R2 or R' is -(C-C 6 )alkenyl, and both Ria and R 3 are H. -40- In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 C12)cycloalkyl)-(CI-C 6 )alkyl-, at least one of R 2 or R 8 is -(C 2
-C
6 )alkynyl, and at least one of
R
3 a and R 3 'b is H. In one embodiment, X is -(Ci-C)alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 5 C 12 )cycloalkyl)-(CI-C 6 )alkyl-, at least one of R 2 or R 8 is -(C 2
-C
6 )alkynyl, and both R 3 ' and
R
3 1 are H. In one embodiment, X is -(C]-C)alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 C 12 )cycloalkyl)-(CI-C 6 )alkyl-, at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and at least one of R and R is H. 10 In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CHr 2 -, Y is -CH 2 -CH, R' is ((C3 C)2)cycloalkyl)-(CI-C 6 )alkyl-, at least one of R 2 or Ra is -(5- to 12-membered)aryl, and both
R
3 a and R 3 b are H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C3
C
12 )cycloalkyl)-(CI-C 6 )alkyl-, at least one of R2 or R8 is ((5- to 12-membered)aryl)-(C 15 C 6 )atkyl-, and at least one of R 3 a and R 3 b is H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C3
C
12 )cycloalkyl)-(CI-C 6 )alkyl-, at least one of R2 or R8 is ((5- to 12-membered)aryl)-(Ci
C
6 )alkyl-, and both R 3 a and R 3 b are H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((3 20 C] 2 )cycloalkyl)-(CI-C 6 )alkyl-, both R 2 and R 8 are ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and at least one of R 3 a and R 3 b is H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C3
C
12 )cycloalkyl)-(CI-C 6 )alkyl-, both R 2 and R 8 are ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and both R 3 ' and R 3 b are H. 25 In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3
-C
1 2 )cycloalkyl) (Ci-C 6 )alkyl-, at least one of R 2 or Ra is -(CI-C 6 )alkyl, and at least one of R a and RIb is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 -CI)cycloalkyl) (Ci-C 6 )alkyl-, at least one of R 2 or R 8 is -(Ci-C 6 )alkyl, and both R 3 a and R 3 b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3
-CI
2 )cycloalkyl) 30 (Ci-C 6 )alkyl-, both R 2 and R 8 are -(CI-C 6 )alkyl, and at least one of R 3 ' and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3
-C
12 )cycloalkyl) (Ci-C 6 )alkyl-, both R 2 and R 8 are -(Ci-C 6 )alkyl, and both R a and R b are H. -41 - In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 -CU)cycloalkyl)
(CI-C
6 )alkyl-, at least one of R 2 or R 8 is -(C 3
-C
12 )cycloalkyl, and at least one of R3" and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 -Cu)cycloalkyl) 5 (C-C 6 )alkyl-, at least one of R 2 or R 8 is -(C 3 -Cu 2 )cycloalkyl, and both R a and R 3 b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3
-C)
2 )cycloalkyl)
(C-C
6 )alkyl-, at least one of R 2 or R 8 is -(C 2
-C
6 )alkenyl, and at least one of R a and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C-C 12 )cycloalkyl)
(C-C
6 )alkyl-, at least one of R2 or R8 is -(C 2
-C
6 )alkenyl, and both R3' and R are H. 10 In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3
-C
12 )cycloalkyl)
(C
1
-C
6 )alkyl-, at least one of R 2 or R 8 is -(C 2
-C
6 )alkynyl, and at least one of R 3 a and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 -C)cycloalkyl)
(C-C
6 )alkyl-, at least one of R 2 or R8 is -(C 2
-C
6 )alkynyl, and both R a and R 3 b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3
-C,
2 )cycloalkyl) 15 (C 1
-C
6 )alkyl-, at least one of R 2 or R8 is -(5- to 12-membered)aryl, and at least one of R 3 a and
R
3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R 1 is ((C 3
-C,
2 )cycloalkyl)
(C
1
-C
6 )alkyl-, at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and both R3a and R 3 " are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3
-C
12 )cycloalkyl) 20 (CrC 6 )alkyl-, at least one of R2 or R8 is ((5- to 12-membered)aryl)-(C-C 6 )alkyl-, and at least one of R 3 ' and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 rCH, R' is ((C 3
-C
1 2 )cycloalkyl)
(C-C
6 )alkyl-, at least one of R 2 or R 8 is ((5- to 12-membered)aryl)-(C-C 6 )alkyl-, and both R3a and R 3 b are H. 25 In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3
C)
2 )cycloalkyl)
(C-C
6 )alkyl-, both R2 and Ra are ((5- to 12-membered)aryl)-(C-C 6 )alkyl-, and at least one of
R
3 " and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3
-C
1 )cycloalkyl)
(CI-C
6 )alkyl-, both R2 and R8 are ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and both R 3 ' and 30 R 3 b are H. In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C C)alkyl, at least one of R2 or Rg is -(CI-C 6 )alkyl, and at least one of R 3 ' and R 3 b is OH. In one embodiment, X is -(CIrC 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C C)alkyl, both of R 2 and R 8 are -(C-C 6 )alkyl, and at least one of R a and R 3 A is OH. - 42 - In one embodiment, X is -(C 1
-C
6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C
C
6 )alkyl, at least one of R 2 or R 8 is -(C 3
-C
1 2 )cycloalkyl, and at least one of R 3 and R 3 " is OH. In one embodiment, X is -(C 1
-C
6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C
C
6 )alkyl, at least one of R 2 or R 8 is -(C 2
-C
6 )alkenyl, and at least one of R a and R 3 b is OH. 5 In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C
C
6 )alkyl, at least one of R 2 or Ra is -(C 2
-C
6 )alkynyl, and at least one of R 3 and R 3 1 is OH. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C
C
6 )alkyl, at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and at least one of Raa and R 3 is OH. 10 In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R, is -(Cr
C
6 )alkyl, at least one of R 2 or R 8 is ((5- to 12-membered)aryl)-(C-C 6 )alkyl-, and at least one of R 3 " and R b is OH. In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(Cr
C
6 )alkyl, both R 2 and R 8 are ((5- to 12-membered)aryl)-(C-C 6 )alkyl-, and at least one of Ra 15 and R 3 b is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C-C 6 )alkyl, at least one of R 2 or R 8 is -(C-C 6 )alkyl, and at least one of R 3 ' and R 3 A is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(CI-C 6 )alkyl, both of
R
2 and R 8 are -(C-C 6 )alkyl, and at least one of R 3 a and R 3 b is OH. 20 In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(Ci-C 6 )alkyl, at least one of R2 or Rg is -(C 3
-CI
2 )cycloalkyl, and at least one of R and R is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C -C 6 )alkyl, at least one of R 2 or R 8 is -(C 2
-C
6 )alkenyl, and at least one of R a and R 3 b is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C -C 6 )alkyl, at least 25 one of R 2 or R 8 is -(C 2
-C
6 )alkynyl, and at least one of R 3 " and R 3 b is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C-C 6 )alkyl, at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and at least one of R 3 a and R 3 b is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(CI-C 6 )alkyl, at least one of R 2 or R 8 is ((5- to 12-membered)aryl)-(Cr.C 6 )alkyl-, and at least one of R 3 a and.R 3 b is 30 OH. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C-C 6 )alkyl, both R 2 and R 8 are ((5- to 12-membered)aryl)-(C-C 6 )alkyl-, and at least one of R 3 a and R 3 b is OH. -43 - In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 C12)cycloalkyl)-(Ci-C 6 )alkyl-, at least one of R 2 or R 8 2 is -(CI-C 6 )alkyl, and at least one of
R
3 " and R"b is OH. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 5 C 1 2)cycloalkyl)-(C-C 6 )alkyl-, both R2 and R 8 2 are -(CI-C 6 )alkyl, and at least one of R 3 " and R b is OH. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 C12)cycloalkyl)-(CrC 6 )alkyl-, at least one of R 2 or R 82 is -(C3-C 1 2)cycloalkyl, and at least one of R 3 and R 3 b is OH. 10 In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 C 12 )cycloalkyl)-(C-C 6 )alkyl-, at least one of R2 or R8 is -(C 2
-C
6 )alkenyl, and at least one of
R
3 a and R 3 b is OH. In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R 1 is ((C 3 C 12 )cycloalkyl)-(CrC 6 )alkyl-, at least one of R 2 or R 8 is -(C 2
-C
6 )alkynyl, and at least one of 15 R 3 a and R3 Ais OH. In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 C 1 2)cycloalkyl)-(C-C 6 )alkyl-, at least one of R 2 or Rg is -(5- to 12-membered)aryl, and at least one of R 3 and R 3 b is OH. In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 20 C 1 )cycloalkyl)-(C-C 6 )alkyl-, at least one of R 2 or R 8 is ((5- to 12-membered)aryl)-(C 1
C
6 )alkyl-, and at least one of R 3 ' and R3b is OH. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 C12)cycloalkyl)-(C-C 6 )alkyl-, both R 2 and R 8 are ((5- to 12-membered)aryl)-(C-C 6 )alkyl-, and at least one of R3a and R b is OH. 25 In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R 1 is ((C 3
-C]
2 )cycloalkyl)
(C-C
6 )alkyl-, at least one of R 2 or R 8 is -(C-C 6 )alkyl, and at least one of R 3 8 and R 3 b is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R1 is ((C 3
-C,
2 )cycloalkyl) (CI-Cs)alkyl-, both R 2 and R 8 are -(CI-C 6 )alkyl, and at least one of R 3 " and R3b is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 -C I)cycloalkyl) 30 (C-C 6 )alkyl-, at least one of R 2 or Rg is -(C 3
-CI
2 )cycloalkyl, and at least one of R 3 " and R 3 b is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((CrCu)cycloalkyl) (CrC 6 )alkyl-, at least one of R 2 or R 8 is -(C 2
-C
6 )alkenyl, and at least one of R 3 a and R 3 " is OH. - 44 - In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3
-C
12 )cycloalkyl)
(CI-C
6 )alkyl-, at least one of R 2 or R 8 is -(C-C 6 )alkynyl, and at least one of R 3 a and R 3 is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3
-C
12 )cycloalkyl) 5 (CI-C 6 )alkyl-, at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and at least one of R 3 " and
R
3 1 is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3
-C
1 2 )cycloalkyl)
(C
1
-C
6 )alkyl-, at least one of R 2 or R 8 is ((5- to 12-membered)aryl)-(Ci-C 6 )alkyl-, and at least one of R 3 a and R 3 b is OH. 10 In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 -Ciz)cycloalkyl)
(CI-C
6 )alkyl-, both R2 and R8 are ((5- to 12-membered)aryl)-(Ci-C 6 )alkyl-, and at least one of Ra and Rl is OH. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C
C
6 )alkyl, at least one of R 2 or R 8 is -(C-C 6 )alkyl, and at least one of R 3 ' and R 3 b is H. 15 In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(Cr
C
6 )alkyl, at least one of R 2 or R 8 is -(CI-C 6 )alkyl, and both R 3 a and R b are H. In one embodiment, X is -(C I-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C
C
6 )alkyl, both R 2 and R 8 are -(C-C 6 )alkyl, and at least one of R 3 a and R 3 b is H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R, is -(C, 20 C 6 )alkyl, at least one of R 2 or R 8 is -(C 3 -CI2)cycloalkyl, and at least one of R 3 ' and R 3 b is H. In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C
C
6 )alkyl, at least one of R 2 or R 8 is -(C 3
-C,
2 )cycloalkyl, and both R 3 a and R b are H. In one embodiment, X is -C,-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C
C
6 )alkyl, both R 2 and R 8 are -(C-C 6 )alkyl, and both R 3 ' and R 3 b are H. 25 In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 C] 2 )cycloalkyl)-(C-C 6 )alkyl-, R 2 is -(C 2
-C
6 )alkenyl, and at least one of R 3 a and R 3 b is H. In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 C]2)cycloalkyl)-CI-C 6 )alkyl-, R 2 is -(C 2
-C
6 )alkenyl, and both R 3 a and R 3 b are H. In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C, 30 C 6 )alkyl, at least one of R 2 or R 8 is -(C 2
-C
6 )alkynyl, and at least one of R 3 " and R 3 b is H. In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C
C
6 )alkyl, at least one of R2 or R8 is -(C 2
-C
6 )alkynyl, and both R and R are H. -45- In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CHr 2 -, Y is -CH 2 -CH, R' is -(Ci Cs)alkyl, at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and at least one of R a and R 3 b is H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CHrT, Y is -CH 2 -CH, R' is -(Cj 5 C)alkyl, at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and both R 3 a and R 3 b are H. In one embodiment, X is -(CI-C)alkoxy, Z is -CHr 2 -, Y is -CH 2 -CH, R' is -(C
C
6 )alkyl, at least one of R2 or Rg is ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and at least one of R3. and R" is H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C 10 C 6 )alkyl, at least one of R 2 or R 8 is ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and both R 3 a and R 3 are H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R 1 is -(C,
C
6 )alkyl, both R2 and R8 are ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and at least one of R 3 , and R is H. 15 In one embodiment, X is -(CI-C)alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C
C
6 )alkyl, both R 2 and Ra are ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and both Ra and R 3 b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(CI-C 6 )alkyl, at least one of R 2 or R 8 is -(CI -C 6 )alkyl, and at least one of R a and R b is H. 20 In one embodiment, X is -(C-C 6 )alkoxy, Z is -CHr 2 -, Y is -CH 2 -CH, R' is -(Ci
C
6 )alkyl, at least one of R 2 or R 8 is -(CI-C 6 )alkyl, and both R a and R 3 b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -'-CH 2 -CH, R 1 is -(CI-C 6 )alkyl, both R 2 and R' are -(Ci-C 6 )alkyl, and at least one of R3a and R b is H. In one embodiment, X is OH, Z is -CHr 2 -, Y is -CH 2 -CH, R 1 is -(CI-C 6 )alkyl, both R 2 25 and R 8 are -(Ci-C 6 )alkyl, and both R 3 ' and R 3 b are H. In one embodiment, X is OH, Z is -CHr 2 -, Y is -CH 2 -CH, R' is -(CI-C 6 )alkyl, at least one of R 2 or R 8 is -(C 3
-C,
2 )cycloalkyl, and at least one of R 3 a and R 3 b is H. In one embodiment, X is OH, Z is -CHr 2 -, Y is -CH 2 -CH, R' is -(CI-C 6 )alkyl, at least one of R 2 orR 8 is -(C 3
-CI
2 )cycloalkyl, and both R a and R 3 b are H. 30 In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is ((C C12)cycloalkyl)-(CI-C 6 )alkyl-, R 2 is -(C-C 6 )alkenyl, and at least one of R 3 ' and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 C,2)cycloalkyl)-(CI-C 6 )alkyl-, R 2 is -(C 2
-C
6 )alkenyl, and both R 3 a and R b are H. - 46 - In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(CI-C 6 )alkyl, at least one of R 2 or R 8 is -(C 2
-C
6 )alkynyl, and at least one of R 3 ' and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(C-C 6 )alkyl, at least one of R 2 or R 8 is -(C 2
-C
6 )alkynyl, and both R 3 and R 3 b are H. 5 In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(CI-C 6 )alkyl, at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and at least one of R a and R 3 " is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(CI-C 6 )alkyl, at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and both R 3 ' and R 3 b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(Ci-C 6 )alkyl, at least 10 one of R 2 or Rg is ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and at least one of R 3 and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(Ci-C 6 )alkyl, at least one of R 2 or R 8 is ((5- to 12-membered)aryl)-(Ci-C 6 )alkyl-, and both R 3 and R b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(CI-C 6 )alkyl, both R 2 15 and R 8 are ((5- to 12-membered)aryl)-(C1-C 6 )alkyl-, and at least one of R 3 ' and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is -(Ci-C 6 )alkyl, both R 2 and R 8 are ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and both R 3 ' and R 3 b are H. In one embodiment, X is -(CI-C6)alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 C12)cycloalkyl)-(Ci-C 6 )alkyl-, at least one of R 2 or R 8 is -(CI-C 6 )alkyl, and at least one of R 3 , 20 and R is H. In one embodiment, X is -(Cl -C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 C) 2 )cycloalkyl)-(Ci-C 6 )alkyl-, at least one of R 2 or R 8 is -(Ci-C 6 )alkyl, and both R 3 and R 3 1 are H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 25 C1z)cycloalkyl)-(C 1
-C
6 )alkyl-, both R 2 and R 8 are -(CI-C 6 )alkyl, and at least one of R 3 ' and
R
3 b is H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R 1 is ((C 3 C 12 )cycloalkyl)-(Ci-C 6 )alkyl-, at least one of R2 or R8 is -(C 3
-C
12 )cycloalkyl, and at least one of R 3 " and R 3 b is H. 30 In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 CI 2 )cycloalkyl)-(C-C 6 )alkyl-, at least one of R 2 or R 8 is -(C 3
-C,
2 )cycloalkyl, and both R 3 " and R 3 b are H. In one embodiment, X is -(C i-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((Cr
C
12 )cycloalkylHCi-C 6 )alkyl-, both R 2 and R 8 are -(CI-C 6 )alkyl, and both R 3 and R 3 b are H. -47- In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 C 12 )cycloalkyl)-(C,-C 6 )alkyl-, R 2 is -(C 2
-C
6 )alkenyl, and at least one of R 3 a and Rb is H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 C 1 2 )cycloalkyl)-(C6-C 6 )alkyl-, R 2 is -(C-C 6 )alkenyl, and both R 3 " and R 3 b are H. 5 In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C
C
1 2 )cycloalkyl)-(Ci-C 6 )alkyl-, at least one of R 2 or R 8 is -(C-C 6 )alkynyl, and at least one of R 3 and R is H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 C 12 )cycloalkyl)(CI-C 6 )alkyl-, at least one of R 2 or R 8 is -(C 2
-C
6 )alkynyl, and both R 3 " and 10 R" are H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 C 12 )cycloalkyl)-(CI-C 6 )alkyl-, at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and at least one of R a and R 3 b is H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 15 C 12 )cycloalkyl)-(Ci-C 6 )alkyl-, at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and both
R
3 a and R 3 b are H. In one embodiment, X is -(C i-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((Cr
C
12 )cycloalkyl)-(Ci-C 6 )alkyl-, at least one of R 2 or R 8 is ((5- to 12-membered)aryl)-(C
C
6 )alkyl-, and at least one of R 3 ' and R 3 b is H. 20 In one embodiment, X is -(Ci-C)alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 C 12 )cycloalkyl)-(C,-C 6 )alkyl-, at least one of R 2 or R 8 is ((5- to 12-membered)aryl)-(C
C
6 )alkyl-, and both R 3 0 and R 3 b are H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 C 12 )cycloalkyl)-(CI-C 6 )alkyl-, both R 2 and Rg are ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, 25 and at least one of R 3 a and R 3 b is H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((Cr C12)cycloalkyl)-(Ci-C 6 )alkyl-, both R 2 and R 8 are ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and both R 3 ' and R 3 b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 -CI2)cycloalkyl) 30 (Ci-C 6 )alkyl-, at least one of R 2 or R 8 is -(CI-C 6 )alkyl, and at least one of R3a and R 3 b is H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 C12)cycloalkyl)-(CrC 6 )alkyl-l, at least one of R 2 or R 8 is -(C 1
-C
6 )alkyl, and both R 3 ' and R 3 b are H. - 48 - In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3
-C
2 )cycloalkyl)
(C-C
6 )alkyl-, both R 2 and R are -(CI-C 6 )alkyl, and at least one of R 3 ' and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R1 is ((C 3 -C1 2 )cycloalkyl)
(C-C
6 )alkyl-, both R 2 and R8 are -(CI-C 6 )alkyl, and both R 3 ' and R 3 b are H. 5 In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 -CIu)cycloalkyl)
(C-C
6 )alkyl-, at least one of R 2 or R 8 is -(C 3
-C
1 2 )cycloalkyl, and at least one of R 3 " and R3b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3
-C
12 )cycloalkyl)
(CI-C
6 )alkyl-, at least one of R 2 or R 8 is -(C 3
-C
12 )cycloalkyl, and both Ra and R 3 b are H. 10 In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3
-C
12 )cycloalkyl)
(CI-C
6 )alkyl-, at least one of R 2 or Rg is -(C 2
-C
6 )alkynyl, and at least one of R 3 a and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3
-C
1 )cycloalkyl)
(CI-C
6 )alkyl-, at least one of R 2 or RB is -(C 2
-C
6 )alkynyl, and both R 3 ' and R A are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 -Cu)cycloalkyl) 15 (C 1
-C
6 )alkyl-, at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and at least one of R a and
R
3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 -Cu)cycloalkyl)
(CI-C
6 )alkyl-, at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and both R 3 and R 3 A are H. 20 In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3
-C
1 2 )cycloalkyl)
(C
1
-C
6 )alkyl-, at least one of R 2 or R 8 is ((5- to 12-membered)aryl)-(C 1
-C
6 )alkyl-, and at least one of R 3 ' and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3
-C
1 2 )cycloalkyl)
(C-C
6 )alkyl-, at least one of R 2 or Rg is ((5- to 12-membered)aryl)-(C-C 6 )alkyl-, and both 25 R 3 2 and R 3 b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3
-C
12 )cycloalkyl)
(CI-C
6 )alkyl-, both R 2 and R8 are ((5- to 12-membered)aryl)-(C-C 6 )alkyl-, and at least one of R" and R is H. In one embodiment, X is OH, Z is -CH 2 -, Y is -CH 2 -CH, R' is ((C 3 -C12)cycloalkyl) 30 (CI-C 6 )alkyl-, both R 2 and R8 are ((5- to 12-membered)aryl)-(C-C 6 )alkyl-, and both R 3 and R are H. In one embodiment, X is -(C 1
-C
6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is ((Cr
C
12 )cycloalkylHCI-C 6 )alkyl-, R 2 is -(CI-C 6 )alkyl, and at least one of R 3 a and R b is H. - 49 - In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 C12)cycloalkyl)-(C-C 6 )alkyl-, R 2 is -(CI-C 6 )alkyl, and both R 3 a and R b are H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R, is ((C 3 C 1 2 )cycloalkyl)-(CI-C 6 )alkyl-, R 2 is -(C3-C12)cycloalkyl, and at least one of R 3 a and R 3 b is H. 5 In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is ((Cr
C
12 )cycloalkyl)-(C-C 6 )alkyl-, R 2 is -(C 3
-C[
2 )cycloalkyl, and both R 3 and R 3 b are H. In one embodiment, X is -(C-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 C1 2 )cycloalkyl)-(C-C 6 )alkyl-, R 2 is -(C 2
-C
6 )alkenyl, and at least one of R 3 l and R 3 b is H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 10 C 12 )cycloalkylHC-C 6 )alkyl-, R 2 is -(C-C 6 )alkenyl, and both R a and R3' are H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is ((Cr C1 2 )cycloalkyl)-(C-C 6 )alkyl-, R 2 is -(5- to 12-membered)aryl, and at least one of R 3 ' and R31 is H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 15 C 12 )cycloalkyl)-(C-C 6 )alkyl-, R 2 is -(5- to 12-membered)aryl, and both R a and R3' are H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R, is ((C 3 CI 2 )cycloalkyl)-(C 1
-C
6 )alkyl-, R 2 is ((5- to 12-membered)aryl)-(C-C 6 )alkyl-, and at least one of R 3 a and R 3 b is H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 20 C1 2 )cycloalkyl)-(CI-C 6 )alkyl-, R 2 is ((5- to 12-membered)aryl)-(C-C 6 )alkyl-, and both R a and R 3 A are H. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 C12)cycloalkyl)-(CI-C 6 )alkyl-, R 2 is -(C-C 6 )alkyl, and at least one of R 3 , and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is ((Cr 25 C12)cycloalkyl)-(C-C 6 )alkyl-, R 2 is -(CI-C 6 )alkyl, and both R 3 ' and R 3 b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is ((Cr C12)cycloalkyl)-(C-C 6 )alkyl-, R 2 is -(C 3 -Ci 2 )cycloalkyl, and at least one of R 3 ' and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is ((Cr C12)cycloalkylMC-C 6 )alkyl-, R 2 is -(C3-C 12 )cycloalkyl, and both R 3 ' and R 3 b are H. 30 In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 C 12 )cycloalkyl)-(C-C 6 )alkyl-, R 2 is -(C-C 6 )alkenyl, and at least one of R a and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 C 1 2)cycloalkyl)-(CI-C 6 )alkyl-, R 2 is -(C 2
-C
6 )alkenyl, and both R 3 9 and R 3 b are H. -50- In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, Rr is ((C 3 C 12 )cycloalkyl)-(CI-C 6 )alkyl-, R 2 is -(5- to 12-membered)aryl, and at least one of R 3 a and R3b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 5 C! 2 )cycloalkyl)-(CI-C 6 )alkyl-, R 2 is -(5- to 12-membered)aryl, and both R 3 a and R 3 b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 C 12 )cycloalkyl)-(Ci-C 6 )alkyl-, R 2 is ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and at least one of R 3 " and R b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 10 C12)cycloalkyl)-(Ci-C 6 )alkyl-, R 2 is ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and both R 3 " and R 3 b are H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is -(C,
C
6 )alkyl, R 2 is -(CI-C 6 )alkyl, and at least one of R 3 ' and R 3 b is H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R 1 is -(Cl 15 C 6 )alkyl, R 2 is -(CI-C 6 )alkyl, and both R 3 ' and R3b are H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is -(C
C
6 )alkyl, R 2 is -(Ci-C 6 )alkyl, and at least one of R 3 a and R 3 b is H. In one embodiment, X is -(C 3
-C
12 )cycloalkoxy, Z is -CH 2 -, Y is a direct bond, R' is (CI-C 6 )alkyl, R 2 is -(C 3 -Cl 2 )cycloalkyl, and both R 3 and R 3 b are H. 20 In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is -(C,
C
6 )alkyl, R 2 is -(C 2
-C
6 )alkenyl, and at least one of R 3 and R 3 b is H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is -(C
C
6 )alkyl, R 2 is -(C-C 6 )alkenyl, and both R 3 a and R 3 A are H. In one embodiment, X is -(C,-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is -(Cl 25 C 6 )alkyl, R 2 is -(5- to 12-membered)aryl, and at least one of R3 and R 3 b is H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is -(Cl
C
6 )alkyl, R 2 is -(5- to 12-membered)aryl, and both R 3 a and R 3 b are H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is -(C,
C
6 )alkyl, R 2 is ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and at least one of R 3 a and R b is H. 30 In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is -(C,
C
6 )alkyl, R 2 is ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and both R 3 ' and R 3 b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is -(Ci-C6)alkyl, R 2 is -(CI-C 6 )alkyl, and at least one of R 3 ' and R 3 b is H. -51- In one embodiment, X is OH, Z is -- CH 2 -, Y is a direct bond, R' is -(Ci-C)alkyl, R 2 is -(Ci-C 6 )alkyl, and both R 3 a and R 3 b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is -(Ci-C 6 )alkyl, R 2 is -(C 3
-C
12 )cycloalkyl, and at least one of R 3 a and R 3 b is H. 5 In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is -(Ci-C 6 )alkyl, R 2 is -(C 3
-C
12 )cycloalkyl, and both R 3 a and R 3 b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is -(Ci-C 6 )alkyl, R 2 is -(C2-C6)alkenyl, and at least one of R 3 a and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is -(Ci-C 6 )alkyl, R 2 10 is -(C 2
-C
6 )alkenyl, and both R 3 ' and R 3 b are H. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is -(Ci-C 6 )alkyl, R 2 is -(5- to 12-membered)aryl, and at least one of R 3 ' and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 C12)cycloalkyl)-(CI-C 6 )alkyl-, R 2 is -(5- to 12-membered)aryl, and both R 3 ' and R 3 b are H. 15 In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R1 is -(Ci-C 6 )alkyl, R 2 is ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and at least one of R 3 a and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is -(Ci-C 6 )alkyl, R 2 is ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and both R 3 a and R 3 b are H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is -(C 20 C 6 )alkyl, R 2 is -(CI-C 6 )alkyl, and at least one of R 3 , and R 3 b is OH. ' In one embodiment, X is -(Ci-C)alkoxy, Z is -CH 2 -, Y is a direct bond, R' is -(Ci
C
6 )alkyl, R 2 is -(C 3 -CuI)cycloalkyl, and at least one of R 3 " and R 3 b is OH. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is -(C
C
6 )alkyl, R 2 is -(C 2
-C
6 )alkenyl, and at least one of R 3 ' and R 3 b is OH. 25 In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is -(C, C6)alkyl, R 2 is -(C 2
-C
6 )alkynyl, and at least one of R a and R 3 b is OH. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is -(Cl
C
6 )alkyl, R 2 is -(5- to 12-membered)aryl, and at least one of R 3 a and R 3 b is OH. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is -(Cl 30 C 6 )alkyl, R 2 is ((5- to 12-membered)aryl)-(Ci-C 6 )alkyl-, and at least one of R 3 " and R 3 b is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is -(CI-C 6 )alkyl, R 2 is -(Ci-C 6 )alkyl, and at least one of R"' and R 3 1 is OH. In one embodiment, X is OH, Z is -- CH 2 -, Y is a direct bond, R' is -(CI-C 6 )alkyl, R 2 is -(C 3 -C,2)cycloalkyl, and at least one of R 3 ' and R 3 b is OH. - 52 - In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R 1 is -- (CI-C)alkyl, R 2 is -(C-C 6 )alkenyl, and at least one of R 3 a and R b is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is -(C 1
-C
6 )alkyl, R 2 is -(C 2
-C
6 )alkynyl, and at least one of Rla and R 3 " is OH. 5 In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is -(CI-C)alkyl, R 2 is -(5- to 12-membered)aryl, and at least one of R 3 a and R 3 b is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is -(C 1
-C
6 )alkyl, R 2 is ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and at least one of R3a and R b is OH. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 10 C12)cycloalkyl)-(Cj-C 6 )alkyl-, R 2 is -(CI-C 6 )alkyl, and at least one of R 3 ' and R 3 b is OH. In one embodiment, X is -(CI-C 6 )alkoxy, Z is L-CH 2 , Y is a direct bond, R' is ((C 3 C 12 )cycloalkyl)-(C 1
-C
6 )alkyl-, R 2 is -(C 3
-C
12 )cycloalkyl, and at least one of R 3 a and R 3 b is OH. In one embodiment, X is -(CI-C 6 )atkoxy, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 15 C, 2 )cycloalkyl)-(Ci-C 6 )alkyl-, R 2 is -(C 2
-C
6 )alkenyl, and at least one of R 3 a and R 3 b is OH. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 C 12 )cycloalkyl)-(CI-C 6 )alkyl-, R 2 is -(C-C 6 )alkynyl, and at least one of R 3 8 and R 3 b is OH. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 C1 2 )cycloalkyl)-(CI-C 6 )alkyl-, R 2 or R 8 is -(5- to 12-membered) aryl, and at least one of R 3 ' 20 and R 3 b is OH. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 CI 2 )cycloalkyl)-(CI-C 6 )alkyl-, R 2 is ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and at least one of R 3 a and R b is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 25 C I)cycloalkyl)-(CI-C 6 )alkyl-, R 2 is -(CI-C 6 )alkyl, and at least one of R and R b is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 C 12 )cycloalkyl)-(Ci-C 6 )alkyl-, R 2 is -(C 3
-C
12 )cycloalkyl, and at least one of R 3 ' and R 3 b is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 30 C 12 )cycloalkyl)-(Ci-C 6 )alkyl-, R 2 is -(C-C 6 )alkenyl, and at least one of R 3 " and R 3 b is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is ((Cj C12)cycloalkyl)-(Ci-C 6 )alkyl-, R 2 is -(C 2
-C
6 )alkynyl, and at least one of R3a and R 3 b is OH. - 53 - In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is ((C3
C
1 2 )cycloalkyl)-(CI-C 6 )alkyl-, R 2 is -(5- to 12-membered) aryl, and at least one of Ra and
R
3 1 is OH. In one embodiment, X is OH, Z is -CH 2 -, Y is a direct bond, R' is ((C 3 5 C12)cycloalkyl)-(CI-C 6 )alkyl-, R 2 is ((5- to 12-membered)aryl)-(CI-C 6 )alkyl-, and at least one of R 3 a and R"b is OH. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, R' is -(CI-C 6 )alkyl, (Y-R 2
R
8 ) is diphenylpropyl, and at least one of R 3 " and R 3 b is H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, R' is -(CI-C 6 )alkyl, (Y-R 2 Rs) is 10 diphenylpropyl, and both R 3 ' and R 3 b are H. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, R 1 is -(Ci-C 6 )alkyl, (Y-R 2 R') is diphenylpropyl, and at least one of R3" and R 3 b is OH. In one embodiment, X is OH, Z is -CH 2 -, R' is -(Ci-C 6 )alkyl, (Y-R 2 R') is diphenylpropyl, and at least one of R 3 a and R 3 b is H. 15 In one embodiment, X is OH, Z is -CH 2 -, R1 is -(Ci-C 6 )alkyl, (Y-R 2 R') is diphenylpropyl, and both R 3 ' and R 3 b are H. In one embodiment, X is OH, Z is -CH 2 -, R' is -(C i-C 6 )alkyl, (Y-R 2 RI) is diphenylpropyl, and at least one of R 3 , and R 3 b is OH. In one embodiment, X is -(Ci-C 6 )alkoxy, Z is -CH 2 -, R' is ((C 3
-C[
2 )cycloalkyl)-(C 20 C 6 )alkyl-, (Y-R 2 Rg) is diphenylpropyl, and at least one of Ra and R 3 b is H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, R' is ((C3-CI2)cycloalkyl)-(C
C
6 )alkyl-, (Y-R 2
R
8 ) is diphenylpropyl, and both R 3 " and R 3 b are H. In one embodiment, X is -(CI-C 6 )alkoxy, Z is -CH 2 -, R' is ((C 3
-C
1 2 )cycloalkyl)-(CI
C
6 )alkyl-, (Y-R 2
R
8 ) is diphenylpropyl, and at least one of R 3 ' and R 3 b is OH. 25 In one embodiment, X is OH, Z is -CH 2 -, R' is ((C 3
-C
12 )cycloalkylHCi-C 6 )alkyl-,
(Y-R
2
R
8 ) is diphenylpropyl, and at least one of R 3 a and R 3 b is H. In one embodiment, X is OH, Z is -CH 2 -, R' is ((C 3
-C
1 2 )cycloalkyl)-(CI-C 6 )alkyl-,
(Y-R
2
R
8 ) is diphenylpropyl, and both R 3 a and R 3 " are H. In one embodiment, X is OH, Z is -CH 2 -, R' is ((C 3 -CI2)cycloalkyl)-(CI-C 6 )alkyl-, 30 (Y-R 2 R') is diphenyl propyl, and at least one of R 3 ' and R3b is OH. Specific compounds of the invention include: 22 -cyclopropyl-7a-((3-methyl-benzyloxymethyl-6,14-endo-ethanotetrahydrothebaine; 2 2 -cyclopropyl-7a-(2-napthylmethoxymethyl)-6,14-3ndo-ethanotetrahydrothebaine; -54- 22-cyclopropyl-7ct-((4-terz-butyl)benzyloxymnethyl)-6, 14-endo-ethanotetrahydrothebaine; 22 -cyclopropyl-7a-((3-phenyl-prop-2.eneyloxymethyl)-6,1I4-endo-ethanotetrahydrothebaine; 2 2-cyclopropyl-7cz-((2-methyl)benzyloxymethy)-6,1I4-endo-ethanotetrahydrothebaine; 22-cyclopropyl-7a-( I -napthylmethoxymethyl)-6,1I4-endo-ethanotetrahydrothebaine; 5 22-cyclopropyl-7ct-(cyclobutylmethoxyrnethyl)-6,1I4-endo-ethanotetrahydrothebaine; 7ct-((2-methyl)benzyloxymethyl).6,1I4-endo-ethanotetrahydrothebaine; 7a-((4-pynidylmethoxymethyl)-6,1I4-endo-ethanotetrahydrothebaine; 7ct-((4-tri fluoromethoxy)benzyloxymethyl)-6, 14-endo-ethanotetrahydrothebaine; 7cx-( I -napthylmethoxymethyl)-6,1I4-endo-ethanotetrahydrothebaine; 10 7a-(cyclobutylmethoxymethyl)-6,1I4-endo-ethanotetrahydrothebaine; 7ac-(3-methoxy)benzyloxyrnethyl)-6, 14-endo-ethanotetrahydrothebaine; 7oa-(benzyloxymethyl)-6,1I4-endoethanotetrahydrooripavine; 7a-(diphenylmethyloxyrnethyI)-3,6-dimethoxy4,5a..epoxy-I 7-methyl-6cc, 14ct-ethano morphinan; 15 1 7 -cyclopropylmethyl-7ax-(3-trifluoromethoxy)benzyloxyethyl36.dimethoxy45a-epoxy 6a, 1 4cz-ethano-morphinan; 3,6-dimethoxy-4,Sct-epoxy- 1 7 -methyl-7ct-(4-phenyl)benzyloxymethyl-6ac, 1 4a-ethano morphinan; I 7 -cyclopropylmethyl-7a-(3-pyridyl)oxymethy-3 ,6-dimethoxy-4,5oL-epoxy-6c, 1 4ct-ethano 20 morphinan; 7a-(4-bromo)benzyloxymethyl-3 ,6-dimethoxy-4,Sct-epoxy- I 7-methyl-6ot, I 4c-ethano morphinan; 7ct-( 1 -naphthylmethyloxymethyl)- I 7 -cyclopropyl-methyl-6-methoxy-4,5a-epoxy-6a, 1 4cc ethano-morphinan; 25 7 a-( 4 -methylbenzyloxymethyl)-3,6-dimethoxy4,5a-epoxy. I 7-methyl-6a, 1 4ct-ethano morphinan; 7 a-benzyloxymethyl-3,6-dimethoxy-4,5a-epoxy80-methy.. 1 7-n-methyl-6a, 14a-ethano morphinan; 7 a-(cyclooctylmethyl)-3,6-dimethoxy-4,5a-epoxy- 1 7-methyl-6ct, I 4ct-ethano-morphinan; 30 and the pharmaceutically acceptable salts, prodrugs and solvates thereof. - 55 - As used herein, the term "-(CI-CIO)alkyl" refers to straight-chain and branched non cyclic saturated hydrocarbons having from I to 10 carbon atoms. Representative straight chain -(CI-CIo) alkyl groups include methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. Representative branched -(CI-Clo)alkyl groups 5 include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, neopentyl, I-methylbutyl, 2 methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2 methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1 dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 5-methylhexyl, 6-methylheptyl, and the like. 10 As used herein, the term "-(Ci-C 6 )alkyl" refers to straight-chain and branched non cyclic saturated hydrocarbons having from I to 6 carbon atoms. Representative straight chain -(C 1
-C
6 )alkyl groups include methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl. Representative branched-chain -(CI-C 6 )alkyl groups include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, neopentyl, I -methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1 15 dimethylpropyl, and 1,2-dimethylpropyl, methylpentyl, 2-methylpentyl, 3-methylpentyl, 4 mehtylpentyl, I-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, and the like. As used herein, the term "-(C 2
-C,
2 )alkenyl" refers to straight chain and branched non cyclic hydrocarbons having from 2 to 12 carbon atoms and including at least one carbon 20 carbon double bond. Representative straight chain and branched -(C 2 -C]2)alkenyl groups include -vinyl, allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3 methyl-i-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, 3 hexenyl, and the like. As used herein, the term "-(C 2
-C
6 )alkenyl" refers to straight chain and branched non 25 cyclic hydrocarbons having from 2 to 6 carbon atoms and including at least one carbon carbon double bond. Representative straight chain and branched -(C 2
-C
6 )alkenyl groups include -vinyl, allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3 methyl-I-butenyl, -2-methyl-2-butenyl, and the like. As used herein, the term "-(C 2 -Cu 2 )alkynyl" refers to straight chain and branched non 30 cyclic hydrocarbons having from 2 to 12 carbon atoms and including at least one carbon carbon triple bond. Representative straight chain and branched -(C 2
-C
2 )alkynyl groups include -acetylenyl, -propynyl, -1 butynyl, -2-butynyl, -I -pentynyl, -2-pentynyl, -3-methyl 1-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl, and the like. - 56 - As used herein, the term "-(C 2
-C
6 )alkynyl" refers to straight chain and branched non cyclic hydrocarbons having from 2 to 6 carbon atoms and including at least one carbon carbon triple bond. Representative straight chain and branched -(C-C 6 )alkynyl groups include -acetylenyl, -propynyl, -l butynyl, -2-butynyl, -1 -pentynyl, -2-pentynyl, -3-methyl 5 1-butynyl, -4-pentynyl, and the like. As used herein, the term "-(C3-C]2)cycloalkyl" refers to cyclic saturated hydrocarbon having from 3 to 12 carbon atoms. Representative (C 3
-C
1 2 )cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. 10 As used herein, "-(C 6
-C
1 4 )bicycloalkyl" means a bicyclic hydrocarbon ring system having from 6 to 14 carbon atoms and at least one saturated cyclic alkyl ring. Representative
-(C
6
-CI
4 )bicycloalkyls include -indanyl, -norbomyl, -1,2,3,4 tetrahydronaphthalenyl, -5,6,7,8-tetrahydronaphthalenyl, -perhydronaphthalenyl, and the like. As used herein, "-(Cs-C20)tricycloalkyl" means a tricyclic hydrocarbon ring system 15 having from 8 to 20 carbon atoms and at least one saturated cyclic alkyl ring. Representative -(Cs-C 2 0)tricycloalkyls include -pyrenyl, -adamantyl, -1,2,3,4 tetrahydroanthracenyl, -perhydroanthracenyl -aceanthrenyl, -1,2,3,4 tetrahydropenanthrenyl, -5,6,7,8-tetrahydrophenanthrenyl, -perhydrophenanthrenyl, tetradecahydro-1H-cyclohepta[a]naphthalenyl, tetradecahydro-1H-cycloocta[e]indenyl, 20 tetradecahydro-1H-cyclohepta[e]azulenyl, hexadecahydrocycloocta[b]naphthalenyl, hexadecahydrocyclohepta[a]heptalenyl, tricyclo-pentadecanyl, tricyclo-octadecanyl, tricyclo nonadecanyl, tricyclo-icosanyl, and the like. As used herein, the term "-(C4-Cu 2 )cycloalkenyl" refers to a cyclic hydrocarbon having from 3 to 12 carbon atoms, and including at least one carbon-carbon double bond. 25 Representative -(C 3 -Cu)cycloalkenyls include -cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl, -cyclononadienyl, -cyclodecenyl, -cyclodecadienyl, -norbornenyl, and the like. 30 As used herein, "-(C7Cl)bicycloalkenyl" means a bi-cyclic hydrocarbon ring system having at least one carbon-carbon double bond in at least one of the rings and from 7 to 14 carbon atoms. Representative -(C 7 -C )bicycloalkenyls include -bicyclo[3.2.0]hept-2-eneyl, -57indenyl, -pentalenyl, -naphthalenyl, -azulenyl, -heptalenyl, -1,2,7,8-tetrahydronaphthalenyl, and the like. As used herein, "-(Cs-C 2 0)tricycloalkenyl" means a tri-cyclic hydrocarbon ring system having at least one carbon-carbon double bond in one of the rings and from 8 to 20 carbon 5 atoms. Representative -(Cs-C20)tricycloalkenyls include -anthracenyl, phenanthrenyl, -phenalenyl, -acenaphthalenyl, as-indacenyl, s-indacenyl, 2,3,6,7,8,9,10,11 octahydro-1H-cycloocta[e]indenyl, 2,3,4,7,8,9,10,11 -octahydro-lH cyclohepta[a]naphthalenyl, 8,9,10,11 -tetrahydro-7H-cyclohepta[a]naphthalenyl, 2,3,4,5,6,7,8,9,10,11,12,13-dodecahydro- 1H-cyclohepta[a]heptalenyl, 10 1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-dicyclohepta[a,c]cyclooctenyl, 2,3,4,5,6,7,8,9,10,11,12,13-dodecahydro-1H-dibenzo[a,d]cyclononenyl, and the like. As used herein, "-(3- to 12-membered)heterocycle" or "-(3- to 12 membered)heterocyclo" means a 3- to 12-membered monocyclic heterocyclic ring which is either saturated, unsaturated, non-aromatic, or aromatic. A 3-membered heterocycle can 15 contain up to I heteroatom; a 4-membered heterocycle can contain up to 2 heteroatoms; a 5 membered heterocycle can contain up to 4 heteroatoms; a 6-membered heterocycle can contain up to 4 heteroatoms; and a 7-membered heterocycle can contain up to 5 heteroatoms. Each heteroatom is independently selected from nitrogen (which can be quaternized), oxygen, and sulfur (including sulfoxide and sulfone). The -(3- to 12-membered)heterocycle 20 can be attached via a nitrogen or carbon atom. Representative -(3- to 12 membered)heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolidinyl, thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3 dihydrofuranyl, dihydropyranyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, 25 tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. As used herein, "-(7- to 12-membered)bicycloheterocycle" or "-(7- to 12 membered)bicycloheterocyclo" means a 7- to 12-membered bicyclic, heterocyclic ring which is either saturated, unsaturated, non-aromatic, or aromatic. A -(7- to 12 30 membered)bicycloheterocycle contains from I to 4 heteroatoms independently selected from nitrogen (which can be quaternized), oxygen, and sulfur (including sulfoxide and sulfone). The -(7- to 12-membered)bicycloheterocycle can be attached via a nitrogen or carbon atom. -58- Representative -(7- to 10-membered)bicycloheterocycles include -quinolinyl, -isoquinolinyl, -chromonyl, -coumarinyl, -indolyl, -indolizinyl, -benzo[b]furanyl, -benzo[b]thiophenyl, indazolyl, -purinyl, -4H-quinolizinyl, -isoquinolyl, -quinolyl, -phthalazinyl, naphthyridinyl, -carbazolyl, -p-carbolinyl, -indolinyl, 5 isoindolinyl, -1,2,3,4-tetrahydroquinolinyl, -1,2,3,4-tetrahydroisoquinolinyl, pyrrolopyrrolyl and the like. As used herein a "-(5- to 12- membered)aryl" means an aromatic carbocyclic ring containing 5 to 12 carbon atoms, including both mono- and bicyclic ring systems. Representative -(5- to 12-membered)aryl groups include -indenyl, -phenyl, -naphthyl, 10 acenaphthyl, -anthryl, -phenanthryl, and the like. As used herein, "-(5- to 12-membered)heteroaryl" means an aromatic heterocycle ring of 5 to 12 members, including both mono- and bicyclic ring systems, where at least one carbon atom (of one or both of the rings) is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur, or at least two carbon atoms of one or both of the 15 rings are replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur. In one embodiment, one of the bicyclic -(5- to 12-membered)heteroaryl rings contains at least one carbon atom. In another embodiment, both of the bicyclic -(5- to 12 membered)heteroaryl rings contain at least one carbon atom. Representative -(5- to 12 membered)heteroaryls include pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, 20 quinolinyl, isoquinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrimidinyl, pyrazinyl, thiadiazolyl, triazinyl, thienyl, cinnolinyl, phthalazinyl, quinazolinyl, and the like. As used herein, the terms "halo" and "halogen" refer to fluoro, chloro, bromo or iodo. 25 As used herein, "-CH 2 (halo)" means a methyl group where one of the hydrogens of the methyl group has been replaced with a halogen. Representative -CH 2 (halo) groups include -CH 2 F, -CH 2 CI, -CH 2 Br, and -CH 2 1. As used herein, "-CH(halo) 2 " means a methyl group where two of the hydrogens of the methyl group have been replaced with a halogen. Representative -CH(halo) 2 groups 30 include -CHF 2 , -CHC1 2 , -CHBr 2 , -CHBrCl, -CHCII, and -CHI 2 . -59- As used herein, "-C(halo) 3 " means a methyl group where each of the hydrogens of the methyl group has been replaced with a halogen. Representative -C(halo) 3 groups include CF 3 , -CC1 3 , -CBr 3 , and -C1 3 . As used herein, the term "optionally substituted" refers to a group that is either 5 unsubstituted or substituted. Optional substituents on optionally substituted groups, when not otherwise indicated, include 1, 2, or 3 groups each independently selected from the group consisting of -(CI
C
6 )alkyl, OH, halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), NH 2 , -NH(Ci-C 6 )alkyl, CN, SH, -(5 to 12-membered)carbocyclic ring, -(5- to 12-membered)heterocycle, phenyl, benzyl, (=0), 10 halo(Ci-C 6 )alkyl-, -(C 2
-C
6 )alkenyl, -(C-C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, OR 4 (such as -OC(halo) 3 and -O(Ci-C 6 )alkyl), CONR 5 R', and COOR 7 , where R 4 is selected from the group consisting of -(C -C 6 )alkyl, -(C-C 6 )alkenyl, -(C2-C 6 )alkynyl, -C(halo) 3 , hydroxy(CI C 6 )alkyl-, -(C 3 -C2)cycloalkyl, -(C 6
-CI
4 )bicycloalkyl, -(Cs-C 2 0)tricycloalkyl, -(C 4 C 1 2)cycloalkenyl, -(C 7
-CI
4 )bicycloalkenyl, -(Cs-C 2 0)tricycloalkenyl, -(5- to 12 15 membered)aryl, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, and -(7 to 12-membered)bicycloheterocycle;
R
5 and R 6 are each independently -(Ci-C 6 )alkyl, -(C 3 Cs)cycloalkyl, ((C 3 -Cs)cycloalkyl)-(CI-C 6 )alkyl-, or together with the nitrogen atom to which they are attached form a (4- to 8- membered)heterocycle; and R is selected from the group consisting of hydrogen, -(C 1
-C
6 )alkyl, -(C-C 6 )alkenyl, -(C-C 6 )alkynyl, -(C-Cl 2 )cycloalkyl, 20 -(C 4 -C2)cycloalkenyl, ((C 3 -C2)cycloalkyl)-(CI -C 6 )alkyl-, and ((C 4
-C
12 )cycloalkenyl)-(Cl
C
6 )alkyl-. As used herein, compounds that bind to receptors and mimic the regulatory effects of endogenous ligands are defined as "agonists". Compounds that bind to receptors and are only partly effective as agonists are defined as "partial agonists". Compounds that bind to a 25 receptor but produce no regulatory effect, but rather block the binding of ligands to the receptor are defined as "antagonists". (Ross and Kenakin, "Ch. 2: Pharmacodynamics: Mechanisms of Drug Action and the Relationship Between Drug Concentration and Effect", pp. 31-32, in Goodman & Gilman's the Pharmacological Basis of Therapeutics, 10 ' Ed. (J.G. Hardman, L.E. Limbird and A.Goodman-Gilman eds., 2001). 30 Compounds of the Invention can be in the form of prodrugs of the compounds of Formula 1, Formula II or Formula III. Prodrugs are covalently bonded carrier molecules that release an active compound of Formula I, Formula II or Formula III in vivo. Non-limiting examples of prodrugs will typically include esters of the Compounds of the Invention that can - 60 be metabolized to the active compound by the action of enzymes in the body. Such prodrugs may be prepared by reacting a compound of Formula I, Formula II or Formula III with an anhydride such as succinic anhydride. Compounds of the Invention can be isotopically-labeled (i.e., radio-labeled). 5 Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, I C, 13C, ' 4 C, 5 N, 80, O, 3 1 P, 32 P, 35 S, ' 8 F and 36 C1, respectively, and preferably 3 H, "C, and 1 4 C. Isotopically-labeled Compounds of the Invention can be prepared by methods known in the art in view of this disclosure. For example, tritiated Compounds of the 10 Invention can be prepared by introducing tritium into the particular compound by catalytic dehalogenation with tritium. This method may include reacting a suitable halogen substituted precursor of a Compound of the Invention with tritium gas in the presence. of an appropriate catalyst such as Pd/C in the presence of a base. Other suitable methods for preparing tritiated compounds are generally described in Filer, Isotopes in the Physical and 15 Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). ' 4 C-labeled compounds can be prepared by employing starting materials having a 1 4 C carbon. Isotopically labeled Compounds of the Invention, as well as the pharmaceutically acceptable salts, prodrugs and solvates thereof, can be used as radioligands to test for the binding of compounds to an opioid or ORL-1 receptor. For example, a radio-labeled 20 Compound of the Invention can be used to characterize specific binding of a test or candidate compound to the receptor. Binding assays utilizing such radio-labeled compounds can provide an alternative to animal testing for the evaluation of chemical structure-activity relationships. In a non-limiting embodiment, the present invention provides a method for screening a candidate compound for the ability to bind to an opioid or ORL-1 receptor, 25 comprising the steps of: a) introducing a fixed concentration of the radio-labeled compound to the receptor under conditions that permit binding of the radio-labeled compound to the receptor to form a complex; b) titrating the complex with a candidate compound; and c) determining the binding of the candidate compound to said receptor. Compounds of the Invention disclosed herein may contain one or more asymmetric 30 centers, thus giving rise to enantiomers, diastereomers, and other stereoisomeric forms. The present invention encompasses all such possible forms, as well as their racemic and resolved forms and mixtures thereof, and the uses thereof. The individual enantiomers may be separated according to methods known to those of ordinary skill in the art in view of the present disclosure. When the compounds described herein contain olefinic double bonds or -61other centers of geometric asymmetry, and unless specified otherwise, they include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present invention as well. As used herein, the term "stereoisomer" is a general term for all isomers of individual 5 molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers). The term "chiral center" refers to a carbon atom to which four different groups are attached. 10 The terms "enantiomer" and "enantiomeric" refer to a molecule that cannot be superimposed on its mirror image and hence is optically active such that the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction. The term "racemic" refers to a mixture of equal parts of enantiomers and which 15 mixture 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 terms "a" and "an" refer to one or more. Compounds of the Invention encompass all salts of the disclosed compounds of 20 Formula I, Formula I or Formula III. The present invention preferably includes any and all non-toxic, pharmaceutically acceptable salts of the disclosed compounds. Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts and basic salts. 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 25 salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicylohexylamine salt, N,N' dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulphate and the like; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, 30 formate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p toluenesulfonate and the like; and amino acid salts such as arginate, glutamate and the like. Acid addition salts can be formed by mixing a solution of the particular compound of the present invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric - 62 acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, and the like. Basic salts can be formed by mixing a solution of the particular compound of the present invention and a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like. 5 Compounds of the Invention also encompass solvates of the disclosed compounds of Formula I, Formula II or Formula III. The term "solvate" as used herein is a combination, physical association and/or solvation of a compound of Formula I, Formula II or Formula III with a solvent molecule such as, e.g. a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of Formula I, Formula II or Formula III is 2:1, 1:1 or 1:2, 10 respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solution-phase and isolatable solvates. A compound of Formula I, Formula II or Formula III or may be present as a solvated form 15 with a pharmaceutically acceptable solvent, such as water, methanol, ethanol, and the like, and it is intended that the invention include both solvated and unsolvated forms of Formula I, Formula II or Formula III compounds. One type of solvate is a hydrate. A "hydrate" relates to a particular subgroup of solvates where the solvent molecule is water. Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, 20 for example, M. Caira et al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparation of solvates, hemisolvates, hydrates, and the like are described by E.C. van Tonder et al., AAPS Pharm. Sci. Tech., 5(l):Article 12 (2004), and A.L. Bingham et al., Chem. Commun., 603-604 (2001). A typical, non-limiting, process of preparing a solvate would involve 25 dissolving a compound of Formula I, Formula II or Formula III in a desired solvent (organic, water, or a mixture thereof) at temperatures above about 20*C to about 25*C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in a crystal of the solvate. 30 The present invention also provides the use of a Compound of the Invention in the manufacture of a medicament for treating or preventing a Condition. In one embodiment, the Condition is pain, such as acute or chronic pain. In one embodiment, a Compound of the Invention has agonist activity at the ji, 8 and/or K receptors. In another embodiment a -63- Compound of the Invention has agonist activity at the p receptor. In another embodiment, a Compound of the Invention has antagonist activity at the ORL-1 receptor. In another embodiment, certain Compounds of the invention can stimulate one receptor (e.g., a p, 8 and/or K agonist) and inhibit a different receptor (e.g., an ORL-I antagonist). In another 5 embodiment, the Compound of the Invention is an agonist at the g receptor, and an antagonist at the ORL-1 receptor. Synthesis of Compounds Compounds of Formula I, Formula II or Formula III can be made using conventional 10 organic synthesis in view of this disclosure, or by the illustrative methods shown in the scheme below. Scheme A 15 N H NR, DEAD - -X, base or
H
3 CO 0 OCH H3CO O OCH3 R,-CHO, NaBHCN H 3 CO OCH3 Thebaine, A B C
,R
1 NR, NN -CHO 2, cat."CHO H3CO
OCH
3 H 3 CO OCH 3 D E NR, NR, 3 3
H
2 , cat.
R
2 -Y-X. base OH H O-y HCO O OCH 3
H
3 CO OCH 3 F G Thebaine, A, is N-demethylated by reaction with a suitable reagent such as diethyl 20 azodicarboxylate (DEAD) in a suitable solvent such as acetonitrile (ACN) at 50-100* C to provide the secondary amine B. Compound C is prepared by alkylation of compound B with an alkyl halide in a suitable solvent such as ACN, dimethylformamide (DMF) or dimethyl - 64 sulfoxide (DMSO) in the presence of an inorganic base such as sodium hydrogen carbonate or an organic base such as diisopropylethylamine. Compound C can also be prepared by reductive amination of compound B with an aldehyde or ketone using sodium cyanoborohydride or sodium triacetoxyborohydride in a suitable solvent such as 5 dichloromethane (DCM). Compound D is prepared by reaction of compound C with an excess of an a,p unsaturated aldehyde, as solvent, at 50-100* C. Compound E is prepared by hydrogenation of compound D in a suitable solvent such as ethanol (EtOH) in the presence of a catalyst such as palladium on carbon (Pd/C). Compound F is prepared by continued hydrogenation of compound E for 3-10 days. Compound G is prepared by reaction of 10 compound F with an alkyl halide in a suitable solvent such as DMF in the presence of a base such as sodium hydride. Aldehyde E, where Z = (CH 2 )m and m = 1, can be "homologated" to Z = (CH2)m and m >1, by a number of "homologation" techniques, known to one skilled in the art. Examples of such homologation techniques include, but are not limited to, synthesis and subsequent hydrolysis of alkoxyalkenes (A.F. Kluge and I.S. Cloudsdale, "Phosphonate 15 reagents for the synthesis of enol ethers and one-carbon homologation to aldehydes", J. Org. Chem., 1979, 44:4847), synthesis and subsequent reduction/hydrolysis of nitroalkenes (N. Ono, "The Nitro Group in Organic Synthesis", Wiley-VCH, New York, 2001, p. 165-167), and synthesis and subsequent reduction of a,p-unsaturated aldehydes (J.C. Stowell, "Carbanions in Organic Synthesis ", John Wiley & Sons, New York, 1979, p. 184-185). 20 - 65 - Scheme B
-CH
3 N-H3 H 1. L- Selectride / DEAD 2. protect
H
3 C-O O OCH 3 R-0 0 OCH 3 P-0 O OCH 3 A H N-R1 N,
R
1 -X, base R3 CHO 3 H 2 . cat. - (>~~(~... CHO - * or - -"H Rr-CHO, NaBH3CN P-0 OCH . P-0 O OCH, K R3 R 3 H 1. R 2 -Y-X, base y- 2 ,, .. /D 2. deprotect P- OCH0 R-O 0 OCH L M Thebaine, A, is O-demethylated by reaction with a suitable reagent such as lithium tri-sec 5 butylborohydride (L-Selectride, Aldrich) in a suitable solvent such as tetrahydrofuran (THF) at 25-65* C (e.g. Rice, K.C., et al. J. Org. Chem., 1996, 61, 6774) to provide the phenol H (R = H). The phenolic group of H is protected with a suitable protecting group (P) to give H (R = P) (e.g. Greene, T.W. "Protective Groups in Organic Synthesis", J. Wiley & Sons, NY, 1981). Compound H (R = P) is reacted with DEAD according to the procedure in Scheme A 10 (A - B) to provide the secondary amine [. Compound J is prepared from I according to the procedure in Scheme A (B -+ C) either by alkylation or reductive amination. Compound K is prepared by reaction of compound J with an excess of an ot,D unsaturated aldehyde, as solvent, at 50-100* C. Compound L is prepared by hydrogenation of compound K in a suitable solvent such as ethanol (EtOH) in the presence of a catalyst such as palladium on 15 carbon (Pd/C). Compound M (R = P) is prepared by reaction of compound L with an alkyl halide in a suitable solvent such as DMF in the presence of a base such as sodium hydride. Removal of the protecting group (P) in compound M (R = P) is achieved according to literature procedure (e.g. Greene, T.W. "Protective Groups in Organic Synthesis", J. Wiley & Sons, NY, 1981) to give compound M (R = H). 20 - 66 - Scheme C 1. L- Selectride -- 2. proted H3C- O OCH3 P-O 0
OCH
3 C Compound C is O-demethylated and the resulting phenolic group protected with a suitable 5 protecting group (P) to give J according to the procedure shown in Scheme B (A - H). Scheme D ,R, ,R, N R4 0/OH R3 R 4 /H 0 0 DEAD, Ph3P P-0CH 3 P-O 0 OCH 3 L N ., deprotect R HO
OCH
3 N 10 Compound N is prepared from compound L via a Mitsunobu reaction (Hughes, D.L. Org. Prep. 1996, 28, 127) using triphenylphosphine and DEAD. Removal of the protecting group (P) in compound N is achieved according to literature procedure (e.g. Greene, T.W. "Protective Groups in Organic Synthesis", J. Wiley & Sons, NY, 1981) to give compound 0. 15 Testing of Compounds p-opioid Receptor Binding Assay Procedures: Radioligand dose-displacement binding assays for p-opioid receptors used 0.3 nM [ 3 H]-diprenorphine (Perkin Elmer, Shelton, CT), with 5 mg membrane protein/well in a final volume of 500 pl binding buffer (10 mM 20 MgCI 2 , I mM EDTA, 5% DMSO, 50 mM HEPES, pH 7.4). Reactions were carried out in the absence or presence of increasing concentrations of unlabeled naloxone. All reactions were conducted in 96-deep well polypropylene plates for 2 hr at room temperature. Binding - 67 reactions were terminated by rapid filtration onto 96-well Unifilter GF/C filter plates (Perkin Elmer, Shelton, CT), presoaked in 0.5% polyethylenimine using a 96-well tissue harvester (Perkin Elmer, Shelton, CT.) followed by performing three filtration washes with 500 Pl of ice-cold binding buffer. Filter plates were subsequently dried at 50*C for 2-3 hours. 5 BetaScint scintillation cocktail (Perkin Elmer, Shelton, CT) was added (50 pl/well), and plates were counted using a Packard Top-Count for I min/well. The data were analyzed using the one-site competition curve fitting functions in GraphPad PRISM v. 3.0 (San Diego, Calif.), or an in-house function for one-site competition curve-fitting. i-opioid Receptor Binding Data: Generally, the lower the Ki value, the more 10 effective the Compounds of the Invention will be at treating or preventing pain or another Condition. Typically, the Compounds of the Invention will have a Ki (nM) of about 1000 or less for binding to g-opioid receptors. In one embodiment the Compounds of the Invention will have a Ki (nM) of about 300 or less for binding to p-opioid receptors. In one embodiment, Compounds of the Invention will have a Ki (nM) of about 100 or less. In 15 another embodiment, Compounds of the Invention will have a Ki (nM) of about 10 or less. In still another embodiment, Compounds of the Invention will have a Ki (nM) of about 1 or less. In still another embodiment, Compounds of the Invention will have a Ki (nM) of about 0.1 or less. i-Opioid Receptor Functional Assay Procedures: [ 3 5 S]GTPyS functional assays 20 were conducted using freshly thawed p-receptor membranes (Perkin Elmer, Shelton, CT). Assay reactions were prepared by sequentially adding the following reagents to binding buffer (100 mM NaCI, 10 mM MgCl 2 , 20 mM HEPES, pH 7.4) on ice (final concentrations indicated): membrane protein (0.026 mg/mL), saponin (10 mg/mL), GDP (3mM) and
[
3 S]GTPyS (0.20 nM; Perkin Elmer, Shelton, CT). The prepared membrane solution (190 25 plUwell) was transferred to 96-shallow well polypropylene plates containing 10 Pl of 20x concentrated stock solutions of the agonist [D-Ala 2 , N-methyl-Phe 4 Gly-o1 5 ]-enkephalin (DAMGO) prepared in dimethyl sulfoxide (DMSO). Plates were incubated for 30 min at about 25*C with shaking. Reactions were terminated by rapid filtration onto 96-well Unifilter GF/B filter plates (Perkin Elmer, Shelton, CT) using a 96-well tissue harvester 30 (Perkin Elmer, Shelton, CT.) followed by three filtration washes with 200 d of ice-cold wash buffer (10 mM NaH 2
PO
4 , 10 mM Na 2
HPO
4 , pH 7.4). Filter plates were subsequently dried at 50*C for 2-3 hr. BetaScint scintillation cocktail (Perkin Elmer, Shelton, CT) was added (50 pl/well) and plates were counted using a Packard Top-Count for I min/well. Data were - 68 analyzed using the sigmoidal dose-response curve fitting functions in GraphPad PRISM v. 3.0, or an in-house function for non-linear, sigmoidal dose-response curve-fitting. t-Opioid Receptor Functional Data: p GTP EC 50 is the concentration of a compound providing 50% of the maximal response for the compound at a p-opioid receptor. 5 Compounds of the Invention will typically have a p GTP EC 5 0 (nM) of about 5000 or less. In certain embodiments, Compounds of the Invention will have a p GTP EC 5 0 (nM) of about 2000 or less; or about 1000 or less; or about 100 or less; or about 10 or less; or about 1 or less; or about 0.1 or less. p GTP E. (%) is the maximal effect elicited by a compound relative to the effect 10 elicited by DAMGO, a standard p agonist. Generally, the p GTP E,. (%) value measures the efficacy of a compound to treat or prevent pain or other Conditions. Typically, Compounds of the Invention will have a p GTP E,. (%) of greater than about 10%; or greater than about 20%. In certain embodiments, Compounds of the Invention will have a p GTP E. (%) of greater than about 50%; or greater than about 65%; or greater than about 15 75%; or greater than about 85%; or greater than about 100%. K-opioid Receptor Binding Assay Procedures: Membranes from recombinant HEK-293 cells expressing the human kappa opioid receptor (kappa) (cloned in house) were prepared by lysing cells in ice cold hypotonic buffer (2.5 mM MgC 2 , 50 mM HEPES, pH 7.4) (10 mUl0 cm dish) followed by homogenization with a tissue grinder/Teflon pestle. 20 Membranes were collected by centrifugation at 30,000 x g for 15 min at 4'C and pellets were resuspended in hypotonic buffer to a final concentration of 1-3mg/mL. Protein concentrations were determined using the BioRad protein assay reagent with bovine serum albumen as standard. Aliquots of kappa receptor membranes were stored at -80 *C. Radioligand dose displacement assays used 0.4 nM [ 3 H]-U69,593 (GE Healthcare, 25 Piscataway, NJ; 40 Ci/mmole) with 15 pg membrane protein (recombinant kappa opioid receptor expressed in HEK 293 cells; in-house prep) in a final volume of 200 pl binding buffer (5% DMSO, 50 mM Trizma base, pH 7.4). Non-specific binding was determined in the presence of 10 pM unlabeled naloxone or U69,593. All reactions were performed in 96 well polypropylene plates for 1 hr at a temperature of about 25*C. Binding reactions were 30 terminated by rapid filtration onto 96-well Unifilter GF/C filter plates (Perkin Elmer, Shelton, CT) presoaked in 0.5% polyethylenimine (Sigma). Harvesting was performed using a 96 well tissue harvester (Perkin Elmer, Shelton, CT) followed by five filtration washes with 200 - 69 pl ice-cold binding buffer. Filter plates were subsequently dried at 50*C for 1-2 hours. Fifty pl/well scintillation cocktail (Perkin Elmer, Shelton, CT) was added and plates were counted in a Packard Top-Count for 1 min/well. K-Opioid Receptor Binding Data: In certain embodiments, the Compounds of the 5 Invention will have a Ki (nM) for K receptors of about 10,000 or more (which, for purposes of this invention, is interpreted as having no binding to the K receptors). Certain Compounds of the Invention will have a Ki (nM) of about 20,000 or less for K receptors. In certain embodiments, Compounds of the Invention will have a Ki (nM) of about 10,000 or less; or about 5000 or less; or about 1000 or less; or about 500 or less; or about 450 or less; or about 10 350 or less; or about 200 or less; or about 100 or less; or about 50 or less; or about 10 or less; or about 1 or less; or about 0.1 or less. x-Opioid Receptor Functional Assay Procedures: Functional [ 35 S]GTPyS binding assays were conducted as follows. Kappa opioid receptor membrane solution was prepared by sequentially adding final concentrations of 0.026 pg/pl kappa membrane protein (in 15 house), 10 pg/mL saponin, 3 pM GDP and 0.20 nM ["S)GTPyS to binding buffer (100 mM NaCl, 10 mM MgC 2 , 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 pl/well) was transferred to 96-shallow well polypropylene plates containing 10 p of 20x concentrated stock solutions of agonist prepared in DMSO. Plates were incubated for 30 min at a temperature of about 25*C with shaking. Reactions were terminated by rapid filtration 20 onto 96-well Unifilter GF/B filter plates (Perkin Elmer, Shelton, CT) using a 96-well tissue harvester (Packard) and followed by three filtration washes with 200 p1 ice-cold binding buffer (10 mM NaH 2
PO
4 , 10 mM Na 2
HPO
4 , pH 7.4). Filter plates were subsequently dried at 50*C for 2-3 hours. Fifty pl/well scintillation cocktail ( Perkin Elmer, Shelton, CT) was added and plates were counted in a Packard Top-Count for 1 min/well. 25 K-Opioid Receptor Functional Data: K GTP ECso is the concentration of a compound providing 50% of the maximal response for the compound at a K receptor. Certain Compounds of the Invention will have a K GTP ECso (nM) of about 20,000 or less to stimulate K opioid receptor function. In certain embodiments, Compounds of the Invention will have a K GTP ECso (nM) of about 10, 000 or less; or about 5000 or less; or about 2000 or 30 less; or about 1500 or less; or about 1000 or less; or about 600 or less; or about 100 or less; or about 50 or less; or about 25 or less; or about 10 or less; or about I or less; or about 0.1 or less. -70 - K GTP E,, (%) is the maximal effect elicited by a compound relative to the effect elicited by U69,593. Certain Compounds of the Invention will have a K GTP E". (%) of greater than about 1%; or greater than about 5%; or greater than aboutl0%; or greater than about 20%. In certain embodiments, Compounds of the Invention will have a K GTP E'. 5 (%) of greater than about 50%; or greater than about 75%; or greater than about 90%; or greater than about 100%. S-opioid Receptor Binding Assay Procedures: S-opioid Receptor Binding Assay Procedures were conducted as follows. Radioligand dose-displacement assays used 0.3 nM [ 3 H]-Naltrindole (Perkin Elmer, Shelton, CT; 33.0 Ci/mmole) with 5 pg membrane 10 protein (Perkin Elmer, Shelton, CT) in a final volume of 500 pl binding buffer (5 mM MgC 2 , 5% DMSO, 50 mM Trizma base, pH 7.4). Non-specific binding was determined in the presence of 25 piM unlabeled naloxone. All reactions were performed in 96-deep well polypropylene plates for 1 hr at a temperature of about 25*C. Binding reactions were terminated by rapid filtration onto 96-well Unifilter GF/C filter plates (Perkin Elmer, Shelton, 15 CT) presoaked in 0.5% polyethylenimine (Sigma). Harvesting was performed using a 96 well tissue harvester (Perkin Elmer, Shelton, CT) followed by five filtration washes with 500 pl ice-cold binding buffer. Filter plates were subsequently dried at 50*C for 1-2 hours. Fifty pl/well scintillation cocktail (Perkin Elmer, Shelton, CT) was added and plates were counted in a Packard Top-Count for I min/well. 20 6-opioid Receptor Binding Data: In certain embodiments, the Compounds of the Invention will have a Ki (nM) for 8 receptors of about 10,000 or more (which, for the purposes of this invention, is interpreted as having no binding to the 5 receptors). Certain Compounds of the Invention will have a Ki (nM) of about 20,000 or less for 8 receptors. In one embodiment, the Compounds of the Invention will have a Ki (nM) of about 10,000 or 25 less; or of about 9000 or less. In another embodiment, the Compounds of the Invention will have a Ki (nM) of about 7500 or less; or of about 6500 or less; or of about 5000 or less; or of about 3000 or less; or of about 2500 or less. In another embodiment, the Compounds of the Invention will have a Ki (nM) of about 1000 or less; or of about 500 or less; or of about 350 or less; or of about 250 or less; or of about 100 or less; or of about 10 or less. 30 6-Opioid Receptor Functional Assay Procedures: Functional ( 3 5 S]GTPyS binding assays were conducted as follows. Delta opioid receptor membrane solution was prepared by sequentially adding final concentrations of 0.026 pg/pl delta membrane protein (Perkin - 71 - Elmer, Shelton, CT), 10 pg/mL saponin, 3 pM GDP and 0.20 nM [ 35 S]GTPyS to binding buffer (100mM NaCl, 10mM MgC 2 , 20mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 p±l/well) was transferred to 96-shallow well polypropylene plates containing 10 pl of 20x concentrated stock solutions of agonist prepared in DMSO. Plates 5 were incubated for 30 min at a temperature of about 25*C with shaking. Reactions were terminated by rapid filtration onto 96-well Unifilter GF/B filter plates (Perkin Elmer, Shelton, CT) using a 96-well tissue harvester (Packard) and followed by three filtration washes with 200 pl ice-cold binding buffer (10 mM NaH 2
PO
4 , 10 mM Na 2
HPO
4 , pH 7.4). Filter plates were subsequently dried at 50"C for 1-2 hours. Fifty pl/well scintillation cocktail (Perkin 10 Elmer, Shelton, CT) was added and plates were counted in a Packard Top-count for I min/well. S-Opioid Receptor Functional Data: S GTP EC 50 is the concentration of a compound providing 50% of the maximal response for the compound at a S receptor. Certain Compounds of the Invention will have a S GTP EC 5 o (nM) of about 20, 000 or less; or about 15 10,000 or less. In certain embodiments, the Compounds of the Invention will have a S GTP
EC
50 (nM) of about 3500 or less; or of about 1000 or less; or of about 500 or less; or of about 100 or less; or of about 90 or less; or of about 50 or less; or of about 25 or less; or of about 10 or less. S GTP E,. (%) is the maximal effect elicited by a compound relative to the effect 20 elicited by met-enkephalin. Certain Compounds of the Invention of the invention will have a 8 GTP E,. (%) of greater than about 1%; or of greater than about 5%; or of greater than about 10%. In one embodiment, the Compounds of the Invention will have a S GTP Emx (%) of greater than about 30%. In other embodiments, the Compounds of the Invention will have a S GTP E, (%) of greater than about 50%; or of greater than about 75%; or of greater 25 than about 90%. In another embodiment, the Compounds of the Invention will have a S GTP E,. (%) of about 100% or greater. ORL-1 Receptor Binding Assay Procedure: Membranes from recombinant HEK 293 cells expressing the human opioid receptor-like receptor (ORL-1) (Perkin Elmer, Shelton, CT) were prepared by lysing cells in ice-cold hypotonic buffer (2.5 mM MgC 2 , 50 30 mM HEPES, pH 7.4) (10 ml/I0 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. - 72 - Protein concentrations were determined using the BioRad protein assay reagent with bovine serum albumen as standard. Aliquots of the ORL- I receptor membranes were stored at 80 0 C. Radioligand binding assays (screening and dose-displacement) used 0.1 nM [ 3
H]
5 nociceptin (Perkin Elmer, Shelton, CT; 87.7 Ci/mmole) with 12 pg membrane protein in a final volume of 500 pl binding buffer (10 mM MgCl 2 , 1 mM EDTA, 5% DMSO, 50 mM HEPES, pH 7.4). Non-specific binding was determined in the presence of 10 nM unlabeled nociceptin (American Peptide Company). All reactions were performed in 96-deep well polypropylene plates for 1 h at room temperature. Binding reactions were terminated by 10 rapid filtration onto 96-well Unifilter GF/C filter plates (Perkin Elmer, Shelton, CT) presoaked in 0.5% polyethylenimine (Sigma). Harvesting was performed using a 96-well tissue harvester (Perkin Elmer, Shelton, CT) followed by three filtration washes with 500 pl ice-cold binding buffer. Filter plates were subsequently dried at 50*C for 2-3 hours. Fifty pl/well scintillation cocktail (Perkin Elmer, Shelton, CT) was added and plates were counted 15 in a Packard Top-Count for 1 min/well. The data from screening and dose-displacement experiments were analyzed using Microsoft Excel and the curve fitting functions in GraphPad PRISMTm, v. 3.0, respectively, or an in-house function for one-site competition curve-fitting. ORL-1 Receptor Binding Data: Certain Compounds of the Invention will have a Ki (nM) of about 1000 or less. In one embodiment, the Compounds of the Invention will have a 20 Ki (nM) of about 500 or less. In other embodiments, the Compounds of the Invention will have a Ki (nM) of about 300 or less; or of about 100 or less; or of about 50 or less; or of about 20 or less. In yet other embodiments, the Compounds of the Invention will have a Ki (nM) of about 10 or less; or of about I or less; or of about 0.1 or less. ORL-1 Receptor Functional Assay Procedure: Membranes from recombinant 25 HEK-293 cells expressing the human opioid receptor-like (ORL-1) (Perkin Elmer, Shelton, CT) were prepared by lysing cells in ice-cold hypotonic buffer (2.5 mM Mg C1 2 , 50 mM HEPES, pH 7.4) (10 ml/10 cm dish) followed by homogenization with a tissue grinder/Teflon pestle. Membranes were collected by centrifugation at 30,000 x g for 15 min at 4*C, and pellets resuspended in hypotonic buffer to a final concentration of 1-3 mg/ml. Protein 30 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. - 73 - Functional [ 35 S]GTPyS binding assays were conducted as follows. ORL-1 membrane solution was prepared by sequentially adding final concentrations of 0.026 pg/gd ORL-I membrane protein, 10 pg/ml saponin, 3 pM GDP and 0.20 nM ["S]GTPyS to binding buffer (100 mM NaCI, 10 mM MgCl 2 , 20 mM HEPES, pH 7.4) on ice. The prepared membrane 5 solution (190 pl/well) was transferred to 96-shallow well polypropylene plates containing 10 pl of 20x concentrated stock solutions of agonist/nociceptin 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 (Perkin Elmer, Shelton, CT) using a 96 well tissue harvester (Packard) and followed by three filtration washes with 200 pl ice-cold 10 binding buffer (10 mM NaH 2
PO
4 , 10 mM Na 2
HPO
4 , pH 7.4). Filter plates were subsequently dried at 50*C for 2-3 hours. Fifty jl/well scintillation cocktail (Perkin Elmer, Shelton, CT) was added and plates were counted in a Packard Top-Count for I min/well. Data were analyzed using the sigmoidal dose-response curve fitting functions in GraphPad PRISM v. 3.0, or an in-house function for non-linear, sigmoidal dose-response curve-fitting. 15 ORL-1 Receptor Functional Data: ORL-1 GTP EC 50 is the concentration of a compound providing 50% of the maximal response for the compound at an ORL-1 receptor. In certain embodiments, the Compounds of the Invention that have a high binding affinity (i.e. low Ki value) will have an ORL-I GTP EC 5 o (nM) of greater than about 10,000 (i.e. will not stimulate at therapeutic concentrations) In certain embodiments Compounds of the 20 Invention will have an ORL-1 GTP EC 5 o (nM) of about 20,000 or less. In one embodiment, the Compounds of the Invention will have an ORL-I GTP EC 50 (nM) of about 10,000 or less; or of about 5000 or less; or of about 1000 or less. In still other embodiments, the Compounds of the Invention will have an ORL-1 GTP EC 50 (nM) of about 100 or less; or of about 10 or less; or of about 1 or less; or of about 0.1 or less. . 25 ORL-1 GTP E, % is the maximal effect elicited by a compound relative to the effect elicited by nociceptin, a standard ORL-I agonist. In certain embodiments, Compounds of the Invention will have an ORL-I GTP E,. of less than 10% (which, for the purposes of this invention, is interpreted as having antagonist activity at ORL-I receptors). Certain Compounds of the Invention will have an ORL-I GTP E. (%) of greater than 1%; or of 30 greater than 5%; or of greater than 10%. In other embodiments the Compounds of the Invention will have an ORL-I GTP E, of greater than 20%; or of greater than 50%; or of greater than 75%; or of greater than 88%; or of greater than 100%. - 74 - In Vivo Assays for Prevention or Treatment of Pain Test Animals: Each experiment uses rats weighing between 200-260 g at the start of the experiment. The rats are group-housed and have free access to food and water at all times, except prior to oral administration of a Compound of the Invention when food is 5 removed for about 16 hours before dosing. A control group acts as a comparison to rats treated with a Compound of the Invention. The control group is administered the carrier for the Compound of the Invention. The volume of carrier administered to the control group is the same as the volume of carrier and Compound of the Invention administered to the test group. 10 Acute Pain: To assess the actions of a Compound of the Invention for the treatment or prevention of acute pain, the rat tail flick test can be used. Rats are gently restrained by hand and the tail exposed to a focused beam of radiant heat at a point 5 cm from the tip using a tail flick unit (Model 7360, commercially available from Ugo Basile of Italy). Tail flick latencies are defined as the interval between the onset of the thermal stimulus and the flick of 15 the tail. Animals not responding within 20 seconds are removed from the tail flick unit and assigned a withdrawal latency of 20 seconds. Tail flick latencies are measured immediately before (pre-treatment) and 1, 3, and 5 hours following administration of a Compound of the Invention. Data are expressed as tail flick latency(s) and the percentage of the maximal possible effect (% MPE), i.e., 20 seconds, is calculated as follows: 20 [(post administration latency) - (pre-administration latency)] % MPE = x 100 (20 s pre-administration latency) The rat tail flick test is described in F.E. D'Amour et al., "A Method for Determining Loss of Pain Sensation," J. Pharmacol. Exp. Ther. 72:74-79 (1941). Inflammatory Pain: To assess the actions of a Compound of the Invention for the 25 treatment or prevention of inflammatory pain, the Freund's complete adjuvant ("FCA") model of inflammatory pain was used. FCA-induced inflammation of the rat hind paw is associated with the development of persistent inflammatory mechanical hyperalgesia and provides reliable prediction of the anti-hyperalgesic action of clinically useful analgesic drugs (L. Bartho el al., "Involvement of Capsaicin-sensitive Neurones in Hyperalgesia and Enhanced 30 Opioid Antinociception in Inflammation," Naunyn-Schmiedeberg's Archives of Pharmacol. - 75 - 342:666-670 (1990)). The left hind paw of each animal was administered a 50 pL intraplantar injection of 50% FCA. Prior to injection of FCA (baseline) and 24 hour post injection, the animal was assessed for response to noxious mechanical stimuli by determining the PWT, as described below. Rats were then administered a single injection of 1, 3, or 10 5 mg/kg of either a Compound of the Invention; 30mg/kg of a control drug selected from Celebrex, indomethacin or naproxen; or carrier. Responses to noxious mechanical stimuli were determined 1, 3, 5 and 24 hours post administration. Percentage reversal of hyperalgesia for each animal was defined as: 10 (post administration PWT) - (pre-administration PWT)] %Reversal =___________ ___ x 100 [(baseline PWT) - (pre-administration PWT)] 15 Compounds of the Invention induced significant anti-hyperalgesia in the FCA test, with no observed side effects at the ED 5 o dose. For example, Compound 11 had an ED 50 of 3.6 mg/kg, and no side effects were observed at this dose (see Fig. 11). At the analgesic (i.e. more than anti-hyperalgesic) dose of 10 mg/kg rats showed slightly reduced activity, but remained alert and oriented to changes in their environment. 20 Neuropathic Pain: To assess the actions of a Compound of the Invention for the treatment or prevention of neuropathic pain, either the Seltzer model or the Chung model can be used. In the Seltzer model, the partial sciatic nerve ligation model of neuropathic pain is used to produce neuropathic hyperalgesia in rats (Z. Seltzer et al., "A Novel Behavioral 25 Model of Neuropathic Pain Disorders Produced in Rats by Partial Sciatic Nerve Injury," Pain 43:205-218 (1990)). Partial ligation of the left sciatic nerve is performed under isoflurane/0 2 inhalation anaesthesia. Following induction of anesthesia, the left thigh of the rat is shaved and the sciatic nerve exposed at high thigh level through a small incision and is carefully cleared of surrounding connective tissues at a site near the trocanther just distal to the point at 30 which the posterior biceps semitendinosus nerve branches off of the common sciatic nerve. A 7-0 silk suture is inserted into the nerve with a 3/8 curved, reversed-cutting mini-needle and tightly ligated so that the dorsal '/3 to /2 of the nerve thickness is held within the ligature. The wound is closed with a single muscle suture (4-0 nylon (Vicryl)) and vetbond tissue glue. - 76- Following surgery, the wound area is dusted with antibiotic powder. Sham-treated rats undergo an identical surgical procedure except that the sciatic nerve is not manipulated. Following surgery, animals are weighed and placed on a warm pad until they recover from anesthesia. Animals are then returned to their home cages until behavioral testing begins. 5 The animal is assessed for response to noxious mechanical stimuli by determining PWT, as described below, prior to surgery (baseline), then immediately prior to and 1, 3, and 5 hours after drug administration. Percentage reversal of neuropathic hyperalgesia is defined as: [ (post administration PWT) - (pre-administration PWT) ] 10 % Reversal = x 100 [ (baseline PWT) - (pre-administration PWT) ] In the Chung model, the spinal nerve ligation model of neuropathic pain is used to produce mechanical hyperalgesia, thermal hyperalgesia and tactile allodynia in rats. Surgery 15 is performed under isoflurane/0 2 inhalation anaesthesia. Following induction of anaesthesia, a 3 cm incision is made and the left paraspinal muscles are separated from the spinous process at the L4 - S2 levels. The L transverse process is carefully removed with a pair of small rongeurs to identify visually the L 4 - L4 spinal nerves. The left L 5 (or L5 and L 6 ) spinal nerve(s) is isolated and tightly ligated with silk thread. A complete hemostasis is confirmed 20 and the wound is sutured using non-absorbable sutures, such as nylon sutures or stainless steel staples. Sham-treated rats undergo an identical surgical procedure except that the spinal nerve(s) is not manipulated. Following surgery animals are weighed, administered a subcutaneous (s.c.) injection of saline or ringers lactate, the wound area is dusted with antibiotic powder and they are kept on a warm pad until they recover from the anesthesia. 25 Animals are then returned to their home cages until behavioral testing begins. The animals are assessed for response to noxious mechanical stimuli by determining PWT, as described below, prior to surgery (baseline), then immediately prior to and 1, 3, and 5 hours after being administered a Compound of the Invention. The animal can also be assessed for response to noxious thermal stimuli or for tactile allodynia, as described below. The Chung model for 30 neuropathic pain is described in S.H. Kim, "An Experimental Model for Peripheral Neuropathy Produced by Segmental Spinal Nerve Ligation in the Rat," Pain 50(3):355-363 (1992). -77- Response to Mechanical Stimuli as an Assessment of Mechanical Hyperalgesia: The paw pressure assay was used to assess mechanical hyperalgesia. For this assay, hind paw withdrawal thresholds (PWT) to a noxious mechanical stimulus were determined using an analgesymeter (Model 7200, commercially available from Ugo Basile of Italy) as 5 described in C. Stein, "Unilateral Inflammation of the Hindpaw in Rats as a Model of Prolonged Noxious Stimulation: Alterations in Behavior and Nociceptive Thresholds," Pharmacol. Biochem. and Behavior 31:451-455 (1988). The maximum weight that was applied to the hind paw was set at 250 g and the end point was taken as complete withdrawal of the paw. PWT was determined once for each rat at each time point and either only the 10 affected (ipsilateral; same side as the injury) rear paw was tested, or both the ipsilateral and contralateral (non-injured; opposite to the injury) rear paw were tested. Response to Thermal Stimuli as an Assessment of Thermal Hyperalgesia: The plantar test can be used to assess thermal hyperalgesia. For this test, hind paw withdrawal latencies to a noxious thermal stimulus are determined using a plantar test apparatus 15 (commercially available from Ugo Basile of Italy) following the technique described by K. Hargreaves et al., "A New and Sensitive Method for Measuring Thermal Nociception in Cutaneous Hyperalgesia," Pain 32(1):77-88 (1988). The maximum exposure time is set at 32 seconds to avoid tissue damage and any directed paw withdrawal from the heat source is taken as the end point. Three latencies are determined at each time point and averaged. 20 Either only the affected (ipsilateral) paw is tested, or both the ipsilateral and contralateral (non-injured) paw are tested. Assessment of Tactile Allodynia: To assess tactile allodynia, rats are placed in clear, plexiglass compartments with a wire mesh floor and allowed to habituate for a period of at least 15 minutes. After habituation, a series of von Frey monofilaments are presented to 25 the plantar surface of the affected (ipsilateral) foot of each rat. The series of von Frey monofilaments consists of six monofilaments of increasing diameter, with the smallest diameter fiber presented first. Five trials are conducted with each filament with each trial separated by approximately 2 minutes. Each presentation lasts for a period of 4-8 seconds or until a nociceptive withdrawal behavior is observed. Flinching, paw withdrawal or licking of 30 the paw are considered nociceptive behavioral responses. Assessment of Respiratory Depression: To assess respiratory depression, rats were prepared by implanting a femoral artery cannula via which blood samples were taken. Blood - 78 samples were taken prior to drug administration, then 1, 3, 5 and 24 hours post-treatment. Blood samples were processed using an arterial blood gas analyzer (e.g., IDEXX VetStat with Respiratory/Blood Gas test cartridges). Comparable devices are a standard tool for blood gas analysis (e.g., D. Torbati et al., 2000 Intensive Care Med. (26) 585-591). For example, 5 compound 11 did not induce respiratory depression at the ED 50 dose for anti-hyperalgesia, nor did it induce respiratory depression at a higher dose that was shown to be analgesic (10 mg/kg) in the FCA model of inflammatory pain (see Figs. I to 5). The following tables show the statistical analysis of the blood gas measurements in 10 drug-treated rats, compared to rats administered water. TABLE 1: Statistical Analysis of Oxygen Tension in Blood Samples p02 15 2-way RM ANOVA Treatment F(4,180) =8.42 p <0.0001 Time F(4,180) = 8.40 p <0.0001 Interaction F(16,180) = 2.95 p < 0.0005 20 Post hoc (Bonferroni-corrected MCT) Water vs. Baseline 1 hour 3 hours 5 hours 24 hours 3 mg/kg Compound 11 ns ns ns ns ns (PO) 10 mg/kg Compound II ns ns ns ns ns (PO) 30 mg/kg Compound 11 ns * ns ns (P0) 30 mg/kg Morphine (SC) ns ns ns "ns"= not significant "*" = statistically significant, p <0.05 vs. water group = statistically significant, p < 0.01 vs. water group = statistically significant, p < 0.001 vs. water group 25 -79- TABLE 2: Statistical Analysis of Oxygen Saturation in Blood Samples s02 2-way RM ANOVA 5 Treatment F(4,180) = 14.55 p <0.0001 Time F(4,180)= 18.32 p<0.0001 Interaction F(16,180)= 8.32 p < 0.0001 Post hoc (Bonferroni-corrected MC) Water vs. Baseline I hour 3 hours 5 hours 24 hours 3 mg/kg Compound I1 ns ns ns ns ns (PO) 10 mg/kg Compound 11 ns ns ns ns ns (PO) I 30 mg/kg Compound 11 ns * ** sns 30 mg/kg Morphine (SC) ns ns ns 10 "ns" = not significant = statistically significant, p < 0.05 vs. water group = statistically significant, p < 0.01 vs. water group = statistically significant, p < 0.001 vs. water group 15 TABLE 3: Statistical Analysis of Carbon Dioxide Tension in Blood Samples pCO2 2-way RM ANOVA 20 Treatment F(4,180) = 21.32 p < 0.0001 Time F(4,180)= 10.19 p <0.0001 Interaction F(16,180) = 10.92 p <0.0005 Post hoc (Bonferroni-corrected MC) Water vs. Baseline 1 hour 3 hours 5 hours 24 hours 3 mg/kg Compound I I ns ns ns ns ns (PO) 10 mg/kg Compound I1 ns ns ns ns ns (PO) I 30 mg/kg Compound 11 ns ns ns ns (PO) 30 mg/kg Morphine (SC) ns ** ns 25 "ns" = not significant = statistically significant, p < 0.01 vs. water group = statistically significant, p < 0.001 vs. water group - 80 - TABLE 4: Statistical Analysis of Total Carbon Dioxide (Including Bicarbonate) in Blood Samples tCO2 5 2-way RM ANO VA Treatment F(4,180) = 6.15 p <0.001 Time F(4,180)= 25.57 p < 0.0001 Interaction F(16,180) = 1.94 p < 0.05 10 Post hoc (Bonferroni-corrected MCT) Water vs. Baseline 1 hour 3 hours 5 hours 24 hours 3 mg/kg Compound 11 * ns ns ns ns (PO) 10 mg/kg Compound II ns ns ns ns ns (PO) 30 mg/kg Compound II ** ** ns ns ns (PO) 30 mg/kg Morphine (SC) ns * ns ns "ns" = not significant "1*"= statistically significant, p < 0.05 vs. water group = statistically significant, p < 0.01 vs. water group = statistically significant, p < 0.001 vs. water group 15 TABLE 5: Statistical Analysis of Blood pH in Blood Samples pH 20 2-way RMANOVA Treatment F(4,180) = 14.54 p <0.0001 Time F(4,180) = 4.48 p < 0.005 Interaction F(16,180) =7.96 p <0.0001 25 Post hoc (Bonferroni-corrected MCT) Water vs. Baseline I hour 3 hours 5 hours 24 hours 3 mg/kg Compound I I ns ns ns ns ns (PO) 10 mg/kg Compound 1.1 ns ns ns ns ns (PO) 30 mg/kg Compound I I ns ns ns ns ns (PO) "ns" = not significant Similarly, at doses up to 20 mg/kg, compound 6 did not induce respiratory depression (see Figs. 6 to 10). 30 Assessment of Gastric Motility: Animals were treated with vehicle, reference compound or test article by oral gavage at a volume of 10 mUkg. At one hour post-dose, all - 81 animals were treated with charcoal meal solution (5% non-activated charcoal powder in a solution of I % carboxymethylcellulose in water) at a volume of 10 mL/kg. At two hours post-dose (one hour post-charcoal), animals were sacrificed by carbon dioxide inhalation or isoflurane overdose and the transit of charcoal meal identified. The stomach and small 5 intestine were removed carefully and each placed on a saline-soaked absorbent surface. The distance between the pylorus and the furthest progression of charcoal meal was measured and compared to the distance between the pylorus and the ileocecal junction. The charcoal meal transit was expressed as a percentage of small intestinal length traveled. For example, compound 11 induced dose-dependent inhibition of gastric motility. 10 Pharmaceutical Compositions Due to their activity, the Compounds of the Invention are advantageously useful in human and veterinary medicine. As described above, the Compounds of the Invention are useful for treating or preventing a Condition in an animal in need thereof. The Compounds 15 of the Invention can be administered to any animal requiring modulation of the opioid and/or ORL- I receptors. When administered to an animal, a Compound of the Invention can be administered as a component of a composition that comprises a pharmaceutically acceptable carrier or excipient. A Compound of the Invention can be administered by any appropriate route, as 20 determined by the medical practitioner. Methods of administration may include intradermal, intramuscular, intraperitoneal, parenteral, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, transmucosal, rectal, by inhalation, or topical (particularly to the ears, nose, eyes, or skin). Delivery can be either local or systemic. In certain embodiments, administration will result in the release of a Compound of 25 the Invention into the bloodstream. Pharmaceutical compositions of the invention can take the form of solutions, suspensions, emulsions, tablets, pills, pellets, multi-particulates, capsules, capsules containing liquids, capsules containing powders, capsules containing multi-particulates, lozenges, sustained-release formulations, suppositories, aerosols, sprays, or any other form suitable for 30 use. In one embodiment, the composition is in the form of a capsule (see, e.g., U.S. Patent No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in - 82 - Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporated herein by reference. Pharmaceutical compositions of the invention preferably comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration 5 to the animal. Such a pharmaceutical excipient can be a diluent, suspending agent, solubilizer, binder, disintegrant, preservative, coloring agent, lubricant, and the like. The pharmaceutical excipient can be a liquid, such as water or an oil, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. The pharmaceutical excipient can be saline, gum acacia, gelatin, 10 starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipient is sterile when administered to an animal. Water is a particularly useful excipient when a Compound of the Invention is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be 15 employed as liquid excipients, particularly for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The invention compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. 20 Specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986). In certain embodiments, the Compounds of the Invention are formulated for oral administration. A Compound of the Invention to be orally delivered can be in the form of 25 tablets, capsules, gelcaps, caplets, lozenges, aqueous or oily solutions, suspensions, granules, powders, emulsions, syrups, or elixirs, for example. When a Compound of the Invention is incorporated into oral tablets, such tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, multiply compressed or multiply layered. An orally administered Compound of the Invention can contain one or more 30 additional agents such as, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, and stabilizers, to provide stable, pharmaceutically palatable dosage - 83 forms. Techniques and compositions for making solid oral dosage forms are described in Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, eds., 2nd ed.) published by Marcel Dekker, Inc. Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are also described in 5 Remington's Pharmaceutical Sciences 1553-1593 (Arthur Osol, ed., 16 'h ed., Mack Publishing, Easton, PA 1980). Liquid oral dosage forms include aqueous and nonaqueous solutions, emulsions, suspensions, and solutions and/or suspensions reconstituted from non effervescent granules, optionally containing one or more suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, coloring agents, flavoring 10 agents, and the like. Techniques and compositions for making liquid oral dosage forms are described in Pharmaceutical Dosage Forms: Disperse Systems, (Lieberman, Rieger and Banker, eds.) published by Marcel Dekker, Inc. When a Compound of the Invention is formulated for parenteral administration by injection (e.g., continuous infusion or bolus injection), the formulation can be in the form of a 15 suspension, solution, or emulsion in an oily or aqueous vehicle, and such formulations can further comprise pharmaceutically necessary additives such as one or more stabilizing agents, suspending agents, dispersing agents, and the like. When a Compound of the Invention is to be injected parenterally, it can be, e.g., in the form of an isotonic sterile solution. A Compound of the Invention can also be in the form of a powder for reconstitution as an 20 injectable formulation. In certain embodiments, a Compound of the Invention is formulated into a pharmaceutical composition for intravenous administration. Typically, such compositions comprise sterile isotonic aqueous buffer. Where necessary, the compositions can also include a solubilizing agent. A Compound of the Invention for intravenous administration can 25 optionally include a local anesthetic such as benzocaine or prilocaine to lessen pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent. Where a Compound of the Invention is to be administered by infusion, it can be 30 dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where a Compound of the Invention is administered by injection, an ampule of - 84 sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration. When a Compound of the Invention is to be administered by inhalation, it can be formulated into a dry aerosol, or an aqueous or partially aqueous solution. 5 In another embodiment, a Compound of the Invention can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990); and Treat et al., Liposomes in the Therapy ofInfectious Disease and Cancer 317-327 and 353-365 (1989)). In certain embodiments, a Compound of the Invention is administered locally. This can be achieved, for example, by local infusion during surgery, topical application, e.g., in 10 conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository or enema, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. In certain embodiments, a Compound of the Invention can be delivered in an 15 immediate release form. In other embodiments, a Compound of the Invention can be delivered in a controlled-release system or sustained-release system. Controlled- or sustained-release pharmaceutical compositions can have a common goal of improving drug therapy over the results achieved by their non-controlled or non-sustained-release counterparts. In one embodiment, a controlled- or sustained-release composition comprises a 20 minimal amount of a Compound of the Invention to treat or prevent the Condition (or a symptom thereof) in a minimum amount of time. Advantages of controlled- or sustained release compositions include extended activity of the drug, reduced dosage frequency, and increased compliance. In addition, controlled- or sustained-release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels of the 25 Compound of the Invention, and can thus reduce the occurrence of adverse side effects. Controlled- or sustained-release compositions can initially release an amount of a Compound of the Invention that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the Compound of the Invention to maintain a level of therapeutic or prophylactic effect over an extended period of time. To 30 maintain a constant level of the Compound of the Invention in the body, the Compound of the Invention can be released from the dosage form at a rate that will replace the amount of - 85 - Compound of the Invention being metabolized and excreted from the body. Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or 5 compounds. Controlled-release and sustained-release means for use according to the present invention may be selected from those known in the art. Examples include, but are not limited to, those described.in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 10 and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, multiparticulates, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying 15 proportions. Suitable controlled- or sustained-release formulations known in the art, including those described herein, can be readily selected for use with the active ingredients of the invention in view of this disclosure. See also Goodson, "Dental Applications" (pp. 115 138) in Medical Applications of Controlled Release, Vol. 2, Applications and Evaluation, R.S. Langer and D.L. Wise eds., CRC Press (1984). Other controlled- or sustained-release 20 systems that are discussed in the review by Langer, Science 249:1527-1533 (1990) can be selected for use according to the present invention. In one embodiment, a pump can be used (Langer, Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); and Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, polymeric materials can be used (see Medical Applications of 25 Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Ranger and Peppas, J Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); and Howard et al., J. Neurosurg. 71:105 (1989)). In yet another embodiment, a controlled- or sustained-release system can be placed in 30 proximity of a target of a Compound of the Invention, e.g., the spinal column, brain, or gastrointestinal tract, thus requiring only a fraction of the systemic dose. - 86 - When in tablet or pill form, a pharmaceutical composition of the invention can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered 5 compositions. In these latter platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time-delay material such as glycerol monostearate or glycerol stearate can also be used. Oral 10 compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade. Pharmaceutical compositions of the invention include single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and 15 caplets that are adapted for controlled- or sustained-release. The amount of the Compound of the Invention that is effective for the treatment or prevention of a condition can be determined by standard clinical techniques. In addition, in vitro and/or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed will also depend on, e.g., the route of administration and the 20 extent of the Condition to be treated, and can be decided according to the judgment of a practitioner and/or each animal's circumstances. Variations in dosing may occur depending upon typical factors such as the weight, age, gender and physical condition (e.g., hepatic and renal function) of the animal being treated, the affliction to be treated, the severity of the symptoms, the frequency of the dosage interval, the presence of any deleterious side-effects, 25 and the particular compound utilized, among other things. Suitable effective dosage amounts can range from about 0.01mg/kg of body weight to about 3000 mg/kg of body weight of the animal per day, although they are typically from about 0.01mg/kg of body weight to about 2500 mg/kg of body weight of the animal per day or from about 0.01mg/kg of body weight to about 1000 mg/kg of body weight of the animal 30 per day. In one embodiment, the effective dosage amount is about 100 mg/kg of body weight of the animal per day or less. In another embodiment, the effective dosage amount ranges from about 0.0 1 mg/kg of body weight to about 100 mg/kg of body weight of the animal per - 87 day of a Compound of the Invention, in another embodiment, about 0.02 mg/kg of body weight to about 50 mg/kg of body weight of the animal per day, and in another embodiment, about 0.025 mg/kg of body weight to about 20 mg/kg of body weight of the animal per day. Administration can be as a single dose or as a divided dose. In one embodiment, an 5 effective dosage amount is administered about every 24h until the Condition is abated. In another embodiment, an effective dosage amount is administered about every 12h until the Condition is abated. In another embodiment, an effective dosage amount is administered about every 8h until the Condition is abated. In another embodiment, an effective dosage amount is administered about every 6h until the Condition is abated. In another embodiment, 10 an effective dosage amount is administered about every 4h until the Condition is abated. The effective dosage amounts described herein refer to total amounts administered; that is, if more than one Compound of the Invention is administered, the effective dosage amounts correspond to the total amount administered. Where a cell capable of expressing the ORL-1 receptor is contacted with a Compound 15 of the Invention in vitro, the amount effective for inhibiting or activating the ORL-l receptor function in a cell will typically range from about 10-1 mol/L to about 104 mol/L, or from about 10- 2 mol/L to about 10~5 moVL, or from about 10-1 mol/L to about 10 6moVL, or from about 1012 mol/L to about 10-9 mol/L of a solution or suspension of the compound in a pharmaceutically acceptable carrier or excipient. In one embodiment, the volume of solution 20 or suspension comprising the Compound of the Invention will be from about 0.01pL to about lmL. In another embodiment, the volume of solution or suspension will be about 200 gL. Where a cell capable of expressing the p-opioid receptors is contacted with a Compound of the Invention in vitro, the amount effective for inhibiting or activating the p opioid receptors function in a cell will typically range from about 1012 molVL to about 10-4 25 mol/L,or from about 10~12 mol/L to about 10-5 mol/L, or from about 10~12 mol/L to about 104 mol/L, or from about 10~2 mol/L to about 10'9 mol/L of a solution or suspension of the Compound of the Invention in a pharmaceutically acceptable carrier or excipient. In one embodiment, the volume of solution or suspension comprising the Compound of the Invention will be from about 0.01 pL to about 1 mL. In another embodiment, the volume of 30 solution or suspension will be about 200 pL. Where a cell capable of expressing the 8-opioid receptors is contacted with a Compound of the Invention in vitro, the amount effective for inhibiting or activating the 8 -88opioid receptors function in a cell will typically range from about 1012 moVL to about 104 mol/L,or from about 1012 mol/L to about 105 mol/L, or from about 10-12 mol/L to about 10-6 mol/L, or from about 10" mol/L to about 10-9 mol/L of a solution or suspension of the Compound of the Invention in a pharmaceutically acceptable carrier or excipient. In one 5 embodiment, the volume of solution or suspension comprising the Compound of the Invention will be from about 0.01sL to about ImL. In another embodiment, the volume of solution or suspension will be about 200 pL. Where a cell capable of expressing the K-opioid receptors is contacted with a Compound of the Invention in vitro, the amount effective for inhibiting or activating the K 10 opioid receptors function in a cell will typically range from about 1012 mol/L to about 104 mol/L,or from about 10~1 mol/L to about 10- mol/L, or from about 1012 mol/L to about 10-6 mol/L, or from about 10-12 mol/L to about 10~' mol/L of a solution or suspension of the Compound of the Invention in a pharmaceutically acceptable carrier or excipient. In one embodiment, the volume of solution or suspension comprising the Compound of the 15 Invention will be from about 0.01 pL to about I mL. In another embodiment, the volume of solution or suspension will be about 200 pL. The Compounds of the Invention can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans. Animal model systems can be used to demonstrate safety and efficacy. Certain Compounds of the Invention will have an 20 ED 50 for treating inflammatory pain ranging from about 0.5 mg/kg to about 20 mg/kg. For example, compound 11 was efficacious in an inflammatory pain model as described above, with an ED 50 of about 3.6 mg/kg. Certain Compounds of the Invention will produce significant analgesia and/or anti-hyperalgesia at doses that do not induce respiratory depression. For example, at the anti-hyperalgesic ED 5 o dose, and at the higher analgesic dose 25 of 10 mg/kg, the measures of blood gases (oxygen tension, oxygen saturation, carbon dioxide tension, total carbon dioxide and pH), at 1, 3, 5 and 24 hours following drug administration, were not different in rats given compound 11 compared to rats given plain water. In contrast, oxygen tension, oxygen saturation and pH are significantly decreased, while carbon dioxide is significantly increased, in blood samples from rats given effective doses of conventional 30 opioids, such as morphine. According to the invention, methods for treating or preventing a Condition in an animal in need thereof can further comprise co-administering to the animal an effective - 89 amount of a second therapeutic agent in addition to a Compound of the Invention (i.e., a first therapeutic agent). An effective amount of the second therapeutic agent will be known or determinable by a medical practitioner in view of this disclosure and published clinical studies. In one embodiment of the invention, where a second therapeutic agent is 5 administered to an animal for treatment of a Condition (e.g., pain), the minimal effective amount of the Compound of the Invention (i.e., the first therapeutic agent) will be less than its minimal effective amount would be in circumstances where the second therapeutic agent is not administered. In this embodiment, the Compound of the Invention and the second therapeutic agent can act either additively or synergistically to treat or prevent a Condition. 10 Alternatively, the second therapeutic agent may be used to treat or prevent a disorder that is different from the Condition for which the first therapeutic agent is being administered, and which disorder may or may not be a Condition as defined hereinabove. In one embodiment, a Compound of the Invention is administered concurrently with a second therapeutic agent as a single composition comprising an effective amount of a Compound of the Invention and an 15 effective amount of the second therapeutic agent. Alternatively, a composition comprising an effective amount of a Compound of the Invention and a second composition comprising an effective amount of the second therapeutic agent are concurrently administered. In another embodiment, an effective amount of a Compound of the Invention is administered prior or subsequent to administration of an effective amount of the second therapeutic agent. In this 20 embodiment, the Compound of the Invention is administered while the second therapeutic agent exerts its therapeutic effect, or the second therapeutic agent is administered while the Compound of the Invention exerts its therapeutic effect for treating or preventing a Condition. The second therapeutic agent can be, but is not limited to, an opioid agonist, a non 25 opioid analgesic, a non-steroidal anti-inflammatory agent, an antimigraine agent, a Cox-II inhibitor, a 5-lipoxygenase inhibitor, an anti-emetic, a p-adrenergic blocker, an anticonvulsant, an antidepressant, a Ca 2 -channel blocker, an anti-cancer agent, an agent for treating or preventing UI, an agent for treating or preventing anxiety, an agent for treating or preventing a memory disorder, an agent for treating or preventing obesity, an agent for 30 treating or preventing constipation, an agent for treating or preventing cough, an agent for treating or preventing diarrhea, an agent for treating or preventing high blood pressure, an agent for treating or preventing epilepsy, an agent for treating or preventing -90anorexia/cachexia, an agent for treating or preventing drug abuse, an agent for treating or preventing an ulcer, an agent for treating or preventing IBD, an agent for treating or preventing IBS, an agent for treating or preventing addictive disorder, an agent for treating or preventing Parkinson's disease and parkinsonism, an agent for treating or preventing a stroke, 5 an agent for treating or preventing a seizure, an agent for treating or preventing a pruritic condition, an agent for treating or preventing psychosis, an agent for treating or preventing Huntington's chorea, an agent for treating or preventing ALS, an agent for treating or preventing a cognitive disorder, an agent for treating or preventing a migraine, an agent for treating, preventing or inhibiting vomiting, an agent for treating or preventing dyskinesia, an 10 agent for treating or preventing depression, or any mixture thereof. Examples of useful opioid agonists include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, 15 dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, 20 nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable derivatives thereof, or any mixture thereof. In certain embodiments, the opioid agonist is selected from codeine, hydromorphone, 25 hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, morphine, tramadol, oxymorphone, pharmaceutically acceptable derivatives thereof, or any mixture thereof. Examples of useful non-opioid analgesics include, but are not limited to, non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, 30 pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic - 91 acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, a pharmaceutically acceptable derivative thereof, or any mixture thereof. Other suitable non-opioid analgesics include the following, non-limiting, chemical classes of analgesic, antipyretic, nonsteroidal anti-inflammatory drugs: salicylic acid derivatives, including 5 aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; para-aminophenol derivatives including acetaminophen and phenacetin; indole and indene acetic acids, including indomethacin, sulindac, and etodolac; heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates), including mefenamic acid and meclofenamic acid; enolic acids, 10 including oxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone); alkanones, including nabumetone; a pharmaceutically acceptable derivative thereof; or any mixture thereof. For a more detailed description of the NSAIDs, 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 15 Therapeutics 617-57 (Perry B. Molinhoff and Raymond W. Ruddon eds., 9h ed 1996); and Glen R. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs in Remington: The Science and Practice of Pharmacy Vol II 1196-1221 (A.R. Gennaro ed. 19 'h ed. 1995), which are hereby incorporated by reference in their entireties. Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, as well as 20 combinations thereof, are described in U.S. Patent No. 6,136,839, which is hereby incorporated by reference in its entirety. Examples of useful Cox-Il inhibitors include, but are not limited to, celecoxib, DUP-697, flosulide, meloxicam, 6-MNA, L-745337, rofecoxib, nabumetone, nimesulide, NS-398, SC-5766, T-614, L-768277, GR-253035, JTE-522, RS 57067-000, SC-58125, SC-078, PD-138387, NS-398, flosulide, D-1367, SC-5766, PD 25 164387, etoricoxib, valdecoxib, parecoxib, a pharmaceutically acceptable derivative thereof, or any mixture thereof. Examples of useful antimigraine agents include, but are not limited to, alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine, ergocominine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxone acetate, fonazine, ketanserin, lisuride, 30 lomerizine, methylergonovine, methysergide, metoprolol, naratriptan, oxetorone, pizotyline, propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone, zolmitriptan, a pharmaceutically acceptable derivative thereof, or any mixture thereof. - 92 - Examples of useful anticonvulsants include, but are not limited to, acetylpheneturide, albutoin, aloxidone, aminoglutethimide, 4 -amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate, calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam, decimemide, diethadione, dimethadione, doxenitroin, eterobarb, ethadione, 5 ethosuximide, ethotoin, felbamate, fluoresone, gabapentin, 5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate, mephenytoin, mephobarbital, metharbital, methetoin, methsuximide, 5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl 5-phenylhydantoin, narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione, phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide, 10 phenylmethylbarbituric acid, phenytoin, phethenylate sodium, potassium bromide, pregabaline, primidone, progabide, sodium bromide, solanum, strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine, topiramate, trimethadione, valproic acid, valpromide, vigabatrin, zonisamide, a pharmaceutically acceptable derivative thereof, or any mixture thereof. 15 Examples of useful Ca 2 -channel blockers include, but are not limited to, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, 20 lidoflazine, lomerizine, bencyclane, etafenone, fantofarone, perhexiline, a pharmaceutically acceptable derivative thereof, or any mixture thereof. Examples of useful therapeutic agents for treating or preventing UI include, but are not limited to, propantheline, imipramine, hyoscyamine, oxybutynin, dicyclomine, a pharmaceutically acceptable derivative thereof, or any mixture thereof. 25 Examples of useful therapeutic agents for treating or preventing anxiety include, but are not limited to, benzodiazepines, such as alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam, temazepam, and triazolam; non-benzodiazepine agents, such as 30 buspirone, gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, and zaleplon; tranquilizers, such as barbituates, e.g., amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, methohexital, pentobarbital, phenobarbital, secobarbital, and thiopental; propanediol - 93 carbamates, such as meprobamate and tybamate; a pharmaceutically acceptable derivative thereof; or any mixture thereof. Examples of useful therapeutic agents for treating or preventing diarrhea include, but are not limited to, diphenoxylate, loperamide, a pharmaceutically acceptable derivative 5 thereof, or any mixture thereof. Examples of useful therapeutic agents for treating or preventing epilepsy include, but are not limited to, carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproic acid, trimethadione, benzodiazepines, -y vinyl GABA, acetazolamide, felbamate, a pharmaceutically acceptable derivative thereof, or any mixture 10 thereof. Examples of useful therapeutic agents for treating or preventing drug abuse include, but are not limited to, methadone, desipramine, amantadine, fluoxetine, buprenorphine, an opiate agonist, 3-phenoxypyridine, levomethadyl acetate hydrochloride, serotonin antagonists, a pharmaceutically acceptable derivative thereof, or any mixture thereof. 15 Examples of non-steroidal anti-inflammatory agents, 5-lipoxygenase inhibitors, anti emetics, p adrenergic blockers, antidepressants, and anti-cancer agents are known in the art and can be selected by those skilled in the art. Examples of useful therapeutic agents for treating or preventing memory disorder, obesity, constipation, cough, high blood pressure, anorexia/cachexia, an ulcer, IBD, IBS, addictive disorder, Parkinson's disease and 20 parkinsonism, a stroke, a seizure, a pruritic condition, psychosis, Huntington's chorea, ALS, a cognitive disorder, a migraine, dyskinesia, depression, and/or treating, preventing or inhibiting vomiting include those that are known in the art and can be selected by those skilled in the art. A composition of the invention is prepared by a method comprising admixing a 25 Compound of the Invention (or a pharmaceutically acceptable salt, prodrug or solvate thereof) with a pharmaceutically acceptable carrier or excipient. Admixing can be accomplished using methods known for admixing a compound (or derivative) and a pharmaceutically acceptable carrier or excipient. In one embodiment, the Compound of the Invention (or pharmaceutically acceptable salt, prodrug or solvate thereof) is present in the 30 composition in an effective amount. - 94 - Examples The following examples are illustrative and not limiting of the compounds, compositions and methods of the present invention. Suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and 5 which are obvious to those skilled in the art in view of this disclosure are within the spirit and scope of the invention. EXAMPLE I (6) 22-cyclopropyl-7a-(benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine /\ - DEAD r-- - tCHO O 0e NaHCO3
H
3 CO OCH 3
H
3 COCH H3CO OCH3 1 2 3 N N \ .CHO H2H B - , Pd Cr- N" O8
H
3 CO 0 oCH3 H 3 CO O OCH 3
H
3 CO O OCH 3 10 4 5 6 A solution of thebaine (1) (15.0 g, 48.2 mmol, Noramco, Inc., Wilmington, DE) in anhydrous ACN (94 mL) was heated to reflux temperature. A solution of DEAD (7.95 mL, 50.5 mmol) in anhydrous ACN (15 mL) was added dropwise over 30 min. The resulting 15 mixture was stirred at reflux temperature for 1.5 h. Pyridine hydrochloride (9.6 g, 83 mmol) was added and the reaction was allowed to cool to room temperature. The product 2 was collected by filtration in several portions and was washed with methanol (MeOH). Yield: 6.97 g (43%). A mixture of compound 2 (6.97 g, 20.9 mmol), NaHCO 3 (3.59 g, 42.7 mmol), and 20 bromomethyl cyclopropane (2.5 mL, 26 mmol) in anhydrous DMF (15 mL) was stirred at reflux temperature for 20 h. Solvent was evaporated and the residue was purified by flash chromatography (silica gel, 10-80% ethyl acetate (ETOAc)/hexanes) to provide compound 3. Yield: 5.63 g (77%). A suspension of compound 3 (7.26 g, 20.7 mmol) in acrolein (15 mL, 228 mmol) was 25 heated to reflux temperature for 6 h. Solvent was evaporated and the residue was purified by - 95 flash chromatography (silica gel, 10-80% ETOAc/hexanes) to provide compound 4. Yield: 5.4 g (64%). A mixture of compound 4 (5.4 g, 13.3 mmol) and 5% Pd/C (0.5 g) in EtOH (200 mL) was stirred under 1 atmosphere of H2 overnight. MS and NMR showed the reduction of the 5 double bond but little reduction of the aldehyde. The hydrogenation was continued five more days until MS showed mainly the mass of the alcohol 5. The reaction mixture was filtered through Celite and solvent was evaporated. The residue was purified by flash chromatography (silica gel, 10-80% ETOAc/hexanes) to provide compound 5. Yield: 2.92 g (53%). 10 NaH (60 % suspension in mineral oil, 100 mg, 2.5 mmol) was added to a solution of compound 5 (206 mg, 0.5 mmol) in anhydrous DMF (10 mL). The resulting mixture was stirred at room temperature for 1 h. Benzyl bromide (0.12 mL, 1 mmol) was added and the reaction was stirred at room temperature overnight. Water (40 mL) was added and the mixture was extracted with EtOAc (2 x 50 mL) and DCM (2 x 50 mL). The extracts were 15 washed with 20 mL each water and brine. After drying over Na 2
SO
4 , solvent was evaporated. The residue was purified by flash chromatography (silica gel, 10-80% ETOAc/hexanes) to provide compound 6 (22-cyclopropyl-7ca-(benzyloxymethyl)-6,14-endo ethanotetrahydrothebaine ). Yield: 114 mg (45%). 'H NMR: SH (400 MHz, CDCl 3 ): 7.35-7.25 (m, 5H), 6.69 (d, 1H), 6.55 (d, IH), 4.55-4.51 20 (m, 3H), 3.85 (s, 3H), 3.76-3.73 (m, IH), 3.53-3.47 (m, IH), 3.36 (s, 3H), 3.01-2.95 (m, 3H), 2.68-2.62 (m, IH), 2.33-2.04 (m, 7H), 1.67-1.63 (m, 1H), 1.45-1.38 (m, 3H), 1.08-1.05 (m, 1H), 0.82-0.72 (m, 2H), 0.49-0.46 (m, 2H), 0.09-0.08 (m, 2H). LC/MS, m/z = 502.2 [M + H]+ (Calc: 502.66). In a similar manner, compound 7 was prepared from compound 5 by using propargyl 25 bromide rather than benzyl bromide in the final step. Compound 7 (22-cyclopropyl-7a (propargyloxymethyl)-6,14-endo-ethanotetrahydrotbebaine) was obtained as the HCI salt by treatment of the free base with HCI in ether. Yield: 10%. 'H NMR: SH (400 MHz, DMSO-d6): 8.76 (brs, 1H), 6.87 (d, IH), 6.68 (d, 1H), 4.75 (s, IH), 4.17 (s, 2H), 3.89-3.87 (m, I H), 3.78 (s, 3H), 3.65-3.63 (m, IH), 3.47-3.17 (m, 7H), 2.95 30 2.78 (m, 4H), 2.32-2.27 (m, 2H), 1.87-1.83 (in, I H), 1.50-1.00 (in, 6H), 0.66-0.50 (m, 4H), 0.39-0.36 (in, 1H). LC/MS, m/z = 450.2 [M + H) (Calc: 450.6). -96- In a similar manner, compound 8 was prepared from compound 5 by using allyl bromide rather than benzyl bromide in the final step. Compound 8 (22-cyclopropyl-7a (allyloxymethyl)-6.14-endo-ethanotetrabydrothebaine) was obtained as the trifluoroacetic acid (TFA) salt by purification of the free base by HPLC (0.1 % TFA in methanol/water). 5 Yield: 8%. 'H NMR: SH (400 MHz, DMSO-d6): 8.36 (brs, IH), 6.87 (d, 1H), 6.67 (d, 1H), 5.96-5.87 (m, IH), 5.31-5.14 (m, 2H), 4.75 (s, IH), 4.02-3.88 (m, 3H), 3.78 (s, 3H), 3.57-3.53 (m, IH), 3.44-3.20 (m, 7H), 2.99-2.67 (m, 4H), 2.35-2.21 (m, 2H), 1.90-1.87 (m, lH), 1.55-1.08 (m, 4H), 0.69-0.62 (m, 3H), 0.44-0.38 (m, 2H). 10 LC/MS, m/z = 452.2 [M + H]f (Calc: 452.6). In a similar manner, compound 101 was prepared from compound 5 by using cyclohexylmethyl bromide (Aldrich) rather than benzyl bromide in the final step. Compound 101 ( 2 2 -cyclopropyl-7a-(cyclohexylmethoxymethyl)-6,14-endo ethanotetrahydrothebaine) was obtained as the HCl salt by treatment of the free base with 15 HC in ether. Yield: 20%. 'H NMR: SH (400 MHz, DMSO-d6): 8.89 (brs, 1H), 6.86 (d, 1H), 6.67 (d, 1 H), 4.73 (s, I H), 3.88 (m, 1H), 3.78 (s, 3H), 3.48-3.18 (m, 12H), 2.96-2.80 (m, 5H), 2.32-2.24 (M, 2H), 1.87 0.37 (m, 19H). LC/MS, m/z = 508.3 [M + H]f (Calc: 507.3). 20 In a similar manner, compound 102 was prepared from compound 5 by using 4 chlorobenzyl bromide rather than benzyl bromide in the final step. Compound 102 (22 cyclopropyl-7a-(4-chlorobenzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine) was obtained as the trifluoroacetic acid (TFA) salt by purification of the free base by HPLC (0.1 % TFA in methanol/water). Yield: 58%. 25 'H NMR: SH (400 MHz, DMSO-d6): 8.38 (brs, 1H), 7.37 (q, 4H), 6.88 (d, 1H), 6.68 (d, 1H), 4.75 (s, 1H), 4.56-4.46 (m, 2H), 3.88 (m, IH), 3.78 (s, 3H), 3.63-3.16 (m, 7H), 2.99-2.26 (m, 7H), 1.91-1.82 (m, IH), 1.57-1.08 (m, 5H), 0.67-0.37 (m, 5H). LC/MS, m/z = 536.2 [M + H]f (Calc: 535.24). In a similar manner, compound 105 was prepared from compound 5 by using 3,4 30 dichlorobenzyl bromide (Aldrich) rather than benzyl bromide in the final step. Compound 105 (22-cyclopropyl-7a-((3,4-dichloro)benzyloxymethyl)-6,14-endo ethanotetrabydrothebaine) was obtained as the trifluoroacetic acid (TFA) salt by purification of the free base by HPLC (0.1 % TFA in methanol/water). Yield: 25%. - 97 - 'H NMR: 8 H (400 MHz, DMSO-d6): 8.40 (brs, 1 H), 7.66-7.59 (m, 2H), 7.37-7.31 (in, 1H), 6.90-6.86 (d, IH), 6.70-6.67 (d, 1 H), 4.76 (s, 1H), 4.58-4.48 (M, 2H), 3.90-3.87 (m, 1H), 3.79 (s, 3H), 3.70-3.19 (in, 8H), 3.00-2.65 (m, 4H), 2.50-2.21 (m, 2H), 1.92-1.86 (m, I H), 1.58 1.00 (in, 5H), 0.68-0.62 (M, 3H), 0.44-0.38 (m, 2H). 5 LC/MS, m/z = 570.0 [M + H]* (Calc: 569.0). In a similar manner, compound 106 was prepared from compound 5 by using 4 trifluoromethylbenzyl bromide (Aldrich) rather than benzyl bromide in the final step. Compound 106 ( 2 2 -cyclopropyl-7a-((4-trifluoromethyl)benzyloxymethyl)-6,14-endo ethanotetrahydrothebaine) was obtained as the HCI salt by treatment of the free base with 10 HCI in ether. Yield: 56%. 'H NMR: 5H (400 MHz, DMSO-d6): 9.15 (brs, IH), 7.66 (q, 4H), 6.87 (d, IH), 6.68 (d, 1H), 4.76 (s, I H), 4.68-4.57 (m, 2H), 3.92-3.89 (m, 1 H), 3.78 (s, 3H), 3.65-3.57 (m, 21), 3.43 3.30 (m, 1H), 3.30-2.75 (m, 7H), 2.45-2.25 (m, 2H), 1.89-1.83 (in, 1H), 1.58-1.08 (in, 6H), 0.90-0.80 (in, IH), 0.72-0.52 (m, 4H), 0.43-0.32 (m, 1H). 15 LCIMS, m/z = 570.1 [M + H]' (Calc: 569.0). In a similar manner, compound 107 was prepared from compound 5 by using 3 methylbenzyl bromide (Aldrich) rather than benzyl bromide in the final step. Compound 107
(
2 2 -cyclopropyl-7a-((3-methyl)benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine) was obtained as the HC salt by treatment of the free base with HCI in ether. Yield: 35%. 20 'H NMR: 8 H (400 MHz, DMSO-d6): 9.00 (brs, 1H), 7.27-7.05 (m, 4H), 6.87 (d, 1H), 6.68 (d, IH), 4.75 (s, IH), 4.48 (s, 2H), 3.91-3.87 (in, 1H), 3.78 (s, 3H), 3.63-3.56 (m, IH), 3.53 3.42 (m, IH), 3.23 (s, 3H), 3.25-3.12 (m, 1H), 3.05-2.70 (m, 2H), 2.45-2.20 (m, 6H), 1.90 1.80 (m, I H), 1.57-1.05 (m, 7H), 0.74-0.50 (m, 4H), 0.44-0.32 (in, 1H). LC/MS, m/z = 516.1 [M + H]+ (Calc: 515.0). 25 In a similar manner, compound 108 was prepared from compound 5 by using 2 bromomethylnaphthalene (Aldrich) rather than benzyl bromide in the final step. Compound 108 (22-cyclopropyl-7-(napthalene-2-ylmethoxymethyl)-6,14-endo ethanotetrahydrothebaine) was obtained as the HCI salt by treatment of the free base with HCI in ether. Yield: 28%. 30 'H NMR: 6H (400 MHz, DMSO-d6): 9.01 (brs, IH), 7.95-7.85 (m, 4H), 7.55-7.45 (m, 3H), 6.87 (d, I H), 6.68 (d, IH), 4.78-4.64 (in, 3H), 3.92-3.87 (m, 1 H), 3.78 (s, 3H), 3.68-3.50 (m, 2H), 3.24 (s, 3H), 3.20-3.15 (m, IH), 3.10-2.75 (m, 4H), 2.50-2.25 (m, 2H), 1.89-1.80 (m, IH), 1.65-1.05 (m, 7H), 0.70-0.55 (m, 4H), 0.40-0.35 (m, 1H). - 98 - LC/MS, m/z = 552.1 [M + H]* (Calc: 551.0). In a similar manner, compound 109 was prepared from compound 5 by using 4-tert butylbenzyl bromide (Aldrich) rather than benzyl bromide in the final step. Compound 109
(
2 2-cyclopropyl- 7 -((4-tert-butyl)benzyloxymethyl)-6,14-endo 5 ethanotetrahydrothebaine) was obtained as the HCl salt by treatment of the free base with HCl in ether. Yield: 51%. 1H NMR: 6 H (400 MHz, DMSO-d6): 9.15 (brs, I H), 7.40-7.25 (in, 4H), 6.86 (d, 1H), 6.68 (d, 1H), 4.74 (s, IH), 4.47 (s, 2H), 3.95-3.85 (m, IH), 3.78 (s, 3H), 3.63-3.44 (m, 2H), 3.35 3.27.(m, 1H), 3.22 (s, 3H), 3.20-2.90 (m, 3H), 2.88-2.70 (m, 2H), 2.40-2.25 (m, 2H), 1.88 10 1.80 (in, IHO, 1.58-1.05 (m, 6H), 1.27 (s, 9H), 0.72-0.52 (m, 4H), 0.44-0.34 (in, iH). LC/MS, m/z = 558.2 [M + H]+ (Calc: 557.0). In a similar manner, compound 110 was prepared from compound 5 by using 1 phenyl-3-bromopropene (Aldrich) rather than benzyl bromide in the final step. Compound 110 (22-cyclopropyl-7a cinnamyloxymethyl)-6,14-endo-ethanotetrahydrothebaine) was 15 obtained as the HCl salt by treatment of the free base with HCI in ether. Yield: 27%. 'H NMR: 8 H (400 MHz, DMSO-d6): 9.15 (brs, IH), 7,48-7.44 (in, 2H), 7.40-7.30 (m, 2H), 7.29-7.21 (m, IH), 6.90-6.83 (m, 1H), 6.72-6.60 (m, 2H), 6.45-6.34 (m, IH), 4.76 (s, I H), 4.16-4.10 (m, 2H), 3.93-3.85 (m I H), 3.77 (s, 3H), 3.62-3.56 (m, IH), 3.52-5.42 (m, 1 H), 3.25 (s, 3H), 3.25-2.90 (m, 3H), 2.89-2.75 (m, 2H), 2.43-2.26 (m, 2H), 1.90-1.80 (m, 1H), 20 1.60-1.05 (m, 7H), 0.70-0.52 (m, 4H), 0.43-0.33 (m, 1H). LC/MS, m/z = 528.1 [M + H]* (Calc: 527.0). In a similar manner, compound 111 was prepared from compound 5 by using 2 methylbenzyl bromide (Aldrich) rather than benzyl bromide in the final step. Compound 111
(
2 2 -cyclopropyl-7a-((2-methyl)benzyloxymethyl)-6,14-endo-ethanotetrabydrothebaine) 25 was obtained as the HCI salt by treatment of the free base with HCl in ether. Yield: 43%. 1H NMR: 8 H (400 MHz, DMSO-d6): 9.01 (brs, I H), 7.36-7.32 (m, 1H), 7.25-7.10 (m, 3H), 6.87 (d, I H), 6.68 (d, I H), 4.75 (s, 1H), 4.55-4.45 (m, 2H), 3.90-3.87 (m, 1 H), 3.78 (s, 3H), 3.67-3.45 (m, 2H), 3.40-3.10 (m, 4H), 3.08-2.70 (in, 4H), 2.42-2.20 (in, 5H), 1.90-1.80 (in, I H), 1.56-1.05 (m, 7H), 0.74-0.50 (m, 4H), 0.47-0.32 (m, I H). 30 LC/MS, m/z = 516.3 [M + H)* (Calc: 515.0). In a similar manner, compound 112 was prepared from compound 5 by using 1 bromomethylnapthalene (Aldrich) rather than benzyl bromide in the final step. Compound 112 (22-cyclopropyl-7a-(napthalene-1- methoxymethyl)-6,14-endo - 99 ethanotetrahydrothebaine) was obtained as the HCI salt by treatment of the free base with HCl in ether. Yield: 41%. 1H NMR: 8 H (400 MHz, DMSO-d6): 8.95 (brs, 1H), 8.12 (d, 1H), 8.02-7.85 (m, 2H), 7.65 7.42 (m, 4H), 6.86 (d, I H), 6.67 (d, I H), 4.97 (s, 2H), 4.75 (s, I H), 3.88-3.82 (m, I H), 3.78 (s, 5 3H), 3.73-3.65 (m, 1H), 3.64-3.56 (m, I H), 3.45-3.30 (m, 3H), 3.22 (s, 3H), 3.20-3.05 (m, 1H), 3.04-2.72 (m, 4H), 2.45-2.22 (m, 2H), 1.90-1.80 (m, IH), 1.56-1.00 (m, 4H), 0.90-0.45 (m, 4H), 0.44-0.32 (m, IH). LC/MS, m/z = 552.3 [M + H]+ (Calc: 551.0). In a similar manner, compound 113 was prepared from compound 5 by using 10 cyclobutylmethyl bromide (Aldrich) rather than benzyl bromide in the final step. Compound 113 ( 2 2 -cyclopropyl-7a-(cyclobutylmethoxymethyl)-6,14-endo ethanotetrahydrothebaine) was obtained as the HCl salt by treatment of the free base with HCl in ether. Yield: 11%. 1 H NMR: 5H (400 MHz, DMSO-d6): 9.02 (brs, I H), 6.86 (d, I H), 6.67 (d, IH), 4.74 (s, I H), 15 3.90-3.87 (m, 1H), 3.78 (s, 3H), 3.56-3.07 (m, 8H), 3.02-2.68 (m, 4H), 2.40-2.20 (m, 2H), 2.05-1.65 (m, 9H), 1.55-1.00 (m, 6H), 0.75-0.47 (m, 4H), 0.44-0.32 (m, 1H). LC/MS, m/z = 480.3 [M + H]* (Calc: 479.0). In a similar manner, compound 114 was prepared from compound 5 by using 3 trifluoromethoxybenzyl bromide rather than benzyl bromide in the final step. Compound 114 20 (1 7 -cyclopropylmethyl-7cx-(3-trifluoromethoxy)benzyloxymethyl-3,6-dimethoxy-4,5a epoxy-6c,14-ethano-morphinan) was obtained as the HCI salt by treatment of the free base with HCl in ether. Yield: 24%. ' H NMR: 8 H (400 MHz, DMSO-d 6 ): 8.85 (brs, IH), 7.49 (d, 2H), 7.35 (d, 2H), 6.88 (d, 1 H), 6.68 (d, 1H), 4.79 (s, 1H), 4.51-4.59 (m, 2H), 3.88-3.89 (m, 1H), 3.78 (s, 3H), 3.51-3.61 (m, 25 2H), 3.31-3.37 (m, 1 H), 3.25 (s, 3H), 3.13-3.21 (m, IH), 2.78-3.02 (m, 4H), 2.32-2.49 (m, 2H), 1.82-1.87 (m, 1H), 1.14-1.55 (m, 6H), 0.54-0.67 (m, 4H), 0.37-0.41 (m, IH). LC/MS, m/z = 586.2 [M + H] 4 (Calc: 585.3). In a similar manner, compound 115 was prepared from compound 5 by using pyridine-3-ylmethyl bromide (Aldrich) rather than benzyl bromide in the final step. 30 Compound 115 (17-cyclopropylmethyl-7a(- pyridine-3-ylmethoxy)methyl -3,6 dimethoxy-4,5a-epoxy-6a,14a-ethano-morphinan) was obtained as the HCl salt by treatment of the free base with HCl in ether. Yield 22%. -100- 'H NMR: 8 H (400 MHz, DMSO-d 6 ): 9.41 (brs, I H), 8.86 (s, 1H), 8.80 (d, 1H), 8.42 (d, 1H), 7.93-7.95 (m, IH), 6.88 (d, 1H), 6.68 (d, 1H), 4.65-4.75 (m, 3H), 3.88-3.89 (m, IH), 3.78 (s, 3H), 3.55-3.68 (m, 3H), 3.31-3.37 (m, 2H), 3.25 (s, 3H), 3.13-3.21 (in, 2H), 2.78-3.02 (m, 2H), 2.32-2.49 (m, 2H), 1.82-1.87 (m, IH), 1.14-1.55 (m, 5H), 0.54-0.67 (m, 4H), 0.37-0.41 5 (m, IH). LC/MS, m/z = 503.3 [M + H)* (Calc: 502.3). EXAMPLE 2 (11) 7a-(benzyloxymethyl)-6-14-endo-ethanotetrahydrothebaine NCH,
-CH
3 A NNZk CHO '"CH PH C H3CO
OCH
3 H 3 CO 0 OCH 3 19 ,CH ,CH 3 0"rBr OH Br0 H3CO OCH 3
H
3 CO OCH 3 10 11 10 In a manner analogous to that described in Example I thebaine, 1, was reacted with acrolein followed by reduction and benzyl ether formation to provide compound 11 (7a (benzyloxymethyl)-6-14-endo-ethanotetrahydrothebaine). 'H NMR: 8 H (400 MHz, CDCl 3 ): 7.40-7.25 (m, 5H), 6.71 (d, IH), 6.57 (d, lH), 4.58-4.48 15 6.71 (m, 1H), 3.86 (s, 3H), 3.74-3.72 (m, 1H), 3.53-3.47 (m, IH), 3.36 (s, 3H), 3.13-3.07 (m, IH), 2.92-2.86 (m, 1H), 2.68-2.67 (m, IH), 2.46-2.42 (m, IH), 2.35-2.04 (m, 7H), 1.68-1.59 (m, IH), 1.46-1.40 (m, 3H), 1.13-1.05 (m, 1H), 0.78-0.72 (m, 1H). LC/MS, m/z = 462.3 [M + H]* (Calc: 462.6). In a similar manner, compound 12 (7a-(propargyloxymethyl)-6,14-endo 20 ethanotetrahydrothebaine) was prepared from compound 10 by using propargyl bromide rather than benzyl bromide in the final step. 'H NMR: SH (400 MHz, CD 3 0D): 6.78 (d, 1H), 6.60 (d, I H), 4.57-4.53 (m, I H), 4.22-4.18 (m, 2H), 3.85 (s, 3H), 3.82-3.76 (m, 1H), 3.57-3.53 (m, IH), 3.38 (s, 3H), 3.22-3.10 (m, IH), 2.55-2.45 (m, 1H), 2.40-2.10 (m, 7H), 1.70-1.58 (m, IH), 1.50-1.30 (m, 3H), 1.23-1.13 (m, 25 1H), 0.80-0.65 (m, I H). LC/MS, m/z = 410 [M + H]* (Calc: 410.5). - 101 - In a similar manner, compound 13 (7a-(allyloxymethyl)-6-14-endo ethanotetrahydrothebaine) was prepared from compound 10 by using allyl bromide rather than benzyl bromide in the final step. 'H NMR: SH (400 MHz, CD 3 0D): 6.75 (d, 1H), 6.60 (d, 1 H), 5.98-5.83 (m, IH), 5.40-5.13 5 (m, IH), 4.55-4.53 (m, IH), 4.05-3.97 (m, 2H), 3.85 (s, 3H), 3.73-3.63 (m, 1H), 3.50-3.42 (m, IH), 3.38 (s, 3H), 3.20-3.10 (m, 1H), 2.90-2.80 (m, IH), 2.75-2.70 (m, 1H), 2.53-2.43 (m, I H), 2.40-2.05 (m, 7H), 1.72-1.60 (m, 1H), 1.53-1.33 (m, 3H), 1.21-1.10 (m, IH), 0.83-0.67 (m, 1H). LC/MS, m/z = 412 [M + H]+ (Calc: 412.5). 10 In a similar manner, compound 201 was prepared from compound 10 by using cyclohexylmethyl bromide (Aldrich) rather than benzyl bromide in the final step. Compound 201 (7a-(cyclohexylmethoxymetbyl)-6,14-endo-ethanotetrahydrothebaine) was obtained as the HCI salt by treatment of the free base with HC in ether. Yield: 29%. 'H NMR: SH (400 MHz, DMSO-d6): 8.96 (brs, I H), 6.87 (d, IH), 6.68 (d, 1H), 4.71 (s, 1H), 15 3.78 (s, 3 H), 3.68 (m, I H), 3.45-3.17 (m, 12 H), 2.85-2.75 (m, 5H), 2.29-2.24 (m, 2H), 1.85 0.56 (m, 15H) LC/MS, m/z = 468.3 [M + H]+ (Calc: 467.3). In a similar manner, compound 204 was prepared from compound 10 by using 4 trifluoromethylbenzyl bromide (Aldrich) rather than benzyl bromide in the final step. 20 Compound 204 (7u-((4-trifluoromethyl)benzyoxymethyl)-6,14-endo ethanotetrahydrothebaine) was obtained as the HCI salt by treatment of the free base with HCl in ether. Yield: 45%. 'H NMR: SH (400 MHz, DMSO-d6): 9.27 (brs, IH), 7.65 (q, 4H), 6.87 (d, IH), 6.69 (d, 1H), 4.73 (s, 1H), 4.67-4.56 (m, 2H), 3.78 (s, 3H), 3.71-3.30 (m, 4H), 3.24 (s, 3H), 3.19-3.10 (m, 25 IH), 2.97-2.74 (m, 6H), 2.50-2.21 (m, 2H), 1.87-1.81 (m, 1H), 1.59-1.52 (m, 1H), 1.44-1.35 (I, IH), 1.24-1.10 (m, 2H), 0.65-0.61 (m, IH). LC/MS, m/z = 530.1 [M + H]* (Calc: 529.0).In a similar manner, compound 205 was prepared from compound 10 by using 2-bromomethylnaphthalene (Aldrich) rather than benzyl bromide in the final step. Compound 205 (7a-((2-naphthyl)methoxymethyl)-6,14 30 endo-ethanotetrahydrothebaine) was obtained as the HCI salt by treatment of the free base with HC in ether. Yield: 15%. H NMR: 8 H (400 MHz, DMSO-d6): 9.37 (brs, 1H), 7.93-7.89 (m, 4H), 7.53-7.49 (m, 3H), 6.87 (d, IH), 6.69 (d, I H), 4.74 (s, 1 H), 4.69-4.63 (m, 2H), 3.78 (s, 3H), 3.71-3.50 (m, 4H), - 102- 3.23 (s, 3H), 3.15-3.11 (m, 1H), 3.02-2.74 (in, 6H), 2.50-2.20 (m, 2H), 1.86-1.81 (m, IH), 1.62-1.55 (m, 1H), 1.45-1.36 (m, IH), 1.22-1.06 (m, 2H), 0.69-0.50 (m, I H). LC/MS, m/z = 512.1 [M + H]+ (Calc: 511.0). In a similar manner, compound 206 was prepared from compound 10 by using 3,4 5 dichlorobenzyl bromide (Aldrich) rather than benzyl bromide in the final step. Compound 206 (7a-((3,4-dichloro)benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine) was obtained as the HCI salt by treatment of the free base with HCI in ether. Yield: 25%. 'H NMR: 8 H (400 MiHz, DMSO-d6): 9.20 (brs, 1H), 7.64-7.60 (m, 2H), 7.37-7.34 (m, 1H), 6.87 (d, 1H), 6.69 (d, IH), 4.75 (s, 1H), 4.57-4.47 (m, 2H), 3.78 (s, 3H), 3.70-3.68 (m, IH), 10 3.63-3.58 (m, 1H), 3.53-3.47 (m, IH), 3.40-3.29 (m, IH), 3.24 (s, 3H), 3.17-3.11 (m, I H), 3.00-2.57 (m, 6H), 2.50-2.22 (m, 2H), 1.88-1.80 (m, IH), 1.56-1.50 (m, I H), 1.42-1.34 (m, 1H), 1.23-1.10 (m, 2H), 0.65-0.55 (in, I H). LC/MS, m/z = 530.1 [M + H]* (Calc: 529.0). In a similar manner, compound 207 was prepared from compound 10 by using 3 15 methylbenzyl bromide (Aldrich) rather than benzyl bromide in the final step. Compound 207 (7a-((3-methyl)benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine) was obtained as the HCl salt by treatment of the free base with HCI in ether. Yield: 56%. 1 H NMR: 5H (400 MHz, DMSO-d6): 9.20 (brs, IH), 7.24-7.08 (m, 4H), 6.87 (d, 1H), 6.69 (d, 1H), 4.73 (s, 11H), 4.51-4.42 (m, 2H), 3.78 (s, 3H), 3.74-3.68 (m, I H), 3.62-3.55 (m, I H), 20 3.50-3.25 (m, 2H), 3.23 (s, 3H), 3.16-3.06 (in, 1H), 2.91-2.73 (m, 6H), 2.45-2.17 (m, 5H), 1.90-1.78 (in, 1H), 1.59-1.48 (in, 1H), 1.45-1.32 (m, 1H), 1.25-1.05 (m, 2H), 0.67-0.55 (m, I H). LC/MS, m/z = 476.2 [M + H]* (Calc: 475.0). In a similar manner, compound 208 was prepared from compound 10 by using 4-tert 25 butylbenzyl bromide (Aldrich) rather than benzyl bromide in the final step. Compound 208 (7ca-((4-tert-butyl)benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine) was obtained as the HCl salt by treatment of the free base with HCI in ether. Yield: 60%. 'H NMR: SH (400 MHz, DMSO-d6): 9.29 (brs, 1 H), 7.31 (q, 4H), 6.87 (d, I H), 6.69 (d, IH), 4.72 (s, I H), 4.46-4.42 (m, 2H), 3.78 (s, 3H), 3.73-3.68 (m, 1H), 3.62-3.35 (m, 3H), 3.33 (s, 30 3H), 3.20-3.07 (m, 1H), 2.95-2.75 (m, 7H), 2.40-2.20 (m, 2H), 1.87-1.77 (m, IH), 1.60-1.00 (m, 3H), 1.27 (s, 9H), 0.64-0.55 (m, 1H). LC/MS, m/z = 518.2 [M + H]+ (Calc: 517.0). - 103 - In a similar manner, compound 209 was prepared from compound 10 by using trans cinnamyl bromide (Aldrich) rather than benzyl bromide in the final step. Compound 209 (7a-((trans-3-phenylprop-2-enyl)oxymethyl)-6,14-endo-ethanotetrahydrothebaine) was obtained as the HC salt by treatment of the free base with HCl in ether. Yield: 68%. 5 1H NMR: 5 H (400 MHz, DMSO-d6): 9.28 (brs, IH), 7.50-7.41 (m, 2H), 7.38-7.21 (m, 3H), 6.91-6.84 (m, 1H), 6.71-6.60 (m, 2H), 6.43-6.32 (m, IH), 4.74 (s, 1H), 4.21-4.08 (m, 2H), 3.78 (s, 3H), 3.71-3.28 (m, 4H), 3.25 (s, 3H), 3.20-3.06 (m, 1H), 3.00-2.70 (m, 6H), 2.40 2.20 (in, 2H), 1.87-1.80 (m, 1H), 1.57-1.03 (m, 4H), 0.69-0.52 (m, IH). LC/MS, m/z = 488.1 [M + H]+ (Calc: 487.0). 10 In a similar manner, compound 210 was prepared from compound 10 by using 2 methylbenzyl bromide (Aldrich) rather than benzyl bromide in the final step. Compound 210 (7a-((2-methyl)benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine) was obtained as the trifluoroacetic acid (TFA) salt by purification of the free base by HPLC (0.1 % TFA in methanol/water). Yield: 23%. 15 'H NMR: 8 H (400 MHz, DMSO-d6): 8.68 (brs, I H), 7.34-7.31 (m, IH), 7.25-7.10 (m, 3H), 6.87 (d, I H), 6.69 (d, IH), 4.73 (s, 1H), 4.50 (s, 2H), 3.79 (s, 3H), 3.72-3.57 (m, 2H), 3.54 3.30 (m, 2H), 3.25 (s, 3H), 3.23-3.10 (m, IH), 2.95-2.53 (in, 5H), 2.42-2.15 (m, 6H), 1.90 1.79 (in, I H), 1.57-1.33 (m, 2H), 1.25-1.05 (m, 2H), 0.70-0.50 (m, IH). LC/MS, m/z = 476.3 [M + H]* (Calc: 475.0). 20 In a similar manner, compound 211 was prepared from compound 10 by using 4 bromomethyl pyridine hydrobromide (Aldrich) rather than benzyl bromide in the final step. Compound 211 (7a-((4-pyridylmethoxymethyl)-6,14-endo-ethanotetrahydrothebaine) was obtained as the trifluoroacetic acid (TFA) salt by purification of the free base by HPLC (0.1 % TFA in methanol/water). Yield: 35%. 25 1 H NMR: 8 H (400 MHz, DMSO-d6): 8.87 (brs, I H), 8.75 (d, 2H), 7.67 (d, 2H), 6.88 (d, IH), 6.70 (d, 1H), 4.79-4.66 (m, 3H), 3.78 (s, 3H), 3.74-3.54 (m, 3H), 3.45-3.33 (m, 1H), 3.26 (s, 3H), 3.24-3.13 (m, 1H), 2.97-2.64 (m, 6H), 2.55-2.15 (m, 2H), 1.93-1.82 (m, 1H), 1.63-1.06 (m, 4H), 0.70-0.55 (m, I H). LC/MS, m/z = 463.1 [M + H]* (Calc: 462.0). 30 In a similar manner, compound 212 was prepared from compound 10 by using 4 trifluoromethoxybenzyl bromide (Aldrich) rather than benzyl bromide in the final step. Compound 212 (7z-((4-trifluoromethoxy)benzyloxymethyl)-6,14-endo - 104 ethanotetrahydrothebaine) was obtained as the HCl salt by treatment of the free base with HCI in ether. Yield: 41%. 'H NMR: 5H (400 MHz, DMSO-d6): 9.23 (brs, IH), 7.49 (d, 21), 7.35 (d, 2H), 6.87 (d, IH), 6.69 (d, IH), 4.73 (s, IH), 4.60-4.45 (in, 2H), 3.78 (s, 3H), 3.73-3.46 (m, 3H), 3.45-3.25 (m, 5 1 H), 3.23 (s, 3H), 3.20-3.06 (m, 1H), 2.95-2.70 (in, 6H), 2.42-2.18 (m, 2H), 1.90-1.77 (m, IH), 1.60-1.05 (in, 4H), 0.68-054 (m, IH). LC/MS, m/z= 546.1 [M + H]* (Calc: 545.0). In a similar manner, compound 213 was prepared from compound 10 by using 1 bromomethylnapthalene (Aldrich) rather than benzyl bromide in the final step. Compound 10 213 (7a-((napthalene -1-ylmethoxymethyl)-6,14-endo-ethanotetrahydrothebaine) was obtained as the HCI salt by treatment of the free base with HCI in ether. Yield: 38%. 'H NMR: 8 H (400 MIHz, DMSO-d6): 9.23 (brs, I H), 8.15-8.06 (m, IH), 7.98-7.85 (in, 2H), 7.64-7.45 (m, 4H), 6.86 (d, 1H), 6.67 (d, IH), 4.96 (s, 2H), 4.73 (s, 1H), 3.78 (s, 3H), 3.75 3.55 (in, 3H), 3.23 (s, 3H), 3.15-3.05 (m, 1H), 2.94-2.73 (m, 6H), 2.44-2.15 (m, 2H), 1.86 15 1.76 (in, IH), 1.63-1.05 (m, 5H), 0.68-0.50 (m, IH). LC/MS, m/z = 512.3 [M + H]* (Calc: 511.0). In a similar manner, compound 214 was prepared from compound 10 by using cyclobutylmethyl bromide (Aldrich) rather than benzyl bromide in the final step. Compound 214 (7a-(cyclobutylmethoxymethyl)-6,14-endo-eth anotetrahydrothebaine) was obtained 20 as the HC salt by treatment of the free base with HCI in ether. Yield: 13%. 'H NMR: 8 H (400 MHz, DMSO-d6): 9.27 (brs, IH), 6.86 (d, 1H), 6.68 (d, IH), 4.71 (s, I H), 3.78 (s, 3H), 3.74-3.65 (m, I H), 3.55-3.30 (m, 3H), 3.23 (s, 3H), 3.15-3.05 (m, I H), 2.90 2.75 (m, 6H), 2.33-2.13 (m, 2H), 2.03-1.65 (m, 7H), 1.54-0.80 (m, 6H), 0.68-0.52 (m, I H). LC/MS, m/z = 440.3 [M + H]+ (Calc: 439.0). 25 In a similar manner, compound 215 was prepared from compound 10 by using 3 methoxybenzyl bromide (Aldrich) rather than benzyl bromide in the final step. Compound 215 (7a-(3-methoxy)benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine) was obtained as the HCI salt by treatment of the free base with HCI in ether. Yield: 36%. 1 H NMR: SH (400 MHz, DMSO-d6): 8.90 (brs, IH), 7.31-7.23 (m, IH), 6.95-6.82 (in, 4H), 30 6.68 (d, I H), 4.74 (s, I H), 4.80 (s, 2H), 3.78 (s, 3H), 3.75 (s, 3H), 3.72-3.30 (in, 5H), 3.23 (s, 3H), 3.20-3.07 (m, I H), 2.94-2.70 (m, 6H), 2.44-2.15 (m, 2H), 1.90-1.87 (m, I H), 1.60-1.50 (m, IH), 1.45-1.32 (m, IH), 1.25-1.05 (m, IH), 0.68-0.55 (m, I H). LC/MS, m/z = 492.3 [M + H]f (Calc: 491.0). - 105 - In a similar manner, compound 216 was prepared from compound 10 by using 4 methylbenzyl bromide (Aldrich) rather than benzyl bromide in the final step. Compound 216 (7a-(4-methylbenzhloxymethyl)-3,6-dimetboxy-4,5cx-epoxy-17-methyl-6a.,14cx-ethano 5 morphinan) was obtained as the HCI salt by treatment of the free base with HCl in ether. Yield: 37%. 'H NMR: 8 H (400 MHz, DMSO-d 6 ): 9.01 (brs, 1H), 7.17-7.22 (m, 4H), 6.86 (d, 1H), 6.70 (d, I H), 4.72 (s, I H), 4.41-4.5 (m, 2H), 3.78 (s, 3H), 3.68-3.70 (m, I H), 3.56-3.67 (m, I H), 3.39 3.48 (m, 2H), 3.30 (s, 3H), 3.11-3.12 (m, 1H), 2.74-2.85 (m, 6H), 2.23-2.33 (m, 5H), 1.81 10 1.92 (in, 1 H), 1.52-1.57 (m, IH), 1.33-1.41 (m, IH), 1.09-1.23 (m, 2H), 0.59-0.64 (in, I H). LC/MS, m/z = 476.3 [M + H]f (Calc: 475.6). In a similar manner, compound 217 was prepared from compound 10 by using diphenylmethylbromide rather than benzyl bromide in the final step. . Compound 217 (7a (diphenylmethyloxymethyl)-3,6-dimethoxy-4,5a-epoxy-1 7-methyl-6a,1 4a-ethano 15 morphinan) was obtained as the HCl salt by treatment of the free base with HCI in ether. Yield: 5.1%. 'H NMR: 8H (400 MHz, DMSO-d 6 ): 9.03 (brs, 1H), 7.66-7.68 (m, 4H), 7.43-7.47 (m, 5H), 6.86 (d, 1H), 6.69 (d, 1H), 4.72 (s, 1H), 4.51-4.56 (m, 2H), 3.78 (s, 3H), 3.62-3.71 (m, 2H), 3.41-3.55 (m, 4H), 3.22 (s, 3H), 3.11-3.14 (m, 1H), 2.74-2.85 (m, 4H), 2.18-2.39 (m, 2H), 20 1.81-1.85 (in, 1H), 1.54-1.61 (m, 1H), 1.33-1.41 (m, 1H), 1.07-1.18 (m, 2H), 0.55-0.61 (m, I H). LC/MS, m/z = 538.2 [M + H]+ (Calc: 537.3). In a similar manner, compound 216 was prepared from compound 10 by using 4 methylbenzylbromide rather than benzyl bromide in the final step. Compound 216 (7a-(4 25 methylbenzhloxymethyl)-3,6-dimetoxy-4,5ax-epoxy-1 7-methyl-6a,14cx-ethano morphinan) was obtained as the HCI salt by treatment of the free base with HCI in ether. Yield: 37%. 'H NMR: SH (400 MHz, DMSO-d 6 ): 9.01 (brs, IH), 7.17-7.22 (m, 4H), 6.86 (d, IH), 6.70 (d, 1H), 4.72 (s, 1H), 4.41-4.5 (m, 2H), 3.78 (s, 3H), 3.68-3.70 (m, 1H), 3.56-3.67 (m, IH), 3.39 30 3.48 (in, 2H), 3.30 (s, 3H), 3.11-3.12 (m, IH), 2.74-2.85 (m, 6H), 2.23-2.33 (m, 5H), 1.81 1.92 (in, 1H), 1.52-1.57 (m, 1N), 1.33-1.41 (m, IH), 1.09-1.23 (m, 2H), 0.59-0.64 (m, 11N). LC/MS, m/z = 476.3 [M + H]f (Calc: 475.6). - 106 - In a similar manner, compound 219 was prepared from compound 10 by using 4 bromolbenzylbromide rather than benzyl bromide in the final step. Compound 219 (7a-(4 bromo)benzyloxymethyl-3,6-dimethoxy-4,5cL-epoxy-1 7-metbyl-6a,1 4a-ethano morphinan) was obtained as the HCI salt by treatment of the free base with HCl in ether. 5 Yield: 93%. 'H NMR: 8 H (400 MHz, DMSO-d 6 ): 9.09 (brs, 11H), 7.55 (d, 2H), 7.31 (d, 2H), 6.86 (d, 1H), 6.69 (d, IH), 4.72 (s, 1H), 4.44-4.53 (m, 2H), 3.78 (s, 3H), 3.58-3.70 (m, 2H), 3.35-3.51 (m, 4H), 3.22 (s, 3H), 3.11-3.14 (m, IH), 2.74-2.85 (m, 5H), 2.26-2.37 (m, I H), 1.81-1.85 (m, 1H), 1.52-1.57 (m, I H), 1.33-1.41 (m, IH), 1.07-1.18 (m, 2H), 0.55-0.61 (m, 1H). LC/MS, 10 m/z = 540.1 [M + H] (Calc: 539.2). In a similar manner, compound 220 was prepared from compound 10 by using cyclooctylmethylbromide rather than benzyl bromide in the final step. Compound 220 (7a (cyclooctylmethyl)-3,6-dimethoxy-4,Scx-epoxy-1 7-methyl-6cc,14r-ethano-morphinan) was obtained as the HCI salt by treatment of the free base with HCI in ether. 15 'H NMR: SH (400 MiHz, DMSO-d 6 ): 8.95 (brs, IH), 6.86 (d, 1H), 6.69 (d, 1H), 5.76 (s, 1H), 4.72 (s, 1H), 3.78 (s, 3H), 3.68-3.70 (m, 1H), 3.39-3.47 (m, 4H), 3.22 (s, 3H), 3.11-3.18 (m, 3H), 2.74-2.85 (m, 5H), 2.26-2.29 (m, 2H), 1.11-1.85 (m, 13H), 0.6-0.85 (m, 2H). LC/MS, m/z = 468.3 [M + H]+ (Calc: 467.6) 20 EXAMPLE 3 (301) 7a-(benzyoxymethyl)-6,14-endo-ethanotetrahydromorphine
,CH
3 -H3 KOH Do -A /Pb\
H
3 CO OCH 3 HO H3 11 301 25 Potassium hydroxide (400 mg, 7.1 mmol) was dissolved in ethylene glycol (4.0 mL) at 70*C. Compound 11 (200 mg) was added and the resulting suspension was irradiated with microwaves at 210*C for 4h (90% conversion by MS analysis). The reaction was quenched by saturated ammonium chloride solution and extracted with chloroform (3x50 mL). Combined organic extract was dried (Na 2 SO4), filtered, and concentrated. The crude material - 107 was purified by flash column chromatography eluting with gradient of methanol in dichloromethane(0-10%) on silica gel to afford 113 mg (59 %) of the free base. Compound 301 (7u-(benzyloxymethyl)-6,14-endo-ethanotetrahydromorphine) was then converted to its HCI salt by treating a dichloromethane solution of the product with IM HCI in ether.. 5 'H NMR: SH (400 MHz, DMSO-d6): 9.29 (s, IH), 8.89 (brs, 1H), 7.40-7.25 (m, 5H), 6.68 (d, I H), 6.55 (d, I H), 4.68 (s, IH), 4.57-4.47 (m, 2H), 3.68-3.55 (m, 2H), 3.54-3.40 (m, IH), 3.30-3.20 (m, 4H), 3.18-3.05 (m, 1H), 2.95-2.65 (m, 6H), 2.45-2.15 (m, 2H), 1.85-1.75 (m, 1H), 1.60-1.48 (m, 1H), 1.45-1.32 (m, 1H), 1.25-1.05 (m, 2H), 0.70-0.55 (m, IH). LC/MS, m/z = 448.2 [M + H]* (Calc: 447.0). 10 EXAMPLE 4 (401) 7a-(] -naphthylmethyloxymethyl)-1 7 -cyclopropyl-methyl-6-methoxy4,5a-epoxy 6,14a-ethano-morphinan KOH II -oHO 0 401 MCI salt 108 401 68mg 20. 1mg 21.mg, 28% two steps 0-704D 3.2mg.+ 13.9mg 15 In a similar manner, compound 401 was prepared by O-demethylation of compound 112. Compound 401 (7a-(I-naphthylmethyloxymethyl)-17-cyclopropyl-methyl-6 methoxy-4,5a-epoxy--6c,14a-ethano-morphinan) was obtained as the HCI salt by treatment of the free base with HCI in ether. Yield: 28%. 20 'H NMR: 8H (400 MHz, DMSO-d 6 ): 9.30 (brs, 1H), 8.65 (s, I H), 8.12 (d, IH), 7.88-7.96 (dd, 2H), 7.48-7.58 (m, 4H), 6.68 (d, 1H), 6.51 (d, IH), 4.97 (s, 2H), 4.70 (s, 11H), 3.50-3.83 (m, 4H), 3.35 (s, 3H), 3.11-3.23 (m, 1H), 2.75-2.89 (m, 4H), 2.24-2.39 (m, 3H), 1.81-1.85 (m, 1H), 1.42-1.54 (m, 2H), 1.06-1.23 (m, 4H), 0.37-0.67 (in, 5H). LC/MS, m/z = 538.3 [M + H]* (Calc: 537.7). 25 - 108 - EXAMPLE 5 (501) (7a-benzyloxymethyl-3,6-dimethoxy-4,5a--epoxy-8-methyl-1 7-n-methyl-6a, 4a-. ethano-morphinan ) NMe Me Crotonaldehyde (trans) ---- "CHO -- / reflux, 48 h. 0, W 01 0"" " Me Me Me Me 1 502 .Me NMe i. Cat 10% Pd/c,
H
2 , 1 atm, THF:EtOH, OH - CHO (1:1), over night; O O i. NaBH 4 , THF:EtOH, , O' Me Me (1:1), rt 4h. Me Me 502 503 .Me Me HCI i. Br N O'0 NaH, DMF, rt. O' Me MeO ove r nig ht; 0 O me me ii. 1M HCI in Me Me 5 503 ether, 2h 501 A suspension of thebaine 1 (622 mg, 2.0 mmol) in crotonaldehyde (5 mL) was heated to reflux (becomes clear solution) for 48 h (MS and TLC check). Monitoring the reaction by TLC became difficult due to polymerization of crotonadehyde. The reaction mixture was 10 diluted with ethyl acetate and washed with IN HCI solution (3x20 mL). Combined acidic aqueous layer was basified with 10% aqueous NaOH solution, extracted with chloroform, dried (Na 2
SO
4 ), filtered and concentrated. The crude material was purified twice by flash chromatography (ISCO) eluting with gradient of 0-10% methanol in dichloromethane -109followed by several triturations with dichloromethane/hexanes gave mixture of two diastereomers (105 mg). Further purification by flash chromatography with slow elution by 1.5% methanol in dichloromethane gave a pure fraction of the major isomer 502 (70 mg, assigned as trans-isomer). 5 1H NMR (300 MHz, Chloroform-d) 8 ppm 10.04 (d, J = 1.7 Hz, 1H), 6.61 (d, J = 8.3 Hz, 1 H), 6.52 (d, J = 8.3 Hz, 1H), 6.08 (dd, J = 8.8, 1.7 Hz, IH), 5.41 (dd, J = 9.1, 0.8 Hz, 1H), 4.56 (d, J = 1.7 Hz, IH), 3.81 (s., 3H), 3.63 (s, 3H), 3.45 (in, IH), 3.30-3.18 (m, 2H), 2.52 (in, 1H), 2.41-2.30 (in, 6H), 2.29 (dd, J = 6.1, 0.8 Hz, 1H), 0.83 (d, J = 6.9 Hz, IH); APCI [M+H] = 382. 10 A solution of 502 (65 mg, 0.17 mmol) in THF:EtOH (1:1) was purged with nitrogen and evacuated three times. Palladium on carbon (10%, 20 mg) was added and the resulting suspension was evacuated and flushed with hydrogen. The reaction mixture was allowed to stir at room temperature under hydrogen atmosphere over night. The mixture was evacuated and flushed with nitrogen and filtered through Celite*. The filtrate was treated with NaBH 4 15 (37 mg, 1.4 mmol) at room temperature for 4h. The reaction mixture was quenched with 25% aqueous NH 4 Cl solution, extracted with chloroform (3x50 mL), dried (Na 2
SO
4 ), filtered and concentrated to give crude 503 as a white solid. It was used without further purification. APCI [M+H] = 386. Sodium hydride (19 mg, 0.46 mmol) was added to a solution of 503 in DMF 20 (anhydrous, 4 mL) under nitrogen atmosphere. The reaction mixture was allowed to stir at room temperature for 30 minutes and benzyl bromide (110 pL, 0.92 mmol) was added. The resulting mixture was allowed stir overnight at room temperature. The mixture was quenched with saturated aqueous NaHCO 3 solution, extracted with chloroform, dried (Na 2
SO
4 ), filtered and concentrated. The crude material was purified by flash 25 chromatography (ISCO) eluting with gradient of 20-100% ethyl acetate in hexanes to obtain title compound as a free base (23 mg). Compound 501 (7a-benzyloxymethyl-3,6 dimethoxy-4,5u--epoxy-80-methyl-17-n-methyl-6z,14a-ethano-morphinan) was then converted to its HCl salt by treating a dichloromethane solution of the product with IM HCI in ether. The HCl salt with 100 % HPLC purity was isolated as a white solid. 30 'H NMR (301 MHz, DMSO-d 6 ) S ppm 8.88 (br s, 1H), 7.44-7.26 (in, SH), 6.86 (d, J = 8.3 Hz, 1H), 6.68 (d, J = 8.3 Hz, 1H), 4.87 (s, 1H), 4.56 (in, 2H), 3.78 (s, 3H), 3.74-3.64 (in, 2H), 3.54 (in., 1H), 3.41-3.34 (in, 2H), 3.18 (s, 3H), 3.05 (m, 1H), 2.87-2.71 (m, 6H), 2.56 (in, -110- I H), 1.67-1.23 (m, 4H), 1.19-1.06 (m, 4H); APCI [M+H] = 476; HPLC (Water/Acetonitrile with 0.1 % HCO 2 H) RT = 8.91 min. EXAMPLE 6 5 The following Tables provide results on the efficacy of binding and activity response of exemplified Compounds of the Invention at the ORLI, g-, 8- and K-opioid receptors. In TABLE 6, binding affinity of certain Compounds of the Invention to the ORL-1, 4-, 8- and K-opioid receptors was determined as described above. In TABLE 7, activity response of certain Compounds of the Invention to the ORLI, 10 V-, 6- and K-opioid receptors was determined as described above for functional assays. TABLE 6: Binding Affinity of Buprenorphine Analog Compounds Ref. Compound K (nM) No. ORL-1 Opioid Receptor IL K 13 inactive 59 6.5 1264 569 1.12 0.17 58 12 inactive 42 5.9 1043 6 '"*'\ 532 2.0 0.12 9.2 \0/ - 111 - Ref. Compound (nM) No. ORL-1 Oplioid Receptor p K 6 N 8 " / - inactive 36 0.43 127 0 N 7 *-1 Inactive 43 1.3 221 00// 101 / ,~1165.91 1.60 0.15 25.58 - b 201 1034.67 0.69 0.05 89.96 o-1b2 103 /\ L..9605.70 14.44 0.15 89.26 202 / __ 2571.83 16.19 2.95 306.06 -112.
Ref. Compound K (nM) No. ORL-1 Opioid Receptor 104 > 20 pM 1.91 25.78 1752.98 203 1116.98 1.47 0.12 164.67 204 13803.96 4.38 0.35 241.20 208 / 4555.05 12.13 2.70 355.34 106 3957.55 2.20 0.40 96.35 205 /> 20 pM 22.53 2.60 324.75 -113- Ref. Compound
K
1 (nM) No. ORL-1 Opioid Receptor K 104 > 20 pM 1.91 25.78 1752.98 207 1602.42 2.58 0.05 23.97 206 1295.55 1.22 0.04 36.08 105/823.29 1.00 0.23 21.06 0\/ 107 / 1.20 0.15 107 211 162.95 2.30 -114- Ref. Compound Ki (nM) No. ORL-1 Opioid Receptor PK 212 -~4.40 5.71 108 ...,/1.87 0.74 109 - / \ 3.58 7.99 N 110 4.35 0.53 213 0.59 0.08 N 214 . 1 29.57 0.15 - 5 Ref. Compound (nM) No. ORL-1 Opiold Receptor p 215 6.37 0.21 \O/ N 210 1.76 0.10 O\ 0 111 1.55 0.07 No 3011 TABLE 7: Activity Response of Buprenorphine Analog Compounds 5 GTPyS (EC5o: nM, Em..: %) Ref. ORLI Opioid Receptor No. p
EC
5 o Emax ECso Emax EC 50 Em, 1 ECso Em. 13 nt nt 946 65 197 62 nt nt -116- GTPyS (EC 5 o: nM, E...: %) Ref. ORLi Opioid Receptor No. I K 8
EC
50 Ema EC 5 o Em. ECse Em. ECso Em. 11 6239 46 28 102 4.7 92 78 113 12 nt nt 680 55 194 66 1574 82 6 2721 42 14.6 27 0.18 117 7.2 69 8 nt nt 1493 23 21 107 242 67 7 nt nt 3714 19 62 98 455 66 101 nt nt 8.97 28.67 0.24 97.33 46.52 79 201 nt nt 21.22 92.33 0.61 87.67 46.32 83 -117- GTPyS (ECso: nM, Emax: %) Ref. ORL1 Opioid Receptor No. p K ECso Emax EC 5 o Ema, EC 5 o Em. EC 50 Em, 103 nt nt > 20 gM 3.00 11.94 88.25 199.44 73 202 nt nt 246.81 86.67 442.42 75.67 603.26 81 104 nt nt > 20 pM 1.00 141.39 21.00 203 nt nt 24.98 77.33 1.53 42.50 1051.02 53 204 nt nt 46.36 53.67 132.65 58.00 445.19 43 208 nt nt 115.39 17.67 473.24 39.00 1006.86 37 106 nt nt > 20 pM -1.67 51.84 38.50 > 20 pM 8 - 118- GTPyS (ECso: nM, Em.: %) Ref. ORLI Opioid Receptor No. p K ECso Emax EC 5 o Ems, EC 5 o Em.: ECso Emax 202 nt nt 246.81 86.67 442.42 75.67 603.26 81 207 nt nt 57.10 82.67 51.12 75.00 148.44 77 206 nt nt 38.52 74.00 34.67 73.50 283.12 66 105 3607.36 23.67 > 20 pM -1.00 5.27 69.50 111.52 46 107 17.37 31 2.32 81 211 1617.53 65 221.69 79 212 49.59 40 166.74 46 - 119 - GTPyS (ECso: nM, Emax: %) Ref. ORLI Opioid Receptor No. K ECso Emax ECSO Em.
1 ECso Em.. ECSO Emax 108 > 20 pM 0 35.14 68 109 > 20 pM 0 193.67 36 110 > 20 pM 0 102.84 63 213 20.04 107 39.12 100 214 343.97 104 49.32 92 215 60.27 105 50.03 98 210 16.15 104 9.58 98 -120- GTPyS (ECso: n M, Em..: %) Ref. ORL1 Opioid Receptor No. pK
EC
50 Em. ECso Em.
1 ECso E... ECso Em, 111 10.51 53 1.28 88 "nt"= not tested Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is 5 intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims. All patents and publications cited herein are fully incorporated by reference in their entirety. 10 - 121 -

Claims (109)

1. A compound of Formula Il: R0 N Ra38 R3Ra X O OCH 3 5 (II1) wherein R' is selected from -(CI-Clo)alkyl, -(C 2 -C 12 )alkenyl, -(C-C 1 2 )alkynyl, -(C 3 C 12 )cycloalkyl, -(C 4 -CuI)cycloalkenyl, ((C 3 -Cu 2 )cycloalkyl)-(Ci-C 6 )alkyl-, ((C 4 10 C 1 2 )cycloalkenyl)-(CI-C 6 )alkyl-, -(5- to 12-membered)aryl, ((5- tol2-membered)aryl)-(Ci C 6 )alkyl-, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, phenyl, and benzyl; any of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -(Ci-C 6 )alkyl, OH, halo, -C(halo) 3 , -CH(halo) 2 , CH 2 (halo), NH 2 , -NH(C-C 6 )alkyl, CN, SH, -(5- to 12-membered)carbocyclic ring, -(5- to 12 15 membered)heterocycle, phenyl, and benzyl; R 2 and R 8 are each independently hydrogen, -(Ci-CIo)alkyl, -(C-C 12 )alkenyl, -(C 2 C 12 )alkynyl, -(C 3 -C, 2 )cycloalkyl, -((C 3 -C, 2 )cycloalkyl)-(CI-C 6 )alkyl, -(C 4 -C2)cycloalkenyl, (C 6 -C 1 4)bicycloalkyl, -(Cs.C20)tricycloalkyl, -(C 7 -C] 4 )bicycloalkenyl, -(Cs-C20)tricycloalkenyl, -(5- to 12-membered)aryl, ((5- tol2-membered)aryl)-(CI-C 6 )alkyl-, -(7- to 12 20 membered)bicyclic ring system, -(7- to 12-membered)bicyclic aryl, -(5- to 12 membered)heteroaryl, -(3- to 12-membered)heterocycle, -(7- to 12-membered) bicycloheterocycle, phenyl and benzyl; any of which is optionally substituted with one or two substituents independently selected from the group consisting of OH, (=O), halo, -C(halo) 3 , -CH(halo) 2 , -CH2(halo), -(Ci-C 6 )alkyl, halo(C 1 -C 6 )alkyl-, -(C-C 6 )alkenyl, - 122 - (C 2 -C 6 )alkynyl, hydroxy(Ci-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(CI-C 6 )alkyl, CN, SH, OR 4 , CONRR 6 and COOR; R 3 ' and R 3 b are each independently selected from hydrogen, -(CI-C 6 )alkyl, -(C 2 C 6 )alkenyl, -(C 2 -C 6 )alkynyl, OH, hydroxy(CI-C 6 )alkyl-, -C(halo) 3 , -CH(halo)2, and 5 CH 2 (halo), or together form (=0); R 4 is selected from -(CI-C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C-C 6 )alkynyl, -C(halo) 3 , hydroxy(CI-C 6 )alkyl-, -(C 3 -C 2 )cycloalkyl, -(C 6 -CI 4 )bicycloalkyl, -(Cs-C 2 0)tricycloalkyl, (C 4 -C 1 2)cycloalkenyl, -(C 7 -CI4)bicycloalkenyl, -(Cs-C 2 D)tricycloalkenyl, -(5- to 12 membered)aryl, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, and 10 (7- to 12-membered)bicycloheterocycle; R 5 and R 6 are each independently -(Ci-C 6 )alkyl, -(C 3 -Cs)cycloalkyl, ((C 3 Cs)cycloalkyl)-(Ci-C 6 )alkyl-, or together with the nitrogen atom to which they are attached form a (4- to 8- membered)heterocycle; R is selected from hydrogen, -(Ci-C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C2-C6)alkynyl, -(C 3 15 Ct I)cycloalkyl, -(C 4 -C I 2 )cycloalkenyl, ((C 3 -C 1 2)cycloalkyl)-(CI -C 6 )alkyl-, and ((C 4 C[ 2 )cycloalkenyl)-(Ci-C 6 )alkyl- ; X is selected from (CI-C 6 )alkoxy and OH; Z is (CH 2 )m; Y is (CH 2 )n-CH or a direct bond, provided that when Y is a direct bond then R 8 is 20 absent; m is an integer 1, 2, 3, 4, 5, or 6; n is an integer 0, 1, 2, 3, 4, 5 or 6; or a pharmaceutically acceptable salt, prodrug or solvate thereof. 25 2. A compound of claim lof the Formula ([IIA): - 123 - R' N R3a -R3b Z Y R R8 x 0 OCH3 (1IIA) wherein R' is selected from -(Ci-Cio)alkyl, -(C-C 12 )alkenyl, -(C2-C 1 2 )alkynyl, -(C 3 C 12 )cycloalkyl, -(C 4 -Cu2)cycloalkenyl, ((C 3 -C,2)cycloalkyl)-(CI-C 6 )alkyl-, ((C 4 5 C1 2 )cycloalkenyl)-(CI-C 6 )alkyl-, -(5- to 12-membered)aryl, ((5- tol2-membered)aryl)-(C, C 6 )alkyl-, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, phenyl, and benzyl; any of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -(CI-C 6 )alkyl, OH, halo, -C(halo) 3 , -CH(halo) 2 , CH 2 (halo), NH 2 , -NH(CI-C 6 )alkyl, CN, SH, -(5- to 12-membered)carbocyclic ring, -(5- to 12 10 membered)heterocycle, phenyl, and benzyl; R 2 and R 8 are each independently hydrogen, -(Ci-Cio)alkyl, -(C 2 -C 12 )alkenyl, -(C 2 C 1 2)alkynyl, -(C 3 -Cu 2 )cycloalkyl, -((C-C,2)cycloalkyl)-(CI-C 6 )alkyl, -(C4-C]2)cycloalkenyl, (C 6 -CI 4 )bicycloalkyl, -(C8.C20)tricycloalkyl, -(C 7 -C]4)bicycloalkenyl, -(Cs-C 2 0)tricycloalkenyl, -(5- to 12-membered)aryl, ((5- tol2-membered)aryl)-(CI-C 6 )alkyl-, -(7- to 12 15 membered)bicyclic ring system, -(7- to 12-membered)bicyclic aryl, -(5- to 12 membered)heteroaryl, -(3- to 12-membered)heterocycle, -(7- to 12-membered) bicycloheterocycle, phenyl and benzyl; any of which is optionally substituted with one or two substituents independently selected from the group consisting of OH, (=O), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(Ci-C 6 )alkyl, halo(CI-C 6 )alkyl-, -(C 2 -C 6 )alkenyl, 20 (C2-C 6 )alkynyl, hydroxy(Ci-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(Ci-C 6 )alkyl, CN, SH, OR 4 , CONRR 6 and COOR'; R 3 ' and R3b are each independently selected from hydrogen, -(C i-C 6 )alkyl, -(C 2 C 6 )alkenyl, -(C 2 -C 6 )alkynyl, OH, hydroxy(CI-C 6 )alkyl-, -C(halo) 3 , -CH(halo) 2 , and CH2(halo), or together form (=0); - 124- R 4 is selected from -(CI-C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C-C 6 )alkynyl, -C(halo) 3 , hydroxy(CI-C 6 )alkyl-, -(C 3 -CI 2 )cycloalkyl, -(C 6 -Ci 4 )bicycloalkyl, -(Cs-C 2 0)tricycloalkyl, (C 4 -C 1 2)cycloalkenyl, -(C 7 -CI 4 )bicycloalkenyl, -(Cs-C 20 )tricycloalkenyl, -(5- to 12 membered)aryl, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, and 5 (7- to 12-membered)bicycloheterocycle; R 5 and R 6 are each independently -(Ci-C 6 )alkyl, -(C 3 -Cs)cycloalkyl, ((Cr Cs)cycloalkyl)-(C-C 6 )alkyl-, or together with the nitrogen atom to which they are attached form a (4- to 8- membered)heterocycle; R 7 is selected from hydrogen, -(Ci-C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -(C 3 10 C 12 )cycloalkyl, -(C 4 -C2)cycloalkenyl, ((C-C 12 )cycloalkyl)-(CI -C 6 )alkyl-, and ((C 4 Ci2)cycloalkenyl)-(CI-C 6 )alkyl- ; X is selected from (Ci-C 6 )alkoxy and OH; Z is (CH2)m; Y is (CH 2 )n-CH or a direct bond, provided that when Y is a direct bond then Rs is 15 absent; m is an integer 1, 2, 3, 4, 5, or 6; n is an integer 0, 1, 2, 3, 4, 5 or 6; or a pharmaceutically acceptable salt, prodrug or solvate thereof. 20 3. A compound of claim 1 of Formula (IIIB): RR N R 3a ... - R 2 x 00\oCH3 R (Il1 B) wherein -125- R' is selected from -(Ci-Cio)alkyl, -(C 2 -C, 2 )alkenyl, -(C 2 -C[ 2 )alkynyl, -(C 3 C 12 )cycloalkyl, -(C 4 -Cu2)cycloalkenyl, ((C 3 -Cu 2 )cycloalkyl)-(Ci-C 6 )alkyl-, ((C 4 C 1 2)cycloalkenyl)-(CI-C 6 )alkyl-, -(5- to 12-membered)aryl, ((5- to 12 membered)aryl)-(CI-C 6 )alkyl-, -(5- to 12-membered)heteroaryl, -(3- to 12 5 membered)heterocycle, phenyl, and benzyl; any of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -(C 3 C 6 )alkyl, OH, halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), NH 2 , -NH(Ci-C 6 )alkyl, CN, SH, -(5- to 12-membered)carbocyclic ring, -(5- to 12-membered)heterocycle, phenyl, and benzyl; 10 R2 and R 8 are each independently hydrogen, -(CI-Clo)alkyl, -(C 2 -C] 2 )alkenyl, -(C 2 C 12 )alkynyl, -(CrCI 2 )cycloalkyl, -((C 3 -C12)cycloalkyl)-(CI-C 6 )alkyl, -(C 4 C12)cycloalkenyl, -(C 6 -C] 4 )bicycloalkyl, -(C 8 .C 20 )tricycloalkyl, -(C 7 C 14 )bicycloalkenyl, -(C8-C20)tricycloalkenyl, -(5- to 12-membered)aryl, ((5- to] 2 membered)aryl)-(C-C 6 )alkyl-, -(7- to 12-membered)bicyclic ring system, -(7- to 12 15 membered)bicyclic aryl, -(5- to 12-membered)heteroaryl, -(3- to 12 membered)heterocycle, -(7- to 12-membered) bicycloheterocycle, phenyl and benzyl; any of which is optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(CI-C 6 )alkyl, halo(CI-C 6 )alkyl-, -(C 2 20 C 6 )alkenyl, -(C2-C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(Cl C 6 )alkyl, CN, SH, OR 4 , CONRR' and COOR'; R 3 ' and R 3 b are each independently selected from hydrogen, -(C-C 6 )alkyl, -(C C 6 )alkenyl, -(C 2 -C 6 )alkynyl, OH, hydroxy(CI-C 6 )alkyl-, -C(halo) 3 , -CH(halo) 2 , and CH2(halo), or together form (=0),; 25 R4 is selected from -(CI-C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -C(halo) 3 , hydroxy(CI-C 6 )alkyl-, -(C 3 -C2)cycloalkyl, -(C 6 -CI 4 )bicycloalkyl, -(C 8 -C20)tricycloalkyl, (C 4 -Cu2)cycloalkenyl, -(C 7 -CI4)bicycloalkenyl, -(Cg-C 2 0)tricycloalkenyl, -(5- to 12 membered)aryl, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, and (7- to 12-membered)bicycloheterocycle; 30 R 5 and R 6 are each independently -(Ci-C 6 )alkyl, -(C3-Cs)cycloalkyl, ((C 3 Cs)cycloalkyl)-(C-C 6 )alkyl-, or together with the nitrogen atom to which they are attached form a (4- to 8- membered)heterocycle; - 126- R 7 is selected from hydrogen, -(Ci-C 6 )alkyl, -(C2-C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -(C 3 C 1 2)cycloalkyl, -(C 4 -C 2 )cycloalkenyl, ((C 3 -C 2 )cycloalkyl)-(CI-C 6 )alkyl-, and ((C 4 C 1 2 )cycloalkenyl)-(CI-C 6 )alkyl- ; X is selected from (Ci-C 6 )alkoxy and OH; 5 Z is (CH 2 )m; Y is (CH 2 )n-CH or a direct bond, provided that when Y is a direct bond then R 8 is absent; m is an integer 1, 2, 3, 4, 5, or 6; n is an integer 0, 1, 2, 3, 4, 5 or 6; 10 or a pharmaceutically acceptable salt, prodrug or solvate thereof.
4. A compound according to any one of claims I to 3 wherein R' is -(Ci-Clo)alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -(Ci-C 6 )alkyl, OH, halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), NH1 2 , -NH(CI 15 C 6 )alkyl, CN, SH, -(5- to 12-membered)carbocyclic ring, -(5- to 12 membered)heterocycle, phenyl, and benzyl.
5. A compound according to claim 4 wherein R' is selected from the group consisting of methyl, ethyl, or isopropyl, and preferably methyl, each of which is optionally substituted 20 with 1, 2, or 3 substituents independently selected from the group consisting of -(Ci C 6 )aLkyl, OH, halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), NH 2 , -NH(CI-C 6 )alkyl, CN, SH, (5- to 12-membered)carbocyclic ring, -(5- to 12-membered)heterocycle, phenyl, and benzyl. 25 6. A compound according to any of claims I to 3 wherein R' is -(C 2 -C 1 2 )alkenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -(Ci-C 6 )alkyl, OH, halo, -C(halo) 3 , -CH(halo) 2 , -CH2(halo), NH 2 , -NH(Cl C6)alkyl, CN, SH, -(5- to 12-membered)carbocyclic ring, -(5- to 12 membered)heterocycle, phenyl, and benzyl. 30
7. A compound according to claim 6 wherein R' is selected from the group consisting of ethenyl and propenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -(CI-C 6 )alkyl, OH, halo, -C(halo) 3 , - 127 - CH(halo)2, -CH 2 (halo), NH 2 , -NH(CI-C 6 )alkyl, CN, SH, -(5- to 12-membered)carbocyclic ring, -(5- to 12-membered)heterocycle, phenyl, and benzyl.
8. A compound according to any of claims 1 to 3 wherein R' is -(C 3 -C 2 )cycloalkyl 5 optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -(Ci-C 6 )alkyl, OH, halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), NH 2 , -NH(C 1 C 6 )alkyl, CN, SH, -(5- to 12-membered)carbocyclic ring, -(5- to 12 membered)heterocycle, phenyl, and benzyl. 10 9. A compound according to any one of claims 1 to 3 wherein R' is-(C 4 -C 1 2 )cycloalkenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -(Ci-C 6 )alkyl, OH, halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), NH 2 , -NH(C 1 C 6 )alkyl, CN, SH, -(5- to 12-membered)carbocyclic ring, -(5- to 12 membered)heterocycle, phenyl, and benzyl. 15
10. A compound according to any one of claims I to 3 wherein R' is ((C 3 C 1 2)cycloalkyl)-(CI-C 6 )alkyl-, each of which is optionally substituted.
11. A compound according to claim 10 wherein R' is selected from the group consisting 20 of cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl, and preferably cyclopropylmethyl, each of which is optionally substituted.
12. A compound according to any of claims I to 3 wherein R' is -(5- to 12 membered)aryl, -(5- to 12-membered)heteroaryl, or -(3- to 12-membered)heterocycle, 25 each of which is optionally substituted with one to three substituents independently selected from the group consisting of -(Ci-C 6 )alkyl, OH, halo, -C(halo) 3 , -CH(halo)2, CH 2 (halo), NH 2 , -NH(Ci-C 6 )alkyl, CN, SH, -(5- to 12-membered)carbocyclic ring, -(5- to 12-membered)heterocycle, phenyl, and benzyl. 30 13. A compound according to any one of claims I to 12 wherein at least one of R 2 or R 8 is -(Ci-Cio)alkyl optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(CI-C 6 )alkyl, halo(CI-C 6 )alkyl-, -(C2-C 6 )alkenyl, -(C2-C 6 )alkynyl, hydroxy(CI -C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(Ci-C 6 )alkyl, CN, SH, OR 4 , CONRR 6 and COOR. - 128 -
14. A compound according to claim 13 wherein at least one of R 2 or R 8 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pentyl and hexyl, each of which is optionally substituted with one or two substituents 5 independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(CI-C 6 )alkyl, halo(Ci-C 6 )alkyl-, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, phenyl, benzyl, NH 2 , -Nl(CI-C 6 )alkyl, CN, SH, OR 4 , CONR 5 R 6 and COOR. 10 15. A compound according to any one of claims 1 to 12 wherein both R 2 and R 8 are -(C, Cio)alkyl optionally substituted with one or two substituents independently selected from the group consisting of OH, (=O), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(CI-C 6 )alkyl, halo(CI-C 6 )alkyl-, -(C 2 -C 6 )alkenyl, -(C-C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(CI-C 6 )alkyl, CN, SH, OR 4 , CONRR and COOR . 15
16. A compound according to claim 15 wherein both R 2 are R 8 are selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pentyl and hexyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), 20 halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(Ci-C 6 )alkyl, halo(CI-C 6 )alkyl-, -(C 2 -C 6 )alkenyl, -(C-C 6 )alkynyl, hydroxy(Ci-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(Ci-C 6 )alkyl, CN, SH, OR 4 , CONR 5 R 6 and COOR'.
17. A compound according to any one of claims 1 to 12 wherein at least one of R 2 or R 8 25 is -(C2-C, 2 )alkenyl optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(CI-C 6 )alkyl, halo(CI-C 6 )alkyl-, -(C-C 6 )alkenyl, -(C 2 -C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(CI-C 6 )alkyl, CN, SH, OR 4 , CONRR' and COOR'. 30 18. A compound according to claim 17 wherein at least one of R 2 or R 8 is selected from the group consisting of 2-methyl-but-2-enyl and propenyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(Ci-C 6 )alkyl, halo(CI-C 6 )alkyl-, - 129- (C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, hydroxy(C-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(C C 6 )alkyl, CN, SH, OR 4 , CONRR 6 and COOR .
19. A compound according to any one of claims I to 12 wherein at least one of R 2 or R 8 5 is -(C 2 -C 1 2 )alkynyl optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(CrC 6 )alkyl, halo(C-C 6 )alkyl-, -(C 2 -C 6 )alkenyl, -(C2-C6)alkynyl, hydroxy(C-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(CI-C 6 )alkyl, CN, SH, OR 4 , CONR 5 R 6 and COOR 7 . 10 20. A compound according to claim 19 wherein at least one of R 2 or R 8 is propynyl optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(CI-C 6 )alkyl, halo(C C 6 )alkyl-, -(C 2 -C 6 )alkenyl, -(C-C 6 )alkynyl, hydroxy(C-C 6 )alkyl-, phenyl, benzyl, NH 2 , NH(C-C 6 )alkyl, CN, SH, OR 4 , CONRR' and COOR 7 . 15
21. A compound according to any one of claims 1 to 12 wherein at least one of R 2 or R8 is -(C 3 -Cu 2 )cycloalkyl, and preferably cyclobutyl or cyclohexyl, optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH2(halo), -(CI-C 6 )alkyl, halo(CI-C 6 )alkyl-, -(C 2 20 C 6 )alkenyl, -(C 2 -C 6 )alkynyl, hydroxy(C-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(CI C 6 )alkyl, CN, SH, OR 4 , CONRR and COOR .
22. A compound according to any one of claims I to 12 wherein both R 2 and R 8 are -(Cr C 12 )cycloalkyl optionally substituted with one or two substituents independently selected 25 from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(C C 6 )alkyl, halo(C-C 6 )alkyl-, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, hydroxy(C-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(CI-C 6 )alkyl, CN, SH, OR 4 , CONRIR 6 and COOR 7 .
23. A compound according to any one of claims I to 12 wherein at least one of R 2 or R 8 30 is -(C 4 -C 1 2 )cycloalkenyl optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(C-C 6 )alkyl, halo(C-C 6 )alkyl-, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, hydroxy(C-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(C-C 6 )alkyl, CN, SH, OR 4 , CONRR and COOR . -130-
24. A compound according to any one of claims I to 12 wherein at least one of R 2 or R8 is -(C 6 -CI4)bicycloalkyl, -(Cs-C 20 )tricycloalkyl, -(C 7 -C 1 4) bicycloalkenyl, or -(Cs C 2 )tricycloalkenyl, each of which is optionally substituted with one or two substituents 5 independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(CI-C 6 )alkyl, halo(CI-C 6 )alkyl-, -(C2-C 6 )alkenyl, -(C 2 -C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(Ci-C 6 )alkyl, CN, SH, OR 4 , CONR 5 R 6 and COOR'. 10 25. A compound according to any one of claims I to 12 wherein at least one of R 2 or R 8 is -(5- to 12-membered)aryl, and preferably phenyl or naphthalenyl, optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(CI-C 6 )alkyl, halo(CI-C 6 )alkyl-, -(C 2 C 6 )alkenyl, -(C 2 -C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(CI 15 C 6 )alkyl, CN, SH, OR 4 , CONRR 6 and COOR.
26. A compound according to claim 25 wherein at least one of R 2 or Ra is phenyl. optionally substituted with one or two substituents independently selected from -(C, C 6 )alkyl, OH, halo, NH 2 , -NH(CI-C 6 )alkyl, CN, (=0), SH, phenyl, -C(halo) 3 , -OC(halo) 3 , 20 and -O(Ci-C 6 )alkyl.
27. A compound according to claim 25 wherein at least one of R 2 or R 8 is benzyl optionally substituted with one or two substituents independently selected from -(CI C 6 )alkyl, OH, halo, NH 2 , -NH(CI-C 6 )alkyl, CN, (=0), SH, phenyl, -C(halo) 3 , -OC(halo) 3 , 25 and -O(Ci-C 6 )alkyl.
28. A compound according to any of claims 1 to 12 wherein both R2 and R8 are -(5- to 12-membered)aryl optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), 30 -(Ci-C 6 )alkyl, halo(CI-C 6 )alkyl-, -(C 2 -C 6 )alkenyl, -(C2-C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(C1-C 6 )alkyl, CN, SH, OR 4 , CONRR' and COOR . - 131 -
29. A compound according to claim 28 wherein both R 2 and R 8 are phenyl optionally substituted with one or two substituents independently selected from -(Ci-C 6 )alkyl, OH, halo, phenyl, NH 2 , -NH(CI-C 6 )alkyl, CN, (=0), and SH. 5 30. A compound according to claim 28 wherein both R 2 and R 8 are benzyl optionally substituted with one or two substituents independently selected from -(Ci-C 6 )alkyl, OH, halo, NH 2 , -NH(Ci-C 6 )alkyl, CN, (=0), and SH.
31. A compound according to any one of claims 1 to 12 wherein at least one of R 2 or R 8 10 is ((5- to 12- membered)aryl)-(CI-C 6 ) alkyl- optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(Ci-C 6 )alkyl, halo(CI-C 6 )alkyl-, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(CI-C 6 )alkyl, CN, SH, OR 4 , CONRR 6 and COOR'. 15
32. A compound according to claim 31 wherein at least one of R 2 or R 8 is phenyl-(Cl C 6 )alkyl optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(Ci-C 6 )alkyl, halo(CI-C 6 )alkyl-, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, phenyl, 20 benzyl, NH 2 , -NH(CI-C 6 )alkyl, CN, SH, OR 4 , CONRR 6 and COOR'.
33. A compound according to claim 31 wherein at least one of R 2 or R 8 is benzyl optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(CI-C 6 )alkyl, halo(C 1 25 C 6 )alkyl-, -(C2-C 6 )alkenyl, -(C2-C 6 )alkynyl, hydroxy(CI-Cs)alkyl-, phenyl, benzyl, NH 2 , NH(C1-C 6 )alkyl, CN, SH, OR 4 , CONRR 6 and COOR 7 .
34. A compound according to any one of claims 1 to 12 wherein both R 2 and R 8 are ((5 to 12- membered)aryl)-(CI-C 6 ) alkyl- optionally substituted with one or two substituents 30 independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(CI-C 6 )alkyl, halo(CI-C 6 )alkyl-, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(CI-C 6 )alkyl, CN, SH, OR 4 , CONRR 6 and COOR. -132-
35. A compound according to claim 34 wherein Y, R 2 and R 8 taken together are diphenylpropyl optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(C 1 C 6 )alkyl, halo(Ci-C 6 )alkyl-, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, 5 phenyl, benzyl, NH 2 , -NH(CI-C 6 )alkyl, CN, SH, OR 4 , CONRR 6 and COOR 7 .
36. A compound according to claim 34 wherein both R 2 and R 8 are benzyl optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo)2, -CH 2 (halo), -(CI-C 6 )alkyl, halo(CI-C 6 )alkyl-, 10 (C2-C 6 )alkenyl, -(C 2 -C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(Ci C 6 )alkyl, CN, SH, OR 4 , CONRR 6 and COOR 7 .
37. A compound according to any one of claims I to 12 wherein at least one of R 2 or R 8 is -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, or -(7- to 12 15 membered)bicycloheterocycle, and preferably pyridinyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(C,-C 6 )alkyl, halo(CI-C 6 )alkyl-, (C 2 -C 6 )alkenyl, -(C-C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(Ci C 6 )alkyl, CN, SH, OR 4 , CONRR and COOR'. 20
38. A compound according to any one of claims 1 to 37 wherein at least one of R 3 a or R 3 b is hydrogen.
39. A compound according to any one of claims 1 to 37 wherein both R 3 a and R 3 b are 25 hydrogen.
40. A compound according to any one of claims I to 37 wherein at least one of R 3 " orR 3 A is OH. 30 41. A compound according to any one of claims I to 37 wherein at least one of R 3 a or R 3 b is -(CI-C 6 )alkyl.
42. A compound according to claim 41 wherein at least one of R 3 , or R3b is selected from the group consisting of methyl, ethyl and isopropyl. - 133 -
43. A compound according to any one of claims I to 37 wherein both R 3 " and R 3 b are (CI-C6)alkyl. 5 44. A compound according to any one of claims 1 to 37 wherein at least one of R 3 a or R 3 b is -CH 2 (halo).
45. A compound according to claim 44 wherein at least one of R 3 a or R 3 b is selected from the group consisting of CH 2 F and CH 2 CL. 10
46. A compound according to any one of claims I to 45 wherein Z is -CH 2 -.
47. A compound according to any one of claims I to 46 wherein Y is -CH. 15 48. A compound according to any one of claims I to 45 wherein Z is -CH 2 - and Y is CH.
49. A compound according to any one of claims I to 45 wherein Y is a direct bond. 20 50. A compound according to any one of claims 1 to 45 wherein Z is -CH 2 - and Y is a direct bond.
51. A compound according to any one of claims I to 46 wherein Y is -CH 2 rCH. 25 52. A compound according to any one of claims I to 45 wherein Z is -CH 2 -CH 2 -.
53. A compound according to any one of claims I to 45 wherein Y is -CH 2 -CH and Z is -CH 2 -CH 2 -. 30 54. A compound according to any one of claims 1 to 45 wherein Z is -CH 2 -CH 2 - and Y is a direct bond.
55. A compound according to any one of claims 1 to 45 wherein Z is -CH 2 - and Y is CH 2 -CH. -134-
56. A compound according to any one of claims 13 to 45 wherein Z is -CH 2 -CH 2 - and Y is -CH. 5 57. A compound according to any one of claims I to 46 wherein Y is -CH 2 -CH 2 -CH.
58. A compound according to any one of claims 1 to 45 wherein Z is -CH 2 -CH 2 -CH 2 -.
59. A compound according to any one of claims I to 45 wherein Y is a direct bond and Z 10 is -CH 2 -CH 2 -CH 2 -.
60. A compound according to any one of claims 1 to 45 wherein Y is -CH 2 -CH 2 -CH and Z is -CH 2 -. 15 61. A compound according to any one of claims I to 45 wherein Y is -CH and Z is CH 2 -CH 2 -CH 2 -.
62. A compound according to any one of claims 1 to 45 wherein Y is -CH 2 -CH 2 -CH and Z is -CH 2 -CH 2 -. 20
63. A compound according to any one of claims 1 to 45 wherein Y is -CH 2 -CH and Z is -CH 2 -CH 2 -CH 2 -.
64. A compound according to any one of claims I to 12 wherein Y is -CH and least one 25 of R 2 or R 8 is phenyl.
65. A compound according to any one. of claims 1 to 12 wherein Y is a direct bond and R 2 is benzyl. 30 66. A compound according to any one of claims 1 to 12 wherein Y is -CH and both R 2 and R 8 are phenyl.
67. A compound according to any one of claims 1 to 66 wherein X is (CI-C 6 )alkoxy. - 135 -
68. A compound according to claim 67 wherein X is methoxy.
69. A compound according to any one of claims 1 to 66 wherein X is OH. 5 70. A compound according to claim 1 of Formula (II): R0 R3a RUb &RU z 110Y R X 0 OCH 3 (II) wherein 10 R' is selected from -(Ci-Cio)alkyl, -(C 2 -C 12 )alkenyl, -(C 2 -CI2)alkynyl, -(C 3 C 1 2)cycloalkyl, -(C4-C 1 2)cycloalkenyl, ((C 3 -Cu 2 )cycloalkyl)-(CI-C 6 )alkyl-, ((C 4 Cu2)cycloalkenyl)-(CI-C 6 )alkyl-, -(5- to 12-membered)aryl, -(5- to 12-membered)heteroaryl, (3- to 12-membered)heterocycle, phenyl, and benzyl; any of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -(Ci-C 6 )alkyl, 15 OH, halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), NH 2 , -NH(Ci-C 6 )alkyl, CN, SH, -(5- to 12 membered)carbocyclic ring, -(5- to 12-membered)heterocycle, phenyl, or benzyl; R 2 is selected from hydrogen, -(Ci-Cio)alkyl, -(C 2 -C,2)alkenyl, -(C 2 -C] 2 )alkynyl, -(C 3 C 1 2)cycloalkyl, -(C 4 -Cu2)cycloalkenyl, -(C 6 -C 14 )bicycloalkyl, -(Cs.C 20 )tricycloalkyl, -(C 7 C14)bicycloalkenyl, -(Cs-C20)tricycloalkenyl, -(5- to 12-membered)aryl, -(5- to 12 20 membered)heteroaryl, -(3- to 12-membered)heterocycle, -(7- to 12 membered)bicycloheterocycle, phenyl or benzyl; any of which is optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(CI-C 6 )alkyl, halo(Ci-C 6 )alkyl-, -(C 2 -C 6 )alkenyl, - 136- (C 2 -C 6 )alkynyl, hydroxy(Ci-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(C 1 -C 6 )alkyl, CN, SH, OR 4 , CONRR 6 and COOR 7 ; Ra and R 3 b are each independently hydrogen, -(C I-C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(Cr C 6 )alkynyl, OH, hydroxy(CI-C 6 )alkyl-, -(C(halo) 3 , -CH(halo) 2 , and -CH 2 (halo), or together 5 form (=0); R4 is selected from the group consisting of -(CI-C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, -(C 3 -C, 2 )cycloalkyl, -(C 6 -CI 4 )bicycloalkyl, -(C 8 C20)tricycloalkyl, -(C 4 -C 1 2 )cycloalkenyl, -(C 7 -CI 4 )bicycloalkenyl, -(Cs-C 2 0)tricycloalkenyl, (5- to 12-membered)aryl, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, 10 and -(7- to 12-membered)bicycloheterocycle; R 5 and R6 are each independently -(Ci-C 6 )alkyl, -(C 3 -Cs)cycloalkyl, ((C 3 Cs)cycloalkyl)-(CI-C 6 )alkyl-, or together with the nitrogen atom to which they are attached form a (4- to 8- membered)heterocycle; R 7 is selected from hydrogen, -(Ci-C 6 )alkyl, -(C-C 6 )alkenyl, -(C2-C 6 )alkynyl, -(C 3 15 C 12 )cycloalkyl, -(C4-CI2)cycloalkenyl, ((C3-C 2 )cycloalkyl)-(Ci-C 6 )alkyl-, and ((C 4 C 1 2)cycloalkenyl)-(CI-C 6 )alkyl- ; X is selected from (Ci-C 6 )alkoxy and OH; Z is (CH 2 )m; Y is (CH 2 )n; 20 m is an integer 1, 2, 3, 4, 5, or 6; n is an integer 0, 1, 2, 3, 4, 5 or 6; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
71. A compound according to claim 70 of Formula (IIA): 25 - 137- R1 N R aa ....- R3b O R2 Z Y X O\0 O CH3 (IIA) wherein R' is selected from -(CI-Cio)alkyl, -(C-C 1 2 )alkenyl, -(C 2 -CI2)alkynyl, -(C 3 5 C 1 2)cycloalkyl, -(C 4 -C2)cycloalkenyl, ((C 3 -C )cycloalkyl)-(CI-C 6 )alkyl-, ((C 4 C 12 )cycloalkenyl)-(Ci-C 6 )alkyl-, -(5- to 12-membered)aryl, -(5- to 12-membered)heteroaryl, (3- to 12-membered)heterocycle, phenyl, and benzyl; any of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -(Ci-C 6 )alkyl, OH, halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), NH 2 , -NH(Ci-C 6 )alkyl, CN, SH, -(5- to 12 10 membered)carbocyclic ring, -(5- to 12-membered)heterocycle, phenyl, or benzyl; R 2 is selected from hydrogen, -(CI-CIO)alkyl, -(C 2 -C 1 2 )alkenyl, -(C 2 -C 1 2 )alkynyl, -(C 3 C1 )cycloalkyl, -(C 4 -C 2)cycloalkenyl, -(C 6 -Cl 4 )bicycloalkyl, -(Cs.C 2 0)tricycloalkyl, -(C 7 C14)bicycloalkenyl, -(C8-C20)tricycloalkenyl, -(5- to 12-membered)aryl, -(5- to 12 membered)heteroaryl, -(3- to 12-membered)heterocycle, -(7- to 12 15 membered)bicycloheterocycle, phenyl or benzyl; any of which is optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo)2, -CH 2 (halo), -(CI-C 6 )alkyl, halo(Ci-C 6 )alkyl-, -(C 2 -C 6 )alkenyl, (C-C 6 )alkynyl, hydroxy(Ci-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(CI-C 6 )alkyl, CN, SH, OR 4 , CONRR 6 and COOR 7 ; 20 R3' and R 3 b are each independently hydrogen, -(CI-C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 C6)alkynyl, OH, hydroxy(Ci-C 6 )alkyl-, -(C(halo) 3 , -CH(halo)2, and -CH 2 (halo), or together form (=0); R 4 is selected from -(CI-C 6 )alkyl, -(C-C 6 )alkenyl, -(C-C 6 )alkynyl, hydroxy(C C 6 )alkyl-, -(C 3 -Cu2)cycloalkyl, -(C 6 -CI4)bicycloalkyl, -(Cs-C 2 0)tricycloalkyl, -(C 4 - 138 - C 1 2)cycloalkenyl, -(C 7 -C 1 4 )bicycloalkenyl, -(Cs-C20)tricycloalkenyl, -(5- to 12 membered)aryl, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, and -(7 to 12-membered)bicycloheterocycle; R5 and R 6 are each independently -(Ci-C 6 )alkyl, -(C 3 -Cs)cycloalkyl, ((C 3 5 Cs)cycloalkyl)-(C 1 -C 6 )alkyl-, or together with the nitrogen atom to which they are attached form a (4- to 8- membered)heterocycle; R 7 is selected from hydrogen, -(Cf-C 6 )alkyl, -(C-C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -(C 3 C 1 2 )cycloalkyl, -(C 4 -CI 2)cycloalkenyl, ((C 3 CI 2)cycloalkyl)-(C I-C 6 )alkyl-, and ((C 4 C 1 2)cycloalkenyl)-(CI -C 6 )alkyl-; 10 X is selected from (Ci-C 6 )alkoxy and OH; Z is (CH2)m; Y is (CH 2 )n; m is an integer 1, 2, 3, 4, 5, or 6; n is an integer 0, 1, 2, 3, 4, 5 or 6; 15 or a pharmaceutically acceptable salt, prodrug or solvate thereof.
72. A compound according to claim 70 of Formula (1IB): Ri N R 3 a R 3 b 0R 2 X OOCH 3 (IIB) 20 wherein R' is selected from -(CI-CIo)alkyl, -(C 2 -C 12 )alkenyl, -(C-C 1 2 )alkynyl, -(C 3 C 1 z)cycloalkyl, -(C 4 -Cu2)cycloalkenyl, ((C 3 -Cu2)cycloalkyl)-(CI-C 6 )alkyl-, ((C 4 C 1 2)cycloalkenyl)-(CI-C 6 )alkyl-, -(5- to 12-membered)aryl, -(5- to 12-membered)heteroaryl, (3- to 12-membered)heterocycle, phenyl, and benzyl; any of which is optionally substituted 25 with 1, 2, or 3 substituents independently selected from the group consisting of -(Ci-C 6 )alkyl, - 139- OH, halo, -C(halo)3, -CH(halo) 2 , -CH 2 (halo), NH 2 , -NH(CI-C 6 )alkyl, CN, SH, -(5- to 12 membered)carbocyclic ring, -(5- to 12-membered)heterocycle, phenyl, or benzyl; R 2 is selected from hydrogen, -(Ci-Cio)alkyl, -(C-CI 2 )alkenyl, -(C 2 -C 12 )alkynyl, -(C 3 C1 2 )cycloalkyl, -(C 4 -C 1 2)cycloalkenyl, -(C 6 -CI 4 )bicycloalkyl, -(C 8 .C 2 0)tricycloalkyl, -(C 7 5 C] 4 )bicycloalkenyl, -(Cs-C 20 )tricycloalkenyl, -(5- to 12-membered)aryl, -(5- to 12 membered)heteroaryl, -(3- to 12-membered)heterocycle, -(7- to 12 membered)bicycloheterocycle, phenyl or benzyl; any of which is optionally substituted with one or two substituents independently selected from the group consisting of OH, (=0), halo, -C(halo) 3 , -CH(halo)2, -CH 2 (halo), -(CI-C 6 )alkyl, halo(CI-C 6 )alkyl-, -(C 2 -C 6 )alkenyl, 10 (C 2 -C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, phenyl, benzyl, NH 2 , -NH(CI-C 6 )alkyl, CN, SH, OR 4 , CONRR 6 and COOR 7 ; R 3 " and R 3 b are each independently hydrogen, -(C I-C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 C 6 )alkynyl, OH, hydroxy(CI-C 6 )alkyl-, -(C(halo) 3 , -CH(halo) 2 , and -CH 2 (halo), or together form (=0); 15 R 4 is selected from -(Ci-C 6 )alkyl, -(C-C 6 )alkenyl, -(C 2 -C 6 )alkynyl, hydroxy(Cl C 6 )alkyl-, -(C 3 -C2)cycloalkyl, -(C 6 -CI 4 )bicycloalkyl, -(Cs-C 2 0)tricycloalkyl, -(C 4 C 1 2)cycloalkenyl, -(C 7 -C)4)bicycloalkenyl, -(Cg-C20)tricycloalkenyl, -(5- to 12 membered)aryl, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, and -(7 to 12-membered)bicycloheterocycle; 20 R 5 and R 6 are each independently -(Ci-C 6 )alkyl, -(C 3 -Cs)cycloalkyl, ((C 3 Cs)cycloalkyl)-(CI-C 6 )alkyl-, or together with the nitrogen atom to which they are attached form a (4- to 8- membered)heterocycle; R 7 is selected from hydrogen, -(CI-C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C-C 6 )alkynyl, -(C 3 C 12 )cycloalkyl, -(C 4 -C12)cycloalkenyl, ((C 3 -C 1 z)cycloalkyl)-(CI-C 6 )alkyl-, and ((C 4 25 Ci 2 )cycloalkenyl)-(Ci-C 6 )alkyl-; X is selected from (Ci-C 6 )alkoxy and OH; Z is (CH 2 )m; Y is (CH 2 )n; m is an integer 1, 2, 3, 4, 5, or 6; 30 n is an integer 0, 1, 2 , 3, 4, 5 or 6; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
73. The compound according to any one of claims 70to 72 wherein R' is optionally substituted -(Ci-Cio)alkyl. -140-
74. The compound of claim 73 wherein R' is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl and tert-butyl, and preferably methyl, each of which is optionally substituted. 5
75. The compound according to any one of claims 70 to 72 wherein R 1 is optionally substituted -(C 2 -CI 2 )alkenyl.
76. The compound of claim 75 wherein R' is selected from the group consisting of 10 ethenyl and propenyl, each of which is optionally substituted.
77. The compound according to any one of claims 70 to 72 wherein R' is optionally substituted ((C 3 -C2)cycloalkyl)-(CI-C 6 )alkyl-. 15 78. The compound of claim 77 wherein R' is selected from the group consisting of cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl, and preferably cyclopropylmethyl, each of which is optionally substituted.
79. The compound according to any one of claims 70 to 72 wherein Z is CH 2 . 20
80. The compound according to any one of claims 70 to 72 wherein Y is CH 2 .
81. The compound according to any one of claims 70 to 72 wherein Y is absent. 25 82. The compound according to any one of claims 70 to 72 wherein both Z and Y are CH 2 .
83. The compound according to any one of claims 70 to 72 wherein R 2 is optionally substituted -(CI-Cio)alkyl. 30 84. The compound of claim 83 wherein R 2 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl, each of which is optionally substituted. -141-
85. The compound according to any one of claims 70 to 72 wherein R 2 is optionally substituted -(C 2 -12)alkenyl.
86. The compound of claim 85 wherein R 2 is selected from the group consisting of 2 5 methyl-but-2-enyl and propenyl, each of which is optionally substituted.
87. The compound according to any one of claims 70 to 72 wherein R 2 is optionally substituted -(C 2 -C 2 )alkynyl. 10 88. The compound of claim 87 wherein R 2 is optionally substituted propynyl.
89. The compound according to any one of claims 70 to 72 wherein R 2 is an optionally substituted -(5- to 12-membered)aryl. 15 90. The compound of claim 89 wherein R 2 is optionally substituted phenyl.
91. The compound of claim 90 wherein R 2 is phenyl substituted with one or two substituents selected from the group consisting of OH, halo, -C(halo) 3 , -CH(halo)2, -CH 2 (halo), -(CI-C 6 )alkyl, halo(C-C 6 )alkyl-, -(C-C 6 )alkenyl, 20 -(C 2 -C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, (=0), and OR 4 .
92. The compound according to any one of claims 70 to 91 wherein at least one of R 3 a or R 3 b is hydrogen. 25 93. The compound according to any one of claims 70 to 91 wherein both R3' and R 3 b are hydrogen.
94. The compound according to any one of claims 70 to 91 wherein at least one of R 3 a or R 3 b is OH. 30
95. The compound according to any one of claims 70 to 90 wherein at least one of R 3 a or R 3 b is -(Ci-C 6 )alkyl. - 142-
96. The compound of claim 95wherein at least one of R 3 ' or R 3 b is selected from the group consisting of methyl, ethyl and isopropyl.
97. The compound according to any one of claims 70 to 91wherein at least one of R 3 a or 5 R 3 ' is -CH2(halo).
98. The compound of claim 97 wherein at least one of R 3 , or R 3 b is selected from the group consisting of CH 2 F and CH 2 CI. 10 99. A compound according to claim I of Formula I: RR N R3 0 R z Y H 3 CO 0 OCH 3 (I) wherein 15 R' is selected from the group consisting of -(CI-Clo)alkyl, -(C 2 -C, 2 )alkenyl, -(C 2 C 1 2)alkynyl, -(C 3 -CI 2 )cycloalkyl, -(C 4 -C,2)cycloalkenyl, ((C 3 -C2)cycloalkyl)-(CI-C 6 )alkyl-, ((C 4 -CI2)cycloalkenyl)-(CI-C 6 )alkyl-, a (5- to 12-membered)aryl, a (5- to 12 membered)heteroaryl, and a (3- to 12-membered)heterocycle; any of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of 20 (Ci-C 6 )alkyl, OH, halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), NH 2 , -NH(CI-C 6 )alkyl, CN and SH; R 2 is selected from the group consisting of hydrogen, -(CI-Cio)alkyl, -(C 2 -C 1 2 )alkenyl, -(Cr-C 2 )alkynyl, -(C3-CI2)cycloalkyl, -(C 4 -C2)cycloalkenyl, -(C 6 -CI 4 )bicycloalkyl, -(CS. C2o)tricycloalkyl, -(C 7 -CI 4 )bicycloalkenyl, -(Cs-C20)tricycloalkenyl, a (5- to 12 - 143 - membered)aryl, a (5- to 12-membered)heteroaryl, a (3- to 12-membered)heterocycle, or a (7 to 12-membered)bicycloheterocycle; any of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of OH, halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(CI-C 6 )alkyl, halo(CI-C 6 )alkyl-, -(C 2 -C 6 )alkenyl, 5 (C 2 -C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, C(=O), NH 2 , -NH(CI-C 6 )alkyl, CN, SH and OR 4 ; R 3 is selected from hydrogen, -(Ci-C 6 )alkyl, -(C2-C 6 )alkenyl, -(C2-C 6 )alkynyl, OH, hydroxyl(CI-C 6 )alkyl-, C(=O), -(C(halo) 3 , -CH(halo) 2 , and -CH 2 (halo); R 4 is selected from the group consisting of -(CI-C 6 )alkyl, -(C-C 6 )alkenyl, -(C 2 C 6 )alkynyl, OH, hydroxy(CI-C 6 )alkyl-, -(C 3 -C )cycloalkyl, -(C 6 -C,4)bicycloalkyl, -(Cs 10 C 2 0)tricycloalkyl, -(C 4 -C z)cycloalkenyl, -(C 7 -CI4)bicycloalkenyl, -(CS-C20)tricycloalkenyl, a (5- to 12-membered)aryl, a (5- to 12-membered)heteroaryl, a (3- to 12-membered)heterocycle, and a (7- to 12-membered)bicycloheterocycle; Z is (CH 2 )m; Y is (CH2)n; 15 m is an integer 1, 2, 3, 4, 5, or 6; n is an integer 0, 1, 2, 3, 4, 5 or 6; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
100. A compound according to claim 99 of Formula (IA): 20 R1 N R3 0 R2 Z z Y H 3 CO OCH 3 (IA) wherein 25 R' is selected from the group consisting of -(C-CIo)alkyl, -(CZ-C12)alkenyl, -(C 2 C2)alkynyl, -(C 3 -C 1 2)cycloalkyl, -(C 4 -C2)cycloalkenyl, ((CrC2)cycloalkyl)-(CI-C 6 )alkyl-, ((C4-C1)cycloalkenyl)-(CI-C 6 )alkyl-, a (5- to 12-membered)aryl, a (5- to 12 - 144 - membered)heteroaryl, and a (3- to 12-membered)heterocycle; any of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of (Ci-C 6 )alkyl, OH, halo, -C(halo) 3 , -CH(halo) 2 , CH 2 (halo), NH 2 , -NH(CI-C 6 )alkyl, CN and SH. R 2 is selected from the group consisting of hydrogen, -(Ci-CIo)alkyl, -(C 2 -C 12 )alkenyl, 5 -(C 2 -C 2 )alkynyl, -(C 3 -C 2 )cycloalkyl, -(C4-CI2)cycloalkenyl, -(C 6 -C 1 4)bicycloalkyl, -(C 8 . C 2 0)tricycloalkyl, -(C7-C 14 )bicycloalkenyl, -(C8-C 2 0)tricycloalkenyl, a (5- to 12 membered)aryl, a (5- to 12-membered)heteroaryl, a (3- to 12-membered)heterocycle, or a (7 to 12-membered)bicycloheterocycle; any of which is optionally substituted with one or two substituents independently selected from the group consisting of OH, 10 halo, -C(halo) 3 , -CH(halo)2, -CH 2 (halo), -(CI-C 6 )alkyl, halo(Ci-C 6 )alkyl-, -(C-C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, C(=O), NH 2 , -NH(Ci-C 6 )alkyl, CN, SH and OR 4 ; R 3 is selected from hydrogen, -(C I-C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, OH, hydroxyl(CI-C 6 )alkyl-, C(=0), -(C(halo) 3 , -CH(halo) 2 , and -CH 2 (halo); R 4 is selected from the group consisting of -(CI-C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 15 C 6 )alkynyl, OH, hydroxy(CI-C 6 )alkyl-, -(C 3 -C 1 2)cycloalkyl, -(C 6 -CI4)bicycloalkyl, -(Cg C 2 0)tricycloalkyl, -(C 4 -C 1 2)cycloalkenyl, -(C 7 -CI4)bicycloalkenyl, -(Cs-C20)tricycloalkenyl, a (5- to 12-membered)aryl, a (5- to 12-membered)heteroaryl, a (3- to 12-membered)heterocycle, and a (7- to 12-membered)bicycloheterocycle; Z is (CH 2 )m; 20 Y is (CH 2 )n; m is an integer 1, 2, 3, 4, 5, or 6; n is an integer 0, 1, 2, 3, 4, 5 or 6 or a pharmaceutically acceptable salt, prodrug or solvate thereof 25 101. A compound according to claim 99 of Formula (IB): - 145- R' N R 3 0 02 z Y H 3 CO 0 OCH 3 (IB) wherein 5 R' is selected from the group consisting of -(Ci-Cio)alkyl, -(C 2 -C 1 2 )alkenyl, -(Cr C 1 2)alkynyl, -(C 3 -Cu 2 )cycloalkyl, -(C 4 -Cu2)cycloalkenyl, ((C 3 -C2)cycloalkyl)-(CI-C 6 )alkyl-, ((C 4 -C 12 )cycloalkenyl)-(CI-C 6 )alkyl-, a (5- to 12-membered)aryl, a (5- to 12 membered)heteroaryl, and a (3- to 12-membered)heterocycle; any of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 10 (CI-C 6 )alkyl, OH, halo, -C(halo) 3 , -CH(halo) 2 , CH 2 (halo), NH 2 , -NH(CI-C 6 )alkyl, CN and SH. R2 is selected from the group consisting of hydrogen, -(Ci-Cio)alkyl, -(C 2 -CI2)alkenyl, -(C 2 -Cu2)alkynyl, -(C 3 -C]2)cycloalkyl, -(C 4 -Cu 2 )cycloalkenyl, -(C6-CI 4 )bicycloalkyl, -(Cs. C2o)tricycloalkyl, -(C7-CI4)bicycloalkenyl, -(Cs-C20)tricycloalkenyl, a (5- to 12 membered)aryl, a (5- to 12-membered)heteroaryl, a (3- to 12-membered)heterocycle, or a (7 15 to 12-membered)bicycloheterocycle; any of which is optionally substituted with one or two substituents independently selected from the group consisting of OH, halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(Ci-C 6 )alkyl, halo(Ci-C 6 )alkyl-, -(C 2 -C 6 )alkenyl, (C2-C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, C(=O), NH 2 , -NH(Ci-C 6 )alkyl, CN, SH and OR 4 ; R 3 is selected from hydrogen, -(Ci-C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, OH, 20 hydroxyl(CI-C 6 )alkyl-, C(=O), -C(halo) 3 , -CH(halo) 2 , and -CH 2 (halo); R 4 is selected from the group consisting of -(Ci-C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 C 6 )alkynyl, OH, hydroxy(CI-C 6 )alkyl-, -(C 3 -C )cycloalkyl, -(C 6 -CI4)bicycloalkyl, -(Cs C20)tricycloalkyl, -(C 4 -C2)cycloalkenyl, -(C7-C4)bicycloalkenyl, -(Cs-C 20 )tricycloalkenyl, a (5- to 12-membered)aryl, a (5- to 12-membered)heteroaryl, a (3- to 12-membered)heterocycle, 25 and a (7- to 12-membered)bicycloheterocycle; Z is (CH 2 )mi; -146- Y is (CH 2 ),; m is an integer 1, 2, 3, 4, 5, or 6; n is an integer 0, 1, 2, 3, 4, 5 or 6 or a pharmaceutically acceptable salt, prodrug or solvate thereof. 5
102. The compound of according to any one of claims 99 to 101 wherein R' is optionally substituted -(CI-Cio)alkyl.
103. The compound of claim 102 wherein R' is selected from the group consisting of 10 methyl, ethyl, propyl, isopropyl, butyl and tert-butyl, and preferably methyl, each of which is optionally substituted.
104. The compound according to any of claims 99 to 101 wherein R, is optionally substituted -(C 2 -Cl 2 )alkenyl. 15
105. The compound of claim 104 wherein R' is selected from the group consisting of ethenyl and propenyl, each of which is optionally substituted.
106. The compound according to any of claims 99 to 101 wherein R' is optionally 20 substituted ((C 3 -Ci z)cycloalkyl)-(Ci-C 6 )alkyl-.
107. The compound of claim 106 wherein R' is selected from the group consisting of cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl, and preferably cyclopropylmethyl, each of which is optionally substituted. 25
108. The compound according to any one of claims 99 to 101 wherein Z is CH 2 .
109. The compound according to any one of claims 99 to 101 wherein Y is CH 2 . 30 110. The compound according to any one of claims 99 to 108 wherein Y is absent. 11. The compound according to any one of claims 99 to 109 wherein both Z and Y are CH 2 . - 147 -
112. The compound according to any one of claims 99 to 111 wherein R 2 is optionally substituted -(CI-CIo)alkyl.
113. The compound of claim 112 wherein R 2 is selected from the group consisting of 5 methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl, each of which is optionally substituted.
114. The compound according to any one of claims 99 to 111 wherein R 2 is optionally substituted -(C 2 -C 1 2 )alkenyl. 10
115. The compound of claim 114 wherein R 2 is selected from the group consisting of 2 methyl-but-2-enyl and propenyl, each of which is optionally substituted.
116. The compound according to any one of claims 99 to Il l wherein R 2 is optionally 15 substituted -(C2-C 12 )alkynyl.
117. The compound of claim 116 wherein R 2 is optionally substituted propynyl.
118. The compound of any one of claims 99 to 111 wherein R 2 is optionally substituted 20 (C 3 -CI 2 )cycloalkyl.
119. The compound according to any one of claims 99 to 111 wherein R 2 is an optionally substituted (5- to 12-membered)aryl. 25 120. The compound of claim 119 wherein R2 is optionally substituted phenyl.
121. The compound of claim 120 wherein R 2 is phenyl substituted with one or two substituents independently selected from the group consisting of OH, halo, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -(CI-C 6 )alkyl, halo(CI-C 6 )alkyl-, -(C 2 -C 6 )alkenyl, 30 -(C2-C 6 )alkynyl, hydroxy(CI-C 6 )alkyl-, C(=O), and OR 4 .
122. The compound according to any one of claims 99 to 121 wherein R 3 is hydrogen.
123. The compound according to any one of claims 99 to 121 wherein R 3 is OH. - 148-
124. The compound according to any one of claims 99 to 121 wherein R 3 is -(Cl C 6 )alkyl. 5 125. The compound of claim 124 wherein R 3 is selected from the group consisting of methyl, ethyl and isopropyl.
126. The compound according to any one of claims 99 to 121 wherein R 3 is -CH 2 (halo). 10 127. The compound of claim 126 wherein R 3 is selected from the group consisting of CH 2 F and CH 2 CI.
128. A compound according to any one of claims 1 to 127 selected from the group consisting of: 15 7a-(allyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 7a-(benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 7a-(propargyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 22-cyclopropyl-7a-(benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 22-cyclopropyl-7a-(allyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 20 22-cyclopropyl-7a-(propargyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; and a pharmaceutically acceptable salt, prodrug or solvate thereof.
129. A compound according to any one of claims I to 127 selected from the group consisting of: 25 2 2 -cyclopropyl-7ax-(cyclohexylmethoxymethyl)-6,14-endo-ethanotetrahydrothebaine; 22-cyclopropyl-7a-(4-chlorobenzyloxymethyl-6,14-endo-ethanotetrahydrothebaine; 2 2 -cyclopropyl-7a-((3,4-dichloro)benzyloxymethyl)-6,14-endo ethanotetrahydrothebaine; 2 2 -cyclopropyl-7ca-((4-trifluoromethyl)benzyloxymethyl)-6,14-endo 30 ethanotetrahydrothebaine; 7a-(cyclohexylmethoxymethyl)-6,14-endo-ethanotetrahydrothebaine; 7a-((4-trifluoromethyl)benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 7c-((2-naphthyl)methoxymethyl)-6,14-endo-ethanotetrahydrothebaine; -149- 7a-((3,4-dichloro)benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 7a-((3-methyl)benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 7a-((4-tert-butyl)benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 7a-((trans-3-phenylprop-2-enyl)oxymethyl)-6,14-endo-ethanotetrahydrothebaine; 5 and a pharmaceutically acceptable salt, prodrug or solvate thereof.
130. A compound according to any one of claims I to 127 selected from the group consisting of: 22-cyclopropyl-7a-((3-methylbenzyloxymethyl_6,14-endo 10 ethanotetrahydrothebaine; 22-cyclopropyl-7a-(2-napthylmethoxymethyl)-6,14-3ndo-ethanotetrahydrothebaine; 22-cyclopropyl-7c-((4-tert-butyl)benzyloxymethyl)-6,14-endo ethanotetrahydrothebaine; 22-cyclopropyl-7a-((3-phenylprop-2-cneyloxymethyl)-6,14-endo 15 ethanotetrahydrothebaine; 22-cyclopropyl-7a-((2-methyl)benzyloxymethyl)-6,14-endo ethanotetrahydrothebaine; 22-cyclopropyl-7a-(1 -napthylmethoxymethyl)-6,14-endo-ethanotetrahydrothebaine; 22-cyclopropyl-7a-(cyclobutylmethoxymethyl)-6,14-endo-ethanotetrahydrothebaine; 20 7a-((2-methyl)benzyloxymethyl)-6,1 4-endo-ethanotetrahydrothebaine; 7a-((4-pyridylmethoxymethyl)-6,14-endo-ethanotetrahydrothebaine; 7a-((4-tri fluoromethoxy)benzyloxymethyl)-6,1 4-endo-ethanotetrahydrothebaine; 7a-(1 -napthylmethoxymethyl)-6,14-endo-ethanotetrahydrothebaine; 7c-(cyclobutylmethoxymethyl)-6,14-endo-ethanotetrahydrothebaine; 25 7a-(3-methoxy)benzyloxymethyl)-6,14-endo-ethanotetrahydrothebaine; 7a-(benzyloxymethyl)-6,14-endoethanotetrahydrooripavine; 7a-(diphenylmethyloxymethyl)-3,6-dimethoxy-4,5a-epoxy- I 7-methyl-6a, I 4a ethano-morphinan; 17-cyclopropylmethyl-7a-(3-trifluoromethoxy)benzyloxymethyl-3,6-dimethoxy 30 4,5a-epoxy-6a, I 4ct-ethano-morphinan; 3,6-dimethoxy-4,5ct-epoxy- I 7-methyl-7a-(4-phenyl)benzyloxymethyl-6ca, I 4a ethano-morphinan; - 150- 17-cyclopropylmethyl-7a-(3-pyridyl)oxymethyl-3,6-dimethoxy-4,5a-epoxy-6a, 14a ethano-morphinan; 7a-(4-bromo)benzyloxymethyl-3,6-dimethoxy-4,5a-epoxy- I 7-methyl-6a, I 4cr ethano-morphinan; 5 7a-(1 -naphthylmethyloxymethyl)- 1 7-cyclopropyl-methyl-6-methoxy-4,5a-epoxy 6a, I 4a-ethano-morphinan; 7a-(4-methylbenzyloxymethyl)-3,6-dimethoxy-4,5a-epoxy- I 7-methyl-6a, 1 4a ethano-morphinan; 7a-benzyloxymethyl-3,6-dimethoxy-4,5a-epoxy-8p-methyl-1 7-n-methyl-6a, 14a 10 ethano-morphinan; 7a-(cyclooctylmethyl)-3,6-dimethoxy-4,5a-epoxy- 1 7-methyl-6a, 1 4a-ethano morphinan; and a pharmaceutically acceptable salt, prodrug or solvate thereof 15 131. A pharmaceutical composition comprising an effective amount of a compound according top any of claims I to 130, and a pharmaceutically acceptable carrier or excipient.
132. A method for modulating opioid receptor function in a cell, comprising contacting a 20 cell capable of expressing an opioid receptor with an effective amount of a compound according to any one of claims I to 130.
133. The method of claim 132 wherein the compound modulates p-opioid receptor function. 25
134. The compound of claim 132 wherein the compound acts as an agonist at the P-opioid receptor.
135. The method according to any one of claims 132 to 134 wherein the compound 30 modulates ORL-1 receptor function.
136. The method of claim 135 wherein the compound acts as an antagonist at the ORL-1 receptor. 35 137. The method of claim 136 wherein the compound has dual activity as an agonist at the p-opioid receptor and as an antagonist at the ORL-1 receptor. - 151 -
138. A method of treating pain in a mammal comprising administering to such mammal in need thereof an effective amount of a compound according to any one of claims I to 127. 5
139. A method for preparing a composition, comprising the step of admixing a compound or pharmaceutically acceptable derivative of the compound according to any one of claims 1 to 127, or a pharmaceutically acceptable salt, prodrug or solvate thereof, with a pharmaceutically acceptable carrier or excipient. 10
140. Use of a compound according to any one of claims I to 127 in the manufacture of a medicament useful for treating or preventing a Condition.
141. The use of claim 140 wherein the Condition is pain. 15
142. A method of treating a Condition in a mammal comprising administering to such mammal in need thereof an effective amount of a compound according to any one of claims I to 127, wherein the effective amount of the compound does not induce significant respiratory depression. 20
143. A method according to claim 152 wherein the Condition is pain.
144. A compound according to any one of claims I to 130 or a pharmaceutically acceptable salt, prodrug or solvate thereof for use in the treatment of pain. 25 - 152 -
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