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CA2372887A1 - Heterocyclic analgesic compounds and their use - Google Patents

Heterocyclic analgesic compounds and their use Download PDF

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Publication number
CA2372887A1
CA2372887A1 CA002372887A CA2372887A CA2372887A1 CA 2372887 A1 CA2372887 A1 CA 2372887A1 CA 002372887 A CA002372887 A CA 002372887A CA 2372887 A CA2372887 A CA 2372887A CA 2372887 A1 CA2372887 A1 CA 2372887A1
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alkyl
occurrence
aryl
heteroaryl
compound
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French (fr)
Inventor
Gregory D. Cuny
Liming Shao
James R. Hauske
Michele L. R. Heffernan
Brian M. Aquila
Xinhe Wu
Fengjiang Wang
Thomas D. Bannister
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Sunovion Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/42—Oxygen atoms attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
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    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/10—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

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  • Chemical Kinetics & Catalysis (AREA)
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  • Addiction (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Hydrogenated Pyridines (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

One aspect of the present invention relates to novel heterocyclic compounds. A second aspect of the present invention relates to the use of the novel heterocyclic compounds as ligands for various cellular receptors, including opiate receptors, other the G-protein coupled receptors, and ion channels. A n additional aspect of the present invention relates to the use of the novel heterocyclic compounds as analgesics.

Description

Heterocyclic Analgesic Compounds and Methods of Use Thereof Related Applications This application claims the benefit of priority to: United States Provisional Patent Application serial number 60/195,809, filed April 11, 2000; United States Provisional Patent Application serial number 60/168,979, filed December 3, 1999; and United States Provisional Patent Application serial number 60/135,721, filed May 25, 1999.
Background of the Invention Pain is an unpleasant sensation varying in severity in a local part of the body or several parts of the body resulting from injury, disease, or emotional disorder. Pain can be classified according to its duration. Acute pain, which lasts less than one month, usually has a readily identifiable cause and signals tissue damage. In addition, acute pain syndromes can be episodic, for example recurrent discomfort from arthritis. Chronic pain can be defined as pain that persists more than one month beyond the usual course of an acute illness or injury, or pain that recurs at intervals over months or years, or pain that is associated with a chronic pathologic process. In contrast to acute pain, chronic pain loses its adaptive biologic function. Depression is common, and abnormal illness behavior often compounds the patient's impairment.
Millions of people suffer from chronic or intractable pain. Persistent pain varies in etiology and presentation. In some cases, symptoms and signs may be evident within a few weeks to a few months after the occurrence of an injury or the onset of disease, e.g. cancer or AIDS. Like many illnesses that at one time were not well understood, pain and its many manifestations may be poorly treated and seriously underestimated.
Inappropriately treated pain seriously compromises the patient's quality of life, causing emotional suffering and increasing the risk of lost livelihood and disrupted social integration.
Severe chronic pain affects both the pediatric and adult population, and often leads to mood disorders, including depression and, in rare cases, suicide.
3o In the last several years, health policy-makers, health professionals, regulators, and the public have become increasingly interested in the provision of better pain therapies.
This interest is evidenced, in part, by the U.S. Department of Health and Human Services' dissemination of Clinical Practice Guidelines for the management of acute pain and cancer pain. There is currently no nationally accepted consensus for the treatment of chronic pain not due to cancer, yet the economic and social costs of chronic pain are substantial, with estimates ranging in the tens of billions of dollars annually.
Three general classes of drugs are currently available for pain management, nonsteriodal anti-inflammatories, opioids, and adjuvant analgesics. The nonsteriodal anti-inflammatories class includes drugs such as aspirin, ibuprofen, diclofenac, acetaminophen, celecoxib, and rofecoxib. The opioid class includes morphine, oxycodone, fentanyl, and pentazocine. Adjuvant analgesics include various antidepressants, anticonvulsants, neuroleptics, and corticosteroids.
1o Opioids are the major class of analgesics used in the management of moderate to severe pain because of their effectiveness, ease of titration, and favorable risk-to-benefit ratio. Opioids produce analgesia by binding to specific receptors both within and outside the CNS. Opioid analgesics are classified as full agonists, partial agonists, or mixed agonist-antagonists, depending on the receptors to which they bind and their intrinsic activities at each receptor.
Three subclasses of opioid receptor have been identified in humans, namely the 8-, K-, and ~-opioid receptors. Analgesia is thought to involve activation of ~
and/or K
receptors. Notwithstanding their low selectivity for p over K receptors, it is likely that morphine and morphine-like opioid agonists produce analgesia primarily through interaction 2o with ~ receptors; selective agonists of K receptors in humans produce analgesia, because rather than the euphoria associated with morphine and congeners, these compounds often produce dysphoria and psychotomimetic effects. The consequences of activating 8 receptors in humans remain unclear.
Although opioids can be very effective in pain management, they do cause several side effects, such as respiratory depression, constipation, physical dependence, tolerance, withdraw. These unwanted effects can severely limit their use.
Opioids are known to produce respiratory depression that is proportional to their analgesia. This respiratory depression can be life threatening. This results in a narrow range between the effective dose and a dose that produces respiratory depression. Because of this narrow therapeutic index, patients receiving opioid therapy must be closely monitored for signs of respiratory failure.
Opioids can also cause constipation in individuals receiving them. This side effect can be severe and may require prolonged hospitalization, or even surgical intervention.
Commonly used full agonists include morphine, hydromorphone, meperidine, methadone, levorphanol, and fentanyl. These opioids are classified as full agonists because there is not a ceiling to their analgesic efficacy, nor will they reverse or antagonize the effects of other opioids within this class when given simultaneously. Side effects include respiratory depression, constipation, nausea, urinary retention, confusion, and sedation.
Morphine is the most commonly used opioid for moderate to severe pain because of its availability in a wide variety of dosage forms, its well-characterized pharmacokinetics and to pharmacodynamics, and its relatively low cost. Meperidine may be useful for brief courses (e.g., a few days) to treat acute pain and to manage rigors (shivering) induced by medication, but it generally should be avoided in patients with cancer because of its short duration of action (2.5 to 3.5 hours) and its toxic metabolite, normeperidine.
This metabolite accumulates, particularly when renal function is impaired, and causes CNS
stimulation, which may lead to dysphoria, agitation, and seizures; meperidine, therefore, should not be used if continued opioid use is anticipated.
The development of physical dependence with repeated use is a characteristic feature of the opioid drugs, and the possibility of developing drug dependence is one of the major limitations of their clinical use. Almost all opioid users rapidly develop drug dependency 2o which can lead to apathy, weight loss, loss of sex drive, anxiety, insomnia, and drug cravings. Although physical dependence is common, addiction and abuse are not common in pain patients who are treated appropriately with opioid drugs.
Historically, the development of analgesic tolerance was believed to limit the ability to use opioids efficaciously on a long-term basis for pain management.
Tolerance, or decreasing pain relief with the same dosage over time, has not proven to be a prevalent limitation to long-term opioid use. Experience with treating cancer pain has shown that what initially appears to be tolerance is usually progression of the disease.
Furthermore, for most opioids, there does not appear to be an arbitrary upper dosage limit, as was once thought.
Cessation of opioid administration may result in a withdrawal syndrome.
Symptoms of withdrawal are often the opposite of the effects achieved by the drug;
withdrawal from morphine, however, results in complex symptoms that may seem unrelated to its effects.
Misunderstanding of addiction and mislabeling of patients as addicts result in unnecessary withholding of opioid medications. Addiction is a compulsive disorder in which an individual becomes preoccupied with obtaining and using a substance, the continued use of which results in a decreased quality of life. Studies indicate that the de novo development of addiction is low when opioids are used for the relief of pain. Furthermore, even opioid addicts can benefit from the carefully supervised, judicious use of opioids for the treatment of pain due to cancer, surgery, or recurrent painful illnesses such as sickle cell disease.
The known opioids have been very effective in pain management. However, they have restricted use because of several potentially severe side effects.
Therefore, there is a to current need for pharmaceutical agents that retain the analgesic properties of the known opioid, but that have reduced side effect profiles.
Summary of the Invention One aspect of the present invention relates to novel heterocyclic compounds. A
second aspect of the present invention relates to the use of the novel heterocyclic compounds as ligands for various cellular receptors, including opiate receptors, other G-protein-coupled receptors, and ion channels. An additional aspect of the present invention relates to the use of the novel heterocyclic compounds as analgesics.
Brief Description of the Figures Figure 1 depicts schematically the combinatorial library described in Example 77, 2o and the reactants, reagents and conditions used to prepare it.
Figure 2 presents the EDsos for certain compounds of the present invention, morphine and fentanyl when administered i.v. to mice and rats (See Example 79).
Figure 3 depicts the changes in p02 and pC02 levels in rats caused by the i.v.
administration of certain compounds of the present invention, morphine and fentanyl.
Changes in these blood gases can be used as an indication of respiratory depression in the rats.
Detailed Description of the Invention Pain is an unpleasant sensation varying in severity in a local part of the body or several parts of the body resulting from injury, disease, or emotional disorder. Pain can be 3o classified according to its duration. Acute pain, which lasts less than one month, usually has a readily identifiable cause (e.g., hip fracture) and signals tissue damage.
The associated effect is often anxiety, and the concomitant physiologic findings are those of sympathetic stimulation (e.g., tachycardia, tachypnea, diaphoresis). In addition, acute pain syndromes can be episodic, for example recurrent discomfort from arthritis.
Chronic pain can be defined as pain that persists more than one month beyond the usual course of an acute illness or injury, or pain that recurs at intervals over months or years, or pain that is associated with a chronic pathologic process. In contrast to acute pain, chronic pain loses its adaptive biologic function. Depression is common, and abnormal illness behavior often compounds the patient's impairment. Chronic pain can be divided broadly into that which is inferred to be predominantly somatogenic and that which is inferred to be predominantly psychogenic. A similar classification based on inferred 1o pathophysiology designates chronic pain as nociceptive (commensurate with ongoing activation of pain-sensitive nerve fibers), neuropathic (due to aberrant somatosensory processing in afferent neural pathways), or psychogenic.
Nociceptive pain can be somatic or visceral. Most chronic pain in the elderly is nociceptive and somatic; arthritis, cancer pain, and myofascial pain are most common.
Relief is likely with removal of the peripheral cause (e.g., reducing periarticular inflammation), and analgesic drugs are often effective.
A common subtype of neuropathic pain, known collectively as peripheral neuropathic pain, is presumably sustained by mechanisms that involve disturbances in the peripheral nerve or nerve root; neuroma formation after axonal injury and nerve 2o compression are the two major processes. Another subtype of neuropathic pain is related to the reorganization of nociceptive information processing by the CNS; it persists without ongoing activation of pain-sensitive fibers. This type of pain, known collectively as the deafferentation syndromes, includes postherpetic neuralgia, central pain (which can result from a lesion at any level of the CNS), phantom limb pain, and others. A third subtype of neuropathic pain, often called sympathetically maintained pain, can be ameliorated by interruption of sympathetic nerves to the painful area; the prototypic disorder is reflex sympathetic dystrophy. The precise mechanisms involved in these disorders are conjectural, but all can produce an unfamiliar pain, often described as burning and stabbing. Currently, this type of pain responds poorly to analgesics.
3o Some patients have persistent pain without either nociceptive foci or evidence of a neuropathic mechanism for the pain. Many others have nociceptive lesions that do not sufficiently explain the degree of pain and disability. Psychopathologic processes account for these complaints in some patients. If no evidence for a psychological cause is found, the pain is referred to as idiopathic. Many patients have an idiopathic pain syndrome that is best described by the generic diagnosis chronic nonmalignant pain syndrome, a term denoting pain and disability disproportionate to an identifiable somatic cause and usually related to a more pervasive set of abnormal illness behaviors. Some of these patients may be labeled by the more formal psychiatric diagnosis of somatoform pain disorder. Others have complaints that constitute a specific pain diagnosis, most commonly the failed low back syndrome or atypical facial pain. Still others have significant organic lesions (e.g., lumbar arachnoiditis) but also have a clear psychological contribution associated with excessive disability.
1o Diagnosis may be difficult, but the relative contributions of both organic and psychological components of the pain can be defined.
Another clinically useful classification of chronic pain is broadly syndromic.
For example, chronic pain may be part of a medical illness (e.g., cancer or arthritis). A mixture of pathophysiologic mechanisms may be involved; e.g., tumor invasion of nerve and bone may cause neuropathic and somatic nociceptive pains, respectively, and psychological factors may be prominent.
Three general classes of drugs are currently available for pain management, nonsteriodal anti-inflammatories, opioids, and adjuvant analgesics. The nonsteriodal anti-inflammatories class includes drugs such as aspirin, ibuprofen, diclofenac, acetaminophen, 2o and rofecoxib. The opioid class includes morphine, oxycodone, fentanyl, and pentazocine.
Adjuvant analgesics include various antidepressants, anticonvulsants, neuroleptics, and corticosteroids.
Of the three classes of pharmaceutical agents used for pain management, opioid are usually most efficacious for treating moderate to severe pain. Although opioids can be very effective in pain management, they do cause several side effects, such as respiratory depression, constipation, physical dependence, tolerance, withdraw. These unwanted effects can severely limit their use. Therefore, there is a current need for pharmaceutical agents that retain the analgesic properties of the known opioid, but have reduced side effect profiles for the treatment of pain.
3o Opioids, specifically ligands for the p-opioid receptor, are the major class of analgesics used in the management of moderate to severe pain because of their effectiveness, ease of titration, and favorable risk-to-benefit ratio.
Unfortunately, the opioids currently available have several unwanted side-effects, such as respiratory depression and constipation. In addition, these agents may lead to tolerance and dependence. Research into the development of new, selective ligands for opioid receptors holds the promise of yielding potent analgesics that lack the side effects of morphine and its congeners. Applicants herein disclose novel analgesics, including selective ligands for opioid receptors. Individual compounds described herein promise to have agonistic, antagonistic, and hybrid effects on opioid and other cellular receptors.
Additionally, new compounds reported herein may possess analgesic properties free from respiratory depression and the potential for physical dependence associated with ~-opioid receptor to ligands, such as morphine and fentanyl. Moreover, new compounds reported herein may possess properties for the treatment of physical or psychological additions, psychiatric disorders, and neurological pathologies, such as tinnitus.
The ~-opioid receptor is a member of a family of cell surface proteins that permit intracellular transduction of extracellular signals. Cell surface proteins provide eukaryotic and prokaryotic cells a means to detect extracellular signals and transduce such signals intracellularly in a manner that ultimately results in a cellular response or a concerted tissue or organ response. Cell surface proteins, by intracellularly transmitting information regarding the extracellular environment via specific intracellular pathways induce an appropriate response to a particular stimulus. The response may be immediate and transient, 2o slow and sustained, or some mixture thereof. By virtue of an array of varied membrane surface proteins, eukaryotic cells are exquisitely sensitive to their environment.
Extracellular signal molecules, such as growth hormones, vasodilators and neurotransmitters, exert their effects, at least in part, via interaction with cell surface proteins. For example, some extracellular signal molecules cause changes in transcription of target gene via changes in the levels of secondary messengers, such as cAMP.
Other signals, indirectly alter gene expression by activating the expression of genes, such as immediate-early genes that encode regulatory proteins, which in turn activate expression of other genes that encode transcriptional regulatory proteins. For example, neuron gene expression is modulated by numerous extracellular signals, including neurotransmitters and membrane ~o electrical activity. Transsynaptic signals cause rapid responses in neurons that occur over a period of time ranging from milleseconds, such as the opening of ligandgated channels, to seconds and minutes, such as second messenger-mediated events. Genes in neural cells that are responsive to transsynaptic stimulation and membrane electrical activity, include genes, called immediate early genes, whose transcription is activated rapidly, within minutes, and transiently (see, e.g., Sheng et al. (1990) Neuron 4: 477-485), and genes whose expression requires protein synthesis and whose expression is induced or altered over the course of hours.
Cell surface receptors and ion channels are among the cell surface proteins that respond to extracellular signals and initiate the events that lead to this varied gene expression and response. Ion channels and cell surface-localized receptors are ubiquitous and physiologically important cell surface membrane proteins. They play a central role in regulating intracellular levels of various ions and chemicals, many of which are important 1 o for cell viability and function.
Cell surface-localized receptors are membrane spanning proteins that bind extracellular signalling molecules or changes in the extracellular environment and transmit the signal via signal transduction pathways to effect a cellular response.
Cell surface receptors bind circulating signal polypeptides, such as neurotransmitters, growth factors and hormones, as the initiating step in the induction of numerous intracellular pathways.
Receptors are classified on the basis of the particular type of pathway that is induced.
Included among these classes of receptors are those that bind growth factors and have intrinsic tyrosine kinase activity, such as the heparin binding growth factor (HBGF) receptors, and those that couple to effector proteins through guanine nucleotide binding 2o regulatory proteins, which are referred to as G protein coupled receptors and G proteins, respectively.
The G protein transmembrane signaling pathways consist of three proteins:
receptors, G proteins and effectors. G proteins, which are the intermediaries in transmembrane signaling pathways, are heterodimers and consist of alpha , beta and gamma subunits. Among the members of a family of G proteins the alpha subunits differ. Functions of G proteins are regulated by the cyclic association of GTP with the alpha subunit followed by hydrolysis of GTP to GDP and dissociation of GDP.
G protein coupled receptors are a diverse class of receptors that mediate signal transduction by binding to G proteins. Signal transduction is initiated via ligand binding to 3o the cell membrane receptor, which stimulates binding of the receptor to the G protein. The receptor G protein interaction releases GDP, which is specifically bound to the G protein, and permits the binding of GTP, which activates the G protein. Activated G
protein _g_ dissociates from the receptor and activates the effector protein, which regulates the intracellular levels of specific second messengers. Examples of such effector proteins include adenyl cyclase, guanyl cyclase, phospholipase C, and others.
G protein-coupled receptors, which are glycoproteins, are known to share certain structural similarities and homologies (see, e-g., Gilman, A.G., Ann. Rev.
Biochem.56: 615-649 (1987), Strader, C.D. et al. The FASEB Journal 3: 1825-1832 (1989), Kobilka, B.K., et al. Nature 329:75-79 (1985) and Young et al. Cell 45: 711-719 (1986)). Among the G
protein-coupled receptors that have been identified and cloned are the substance P receptor, the angiotensin receptor, the alpha - and beta -adrenergic receptors and the serotonin to receptors. G protein-coupled receptors share a conserved structural motif.
The general and common structural features of the G protein-coupled receptors are the existence of seven hydrophobic stretches of about 20-25 amino acids each surrounded by eight hydrophilic regions of variable length. It has been postulated that each of the seven hydrophobic regions forms a transmembrane alpha helix and the intervening hydrophilic regions form alternately intracellularly and extracellularly exposed loops. The third cytosolic loop between transmembrane domains five and six is the intracellular domain responsible for the interaction with G proteins.
G protein-coupled receptors are known to be inducible. This inducibility was originally described in lower eukaryotes. For example, the cAMP receptor of the cellular 2o slime mold, Dictyostelium, is induced during differentiation (Klein et al., Science 241:
1467-1472 (1988). During the Dictyostelium discoideum differentiation pathway, cAMP, induces high level expression of its G protein-coupled receptor. This receptor transducer the signal to induce the expression of the other genes involved in chemotaxis, which permits multicellular aggregates to align, organize and form stalks (see, Firtel, R.A., et al. Cell 58:
235-239 (1989) and Devreotes, P., Science 245: 1054-1058 (1989)).
De anitions For convenience, certain terms employed in the specification, examples, and appended claims are collected here.
The abbreviation "CNS" refers to the central nervous system of an organism.
The term "cell surface proteins" includes molecules that occur on the surface of cells, interact with the extracellular environment, and transmit or transduce information regarding the environment intracellularly.
The term "extracellular signals" includes a molecule or a change in the environment that is transduced intracellularly via cell surface proteins that interact, directly or indirectly, with the signal. An extracellular signal is any compound or substance that in some manner specifically alters the activity of a cell surface protein. Examples of such signals include, but are not limited to, molecules such as acetylcholine, growth factors, hormones and other mitogenic substances, such as phorbol mistric acetate (PMA), that bind to cell surface receptors and ion channels and modulate the activity of such receptors and channels.
1o Extracellular signals also includes as yet unidentified substances that modulate the activity of a cell surface protein and thereby affect intracellular functions and that are potential pharmacological agents that may be used to treat specific diseases by modulating the activity of specific cell surface receptors.
The term "EDS°" means the dose of a drug which produces 50% of its maximum response or effect. Alternatively, the dose which produces a pre-determined response in 50% of test subjects or preparations.
The term "LDS°" means the dose of a drug which is lethal in 50% of test subjects.
The term "therapeutic index" refers to the therapeutic index of a drug defined as LDSO/EDSO~
The term "structure-activity relationship (SAR)" refers to the way in which altering the molecular structure of drugs alters their interaction with a receptor, enzyme, etc.
The term "agonist" refers to a compound that mimics the action of natural transmitter or, when the natural transmitter is not known, causes changes at the receptor complex in the absence of other receptor ligands.
The terms "inverse agonist" and "negative antagonist" refer to compounds that are selective ligands for an inactive form of a cellular receptor which exists as an equilibrating mixture of active and inactive forms.
The term "antagonist" refers to a compound that binds to a receptor site, but does not cause any physiological changes unless another receptor ligand is present.
3o The term "competitive antagonist" refers to a compound that binds to a receptor site;
its effects can be overcome by increased concentration of the agonist.
-lo-The term "partial agonist" refers to a compound that binds to a receptor site but does not produce the maximal effect regardless of its concentration.
The term "ligand" refers to a compound that binds at the receptor site.
The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
The term "electron-withdrawing group" is recognized in the art, and denotes the tendency of a substituent to attract valence electrons from neighboring atoms, i.e., the substituent is electronegative with respect to neighboring atoms. A
quantification of the level of electron-withdrawing capability is given by the Hammett sigma (6) constant. This well known constant is described in many references, for instance, J. March, Advanced Orsanic Chemistry, McGraw Hill Book Company, New York, (1977 edition) pp. 251-259.
The Hammett constant values are generally negative for electron donating groups (a[P] _ -0.66 for NH2) and positive for electron withdrawing groups (~[P] = 0.78 for a vitro group), a[P] indicating para substitution. Exemplary electron-withdrawing groups include vitro, acyl, formyl, sulfonyl, trifluoromethyl, cyano, chloride, and the like.
Exemplary electron-donating groups include amino, methoxy, and the like.
The term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl 2o substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C3p for straight chain, C3-C30 for branched chain), and more preferably or fewer. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
Moreover, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a vitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), CF3, -CN and the like. Exemplary substituted alkyls are described below.
Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.
The term "aralkyl", as used herein, refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Preferred alkyl groups are lower alkyls. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl.
The term "aryl" as used herein includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics."
The aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, vitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, 3o carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, or the like. The term "aryl"
also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
The terms "heterocyclyl" or "heterocyclic group" refer to 3- to 10-membered ring structures, more preferably 3- to 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can also be polycycles. Heterocyclyl groups include, for 1o example, azetidine, azepine, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, vitro, sulfhydryl, imino, amido, 2o phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
The terms "polycyclyl" or "polycyclic group" refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings".
Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, vitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, 3o ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.

The term "carbocycle", as used herein, refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.
As used herein, the term "nitro" means -N02; the term "halogen" designates -F, -Cl, -Br or -I, the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" means -S02-.
The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the general formula:
R' io Rio ~ +
or °N~ Rio wherein R9, Rl p and R' 1 p each independently represent a hydrogen, an alkyl, an alkenyl, l o -(CH2)m-Rg, or R9 and Rl p taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; Rg represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In preferred embodiments, only one of R9 or Rlp can be a carbonyl, e.g., R9, Rlp and the nitrogen together do not form an imide. In even more preferred embodiments, R9 and Rl p (and optionally R' 1 p) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2)m-Rg. Thus, the term "alkylamine" as used herein means an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R9 and Rlp is an alkyl group.
The term "acylamino" is art-recognized and refers to a moiety that can be 2o represented by the general formula:
O

wherein R, is as defined above, and R'l1 represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-Rg, where m and Rg are as defined above.
The term "amido" is art recognized as an amino-substituted carbonyl and includes a moiety that can be represented by the general formula:

O
,R9 N
Rio wherein R9, Rlp are as defined above. Preferred embodiments of the amide will not include imides which may be unstable.
The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In preferred embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2)m-Rg, wherein m and Rg are defined above. Representative alkylthio groups include methylthio, ethyl thio, and the like.
The term "carbonyl" is art recognized and includes such moieties as can be represented by the general formula:
~X-Rm ~ or-X~R , m wherein X is a bond or represents an oxygen or a sulfur, and R11 represents a hydrogen, an alkyl, an alkenyl, -(CH2)m-Rg or a pharmaceutically acceptable salt, R'11 represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-Rg, where m and Rg are as defined above.
Where X is an oxygen and R11 or R'I1 is not hydrogen, the formula represents an "ester".
Where X is an oxygen, and R11 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when RI1 is a hydrogen, the formula represents a "carboxylic acid". Where X is an oxygen, and R'11 is hydrogen, the formula represents a "formate". In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiolcarbonyl" group. Where X is a sulfur and R11 or R'11 is not 2o hydrogen, the formula represents a "thiolester." Where X is a sulfur and RI
I is hydrogen, the formula represents a "thiolcarboxylic acid." Where X is a sulfur and R1 I' is hydrogen, the formula represents a "thiolformate." On the other hand, where X is a bond, and R11 is not hydrogen, the above formula represents a "ketone" group. Where X is a bond, and R11 is hydrogen, the above formula represents an "aldehyde" group.
The terms "alkoxyl" or "alkoxy" as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(CH2)m-Rg, where m and Rg are described above.
The term "sulfonate" is art recognized and includes a moiety that can be represented by the general formula:
O
I I
-g- OR41 O
in which R41 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. The terms triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, p-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
The term "sulfate" is art recognized and includes a moiety that can be represented by the general formula:
O
I I
O- i-OR4i O
in which R41 is as defined above.

The term "sulfonamido" is art recognized and includes a moiety that can be represented by the general formula:
O
I I
~i~~l-R~m R O

in which Rg and R' 11 are as defined above.
The term "sulfamoyl" is art-recognized and includes a moiety that can be represented by the general formula:
Rio -S-N
II ~R

in which Rg and Rlp are as defined above.
The term "sulfonyl", as used herein, refers to a moiety that can be represented by the 1 o general formula:
O
I I
S-R~
O
in which R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
The term "sulfoxido" as used herein, refers to a moiety that can be represented by the general formula:
O
I I
-S~R44 in which R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.
A "phosphoryl" can in general be represented by the formula:

y Ii -p I
~R4 6 wherein Ql represented S or O, and R46 represents hydrogen, a lower alkyl or an aryl.
When used to substitute, e.g., an alkyl, the phosphoryl group of the phosphorylalkyl can be represented by the general formula:
y y II II
p-~- -Qz p~ OR46 or ~R46 ~R46 wherein Q1 represented S or O, and each R46 independently represents hydrogen, a lower alkyl or an aryl, Q2 represents O, S or N. When Ql is an S, the phosphoryl moiety is a "phosphorothioate".
A "selenoalkyl" refers to an alkyl group having a substituted seleno group attached 1o thereto. Exemplary "selenoethers" which may be substituted on the alkyl are selected from one of -Se-alkyl, -Se-alkenyl, -Se-alkynyl, and -Se-(CH2)m R~, m and R~ being defined above.
Analogous substitutions can be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.
As used herein, the definition of each expression, e.g. alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
It will be understood that "substitution" or "substituted with" includes the implicit 2o proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
The phrase "protecting group" as used herein means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
to Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M.
Protective Groups in Organic Synthesis, 2°d ed.; Wiley: New York, 1991 ).
Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in 2o this invention.
If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, it may be isolated using chiral chromatography methods, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
3o Contemplated equivalents of the compounds described above include compounds which otherwise correspond thereto, and which have the same general properties thereof (e.g., functioning as analgesics), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound in binding to opioid receptors. In general, the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.
For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. Also for purposes of this invention, the term "hydrocarbon" is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom. In a broad aspect, the permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds which can be substituted or unsubstituted.
Compounds of the Invention.
In certain embodiments, the compounds of the present invention are represented by A:

X C
CH2 I y N R2 n Rs R~
N
CCR5Rs) m Ra A
wherein m is l, 2, 3 or 4;
n is 1 or 2;
y is 1, or 2;
R, represents alkyl, aryl, heteroaryl, or cycloalkyl;
RZ represents independently for each occurrence H, alkyl, fluoroalkyl, aryl, heteroaryl, or cycloalkyl;

R, and R, may be connected through a covalent bond;
R3 represents independently for each occurrence H, alkyl, aryl, OR2, OC(O)R2, CH,ORZ, or COzR2; wherein any two instances of R3 may be connected by a covalent tether whose backbone consists of 1, 2, 3, or 4 carbon atoms;
R4 represents independently for each occurrence H, alkyl, aryl, heteroaryl, alkenyl, or cycloalkyl;
RS represents independently for each occurrence H, alkyl, CHZY, aryl, heteroaryl, F, OR2, or OC(O)Rz;
R6 represents independently for each occurrence H, alkyl, CHZY, aryl, heteroaryl, F, to ORZ, or OC(O)R2;
Y represents independently for each occurrence ORZ, N(RZ)2, SRZ, S(O)R2, S(O)ZR2, or P(O)(ORZ)2;
a covalent bond may connect R4 and an instance of RS or R6 that is attached to the carbon chain between R4 and the ring nitrogen explicitly shown in A;
any two geminal or vicinal instances of RS and R6 may be connected through a covalent bond;
X represents C(R3)2, O, S, SO, SO2, NRz, NC(O)ORZ, or C=O; and the stereochemical configuration at any stereocenter of a compound represented by A is R, S, or a mixture of these configurations.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)Z, O, NRZ, or C=O.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)2, O, or NR2.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3),.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein m is 2 or 3.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein n is 1.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein y is 1.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein RZ represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein R3 represents independently for each occurrence H
or alkyl.
to In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein RQ represents cycloalkyl, aryl, or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)Z, O, NR2, or C=O; and n is 1.
2o In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)2, O, or NRZ; and n is 1.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)Z; and n is 1.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)2, O, NR2, or C=O; and y is 1.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)Z, O, or NR2; and y is 1.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)z; and y is 1.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)2, O, NRZ, or C=O; and R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)2, O, or NR2; and R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)2; and R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)2, O, NRz, or C=O; and Rz represents l0 independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)Z, O, or NRz; and RZ
represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by i5 A and the attendant definitions, wherein X is C(R3)2; and RZ represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)Z, O, NRz, or C=O; n is 1;
and R, represents aryl or heteroaryl.
2o In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)2, O, or NRZ; n is 1; and R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)Z; n is 1; and R, represents aryl or 25 heteroaryl.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)Z, O, NRZ, or C=O; n is l;
R, represents aryl or heteroaryl; and R, represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by 3o A and the attendant definitions, wherein X is C(R3)2, O, or NR2; n is 1; R, represents aryl or WO 00/71518 PCT/~JS00/14579 heteroaryl; and Rz represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)z; n is 1; R, represents aryl or heteroaryl;
and RZ represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)z, O, NR2, or C=O; n is 1;
R, represents aryl or heteroaryl; Rz represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
In certain embodiments, the compounds of the present invention are represented by 1o A and the attendant definitions, wherein X is C(R3)2, O, or NRZ; n is 1; R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)2; n is 1; R, represents aryl or heteroaryl;
RZ represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)z, O, NR2, or C=O; n is l;
R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; R3 represents 2o independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)2, O, or NRZ; n is 1; R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)2; n is 1; R, represents aryl or heteroaryl;
R~ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)2, O, NR2, or C=O; n is 1;
R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl;
and RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)Z, O, or NRz; n is l; R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl;
and RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
to In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)2; n is l; R, represents aryl or heteroaryl;
RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; and RS
represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)2, O, NR2, or C=O; n is l;
R, represents aryl or heteroaryl; Rz represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl;
RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 2o represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)2, O, or NR2; n is l; R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl;
RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)2; n is l; R, represents aryl or heteroaryl;
RZ represents independently for each occurrence alkyl; R3 represents independently for each 3o occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.

In certain embodiments, the compounds of the present invention are represented by A and the attendant definitions, wherein X is C(R3)2; m is 2; n is l; R, represents aryl; RZ
represents independently for each occurrence alkyl; R3 represents independently for each occurrence H; R4 represents aryl; RS represents independently for each occurrence H or alkyl; and R6 represents independently for each occurrence H or alkyl.
In assays based on opioid receptors from mammalian brain, certain compounds according to general structure A have ICso values less than 10 ~M against at least one subclass of opioid receptor, more preferably less than 5 p,M, and most preferably less than 1 i o p,M.
In certain embodiments, the compounds of the present invention are represented by B:
R~

n O
N
(CR5R6) m is B
wherein m is 1, 2, 3 or 4;
n is 1 or 2;
R, represents H, alkyl, aryl, heteroaryl, or cycloalkyl;
2o Rz represents independently for each occurrence H, alkyl, fluoroalkyl, aryl, heteroaryl, or cycloalkyl;
R, and RZ may be connected through a covalent bond;
R3 represents independently for each occurrence H, alkyl, aryl, OR2, OC(O)R2, CHZOR2, or COzRz; wherein any two instances of R3 may be connected by a covalent tether 25 whose backbone consists of 1, 2, 3, or 4 carbon atoms;

R4 represents independently for each occurrence H, alkyl, aryl, heteroaryl, alkenyl, or cycloalkyl;
RS represents independently for each occurrence H, alkyl, CHZY, aryl, heteroaryl, F, ORz, or OC(O)Rz;
R6 represents independently for each occurrence H, alkyl, CHZY, aryl, heteroaryl, F, ORz, or OC(O)Rz;
Y represents independently for each occurrence ORz, N(Rz)z, SRz, S(O)Rz, S(O)zRz, or P(O)(ORz)z;
a covalent bond may connect R4 and an instance of RS or R6 that is attached to the to carbon chain between R4 and the ring nitrogen explicitly shown in B;
any two geminal or vicinal instances of RS and R6 may be connected through a covalent bond;
X represents C(R3)z, O, S, SO, SOz, NRz, NC(O)ORz, or C=O; and the stereochemical configuration at any stereocenter of a compound represented by B
isRorS.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)z, O, NRz, or C=O.
In certain embodiments, the compounds of the present invention are represented by 2o B and the attendant definitions, wherein X is C(R3)z, O, or NRz.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)z.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein m is 2 or 3.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein n is 1.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by 3o B and the attendant definitions, wherein Rz represents independently for each occurrence alkyl.

In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein R3 represents independently for each occurrence H
or alkyl.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein R4 represents cycloalkyl, aryl, or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by to B and the attendant definitions, wherein R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)z, O, NRZ, or C=O; and n is 1.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)2, O, or NRZ; and n is 1.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)z; and n is 1.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)2, O, NRZ, or C=O; and R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)Z, O, or NR2; and R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)z; and R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)2, O, NRZ, or C=O; and RZ
represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by 3o B and the attendant definitions, wherein X is C(R3)Z, O, or NR2; and RZ
represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)2; and R, represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)~, O, NRZ, or C=O; n is 1;
and R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)Z, O, or NR2; n is 1; and R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)Z; n is 1; and R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)2, O, NRZ, or C=O; n is l;
R, represents aryl or heteroaryl; and RZ represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)2, O, or NR2; n is 1; R, represents aryl or heteroaryl; and RZ represents independently for each occurrence alkyl.
2o In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)z; n is 1; R, represents aryl or heteroaryl;
and Rz represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)2, O, NRz, or C=O; n is l;
R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)" O, or NR2; n is 1; R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; and R3 represents 3o independently for each occurrence H or alkyl.

In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)2; n is 1; R, represents aryl or heteroaryl;
R, represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)Z, O, NR2, or C=O; n is l;
R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)2, O, or NR2; n is l; R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)2; n is 1; R, represents aryl or heteroaryl;
RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)2, O, NR2, or C=O; n is l;
R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl;
and RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)2, O, or NR2; n is 1; R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl;
and RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by 3o B and the attendant definitions, wherein X is C(R3)2; n is 1; R, represents aryl or heteroaryl;
Rz represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; and RS
represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)2, O, NRZ, or C=O; n is 1;
R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl;
RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)Z, O, or NR2; n is 1; R, represents aryl or to heteroaryl; RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl;
RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by B and the attendant definitions, wherein X is C(R3)z; n is l; R, represents aryl or heteroaryl;
Rz represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; RS
represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In assays based on opioid receptors from mammalian brain, certain compounds according to general structure B have ICso values less than 10 ~M against at least one subclass of opioid receptor, more preferably less than 5 pM, and most preferably less than 1 ~,M.
In certain embodiments, the compounds of the present invention are represented by C:

R~
N RZ
~R6R5C~

N
i m ~CR5R6~
Ra C
wherein m is 1, 2, 3 or 4;
y is 0, 1 or 2;
R, represents H, alkyl, aryl, heteroaryl, or cycloalkyl;
Rz represents independently for each occurrence H, alkyl, fluoroalkyl, aryl, heteroaryl, or cycloalkyl;
R, and Rz may be connected through a covalent bond;
to R3 represents independently for each occurrence H, alkyl, aryl, ORz, OC(O)Rz, CHZORz, Or COZRz;
R4 represents H, alkyl, aryl, heteroaryl, alkenyl, or cycloalkyl;
RS represents independently for each occurrence H, alkyl, CHZY, aryl, heteroaryl, F, ORz, or OC(O)Rz;
is R6 represents independently for each occurrence H, alkyl, CHzY, aryl, heteroaryl, F, ORz, or OC(O)Rz;
Y represents independently for each occurrence ORz, N(Rz)z, SRz, S(O)Rz, S(O)zRz, or P(O)(ORz)z;
a covalent bond may connect R4 and an instance of RS or R6 that is attached to the 2o carbon chain between R4 and the ring nitrogen explicitly shown in C;
any two geminal or vicinal instances of RS and R6 may be connected through a covalent bond; and the stereochemical configuration at any stereocenter of a compound represented by C is R, S, or a mixture of these configurations.

In certain embodiments, the compounds of the present invention are represented by C and the attendant definitions, wherein m is 2 or 3.
In certain embodiments, the compounds of the present invention are represented by C and the attendant definitions, wherein y is 1.
In certain embodiments, the compounds of the present invention are represented by C and the attendant definitions, wherein R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by C and the attendant definitions, wherein RZ represents independently for each occurrence 1 o alkyl.
In certain embodiments, the compounds of the present invention are represented by C and the attendant definitions, wherein R3 represents independently for each occurrence H
or alkyl.
In certain embodiments, the compounds of the present invention are represented by C and the attendant definitions, wherein R4 represents cycloalkyl, aryl, or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by C and the attendant definitions, wherein RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by 2o C and the attendant definitions, wherein R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by C and the attendant definitions, wherein R, represents aryl or heteroaryl; and RZ represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by C and the attendant definitions, wherein R, represents aryl or heteroaryl; RZ
represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
In certain embodiments, the compounds of the present invention are represented by 3o C and the attendant definitions, wherein R, represents aryl or heteroaryl;
RZ represents WO 00/71518 PCT/iJS00/14579 independently for each occurrence alkyl; R3 represents independently for each occurrence H
or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by C and the attendant definitions, wherein R, represents aryl or heteroaryl; RZ
represents independently for each occurrence alkyl; R3 represents independently for each occurrence H
or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; and RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by C and the attendant definitions, wherein R, represents aryl or heteroaryl; Rz represents 1o independently for each occurrence alkyl; R3 represents independently for each occurrence H
or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In assays based on opioid receptors from mammalian brain, certain compounds according to general structure C have ICso values less than 10 ~.M against at least one subclass of opioid receptor, more preferably less than 5 ~M, and most preferably less than 1 p,M.
2o In certain embodiments, the compounds of the present invention are represented by D:
R~

\RsRSG/ y N
m ~CR5R6~

D
wherein m is 1, 2, 3 or 4;
y is 0, 1 or 2;
R, represents H, alkyl, aryl, heteroaryl, or cycloalkyl;
RZ represents independently for each occurrence H, alkyl, fluoroalkyl, aryl, heteroaryl, or cycloalkyl;
R, and RZ may be connected through a covalent bond;
R3 represents independently for each occurrence H, alkyl, aryl, ORZ, OC(O)R,, CHZORZ, or COZRz;
R4 represents H, alkyl, aryl, heteroaryl, alkenyl, or cycloalkyl;
to RS represents independently for each occurrence H, alkyl, CHZY, aryl, heteroaryl, F, OR2, or OC(O)R2;
R6 represents independently for each occurrence H, alkyl, CHZY, aryl, heteroaryl, F, OR2, or OC(O)Rz;
Y represents independently for each occurrence ORZ, N(RZ)2, SRZ, S(O)R"
S(O)ZRZ, or P(O)(ORZ)z;
a covalent bond may connect R4 and an instance of RS or R6 that is attached to the carbon chain between R4 and the ring nitrogen explicitly shown in D;
any two geminal or vicinal instances of RS and R6 may be connected through a covalent bond; and 2o the stereochemical configuration at any stereocenter of a compound represented by DisRorS.
In certain embodiments, the compounds of the present invention are represented by D and the attendant definitions, wherein m is 2 or 3 In certain embodiments, the compounds of the present invention are represented by D and the attendant definitions, wherein y is 1.
In certain embodiments, the compounds of the present invention are represented by D and the attendant definitions, wherein R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by D and the attendant definitions, wherein RZ represents independently for each occurrence alkyl.

In certain embodiments, the compounds of the present invention are represented by D and the attendant definitions, wherein R3 represents independently for each occurrence H
or alkyl.
In certain embodiments, the compounds of the present invention are represented by D and the attendant definitions, wherein R4 represents cycloalkyl, aryl, or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by D and the attendant definitions, wherein RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by to D and the attendant definitions, wherein R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by D and the attendant definitions, wherein R, represents aryl or heteroaryl; and Rz represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by D and the attendant definitions, wherein R, represents aryl or heteroaryl; RZ
represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
In certain embodiments, the compounds of the present invention are represented by 2o D and the attendant definitions, wherein R, represents aryl or heteroaryl;
RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H
or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by D and the attendant definitions, wherein R, represents aryl or heteroaryl; RZ
represents independently for each occurrence alkyl; R3 represents independently for each occurrence H
or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; and RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by D and the attendant definitions, wherein R, represents aryl or heteroaryl; RZ
represents 3o independently for each occurrence alkyl; R3 represents independently for each occurrence H
or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In assays based on opioid receptors from mammalian brain, certain compounds according to general structure D have ICso values less than 10 ~M against at least one subclass of opioid receptor, more preferably less than 5 ~M, and most preferably less than 1 ~M.
In certain embodiments, the compounds of the present invention are represented by 1o E:

HZC/ ° N
R~
N
~CR5R6) m E
wherein m is 1, 2, 3 or 4;
n is 1 or 2;
R, represents H, alkyl, aryl, heteroaryl, or cycloalkyl;
RZ represents independently for each occurrence H, alkyl, fluoroalkyl, aryl, heteroaryl, or cycloalkyl;
R, and RZ may be connected through a covalent bond;
2o R3 represents independently for each occurrence H, alkyl, aryl, OR2, OC(O)R2, CHZOR2, or COzR2; wherein any two instances of R3 may be connected by a covalent tether whose backbone consists of l, 2, 3, or 4 carbon atoms;
R4 represents H, alkyl, aryl, heteroaryl, alkenyl, or cycloalkyl;
RS represents independently for each occurrence H, alkyl, CH~Y, aryl, heteroaryl, F, ORz, or OC(O)R2;
R6 represents independently for each occurrence H, alkyl, CHZY, aryl, heteroaryl, F, ORz, or OC(O)Rz;
Y represents independently for each occurrence ORz, N(Rz)z, SRz, S(O)Rz, S(O)zRz, or P(O)(ORz)z;
a covalent bond may connect R4 and an instance of RS or R6 that is attached to the carbon chain between R4 and the ring nitrogen explicitly shown in E;
any two geminal or vicinal instances of RS and R6 may be connected through a covalent bond;
X represents C(R3)z, O, S, SO, SOz, NRz, NC(O)ORz, or C=O; and the stereochemical configuration at any stereocenter of a compound represented by E
l0 is R, S, or a mixture of these configurations.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)z, O, NRz, or C=O.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)z, O, or NRz.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)z.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein m is 2 or 3.
2o In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein n is 1.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein Rz represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein R3 represents independently for each occurrence H
or alkyl.
3o In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein R4 represents cycloalkyl, aryl, or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)2, O, NRZ, or C=O; and n is 1.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)2, O, or NR2; and n is 1.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)Z; and n is 1.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)Z, O, NRz, or C=O; and R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)2, O, or NR2; and R, represents aryl or heteroaryl.
2o In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)Z; and R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)2, O, NR2, or C=O; and RZ
represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3),, O, or NRZ; and RZ
represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)2; and Rz represents independently for 3o each occurrence alkyl.

In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)Z, O, NR2, or C=O; n is 1;
and R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by s E and the attendant definitions, wherein X is C(R3)2, O, or NRz; n is 1; and R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)Z; n is 1; and R, represents aryl or heteroaryl.
1o In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)2, O, NRZ, or C=O; n is l;
R, represents aryl or heteroaryl; and Rz represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)2, O, or NR2; n is 1; R, represents aryl or 15 heteroaryl; and Rz represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)z; n is l; R, represents aryl or heteroaryl;
and RZ represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by 2o E and the attendant definitions, wherein X is C(R3)Z, O, NRZ, or C=O; n is 1; R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)2, O, or NRZ; n is 1; R, represents aryl or 25 heteroaryl; RZ represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)Z; n is 1; R, represents aryl or heteroaryl;
R, represents independently for each occurrence alkyl; and R3 represents independently for 3o each occurrence H or alkyl.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)2, O, NR2, or C=O; n is 1;
R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)2, O, or NR2; n is 1; R, represents aryl or heteroaryl; Rz represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
1o In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)~; n is 1; R, represents aryl or heteroaryl;
RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)z, O, NRz, or C=O; n is 1;
R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl;
and RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by 2o E and the attendant definitions, wherein X is C(R3)2, O, or NRZ; n is l; R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl;
and RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)z; n is 1; R, represents aryl or heteroaryl;
RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; and RS
represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by 3o E and the attendant definitions, wherein X is C(R3)2, O, NR2, or C=O; n is 1; R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl;

WO 00/71518 PCT/~1500/14579 RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by E and the attendant definitions, wherein X is C(R3)Z, O, or NRZ; n is 1; R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl;
RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by to E and the attendant definitions, wherein X is C(R3)2; n is 1; R, represents aryl or heteroaryl;
RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; RS
represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In assays based on opioid receptors from mammalian brain, certain compounds according to general structure E have ICso values less than 10 ~M against at least one subclass of opioid receptor, more preferably less than 5 ~M, and most preferably less than 1 ~,M.
In certain embodiments, the compounds of the present invention are represented by F:

Rs C

Rs R~
N
\CRSRs/
I m Ra F

wherein m is 1, 2, 3 or 4;
y is 0, l, or 2;
R, represents H, alkyl, aryl, heteroaryl, or cycloalkyl;
Rz represents independently for each occurrence H, alkyl, fluoroalkyl, aryl, heteroaryl, or cycloalkyl;
R, and Rz may be connected through a covalent bond;
R3 represents independently for each occurrence H, alkyl, aryl, ORz, OC(O)Rz, CHZORz, or COzRz;
to R4 represents independently for each occurrence H, alkyl, aryl, heteroaryl, alkenyl, or cycloalkyl;
RS represents independently for each occurrence H, alkyl, CHZY, aryl, heteroaryl, F, ORz, or OC(O)Rz;
R6 represents independently for each occurrence H, alkyl, CHZY, aryl, heteroaryl, F, ORz, or OC(O)Rz;
Y represents independently for each occurrence ORz, N(Rz)z, SRz, S(O)Rz, S(O)zRz, or P(O)(ORz)z;
a covalent bond may connect R4 and an instance of RS or R6 that is attached to the carbon chain between R4 and the ring nitrogen explicitly shown in F;
2o any two geminal or vicinal instances of RS and R6 may be connected through a covalent bond;
X represents O, S, SO, SOz, NRz, NC(O)ORz, or C=O; and the stereochemical configuration at any stereocenter of a compound represented by F
is R, S, or a mixture of these configurations.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is O, NRz, or C=O.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is O or NRz.
3o In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is NRz.
In certain embodiments, the compounds of the present invention are represented by WO 00/71518 PCT/iJS00/14579 F and the attendant definitions, wherein m is 2 or 3.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein y is 1.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein RZ represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by 1o F and the attendant definitions, wherein R3 represents independently for each occurrence H
or alkyl.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein R4 represents cycloalkyl, aryl, or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
2o In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is O, NRZ, or C=O; and y is 1.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is O or NRZ; and y is 1.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is NR2; and y is 1.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is O, NR2, or C=O; and R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by 3o F and the attendant definitions, wherein X is O or NR2; and R, represents aryl or heteroaryl.

In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is NR2; and R, represents aryl or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is O, NR2, or C=O; and R, represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is O or NR,; and RZ represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by to F and the attendant definitions, wherein X is NR2; and RZ represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is O, NR2, or C=O; R, represents aryl or heteroaryl; and Rz represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is O or NRZ; R, represents aryl or heteroaryl; and Rz represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is NR2; R, represents aryl or heteroaryl; and R
2o represents independently for each occurrence alkyl.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is O, NR2, or C=O; R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is O or NRZ; R, represents aryl or heteroaryl; RZ
represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
In certain embodiments, the compounds of the present invention are represented by 3o F and the attendant definitions, wherein X is NRZ; R, represents aryl or heteroaryl; Rz represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is O, NRZ, or C=O; R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is O or NR2; R, represents aryl or heteroaryl; RZ
represents independently for each occurrence alkyl; R3 represents independently for each to occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is NR~; R, represents aryl or heteroaryl; RZ
represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is O, NR2, or C=O; R, represents aryl or heteroaryl; RZ represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl;
and R; represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is O or NRZ; R, represents aryl or heteroaryl; RZ
represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; and R;
represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is NRZ; R, represents aryl or heteroaryl; R, represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; and R;
represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
3o In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is O, NR,, or C=O; R, represents aryl or heteroaryl; R, represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl;
RS represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is O or NRZ; R, represents aryl or heteroaryl; RZ
represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; RS
represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents to independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In certain embodiments, the compounds of the present invention are represented by F and the attendant definitions, wherein X is NRZ; R, represents aryl or heteroaryl; Rz represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; RS
represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
In assays based on opioid receptors from mammalian brain, certain compounds according to general structure F have ICSO values less than 10 pM against at least one 2o subclass of opioid receptor, more preferably less than 5 ~,M, and most preferably less than 1 ~M.
In certain embodiments, the present invention relates to a compound represented by A, C, E, or F and the corresponding attendant defintions, wherein said compound is a single stereoisomer.
In certain embodiments, the present invention relates to a formulation, comprising a compound represented by A, B, C, D, E, or F and the corresponding attendant defintions;
and a pharmaceutically acceptable excipient.
In certain embodiments, the present invention relates to a method of treating pain, 3o drug addiction, or tinnitus in a mammal, comprising the step of administering to a mammal with pain, drug addiction, or tinnitus an effective amount of a formulation comprising a compound represented by A, B, C, D, E, or F and the corresponding attendant defintions;
and a pharmaceutically acceptable excipient. In certain embodiments of this method, said mammal is a primate, equine, canine or feline. In certain embodiments of this method, said mammal is a human. In certain embodiments of this method, said formulation is administered orally. In certain embodiments of this method, said formulation is administered intravenously. In certain embodiments of this method, said formulation is administered sublingually. In certain embodiments of this method, said formulation is administered ocularly.
to In certain embodiments, the present invention relates to ligands for G-protein-coupled or opioid receptors, wherein the ligands are represented by any of generalized structures A, B, C, D, E and F, and any of the sets of definitions associated with one of those structures. Preferably the ligands of the present invention are antagonists, agonists, partial agonists or inverse agonists of one or more G-protein-coupled or opioid receptor. In any event, the ligands of the present invention preferably exert their effect on the receptors at a concentration less than about 10 micromolar, more preferably at a concentration less than about 1 micromolar, and most preferably at a concentration less than 100 nanomolar.
In other embodiments, the ligands of the present invention bind to multiple families of G-protein-coupled receptors. In certain embodiments, the ligands of the present invention bind selectively to a single family of G-protein-coupled or opioid receptors. In other embodiments, the ligands of the present invention bind selectively to a subtype of receptor within a family of G-protein-coupled or opioid receptors.
In certain embodiments, the selectivity of a ligand for a specific family or subtype of receptor renders that ligand an effective therapeutic agent for an acute or chronic ailment, disease or malady. In certain embodiments, the selectivity of a ligand for a specific family or subtype of receptor consists of a binding affinity for that family or subtype of receptor at least a factor of ten greater than its binding affinity for other families or subtypes of G-protein-coupled or opioid receptors. In certain embodiments, the selectivity of a ligand for a specific family or subtype of receptor consists of a binding affinity for that family or 3o subtype of receptor at least a factor of one hundred greater than its binding affinity for other families or subtypes of G-protein-coupled or opioid receptors. In certain embodiments, the selectivity of a ligand for a specific family or subtype of receptor consists of a binding affinity for that family or subtype of receptor at least a factor of one thousand greater than its binding affinity for other families or subtypes of G-protein-coupled or opioid receptors.
The present invention contemplates pharmaceutical formulations (see below) of the ligands of the present invention. In certain embodiments, the pharmaceutical formulations will comprise ligands of the present invention that effect only a specific family or subtype of G-protein-coupled or opioid receptor, and thereby have a therapeutic effect on an acute or chronic ailment, disease or malady that is at least in part due to biochemical or physiological processes associated with the receptor(s). In certain embodiments, the pharmaceutical formulations will comprise ligands of the present invention that effect only a subtype of receptor, and thereby have a therapeutic effect on an acute or chronic ailment, disease or l0 malady that is at least in part due to biochemical or physiological processes associated with the specific subtype of receptor. The Background of the Invention (see above) teaches examples of acute or chronic ailments, diseases or maladies that are caused or exacerbated by biochemical or physiological processes associated with specific G-protein-coupled or opioid receptors. One of ordinary skill in the art will be able to accumulate, by reference to the scientific literature, a more comprehensive list of acute or chronic ailments, diseases or maladies that are caused or exacerbated by biochemical or physiological processes associated with specific G-protein-coupled or opioid receptors. The present invention contemplates pharmaceutical formulations of ligands of the present invention that will be of medicinal value against the aforementioned acute or chronic ailments, diseases or maladies.
Biochemical Activitv at Cellular Receptors. and Assays to Detect That Activity Assaying processes are well known in the art in which a reagent is added to a sample, and measurements of the sample and reagent are made to identify sample attributes stimulated by the reagent. For example, one such assay process concerns determining in a chromogenic assay the amount of an enzyme present in a biological sample or solution.
Such assays are based on the development of a colored product in the reaction solution. The reaction develops as the enzyme catalyzes the conversion of a colorless chromogenic substrate to a colored product.
Another assay useful in the present invention concerns determining the ability of a ligand to bind to a biological receptor utilizing a technique well known in the art referred to as a radioligand binding assay. This assay accurately determines the specific binding of a radioligand to a targeted receptor through the delineation of its total and nonspecific binding components. Total binding is defined as the amount of radioligand that remains following the rapid separation of the radioligand bound in a receptor preparation (cell homogenates or recombinate receptors) from that which is unbound. The nonspecific binding component is defined as the amount of radioligand that remains following separation of the reaction mixture consisting of receptor, radioligand and an excess of unlabeled ligand.
Under this condition, the only radioligand that remains represents that which is bound to components other that receptor. The specific radioligand bound is determined by subtracting the nonspecific from total radioactivity bound. For a specific example of radioligand binding assay for ~-opioid receptor, see Wang, J. B. et al. FEBS Letters 1994, 338, 217.
Assays useful in the present invention concern determining the activity of receptors to the activation of which initiates subsequent intracellular events in which intracellular stores of calcium ions are released for use as a second messenger. Activation of some G-protein coupled receptors stimulates the formation of inositol triphosphate (IP3, a G-protein-coupled receptor second messenger) through phospholipase C-mediated hydrolysis of phosphatidylinositol, Berridge and Irvine (1984). Nature 312:315-21. IP3 in turn stimulates the release of intracellular calcium ion stores.
A change in cytoplasmic calcium ion levels caused by release of calcium ions from intracellular stores is used to determine G-protein-coupled receptor function.
This is another type of indirect assay. Among G-protein-coupled receptors are muscarinic acetylcholine receptors (mAChR), adrenergic receptors, sigma receptors, serotonin receptors, dopamine 2o receptors, angiotensin receptors, adenosine receptors, bradykinin receptors, metabotropic excitatory amino acid receptors and the like. Cells expressing such G-protein-coupled receptors may exhibit increased cytoplasmic calcium levels as a result of contribution from both intracellular stores and via activation of ion channels, in which case it may be desirable although not necessary to conduct such assays in calcium-free buffer, optionally supplemented with a chelating agent such as EGTA, to distinguish fluorescence response resulting from calcium release from internal stores. Another type of indirect assay involves determining the activity of receptors which, when activated, result in a change in the level of intracellular cyclic nucleotides, e.g., cAMP, cGMP. For example, activation of some dopamine, serotonin, metabotropic glutamate receptors and muscarinic acetylcholine 3o receptors results in a decrease in the cAMP or cGMP levels of the cytoplasm.
Furthermore, there are cyclic nucleotide-gated ion channels, e.g., rod photoreceptor cell channels and olfactory neuron channels [see, Altenhofen, W. et al. (1991) Proc. Natl.

Acad. Sci U.S.A. 88:9868-9872 and Dhallan et al. (1990) Nature 347:184-187]
that are permeable to canons upon activation by binding of cAMP or cGMP. A change in cytoplasmic ion levels caused by a change in the amount of cyclic nucleotide activation of photo-receptor or olfactory neuron channels is used to determine function of receptors that cause a change in cAMP or cGMP levels when activated. In cases where activation of the receptor results in a decrease in cyclic nucleotide levels, it may be preferable to expose the cells to agents that increase intracellular cyclic nucleotide levels, e.g., forskolin, prior to adding a receptor-activating compound to the cells in the assay. Cell for this type of assay can be made by co-transfection of a host cell with DNA encoding a cyclic nucleotide-gated to ion channel and a DNA encoding a receptor (e.g., certain metabotropic glutamate receptors, muscarinic acetylcholine receptors, dopamine receptors, serotonin receptors and the like, which, when activated, causes a change in cyclic nucleotide levels in the cytoplasm.
Any cell expressing a receptor protein which is capable, upon activation, of directly increasing the intracellular concentration of calcium, such as by opening gated calcium channels, or indirectly affecting the concentration of intracellular calcium as by causing initiation of a reaction which utilizes Ca<2+> as a second messenger (e.g., G-protein-coupled receptors), may form the basis of an assay. Cells endogenously expressing such receptors or ion channels and cells which may be transfected with a suitable vector encoding one or more such cell surface proteins are known to those of skill in the art or may be 2o identified by those of skill in the art. Although essentially any cell which expresses endogenous ion channel and/or receptor activity may be used, it is preferred to use cells transformed or transfected with heterologous DNAs encoding such ion channels and/or receptors so as to express predominantly a single type of ion channel or receptor. Many cells that may be genetically engineered to express a heterologous cell surface protein are known.
Such cells include, but are not limited to, baby hamster kidney (BHK) cells (ATCC No.
CCL10), mouse L cells (ATCC No. CCLL3), DG44 cells [see, Chasin (1986) Cell.
Molec.
Genet. 12:555] human embryonic kidney (HEK) cells (ATCC No. CRL1573), Chinese hamster ovary (CHO) cells (ATCC Nos. CRL9618, CCL61, CRL9096), PC12 cells (ATCC
No. CRL1721) and COS-7 cells (ATCC No. CRL1651). Preferred cells for heterologous cell 3o surface protein expression are those that can be readily and efficiently transfected. Preferred cells include HEK 293 cells, such as those described in U.S. Pat. No.
5,024,939.
Any compound which is known to activate ion channels or receptors of interest may be used to initiate an assay. Choosing an appropriate ion channel- or receptor-activating reagent depending on the ion channel or receptor of interest is within the skill of the art.
Direct depolarization of the cell membrane to determine calcium channel activity may be accomplished by adding a potassium salt solution having a concentration of potassium ions such that the final concentration of potassium ions in the cell-containing well is in the range of about 50-150 mM (e.g., 50 mM KCl). With respect to ligand-gated receptors and ligand-gated ion channels, ligands are known which have affinity for and activate such receptors.
For example, nicotinic acetyloholine receptors are known to be activated by nicotine or acetylcholine; similarly, muscarinic and acetylcholine receptors may be activated by addition of muscarine or carbamylcholine.
to Agonist assays may be carned out on cells known to possess ion channels and/or receptors to determine what effect, if any, a compound has on activation or potentiation of ion channels or receptors of interest. Agonist assays also may be carned out using a reagent known to possess ion channel- or receptor-activating capacity to determine whether a cell expresses the respective functional ion channel or receptor of interest.
Contacting a functional receptor or ion channel with agonist typically activates a transient reaction; and prolonged exposure to an agonist may desensitize the receptor or ion channel to subsequent activation. Thus, in general, assays for determining ion channel or receptor function should be initiated by addition of agonist (i.e., in a reagent solution used to initiate the reaction). The potency of a compound having agonist activity is determined by 2o the detected change in some observable in the cells (typically an increase, although activation of certain receptors causes a decrease) as compared to the level of the observable in either the same cell, or substantially identical cell, which is treated substantially identically except that reagent lacking the agonist (i.e., control) is added to the well. Where an agonist assay is performed to test whether or not a cell expresses the functional receptor or ion channel of interest, known agonist is added to test-cell-containing wells and to wells containing control cells (substantially identical cell that lacks the specific receptors or ion channels) and the levels of observable are compared. Depending on the assay, cells lacking the ion channel and/or receptor of interest should exhibit substantially no increase in observable in response to the known agonist. A substantially identical cell may be derived from the same cells from which recombinant cells are prepared but which have not been modified by introduction of heterologous DNA. Alternatively, it may be a cell in which the specific receptors or ion channels are removed. Any statistically or otherwise significant difference in the level of observable indicates that the test compound has in some manner altered the activity of the specific receptor or ion channel or that the test cell possesses the specific functional receptor or ion channel.
In an example of drug screening assays for identifying compounds which have the ability to modulate ion channels or receptors of interest, individual wells (or duplicate wells, etc.) contain a distinct cell type, or distinct recombinant cell line expressing a homogeneous population of a receptor or ion channel of interest, so that the compound having unidentified activity may be screened to determine whether it possesses modulatory activity with respect to one or more of a variety of functional ion channels or receptors. It is also contemplated that each of the individual wells may contain the same cell type so that multiple compounds to (obtained from different reagent sources in the apparatus or contained within different wells) can be screened and compared for modulating activity with respect to one particular receptor or ion channel type.
Antagonist assays, including drug screening assays, may be carried out by incubating cells having functional ion channels and/or receptors in the presence and absence of one or more compounds, added to the solution bathing the cells in the respective wells of the microtiter plate for an amount of time sufficient (to the extent that the compound has affinity for the ion channel and/or receptor of interest) for the compounds) to bind to the receptors and/or ion channels, then activating the ion channels or receptors by addition of known agonist, and measuring the level of observable in the cells as compared to the level of 2o observable in either the same cell, or substantially identical cell, in the absence of the putative antagonist.
The assays are thus useful for rapidly screening compounds to identify those that modulate any receptor or ion channel in a cell. In particular, assays can be used to test functional ligand-receptor or ligand-ion channel interactions for cell receptors including ligand-gated ion channels, voltage-gated ion channels, G-protein-coupled receptors and growth factor receptors.
Those of ordinary skill in the art will recognize that assays may encompass measuring a detectable change of a solution as a consequence of a cellular event which allows a compound, capable of differential characteristics, to change its characteristics in response to the cellular event. By selecting a particular compound which is capable of differential characteristics upon the occurrence of a cellular event, various assays may be performed. For example, assays for determining the capacity of a compound to induce cell injury or cell death may be carned out by loading the cells with a pH-sensitive fluorescent indicator such as BCECF (Molecular Probes, Inc., Eugene, Oreg. 97402, Catalog #B 1150) and measuring cell injury or cell death as a function of changing fluorescence over time.
In a further example of useful assays, the function of receptors whose activation results in a change in the cyclic nucleotide levels of the cytoplasm may be directly determined in assays of cells that express such receptors and that have been injected with a fluorescent compound that changes fluorescence upon binding cAMP. The fluorescent compound comprises cAMP-dependent-protein kinase in which the catalytic and regulatory subunits are each labelled with a different fluorescent-dye [Adams et al.
(1991) Nature 1o 349:694-697]. When cAMP binds to the regulatory subunits, the fluorescence emission spectrum changes; this change can be used as an indication of a change in cAMP
concentration.
The function of certain neurotransmitter transporters which are present at the synaptic cleft at the junction between two neurons may be determined by the development of fluorescence in the cytoplasm of such neurons when conjugates of an amine acid and fluorescent indicator (wherein the fluorescent indicator of the conjugate is an acetoxymethyl ester derivative e.g., S-(aminoacetamido)fluorescein; Molecular Probes, Catalog #A1363) are transported by the neurotransmitter transporter into the cytoplasm of the cell where the ester group is cleaved by esterase activity and the conjugate becomes fluorescent.
2o In practicing an assay of this type, a reporter gene construct is inserted into an eukaryotic cell to produce a recombinant cell which has present on its surface a cell surface protein of a specific type. The cell surface receptor may be endogenously expressed or it may be expressed from a heterologous gene that has been introduced into the cell. Methods for introducing heterologous DNA into eukaryotic cells are-well known in the art and any such method may be used. In addition, DNA encoding various cell surface proteins is known to those of skill in the art or it may be cloned by any method known to those of skill in the art.
The recombinant cell is contacted with a test compound and the level of reporter gene expression is measured. The contacting may be effected in any vehicle and the testing 3o may be by any means using any protocols, such as serial dilution, for assessing specific molecular interactions known to those of skill in the art. After contacting the recombinant cell for a sufficient time to effect any interactions, the level of gene expression is measured.

The amount of time to effect such interactions may be empirically determined, such as by running a time course and measuring the level of transcription as a function of time. The amount of transcription may be measured using any method known to those of skill in the art to be suitable. For example, specific mRNA expression may be detected using Northern blots or specific protein product may be identified by a characteristic stain.
The amount of transcription is then compared to the amount of transcription in either the same cell in the absence of the test. compound or it may be compared with the amount of transcription in a substantially identical cell that lacks the specific receptors. A
substantially identical cell may be derived from the same cells from which the recombinant cell was prepared but which had to not been modified by introduction of heterologous DNA. Alternatively, it may be a cell in which the specific receptors are removed. Any statistically or otherwise significant difference in the amount of transcription indicates that the test compound has in some manner altered the activity of the specific receptor.
If the test compound does not appear to enhance, activate or induce the activity of the cell surface protein, the assay may be repeated and modified by the introduction of a step in which the recombinant cell is first tested for the ability of a known agonist or activator of the specific receptor to activate transcription if the transcription is induced, the test compound is then assayed for its ability to inhibit, block or otherwise affect the activity of the agonist.
2o The transcription based assay is useful for identifying compounds that interact with any cell surface protein whose activity ultimately alters gene expression. In particular, the assays can be used to test functional ligand-receptor or ligand-ion channel interactions for a number of categories of cell surface-localized receptors, including: ligand-gated ion channels and voltage-gated ion channels, and G protein-coupled receptors.
Any transfectable cell that can express the desired cell surface protein in a manner such the protein functions to intracellularly transduce an extracellular signal may be used.
The cells may be selected such that they endogenously express the cell surface protein or may be genetically engineered to do so. Many such cells are known to those of skill in the art. Such cells include, but are not limited to Ltk< - > cells, PC 12 cells and COS-7 cells.
3o The preparation of cells which express a receptor or ion channel and a reporter gene expression construct, and which are useful for testing compounds to assess their activities, is exemplified in the Examples provided herewith by reference to mammalian Ltk< -> and WO 00/71518 PCT/iJS00/14579 COS-7 cell lines, which express the Type I human muscarinic (HM1) receptor and which are transformed with either a c-fos promoter-CAT reporter gene expression construct or a c-fos promoter-luciferase reporter gene expression construct.
Any cell surface protein that is known to those of skill in the art or that may be identified by those of skill in the art may used in the assay. The cell surface protein may endogenously expressed on the selected cell or it may be expressed from cloned DNA.
Exemplary cell surface proteins include, but are not limited to, cell surface receptors and ion channels. Cell surface receptors include, but are not limited to, muscarinic receptors (e.g."
human M2 (GenBank accession #M16404); rat M3 (GenBank accession #M16407);
human 1o M4 (GenBank accession #M16405); human MS (Bonner et al. (1988) Neuron 1:403-410);
and the like); neuronal nicotinic acetylcholine receptors (e.g., the alpha 2, alpha 3 and beta 2 subtypes disclosed in U.S. Ser. No. 504,455 (filed Apr. 3, 1990), hereby expressly incorporated by reference herein in its entirety); the rat alpha 2 subunit (Wada et al. (1988) Science 240:330-334); the rat alpha 3 subunit (Boulter et al. (1986) Nature 319:368-374);
the rat alpha 4 subunit (Goldman et al. (1987) cell 48:965-973); the rat alpha 5 subunit (Boulter et al. (1990) J. Biol. Chem. 265:4472-4482); the rat beta 2 subunit (Deneris et al.
(1988) Neuron 1:45-54); the rat beta 3 subunit (Deneris et al. (1989) J. Biol.
Chem. 264:
6268-6272); the rat beta 4 subunit (Duvoisin et al. (1989) Neuron 3:487-496);
combinations of the rat alpha subunits, beta subunits and alpha and beta subunits; GABA
receptors (e.g., 2o the bovine alpha 1 and beta 1 subunits (Schofield et al. (1987) Nature 328:221-227); the bovine alpha 2 and alpha 3 subunits (Levitan et al. (1988) Nature 335:76-79);
the gamma subunit (Pritchett et al. (1989) Nature 338:582-585); the beta 2 and beta 3 subunits (Ymer et alo (1989) EMBO J. 8:1665-1670); the delta subunit (Shivers, B.D. (1989) Neuron 3:327-337); and the like); glutamate receptors (e.g., receptor isolated from rat brain (Hollmann et al. (1989) Nature 342:643-648); and the like); adrenergic receptors (e.g., human beta 1 (Frielle et al. (1987) Proc. Natl. Acad. Sci. 84.:7920-7924); human alpha 2 (Kobilka et al.
(1987) Science 238:650-656); hamster beta 2 (Dixon et al. (1986) Nature 321:75-79); and the like); dopamine receptors (e.g., human D2 (Stormann et al. (1990) Molec.
Pharm.37:1-6); rat (Bunzow et al. (1988) Nature 336:783-787); and the like); NGF
receptors (e.g., 3o human NGF receptors (Johnson et al. (1986) Cell 47:545-554); and the like);
serotonin receptors (e.g., human SHTla (Kobilka et al. (1987) Nature 329:75-79); rat SHT2 (Julius et al. (1990) PNAS 87:928-932); rat SHTIc (Julius et al. (1988) Science 241:558-564); and the like).

Reporter gene constructs are prepared by operatively linking a reporter gene with at least one transcriptional regulatory element. If only one transcriptional regulatory element is included it must be a regulatable promoter, At least one of the selected transcriptional regulatory elements must be indirectly or directly regulated by the activity of the selected cell-surface receptor whereby activity of the receptor can be monitored via transcription of the reporter genes.
The construct may contain additional transcriptional regulatory elements, such as a FIRE sequence, or other sequence, that is not necessarily regulated by the cell surface protein, but is selected for its ability to reduce background level transcription or to amplify to the transduced signal and to thereby increase the sensitivity and reliability of the assay.
Many reporter genes and transcriptional regulatory elements are known to those of skill in the art and others may be identified or synthesized by methods known to those of skill in the art.
A reporter gene includes any gene that expresses a detectable gene product, which may be RNA or protein. Preferred reporter genes are those that are readily detectable. The reporter gene may also be included in the construct in the form of a fusion gene with a gene that includes desired transcriptional regulatory sequences or exhibits other desirable properties.
Examples of reporter genes include, but are not limited to CAT
(chloramphenicol acetyl transferase) (Alton and Vapnek (1979), Nature 282: 864-869) luciferase, and other enzyme detection systems, such as beta-galactosidase; firefly luciferase (deWet et al. (1987), Mol. Cell. Biol. 7:725-737); bacterial luciferase (Engebrecht and Silverman (1984), PNAS
1: 4154-4158; Baldwin et al. (1984), Biochemistry 23: 3663-3667); alkaline phosphatase (Toh et al. (1989) Eur. J. Biochem. 182: 231-238, Hall et al. (1983) J. Mol.
Appl. Gen. 2:
101).
Transcriptional control elements include, but are not limited to, promoters, enhancers, and repressor and activator binding sites, Suitable transcriptional regulatory elements may be derived from the transcriptional regulatory regions of genes whose expression is rapidly induced, generally within minutes, of contact between the cell surface 3o protein and the effector protein that modulates the activity of the cell surface protein.
Examples of such genes include, but are not limited to, the immediate early genes (see, Sheng et al. (1990) Neuron 4: 477-485), such as c-fos, Immediate early genes are genes that are rapidly induced upon binding of a ligand to a cell surface protein. The transcriptional control elements that are preferred for use in the gene constructs include transcriptional control elements from immediate early genes, elements derived from other genes that exhibit some or all of the characteristics of the immediate early genes, or synthetic elements that are constructed such that genes in operative linkage therewith exhibit such characteristics. The characteristics of preferred genes from which the transcriptional control elements are derived include, but are not limited to, low or undetectable expression in quiescent cells, rapid induction at the transcriptional level within minutes of extracellular simulation, induction that is transient and independent of new protein synthesis, subsequent 1o shut-off of transcription requires new protein synthesis, and mRNAs transcribed from these genes have a short half life. It is not necessary for all of these properties to be present.
In vivo Activity Assays Various experimental procedures, well known in the art, are useful in the present invention to assess the analgesic effect of compounds, such as the "tail flick" and "hot plate"
tests. The "tail flick" test can be performed by applying a noxious thermal stimulus to the rat's tail and determining the time until the nociceptive tail flick occurs.
Analgesia is demonstrated by an increase in time to occurrence of a tail flick response.
The "hot plate"
test is similarly performed, except that the noxious thermal stimulus is applied to the rat's paws.
2o An experimental procedure, well known in the art, useful in the present invention to assess the ability of compounds to cause respiratory depression is to monitor blood gases.
This method employees measuring the partial pressures of oxygen and carbon dioxide in blood samples taken from animals following compound administration. A decrease in the partial pressures of oxygen and an increase in the partial pressure of carbon dioxide may be indicative of respiratory depression.
An experimental procedure, well known in the art, useful in the present invention to assess the ability of compounds to cause inhibition of gastrointestinal motility is the "charcoal meal test". This method measures the propulsion of intestinal contents following administration of test compounds. A decrease in the propulsion of intestinal contents may 3o be indicative of inhibition of gastrointestinal motility.
Various experimental procedures, well known in the art, are useful in the present invention to assess the ability of compounds to cause tolerance. Tolerance can be defined as a condition characterized by unresponsiveness or decreased responsiveness following prolonged or multiple exposure to a compound compared to the responsiveness demonstrated upon initial exposure.
Various experimental procedures, well known in the art, are useful in the present invention to assess the ability of compounds to cause physical dependence. In the present invention, the ability of test compounds to cause physical dependence was accessed by giving animals escalating doses of test compounds for five days. After the final dose the animals were given naloxone, an opioid antagonist and observed for behavioral signs of dependence, such as vertical jumping.
Pharmaceutical Compositions In another aspect, the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable Garners (additives) and/or diluents. As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (I) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually;
(6) ocularly; (7) transdermally; or (8) nasally.
The phrase "therapeutically-effective amount" as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.
3o The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irntation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The phrase "pharmaceutically-acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each Garner must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, to glucose and sucrose; (2) starches, such as corn starch and potato starch;
(3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
(4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol;
(11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline;
(18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances employed in 2o pharmaceutical formulations.
As set out above, certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids. The term "pharmaceutically-acceptable salts" in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification. Representative salts include the hydrobromide, hydrochloride, 3o sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like.
(See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci.
66:1-19) The pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, malefic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
In other cases, the compounds of the present invention may contain one or more to acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases. The term "pharmaceutically-acceptable salts" in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the 2o formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra) Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.
Generally, out of one hundred per cent, this amount will range from about 1 per cent to to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the Garner and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid Garners, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.
In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable Garners, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, 3o mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
to A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or 2o controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredients) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
Examples of embedding compositions which can be used include polymeric substances and waxes. The 3o active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, 1o perfuming and preservative agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirntating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such Garners as are known in the art to be appropriate.
Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically-acceptable Garner, and with any preservatives, buffers, or propellants which may be required.
The ointments, pastes, creams and gels may contain, in addition to an active 3o compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can to be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the 2o blood of the intended recipient or suspending or thickening agents.
Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of 3o microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.
Alternatively, delayed absorption of a parenterally-administered drug form is accomplished to by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide.
Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in 2o combination with a pharmaceutically acceptable carrier.
The preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by inj ection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, 3o intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal inj ection and infusion.

The phrases "systemic administration," "administered systemically,"
"peripheral administration" and "administered peripherally" as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
l0 Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide 2o thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is 3o achieved.
In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
Generally, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day.
If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).
In another aspect, the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the subject compounds, as described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: ( 1 ) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous 2o injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin, lungs, or oral cavity; or (4) intravaginally or intravectally, for example, as a pessary, cream or foam; (5) sublingually;
(6) ocularly; (7) transdermally; or (8) nasally.
The compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other pharmaceuticals.
The term "treatment" is intended to encompass also prophylaxis, therapy and cure.
The patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep;
and poultry 3o and pets in general.
The compound of the invention can be administered as such or in admixtures with pharmaceutically acceptable carriers and can also be administered in conjunction with antimicrobial agents such as penicillins, cephalosporins, aminoglycosides and glycopeptides. Conjunctive therapy, thus includes sequential, simultaneous and separate administration of the active compound in a way that the therapeutical effects of the first administered one is not entirely disappeared when the subsequent is administered.
The addition of the active compound of the invention to animal feed is preferably accomplished by preparing an appropriate feed premix containing the active compound in an effective amount and incorporating the premix into the complete ration.
Alternatively, an intermediate concentrate or feed supplement containing the active to ingredient can be blended into the feed. The way in which such feed premixes and complete rations can be prepared and administered are described in reference books (such as "Applied Animal Nutrition", W.H. Freedman and CO., San Francisco, U.S.A., 1969 or "Livestock Feeds and Feeding" O and B books, Corvallis, Ore., U.S.A., 1977).
Combinatorial Libraries The subject reactions readily lend themselves to the creation of combinatorial libraries of compounds for the screening of pharmaceutical, agrochemical or other biological or medically-related activity or material-related qualities. A combinatorial library for the purposes of the present invention is a mixture of chemically related compounds which may 2o be screened together for a desired property; said libraries may be in solution or covalently linked to a solid support. The preparation of many related compounds in a single reaction greatly reduces and simplifies the number of screening processes which need to be carned out. Screening for the appropriate biological, pharmaceutical, agrochemical or physical property may be done by conventional methods.
Diversity in a library can be created at a variety of different levels. For instance, the substrate aryl groups used in a combinatorial approach can be diverse in terms of the core aryl moiety, e.g., a variegation in terms of the ring structure, and/or can be varied with respect to the other substituents.
A variety of techniques are available in the art for generating combinatorial libraries of small organic molecules. See, for example, Blondelle et al. (1995) Trends Anal. Chem.
14:83; the Affymax U.S. Patents 5,359,115 and 5,362,899: the Ellman U.S.
Patent 5,288,514: the Still et al. PCT publication WO 94/08051; Chen et al. (1994) JACS
116:2661: Kerr et al. (1993) JACS 115:252; PCT publications W092/10092, and W091/07087; and the Lerner et al. PCT publication W093/20242).
Accordingly, a variety of libraries on the order of about 16 to 1,000,000 or more diversomers can be synthesized and screened for a particular activity or property.
In an exemplary embodiment, a library of substituted diversomers can be synthesized using the subject reactions adapted to the techniques described in the Still et al.
PCT publication WO 94/08051, e.g., being linked to a polymer bead by a hydrolyzable or photolyzable group, e.g., located at one of the positions of substrate.
According to the Still et al. technique, the library is synthesized on a set of beads, each bead including a set of tags identifying the particular diversomer on that bead. In one embodiment, which is particularly l0 suitable for discovering enzyme inhibitors, the beads can be dispersed on the surface of a permeable membrane, and the diversomers released from the beads by lysis of the bead linker. The diversomer from each bead will diffuse across the membrane to an assay zone, where it will interact with an enzyme assay. Detailed descriptions of a number of combinatorial methodologies are provided below.
A) Direct Characterization A growing trend in the field of combinatorial chemistry is to exploit the sensitivity of techniques such as mass spectrometry (MS), e.g., which can be used to characterize sub-femtomolar amounts of a compound, and to directly determine the chemical constitution of 2o a compound selected from a combinatorial library. For instance, where the library is provided on an insoluble support matrix, discrete populations of compounds can be first released from the support and characterized by MS. In other embodiments, as part of the MS sample preparation technique, such MS techniques as MALDI can be used to release a compound from the matrix, particularly where a labile bond is used originally to tether the compound to the matrix. For instance, a bead selected from a library can be irradiated in a MALDI step in order to release the diversomer from the matrix, and ionize the diversomer for MS analysis.
B) Multipin Synthesis 3o The libraries of the subject method can take the multipin library format.
Briefly, Geysen and co-workers (Geysen et al. (1984) PNAS 81:3998-4002) introduced a method for generating compound libraries by a parallel synthesis on polyacrylic acid-grated polyethylene pins arrayed in the microtitre plate format. The Geysen technique can be used to synthesize and screen thousands of compounds per week using the multipin method, and the tethered compounds may be reused in many assays. Appropriate linker moieties can also been appended to the pins so that the compounds may be cleaved from the supports after synthesis for assessment of purity and further evaluation (c.f., Bray et al. (1990) Tetrahedron Lett 31:5811-5814; Valerio et al. (1991) Anal Biochem 197:168-177;
Bray et al. (1991) Tetrahedron Lett 32:6163-6166).
C) Divide-Couple-Recombine In yet another embodiment, a variegated library of compounds can be provided on a to set of beads utilizing the strategy of divide-couple-recombine (see, e.g., Houghten (1985) PNAS 82:5131-5135; and U.S. Patents 4,631,211; 5,440,016; 5,480,971). Briefly, as the name implies, at each synthesis step where degeneracy is introduced into the library, the beads are divided into separate groups equal to the number of different substituents to be added at a particular position in the library, the different substituents coupled in separate reactions, and the beads recombined into one pool for the next iteration.
In one embodiment, the divide-couple-recombine strategy can be carried out using an analogous approach to the so-called "tea bag" method first developed by Houghten, where compound synthesis occurs on resin sealed inside porous polypropylene bags (Houghten et al. (1986) PNAS 82:5131-5135). Substituents are coupled to the compound-2o bearing resins by placing the bags in appropriate reaction solutions, while all common steps such as resin washing and deprotection are performed simultaneously in one reaction vessel.
At the end of the synthesis, each bag contains a single compound.
D) Combinatorial Libraries by Light-Directed, Spatially Addressable Parallel Chemical Synthesis A scheme of combinatorial synthesis in which the identity of a compound is given by its locations on a synthesis substrate is termed a spatially-addressable synthesis. In one embodiment, the combinatorial process is carned out by controlling the addition of a chemical reagent to specific locations on a solid support (Dower et al. (1991) Annu Rep 3o Med Chem 26:271-280; Fodor, S.P.A. (1991) Science 251:767; Pirrung et al.
(1992) U.S.
Patent No. 5,143,854; Jacobs et al. (1994) Trends Biotechnol 12:19-26). The spatial resolution of photolithography affords miniaturization. This technique can be carned out through the use protection/deprotection reactions with photolabile protecting groups.

The key points of this technology are illustrated in Gallop et al. (1994) J
Med Chem 37:1233-1251. A synthesis substrate is prepared for coupling through the covalent attachment of photolabile nitroveratryloxycarbonyl (NVOC) protected amino linkers or other photolabile linkers. Light is used to selectively activate a specified region of the synthesis support for coupling. Removal of the photolabile protecting groups by light (deprotection) results in activation of selected areas. After activation, the first of a set of amino acid analogs, each bearing a photolabile protecting group on the amino terminus, is exposed to the entire surface. Coupling only occurs in regions that were addressed by light in the preceding step. The reaction is stopped, the plates washed, and the substrate is again to illuminated through a second mask, activating a different region for reaction with a second protected building block. The pattern of masks and the sequence of reactants define the products and their locations. Since this process utilizes photolithography techniques, the number of compounds that can be synthesized is limited only by the number of synthesis sites that can be addressed with appropriate resolution. The position of each compound is precisely known; hence, its interactions with other molecules can be directly assessed.
In a light-directed chemical synthesis, the products depend on the pattern of illumination and on the order of addition of reactants. By varying the lithographic patterns, many different sets of test compounds can be synthesized simultaneously; this characteristic leads to the generation of many different masking strategies.
E) Encoded Combinatorial Libraries In yet another embodiment, the subject method utilizes a compound library provided with an encoded tagging system. A recent improvement in the identification of active compounds from combinatorial libraries employs chemical indexing systems using tags that uniquely encode the reaction steps a given bead has undergone and, by inference, the structure it carnes. Conceptually, this approach mimics phage display libraries, where activity derives from expressed peptides, but the structures of the active peptides are deduced from the corresponding genomic DNA sequence. The first encoding of synthetic combinatorial libraries employed DNA as the code. A variety of other forms of encoding 3o have been reported, including encoding with sequenceable bio-oligomers (e.g., oligonucleotides and peptides), and binary encoding with additional non-sequenceable tags.
1) Tagging with sequenceable bio-oligomers The principle of using oligonucleotides to encode combinatorial synthetic libraries was described in 1992 (Brenner et al. (1992) PNAS 89:5381-5383), and an example of such a library appeared the following year (Needles et al. (1993) PNAS
90:10700-10704).
A combinatorial library of nominally 77 (= 823,543) peptides composed of all combinations of Arg, Gln, Phe, Lys, Val, D-Val and Thr (three-letter amino acid code), each of which was encoded by a specific dinucleotide (TA, TC, CT, AT, TT, CA and AC, respectively), was prepared by a series of alternating rounds of peptide and oligonucleotide synthesis on solid support. In this work, the amine linking functionality on the bead was specifically differentiated toward peptide or oligonucleotide synthesis by simultaneously preincubating to the beads with reagents that generate protected OH groups for oligonucleotide synthesis and protected NH2 groups for peptide synthesis (here, in a ratio of 1:20). When complete, the tags each consisted of 69-mers, 14 units of which carried the code. The bead-bound library was incubated with a fluorescently labeled antibody, and beads containing bound antibody that fluoresced strongly were harvested by fluorescence-activated cell sorting (FACS). The DNA tags were amplified by PCR and sequenced, and the predicted peptides were synthesized. Following such techniques, compound libraries can be derived for use in the subject method, where the oligonucleotide sequence of the tag identifies the sequential combinatorial reactions that a particular bead underwent, and therefore provides the identity of the compound on the bead.
2o The use of oligonucleotide tags permits exquisitely sensitive tag analysis.
Even so, the method requires careful choice of orthogonal sets of protecting groups required for alternating co-synthesis of the tag and the library member. Furthermore, the chemical lability of the tag, particularly the phosphate and sugar anomeric linkages, may limit the choice of reagents and conditions that can be employed for the synthesis of non-oligomeric libraries. In preferred embodiments, the libraries employ linkers permitting selective detachment of the test compound library member for assay.
Peptides have also been employed as tagging molecules for combinatorial libraries. Two exemplary approaches are described in the art, both of which employ branched linkers to solid phase upon which coding and ligand strands are alternately 3o elaborated. In the first approach (Kerr JM et al. (1993) J Am Chem Soc 115:2529-2531), orthogonality in synthesis is achieved by employing acid-labile protection for the coding strand and base-labile protection for the compound strand.

In an alternative approach (Nikolaiev et al. (1993) Pept Res 6:161-170), branched linkers are employed so that the coding unit and the test compound can both be attached to the same functional group on the resin. In one embodiment, a cleavable linker can be placed between the branch point and the bead so that cleavage releases a molecule containing both code and the compound (Ptek et al. (1991) Tetrahedron Lett 32:3891-3894).
In another embodiment, the cleavable linker can be placed so that the test compound can be selectively separated from the bead, leaving the code behind. This last construct is particularly valuable because it permits screening of the test compound without potential interference of the coding groups. Examples in the art of independent cleavage and sequencing of peptide library members and their corresponding tags has confirmed that the tags can accurately predict the peptide structure.
2) Non-sequenceable Tagging: Binary Encoding An alternative form of encoding the test compound library employs a set of non-sequencable electrophoric tagging molecules that are used as a binary code (Ohlmeyer et al. (1993) PNAS 90:10922-10926). Exemplary tags are haloaromatic alkyl ethers that are detectable as their trimethylsilyl ethers at less than femtomolar levels by electron capture gas chromatography (ECGC). Variations in the length of the alkyl chain, as well as the nature and position of the aromatic halide substituents, permit the synthesis of at least 40 such tags, which in principle can encode 240 (e.g., upwards of 1012) different molecules. In the original report (Ohlmeyer et al., supra) the tags were bound to about 1 %
of the available amine groups of a peptide library via a photocleavable o-nitrobenzyl linker.
This approach is convenient when preparing combinatorial libraries of peptide-like or other amine-containing molecules. A more versatile system has, however, been developed that permits encoding of essentially any combinatorial library. Here, the compound would be attached to the solid support via the photocleavable linker and the tag is attached through a catechol ether linker via carbene insertion into the bead matrix (Nestler et al. (1994) J Ors Chem 59:4723-4724). This orthogonal attachment strategy permits the selective detachment of library members for assay in solution and subsequent decoding by ECGC after oxidative detachment of the tag sets.
Although several amide-linked libraries in the art employ binary encoding with the electrophoric tags attached to amine groups, attaching these tags directly to the bead matrix provides far greater versatility in the structures that can be prepared in encoded combinatorial libraries. Attached in this way, the tags and their linker are nearly as unreactive as the bead matrix itself. Two binary-encoded combinatorial libraries have been reported where the electrophoric tags are attached directly to the solid phase (Ohlmeyer et al. (1995) PNAS 92:6027-6031) and provide guidance for generating the subject compound library. Both libraries were constructed using an orthogonal attachment strategy in which the library member was linked to the solid support by a photolabile linker and the tags were attached through a linker cleavable only by vigorous oxidation. Because the library members can be repetitively partially photoeluted from the solid support, library members can be utilized in multiple assays. Successive photoelution also permits a very high 1o throughput iterative screening strategy: first, multiple beads are placed in 96-well microtiter plates; second, compounds are partially detached and transferred to assay plates; third, a metal binding assay identifies the active wells; fourth, the corresponding beads are rearrayed singly into new microtiter plates; fifth, single active compounds are identified; and sixth, the structures are decoded.
Exemplification The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.
Example 1 Synthesis of N-Boc-3-piperidinemethanol (21 ~OH
OOH Boc20, NEt3 ~ ~Bu O' _O

A solution of 3-piperidinemethanol (1) (15.20 g, 0.132 mol) in 30 mL of THF
and 30 mL of HZO was cooled in ice-water bath and NEt3 (20 mL) was added with stirnng. Stirring and cooling were continued while di-tert-butyl dicarbonate (34.56 g, 1.2 eq.) was introduced. The mixture was warmed to room temperature and stirred overnight.
100 mL
of ethyl acetate and 20 mL of HZO were added to mixture. The aqueous layer was extracted - 75 _ with ethyl acetate (2 x 100 mL). The extracts were combined and washed with aqueous potassium carbonate (sat., 2 x 50 mL), aqueous HCl (5%, 2 x 50 mL), brine (SO
mL), and dried over anhydrous sodium sulfate, filtered and evaporated. Colorless oil 28.5g (100%).
TLC Rf= 0.21 (ethyl acetate/hexane, 1:2).
Example 2 Synthesis of N-Boc-~peridin-3-yl-formaldehyde (31 'OH
PCC, CH2C12 N N
O/~OiBu O/~O~Bu To a stirred suspension of pyridinium chlorochromate (98%, 34.0g, 0.155 mol) and to Celite (24 g) in 200 mL of dry CHZC12 was added N-Boc-3-piperidinemethanol (2) (22.15 g, 0.103 mol) in 30 mL of CHZCIz in one portion, and the mixture was stirred at room temperature overnight. The mixture was filtered by passing through a funnel filled with 20 g of Celite. After the solvent was removed, the remaining oily residue was purified by a flash column (silica gel; hexane:ethyl acetate, 4:1) to afford 3 as a colorless oil 17.5g (80%).
Example 3 Synthesis of N-(1-Boc-piperidin-3- l~yl~-aniline (41 PhNH2 N NaBHgCN
N
~ ;Bu 0i 'O /~ ;Bu O O

To a solution of N-Boc-piperidin-3-yl-formaldehyde 3 ( 5.20 g, 24.4 mmol) in 2o mL of dry methanol and 50 mL of trimethylorthoformate was added aniline (2.50 g, 1.1 eq.), and the mixture was stirred at room temperature for 30 minutes. NaBH3CN (95%, 1.84 g, 1.1 eq.) was introduced in one portion, and the mixture was stirred at room temperature overnight. The mixture was quenched with 30 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 100 mL). The extracts were combined and washed with aqueous NaHC03 (sat., 2 x 50 mL), brine (50 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by a flash column chromatography (silica gel, hexane:ethyl acetate (1:1) to afford N-(1-Boc-piperidin-3-ylmethyl)-aniline 4 as white solid (5.60 g, 79%). IR (film, crri') 3520, 3263, 3004, 2976, 2932, 2854, 1688, 1589, 1521, 1482, 1422, 1365, 1267, 1243, 1175, 1150, 794, 709; 'H
NMR (CDC13, ppm) 7.20 (t, 2H, J = 7.8 Hz), 6.72 (t, 1H, J = 6.8 Hz), 6.63 (d, 2H, J = 8.3 Hz), 4.00-3.78 (m, 3H), 3.07-2.70 (m, 4H), 2.00-1.20 (m, 5H), 1.48 (s, overlap, 9H).
Example 4 to Synthesis of N-f 1-Boc-piperidin-3-ylmethyll-N-phenyl-propionamide (51 ~coci CHZCIz, r.t.

To a solution of N-(1-Boc-piperidin-3-ylmethyl)-aniline 4 (4.60 g, 15.8 mmol) and N,N-diisopropylethylamine (1.40 mL, 15.8 mmol) in 25 mL of dry methylene chloride was added propionyl chloride (1.40 mL, 15.8 mmol) dropwise at 0 °C. After being stirred at room temperature overnight, the reaction mixture was quenched with 30 mL of H20 and extracted with ethyl acetate (3 x 100 mL). The extracts were combined and washed with aqueous HCl (5%, 20 mL), NaHC03 (sat., 2 x 30 mL), brine (50 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by a flash column chromatography (silica gel, hexane:ethyl acetate) to afford N-(1-2o Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 as a colorless oil (4.50 g, 82%). IR
(film, cm') 2975, 2934, 2854, 1690, 1663, 1591, 1496, 1422, 1402, 1365, 1265, 1242, 1176, 1149, 1038, 962,775, 702; 'H NMR (CDC13, ppm) 7.44-7.22 (m, SH), 4.09-3.22 (m, 4H), 2.80-2.09 (m, 2H), 2.06 (q, 2H, J = 7.5 Hz), 1.75-1.19 (m, SH), 1.48(s, overlap, 9H), 1.06 (t, 3H, J = 7.5 Hz).
Example S
Synthesis of N-(1-Phenethvl-piperidin-3-vlmethvll-N-phenyl-propionamide (6~

\ ~ /
N
1)TFA, CHZCIZ
NJ O~ _ 2) PhCH2CH0 ~ NaB(OAc)3H
O"O
I
tBu Trifluoroacetic acid (5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (1.21 g, 3.49 mmol) in 5 mL of dry CH,CIz at 0 °C
(ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC
5 showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (5.0 mL) and phenylacetaldehyde (5.3 mL, 2M/in DMF, 5.3 mmol) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 1.18 g, 5.3 mmol.) was introduced in one portion, and the mixture was stirred at room temperature overnight. The mixture was quenched with 10 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 60 mL). The extracts were combined and washed with aqueous NaHC03 (sat., 2 x 10 mL), brine (30 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by a flash column chromatography to give 6. IR (film, cm~') 3060, 3026, 2934, 2854, 2800, 2765, 1662, 1495, 1452, 1401, 1262, 1203, 1150, 1106, 966, 1033, 775, 749; LRMS 351.
Example 6 Synthesis of N-(1-Benzyl-piperidin-3-ylmethyll-N-phen ~~l-propionamide (71 1) TFA, CHZCIZ
2) PhCHO
NaB(OAc)3H

2o Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (31 mg, 0.090 mmol) in 0.5 mL of dry _~8_ CHzCIz at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and benzaldehyde (13.6 pL, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 28.45 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 10 mL). The extracts were combined and washed with aqueous NaHC03 (sat., 2 x 5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-(1-Benzyl-piperidin-3-ylmethyl)-N-phenyl-propionamide 7 as a colorless oil (26.6 mg, 88%). LRMS 337.
Example 7 N-(1-(Thiophen-2-ylmethyl)-piperidin-3- l~vl]-N-phenyl-propionamide (8) 1 ) TFA, CH2CIz 2) thiopheneCHO, NaB(OAc)3H
N

Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (31 mg, 0.090 mmol) in 0.5 mL of dry CH,Ch at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and 2-thiophene carboxaldehyde (12.5 ~L, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 28.45 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 10 mL). The extracts were combined and washed with aqueous NaHC03 (sat., 2 x 5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-[1-(Thiophen-2-ylmethyl)-piperidin-3-ylmethyl]-N-phenyl-propionamide 8 as a colorless oil (25.2 mg, 82%). LRMS 343.
Example 8 Synthesis of (N-[1-(4-pvridinyl-N-oxidomethyll-ni~eridin-3-ylmethvl]-N-phenyl-pro~ionamide (9) 1) TFA, CHZCIz N
2)ArCHO
NaB(OAc)3H

Trifluoroac:a:;.;.; acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (31 mg, 0.090 mmol) in 0.5 mL of dry CH,CI, at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and 4-pyridinecarboxaldehyde N-oxide (17 mg, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 28.45 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 10 mL). The extracts were combined and washed with aqueous NaHC03 (sat., 2 x 5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford 9 as a colorless oil (18.7 mg, 59%). LRMS 354.
Example 9 Synthesis of,~N-(1-(4-Methoxybenzyl)-niperidin-3-ylmeth~]-N-phenyl-propionamide (101 I~
N / I /
1) TFA, CHZ( NJ O' v 2 ArCHO
~ NaB(OAc)~
O-' _O
I
tBu Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (31 mg, 0.090 mmol) in 0.5 mL of dry CHZCIZ at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 30 5 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and 4-anisaldehyde (16.7 ~L, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 28.45 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 10 mL). The extracts were combined and washed with aqueous NaHC03 (sat., 2 x 5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1 ) to afford N-[ 1-(4-Methoxybenzyl)-piperidin-3-ylmethyl]-N-phenyl-propionamide 10 as a colorless oil (18.7 mg, 59%). LRMS 366.
Example 10 ~nthesis of (N-f 1-(1H-Imidazol-2- l~yh~peridin-3-ylmeth~]-N-phenyl-propionamide (111 IJ N /
1) TFA, CHZCIZ
2)ArCHO
NaB(OAc)3 H

Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (21 mg, 0.061 mmol) in 0.5 mL of dry CHzCI, at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and 2-imidazole carboxaldehyde (8.7 mg, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 20.3 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 10 mL). The extracts were combined and washed with aqueous NaHC03 (sat., 2 x 5 mL), brine ( 10 mL), and dried over anhydrous sodium sulfate. After the solvent was to removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-[1-(1H Imidazol-2-ylmethyl)-piperidin-3-ylmethyl]-N-phenyl-propionamide 11 as a colorless oil (10.7 mg, 54%). LRMS 327.
Example I1 Synthesis of (N-(1-(Pyridin-3-vlmeth~)-piperidin-3-ylmethylJ-N-phenyl-propionamide (12) N
1) TFA, CHZC12 2)ArCHO
NaB(OAc)3H

Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (21 mg, 0.061 mmol) in 0.5 mL of dry CHZCIz at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 30 2o minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and 3-pyridine carboxaldehyde (8.6 ~L, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 20.3 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 10 mL). The extracts were combined and washed with aqueous NaHC03 (sat., 2 x 5 mL), brine ( 10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-[1-(Pyridin-3-ylmethyl)-piperidin-3-ylmethyl]-N-phenyl-propionamide 12 as a colorless oil (15.6 mg, 76%). LRMS 338.
Example 12 Synthesis of Furan-2-carboxylic acid N-(1-Boc-pineridin-3-ylmetl~ll-N-phenyl amide (131 o coca N
CHzCl2, r.t.
J "
N
/~ tBu O~O~
OU

To a stirred suspension of N-(1-Boc-piperidin-3-ylmethyl)-aniline 4 (61.0 mg, 0.21 mmol) and piperidinomethyl polystyrene resin (60 mg) in 0.6 mL of dry CH,C1, was added 2-furoyl chloride (95%, 35.1 mg, 1.2 eq.) at room temperature. After being shaken at room 1o temperature for 4 hours, the reaction mixture was passed through an aminopropyl NHZ
cartridge and washed with CHzCh. Removal of CH,CI, afforded furan-2-carboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl amide 13 (75 mg, 93%). LRMS 285 (M-100)+.
Example 13 Synthesis of Furan-2-carboxylic acid N-(1-pheneth~p~eridin-3-ylmethyl)-N-phenyl amide N ~ 1) CHZC12-TFA
50 %, r.t.
NJ O 2) PhCHZCHO, DMF
NaB(OAc)3H
O
~Bu Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of furan-2-carboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl amide 13 (46 mg, 0.12 mmol) in 0.5 mL of 2o dry CHZCh at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs (LRMS 285). The crude compound was dissolved in DMF (0.5 mL) and was added phenylacetaldehyde (150 ~L, 2M/in DMF). The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 55 mg, 2 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 10 mL). The extracts were combined and washed with aqueous NaHC03 (sat., 2 x S
mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford Furan-2-carboxylic acid N-(1-phenethylpiperidin-3-ylmethyl)-N-phenyl amide 14 as a colorless oil (20.3 mg, 44%). LRMS 389.
Example 14 Synthesis of Thiophene-2-carboxylic acid N-(1-Boc-piperidin-3-vlmethyll-N-nhenyl amide \ ~\
s coci /
/ \ I ~N
-N
H
CHZCIZ, r.t. N O ~ S
N
~ ;Bu 0i 'O
O' 'O I
tB a 15 To a stirred suspension of N-(1-Boc-piperidin-3-ylmethyl)-aniline 4 (60.9 mg, 0.21 mmol) and piperidinomethyl polystyrene resin (60 mg) in 0.6 mL of dry CHZCIz was added 2-thiophenecarbonyl chloride (97%, 39.2 mg, 1.2 eq.) at room temperature.
After being shaken at room temperature for 4 hours, the reaction mixture was passed through an aminopropyl NHZ cartridge and washed with CHZCh. Removal of CH,CI, afforded 2o thiophene-2-carboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl amide 15 (82.1 mg, 98%). LRMS 300 (M-100)+.
Example 15 Synthesis of Thiophene-2-carboxylic acid N-(1-phenethylpiperidin-3-ylmethyll-N-phenyl amide 16 1 ) CHZCIz-TFA

50 %, r.t.

2) PhCH2CH0, DMF

NaB(OAc)3H

Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of thiophene-2-carboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl amide 15 (46.7 mg, 0.12 mmol) in 0.5 mL of dry CHZC12 at 0 °C (ice-water). The reaction mixture was stirred at room 5 temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs (LRMS 301). The crude compound was dissolved in DMF (0.5 mL) and phenylacetaldehyde (150 ~.L, 2M/in DMF) was added.
The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 55 mg, 2 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight.
1o The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 10 mL). The extracts were combined and washed with aqueous NaHC03 (sat., 2 x 5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford thiophene-2-carboxylic acid N-(1-15 phenethylpiperidin-3-ylmethyl)-N-phenyl amide 16 as an oil (25..w; irdg, 53%). LRMS 405.
Example 16 Synthesis of N-(1-Boc-piperidin-3- lm~eth_yl)-N-(pyridin-3-yl) amine (171 O NH2 N\
H I~N N
H
N NaBH3CN
N
;Bu t O /~O,Ba O

2o To a solution of N-Boc-piperidin-3-yl-formaldehyde 3 (0.89 g, 4.16 mmol) in 3 mL
of dry methanol and 3 mL of trimethylorthoformate was added 3-aminopyridine (0.39 g, 1 eq.), and the mixture was stirred at room temperature for 1.5 hours. NaBH3CN
(95%, 0.29 g, 1.05 eq.) was introduced in one portion, and the mixture was stirred at room temperature overnight. The mixture was quenched with 10 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 30 mL). The extracts were combined and washed with aqueous NaHC03 (sat., 2 x 10 mL), brine (20 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate) to afford N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amine 17 as a white solid (0.91g, 75%). LRMS 292.
Example 17 Synthesis ofN-(1-Boc-~peridin-3-ylmethyl)-N-(pyridin-3-yll propionamide (18) ~COCI
CHZC12, r.t.
N
N
NJ O
O
tBu To a solution ofN-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amine 17 (100 mg, 0.34 mmol) and piperidinomethyl polystyrene resin (100 mg) in 1 mL of dry CHZCIz was added propionyl chloride (30 ~L, 1 eq.) at room temperature. After being shaken at room temperature overnight, the reaction mixture was passed through an aminopropyl NHZ
cartridge and washed with CHZCIz. Removal of CH~Ch afforded N-(1-Boc-piperidin-ylmethyl)-N-(pyridin-3-yl) propionamide 18 (85 mg, 71%). LRMS 248 (M-100)+.
Example 18 2o Synthesis of N-(1-Phenethyl-~peridin-3-vlmethyl)-N-(pyridin-3-~) propionamide (19) N
\
N
1) CHzCl2-TFA
50 %, r.t. NJ O%~
2) PhCHzCHO, DMF
NaB(OAc)gH

Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) propionamide 18 (42.5 mg, 0.12 mmol) in 0.5 mL of dry CHZC12 at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. After removal of the solvents, the residue was dried under vacuum for 3 hrs (LRMS 248). The crude compound was dissolved in DMF (0.5 mL) and phenylacetaldehyde (122 ~L, 2M/in DMF) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 58 mg, 2 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 10 mL).
l0 The extracts were combined and washed with aqueous NaHC03 (sat., 2 x 5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-(1-Phenethyl-piperidin-3-ylmethyl)-N-(pyridin-3-yl) propionamide 19 as an oil (9.2 mg, 28%). IR (film, cm') 3026, 2933, 2852, 2794, 2765, 1666, 1479, 1421, 1396, 1261, 1237, 1214, 1188, 1159, 1114, 1078, 1026, 749, 719. LRMS
352.
Example 19 Synthesis of Furan-2-carboxylic acid N-(1-Boc-~peridin-3- l~yll-N-(pyridin-3-yl) amide (201 N
N
O COCI
~ ~ N
~N
H
CHZC12, r.t. NJ O O
N
~Bu O' _O
O O I
17 tBu 20 To a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amine 17 (99 mg, 0.34 mmol) and piperidinomethyl polystyrene resin (100 mg) in 1 mL of dry CH,CIz was added 2-furoyl chloride (95%, 56.0 mg, 1.2 eq.) at room temperature. After being shaken at room temperature overnight, the reaction mixture was passed through an aminopropyl NHZ
cartridge and washed with CHZC12. Removal of CHZC1, afforded furan-2-carboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amide 20 (80 mg, 61%). LRMS 286 (M-100)+.
_ 87 -Exam Ip a 20 Synthesis of Furan-2-carboxylic acid N-(1-phenethyl-pineridin-3-ylmeth~l-N-(~yridin-3-~l~
amide 21 N
1 ) CHZC12-TFA
50 %, r.t.
2) PhCH2CH0, DMF
NaB(OAc)gH

Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of furan-2-carboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amide 20 (37 mg, 0.096 mmol) in 0.5 mL of dry CH,C1, at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. After removal of the solvents, the residue was dried under vacuum for 3 hrs (LRMS 286). The crude compound was dissolved in DMF (0.5 mL) and phenylacetaldehyde (95 p.L, 2M/in DMF) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 45 mg, 2 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with S mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 10 mL).
The extracts were combined and washed with aqueous NaHC03 (sat., 2 x 5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford furan-2-carboxylic acid N-(1-phenethyl-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amide 21 as an oil (21.8 mg, 58%). IR (film, crri') 3024, 2932, 2854, 2801, 2767, 1647, 1574, 1478, 1424, 1397, 1306, 1226, 1186, 1113, 1027, 1011, 752, 715; 'H NMR (CDC13, ppm) 8.61 (d, 1H), 8.51 (d, 1H), 7.58 (m, 1H), 7.36 (m, 1H), 7.29-7.18 (m, 6H), 6.26 (m, 2H), 3.85 (ddd, 2H, J = 32.7, 13.7, 6.6 Hz), 2.96 (m, 2H), 2.81 (m, 2H), 2.62 (m, 2H), 2.04 (m, 3H), 1.76 (m, 2H), 1.60 (m, 1H), 1.19 (m, 1H).
LRMS 390.
Example 21 Synthesis of Cyclopropanecarboxylic acid N-(1-Boc-piperidin-3-vlmethyl~(~vridin-3-~l amide 22 _88_ N
N
\
N / D-COCI
CHZCIz, r.t.
J "
N
/~ /tBu O' -O

To a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amine 17 (56 mg, 0.19 mmol) and piperidinomethyl polystyrene resin (3.5 mM/g, 60 mg) in 0.6 mL
of dry CHZCh was added cyclopropanecarbonyl chloride (98%, 21 ~L, 1.2 eq.) at room temperature. After being shaken at room temperature overnight, the reaction mixture was passed through an aminopropyl NHZ cartridge and washed with CH~Ch. Removal of CH~CIz afforded Cyclopropanecarboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amide 22 (50 mg, 73%). LRMS 260 (M-100)+.
Example 22 1o Synthesis of C~propanecarboxylic acid N-(1-phenethyl-piperidin-3-ylmeth~l-N-(pyridin-3-yll amide (23) N
N ~ \
\ /
N / 1) CHZCIz-TFA
N
50 %, r.t. N
N ~ O ..
2) PhCH2CH0, DMF
NaB(OAc)3H
O O
I /
tBu 22 ~ ~ 23 Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of Cyclopropanecarboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amide 22 (46 mg, 0.128 mmol) in 0.5 mL of dry CHzCl2 at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. After removal of the solvents, the residue was dried under vacuum for 3 hrs (LRMS 260). The crude compound was dissolved in DMF (0.5 mL) and phenylacetaldehyde (130 ~L, 2M/in DMF) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 57 mg, 2 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 10 mL). The extracts were combined and washed with aqueous NaHC03 (sat., 2 x 5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford cyclopropanecarboxylic acid N-(1-phenethyl-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amide 23 as oil (23.5 mg, 51%). IR (film, cm') 3026, 2931, 2854, 2800, 2765, 1657, 1582, 1573, 1479, 1445, 1408, 1263, 1202, 1188, 1118, 1025, 748, 735; 'H NMR (CDCl3, ppm) 8.62 (m, 2H), 7.65 (d, 1H, J = 8.1 Hz), 7.41 (dd, 1H, J = 12.7, 4.8 Hz), 7.33-7.19 (m, 5H), 3.72 (m, 2H), 2.90 (m, 2H), 2.80 (m, 2H), 2.58 (m, 2H), 2.03 to (m, 1H), 1.87 (m, 2H), 1.70 (m, 2H), 1.56 (m, 1H), 1.26 (m, 2H), 1.09 (m, 3H), 0.69(m, 1H); LRMS 364.
Example 23 Synthesis of N-Boc-(R )-nipecotic acid (25) 'OH
O/ I ) Boc20 2) OH _ N
H O' -O
I
24 tBu 25 A solution of ethyl N-Boc-(R )-nipecotate-L-tartrate (24) (10.00 g, 32.5 mol) in 50 mL of dioxane and 50 mL of HBO was cooled in ice-water bath and NEt3 (9 mL) was added with stirnng. Stirnng and cooling were continued while di-tert-butyl dicarbonate (7.44 g, 1.05 eq.) was introduced. The mixture was warmed to room temperature and stirred for 4 h.
100 mL of Ethyl acetate and 20 mL of HZO were added to mixture. The aqueous layer was 2o extracted with ethyl acetate (2 x 100 mL). The extracts were combined and washed with aqueous potassium carbonate (sat., 2 x 50 mL), aqueous HCl (5%, 2 x 50 mL), brine (50 mL), and dried over anhydrous sodium sulfate, filtered and evaporated to give ethyl N-Boc-(R)-nipecotate as a colorless oil 8.37 g (100%).
To a solution of ethyl N-Boc-(R)-nipecotate (7.61 g, 29.6 mmol) in 25 mL of methanol was added LiOH (2.48 g, 2 eq.) in 25 mL of H20 dropwise at 4 °C. The reaction mixture was stirred overnight at 4 °C. The pH of the mixture was adjusted to ca. 1 by adding aqueous HCl (10 % w/w). The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The extracts were combined and washed with aqueous NH4C1 (sat., 2 x 50 mL), brine (50 mL), and dried over anhydrous NazS04, filtered and evaporated to give N-Boc-(R)-nipecotic acid 25 as a white solid 6.25 g (92%).
Example 24 Synthesis of (R)-1-Boc-piperidine-3-carboxylic acid phenyl amide (26) o ~\
OH
NJ PhNH2, DCC NJ
O% \ O%\

To a solution of N-Boc-(R)-nipecotic acid 25 (4.00 g, 17.5 mmol) and aniline (1.67 mL, 1.05 eq.) in 30 mL of dry CH,CI, was added DCC (4.88 g, 1.05 eq.) in one portion at 0 °C. The mixture was stirred at room temperature for 4 hours. Filtration and removal of the solvent gave an oily crude product, which was purified by flash column chromatography (silica gel, hexane:ethyl acetate) to afford (R)-1-Boc-piperidine-3-carboxylic acid phenyl amide 26 as a colorless oil (5.26 g, 99%).
Example 25 Synthesis of (Rl-1-Pheneth~piperidine-3-carboxylic acid phenyl amide (27) o \
o \ ~ /
'N
_ / H
H 1) TFA, CHZC12 N
N 2)PhCHzCHO
/~ NaB(OAc)gH
O' -O
I /
tBu 26 \ 27 Trifluoroacetic acid (0.5 mL) was added dropwise to (R)-1-Boc-piperidine-3-carboxylic acid phenyl amide 26 (46.7 mg, 0.154 mmol) in 0.5 mL of dry CH~CIz at 0 °C
(ice-water). The reaction mixture was stirred at room temperature for 30 minutes. After 2o removal of the solvents, the residue was dried under vacuum for 3 hrs (LRMS
309). The crude compound was dissolved in DMF (0.5 mL) and phenylacetaldehyde (154 ~L, 2M/in DMF) was added. The mixture was stirred at room temperature for 30 min.
NaB(OAc)3H
(95%, 101 mg, 2 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 10 mL). The extracts were combined and washed with aqueous NaHC03 (sat., 2 x S mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford (R)-1 Phenethyl piperidine-3-carboxylic acid phenyl amide 27 as an oil (8.2 mg, 17%). LRMS
l0 309.
Example 26 Synthesis of (R)-N-(1-Boc-~iperidin-3-vlmethvl)-aniline (281 o ~ \ ~ \
N / N /
H H
NJ Borane NJ
0%\Q
'B a tBu (R)-1-Boc-piperidine-3-carboxylic acid phenyl amide 26 (5.26 g, 17.28 mmol) in mL of dry THF was added slowly to 34.5 mL of 1.0 M borane in THF while stirring in an ice bath. The mixture was refluxed for 2 hours, then cooled in an ice bath, and quenched with 20 mL of aqueous HCl (10%), then treated with NaOH (10%) to pH ~10. The mixture 2o was extracted with ethyl acetate (3 x 100 mL). The extracts were combined and washed with brine (2 x 50 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was passed through a short column (silica gel, ethyl acetate) to afford (R)-N-(1-Boc-piperidin-3-ylmethyl)-aniline 28 as a colorless oil ( 4.59 g, 91 %).
Example 27 Smthesis of (R ) N-(1-Pheneth~-nineridin-3- l~methyl)-N-phen ~~l-pro~ionamide (30) I\
N /
N J O' I\

Following a procedure similar to that described in Examples 4 and 5, (R)-N-(1-Boc-piperidin-3-ylmethyl)-aniline 28 was converted first to (R)-N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 29, and then to (R) N-(1-Phenethyl-piperidin-3-ylmethyl)-N-phenyl-propionamide 30 (LRMS 350).
Example 28 Synthesis of (Sl-N-(1-Boc-~iperidin-3- I~yll-N-phenyl-propionamide (311 \ \ \
N I / I ~ I
HPLC
NJ o~

Resolution of (racemic)-5 was effected by HPLC on a Chiralpak AD
semipreparative column (hexane/isopropyl alcohol, 95:5). The first compound to separate was (R)-29. The second was (S)-N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 31.
Examwle 29 Synthesis of (S) N-(1-Phenethvl-~iperidin-3- l~yll-N-phen~propionamide (32) I\
'~~..". \ N /
~~~~o~."\N /
N ~ O' NJ o~

I\
Following the procedures described in Example 5, (,S~-N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 31 was converted to (S~ N-(1-Phenethyl-piperidin-3-ylmethyl)-N-phenyl-propionamide 32 (LRMS 350).
Example 30 Lack of acute in vivo toxici~ of 6 in mice A 7 mg/mL solution of 6 in 50 mM aqueous sodium acetate was prepared. A dose of 1 mg/kg was administered to four male mice via tail vein injections. The mice showed no adverse effects from the compound. Furthermore, a dose of 10 mg/kg was administered to four male mice via intraperitoneal injections. Likewise, the mice showed no adverse effects from the compound at this concentration.
Example 31 In vivo analgesia of 6 in mice A "tail-flick" analgesia model known in the art was utilized (D'Amour et al J.
Pharmacol. Exp. Ther. 1941, 7~, 74). Groups of four male mice weighing ~22 g were treated with 6. Compound 6 was dissolved in a vehicle of 50 mM aqueous sodium acetate for both intraperitoneal and intravenous administration. The control group received vehicle alone. Before treatment (0 minute), pre-selection was done by using a focused beam of 2o radiant heat applied to the middle dorsal surface of the animal tail to elicit a tail flick response within 6-7.5 seconds. Compound 6 was administered for 30 minutes and 1 minute for ip and iv injection, respectively, before the stimulation by the focused beam of radiant heat used as pre-selection. The time required to elicit the tail-flick response was recorded for each animal and a maximum cut-off of 15 seconds was set. Prolongation by 50% or more of the time required to elicit a tail-flick response relative to pretreated animals indicated analgesic activity. The results of these experiments are recorded in Table 2. See also Figure 2.
Table 2 Compound Route EDso 6 ip 7 mg/kg 6 iv 0.3 mg/kg Example 32 A~onism of Opiate Receptors This Example demonstrates significant agonism of opiate ~., K, and 8 receptors by (,S~-32 and significant agonism of opiate ~, K by (R)-30, utilizing procedures outlined by Maguire et al. (Eur. J. Pharmacol. 1992, 213, 219). The results are recorded in Table 3.
to Table 3 Com ound (R)-30 0.3 M 0.3 M -(.S~-32 0.1 M 0.1 M 0.1 M

Example 33 1-Pheneth~rlpiperidine-3-carboxylic acid phenvlamide 35 N~ OH PhNHy DCC N~ H
of \p of \p N
J
1) TFA, CHzCIZ N
2)PhCH2CH0 NaB(OAc)3H
/
15 To a solution of N-Boc-nipecotic acid 33 (102 mg, 0.445 mmol) and aniline (41 ~L, 1.0 eq.) in 2 mL of dry Cl-IZCIz was added DCC-resin (430 mg). The reaction mixture was shaken at room temperature overnight. Filtration and removal of the solvent gave oily crude product, which was purified by flash column chromatography (silica gel, hexane:ethyl acetate) to afford 1-Boc-piperidine-3-carboxylic acid phenyl amide 34 as a colorless oil (120 mg, 89%).
Trifluoroacetic acid (0.5 mL) was added dropwise to 1-Boc-piperidine-3-carboxylic acid phenyl amide 34 (62 mg, 0.20 mmol) in 0.5 mL of dry CH,CI, at 0 °C
(ice-water). The reaction mixture was stirred at room temperature for 30 minutes. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude product was used in the next step without purification.
1o The crude compound from the previous step was dissolved in DMF (0.5 mL) and phenylacetaldehyde (400 uL, 2 M/in DMF) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 90 mg, 2 eq.) was introduced in one portion, and the mixture was :shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 10 mL).
The extracts were combined and washed with aqueous NaHC03 (sat., 2 x 5 mL), brine ( 10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford 1-Phenethylpiperidine-3-carboxylic acid phenylamide 35.
LRMS 309.
Exam~ole 34 1-Pheneth~pineridine-3-carboxylic acid N-phenyl-N-ethylamide 37 O O \ O
N
OH N
NJ PHZNHEt, DCC NJ ~ 1) TFA, CHZCIZ N
2)PhCH2CH0 /~ /~ NaB(OAc)3H
O' -O O~O
I I
tBu tBu \ 37 To a solution of N-Boc-nipecotic acid 33 (113 mg, 0.493 mmol) and ethylaniline (62 ~.L, 1.0 eq.) in 2 mL of dry CHZCl2 was added DCC-resin (480 mg). The reaction mixture was shaken at room temperature overnight. Filtration and removal of the solvent gave an oily crude product, which was purified by flash column chromatography (silica gel, hexane:ethyl acetate) to afford 1-Boc-piperidine-3-carboxylic acid N-phenyl-N-ethhylamide 36 as a colorless oil (150 mg, 92%).
Trifluoroacetic acid (0.5 mL) was added dropwise to a 1-Boc-piperidine-3-carboxylic acid N-phenyl-N-ethhylamide 36 (56 mg, 0.168 mmol) in 0.5 mL of dry CHZCIZ
at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 30 minutes.
After removal of the solvents, the residue was dried under vacuum for 3 hrs.
The crude 1 o product was used in the next step without purification.
The crude compound from the previous step was dissolved in DMF (0.5 mL) and phenylacetaldehyde (67 mg, 3 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 112 mg, 3 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL
of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 10 mL). The extracts were combined and washed with aqueous NaHC03 (sat., 2 x 5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford 1-Phenethylpiperidine-3-carboxylic acid N-phenyl-N-ethylamide 37. LRMS
336.
Example 35 Methoxyacetic acid N-(1-pheneth~piperidin-3- l~yl)-N-phenylamide 39 / ~ ~COCI
J
N CHZC12, r.t.
/~ ;Bu O"O

N /
1) TFA, CHZC12 NJ O
2)PhCH2CH0 NaB(OAc)3H

To a stirred suspension of N-(1-Boc-piperidin-3-ylmethyl)-aniline 4 (101 mg, 0.348 mmol) and piperidinomethyl polystyrene resin (110 mg) in 2 mL of dry CH,Ch was added methoxyacetyl chloride (97%, 34 pL, 1.05 eq.) at room temperature. After being shaken at room temperature for 4 hours, the reaction mixture was passed through an aminopropyl NHZ
cartridge and washed with CH~C12. Removal of CHZC12 afforded methoxyacetic acid N-(1-Boc-piperidin-3-ylmethyl)-N-phenylamide 38 (70 mg, 56%).
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of methoxyacetic acid N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl amide 38 (61.8 mg, 0.17 mmol) in 0.5 mL of to dry CH~CIz at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 20 minute. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude product was used in the next step without purification.
The crude compound from the previous step was dissolved in DMF (1.0 mL) and phenylacetaldehyde (68.3 mg, 3 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 108 mg, 3 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 10 mL).
The extracts were combined and washed with aqueous NaHC03 (sat., 2 x 5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford Methoxyacetic acid N-(1-phenethylpiperidin-3-ylmethyl)-N-phenylamide 39 as a colorless oil (31 mg, 49%). LRMS 363.
Example 36 N-(1-l3'-Phenvl)prop~nl ineridin-3-ylmethvll-N-phenvlpronionamide 44 N / N /
NJ Oi v 1) TFA, CHZC12 NJ O
2) PhCH2CHZCHO
~ NaB(OAc)3H
O' _O
I
tBu /

Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of compound N-(1-1o Boc-piperidin-3-ylmethyl)-N-phenylpropionamide 5 (58 mg, 0.167 mmol) in 0.5 mL of dry CHZC1, at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude product was used in the next step without purification.
The crude compound from the previous step was dissolved in DMF (0.5 mL) and benzaldehyde (46 ~L, 2 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 75 mg, 2 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 10 mL). The extracts were 2o combined and washed with aqueous NaHC03 (sat., 2 x 5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAclMeOH, 9:1) to afford N-(1-(3'-Phenyl)propylpiperidin-3-ylmethyl)-N-phenylpropionamide 44 as a colorless oil (49 mg, 80%). LRMS 364.

Example 37 N-Boc-3-Azetidinecarbox relic acid 46 O OH O OH
BoczO, NEt3 THF-HZO
N
H ~ /tB a O' _O

A solution of 3-Azetidinecarboxylic acid (45) (250 mg, 2.47 mmol) in 5 mL of THF
and 5 mL of HZO was cooled in an ice-water bath and NEt3 (689 ~L) was added with stirnng. Stirnng and cooling were continued while di-tert-butyl dicarbonate (570 mg, 1.05 eq.) was introduced. The mixture was warmed to room temperature and stirred overnight.
20 mL of Ethyl acer.r a and 10 mL of H,O were added to mixture. The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The extracts were combined and washed with 1o aqueous potassium carbonate (sat., 2 x 10 mL), aqueous HCl (5%, 2 x 10 mL), brine (10 mL), and dried over anhydrous sodium sulfate, and filtered. Removal of solvents gave 46 as a white solid 0.50 g (100%) Example 38 N-(1-Boc-Azetidine-3- 1Y meth~laniline 48 O OH O NHPh NHPh PhNH2, DCC ~ 1 ) Borane N N N
O~O/tgu O~O/~Bu ~ /tBu O O

To a solution of N-Boc-3-Azetidinecarboxylic acid 46 (0.50 g, 2.48 mmol) and aniline (274 ~L, 1.1 eq.) in 5 mL of dry CHZCIz was added DCC (730 mg, 1.1 eq.) in one 2o portion at 0 °C. The mixture was stirred at room temperature for 3 hours. Filtration and removal of the solvent gave an oily crude product, which was purified by flash column - loo-chromatography (silica gel, hexane:ethyl acetate) to afford 1-Boc-Azetidine-3-carboxylic acid phenylamide 47 as a colorless oil (660 mg, 96%).
1-Boc-Azetidine-3-carboxylic acid phenylamide 47 (650 mg, 2.35 mmol) in 5 mL
of dry THF was added slowly to 5 mL of 1.0 M borane in THF while stirnng in an ice bath.
The mixture was refluxed for 3 hours, then cooled in ice bath and quenched with 5 mL of aqueous HCl (10%), then treated with NaOH (10%) to pH ~10. The mixture was extracted with ethyl acetate (3 x 20 mL). The extracts were combined and washed with brine (2 x 10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was passed through a short column (silica gel, ethyl acetate) to afford N-(1-Boc-azetidine-3-ylmethyl)aniline 48 as a colorless oil ( 520 mg, 84%).
Example 39 N-(1-phenethylazetidine-3- l~methyl)-N-phenylpropionamide 50 NHPh INPh ~COCI
1) TFA, CHZC12 N CHzCl2, r.t. N 2)PhCHZCHO
/~gu t NaB(OAc)3H N
o~o O~O/ Bu 15 To a solution of N-(1-Boc-Azetidine-3-ylmethyl)aniline 48 (218.6 mg, 0.791 mmol) and piperidinomethyl polystyrene resin (250 mg) in 2 mL of dry CHzCh was added propionyl chloride (77 pL, 1 eq.) at room temperature. After being shaken at room temperature overnight, the reaction mixture was passed through an aminopropyl NHz cartridge and washed with CHZC12, Removal of CHZCl2 afforded N-(1-Boc-azetidine-3-20 ylmethyl)-N-phenylpropionamide 49 (241 mg, 96%).
Trifluoroacetic acid (2 mL) was added dropwise to a solution of N-(1-Boc-azetidine-3-ylmethyl)-N-phenylpropionamide 49 (241 mg, 0.757 mmol) in 2 mL of dry CHZCh at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 20 minute. After removal of the solvents, the residue was dried under vacuum for 2 hrs. The crude product 6 - lol -was used in the next step without purification.
The crude compound from the previous step was dissolved in DMF (3 mL) and phenylacetaldehyde (303 mg, 3 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 481 mg, 3 eq.) was introduced in one portion, and the mixture was stirred at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 10 mL).
The extracts were combined and washed with aqueous NaHC03 (sat., 2 x 5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by flash column chromatography. N-(1-1o phenethylazetidine-3-ylmethyl)-N-phenylpropionamide 50 (124 mg, 51%). LRMS
322.
Example 40 Cyclopropanecarboxylic acid N-(1-phenethylpiperidin-3- l~meth~l-N-phenamide 52.

NHPh NPh NPh D--COCI
1 ) TFA, CHZCIz N CHZC12, r.t. N~ 2)PhCH2CH0 /tgu t NaB(OAc)3H N
O~O O/~O/ Bu To a solution of N-(1-Boc-Azetidine-3-ylmethyl)-aniline 48 (108.7 mg, 0.393 mmol) and piperidinomethyl polystyrene resin (130 mg) in 2 mL of dry CHZCI, was added cyclopropanecarbonyl chloride (98%, 40 pL, 1.1 eq.) at room temperature. After being shaken at room temperature overnight, the reaction mixture was passed through an aminopropyl NH, cartridge and washed with CHZC12. Removal of CHZCIZ afforded 2o cyclopropanecarboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-phenamide 51 (120 mg, 92%).
Trifluoroacetic acid (2 mL) was added dropwise to a solution of cyclopropane-carboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-phenamide 51 (87.5 mg, 0.265 mmol) in 2 mL of dry CH~Ch at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 20 minute. After removal of the solvents, the residue was dried under vacuum for 2 hrs. The crude product was used in the next step without purification.
The crude compound from the previous step was dissolved in DMF (3 mL) and phenylacetaldehyde (106 mg, 3 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 168 mg, 3 eq.) was introduced in one portion, and the mixture was stirred at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3 x 10 mL).
The extracts were combined and washed with aqueous NaHC03 (sat., 2 x 5 mL), brine (10 1o mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by flash column chromatography to afford cyclopropanecarboxylic acid N-(1-phenethylpiperidin-3-ylmethyl)-N-phenamide 52 (46 mg, 50%). LRMS 344.
Example 41 N-yl-Boc-morpholin-2- 1-y meth,~)aniline 55 O
CO OH CO NHPh O NHPh PhNH2, DCC BH3 N N N
CH2C12 ~ THF, reflux O O'Bu O O'Bu O O'Bu To a solution of N-Boc-2-carboxymorpholine 53 (20 g, 86.95 mmol), aniline (8.71 ml, 95.58 mmol) in CHZCIz (200 ml) at 0 °C was added DCC (21.19 g, 102.69 mmol) in 2o several portions. The mixture was stirred at room temperature for 3 hrs.
The white precipitate was removed by filtration. The filtrate was washed with 5% HCI, sat. NaHC03 and then dried over NazS04, filtered and evaporated. The residue was dried by azotropic evaporation with benzene to give 54 as a white solid. LRMS calculated for C,6HZZN2O4 306, found 306.
To a solution of N-Boc-morpholine-2-carboxylic acid phenylamide 54 from the previous experiment in THF (100 ml) at 0 °C was added BH3-THF solution (1.0 M, 180 ml) through an addition funnel. After addition, the mixture was refluxed for 7 hrs. The reaction was quenched by slow addition of aq. NaHC03. THF was removed by evaporation.
The residue was extracted with EtOAc (3x50 ml). The combined organic solution was dried with NazS04, filtered and evaporated. The residue crystallized upon standing at room temperature to give 55 as a white solid (17.15 g). More solid (about 2 g) was obtained from the mother liquid (76%).
Example 42 N-(2'-phen 1y eth~morpholin-2- r~l-meth ly_l-N-~hen~propionamide 57 O
~NHPh O
N v 'CI
O"OtBu Py, CH2C12 N' c~
1 ) TFA, CH2C12 N
2) PhCH2CH2Br \

to To a solution of N-(1-Boc-morpholin-2-yl-methyl)-aniline 55 (7.49 g, 25.65 mmol), pyridine (3.1 ml, 38.48 mmol) in CHZC12 (50 ml) at 0 °C was added propionyl chloride (2.45 ml, 28.20 mmol). After stirnng for 30 min, the mixture was washed with sat.
NaHC03, dried over NazS04, filtered and evaporated to give a colorless oil, which crystallized upon standing at room temperature to give a white solid 56 (5.49 g, 60%).
To a solution of N-(1-Boc-morpholin-2-yl-methyl)-N-phenyl-propionamide 56 (5.40 g, 15.50 mmol) in CHZCIZ (10 ml) at 0 °C was added TFA (10 ml). After stirring for 2.5 hr, solvent and excess TFA was removed by evaporation. The residue was dissolved in 20 ml of CH,CIz, neutralized with sat. NaHC03. Organic layer was separated, washed with sat.
NaHC03, and dried with NazS04. After evaporation of the solvent, the light yellow oil was 2o dissolved in CH3CN (10 ml), to which HZO (10 ml), KZC03 (4.80 g) and (2-bromoethyl) benzene (2.2 ml) was added. The mixture was stirred at 70 °C for 6 hrs.
After cool down to room temperature, the organic layer was separated. Aqueous layer was extracted with EtOAc (2x 10 ml). The combined organic solution was dried with Na,S04, filtered and evaporated. The crude product was purified by flash silica gel chromatography (4% MeOH
in CHZC12 ) to give a colorless oil 57 (5.00, 92%). 'H-NMR (300 MHz, CDC13) b 7.5-7.20 (m, )OH), 3.90-3.55 (m, SH), 2.90-2.50 (m, 6H), 2.20 (m, 1H), 2.00 (m, 3H), 1.0 (m, 3H), LRMS calculated for CZZHz8N20, 352, found 352.
Example 43 HPLC Separation of the Enantiomers of 57 O O O
O N~ O N~ O ,,~wN~
HPLC
N \ I Separation N \ I + N
57 ~ ~ 151 ~ ~ 152 The enantiomers of 57 were separated using a preparative HPLC procedure. The conditions were as follows: ChiralPak AD column; 10% i-PrOH in hexane; ~. = 5 mL/min;
and 7~ = 254 nm. The absolute configuration of the chiral centers was not determined. The first peak (retention time = 10.45 min) was arbitrarily assigned structure 152, and the second peak (retention time = 11.99 min) was arbitrarily assigned struct~.~Ac 151.
Example 44 Cyclopropanecarboxylic acid N-(2'-phen 1y eth, l~rpholin-2-yl-methyl)-N-phenyl amide 59 O
O NHPh O O N
N ~y N /
O"OtBu O~O~Bu\

1 ) TFA, CH2C12 2) PhCH2CH2Br To a solution of N-(1-Boc-morpholin-2-yl-methyl)-aniline 55 (91.5 mg, 0.313 mmol), piperidinomethyl polystyrene resin (116 mg) in 1 mL of dry CH,C12 was added cyclopropanecarbonyl chloride (98%, 34 ~L, 1.2 eq.) at room temperature. After being shaken at room temperature 1 h, the reaction mixture was passed through an aminopropyl NHZ cartridge and washed with CHZCIz. Removal of CHZCI, afforded Cyclopropanecarboxylic acid N-(2'-Boc-morpholin-2-yl-methyl)-N-phenyl amide 58 (91 mg, 81 %).
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of Cyclopropane-1o carboxylic acid N-(2'-Boc-morpholin-2-yl-methyl)-N-phenyl amide 58 (63.2 mg, 0.175 mmol) in 0.5 mL of dry CH,CIZ at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 20 minute. After removal of the solvents, the residue was dried under vacuum for 2 hrs. The crude product was used in the next step without purification.
The crude product was dissolved in 2 ml of CH3CN, to which K~C03 (75 mg) and (2-bromoethyl) benzene (47 ~L, 2 eq.) was added. The mixture was stirred at 50 °C for 4 hrs.
After cool down to room temperature, 2 mL of NaHC03 (sat.) and 10 mL of EtOAc were added. The organic layer was separated. Aqueous layer was extracted with EtOAc (2x 5 mL). The combined organic solution was dried over NazS04, filtered and evaporated. The crude product was purified by flash silica gel chromatography to give a colorless oil 2o Cyclopropanecarboxylic acid N-(2'-phenylethylmorpholin-2-yl-methyl)-N-phenyl amide 59 (55 mg, 86%). LRMS 364.

Example 45 N-(1-Boc-piperidin-3-(R)-vlcarboxvl-N (nvridin-3-vllamide 64 O O
OH ~ DCC N~N
~N H

Boc Boc A solution of R-Boc-nipecotic acid (6.54 mmol, 1.50 g) and 3-aminopyridine (1.1 equiv, 7.20 mmol, 677 mg) in CH,CIz at 0 °C was treated with DCC (2.0 equiv, 13.08 mmol, 2.70 g) under Ar. The reaction mixture was allowed to warm to 25 °C and stirred for 12 h. The reaction mixture was then filtered to remove the urea and the solvents were removed in vacuo. Chromatography (Si02, 2.5 cm X 30.5 cm, 3:1 hexane-EtOAc) gave 64 (1.26 g, 2.00 g theoretical, 63%) as a white solid: Rf0.33 (Si02, 3:1 hexane-EtOAc), LRMS
m/z 305 (M+, C,6H,3N3O3~ requires 305).
Example 46 N-(1-Pheneth ~~l-piperidin-3-R- lmethyl)-N (,~~ridin-3-yl)cyclopropionamide 66 o ~N
'H 1. LAH-THF
N 2. CH CHCOCI
( 2)2 ~N
N
1. TFA-CH2C12 N~ o 2. PhCH2CH0, Na(OAc)3BH

A solution of 64 (0.33 mmol, 100 mg) in THF at 0 °C was treated with 1M
LAH in THF (2.0 equiv, 0.655 mmol, 655 pL) under Ar. The reaction mixture was allowed to warm to 25 °C and stirred for 1 h. The reaction mixture was then cooled to 0 °C and quenched with 10% aqueous HCI. The pH was then adjusted to 10 with 10% aqueous NaOH and the reaction mixture was extracted with 3 X EtOAc (25 mL). The organics were dried with NaCI
~Sa~~ and MgS04 ~5~. The resulting amine was carried directly to the next step.
The above solution in CH~Cl2 at 0 °C was treated with cyclopropanecarbonyl chloride (1.1 equiv, 0.36 mmol, 33 pL) and diisopropylethylamine (2.0 equiv, 0.652 mmol, 114 pL) under Ar. The reaction mixture warmed to 25 °C and stirred for 12 h. After the reaction mixture was quenched with 10% aqueous NaHC03 and then extracted with EtOAc (25 mL). Chromatography (SiOz, 1.3 cm X 30.5 cm, 3:1 EtOAc -Hexane) provided 65 (53 mg, 117 mg theoretical, 45%) as a golden oil: Rf 0.32 (SiO~, 3:1 EtOAc -Hexane);
LRMS m/z 359 (M+, CZ°HZ9N3O3, requires 359).
1o Compound 65 (0.15 mmol, 33 mg) was treated with 20% TFA-CHzCIz under Ar.
The reaction mixture stirred for 1 h. The solvents were removed in vacuo and the resulting oil was dried for 3 h under vaccum. The resulting crude amine salt was used directly without purification.
The above compound and phenylacetaldehyde (2.0 equiv, 0.29 mmol, 34 pL) were dissolved in DMF (500 ~L) under Ar. After stirnng for 1 h at 25 °C, the reaction mixture was treated with Na(OAc)3BH (2.0 equiv, 62 mg, 0.29 mmol) and stirred for 12 h at 25 °C.
The reaction mixture was quenched with 10% aqueous NaHC03.and then extracted with 3 x EtOAc (25 mL). Chromatography (PTLC, Si02, 20 cm X 20 cm, 1 mm, 9:1 EtOAc -CH30H) provided 66 (19 mg, 53 mg theoretical, 36%) as a 2o golden oil: Rf 0.26 (SiOz, 3:1 EtOAc -Hexane); LRMS mlz 363 (M+, C_3H~9N30, requires 363).
Example 47 N-(1-tert-Butyloxy-~i~peridin-3-S-ylcarboxyl-N (pyridin-3-yllamide 67 iN
DCC ~ N
+ H
N H2N I ~ N CH2CI2 N
Boc Boc A solution of S-Boc-nipecotic acid (6.54 mmol, 1.50 g) and 3-aminopyridine (1.l equiv, 7.20 mmol, 677 mg) in CHZCh (25 mL) at 0 °C was treated with DCC
(2.0 equiv, 13.08 mmol, 2.70 g) under Ar. The reaction mixture was allowed to warm to 25 °C and stirred for 12 h. The reaction mixture was then filtered to remove the urea and the solvents were removed in vacuo. Chromatography (Si0" 2.5 cm X 30.5 cm, 3:1 hexane-EtOAc) gave 67 (1.08 g, 2.00 g theoretical, 54%) as a white solid: Rf 0.33 (Si02, 3:1 hexane-EtOAc), LRMS m/z 305 (M+, C,6Hz3N3O3~ requires 305). ' Example 48 N-(1-Phenethyl-pineridin-3-S~lmeth~l-N (pyridin-3-yl)c~propionamide 69 \ ~op"...yN , N

N 1. LAH-THF ° N 1. TFA-CH2C12 N O
H -2. CH CHCOCI ~ 2. PhCH CHO, N ( 2)2 N O~ 2 Boc Boc Na(OAc)3BH
67 68 ~ / 69 A solution of 67 (3.37 mmol, 1.03 g) in THF (5 mL) at 0 °C was treated with 1M
LAH in THF (2.0 equiv, 6.74 mmol, 6.74 mL) under Ar. The reaction mixture was allowed to to warm to 25 °C and stirred for 1 h. The reaction mixture was then cooled to 0 °C and quenched with 10% aqueous HCI. The pH was then adjusted to 10 with 10% aqueous NaOH and the reaction mixture was extracted with 3 x EtOAc (25 mL). The organics were dried with NaCI ~Saa and MgS04. The resulting amine was carried directly to the next step.
The above solution in CH~CIz at 0 °C was treated with cyclopropanecarbonyl chloride (1.5 equiv, 3.66 mmol, 332 ~L) and diisopropylethylamine (1.1 equiv, 2.68 mmol, 467 pL) under Ar. The reaction mixture warmed to 25 °C and ~arirred for 12 h. After the reaction mixture was quenched with 10% aqueous NaHC03 and then extracted with EtOAc (25 mL). Chromatography (SiOz, 1.3 cm x 30.5 cm, 3:1 EtOAc -Hexane) provided 68 (263 mg, 877 mg theoretical, 30%) as a golden oil: Rf 0.32 (Si02, 3:1 EtOAc -Hexane);
2o LRMS m/z 359 (M+, Cz°HZ9N3O3, requires 359).
Compound 68 (3.37 mmol, 1.21 g) was treated with 20% TFA-CH,Cl2 under Ar.
The reaction mixture stirred for 1 h. The solvents were removed in vacuo and the resulting oil was dried for 3 h under vacuum. The resulting crude amine salt was used directly without purification.
The above compound and phenylacetaldehyde (2.0 equiv, 6.74 mmol, 790 pL) were dissolved in DMF (10 mL) under Ar. After stirring for 1 h at 25 °C, the reaction mixture was treated with Na(OAc)3BH (2.0 equiv, 1.43 g, 6.74 mmol) and stirred for 12 h at 25 °C.
The reaction mixture was quenched with 10% aqueous NaHC03.and then extracted with 3 x EtOAc (25 mL). Chromatography (PTLC, SiO,, 20 cm X 20 cm, 1 mm, 9:1 EtOAc -CH30H) provided 69 (0.200 g, 1.22 g theoretical, 16%) as a golden oil: Rf 0.26 (Si0" 3:1 EtOAc -Hexane); LRMS m/z 363 (M+, C,3Hz9N30, requires 363).
Example 49 (Rl-Cyclopropanecarboxylic acid N-(1-pheneth,~lpiperidin-3- 1~~1-N-phenamide \ \
N I / N I /
~~ H
N ~ NJ O
,Bu ~ ~Bu O O O O

1o Following a procedure similar to that described in Example 48, compound 28 gave (R)-Cyclopropanecarboxylic acid N-(1-phenethylpiperidin-3-ylmethyl)-N-phenamide 71.
LRMS 362.
Example SO
(Sl-Cyclo~ropanecarboxylic acid N-(1-pheneth~piperidin-3ylmethyl)-N-phenamide \ \
o."~:\N I / ~.."..\N I /
H
N N O
,Bu ~ ~Bu O O O O

I\
~~..".~\N /
N O
I\

Following a procedure similar to that described in Example 48, compound 31 gave (S~-Cyclopropanecarboxylic acid N-(1-phenethylpiperidin-3-ylmethyl)-N-phenamide 73.
LRMS 362.
Example 51 Cvcl~ropanecarboxylic acid N-(1-Phenethylpiperidin-3 ylmethyll-N-(pvridin-2-,~11 amide _76 O NH2 N \
N
H ~ i N / D-COCI
J
N NaBH3CN CHZC12, r.t.
N
~ /tBu t O%\O O~\O/ Ba 3 74 N \
N \ N
I 1 ) CHZC12-TFA
N / 50 %, r.t. _ NJ O
NJ O.~ 2) PhCH2CH0, DMF
\~ NaB(OAc)3H
O~O
tBu \ 76 1o Following the procedures described in Examples 3-5, compound 3 gave Cyclopropanecarboxylic acid N-(1-Phenethylpiperidin-3-ylmethyl)-N-(pyridin-2-yl) amide 76. LRMS 359.

Example 52 N-Benz~propanolamine 77 OH OH NaBH OH

OHC ~ MeOH
~H
NH2 N~Ph N~Ph 3-Amino-1-propanol (60.5 mL, 792 mmol) was added to a solution of benzaldehyde (76.6 mL, 754 mmol) in MeOH (1.51 L, 0.5 M), and the solution was stirred and heated to 75°C. After 25 minutes, the reaction was cooled to room temperature, and then to 0°C in an 1o ice bath. Solid NaBH4 (28.52g, 754 mmol) was added over 20 minutes, and the reaction was allowed to warm to room temperature, with stirring, overnight. Water was added, the solvent was removed in vacuo, and EtOAc was added. The organic layer was removed and treated with 5% aqu~;:ous HCI. The new aqueous layer was removed, EtOAc was added, and 10% aqueous NaOH was added dropwise to basify the solution. The aqueous layer was 15 extracted with EtOAc (2x), and the combined organics were dried with NazS04, and concentrated in vacuo to obtain pure N-benzylpropanolamine (77). Crude product 77 was used without purification in the next step. 'H NMR (CD30D) 7.4-7.2 (5H, m), 4.95 (2H, broad s), 3.75 (2H, broad s), 3.64 (2H, t, J = 6.2 Hz), 2.70 (2H, t, J = 7.1 Hz), 1.77 (2H, q, J
= 6.7 Hz). '3C NMR (CD30D) 140.79, 129.61, 128.28, 61.78, 54.68, 47.56, 33.10 ppm.
2o LRMS: 165.91.
Example 53 4-Benzyl-2-chloromethyl-1,4-oxazepane 79 ~CI
H
N
N Ph ~ N
CI >
77 Ph~ 78 Ph' 79 N-benzylpropanolamine (77) (5.00 g, 30.3 mmol) was dissolved in epichlorohydrin (23.7 mL, 303 mmol) and heated to 40°C. When the reaction was judged complete by TLC
(3 h), the epichlorohydrin was removed under high vacuum overnight.
(Intermediate 78:
LRMS: 257.58.) HZS04 (9.2 mL, 3.3M) was added, with stirnng at room temperature, and the reaction was heated to 150°C in a preheated oil bath until the reaction was judged complete by TLC (0.5 h). The reaction was removed from heat and cooled by the addition of ice. CHZCIz was added, and the organic layer was removed and discarded.
EtOAc was added to the acidic aqueous layer, and 10% KOH was added dropwise until the aqueous layer was basic. The organic layer was removed; the aqueous layer was extracted with EtOAc (2x), and the combined organics were dried over sodium sulfate, filtered and to concentrated in vacuo to obtain 4-benzyl-2-chloromethyl-1,4-oxazepane (79), which was used without purification in the next step. 'H NMR (CD30D) 7.4-7.2 (5H, m), 3.93-3.75 (3H, m), 3.67 (2H, broad d, J = 1.3 Hz), 3.44 (2H, dd, J = 5.9, 4.3 Hz), 2.95 (1H, ddd, J =
13.7, 2.5, 1.2 Hz), 2.79 (1H, dddd, J = 12.6, 6.8, 4.1, 1.2 Hz), 2.64-2.52 (2H, m), 2.0 - 1.65 (2H, m) ppm. '3C NMR (CD30D) 139.89, 130.33, 129.46, 128.39, 79.26, 68.31, 63.64, 59.59, 55.30, 46.57, 31.35 ppm. '3C NMR (CDCl3) 139.10, 128.82, 128.32, 127.11, 78.27, 67.43, 62.79, 58.55, 54.26, 45.80, 30.55 ppm. LRMS: 239.54.
Example 54 (4-Benzyl-1.4-oxazepan-2-ylmethyl)-phenyl amine 80 O aniline O
~CI Nal, n-BuOH ~NH
i j ~
Ph Ph Aniline (2.59 mL, 28.4 mmol) and NaI (4.06 g, 27.1 mmol) were added to a solution of 4-benzyl-2-chloromethyl-1,4-oxazepane (79) (6.49 g, 27.1 mmol) in h-butanol (68 mL, 0.4 M), and the reaction was heated to 110°C until the reaction was judged complete by TLC (4 h). The reaction was cooled to room temperature, and water and CHZCIz were added. The organic layer was removed, and the aqueous layer was extracted with CHZCIz (2x). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to achieve (4-benzyl-1,4-oxazepan-2-ylmethyl)-phenyl amine 80, which was used without purification in the next reaction. 'H NMR (partial, CDC13) 4.08-3.86 (3H, m), 3.80 ( 1 H, d, J = 13.3 Hz), 3.73 ( 1 H, d, J = 13.3 Hz), 3.22-3.05 (2H, m), 2.95-2.70 (3H, m), 2.64 (1H, dd, J = 13.6, 7.6 Hz), 2.1-1.9 (2H, m) ppm. '3C NMR
(CDC13) 148.33, 139.38, 129.28, 129.11, 128.46, 127.23, 117.44, 113.13, 76.70, 67.49, 62.92, 59.35, 54.76, 46.93, 30.75 ppm. LRMS: 296.68.
Example 55 4-Benzyl-1,4-oxazepan-2-ylmethylLphenvlropionamide 81 to O O
O NH CI~ O N
~Pr EtN CH CI ~ i z , 2 2 Ph Ph iPr,EtN (4.72 mL, 27.1 mmol) was added to a solution of (4-benzyl-1,4-oxazepan-ylmethyl) phenyl amine (80) (27.1 mmol) in CH,CIz. The solution was cooled to 0°C in an ice bath, then propionyl chloride (5.17 mL, 59.6 mmol) was added dropwise. The reaction was allowed to warm slowly to room temperature, with stirring, overnight.
CH,CI, and 10%
aqueous NaOH was added. The organic layer was removed and the aqueous layer extracted with CH,C12 (2x). The organic extracts were dried with sodium sulfate, filtered and 2o concentrated in vacuo. The resulting oily residue was purified by silica gel chromatography (97:1:2 :: Hexanes:CH2C12:2N NH3 in EtOH) to obtain 4-benzyl-1,4-oxazepan-2-ylmethyl)-N-phenylpropionamide (81) as a pale yellow oil. 'H NMR (CDC13, ppm)7.36-7.19 (8H, m), 6.94 (2H, broad d, J = 6.5 Hz), 3.89-3.38 (5H, m), 3.65 (1H, d, J = 13.3 Hz), 3.54 (1H, d, J =
13.3 Hz), 2.88-2.75 (2H, m), 2.55 (1H, ddd, J = 12.5, 8.9, 4.2 Hz), 2.34 (1H, dd, J = 13.5, 8.9 Hz), 1.98-1.68 (4H, m), 0.98 (3H, t, J = 7.5 Hz). '3C NMR (CDCl3) 174.05, 143.19, 139.64, 129.60, 129.15, 128.46, 128.35, 127.79, 127.10, 76.80, 67.25, 62.61, 59.05, 54.43, 51.64, 30.42, 27.91, 9.70 ppm. LRMS: 352.72.

Example 56 (4-Phenethyl-1,4-oxazepan-2-ylmethyl)-N-phenylpropionamide 82 O H2, Pd/C O
O ~ PhCH2CH0 O
~N MeOH ~N
i i N
Ph 81 Ph 82 Phenylacetaldehyde (0.17mL, 1.42 mmol) was added to 4-benzyl-1,4-oxazepan-2-ylmethyl)-N-phenylpropionamide (81) (0.115g, 0.326 mmol) dissolved in MeOH
(9.5 mL).
% Pd/C (0.1 O 1 g) was added, and the mixture was shaken under 40 psi H, until the to consumption ofH2 ceased and the reaction was judged complete by TLC
(4.25h). The crude reaction mixture was passed through a column of Celite, concentrated in vacuo, and purified by flash column chromatography (50:48:2:: Hexanes: CH,CIz: 2N NH3 in EtOH) to obtain pure (4-phenethyl-1,4-oxazepan-2-ylmethyl)-N-phenylpropionamide (82). 'H NMR
(CDC13) 7.50-7.10 (10H, m), 3.95-3.77 (2H, m), 3.79-3.59 (3H, m), 2.97-2.86 (2H, m), 2.78 (4H, s), 2.68 ( 1 H, ddd, J = 12.9, 9.0, 4.0 Hz), 2.51 ( 1 H, dd, J = 13.5, 9.1 Hz), 2.08 (2H, q, J
= 7.5 Hz), 1.98-1.76 (2H, m), 1.07 (3H, t, J = 7.5 Hz) ppm. '3C NMR (CDCl3) 174.17, 143.32, 140.46, 129.64, 128.83, 128.55, 128.45, 127.85, 126.07, 76.28, 67.12, 60.10, 59.63, 53.93, 51.81, 34.23, 30.29, 28.02, 9.78 ppm. LRMS: 366.98.
Example 57 (R)- & (S')-(4-Phenethyl-1,4-oxazepan-2-ylmethvl)-N-phenvlpropionamide 83 & 84 N
chiral separation Ph 82 S3 t34 The enantiomers of (4-phenethyl-1,4-oxazepan-2-ylmethyl)-N-phenylpropionamide (82) were separated on a chiral column (Chiralpak AD Column number ADOOCG-1F001) with (9:1) Hexanes: iPrOH (7~ = 235 nm; flow rate = 5 mL/min). Using an analytical Chiralpak column with 90:10 hexanes:isopropanol (~, = 220 nm; flow rate = 1 mL/min), the first compound to elute from the column (9.175 min) was randomly assigned 83 (R), and the second compound to elute from the column ( 13.909 min) was assigned 84 (S).
The absolute configurations of ~ 3 ~i.nd 84 were not established.
to Example 58 4-Benzyl-1,4-ozazepan-2-ylmethyl)-N-phenylcyclopropanamide 85 O O
O NH CI~ O
P r CH CI
Y, 2 2 Ph Ph Pyridine (3.64 mL, 45.0 mmol) was added to a solution of crude amine 80 (30.0 mmol) in CH,Ch. The solution was cooled to 0°C in an ice bath, then cyclopropyl carbonyl chloride (2.99 mL, 33.0 mmol) was added dropwise. The reaction was allowed to warm slowly to room temperature and stirred until the reaction was judged complete by TLC (3.25 h). CHZC12 and saturated NaHC03 were added. The organic layer was removed and the 2o aqueous layer extracted with CHZCIz (2x). The organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The resulting oily residue was purified by alumina gel chromatography (96:2:2 :: Hexanes : CHZC12 : 2N NH3 in EtOH) to obtain 4-benzyl-1,4-ozazepan-2-ylmethyl)-N-phenylcyclopropanamide (85) as a pale yellow oil. 'H
NMR (CDjOD) 7.46-7.24 (8H, m), 7.13 (2H, broad d, J = 7.2 Hz), 3.90 -3.42 (5H, m), 2.92-2.76 (2H, m), 2.62-2.51 (1H, m), 2.30 (1H, dd, 13.7, 8.5 Hz), 1.40-1.20 (2H, m), 0.96-0.82 (3H, m), 0.61 (2H, dd, J = 7.9, 2.8 Hz) ppm. '3C NMR (CD30D) 175.84, 144.04, 140.20, 130.82, 130.54, 129.55, 129.08, 128.43, 77.04, 68.00, 63.63, 59.72, 55.83, 52.94, 31.28, 13.76, 9.34, 9.07 ppm. LRMS: 364.57.
Example 59 4-Phenet~l-1 4-ozazepan-2- l~yl)-N-phenylc~lopropanamide 87 O H2, Pd/C O
O N~ PhCH2CH0 O N
MeOH
i i N
Ph 86 Ph 87 Phenylacetaldehyde (0.091 mL, 0.780 mmol) was added to N-benzylamine 86 (0.055g, 0.156 mmol) dissolved in MeOH (5.2mL, 0.03M). 10 % Pd/C (0.0557g) was added, and the mixture was shaken under 40 psi H, until the cori:~,~~xnption of H, ceased and the reaction was judged complete by TLC. The crude reaction mixture was passed through a column of Celite, concentrated in vacuo, and purified by flash column chromatography (50:48:2:: Hexanes: CH,Ch: 2N NH3 in EtOH) to obtain pure 4-phenethyl-1,4-ozazepan-2-ylmethyl)-N-phenylcyclopropanamide (87). 'H NMR (CDC13) 7.47 (2H, m), 7.37-7.26 (5H, 2o m), 7.24-7.17 (3H, m), 3.94-3.80 (3H, m), 3.69 (1H, broad dd, J = 13.3, 7.8 Hz), 3.62 (1H, ddd, J = 11.7, 6.2, 5.3 Hz), 2.96-2.86 (2H, m), 2.77 (4H, s), 2.67 (1H, ddd, J
= 12.8, 8.9, 4.1 Hz), 2.50 (1H, dd, J = 8.9, 6.7 Hz) 2.0-1.74 (2H, m), 1.42-1.28 (1H, m), 1.04 (2H, dtd, J =
7.8, 3.4, 1.1 Hz), 0.67-0.60 (2H, m) ppm. '3C NMR (CDC13) 173.79, 143.39, 140.46, 129.52, 128.82, 128.61, 128.44, 127.53, 126.05, 76.41, 67.15, 60.06, 59.53, 53.90, 52.09, 34.21, 30.28, 12.92, 8.71, 8.50 ppm. LRMS: 378.80.
Example 60 ~R)- & (S1-4_phenethyl-1,4-ozazepan-2-vlmeth~)-N-phen~vclopropanamide 88 & 89 O O O
O N~ chiral separation O N~ O N
i N ~ I N ~ I N
Ph $7 Ph $$ Ph 89 The enantiomers of 4-phenethyl-1,4-ozazepan-2-ylmethyl)-N-phenylcyclopropanamide (87) were separated on a chiral column (Chiralpak AD
Column number ADOOCG-1F001) with (9:1) Hexanes: iPrOH (~, = 235 nm; flow rate = 5 mL/min).
Using an analytical Chiralpak column with 90:10 hexanes:isopropanol (~, = 220 nm; flow rate = 1 mL/min), the first compound to elute from the column (9.017 min) was randomly to assigned 88 (R), and the second compound to elute from the column (14.275 min) was assigned 89 (S). The the absolute configurations of 88 and 89 have not been established.
Example 61 1,4-Dioxa-8-aza-spiro[4.5]-decane-6-carboxylic acid methyl ester 91 O O HO~OH p O
N Y -OMe P~ ~ home CsHs N
H H

PTSA (24.7, 130 mmol) and ethylene glycol (24.8 mL, 439 mmol) were added to methyl-4-oxo-3-piperidine carboxylate hydrochloride (90) (25.1g, 130 mmol) in benzene (52 mL, 2.5 M). The solution was stirred and heated to reflux overnight. HZO
was removed using a Dean Stark trap. When the reaction was judged complete by TLC, 5%
aqueous NaHC03 and CHZC12 were added, and the organic layer was removed. The aqueous layer was extracted with CHZCIz (5x), and the combined organics were dried over sodium sulfate, filtered and concentrated ira vacuo, and purified by silica gel chromatography with 20:1 CH~C1,:2N NH3 in EtOH to provide 91 (16.7g, 64%). 'H NMR (CDC13) 3.82-3.70 (4H, m), 3.48 (3H, s), 3.00-2.50 (4H, m), 2.43 (1H, t), 1.76 (1H, m), 1.30 (1H, m) ppm.
'3C NMR
(CDCl3): 171.83, 106.57, 64.34, 64.17, 51.36, 48.91, 46.54, 43.69, 33.97 ppm.
Example 62 8-Benzyloxycarbonyl-1,4-dioxa-8-aza-spiro[4.5]decane-6-carboxylic acid methyl ester 92 CI
O O~O I ~ ~ O
OMe ~ OMe NJ Et3N, CH2CI2 NJ
H ~
W

Triethylamine (29.0 mL, 208 mmol) was added to a solution of 1,4-dioxa-8-aza-spiro[4.5]-decane-6-carboxylic acid methyl ester (91) (16.6, 82.5 mmol) in CH,CIz (159 mL, 0.5 M). The solution was cooled to 0 °C in an ice bath, then benzoylchloroformate (12.8 mL, 89.9 mmol) was added dropwise, with stirring, over 40 minutes. When the reaction was judged complete by TLC (0.75 h), the solution was concentrated in vacuo and purified by silica gel chromatography (10:3 Hexanes: EtOAc) to provide pure 8-benzyloxycarbonyl-1,4-dioxa-8-aza-spiro[4.5]-decane-6-carboxylic acid methyl ester (92) (23.43g, 85%). 'H
NMR (CDCl3): 7.41-7.25 (5H, m), 5.10 (2H, broad s), 4.02-3.50 (11 H, m), 2.80-2.62 (1H, broad s), 2.20-2.00 (1H, broad s), 1.70-1.50 (1H, broad s) ppm. '3C NMR
(CDC13): 170.26, 154.88, 136.47, 128.32, 127.86, 127.74, 106.78, 67.09, 64.90, 64.59, 51.71, 48.63, 43.94, 41.76, 33.15 ppm.
Exam 1w a 63 8-Benzvloxvcarbonvl-1,4-dioxa-8-aza-spiro[4.S~decane-6-carboxylic acid 93 O~O O KOH O O O
OMe ~0% aqueous MeOH OH
N N
O' _O I W O' -O

8-Benzyloxycarbonyl-1,4-dioxa-8-aza-spiro[4.5]decane-6-carboxylic acid (92) (15.04g, 44.8 mmol) was dissolved in 70% aqueous MeOH (136 mL, 0.33M). KOH
(3.76g, 89.7 mmol) was added, and the solution was stirred at room temperature until judged complete by TLC (6.75 h). The reaction was concentrated in vacuo, the CH~CIz and Hz0 were added. The organic layer was removed and discarded. The aqueous layer was carefully acidified to pH = 6 with saturated NH4C1. The organic layer was removed and concentrated in vas°ta>. The crude product 93 was used in the next reaction without further 1o purification (13.3g, 93% yield). 'H NMR (CDC13) 9.8-9.2 (1H, broad s), 7.45-7.22 (5H, broad s), 5.18-5.10 (2H, broad s), 4.10-3.94 (4H, m), 3.92-3.78 (2H, m), 3.70-3.54 (2H, m), 2.82-2.70 (1H, broad s), 2.14-2.00 (1H, m), 1.70-1.54 (1H, m) ppm. '3C NMR
(CDCI3) 174.35, 155.36, 136.58, 128.63, 128.17, 128.02, 107.14, 67.59, 65.17, 64.87, 48.75, 43.93, 41.96, 33.58 ppm. LRMS: 321.3.
Exam~nle 64 8-Benzyloxycarbonyl-1,4-dioxa-8-aza-spiro[4.5]decane-6-carboxylic acid anilide p O EDCI, aniline ~ O

N N Ph O' _O I ~ O' -O

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 2.13g, 11.1 mmol) and aniline (1.29 mL, 14.2 mmol) were added to a stirnng solution of acid 93 in CH~CIz (66.7 mL, 0.14M). The solution was stirred until judged complete by TLC
(3 h).
CHZCl2 and HZO were added. The organic was removed, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified with 1:l Hexanes:
EtOAc to obtain pure 8-benzyloxycarbonyl-1,4-dioxa-8-aza-spiro[4.5]-decane-6-carboxylic acid anilide (94) (2.26g, 61% yield). 'H NMR (CDCl3): 8.20-8.00 (1H, broad s), 7.50 (2H, broad dd, J = 8.7, 1.1 Hz), 7.39-7.26 (7H, m), 7.09 (1H, tt, J = 7.4, 1.0 Hz), 5.17 (1H, d, J =
12. 5 Hz), 5 .11 ( 1 H, d, 12. 5 Hz), 4.3 5 ( 1 H, d, J = 12.9 Hz), 4.16-3 .
94 (4H, m), 3 .51 ( 1 H, dd, J = 13.7, 11.1 Hz), 3.15 (1H, t, J = 11.8 Hz), 2.75 (1H, dd, J = 10.9, 4.5 Hz), 1.90-1.57 (3H, l0 m) ppm. '3C NMR (CDCl3): 167.20, 155.24, 138.02, 136.69, 129.23, 128.69, 128.25, 128.16, 124.36, 119.63, 108.22, 67.56, 65.26, 64.91, 50.24, 43.73, 41.87, 34.80 ppm.
LRMS: 396.7.
Example 65 8-Benzyloxycarbonyl-1 4-dioxa-8-aza-spiro[4.5]-decane-6-ylmethylphenylamine 95 0 O BH~FHF
NY ~NH N Y -NH
Ph J Ph O~O ~ w 0~..',:~~'..

Borane-THF (5.04 mL, 5.04 mmol) was added dropwise to a stirring 0°C
solution of amide 94 (1.03g, 2.52 mmol) in THF (2.9 mL, 0.86 M). The reaction was allowed to warm to room temperature, and was then heated to reflux until the reaction was judged complete by TLC (2.5 h). The reaction was cooled to room temperature, cooled in an ice bath, and quenched with 5% HCI. CHZCI, was added, and 10% aqueous NaOH was added dropwise until the aqueous layer was basic. The organic layer was removed, and the aqueous layer was extracted with CHZC12 (2x). The organics were dried over sodium sulfate, filtered and purified by silica gel chromatography (8:1:1 :: Hexanes: EtOAc: CHZCl2) to obtain 8-benzyloxycarbonyl-1,4-dioxa-8-aza-spiro[4.5]-decane-6-ylmethylphenylamine (95) (0.72g, 73%). 'H NMR (CDCl3): 7.36 (5H, broad s), 7.16 (2H, t, J = 7.1 Hz), 6.72-6.44 (3H, m), 5.22-5.00 (2H, broad s), 4.05 - 3.95 (4H, m), 3.72 (1H, dd, J = 13.6, 3.9 Hz), 3.66 - 3.30 (4H, m), 2.97 ( 1 H, dd, J = 13.3, 8.2 Hz), 2.20-1.98 ( 1 H, broad s), 1.84-1.64 ( 1 H, broad s), 1.64-1.48 (1H, broad s) ppm. '3C NMR (partial, CDCl3): 155, 148.15, 138, 129.41, 128.75, 128.3, 128.16, 117.28, 112.83, 108.64, 67.50, 65.04, 64.70, 44.92, 42.53, 42.19, 41.21, 33.16 ppm. LRMS: 382.88.
Examwle 66 to (8-Benzyloxycarbonyl-1,4-dioxa-8-aza-spiro[4.5]decane-6-ylmethyl1-N-phenylpropionamide 96 O ~O O ~O
NH CI' v N
NJ Ph iPr2EtN, CH2CI2 NJ Ph O' -O I w O' _O I w iPr~EtN (0.78 mL, 4.48 mmol) was added to a solution of amine 95 (0.718, 1.86 mmol) in CHZC12 (4.6 mL, 0.4M). The solution was cooled to 0 °C, then propionyl chloride (0.19 mL, 2.23 mmol) was added dropwise with stirnng. The reaction was allowed to slowly warm to room temperature. When the reaction was judged complete by TLC
(4.25 h), CHZC12 and HZO were added. The organic layer was separated and washed with 5%
2o aqueous HCI, then saturated aqueous NaHC03 and with brine. The organic extracts were dried over NazS04, then were purified by silica gel chromatography (6:2:2 ::
Hexanes:
EtOAc: CHZCIz) to obtain (8-benzyloxycarbonyl-1,4-dioxa-8-aza-spiro[4.5]-decane-6-ylmethyl)-N-phenylpropionamide (96) (0.71g, 87%). 'H NMR (CDC13): 7.60-7.08 (8H, m), 7.05 - 6.88 (2H, broad s), 5.20 (1H, d, J = 13 Hz), 5.05 (1H, d, J = 13 Hz), 4.30-3.80 (8H, m), 3.60-3.30 (1H, m), 3.20-2.90 (2H, m), 2.20-1.40 (4H, m), 1.18-0.90 (3H, t) ppm.
LRMS: 438.84.

Example 67 (8-Pheneth~-1 4-dioxa-8-aza-sRiro[4 5~]decane-6-ylmethyll-N-phenylpropionamide p O Pd/C, H2 O O
N~ PhCH2CH0, MeOH
J Ph O
gg ~ 97 Phenylacetaldehyde (0.87 mL, 7.40 mmol) was added to a solution of (8-benzyloxycarbonyl-1,4-dioxa-8-aza-spiro[4.5]-decane-6-ylmethyl)-N-phenylpropionamide (96) in MeOH (49.4 mL, 0.03M) in a hydrogenation flask. 20% Pd/C (0.53g) was added, and the mixture was shaken under 40 psi H, until the consumption of HZ ceased and the reaction was judged complete by TLC (3.5 h). The crude reaction mixture was passed through a column of Celite, concentrated in vacuo, and purified by flash column chromatography (60:38:2:: Hexanes: CHZC1,: 2N NH3 in EtOH) to obtain pure (8-phenethyl-1,4-dioxa-8-aza-spiro[4.5]-decane-6-ylmethyl)-N-phenylpropionamide (97) (0.59g, 92%).
'H NMR (CDC13): 7.42-7.12 (10H, m), 4.08 (1H, dd, J = 13.4, 9.5 Hz), 3.96-3.77 (4H, m), 3.65 (1H, broad d, J = 10.9 Hz), 2.92-2.80 (1H, m), 2.80-2.64 (3H, m), 2.64-2.51 (2H, m), 2.33 (2H, broad t, J = 10.3 Hz) 2.20-1.94 (3H, m), 1.72 (1H, dt, J = 13.3, 13.2, 3.7 Hz), 1.58 (1H, ddd, J = 13.1, 10.9, 4.3 Hz), 1.03 (3H, t, J = 7.4 Hz) ppm. LRMS: 408.86.
2o Example 68 1-t-Butoxvcarbon~piperidine-3-ylmethylcarboxylic acid anilide 99 aniline EDCI

~~COOH
O I /
N N
BOC BOC

EDCI (4.23 g, 2.20 mmol) and aniline (2.56 mL, 28.1 mmol) were added to a stirnng solution of N-BOC-3-piperidine acetic acid (98) (4.5g, 18.5 mmol) in CH~CI, (132 mL, 0.14 M). The solution was stirred at room temperature overnight. The reaction was judged complete by TLC. CHZCIz and H,O were added. The organic layer was removed and the aqueous layer was extracted with CHZCh. The combined organics were dried over Sodium sulfate, filtered and concentrated in vacuo. Silica gel purification (90:5:5 :: Hexanes:
EtOAc: CH,C12) rarwvided pure 1-t-Butoxycarbonylpiperidine-3-ylmethylcarboxylic acid l0 anilide (99) (4.10g, 70%). 'H NMR (CDC13): 9.03 (1H, broad s), 7.62 (2H, broad s), 7.32 (2H, t, J = 8.0 Hz), 7.01 ( 1 H, t, J = 7.4 Hz), 3.92-3.3.80 ( 1 H, m), 3.70-3.15 (3H, m), 3.0-2.8 (1H, m), 2.50-2.35 (1H, m), 2.25-2.10 (2H, m), 1.95-1.80 (1H, m), 1.70-1.40 (2H, m), 1.44 (9H, s) ppm. '3C NMR (partial, CDC13): 129.02, 124.12, 119.95, 40.77, 33.23, 31.06, 28.59 ppm.
Example 69 1-t-Butoxycarbon~piperidine-3- l~ethylphenylamine 100 N ~ TH~ N w N N
BOC BOC

1M Borane-THF (6.28 mL, 6.26 mmol) was added dropwise to a stirring, 0°C
solution of 1-t-Butoxycarbonylpiperidine-3-ylmethylcarboxylic acid anilide (99) (1g, 3.14 mmol) in THF (3.7 mL). The ice bath was removed, and the reaction was heated to reflux until the reaction was judged complete by TLC (2.5 h). The reaction was cooled to room temperature and quenched with the addition of 5% aqueous HCI. The reaction was diluted with CHZCh and 10% aqueous NaOH was added dropwise until the aqueous layer was basic. The organic layer was removed, and the aqueous layer was extracted (2x) with CHZCIz. The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo, and purified by flash column chromatography (90:5:5 :: Hexanes: EtOAc:
CHZCIz) to obtain pure 1-t-Butoxycarbonylpiperidine-3-ylethylphenylamine (100) (0.90g, 94%). 'H
NMR (CDC13): 7.24-7.15 (2H, m), 6.72 (1H, broad t, J = 7.3 Hz), 7.66-6.59 (2H, m), 4.0 (1H, broad s), 3.93 (2H, dt, J = 13.1, 4.0 Hz), 3.78-3.56 (1H, m), 3.18 (2H, t, J = 7.1 Hz), 2.85 (1H, broad t, J = 10.8 Hz), 2.58 (1H, broad s), 1.94-1.82 (1H, m), 1.74-1.38 (4H, m), 1.45 (9H, s), 1.24-1.08 (1H, m). '3C NMR (CDCl3):154.92, 148.36, 129.27, 117.21, 112.71, 79.37, 53.54, 49.27, 41.44, 33.82, 33.36, 30.99, 28.53, 24.87 ppm.
Example 70 (1-t-Butoxycarbon,~lpiperidine-3=ylethyll-N-phen~propionamide 101 O Ph NHPh ~ N' CI
O
Cf-~2CN N
BOC BOC

tPr~EtN (0.60 mL, 3.47 mmol) was added to a 0 °C solution of 100 (0.88g, 2.89 2o mmol) in CHZCIz (7.22 mL, 0.4M). Propionyl chloride (0.30 mL, 3.47 mmol) was added dropwise, and the solution was allowed to warm to room temperature. When the reaction was judged complete by TLC (5h), the reaction was diluted with CHZCIz. H,0 was added, and the organic layer was separated. The organic layer was washed with 5%
aqueous HCI, then saturated NaHC03, then brine. The crude product was dried over sodium sulfate, filtered and concentrated in vacuo, and purified by silica gel chromatography (8:1:1 ::
Hexanes: EtOAc: CHZCIz) to obtain pure (1-t-Butoxycarbonylpiperidine-3-ylethyl)-N-phenylpropionamide (101) (0.81g, 78%). 'H NMR (CDC13): 7.46-7.29 (3H, m), 7.14 (2H, J
= 7.6 Hz), 3.90-3.60 (4H, m), 2.74 (2H, broad t, J = 11.0 Hz), 2.47 ( 1 H, broad s), 2.01 (2H, q, J = 7.3 Hz), 1.84 (1H, broad d, J = 11.8 Hz), 1.64-1.54 (1H, m), 1.52-1.34 (4H, m), 1.42 (9H, s), 1.02 (3H, t, J = 7.4 Hz) ppm. '3C NMR (CDC13): 173.62, 154.92, 142.73, 129.82, 128.37, 127.98, 79.33, 53.56, 47.19, 44.37, 33.84, 31.47, 30.73, 28.54, 27.94, 24.80, 9.72 ppm. LRMS: 360.44.
Example 71 (1-Pheneth~~lpiperidine-3-ylethyl)-N-phenylpropionamide 102 Ph Ph 1. TFA
2. Na(OAc)3BH O
O Ph~CHO N
N
BOC
Ph Trifluoroacetic acid (0.38 mL, 4.99 mmol) in CHZCIz (0.38 mL) was added dropwise to a 0 °C stirring solution of 101 in CH,C12 (0.40 mL). When the reaction was judged complete by TLC, the solvent and excess trifluoroacetic acid were removed in vacuo. The crude residue was dissolved in DMF (1.54 mL, 0.18M), then phenylacetaldehyde (0.10 mL, 0.832 mmol), acetic acid (0.078 mL), and Na(OAc)3BH (0.118g, 0.555 mmol) were added sequentially. When the reaction was judged complete by TLC, saturated aqueous K,C03 was added. The organic layer was removed, and 5% aqueous HCl was added. The organic layer was discarded, and the aqueous layer was basified with saturated aqueous NH40H.
The organic layer was removed, dried with NazS04, and concentrated in vacuo.
Purification 2o by silica gel chromatography (98:2 :: CHzCIz : 2N NH3 in EtOH) provided (1-phenethylpiperidine-3-ylethyl)-N-phenylpropionamide (102). '3C NMR: 173.64, 142.77, 140.45, 129.82, 128.84, 128.50, 128.45, 127.95, 126.13, 61.08, 60.03, 54.27, 47.06, 33.89, 33.46, 32.57, 30.86, 28.00, 25.31, 9.74 ppm.
Example 72 ~1-Benz~niperidine-3=ylethyl)-N-phen~propionamide 103 Ph Ph 1. TFA
~~ N ~ 2. Na(OAc)3BH O
N O Ph~CHO
BOC Ph Trifluoroacetic acid (0.38 mL, 4.99 mmol) in CH~C12 (0.38 mL) was added dropwise to a 0 °C stirring solution of 101 (0.115g, 0.318 mmol) in CH,CIZ (0.40 mL). When the reaction was judged complete by TLC, the solvent and excess trifluoroacetic acid were removed in vacuo. The crude residue was dissolved in DMF (1.54 mL, 0.18M), then phenylacetaldehyde (0.10 mL, 0.832 mmol), acetic acid (0.078 mL), and Na(OAc)3BH
(0.118g, 0.555 mmol) were added sequentially. When the reaction was judged complete by to TLC, saturated aqueous K,COj was added. The organic layer was removed, and 5%
aqueous HCl was added. The organic layer was discarded, and the aqueous layer was basified with saturated aqueous NH40H. The organic layer was removed, dried with NazS04, and concentrated in vacuo. Purification by silica gel chromatography (99:1 ::
CHZCI, : 2N NH3 in EtOH) provided (1-benzylpiperidine-3-ylethyl)-N-phenylpropionamide (103). 'H NMR (CDCl3): 7.46-7.24 (8H, m), 7.15 (2H, broad d, J = 7.8 Hz), 3.72 (2H, J =
7.8 Hz), 3.52 ( 1 H, J = 13.2 Hz), 3.45 ( 1 H, d, J = 13.2 Hz), 2.79 (2H, broad d, J = 8.2 Hz), 2.03 (2H, q, J = 7.3 Hz), 1.91 (1H, td, J = 11.0, 3.3 Hz), 1.84-1.30 (7H, m), 1.05 (3H, t, J =
7.4 Hz), 0.98-0.84 (1H, m) ppm. '3C NMR (CDCI3): 173.65, 142.93, 138.4, 129.83, 129.35, 128.52, 128.31, 127.95, 127.07 63.68, 60.21, 54.22, 47.34, 34.14, 32.51, 30.84, 28.04, 25.34, 9.78 ppm. LRMS: 350.95.
Example 73 5-Benzyl-1-oxa-5-azaspiro[2,5]octane 110 O Me3Sl O
NaH, DMSO
N ~ N
Bn Bn Trimethylsulfonium iodide (2.13g, 10.4 mmol) in DMSO (15 mL) was added to NaH (0.4907g, 20.4 mmol) in DMSO (70 mL). 1-benzyl-3-piperidone hydrochloride hydrate (109) (0.996g, 4.41 mmol) was taken up in DMSO (15 mL) and was added to the reaction mixture at room temperature. When the reaction was judged complete by TLC (0.5 h), the reaction was poured over ice and the product was extracted with CH~Cl2. The organics were washed with H,O, dried over sodium sulfate, filtered and concentrated in vacuo. Purification with alumina gel chromatography (900:100:3 CH,CI,:Hexanes:2 N NHj to in EtOH) provided y-:~ure 5-benzyl-1-oxa-5-azaspiro[2,5]octane (110). '3C
NMR (CDC13):
137.54, 128.69, 127.83, 126.67, 62.55, 59.28, 53.32, 52.96, 52.48, 30.90, 23.51 ppm.
Example 74 1-Benzylpiperidine-3-hydroxy-3-ylmethylphenylamine 111 p OH
PhNH2 ~~NH
N N Ph i i Bn Bn 110 (0.89g, 4.38 mmol) was dissolved in aniline (2.0 mL, 21.9 mmol) in a sealed tube apparatus, and the reaction was heated to 200°C. When the reaction was judged 2o complete by TLC (2.5 h), Hz0 and EtOAc were added. The aqueous layer was brought to pH = 8, and the organic layer was removed, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography (60:38:0.2 Hexanes:CH2C12:2N NH3 in EtOH) provide 0.132g (10% for two steps) of 1-benzylpiperidine-3-hydroxy-3-ylmethylphenylamine (111). 'H NMR (CDCl3): 7.42-7.30 (5H, m), 7.28-7.21 (2H, m), 6.81-6.74 (1H, m), 6.73-6.66 (2H, m), 4.15 (1H, broad t), 3.68 ( 1 H, d, J = 13.2 Hz), 3 .5 7 ( 1 H, d, J = 13.2 Hz), 3.45 ( 1 H, broad s), 3.19 (2H, d, J = 5.5 Hz), 2.86 (2H, t, J = 11.4 Hz), 2.22-2.04 (2H, m), 1.96-1.74 (2H, m), 1.72-1.60 (1H, m), 1.50-1.32 (1H, m) ppm. '3C NMR (CDC13): 148.94, 138.09, 129.31, 129.10, 128.44, 127.31, 117.41, 113.17, 70.15, 62.85, 62.1 l, 53.47, 51.48, 33.88, 21.76 ppm. LRMS:
297.08.
Example 75 (1-Benzylpiperidine-3-h dy rox,Y-3- 1~~1-N-phenylpropionamide 112 OH O OH O
NH C~~/ N
~~ Ph ~~ Ph N ~Pr EtN N
Bn CI~2C12 Bn iPrzEtN (0.078 mL, 0.45 mmol) was added to a 0 °C solution of amine 111 (0.120g, 0.405 mmol) in CHZC12 (1.0 mL, 0.4M). Propionyl chloride (0.039 mL, 0.45 mmol) was added dropwise with stirring. The reaction was allowed to warm to room temperature.
When the reaction was judged complete by TLC (overnight), the reaction was diluted with CHzCI, and quenched with HZO. The organic layer was remove: a.nd the organic layer was extracted with CH,CI, (2x). The organics were then washed with 5% aqueous HCI, saturated aqueous NaHC03, and brine. The crude product was dried over sodium sulfate, filtered and concentrated in vacuo, and purified by silica gel chromatography (96:4::
2o Hexanes : 2N NH3 in EtOH) to obtain pure (1-benzylpiperidine-3-hydroxy-3-ylethyl)-N-phenylpropionamide (112) (0.117g, 82%). 'H NMR (CDC13): 7.44-7.05 (10 H, m), 3.99 ( 1 H, 14.3 Hz), 3 . 8 8 ( 1 H, 14.2 Hz), 3 . 51 ( 1 H, d, J = 13 .2 Hz), 3 .42 ( 1 H, d, J = 13 .2 Hz), 2.28-2.30 (2H, m), 2.32-2.14 (1H, m), 2.08 (2H, q, J = 7.4 Hz), 1.72-1.46 (3H, m), 1.46-1.26 (2H, m), 1.03 (3H, t, J = 7.4 Hz) ppm. '3C NMR (CDCl3): 144.76, 129.59, 129.16, 128.32, 128.16, 127.71, 127.16, 72.17, 62.78, 61.97, 57.66, 53.34, 34.17, 28.02, 9.76 ppm. LRMS:
352.76.

Example 76 jl-Phenethyl~ineridine-3-hydroxy-3-yleth~l-N-phenvlpropionamide 113 OH
OH O O
N H2,~ ~N
~ J Ph J Ph Ph CHO N
MeOH
Bn Ph Phenylacetaldehyde (0.17 mL, 1.42 mmol) and Pd/C (0.1 O 1 g) were added to a solution of 112 (0.0793g, 0.225 mmol) in MeOH (9.45 mL) in a hydrogenation flask, and the mixture was shaken under 40 psi of H, until the consumption of H, ceased and the reaction was judged complete by TLC. The crude reaction mixture was passed through a to column of Celite, concentrated in vacuo, and purified by silica gel chromatography (80:18:2:: Hexanes: CHZCh: 2N NH3 in EtOH) to provide (1-phenethylpiperidine-3-hydroxy-3-ylethyl)-N-phenylpropionamide (113). t3C NMR (CDCl3): 176.66, 144.74, 140.52, 129.63, 128.84, 128.47, 128.18, 127.76, 126.11, 72.04, 62.27, 59.96, 58.11, 53.51, 34.16, 33.58, 28.07, 22.10, 9.85 ppm.
Example 77 Synthesis of a Combinatorial Library of Compounds of the Present Invention (See Figure 1) Reactions on a Solid Support ~OH ~' CDI, THF ~O~N~OH S03-PY_ ~O~N~O
Wang resin 2' HN~ ~ Et3N, DMS ~O

THF, rt Rt-NH2 NaCNBH3, 1 % HOAc in TMOF
O
O O
2 TFA/CH2C12 O~N N~R2. RZ~CI ~ ,Rt HN~Rt R ~--- ~Rt DIEA, CHzCl2, rt ~O N~H
118 11~ 116 Reactions in Solution o ~ o HN N~R2 + KzCCs, CHsCN, 50° C, 24 h ~Ri ~ / Br N~R~R

A library of 96 compounds was synthesized from twelve anilines, eight acid chlorides, and (2-bromoethyl)benzene. The reductive amination and acylation reactions were carned out using solid-phase chemistry, while the alkylation of piperidine with (2-bromoethyl)benzene was performed in solution.
A. Preparation of aldehyde functionalized resin 11 S.
to To the Wang resin (9.6 g, 0.70 mmol/g) in a 250-ml peptide synthesis vessel was added 100 ml of 0.4 N CDI in anhydrous THF, and shaken at room temperature for hours. The resin was thoroughly washed with CH~CI, (3 X 100 ml ) and THF (3 X
100 ml) to remove the excess CDI and then treated with 100 ml of 0.4 N 3-piperidinemethanol in THF at room temperature for 17 hours. The resulting resin (114) was washed with DMF (3 X 100 ml), MeOH (4 X 100 ml), and CHZCIz (4 X 100 ml) and dried in vacuo. To the alcohol resin 114 was added 100 ml solution of sulfur trioxide pyridine complex (5.35 g, 33.6 mmol) and triethylamine (4.68 ml, 33.6 mmol) in DMSO, and the resulting slurry was shaken at room temperature for 1 hour. The resulting aldehyde-functionalized resin 115 was washed with DMF (3 X 100 ml), MeOH (4 X 100 ml), and CH,CI, (4 X 100 ml) and dried 2o in vacuo. Resin 115 was equally divided into 12 reactors, in which the aldehyde would react with 12 anilines, respectively.
B. Preparation of resins 116.
To resin 115 (about 0.8 g, 0.56 mmol) was added aniline (5.6 mmol) in 8 ml of trimethyl orthoformate (TMOF) and the mixture shaken at room temperature for 1 hour.
NaCNBH3 (700 mg, 11.2 mmol) was added into the mixture followed by 0.08 ml AcOH.
After shaking at room temperature for 3 hours, resulting resin 116 was extensively washed with DMF (3 X 10 ml), MeOH (4 X 10 ml), and CHZCI, (4 X 10 ml) and dried in vacuo.
Twelve resins 116 were obtained by using twelve anilines in the reductive amination.
C. Preparation of compounds 118.

Twelve resins 116 were respectively distributed into 96-well reaction block from column 1 to column 12 at 100 mg (0.07 mmol) per well (See Figure 1). Eight acid chlorides in CH,Ch were respectively dispensed into eight rows, from row A to row H, at 1 ml (containing 0.7 mmol acid chloride) per well; then diisopropylethylamine was dispensed into 96 wells at 0.122 ml (0.7 mmol) per well. The reaction block was shaken at room temperature for 3 hours and the resins were washed with DMF (3 X 1 ml/well), MeOH (4 X
1 ml/well), and CHZCIz (4 X 1 ml/well) and dried in vacuo. The resulting resins 117 were treated with a solution of 50% TFA in CH~CIz at 1 ml per well at room temperature for 30 min to release the polymer-bond piperidines 118 into a 96-deep well plate.
After washing to the resins with CHzCl2 (2 X 0.5 ml/well), the volatiles were removed under high vacuum to afford the crude compounds.
D. Preparation of compounds 119.
To piperidi~z~, 118 in the 96-deep well plate was added acetonitrile at 0.6 ml per well, dissolving the compounds, and the solutions were transferred into a 96-well reaction block. (2-Bromoethyl)benzene was then dispensed into the 96 wells at 0.010 ml (0.07 mmol) per well followed by KZC03 at 50 mg per well. The mixtures were agitated at 50° C
for 24 hours. After the reaction block cooling to room temperature, tris-(2-aminoethyl) amine polystyrene (2.45 mmol/g) was distributed into 96 wells at 50 mg per well. The mixtures were shaken at 50° C for another 24 hours. The solutions were filtered into a 96-well format SPE plate with NH, sorbent, washed the resins with CH,C12 (2 X 0.6 ml/well), collected the CH~CI, washes into the SPE plate. The compounds were eluted and collected in a 96-deep well plate. The volatiles were removed under high vacuum to afford 96 final compounds 119, which were submitted to HPLC and mass spectra analyses.
Example 78 Opiate receptor binding of certain compounds of the present invention (ICS
The opioid (~, x, 8) receptor-binding capabilities of compounds described herein were determined according to the procedures outlined by Wang et al. (FEBS
Letters 1994, 338, 217), Maguire et al. (Eur. J. Pharmacol. 1992, 213, 219), and Simonin et al. (Mol.
Pharmacol. 1994, 46, 1015). Certain results from these assays are tabulated below.
Compound ~ K b (~) (~ (~

6 <1 <1 >10 30 <1 <5 >10 32 <1 >10 >10 39 <5 <10 >10 Racemic 71 <1 <1 >10 14 <1 <5 >10 16 <1 <5 >10 23 <1 <10 >10 66 <5 <5 >10 69 <1 <5 >10 76 <1 <5 >10 19 <1 <10 >10 113 <10 >10 >10 <5 <10 >10 97 <1 <5 >10 57 <1 <1 >10 59 <1 <1 >10 44 <1 <5 >10 7 <5 <$ >10 103 <10 <5 >10 102 <1 <5 >10 50 <1 <5 >10 52 <1 <5 >10 82 <1 <5 >10 83 <1 <5 >10 84 <1 <1 >10 87 <1 <1 37 <S <5 >10 129 <1 <1 <10 125 <5 10 >10 126 <1 <1 >10 127 <5 <10 >10 128 <1 <5 >10 121 <1 >10 >10 120 <5 <5 >10 123 <1 <5 >10 124 <1 <10 >10 141 <10 <5 >10 140 <1 <5 >10 139 <1 <1 >10 134 <5 <10 <5 135 <5 >10 >10 137 <5 >10 >10 8 <5 <5 >10 11 >10 >10 <5 12 <5 <5 >10 19 <1 <10 >10 21 <I <10 <10 130 <1 <5 >10 150 <1 <10 >10 88 <1 <5 >10 89 <1 <1 >10 71 <1 <1 >10 73 <1 <5 >10 163 <1 <5 <5 170 <5 >10 >10 171 <10 <10 >10 176 <1 >10 >10 177 <1 <10 >10 178 <1 <10 <5 179 <1 >10 >10 180 <1 <5 >10 182 <1 >10 185 <1 >10 186 <1 >10 195 <1 <5 >10 196 <1 <5 <5 197 <1 <1 <10 198 <1 <1 >10 199 <1 <5 >10 204 <5 <S >10 Example 79 Analgesia in Mice and Rats (See Figure 21 This Example establishes in vivo analgesia in mice and rats for compounds 6, 30, 32, 66, and 69. A "tail-flick" analgesia model known in the art was utilized (D'Amour et al. J.
Pharmacol. Exp. Ther. 1941, 72, 74). Groups of four male mice (weighing ~22 g) or rats were used for each dose. Three doses (l, 0.5, and 0.1 mg/kg) of compounds 6, 30, 32, 66, and 69 were dissolved in a vehicle of 50 mM aqueous sodium acetate, and were 141 <10 <5 >10 140 <1 <5 >10 administered intravenously. The control group received vehicle alone. Before treatment (t = 0 minutes), pre-selection was done by using a focused beam of radiant heat applied to the middle dorsal surface of the animal tail to elicit a tail flick response within 6-7.5 seconds.
Compounds 6, 30, 32, 66, and 69 were then administered i.v. for 1 minute before stimulation by the focused beam of radiant heat. The time required to elicit the tail-flick response was recorded for each animal and a maximum cut-off of 15 seconds was set.
Prolongation by 50% or more of the time required to elicit a tail-flick response relative to control animals indicated analgesic activity.
l0 Example 80 N Phenyl-N [1-(4-Phen~but~piperidin-3-vlmethYl] propionamide (1201 I~ i~
N
I ) TFA, CH,CIz 2) Ph(CHZ)3CH0 NaB(OAc)3H
Trifluoroacetic acid (1.0 mL) was added dropwise to a solution of compound N-(1-Boc-piperidin-3-ylmethyl)-N-phenylpropionamide (108 mg, 0.31 mmol) in 1.0 mL
of dry CHzCIz at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the crude product was used in the next step without purification.
The crude compound from the previous step was dissolved in DMF (0.5 mL) and 4-phenylbutyraldehyde (49 ~L, 1.1 equiv) was added. The mixture was stirred at room temperature for 60 min. NaB(OAc)3H (95%, 340 mg, ~ eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with mL of with NaOH (10%), then extracted with ethyl acetate (3 x 10 mL). The extracts were combined and washed with aqueous NaHC03 (sat., 2 x 5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (CHzChlMeOH, 95:5) to afford N
5 Phenyl-N [1-(4-Phenylbutyl) piperidin-3-ylmethyl] propionamide (120) as a colorless oil.
LRMS 379(M+H+).
Exam~nle 81 N (2-Fluoronhenyll-N (1-Pheneth~niperidin-3-vlmeth~l propionamide (121) to O

PhNH2, DCC NH
~OH F

N~ Boc Boc \

BH3 ~~NH
THF, reflux ' N J \ F
Boc To a solution of piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 1 (1.0 g, 4.4 mmol), 2-fluoroaniline (463 p1, 4.8 mmol) in CH,C12 (25 ml) at 0 °C was added DCC (0.99 g, 4.8 mmol) in several portions. The mixture was stirred at room temperature overnight.
The white precipitate was removed by filtration. After removal of solvent, the residue was purified by column chromatography (silica gel, hexane/ethyl acetate, 4:1) to give 3-(2-fluorophenylcarbamoyl)piperidine-1-carboxylic acid tent-butyl ester (2) as a colorless oil (1.13 g, 80%).
2o To a solution of 3-(2-fluorophenylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (2) (1.13 g, 3.5 mmol) in THF (4 ml) at 0 °C was added BH3-THF
solution (1.0 M, 3.5 ml) slowly. The mixture was refluxed for 2 hrs. The reaction was quenched by slow addition of MeOH at 0 °C. The solvent was removed by evaporation. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate, 85:15) to give 3-[(2-Fluorophenylamino)methyl] piperidin-1-carboxylic acid tert-butyl ester (3) as a colorless oil (0.97 g, 90%).

~~NH \ ~
-CI N
N \ F ~~/ F
Boc I / Py, CH2CI2 goc I

N-C~/ F
1 ) TFA, CH2C12_ N I
2) PhCH2CH2Br \

/ ( 121 To a solution of 3-[(2-Fluorophenylamino)methyl] piperidin-1-carboxylic acid tert-butyl ester (3) (150 mg, 0.49 mmol), N,N-diisopropylehylamine (435 ~1, 2.5 mmol) in 1o CHZC12 (1 ml) at 0 °C was added propionyl chloride (130 ~ ~,: ".5 mmol). The reaction mixture was shaken overnight. The mixture was poured into 10% NaOH (5 mL), then extracted with ethyl acetate (3 x 10 mL). The extracts are combined and washed with aqueous NaHC03 (sat., 2 x 5 mL), dried over NazS04, filtered and evaporated to give a slightly yellow oil, which was purified by column chromatography (silica gel, hexane/ethyl acetate, 4:1) to give 3-{[(2-fluorophenyl)propionylamino]methyl} piperidine-1-carboxylic acid tert-butyl ester (4) ( 162 mg, 92%).
To a solution of 3-{[(2-fluorophenyl)propionylamino]methyl} piperidine-1-carboxylic acid tent-butyl ester (4) (162 mg, 0.45 mmol) in CHZCIZ (1 ml) at 0 °C was added 2o TFA (1 ml). After stirring for 30 min., solvent and excess TFA was removed by evaporation. The residue was dissolved in 1.5 ml of CH3CN (10 ml), to which KZC03 (1245 mg) and (2-bromoethyl) benzene (123 ~1, 0.9 mmol) were added. The mixture was stirred at 50 °C overnight. After cooling down to room temperature, 5 mL of 10%
NaOH was added.
The organic layer was separated. The aqueous layer was extracted with EtOAc (2x 10 ml).
The combined organic layers were washed with brine and dried with NazS04, filtered and evaporated. The crude product was purified by flash silica gel chromatography (5% MeOH
in CHZCI, ) to give colorless N (2-Fluorophenyl)-N (1-Phenethylpiperidin-3-ylmethyl) propionamide (121) (141 mg, 85%). LRMS 369 (M+H+) Example 82 1o N (1-Phenethylpiperidin-3-vlmethyl)-N phenyl isobutvramide (1231 \ Ycoci _ N
N
CHZCI2, r.t.
NJ O
Ni Boc I) CHZCIZ-TFA
50 %, r.t.
2) PhCH~CH,Br N
N~ O

To a stirred suspension of 3-phenylaminomethylpiperidine-1-carboxylic acid tert-butyl ester (1) (220 mg, 0.76 mmol) and piperidinomethyl polystyrene resin (350 mg) in 2.5 mL of dry CHZCIz was added isobutyryl chloride (122 ~,1, 1.5 eq.) at room temperature.
After being shaken at room temperature for 3 hours, the reaction mixture was passed through an aminopropyl NHZ cartridge and washed with CH~CIz. Removal of CHZCIz afforded 3-[(isobutyrylphenylamino)methylpiperidine-1-carboxylic acid tent-butyl ester (2) (259 mg, 95%).
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of 3-[(isobutyrylphenylamino)methylpiperidine-1-carboxylic acid tert-butyl ester (2) (106 mg, 0.29 mmol) in 0.5 mL of dry CHzCIz at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude product was used for the next step without purification.
The crude compound from the previous step was dissolved in 1.0 mL of CH3CN, to which KZC03 (122 mg) and (2-bromoethyl) benzene (82 p1, 2 eq.) were added. The mixture 1o was stirred at 50 °C overnight. After cooling down to room temperature, S mL of 10%
NaOH was added. The organic layer was separated. The aqueous layer was extracted with EtOAc (2x 10 ml). The combined organic layers were dried with Na,S04, filtered and evaporated. The remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N (1-Phenethylpiperidin-3-ylmethyl)-N
phenyl isobutyramide (123) as a colorless oil (92 mg, 86%). LRMS 365.
Example 83 N Phenyl-N L-(3-Phen~lpropylyl)piperidin-3-ylmethyl)] isobutyramide (124) N Phenyl-N [1-(3-Phenylpropylyl)piperidin-3-ylmethyl)] isobutyramide (124) was synthesized using the procedure outlined in Example 84. LRMS 379.

Example 84 N f 1-(1-Methyl-2-Phenethyl) piperidin-3-ylmethyl]-N phenyl propionamide (125 & 1261 / 1)TFA,CHzCl2 2) KZC03 ~Br N O
Boc Trifluoroacetic acid (1.0 mL) was added dropwise to a solution of (R)-N-(1-Boc-piperidin-3-ylmeti~y i i-N-phenylpropionamide (1 O1 mg, 0.29 mmol) in 1.0 mL
of dry CHzCl2 at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 30 min. TLC
showed the reaction was complete. After removal of the solvents, the crude product was to used for the next step without purification.
The crude compound was dissolved in acetonitrile (1.0 mL) and 2-bromo-1-phenyl propane (293 p.L), and K,C03 (120 mg) were added. The mixture was stirred at 50 °C
overnight. The mixture was quenched with 5 mL of aqueous KOH (10%), then extracted with ethyl acetate (3 x 10 mL). The extracts were combined and washed with aqueous NaHC03 (sat., 2 x 5 mL), brine ( 10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 95:5) to afford N [1-(1-Methyl-2-Phenethyl) piperidin-3-ylmethyl]-N phenyl propionamide as a colorless oil (66 mg, 62%) LRMS 365.
The diastereomers of N [1-(1-Methyl-2-phenethyl)piperidin-3-ylmethyl] N phenyl propionamide were separated on a chiral column (Chiralpak AD. Column number ADOOCG-1F001) with Hexanes (0.2% of diethylamine) : iPrOH (98:2). The first compound to elute from the column was 125, and the second compound to elute from the column was 126.
Example 85 N Phenyl-N [1-(2- phen~propvll niperidin-3-ylmethyl]propionamide (127 & 1281 ~ -N
1) TFA, CHZCIz N
2) NaBH(OAc)3 N O ~ ~O
Boc 127 & 128 Trifluoroacetic acid (1.0 mL) was added dropwise to a solution of compound (R)-N-(1-Boc-piperidin-3-ylmethyl)-N-phenylpropionamide (158 mg, 0.46 mmol) in 1.0 mL of dry CH,C12 at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the crude product was used for next step.
to The crude compound was dissolved in DMF (1.5 mL) and 2-phenylpropionaldehyde (93 pL, 1.5 equiv) was added. The mixture was stirred at room temperature for 30 min.
NaB(OAc),H (153 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of NaOH
(10%), then extracted with ethyl acetate (3 x 10 mL). The extracts were ~°,:;x:;:bined and washed with aqueous NaHC03 (sat., 2 x 5 mL), brine (10 mL), and dried over anhydrous sodium sulfate.
After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 95:5) to afford N Phenyl-N [1-(2-phenylpropyl) piperidin-3-ylmethyl]propionamide as a colorless oil (119 mg, 71%). LRMS 365.
The diastereomers of N Phenyl-N [1-(2-phenylpropyl)piperidin-3 2o ylmethyl]propionamide were separated on a chiral column (Chiralpak AD.
Column number ADOOCG-1F001) with Hexanes (0.2% of diethylamine) : iPrOH (98:2). The first compound to elute from the column was 127, and the second compound to elute from the column was 128.
Example 86 N Ll-(1-phenet~lpineridin-3-~leth~]-N Phenvlpronionamide (129) H
1) MsCI ~ -NH
2) PhNHz N
NJ Boc Boc y o cW
2) TFA, CHZCIz 3) PhCH2CHZBr To a stirred suspension of 3-(1-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (1) (31 mg, 0.135 mmol) and piperidinomethyl polystyrene resin (60 mg) in 0.5 mL of CHZCl2 was added methanesulfonyl chloride (15.7 ~.L, 1.5 eq.). The mixture was stirred at room temperature for 60 min. After removal of solvent, aniline (50 ~,L) was introduced.
The mixture was heated at 95 °C overnight. The crude product was purified by preparative to thin layer chromatography (EtOAc/Hexane, 1:2) to afford 3-(1 phenylaminoethyl)piperidine-1-carboxylic acid tert-butyl ester (2) (21 mg, 51%).
Compound 129 was then prepared from 2, using the final steps of the procedure described in Example 81. LRMS 365.
Example 87 1-(1-~heneth~piperidin-3- 1y meth,Xll-3 4-dihydro-1H quinolin-2-one (1301 I 1) NaH
N O
H
~I
N
Boc 1) TFA, CHZC12 2) PhCHZCHZBr To a solution of 3,4-dihydro-1H quinolin-2-one (96 mg, 0.65 mmol) in 1.5 mL of DMF was added NaH (26 mg, 1 eq.). The mixture was stirred at room temperature for 45 min. 3-Iodomethylpiperidine-1-carboxylic acid tent-butyl ester (200 mg, 0.62 mmol) in 0.5 mL of DMF was introduced slowly to the reaction mixture. The reaction was continued for 1 h. at room temperature. The mixture was diluted with 10 mL of EtOAc and washed with aqueous HCl (5%, 5 mL), NaHC03 (sat., 5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by to preparative thin layer chromatography (EtOAc/Hexane, 3:7) to afford 3-(2-oxo-3,4-dihydro-2H quinolin-1-ylmethyl)piperidine-1-carboxylic acid tert-butyl ester (2) as a colorless oil (80 mg, 37%).
3-(2-oxo-3,4-dihydro-2H quinolin-1-ylmethyl)piperidine-1-carboxylic acid tert-butyl ester (2) was converted to 1-(1-phenethylpiperidin-3-ylmethyl)-3,4-dihydro-1H
quinolin-2-one (130) (68 mg, 85%), using the final steps of the procedure described in Example 81. LRMS 349.
Example 88 N 4-tert-Butoxycarbonvl-1-Carbobenz~y~2-anilinocarboxylpiperazine (131) Cbz O Cbz O
N ~ N I /
OH ~ DCC ~ H
N + H2N / CH2C12 N
i i Boc Boc 131 A solution of 4-Boc-1-Cbz-piperazine-2-carboxylic acid (2.66 mmol, 0.970 g) and aniline (1.1 equiv, 2.93 mmol, 270 ~L) in CHZCl2 (15 mL) at 0 °C was treated with DCC
(2.0 equiv, 5.32 mmol, 1.10 g) under Ar. The reaction mixture was allowed to warm to 25 °C and stirred for 12 h. The reaction mixture was then filtered to remove the urea and the solvents were removed in vacuo. Chromatography (Si02, 2.5 cm X 30.5 cm, 1:1 hexane-EtOAc) of the crude material gave 131 (1.15 g, 1.17 g theoretical, 98%) as a white foam. LRMS m/z 439 (M+, Cz4Hz9NsOs requires 439).
to Example 89 N 4-tert-Butoxycarbonyl-1-Carbobenzvloxy(2-anilinomethyl)piperazine (132) Cbz O I ~ Cbz CN N / BH3 ~N~N /
N H THF N H
i i Boc 131 Bcc 132 A solution of 131 (0.519 mmol, 228 mg) in THF (1.5 mL) at 0 °C was treated with 1.0 M BH3-THF (2.5 equiv, 1.30 mmol) under Ar. The reaction mixture was then heated to 80 °C and allowed to stir for 12 h. The reaction mixture was then cooled to 0 °C and quenched with 10% aqueous HCI. The pH was adjusted to 10 with 10% aqueous NaOH
and 2o the reaction mixture was extracted with EtOAc (3 x 25 mL). The organics were washed with brine, and dried over MgS04 to give crude 132.
Example 90 ~4-tert-But~y-1-Carbobenzvloxypinerazin-2-ylmethvll-N
(anilinolcyclopropionamide Cbz I ~ Cbz N / COCI N
H N
iPrNEt CH CI N O
Boc z 2 Boc A solution of the crude aniline intermediate (132) (0.519 mmol) in CHZCIz at 0 °C
was treated with cyclopropanecarbonyl chloride (1.5 equiv, 0.779 mmol, 77 pL) and diisopropylethylamine (2.0 equiv, 1.04 mmol, 181 qL) under Ar. After warming to 25 °C
and stirnng for 12 h, the reaction mixture was quenched with 10% aqueous NaHC03. The to reaction mixture was then made acidic with 10% aqueous HCl and extracted with EtOAc (3 x 25 mL). Chromatography (PTLC, Si02, 20 cm X 20 cm, 1 mm, 1:2 EtOAc-Hexane) provided 133 (136 mg, 256 mg theoretical, 53%) as a colorless oil: Rf 0.22 (Si02, 1:2 EtOAc -Hexane); LRMS m/z 493 (M+, CZ8H35N3O5 requires 493).
Example 91 N 1-Carbobenzvloxy(4-phenethyl-piperazin-2-ylmeth~l-N
(anilinolcvclopropionamide Cbz I ~ Cbz N / 1. TFA/CH CI2 N _ N
H H Br N O~ 2. PhC 2C 2 / N O
i Boc A solution of 133 (0.079 mmol, 39 mg) in CHZC12 (1 mL) at 25 °C was treated with 50% TFA in CHZCl2 (1 mL). The reaction mixture stirred for 2 h. The solvents were removed in vacuo and the resulting oil was dried under high vacuum for 12 h.
The resulting oil was then treated with phenethyl bromide (4.5 equiv, 0.36 mmol, 49 ~uL) and KZC03 (5.0 equiv, 0.39 mmol, 55 mg) in CH3CN (250 q.L). The reaction mixture was stirred for 12 h at 60 °C. The reaction mixture was purified directly by chromatography (PTLC, SiOz, 20 cm X 20 cm, 1 mm, 1:2 EtOAc-Hexane) which provided 134 (29 mg, 38 mg theoretical, 76%) as a colorless oil: Rf 0.28 (Si02, 1:2 EtOAc -Hexane); LRMS m/z 497 (M+, C31H35N303 requires 497).
Example 92 N 4-Phenethyl-~inerazin-2- l~yll-N (anilinolcyclopropionamide (1351 to Cbz N I / H Pd-C 10% N I /
N 2' N
CH OH
/ I N O~ 3 / ( N O

A solution of 134 (0.048 mmol, 24 mg) in CHjOH (1 mL) at 25 °C was treated with 10% Pd-C (20mg) and then placed under a hydrogen atmosphere. The reaction mixture stirred for 12 h and then was filtered through a pad of Celite. The solvents were removed in vacuo. The reaction mixture was purified directly by chromatography (PTLC, SiOz, 20 cm X 20 cm, 1 mm, EtOAc-10% CH30H) which provided 135 ( 12 mg, 18 mg theoretical, 67%) as a colorless oil: Rf 0.22 (SiOz, EtOAc-10% CH30H); LRMS m/z 363 (M+, CZjHz9N3O requires 363).
Example 93 N 1-Meth(4-tent-Butvlox'r~iperazin-2-vlmethyll-N (anilino)c~lopropionamide (136) Cbz N I ~ H Pd-C 10% N
~N 2' CH O ~ ~N
N O~ ~ 2 )n N
Boc CH30H Boc A solution of 133 (0.18 mmol, 90 mg) in CH30H (1.5 mL) at 25 °C was treated with 10% Pd-C (20mg) and paraformaldehyde (11 mg) and then placed under a hydrogen atmosphere. The reaction mixture stirred for 12 h and then was filtered through a pad of celite. The solvents were removed in vacuo and the resulting oil was purified by chromatography (PTLC, Si02, 20 cm X 20 cm, 1 mm, EtOAc-10% CH30H) which provided 136 (38 mg, 68 mg theoretical, 56%) as a colorless oil: Rf 0.40 (Si02, EtOAc-10%
CH30H ); LRMS m/z 373 (M+, CZ,H3,N3O3 requires 373).
Example 94 N 1-Meth(4-phenethyl-piperazin-2-ylmethvll-N (anilino~yclopropionamide (137) N I / 1. TFA/CH2CI2 N
N N
2. PhCH CH Br N O~ 2 2 ~ I N O
Boc Compound 136 (0.091 mmol, 34 mg) was treated with 50% TFA in CHZCIz (1 mL) at 25 °C. The reaction mixture stirred for 2 h. The solvents were removed in vacuo and the resulting oil was dried under high vacuum for 12 h. The resulting oil was then treated with phenethyl bromide (2.0 equiv, 0.18 mmol, 25 ~L) and KZC03 (2.0 equiv, 0.18 mmol, 25 mg) 2o in CH3CN (300 ~,L). The reaction mixture stirred for 12 h at 60 °C.
The reaction mixture was purified directly by chromatography (PTLC, SiOz, 20 cm X 20 cm, 1 mm, EtOAc-10%
CH30H) which provided 137 (34 mg, 34 mg theoretical, 99%) as a colorless oil:
Rf 0.33 (SiOz, EtOAc-10% CH30H ); LRMS m/z 377 (M+, Cz4H3,N30 requires 377).

Example 95 ~1-C~clohexylethvl-pineridin-3-R-ylmeth~l-N (anilino-3-yl)propionamide (1391 \
I , ~~ N ~~ N
1. H2, Pd-C 10%
Cbz O + Br 2. K2C03/CH3CN ~N O
138 w139 A solution of 138 (0.471 mmol, 116 mg) in CH30H (1 mL) at 25 °C was treated with 10% Pd-C (20 mg) and then placed under a hydrogen atmosphere. The reaction mixture stirred for 12 h and h:en was filtered through a pad of Celite. The solvents were removed in to vacuo and the resulting oil was then treated with 1-bromo-2-cyclohexylethane (1.5 equiv, 0.707 mmol, 111 p.L) and KZC03 (1.5 equiv, 0.707 mmol, 98 mg) in CH3CN (1 mL).
The reaction mixture stirred for 12 h at 60 °C. The reaction mixture was then purified directly by chromatography (PTLC, Si02, 20 cm X 20 cm, 1 mm, EtOAc-10% CH30H) which provided 139 (137 mg, 168 mg theoretical, 82%) as yellow oil: Rf 0.29 (Si02, EtOAc-10%
15 CH30H ); LRMS m/z 356 (M+, C23Hs6Nz0 requires 356).
Example 96 N-(1-(3-ethvlindole~pineridin-3-R-ylmeth~l-N (anilino-3 yl)pro~ionamide 140) \ Br I i I
~~ N \ ~ / ~ ~~ N
I > 1. H2, Pd-C 10%
N O~ + H 2. K2C03/CH3CN ' N O
Cbz HN
2p 138 140 A solution of 138 (0.451 mmol, 172 mg) in CH30H (1 mL) at 25 °C was treated with 10% Pd-C (20mg) and then placed under a hydrogen atmosphere. The reaction mixture was stirred for 12 h and then was filtered through a pad of Celite. The solvents were removed in vacuo and the resulting oil was then treated with 3-(2-bromoethyl)indole (1.5 equiv, 0.677 mmol, 152 mg) and KZC03 (1.5 equiv, 0.677 mmol, 94 mg) in CH3CN (1 mL). The reaction mixture stirred for 12 h at 60 °C. The reaction mixture was then purified directly by chromatography (PTLC, Si02, 20 cm X 20 cm, 1 mm, EtOAc-10% CH30H) which provided 140 (176 mg, 88 mg theoretical, 50%) as yellow oil: Rf 0.22 (SiOz, EtOAc-10%
CHjOH );
LRMS m/z 389 (M+, CZSH3,N3O requires 389).
l0 Example 97 N-(1-(1.l-difluoroethylbenzene)piperidin-3-R-ylmethvll-N (anilino-3-~lpropionamide I, ~~ N ~ ~~ N
I 1. H2, Pd-C 10%
N O 2. K2C03/CH3CN N O' Cbz + F gr I /
138 F F 'F 141 A solution of 138 (0.487 mmol, 185 mg) in CH30H (1 mLj at 25 °C was treated with 10% Pd-C (20mg) and then placed under a hydrogen atmosphere. The reaction mixture stirred for 12 h and then was filtered through a pad of celite. The solvents were removed in vacuo and the resulting oil was then treated with (2-bromo-1,1-difluoroethyl)benzene (1.5 2o equiv, 0.731 mmol, 162 mg) and KzC03 (1.5 equiv, 0.731 mmol, 101 mg) in CH3CN (1 mL). The reaction mixture stirred for 12 h at 60 °C. The reaction mixture was then purified directly by chromatography (PTLC, Si02, 20 cm X 20 cm, 1 mm, 2:1 Hexane-EtOAc ) which provided 141 (20 mg, 188 mg theoretical, 11%) as yellow oil: Rf 0.52 (Si02, 2:1 Hexane-EtOAc ); LRMS m/z 386 (M+, C23Hz$FzNzO requires 386).
Example 98 1-Benzyl-azepan-2-one (1421 Ph~Br NH O NaH, THF N O
Azepan-2-one I
1-Benzyl-azepan-2-one To a stirnng 0°C suspension of NaH (18.3g, 763 mmol) in THF (195 mL) was added by addition funnel azepan-2-one (75.0 g, 667 mmol) in THF. An additional 2 L
of solvent was added as the reaction progressed in order to maintain agitation of the very viscous reaction suspension. Following addition, the reaction was allowed to warm to room temperature, and when the evolution of Hz ceased after stirring overnight, benzyl bromide l0 was added dropwise by addition funnel and the reaction was stirred overnight. The crude product was filtered through Celite and concentrated in vacuo.
Recrystallization from hexanes and ethyl acetate provided pure 1-benzyl-azepan-2-one (142) as a white fluffy solid.
'H NMR (CDCl3) 7.38-7.24 (5H, m), 4.61 (2H, s), 3.33-3.29 (2H, m), 2.65-2.61 (2H, m), 1.77-1.66 (4H, m), 1.56-1.46 (2H, m) ppm. '3C NMR (CDC13, 75 MHz) 176.13, 138.06, 128.67, 128.31, 127.43, 51.20, 49.04, 37.33, 30.12, 28.26, 23.58 ppm.
Example 99 1-Benzyl-2-oxo-azepane-3-carboxylic acid methyl ester (1431 O
a. LDA, THF home N ~O O N ~O
b. II
MeO~OMe I
1-Benzyl-azepan-2-one 1-Benzyl-2-oxo-azepane-3-carboxylic acid methyl ester LDA was prepared as follows: Diisopropyl amine (15.2 mL, 110 mmol) freshly distilled under N, and over CaH2 was added to 110 mL of anhydrous THF in a dry flask, and the solution was cooled to 0°C in an ice bath. nBuLi (73.3 mL, 111 mmol) was added dropwise, and the reaction was stirred at 0°C for 1 hour. The freshly prepared LDA was added dropwise to a -70°C solution of 1-Benzyl-azepan-2-one (142) (10.98 g, 544.0 mmol) dissolved in anhydrous Et20 (70 mL). The reaction was stirred at -70°C
for 1 hour, then dimethyl carbonate (4.55 mL, 544 mmol) was added dropwise. The reaction was allowed to warm to room temperature overnight. The reaction was judged complete by HPLC, and was to slowly poured into 5N HCl stirring in an ice bath. The organic layer was extracted. The aqueous layer was washed with CHZC12 two times, and the combined organics were dried with sodium sulfate, filtered and concentrated in vacuo. Crude material was purified on an automated flash column with 80:20 Hexanes:EtOAc to obtain 10.85g, (77%) of 1-benzyl-2-oxo-azepane-3-carboxylic acid methyl ester (143) as a pale yellow oil. 'H NMR
(CDC13) 7.42-7.10 (5H, broad s), 4.61 (1H, d, J = 14.7 Hz), 4.50 (1H, d, J = 14.7 Hz), 3.74 (3H, s), 3.7-3.64 (1H, m), 3.40-3.13 (2H, m), 2.12-1.98 (1H, m), 1.92-1.73 (2H, m), 1.66-1.42 (2H, m), 1.32-1.16 (1H, m) ppm. '3C NMR (CDC13, 75 MHz) 171.94, 171.04, 137.28, 128.55, 128.24, 127.43, 52.15 (2), 51.27, 48.31, 27.87, 27.41, 25.91 ppm. LRMS:
261.73.
2o Example 100 (1-Benzyl-azepan-3-yl)-methanol (144).
O
~OH
home LiAIH4 THF N
N O
1-Benzyl-2-oxo-azepane-3- (1-Benzyl-azepan-3-yl)-methanol carboxylic acid methyl ester 144 1-Benzyl-2-oxo-azepan-2-carboxylic acid methyl ester (143) (0.2154g, 0.8243 mmol) dissolved in anhydrous THF (2.9 mL) was added to a stirring suspension of LiAIH~
in THF (1.5 mL) over approx. 1.5 hours. The reaction mixture was stirred overnight. The reaction was judged complete by TLC and was quenched by the sequential addition of HZO
(0.4 mL), then 2N NaOH (1.0 mL) and H20 (0.4 mL). The mixture was stirred at room temperature for 30 minutes, then was filtered, dried with NazS04, and concentrated in vacuo.
Crude material was purified by automated silica gel chromatography with 15:85:5 CHZC12 Hexanes : 2N NH3 in EtOH to obtain 0.1062g (59%) of pure (1-benzyl-azepan-3-yl)-methanol (144). 'H NMR (CDC13) 7.40- 7.23 (5H, m), 3.65 (2H, s), 3.54 (1H, dd, J = 10.4, 3.5 Hz), 3.43 ( 1 H, dd, J = 10.4, 5.4 Hz), 2.82 ( 1 H, J = 13.3, 3.1 Hz), 2.77 (2H, m), 2.44 ( 1 H, 1o ddd, J = 12.2, 8.6, 3.3 Hz), 1.90 - 1.45 (6H, m) ppm. '3C NMR (CDCl3, 75 MHz) 139.14, 128.97, 128.14, 126.91, 67.20, 63.85, 58.49, 56.87, 39.59, 29.68, 29.43, 25.23 ppm. LRMS:
219.64.
Example 101 Azepan-3-yl-methanol (1451 'OH
H2, 10% Pd/C
N MeOH OH
NH
(1-Benzyl-azepan- Azepan-3-yl-methanol 3-yl)-methanol 145 (1-Benzyl-azepan-3-yl)-methanol (144) (0.0922g, 0.4192 mmol) dissolved in MeOH
(1 mL) was added to a stirring suspension of 10% Pd/C (14.4 mg) in 5 mL MeOH.
The reaction was purged with HZ, and the reaction was stirred at room temperature overnight.
The reaction was judged complete by'H-NMR analysis of an aliquot from the reaction. The reaction was filtered through a pad of Celite wet with MeOH and was rinsed with MeOH, and concentrated in vacuo to obtain pure azepan-3-yl-methanol (145) in 60%
yield (0.0323g). Compound 145 was used in the next Example without further purification. 'H

NMR (CDCl3, partial) 3.14-2.70 (4H, m), 1.92-1.73 (4H, m), 1.68-1.42 (3H, m) ppm. '3C
NMR (CDC13, 75 MHz) 67.32, 52.01, 50.33, 41.31, 31.05, 29.76, 25.44 ppm.
Example 102 3-H, d~ymethyl-azepan-1-carboxylic acid benzyl ester (146) OH CbzCl THF/H20, K2C03 NH
Azepan-3-yl-methanol 3-Hydroxymethyl-azepane-1 145 carboxylic acid benzyl ester Potassium carbonate was added to a mixture of azepan-3-yl-methanol (145) (0.032g, l0 0.2485 mmol) in THF/H20 (2:1, 0.31 mL). The suspension was cooled to 0°C, and (benzyloxy)carbonyl chloride (0.071 mL, 0.497 mmol) was added dropwise. The reaction was allowed to warm to room temperature overnight, and was then concentrated in vacuo.
CHzCIz and H20 were added. The organics were extracted, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by automated silica gel chromatography with 75:25 Hexanes : EtOAc to obtain 3 Hydroxymethyl-azepan-1-carboxylic acid benzyl ester (146) in approximately 94%
yield.
Because 146 bears a Cbz group, many of the peaks in the 'H and '3C NMR spectra appear as two sets of peaks. When provided, the value in parentheses is for the smaller of the two sets of peaks that corresponds to the same proton or carbon. 'H NMR
(CDCl3) 7.38-7.26 (5H, m), 5.13 (2H, s), (3.77) 3.73 (2H, q, J = 5.4 Hz), 3.53-3.42 (2H, m), 3.36 (3.31) 1H, d, J = 4.3 Hz), 3.23-3.12 (1H, m), 2.10-1.20 (7H, m) ppm. '3C NMR (CDC13, 75 MHz) 157.02 (156.06), (136.89) 136.74, 128.42, 127.91, 127.66, 67.16 (66.87), (65.27) 64.69, (48.12) 47.89, (42.13) 41.23, (30.05) 29.78, 28.78 (28.11), (24.87) 24.61, 14.13 ppm.
Exam In a 103 3-Form~pane-1-carboxylic acid benzyl ester (147) OAc AcO~ ~ ~pAc I~
O
~OH O ~O
J J

O// O O~O
3-Hyd roxymethyl-azepane-1- 3-Formyl-azepane-1-carboxyl is carboxylic acid benzyl ester acid benzyl ester Dess-Martin periodinane (2.78g, 6.56 mmol) was slowly added to a stirnng 0°C
solution of 3-hydroxymethyl-azepane-1-carboxylic acid benzyl ester (146) (1.2516g, 5.02 mmol) in CHZCIz (18.2 mL). The reaction was stirred for 1 hour until the reaction was judged complete by HPLC. The reaction was concentrated in vacuo, and a minimal amount of CHzCIz was added. Et20 was added to precipitate the periodinane by-product, and the to reaction was filtered, concentrated, and immediately purified through an automated silica gel column with 1:1 Hexanes : EtOAc to obtain pure 3-formyl-azepane-1-carboxylic acid benzyl ester (147) (0.3086g) in 62% yield.
Because 147 bears a Cbz group, many of the peaks in the 'H and '3C NMR spectra appear as two sets of peaks. When provided, the value in parentheses is for the smaller of the two sets of peaks that correspond to the same proton or carbon. 'H NMR
(CDC13) 9.67 (9.56) (1H, s), 7.32-7.22 (5H, m), (5.09, 2H, s) 5.12 (1H, d, J = 12.6 Hz) 5.02 (1H, d, J =
12.3 Hz), (3.80) 3.75 (1H, t, J = 6.3 Hz), 3.60-3.28 (3H, m), 2.70-2.53 (1H, m), 1.90-1.40 (6H, m) ppm. '3C NMR (CDCl3, 75 MHz) 202.52 (202.35), 155.98 (155.55), (136.59) 136.44, 128.31, 127.81, 127.61, 66.97, (51.57) 51.20, (48.68) 48.20, 46.02 (45.43), 28.67 (28.23), (26.27) 26.09, (24.37) 24.30 ppm.
Example 104 3-Phenylaminometh~zepane-1-carboxylic acid benzyl ester (148) ~O
~ NH2 N
O NaBH~CN
5% HOAc m MeOH
3-Formyl-azepane-1-carboxylic 3-Phenylam inomethyl-azepane-1-acid benzyl ester carboxylic acid benzyl ester Aniline (0.126 mL, 1.38 mmol) was added to a solution of 3-formyl-azepane-1-carboxylic acid benzyl ester (147) (0.300g, 1.15 mmol) in 5% HOAc in MeOH ( 11.5 mL).
The reaction was stirred for approx. 20 minutes, then NaBH3CN (0.2164g, 3.44 mmol) was slowly added and the reaction was stirred at room temperature overnight. The reaction was then concentrated in vacuo and EtOAc and a few drops of 10% NaOH were added.
The organic was washed with saturated NaCI (aq), dried with Na2S04, concentrated in vacuo, to 1o give crude 3-phenylaminomethyl-azepane-1-carboxylic acid benzyl ester (148). Compound 148 was used in the next step without further purification.
Example 105 3-[(Phenyl-propionyl-amino)-methyll-azepane-1-carboxylic acid benzyl ester (1491 ci/ v _ EtiPr2N, CH2CI2 ~ o 3-Phenylaminomethyl-azepane-1- 3-[(Phenyl-propionyl-amino)-methyl]-azepane-1-carboxylic acid benzyl ester carboxylic acid benzyl ester Et(iPr)ZN (0.24 mL, 1.38 mmol) was added to a stirnng solution of crude 3-phenylaminomethyl-azepane-1-carboxylic acid benzyl ester (148) in CHZC12 (2.3 mL) under NZ. The reaction was cooled to 0°C in an ice bath, then propionyl chloride (0.22 mL, 2.53 mmol) was added dropwise. The reaction was allowed to warm to room temperature overnight. The reaction was then judged complete by TLC. It was concentrated in vacuo and EtOAc and 10% NaOH (aq) were added. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo, and purified by automated silica gel chromatography with 96:2:2 Hexanes : CHZCl2 : 2N NH3 in EtOH to obtain 3-[(phenyl propionyl-amino)-methyl]-azepane-1-carboxylic acid benzyl ester (149) (0.3266g) in 72%
1o yield for two steps.
Because 149 bears a Cbz group, many of the peaks in the 'H and '3C NMR spectra appear as two sets of peaks. When provided, the value in parentheses is for the smaller of the two sets of peaks that corresponds to the same proton or carbon. 'H NMR
(CDC13) 7.55-7.20 (9H, m), 7.15-6.90 (1H, m), 5.24-5.05 (2H, m), 4.20-4.05 (1H, m), 4.00-3.05 (5H, m), 2.95-2.75 (1H, m), 2.07-2.00 (2H, m), 2.00-0.85 (9H, m) ppm. '3C NMR (CDC13, 75 MHz) (174.1) 1743.98, 156.15 (156.03), 142.71, (137.11) 136.97, 129.78 (129.67), (128.69) 128.55, 128.47, 128.26, 128.06, 127.84, 127.61, 67.14 (66.90), 52.33 (51.87), 49.67 (49.46), 47.64 (47.12), (38.83) 38.30, 32.01 (31.58), (27.87) 27.73, 24.75 (24.47), 9.63 ppm. LRMS:
394.37.
Exam 1w a 106 N (1-Phenethylaminometh~pane-3-ylmeth~)-N phen~propionamide (150 Ph off~,CHO
10 /o t'd/C N
N ~ MeOH
N O
N O
~O
O
3-[(Phenyl-propionyl-amino)-methyl]-a N-(1-Phenethyl-azepan-3-ylmethyl)-zepane-1-carboxylic acid benzyl ester N-phenyl-propionamide 3-[(phenyl-propionyl-amino)-methyl]-azepane-1-carboxylic acid benzyl ester (149) and phenylacetaldehyde (0.148 mL, 1.27 mmol) in 1.5 mL MeOH were added to a suspension of 10% Pd/C (0.0553g) in 7.0 mL MeOH. The reaction mixture was shaken under 40 psi HZ until the consumption of H, ceased and the reaction was judged complete by TLC. The crude reaction mixture was passed through a column of Celite wet with MeOH, concentrated in vacuo, and purified by flash column chromatography 80:18:2 Hexanes CHZC12 : 2 N NH3 in EtOH to obtain N (1-Phenethylaminomethyl-azepane-3-ylmethyl)-N
phenylpropionamide (150) (0.0404g) in 43% yield. 'H NMR (CDCl3) 7.47-7.15 (10 H, m), 3.64 (2H, broad dd, J = 7.5, 1.8 Hz), 2.82-2.59 (4H, m), 2.74 (4H, broad s), 2.45 (1H, dd, J =
13.3, 8.6 Hz), 2.07 (2H, q, J = 7.4 Hz), 1.96-1.82 (1H, m), 1.76-1.26 (5H, m), 1.07 (3H, t, J
= 7.4 Hz) ppm. '3C NMR (CDCl3, 75 MHz) 174.23, 143.08, 140.88, 129.85, 128.93, 128.46 (2), 127.91, 126.01, 61.22, 58.35, 56.34, 53.02, 37.84, 34.21, 31.14, 28.80, 28.11, 25.00, 9.92 ppm. LRMS: 364.30.
Example 107 Synthesis of Diazepine 154 Ph' B )r Ph~N N~Ph N
U

iPrOH, Et3N (2 equiv.) N
Br reflux >3 hrs.
153 154 Ph Dibromide 153 (30.0 g, 122 mmol) in 500 mL of isopropanol was cooled to 0 °C. A
2o solution of dibenzylethylenediamine (122 mmol, 28.8 mL) and triethylamine (TEA) (269 mmol, 2.2 equiv., 37.5 mL) in 125 mL of isopropanol was added dropwise to the well-stirred solution over 1 hr. (a white precipitate, TEA-HBr, is formed). After complete addition and rinsing of the addition funnel with isopropanol (3 x 10 mL), the cooling bath was removed and the solution was heated to a gentle reflux for 3 hours. The solution was placed in a -20 °C freezer overnight. The precipitated TEA-HBr was removed by filtration and the filter cake was washed with cold isopropanol. The filtrate was concentrated on a rotary evaporator and the residue was dissolved in 300 mL of THF. This solution was cooled to -20 °C and then filtered to remove additional TEA-HBr. The filtrate was concentrated on a rotary evaporator and placed under 1 mm Hg vacuum overnight to give acid 154, a sticky brown foam (33g) which was not purified fiuther.
Example 108 Synthesis of Diazepine 155 Ph Ph N
N
LiAlH4 N THF HO N
Ph 154 Ph 155 1o Crude acid 154 (33g) in 400 mL of THF was cooled to 0 °C. 250 mL of a 1 M
solution of LAH in THF was added dropwise over 45 minutes. The cooling bath was removed and the solution was heated to a gentle reflux for 45 minutes and cooled to 0 °C.
The vigorously stirred cold solution was quenched by dropwise addition of 10 mL water, 10 mL 1M NaOH, and 30 mL of water. The suspension was stirred for 30 minutes, filtered and the filter cake was washed with THF and methylene chloride. The filtrate was concentrated on a rotary evaporator. The residue was dissolved in methylene chloride, filtered, and the filtrate was concentrated on a rotary evaporator and then placed under 1 mm Hg vacuum overnight to give a yellow viscous oil (155) (28g, 74% crude yield for two steps). The product can be purified by silica gel chromatography to obtain a colorless oil using EtOAc 2o with 0.5% ammonium hydroxide as eluent, but crude material was normally not purified.
Examwle 109 Synthesis of Diazepine 156 Ph ~ Ph CH Cl 1 HO 2 2 ~S1°O
N Et3N ~ N
D~ 156 ~Ph Ph' Crude alcohol 155 (28g, 90.3 mmol) in 100 mL of methylene chloride was stirred at 25 °C. TEA (1.1 equiv., 99.3 mmol, 13.8 mL) was added followed by TBDMSCI (1.05 equiv., 94.8 mmol, 14.3 g) and DMAP ( 0.02 equiv., 1.8 mmol, 220 mg) in 50 mL
of methylene chloride. The solution became clouded and the resulting suspension was stirred overnight and then filtered. The filtrate was concentrated on a rotary evaporator. The residue was dissolved in 150 mL of chloroform and the solution was washed in a separatory funnel with water, with brine, then dried over sodium sulfate and filtered.
The filtrate was to concentrated on a rotary evaporator and then placed under 1 mm Hg vacuum overnight to give a yellow-brown viscous oil that was purified on silica gel using 80:20 hexane: EtOAc containing ca. 0.5% ammonium hydroxide. Colorless oil 156 (32 g, 83%) was obtained.
Example 110 Synthesis of Diazepine 157 ~Ph H
N H2, Pd(OH)2 N
1 MeOH, 50 psi ~ _ Si-p N ~ 1 O N
H
156 ~Ph 157 Crude diamine 156 (16g, 37.7 mmol) in SO mL of methanol was placed in a dry Parr 2o bottle and 20% palladium hydroxide catalyst (ca. 3 g) was added. After vacuum purging, the suspension was hydrogenated on a Parr shaker at 50 psi hydrogen pressure overnight.

The suspension was filtered and the filter cake was washed with methylene chloride. The filtrate was concentrated on a rotary evaporator to give colorless oil 157, which partly solidified upon standing (9.1 g, 99%).
Example Ill S~mthesis of Diazepine 158 2 eq. O
Ph N Ph~CI N
-.C ~ ° -~ . /~
Si O NMM Si-O
N ~ N

Ph ~O

to Diamine 157 (2.1 g, 8.6 mmol) was converted at 0 °C by standard procedures to bis-amide 158 using methylene chloride as solvent (80 mL) and 2.2 equivalents (18.9 mmol) of both N-methylmorpholine and phenylacetyl chloride, aqueous workup, and silica gel chromatography. Bis-amide 158 was isolated as a colorless foam (3.9 g, 94%).
Exam lp a 112 Svnthesis of Diazepine 159 Ph~ Ph N n-Bu4NF Hp N
Si-O ' THF
N N
Ph ~p Ph ~O

2o Silyl ether 158 (3.9 g, 8.1 mmol) was converted at 25 °C by standard procedures to alcohol 159 using THF as solvent (80 mL) and 1.1 equivalents (8.9 mmol) of a commercial 1 M solution of tetra-butylammonium fluoride in THF, aqueous workup, and silica gel chromatography. Alcohol 159 was isolated as a colorless foam (2.2 g, 73%).
Example 113 Synthesis of Diazepine 160 Ph~ I ~ o Ph N ~ I N
Ho~ ~ ~oA°), o ~-(~N CH2C12 N
Ph ~p Ph ~O

to Alcohol 159 (2.16 g, 5.9 mmol) was converted at 25 °C by standard procedures to aldehyde 160 using methylene chloride as solvent (50 mL) and 1.2 equivalents (8.9 mmol) of commercial Dess-Martin periodinane reagent, treatment with 50 mL 1 N NaOH, aqueous workup, and silica gel chromatography. Aldehyde 160 was isolated as a colorless solid (1.8 g, 85%).
IS
Example 114 Synthesis of Diazepine 161 Ph~o Ph~O
o N Ph-NH2 N
- PhwN
N NaBH3CN H N
Ph ~o Ph ~O

Aldehyde 160 (1.08 g, 3.0 mmol) was converted at 25 °C by standard procedures to amine 161, using 99:1 trimethylorthoformate:acetic acid as solvent (20 mL), 1.1 equivalents of aniline (3.3 mmol), and after 1 hour adding 1.5 equivalents (8.9 mmol) of commercial 1M
sodium cyanoborohydride THF solution. Aqueous workup and silica gel chromatography (eluent: 90:10:1 ethyl acetate:hexane:ammonium hydroxide) gave amine 161 as a colorless foam (0.93 g, 70%).
Exam lp a 115 Synthesis of Diazepine 162 Ph~O ph N LiAlH4 N
PhwN ~ THF~ Ph~N
H N H N
Ph ~O ph J

Amine 161 (0.90 g, 2.0 mmol) was converted by standard procedures to amine 162, using THF as solvent (15 mL), and adding 6 equivalents (12 mmol) of commercial lithium aluminum hydride in THF solution at 0 °C followed by 1 hr. at reflux. Dropwise water/1N NaOH/water quench, dilution with methylene chloride (50 mL), filtration of the slurry, and silica gel chromatography (eluent: 100:1 ethyl acetate:ammonium hydroxide) gave amine 162 as a colorless oil (0.58 g, 69%). Physical data for compound 162: 'H NMR
(CDC13, free base): b 7.1-7.4 (m, 12H), 6.68 (t, J = 7.3 Hz, 1H), 6.56 (dd, J
= 7.5 Hz, 1.0 Hz, 2H), 2.99 (d, J = 6.9 Hz, 2H), 2.61-2.98 (m, 16H), 2.22 (m, 1H). MS (M+1):
414.3.
Example 116 Synthesis of Diazepine 163 Ph~ Ph N EtCOCI N
Ph~N~ ~ N~ PhwN
H N CHzCl2 O N
Ph J Ph J

Amine 162 (0.55 g, 1.3 mmol) was converted at 0 °C by standard procedures to amide 163 using methylene chloride as solvent (5 mL) and 1.1 equivalents (1.5 mmol) of both N-methylmorpholine and propionyl chloride, aqueous workup, and silica gel chromatography. Amide 163 was isolated as a colorless foam (0.56 g, 90%). The HCl salt was prepared by dissolution of 163 in methanol (1.5 mL), addition of 1.5 mL of commercial 4N HCl in dioxane, and concentration in vacuo. Physical data for compound 163:
'3C
NMR (CDC13, free base): 8 174.3, 143.1, 140.8, 130.0, 129.0, 128.55, 128.53, 128.0, 126.1, 61.2, 57.8, 56.5, 51.5, 38.1, 34.2, 28.2, 10Ø 'H NMR (CDC13, free base): 8 7.1-7.4 (m, 15H), 3.62 (d, J = 7.2 Hz, 2H), 2.49-2.78 (m, 16H), 2.05 (m, 1H), 2.04 (q, J =
7.5 Hz, 2H), 1.04 (t, J=7.5 Hz, 3H). MS (M+1): 470.3.
Exam l~n a 117 Synthesis of (1-Benz ~~l-piperidin-3-yl)-phenyl-amine (164) PhNH2, NaCNBH3 H
MeOH, RT, 12 hr _ N
N N
i i Bn Bn To a solution of 1-benzyl-piperidin-3-one hydrochloride salt (2.02 g, 8.95 mmol), 2o aniline (1.67 ml, 17.89 mmol) in MeOH (20 ml) at room temperature was added NaCNBH3 (1.8 g, 28.64 mmol) in several portions. The mixture was stirred over night.
The mixture was taken up in 50 ml of water, the pH was increased to 12 with 2N KOH and extracted with CHzCIz (3x50 ml). Standard work-up of the organic solution provided 164 as a dried residue which was used in the next step without further purification. LRMS
(calculated for C,gH22Nz) 266, found 266.
Example 118 Synthesis ofN-(1-Benz ~~l-piperidin-3-yll-N-phen ~~l-pro~ionamide (1651 To the crude (1-benzyl-piperidin-3-yl)-phenyl-amine (164) (1.11 g) in CHzCl2 (5 ml) at 0 °C was added i-PrZNEt (1.45 ml) and propionyl chloride (0.54 ml).
The mixture was stirred for 2 hr. The mixture was diluted with CHzCIz (20 ml), washed with sat. NaHC03 (2x10 ml), brine (10 ml) and water (10 ml) and dried with NazS04. After filtration, the to filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (0.5% to 2% MeOH in CHZCIz) to give 165 as a colorless oil.
LRMS
(calculated for CZ,HZ6N20) 322, found 322; IR (film) 3059, 2937, 2863, 2797, 1657, 1594, 1499, 1390, 1264, 1101, 1074, 739, 703 cni'.
Example 119 Synthesis of N-phenyl-N-piperidin-3-yl-propionamide (1661 H2, Pd-C
MeOH, RT
N N
Bn H

2o A mixture of N-(1-benzyl-piperidin-3-yl)-N-phenyl-propionamide (165) (150 mg) and Pd-C(10%, 50 mg) and MeOH (50 ml) was stirred under HZ (1 atm) for 24 hr.
The catalyst was removed by filtration through Celite to give 166 as a colorless oil (105 mg, 97%). 'H-NMR (300 MHz, CDCl3) 8 7.41 (m, 3H), 7.10 (m, 2H), 3.20 (m 1H), 2.90 (m, 1H), 2.40-2.20 (m, 2H), 1.90 (m, 2H), 1.60 (m, 4H), 1.20 (m, 1H), 1.00 (t, 3H) ppm; LRMS
(calculated for C,4H~,N20) (M+1)+ 233, found 233.

Example 120 Synthesis of 3-(Phenyl-propionYl-amino~,pineridine-1-carboxylic acid test-butyl ester (1671 O O
(BOC)20,i-Pr2NEt N
N \ TH F, RT \
N
i N
H

s To a solution of N-phenyl-N-piperidin-3-yl-propionamide (166) (105 mg, 0.45 mmol) and i-Pr2NEt (0.26 ml, 1.5 mmol) in THF (2 ml) was added di-tert-butyl dicarbonate (1.0 in THF, 1.0 ml, 1.0 mmol). The mixture was stirred overnight. After removal the 1o solvent, the residue was dissolved in CHZCIz (10 ml), washed with sat.
NaHC03, brine and water and dried over NazS04. After filtration, the filtrate was concentrated under vacuum.
The residue was filtered through a short silica gel pad to give 167 as a light yellow oil. 'H-NMR (300 MHz, CDC13) b 7.40 (m, 3H), 7.10 (m, 2H), 4.80 (m, 1H), .20 (m, 1H), 4.00 (m, 1H), 2.40 (m, 2H), 1.95 (m, 3H), 1.61 (m, 1H), 1.51 (m, 1H), 1.50 (s, 9H), 1.30 (m, 1H), 15 1.00 (t, 3H) ppm; LRMS (calculated for CHZ8Nz03- BOC)+ 232, found 232; IR
(film) 2978, 2937, 2860, 1693, 1662, 1698, 1494, 1422, 1363, 1264, 1151, 1386, 1182 crri'.
Example 121 HPLC Separation of 3-fSl-fPhen ~~l-propionyl-amino)-piperidine-1-carboxylic acid tent-butt 2o ester~168 and 3-(R)-(Phen ~~1-propionyl-amino)-piperidine-1-carboxylic acid tert-but 1 O O O
HPLC
N I ~ Separation .'~N I ~ N
O' _O- \ O' _O- \
O O

The enantiomers of 167 were separated on a chiral column (Chiralpak AD Column;
p, = 5 ml/min; 7~ = 254 nm) with (9:1) Hexanes: iPrOH. The first compound to elute from the column (retention time = 4.956 minutes) was randomly assigned structure 168 (,5~; and the second compound to elute from the column (retention time = 5.540 minutes) was assigned structure 169 (R).
Example 122 to Synthesis of (Rl-N-(1-pheneth,~l-nineridin-3-~l-N-phenyl-propioamide (1701 O p 1. 20%TFA/CH2CI2, 1 hr N
N I ~ 2. PhCH2CH2Br, CH3CN-H20 K2CO3, 70 °C, 12 hr N /
N
O~O

3(R)-(Phenyl-propionyl-amino)-piperidine-1-carboxylic acid tert-butyl ester (169) (100 mg) was dissolved in a mixture of TFA-CHzCIz (1 ml, 20%) and stirred for 1 hr. After removal of solvent, the residue was dried under vacuum for 30 min and dissolved in 5 ml of CHZCl2, washed with sat. KZC03, dried (Na2S04), filtered. After evaporation of the solvent, the residue was dissolved in CH3CN (1m1). Then KZC03 (125 mg, 3eq), water (1 ml) and (2-bromoethyl)benzene (0.05 ml, 1.2 eq) was added. The mixture was heated at 70 °C for 12 hr. After cooling to room temperature, the mixture was diluted with sat.
NaHC03 (5 ml), extracted with CH2C12 (2x10 ml). The combined organic layers were dried (Na.,S04), filtered and evaporated. The residue was purified by silica gel chromatography (100%
CHZCIz, 2%-4%MeOH in CHZCl2) to give 170 as a colorless oil. 'H-NMR (300 MHz, CDC13) 8 7.40 (m, 3H), 7.10 (m, 2H), 4.80 (m, 1H), .20 (m, 1H), 4.00 (m, 1H), 2.40 (m, 2H), 1.95 (m, 3H), 1.61 (m, 1H), 1.51 (m, 1H), 1.50 (s, 9H), 1.30 (m, 1H), 1.00 (t, 3H) ppm;
LRMS (calculated for CZZHZ8N202)+ 336, found 336; IR (film) 2978, 2937, 2860, 1693, 1662, 1698, 1494, 1422, 1363, 1264, 1151, 1386, 1182 crri'.
Example 123 to Synthesis of (Sl-N-(1-~henethyl-pineridin-3=yl)-N-phenyl-propioamide (1711 O O
,''N 1. 20%TFA/CH2CI2, 1 hr ''~N
2. PhCH2CH2Br, CH3CN-H20 K2C03, 70 °C, 12 hr N
O O
168 ~ I 171 3(S)-(Phenyl-propionyl-amino)-piperidine-1-carboxylic acid tent-butyl ester (168) (100 mg) was dissolved in a mixture of TFA-CHZCIz (1 ml, 20%) and stirred for 1 hr. After removal of solvent, the residue was dried under vacuum for 30 min and dissolved in 5 ml of CHZC12, washed with sat. KZC03, dried (NazS04), filtered. After evaporation of the solvent, the residue was dissolved in CH3CN (1m1). Then KZC03 (125 mg, 3eq), water (1 ml) and (2-bromoethyl)benzene (0.05 ml, 1.2 eq) was added. The mixture was heated at 70 °C for 12 hr. After cool to room temperature, the mixture was diluted with sat.
NaHC03 (5 ml), extracted with CHZCIz (2x10 ml). The combined organic layers were dried (NazS04), filtered and evaporated. The residue was purified by silica gel chromatography (100%
CHZCl2, 2%-4%MeOH in CHZCIz) to give 171 as a colorless oil. 'H-NMR (300 MHz, CDC13) 8 7.40 (m, 3H), 7.10 (m, 2H), 4.80 (m, 1H), .20 (m, 1H), 4.00 (m, 1H), 2.40 (m, 2H), 1.95 (m, 3H), 1.61 (m, 1H), 1.51 (m, 1H), 1.50 (s, 9H), 1.30 (m, 1H), 1.00 (t, 3H) ppm;

LRMS (calculated for CZZHz8N20z)+ 336, found 336; IR (film) 2978, 2937, 2860, 1693, 1662, 1698, 1494, 1422, 1363, 1264, 1151, 1386, 1182 cm'.
Example 124 Synthesis of (1-Benzyl-1 2 5 6,tetrahydro-pyridin-3-~l methanol (1727 OH BnBr I ~ OH
acetone, 70 °C
N 12 hr Bn ~OH
NaBH4, MeOH
o °C, 2 hr Bn 172 To a solution of 3-hydroxymethylpyrridine (5.0 g, 45.9 mmol) in acetone (50 ml) 1o was added benzyl bromide (7.0 ml). The mixture was refluxed for 24 hr. The mixture was cooled to room temperature. The solvent was removed. The residue was dissolved in MeOH (100 ml), cooled by an ice-water bath. NaBH4 (1.5 eq.) was added slowly.
After addition, the mixture was stirred for 2 hr at 0 °C. After removal of MeOH, aq. NaHC03 (100 ml) was added. The mixture was extracted with EtOAc (3x100 ml). The combined organic solution was dried (Na2S04), filtered. The filtrate was concentrated under vacuum.
Silica gel chromatography (2%-10% MeOH in CHzCIz) provided 172 as a light yellow oil (8.2 g, 88%). 'H-NMR (300 MHz, CDC13) 8 7.40-7.20 (m, 5H), 5.70 (broad s, 1H), 4.00 (s, 2H), 3.65 (s, 2H), 3.00 (s, 2H), 2.55 (t, 2H), 2.20 (broad s, 2H) ppm; LRMS
(calculated for C,3H,~N0) 203, found 203.
Example 125 Synthesis of~3-Benzyl-3-aza-bic~[4.l.OJhept-1-yl)-methanol (1731 ~OH _ OH

N ZnEt2, CH2CI2 N
Bn Bn To a solution of ZnEt2 (17.3 ml, 1.0 M) in CHzCl2 (20 ml) at 0 °C was added CHZIZ
(1.4 ml) (CAUTION: exothermic!). After stirnng for 15 min, a solution of 172 (352 mg, 1.73 mmol) in CHZC12 (2 ml) was added. The mixture was stirred from 0 °C to room temperature overnight. 5% HCl was added to bring the mixture to a homogeneous solution.
(white solid dissolved). The two layers were separated. Aqueous layer was neutralized with 2N KOH to pH=10-12, extracted with CHZCIz (twice). The combined organic solution was dried (KZC03/Na2S04), filtered and concentrated. The LRMS of the crude mixture showed 1o that the ratio of 173 to 172 was about 1:1. The product was not isolated from the starting material due to their similar polarities. LRMS (calculated for C,4H,9N0) 217, found 217.
Example 126 Synthesis of 3-Benz-3-aza-bicycloj4.1.0]heptane-1-carbaldehyde (1741 ~OH DMSO, (CICO)2, ~ ~O
N CH2C12, -55 °C; N
Bn EtsN, RT Bn To a solution of oxalyl chloride (0.22 ml, 2.54 mmol) in CHzCl2 (2 ml) at -55 °C was added a solution of DMSO (0.30 ml, 4.24 mmol) in CHZC12 (1 ml). The mixture was stirred 2o for 2 min. Then, a solution of 173 (230 mg, 1.06 mmol) in CHZCIz (1 ml) was added dropwise. After stirring for 15 min at -55 °C, Et3N (1.4 ml) was added slowly. The mixture was stirred for 5 min and then warmed to room temperature. Aqueous NaHC03 (S
ml) was added. The two layers were separated; and the aqueous layer was extracted with CHzCl2 (2x5 ml). The combined organics were dried (NazS04), filtered and evaporated to give the crude product. Chromatography (1% MeOH in CHZCIz) gave 174 as a light red liquid. 'H-NMR (300 MHz, CDC13) (partial) 8 9.42 (s, 1H), 7.30 (m, SH); LRMS (calculated for C,4H"NO) 215, found 215.
Exa ale 127 Synthesis of (3-Benzyl-3-aza-bic~[4.1.0]hept-1- 1y meth,~l-phen 1-amine 175) ~O PhNH2, NaCNBH3~ N \
N MeOH, RT, 2 hr H
i N
Bn Bn to To a solution of 3-Benzyl-3-aza-bicyclo[4.1.0]heptane-1-carbaldehyde (174) (300 mg, 1.39 mmol) in 5%HOAc in MeOH (2 ml) was added aniline (0.38 ml, 4.18 mmol) and NaCNBH3 (250 mg, 3.97 mmol). The mixture was stirred at room temperature 2 hrs.
MeOH was removed by evaporation. Water (5 mL) was added to the residue. The mixture was neutralized with 2N KOH to pH = 10. Extraction with CHZCIz (2x10 ml) followed by is standard work-up provided crude 175 which was purified by silica gel chromatography (1%
MeOH in CHZCIz). LRMS (calculated for CzoHzSNz, M+1) 293, found 293.
Example 128 Synthesis ofN (3-Benzyl-3-aza-bicyclo[4.1.0]hept-1- l~thyl)-N
phen~propionamide ( N ~ N
EtCOCI, i-Pr2NEt N N /
Bn Bn To the a solution of 3-Benzyl-3-aza-bicyclo[4.1.0]hept-1-ylmethyl)-phenyl-amine (175) (250 mg, 0.86 mmol) in CHZCIz (2 ml) at 0 °C was added i-PrzNEt (0.30 ml, 1.72 mmol)) and propionyl chloride (0.11 ml, 1.29 mmol). The mixture was stirred for 2 hrs.
The mixture was diluted with CHZC12 (5 ml), washed with sat. NaHC03 (2x5 ml), brine (5 ml) and water (5 ml) and dried with NazS04. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (0.5% to 2% MeOH
in CHZC12) to give 176 as a colorless oil. 'H-NMR (300 MHz, CDC13) 8 7.41-7.20 (m, 10H), 4.20 (d, 1H), 3.42 (AB, 2H), 3.21 (d, 1H), 2.65 (q, 2H), 2.20-2.00 (m, 4H), 1.80-1.60 (m, 2H), 1.30 (m, 1H), 1.05 (t, 3H), 0.80-0.20 (m, 2H) ppm; LRMS (calculated for Cz3H28N20) 348, found 348; IR (film) 3308, 3105, 3064, 2978, 2937, 2874, 2811, 1689m 1666, 1598, 1540, 1499, 1445, 1314, 1246, 1196, 1074, 757 cm'.
Exam In a 129 Solid-phase Synthesis of N-[1-(4-Fluoropheneth~2,piperidine-3-ylmeth~l-N-phenyl-propionamide (177 OH
O
I

O - N \ Fmoc O
Na(OAc)3BH, 5% HOAc in DMF PyBroP, DIEA N
1 DMF, rt Fmoc I
N \
1. piperidine 2. F ~/ \ T'N , F BH3, THF
~OH O \
PyBOP, NMM, DMF
O'I ~I
O ~N~
I II
N ~ CI~
F

N / F \ I
\ I 177 ~O = P ~ ' O ~ \ OMe I
O
2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene To 2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene (100 mg, 0.46 mmol/g) was added 1 ml DMF followed by 91 ~1 aniline (0.46 mmol). After shaking at room temperature for 30 min, 195 mg of Na(OAc)3BH (0.92 mmol) and 50 ~l HOAc were added, then the reaction mixture was agitated at room temperature overnight. The resulting resin (1) was thoroughly washed with DMF (3 X 1 ml), MeOH (4 X 1 ml), and CHZC12 (4 X 1 ml), then dried in vacuo. To 1 was added N-Fmoc-nipecotic acid (81 mg, 0.23 mmol) and PyBroP
(107 mg, 0.23 mmol) in 1 ml DMF followed by 40 p1 N,N-diisopropylethylamine (0.23 mmol), and the resulting slurry was shaken at room temperature for 2 hours.
The resulting to resin 2 was washed with DMF (3 X 1 ml), MeOH (4 X 1 ml), and CHZC12 (4 X 1 ml) and dried in vacuo.

Resin 2 was treated with 1 ml 25% piperidine in DMF at room temperature for 30 min, then washed with DMF (3 X 1 ml), MeOH (4 X 1 ml), and CHZCl2 (4 X 1 ml) and dried in vacuo. To the resulting resin was added 4-fluorophenylacetic acid (36 mg, 0.23 mmol) and PyBOP (120 mg, 0.23 mmol) in 1 ml DMF followed by 26 ~l N-methylmorpholine (0.23 mmol). After shaking at room temperature for 3 hours, the resulting resin (3) was washed extensively with DMF (3 X 1 ml), MeOH (4 X 1 ml), and CHZCIz (4 X
1 ml) and dried in vacuo. Resin 3 was treated with lml of 1 M BH3-THF solution at room temperature for 20 hours. After washing with THF (3 X 1m1) and MeOH (3 X 1 ml), the resin suspended in 1 ml MeOH was heated at 60° C for 6 hours. The resulting resin (4) was to washed with MeOH (4 X 1 ml) and CHzCl2 (4 X 1 ml) and dried in vacuo.
Propionyl chloride (28 ~1, 0.322 mmol) was added to the Resin 4 suspended in 1.5 ml CHzCl2, and the mixture was agitated at room temperature for 24 hours. The mixture was filtered and washed with CHzCIz (2 X 1 ml). Removal of the volatiles under a stream of nitrogen followed by lyophilizing with 50% CH3CN in water afforded the compound 177 as colorless oil (9.0 mg, 53%). LRMS 369.
Exam Ip a 130 Solid-phase synthesis ofN-[1-(2-Meth~phenethyl)-piperidine-3-~1~~-N-phenXl-propionamide (178) N
N~

Compound 178 was synthesized using a procedure similar to that described in Example 129. Compound 178 was obtained as colorless oil (8.3 mg, 50%). LRMS
365.
Example 131 Chromatographic Separation of ,~R)- & (S1-N (1-Pheneth~pan-3-ylmethyl)-N
phenethylPropionamide (179 & 180) 'N 'N N
Chiralpak AD ~O~ +
N N N

The enantiomers of N (1-Phenethyl-azepan-3-ylmethyl)-N phenethylpropionamide (150) were separated on a 2 cm ID Chiralpak AD column (Column number ADOOCJ-AB009), using 92:8:0.1 Hexanes: EtOH: EtZNH (~, = 235 nm; flow rate = 6 mL/min). On an analytical Chiralpak AD column (using 95:5:0.1 Hexanes: EtOH: EtzNH; flow = 1 mL/min;
~, = 230 nm, run time = 30 minutes), the first compound to elute from the column (9.871 min) was assigned 180 (S), and the second compound to elute from the column (22.826 min) was assigned 179 (R). The absolute configuration has not been determined l0 conclusively.
Example 132 ~R)-N (1-tent-But~ypiperidin-3-ylmeth~l-N anilinotrifluoroacetamide (1811 / TFAA
H N
iPrNEt Boc CH2C12 Boc A solution of the aniline intermediate (1.72 mmol, 500 mg) in CHZCIz (5 mL) at 0 °C
was treated with trifluoroacetic anhydride (TFAA) (1.2 equiv, 2.06 mmol, 292 pL) and diisopropylethylamine (1.5 equiv, 2.58 mmol, 450 ~L) under Ar. After warming to 25 °C
and stirring for 12 h, the reaction mixture was quenched with 10% aqueous NaHC03. The reaction mixture was then made acidic with 10% aqueous HCl and extracted with EtOAc (25 mL). Chromatography (PTLC, Si02, 20 cm X 20 cm, 1 mm, 1:4 EtOAc-Hexane) provided 181 (655 mg, 665 mg theoretical, 98%) as a colorless oil: Rf 0.22 (SiOz, 1:4 EtOAc -Hexane); LRMS m/z 386 (M+, C,9HZSF3N203, requires 386).

Example 133 ~R)-N 1-(pheneth~lpi~peridin-3-ylmethyll-N anilinotrifluoroacetamide (182) I\ ~\
/ 1. TFA/CH2C12 ~~~
N O CF3 2. PhCH2CH2Br / I N O CF3 i Boc A solution of 181 (0.285 mmol, 110 mg) in CHZC12 (1 mL) at 25 °C was treated with 50% TFA in CHZC12 (1 mL). The reaction mixture stirred for 2 h. The solvents were removed in vacuo and the resulting oil was dried under high vacuum for 12 h.
The resulting to oil was then treated with phenethyl bromide (2.0 equiv, 0.57 mmol, 78 ~L) and KZC03 (2.5 equiv, 0.71 mmol, 98 mg) in CH3CN (1 mL). The reaction mixture stirred for 12 h at 60 °C.
The reaction mixture was purified directly by chromatography (PTLC, Si02, 20 cm X 20 cm, 1 mm, 9:1 EtOAc-CH30H) which provided 182 (107 mg, 111 mg theoretical, 96%) as a colorless oil: Rf 0.30 (Si02, 9:1 EtOAc-CH30H ); LRMS m/z 390 (M+, CZZHzsF3Nz0, requires 390).
Examwle 134 N-1-acetophenone-3-anilinocarboxypiperidine (183) O \
Br o \ I

+ H
~\H \ CH3CN ~ I N
N I/ \
H

A solution of the aminoamide (5.91 mmol) in CH3CN (20_ mL) was treated with bromoacetophenone (1.1 equiv, 8.87 mmol, 1.23 g) and KZC03 (1.5 equiv, 8.87 mmol, 1.23 g) under Ar. After warming to 60 °C and stirnng for 12 h, the reaction mixture was quenched with 10% aqueous NaHC03 and extracted with EtOAc (3 X 25 mL).
Chromatography (Si02, 2.5 cm X 30.5 cm, 1:1 hexane-EtOAc then 9:1 EtOAc-CH30H) provided 183 (1.08 g, 2.10 g theoretical, 51%) as a yellow foam: Rf 0.45 (SiOz, 9:1 EtOAc -CH30H); LRMS m/z 322 (M+, CZ°HzZN20z, requires 322).
Example 135 N 1-~2'-oxo-phenethylpiperidin-3- l~yll-N aniline (184) O \ \
I , H BH3 C~H
THF ~ I N
\

OH
A solution of 183 (0.775 mmol, 250 mg) in THF (3 mL) at 0 °C was treated with 1.0 M BH3-THF (2.0 equiv, 1.55 mmol) under Ar. The reaction mixture was then heated to 75 to °C and allowed to stir for 12 h. The reaction mixture was then cooled to 0 °C and quenched with 10% aqueous HCI. The pH was adjusted to 10 with 10% aqueous NaOH and the reaction mixture was extracted with EtOAc (3 X 25 mL). The organics were dried with NaCI ~Sat> and MgS04 ~5~. The reaction mixture was purified directly by chromatography (PTLC, Si02, 20 cm X 20 cm, 1 mm, 9:1 EtOAc-CH30H) which provided 184 (184 mg, mg theoretical, 76%) as a colorless oil: Rf 0.40 (Si02, 9:1 EtOAc-CH30H); LRMS
mlz 310 (M+~ ~20H26N2O~ requires 310).
Exam 1p a 136 N 1-(2'-acetox~pheneth~piperidin-3- 1~~)-N anilinopropionamide (1851 \ \
I ~ ~ I
COCI ~~N
N iPr2NEt ~ I N J O' \ CH2CI2 \

OH O\
'O
A solution of 184 (0.58 mmol, 181 mg) in CHZCl2 (2 mL) at 0 °C was treated with propionyl chloride (2.5 equiv, 1.45 mmol, 126 p,L) and diisopropylethylamine (2.5 equiv, 1.45 mmol, 253 ~L) under Ar. After warming to 25 °C and stirring for 12 h, the reaction mixture was purified directly by chromatography (PTLC, SiOz, 20 cm x 20 cm, 1 mm, 1:1 EtOAc-Hexane) which provided 185 (193 mg, 245 mg theoretical, 70%) as a colorless oil: Rf 0.36 (SiOz, 1:1 EtOAc -Hexane); LRMS m/z 422 (M+, C26H34N203, requires 422).
Example 137 N 1~2'-oxo-pheneth,~lniperidin-3- l~methyl)-N anilinopropionamide (1861 ~~N 1 M LiOH ~~N
'N J O THF-CH30H-H20 ~ 'N J O' I 3:1:1 185 1' 186 O\ ~ OH
'O
A solution of 185 (0.457 mmol, 193 mg) in THF-CH30H-Hz0 3:1:1 (1 mL) at 0 °C
was treated with 1 M LiOH (2.0 equiv, 0.914 mmol, 914 p.L). After warming to 25 °C and stirnng for 3 h, the reaction mixture was quenched with pH 7 buffer and then extracted with EtOAc (3 x 10 mL). The organics were dried with NaCI ~Sat~ and MgS04 ~5~. The resulting oil was purified by chromatography (PTLC, Si02, 20 cm x 20 cm, 1 mm, 9:1 EtOAc-CH30H) to give 186 as a colorless oil (114 mg, 167 mg theoretical, 68%): Rf 0.28 (Si02, 9:1 EtOAc -CH30H); LRMS m/z 366 (M+, C23H3°NZO2, requires 366).
Example 138 2o Synthesis and Purification of the Four Diastereomers of N [1-(1-pheneth~piperidin-3-,~lleth~l-N Phen~nropionamide (195. 196, 197. 198) -NH
N
Boc See Example 86 187 188 for synthesis ast-elutin .f g slow-eluting diastereomer diastereomer The starting mono-Boc-diamine (see Example 86) was separated into diastereomers 187 and 188 using HPLC with a semi-prep silica gel column (Hexane:'PrOH, 90:10).
Diastereomer 187 was the first compound to elute from the column (7.72 min) (LRMS 305, 249, 205); while 188 was the second compound to elute from the column (8.43 min) (LRMS
305, 249, 205).
cW

cW

Following standard procedures described elsewhere in the Exemplification, diastereomers 187 and 188 were converted to the diastereomeric amides 189 and 190, 1o respectively.

N N
HPLC ~ -N
Boc I \ Boc I \ + Boc I \
/ / /

single single single diastereomer enantiomer enantiomer 190 t~LC 193 194 single single + single diastereomer enantiomer enantiomer Using chiral chromatography, diastereomer 189 was then separated into its two constituent enantiomers, 191 and 192. Specifically, HPLC with a semi-prep Chiralpak AD
column (Hexane:'PrOH, 95:5) was used to provide 191 (the first compound to elute from the column) and 192 (the second compound to elute from the column). Using an analytical Chiralpak AD column (Hexane:'PrOH, 95:5), the retention time for 191 was 8.35 min (LRMS 261, M-100); while the retention time for 192 was 9.46 min (LRMS 261, M-100).
Likewise, diastereomer 190 was separated into its two constituent enantiomers, and 194. Specifically, HPLC with a semi-prep Chiralpak AD column (Hexane:'PrOH, 95:5) to was used to provide 193 (the first compound to elute from the column) and 194 (the second compound to elute from the column). On an analytical Chiralpak AD
column(Hexane:'PrOH, 95:5), the retention time for 193 was 7.78 min (LRMS 261, M-100);
while the retention time for 194 was 11.90 min (LRMS 261, M-100).

O
N' v 1) TFA, CHZCIz \ 2) PhCHZCHzBr N
Boc single enantiomer enantaomer 192 single enantiomer 1) TFA, CHZCIZ_ 196 single enantiomer 2) PhCH2CHZBr 193 single enantiomer 1) TFA, CHZC12' 197 single enantiomer 2) PhCHZCH2Br 1) TFA, CHZCl2 194 single enantiomer - 198 single enantiomer 2) PhCH2CHZBr Finally, following standard procedures described elsewhere in the Exemplification, single enantiomers 191, 192, 193 and 194 were converted to enantiomerically pure tertiary amine-amides 195 (LRMS 365), 196 (LRMS 365), 197 (LRMS 365), and 198 (LRMS
365), respectively.
Exam In a 139 N (1-Indan-2-,yl-pineridin-3-vlmeth,~ll-N-phenylpropionamide (199) to \ \/
( / 1) TFA, CHZC12 ~N
2) KzC03 N O~ ~~ I
Boc Trifluoroacetic acid (1.0 mL) was added dropwise to a solution of compound (R)-N-(1-Boc-piperidin-3-ylmethyl)-N-phenylpropionamide (200 mg, 0.58 mmol) in 1.0 mL of dry CHZC12 at 0 °C (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the crude product was used for next step without purification.
The crude compound from the previous step was dissolved in CH3CN (1.3 mL) and KZC03 (240 mg) and 2-iodoindan (283 mg, 1.16 mmol) were added. The mixture was heated at 50 °C overnight. The reaction mixture was poured into 10 mL
of H20, then extracted with ethyl acetate (3 x 10 mL). The extracts were combined and washed with aqueous NaOH (10%, 2 x 5 mL), HCl (5%, 2 x 5 mL), brine (10 mL), dried over anhydrous 1o sodium sulfate, and filtered. The crude product was purified by a preparative thin layer chromatography (CHZCl2/MeOH, 95:5) to afford N (1-Indan-2-yl-piperidin-3-ylmethyl)-N-phenylpropionamide as a colorless oil. LRMS 363.
Example 140 1-f 1-~4-Chloro-phenyl)-cyclobutanecarbonyl]-piperidine-3-carboxylic acid phenylamide cooH ~ /
C ~ N
PyBroP
rPr2NEt CI
N ~ CH2CI2 H /

A solution of 200 (2.95 mmol, 603 mg), 1-(4-Chlorophenyl)-1-cyclobutane carboxylic acid (201) (1.5 equiv, 4.43 mmol, 932 mg) and iPr2NEt (3.0 equiv, 8.85 mmol, 1.5 mL) in CHZCl2 (10 mL) was treated with PyBroP (1.5 equiv, 4.43 mmol, 2.07 g) under Ar at 0 °C. After warming to 25 °C and stirnng for 12 h, the reaction mixture was quenched with 10% aqueous HCl and extracted with EtOAc (3 x 25 mL). The organic layer was then washed with NaHC03 (sat) and dried with NaCI ~Saa and MgS04 ~5~.
Chromatography (Si02, 2.5 cm x 30.5 cm, 2:1 hexane-EtOAc) provided 202 (0.851 g, 1.17 g theoretical, 73%) as a white foam: Rf 0.17 (SiOz, 2:1 hexane-EtOAc); LRMS m/z 396 (M+, C,3HZSC1N20~, requires 396).

Example 141 ~1-[1-(4-Chloro-phen~)-cyclobutylmeth~l-piperidin-3ylmeth~l-phenyl-amine (2031 O
I , CI H Red~AI CI C~H
I N Toluene \ I N
~O
202 ~ 203 A solution of 202 (0.504 mmol, 200 mg) in Toluene (2 mL) at 0 °C was treated with 3.0 M Red-A1 (3.5 equiv, 1.76 mmol) under Ar. The reaction mixture stirred for 12 h and returned to 25 °C. The reaction mixture was then cooled to 0 °C, quenched with 10%
aqueous NaOH and extracted with EtOAc (3 X 25 mL). The organics were dried with NaCI
~Sat~ and NazS04 ~5~. The reaction mixture was purified by chromatography (PTLC, SiOz, 20 cm X 20 cm, 1 mm, 2:1 hexane-EtOAc) which provided 203 (170 mg, 186 mg theoretical, 91%) as a colorless oil: Rf 0.61 (SiOz, 2:1 hexane-EtOAc); LRMS mlz 368 (M+, CzsHz9ClNz, requires 368).
Example 142 Cyclobutanecarboxylic acid 11-L-(4-chloro-phenyl-cyclobu lmeth~]-piperidin-3-,1~~)-phenyl-amide (204) I
N ~COCI ~N
CI H CI C. J
iPr2NEt ~ I N O' A solution of 203 (0.276 mmol, 102 mg) in CHZC12 (2 mL) at 0 °C was treated with cyclobutanecarbonyl chloride (1.5 equiv, 0.414 mmol, 50 pL) and diisopropylethylamine (1.5 equiv, 0.414 mmol, 72 pL) under Ar. After warming to 25 °C and stirnng for 12 h, the 2o reaction mixture was purified directly by chromatography (PTLC, SiO,, 20 cm X 20 cm, 1 mm, 8:1 hexane-acetone) which provided 204 (100 mg, 124 mg theoretical, 81%) as a yellow oil: Rf 0.27 (Si02, 8:1 hexane-acetone); LRMS m/z 451 (M+, CZgH35C1Nz0, requires 451 ).
Example 143 N [1-(3-methylbutane)-piperidin-3-R-ylmethyl]-N (anilino-3-~)propionamide (2051 ~~ N ~~ N
1. H2, Pd-C 10%
N O + ~ 2. K2C03/CH3CN ~N O
Cbz Br A solution of 138 (0.170 mmol, 65 mg) in CH30H (1 mL) at 25 °C was treated with 10% Pd-C (20 mg) and then placed under a hydrogen atmosphere. The reaction mixture stirred for 12 h and then was filtered through a pad of Celite. The solvents were removed in vacuo and the resulting oil was then treated with 1-bromo-3-methylbutane (1.5 equiv, 0.255 mmol, 31 ~,L) and KZC03 (1.5 equiv, 0.255 mmol, 35 mg) in CH3CN (0.5 mL). The reaction mixture stirred for 12 h at 65 °C. The reaction mixture was then purified directly by chromatography (PTLC, Si02, 20 cm X 20 cm, 1 mm, EtOAc-10% CH30H) which provided 205 (36 mg, 54 mg theoretical, 67%) as colorless oil: Rf 0.60 (SiOz, EtOAc-10%
CH30H ); LRMS m/z 316 (M+, Cz°H32Nz0, requires 316).
Example 144 N 4-tent-ButoxYcarbon~-1-carbobenzyloxy[2-(2'-fluoroanilinocarboxyl]piperazine (206) Cbz O Cbz O
CN OH I DCC CN N ~
N + H2N ~ CH2C12 N H F
Boc F Boc A solution of 4-Boc-1-Cbz-piperazine-2-carboxylic acid (5.49 mmol, 2.00 g) and fluoroaniline (1.5 equiv, 8.24 mmol, 796 ~.L) in CHzCl2 (10 mL) at 0 °C
was treated with DCC (1.5 equiv, 8.24 mmol, 1.70 g) under Ar. The reaction mixture was allowed to warm to 25 °C and stirred for 12 h. The reaction mixture was then filtered to remove the urea and the solvents were removed in vacuo. Chromatography (Si02, 2.5 cm X 30.5 cm, 3:1 hexane-EtOAc) to give 206 (1.83 g, 2.51 g theoretical, 73%) as a white foam:
Rf 0.11 (Si0"
3:1 hexane-EtOAc); LRMS m/z 457 (M+, C,4HZ8FN305~ requires 457).
Example 145 N 4-tent-Butoxycarbonyl-1-Carbobenzvloxy[2-(2'-fluoroanilinomethyl~]piperazine (2071 Cbz O I ~ Cbz CN N / BH3 ~N~N /
N H F THF N H F
i i Boc 206 Boc A solution of 206 (2.19 mmol, 1.00 g) in THF (8.0 mL) at 0 °C was treated with 1.0 M BH3-THF (3.0 equiv, 6.57 mmol) under Ar. The reaction mixture was then heated to 75 °C and allowed to stir for 12 h. The reaction mixture was then cooled to 0 °C and quenched 1o with 10% aqueous HCI. The pH was adjusted to 10 with 10% aqueous NaOH and the reaction mixture was extracted with EtOAc (3 X 25 mL). The organics were dried with NaCI ~Sat~ and MgS04 ~5~. Chromatography (Si02, 2.5 cm X 30.5 cm, 3:1 hexane-EtOAc) to give 207 (0.744 g, 0.971 g theoretical, 77%) as a colorless oil: Rf 0.35 (SiOz, 3:1 hexane-EtOAc); LRMS m/z 443 (M+, C24HsoFNsOa, requires 443).
Example 146 N (4-tert-Butyloxy-1-CarbobenzYlox_ypiperazin-2- l~yl~2'-fluoroanilino~
cvclobutylcarboxamide (2081 F
Cbz ~ ~ Cbz N / COCI N
N ~ N
H F
iPrNEt Boc CH2CI2 Boc O

2o A solution of 207 (0.248 mmol, 110 mg) in CHZC12 (1 mL) at 0 °C was treated with cyclobutanecarbonyl chloride (1.5 equiv, 0.779 mmol, 77 pL) and diisopropylethylamine (2.0 equiv, 1.04 mmol, 181 qL) under Ar. After warming to 25 °C and stirring for 12 h, the reaction mixture was purified directly by chromatography (PTLC, SiOZ, 20 cm X
20 cm, 1 mm, 1:1 hexane-EtOAc) which provided 208 (130 mg, 130 mg theoretical, 99%) as a colorless oil: Rf 0.45 (SiOz, 1:1 hexane-EtOAc); LRMS mlz 525 (M+, C,9H36FN305, requires 525).
Example 147 N 1-Meths(4-tent-Butyloxypiperazin-2- l~ethyl)-N (2'-fluoroanilino~
c cly obutylcarboxamide (209) Cbz F ~ I F
N I / H Pd-C 10% N I /
~N 2r CH O ~ ~N
N O ~ 2 ~~ N O
Boc CH30H Boc to A solution of 208 (0.247 mmol, 130 mg) in CH30H (2.0 mL) at 25 °C
was treated with 30% Pd-C (20mg) and paraformaldehyde (74 mg) and then placed under a hydrogen atmosphere. The reaction mixture stirred for 12 h and then was filtered through a pad of celite. The solvents were removed in vacuo and the resulting oil was purified by chromatography (PTLC, Si02, 20 cm X 20 cm, 1 mm, EtOAc-20% CH30H) which provided 209 (74 mg, 100 mg theoretical, 74%) as colorless oil: Rf 0.58 (SiOz, EtOAc-20%
CH30H ); LRMS m/z 405 (M+, CzZH3zFN303, requires 405).
Example 148 N 1-Methyl(4-phenethyl-piperazin-2- l~yll-N (2'-fluoroanilinol-c cl~ylcarboxamide F ~ F
N I / 1. TFA/CH2C12 N
N N
2. PhCH CH Br N O~ 2 2 / I N O
Boc 209 \ 210 Compound 209 (0.182 mmol, 74 mg) was treated with 50% TFA in CHZC12 (1 mL) at 25 °C. The reaction mixture stirred for 2 h. The solvents were removed in vacuo and the resulting oil was dried under high vacuum for 5 h. The resulting oil was then treated with phenethyl bromide (2.0 equiv, 0.364 mmol, 50 ~L) and KZC03 (4.0 equiv, 0.728 mmol, 100 mg) in CH3CN (1.0 mL). The reaction mixture stirred for 12 h at 60 °C.
The reaction mixture was purified directly by chromatography (PTLC, Si02, 20 cm X 20 cm, 1 mm, EtOAc-10% CH30H) which provided 210 (64 mg, 75 mg theoretical, 85%) as colorless oil:
Rf 0.46 (Si02, EtOAc-10% CH30H ); LRMS m/z 409 (M+, CZSH3zFNs0, requires 409).
Example 149 N 1-carbobenz~Y[3-(2'-methylanilino)carboxy]pinerazine (2111 OH + I ~ BOP N /
N H2N / ~Pr2NEt H
N
Cbz CH2CI2 Cbz A solution of Cbz-nipecotic acid (3.80 mmol, 1.00 g), o-toluidine (2.0 equiv, 7.60 mmol, 811 ~.L) and diisopropylethylamine (2.0 equiv, 7.60 mmol, 1.3 mL) in CHzCl2 (10 mL) at 0 °C was treated with BOP (2.0 equiv, 7.60 mmol, 3.36 g) under Ar. The reaction mixture was allowed to warm to 25 °C and stirred for 12 h. The reaction mixture was quenched with 10% aqueous HCl and extracted with EtOAc (3 X 25 mL). The organic layer was then washed with NaHC03 (sat) and dried with NaCI ~Sa~~ and MgS04 Chromatography (Si02, 2.5 cm X 30.5 cm, 2:1 hexane-EtOAc) provided 211 (1.16 g, 1.34 g theoretical, 87%) as a white foam: Rf 0.34 (Si02, 2:1 hexane-EtOAc); LRMS m/z 352 (M+, CZ,H24N~03, requires 352).
Example 1 SO
N 1-carbobenz loxy[3-(2'-methylanilinolmeth~lninerazine (212) o ~ w I w / BH3 ~~H /
N THF \ JN
Cbz 211 Cbz A solution of 211 (0.567 mmol, 0.200 g) in THF (1.0 mL) at 0 °C was treated with 1.0 M BH3-THF (2.0 equiv, 1.13 mmol) under Ar. The reaction mixture was then heated to 80 °C and allowed to stir for 12 h. The reaction mixture was then cooled to 0 °C and quenched with 10% aqueous HCI. The pH was adjusted to 10 with 10% aqueous NaOH
and the reaction mixture was extracted with 3 X EtOAc (25 mL). The organics were dried with NaCI ~Sat~ and MgS04 ~5~. The reaction mixture was purified by chromatography (PTLC, SiOz, 20 cm X 20 cm, 1 mm, 3:1 hexane-EtOAc) which provided 212 (102 mg, 192 mg theoretical, 53%) as a colorless oil: Rf 0.54 (SiOz, 3:1 hexane-EtOAc); LRMS
m/z 338 (M+, CZ,H26N202, requires 338).
to Exam In a 1 SI
N-~Carbobenz~ypiperazin-3- l~~l-N (2'-methylanilino)c cl~ylcarboxamide coca N ~ N
H
iPrNEt Cbz 212 CH2CI2 Cbz A solution of 212 (0.301 mmol, 102 mg) in CHZC12 (1 mL) at 0 °C was treated with cyclobutanecarbonyl chloride (1.5 equiv, 0.452 mmol, 52 pL) and diisopropylethylamine (1.5 equiv, 0.452 mmol, 79 qL) under Ar. After warming to 25 °C and stirnng for 12 h, the reaction mixture was purified directly by chromatography (PTLC, Si02, 20 cm X
20 cm, 1 mm, 2:1 hexane-EtOAc) which provided 213 (127 mg, 127 mg theoretical, 99%) as a colorless oil: Rf 0.16 (Si02, 2:1 hexane-EtOAc); LRMS m/z 420 (M+, CZ,H3zN2O3, requires 420).
Example 152 ~Phenethyl-piperazin-3-ylmethyl~ N~2'-methylanilino~c cly obutylcarboxamide (214 1. H2, Pd-C 30%
~~ N _ ~~ N
N O 2. PhCH2CH2Br / I N O
Cbz A solution of 213 (0.302 mmol, 127 mg) in CH30H (1 mL) at 25 °C was treated with 30% Pd-C (25 mg) and then placed under a hydrogen atmosphere. The reaction mixture stirred for 12 h and then was filtered through a pad of celite. The solvents were removed in vacuo and the resulting oil was then treated with phenethyl bromide (1.5 equiv, 0.453 mmol, 62 ~L) and KzC03 (2.0 equiv, 0.604 mmol, 83 mg) in CH3CN (1.0 mL). The reaction mixture stirred for 12 h at 65 °C. The reaction mixture was then purified directly by chromatography (PTLC, Si02, 20 cm X 20 cm, 1 mm, EtOAc-10% CH30H) which provided 214 (51 mg, 118 mg theoretical, 43%) as colorless oil: Rf 0.45 (SiOz, EtOAc-10%
to CH30H ); LRMS m/z 390 (M+, CZ6H34Nz0, requires 390).

Incorporation By Reference All of the patents and publications cited herein are hereby incorporated by reference.
Equivalents Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims (204)

We claim:
1. A compound represented by A:
wherein m is 1, 2, 3 or 4;
n is 1 or 2;
y is 1 or 2;
R1 represents alkyl, aryl, heteroaryl, or cycloalkyl;
R2 represents independently for each occurrence H, alkyl, fluoroalkyl, aryl, heteroaryl, or cycloalkyl; provided that R2 is not nitrophenyl;
R1 and R2 may be connected through a covalent bond;
R1 represents independently for each occurrence H, alkyl, aryl, OR2, OC(O)R1, CH2OR2, or CO2R2; wherein any two instances of R3 may be connected by a covalent tether whose backbone consists of 1, 2, 3, or 4 carbon atoms;
R4 represents independently for each occurrence H, alkyl, aryl, heteroaryl, alkenyl, or cycloalkyl;
R5 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
R16 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
Y represents independently for each occurrence OR2, N(R2)2, SR2, S(O)R2, S(O)2R2, or P(O)(OR2)2;
a covalent bond may connect R4 and an instance of R5 or R6 that is attached to the carbon chain between R4 and the sing nitrogen explicitly shown in A;

any two geminal or vicinal instances of R5 and R6 may be connected through a covalent band;
X represents C(R3)=, O, S, SO, SO2, NR2, NC(O)OR2, or C=O; and the stereochemical configuration at any stereocenter of a compound represented by A
is R, S, or a mixture of those configurations.
2. The compound of claim 1, wherein X is C(R3)2, O, NRr, or C=O.
3. The compound of claim 1, wherein X is C(R3)2, O, or NR2
4. The compound of claim 1, wherein X is C(R3)2.
5. The compound of claim 1, wherein m is 2 or 3.
6. The compound of claim 1, wherein n is 1.
7. The compound of claim 1, wherein y is 1.
8. The compound of claim 1, wherein R1 represents aryl or heteroaryl.
9. The compound of claim 1, wherein R2 represents independently for each occurrence alkyl
10. The compound of claim 1, wherein R3 represents independently for each occurrence H
or alkyl.
11. The compound of claim 1, wherein R1, represents cycloalkyl, aryl, or heteroaryl.
12. The compound of claim 1, wherein its represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
13. The compound of claim 1, wherein R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
14. The compound of claim 1, wherein X is C(R,)2, O, NR2, or C=O; and n is 1.
15. The compound of claim 1, wherein X is C(R3)2, O, or NR2; and n is 1.
16. The compound of claim 1, wherein X is C(R3)2; and n is 1.
17. The compound of claim 1, wherein X is C(R3)2, O, NR2, or Cue; and y is 1.
18. The compound of claim 1, wherein X is C(R3)2, O, or NR2; and y is 1.
19. The compound of claim 1, wherein X is C(R3)2; and y is 1.
20. The compound of claim 1, wherein X is C(R3)2, O, NR2, or C=O; and R1 represents aryl or heteroaryl.
21. The compound of claim 1, wherein X is C(R3)2, O or NR2; and R1 represents aryl or heteroaryl.
22. The compound of claim 1, wherein X is C(R1)2; and R1 represents aryl or heteroaryl.
23. The compound of claim 1, wherein X is C(R1)2, O, NR2, or C=O; and R2 represents independently for each occurence alkyl.
24. The compound of claim 1, wherein X is C(R3)2, O, or NR2; and R2 represents independently for each occurrence alkyl.
25. The compound of claim 1, wherein X is C(R3)2; and R1 represents independently for each occurrence alkyl.
26. The compound of claim 1, wherein X is C(R3)2, O, NR2, or C=O; n is f; and represents aryl or heteroaryl.
27. The compound of claim 1, wherein X is C(R3)2, O, or NR2; n is 1; and R1 represents aryl or heteroaryl.
28. The compound of claim 1, wherein X is C(R3)2; n is 1; and R1 represents aryl or heteroaryl.
29. The compound of claim 1, wherein X is C(R3)2, O, NR2, or C=O; n is 1; R1 represents aryl or heteroaryl; and R2 represents independently for each occurrence alkyl.
30. The compound of claim 1, wherein X is C(R3)3, O, or NR2; n is 1; R, represents aryl or heteroaryl; and R2 represents independently for each occurrence alkyl.
31. The compound of claim 1, wherein X is C(R3)2=; n is 1; R1 represents aryl or heteroaryl;
and R2 represents independently for each occurrence alkyl.
32. The compound of claim 1, wherein X is C(R1)=, O, NR2, or C=O; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; and represents independently for each occurrence H or alkyl.
33. The compound of claim 1, wherein X is C(R3)2, O, or NR2; n is 1; R, represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; and R, represents independently for each occurrence H of alkyl.
34. The compound of claim 1, wherein X is C(R3)=; n is 1; R, represents aryl or heteroaryl;
R2 represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
35. The compound of claim 1, wherein X is C(R3)2, O, NR2, or C=O; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
36. The compound of claim 1, wherein X is C(R3)2, O, or NR2; n 1, represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
37. The compound of claim 1, wherein X is C(R3)2; n is 1; R, represents aryl or heteroaryl;
R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R, represents cycloalkyl, aryl, or heteroaryl.
38. The compound of claim l, wherein X is C(R3)2, O, NR2, or C=O; a is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R1 represents independently for each occurrence H or alkyl; R, represents cycloalkyl, aryl, or heteroaryl; and R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
39. The compound of claim 1, wherein X is C(R3)2, O, or NR2; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; and R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
40. The compound of claim 1, wherein X is C(R3)2; n is 1; R1 represents aryl or heteroaryl;
R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; and represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
41. The compound of claim 1, wherein X is C(R3)2, O, NR2, or C=O; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R, represents cycloalkyl, aryl, or heteroaryl; R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
42. The compound of claim l, wherein X is C(R3)2, O, or NR2; n is 1; R, represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R4 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
43. The compound of claim 1, wherein X is C(R3)2; n is 1; R1 represents aryl or heteroaryl;
R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
44. The compound of claim 1, wherein X is C(R3)2; m is 2; n is 1; R1 represents aryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H; R4 represents aryl; R1 represents independently for each occurrence H or alkyl; and R6 represents independently for each occurrence H or alkyl.
45. A compound represented by B:

wherein m is 1, 2, 3 or 4;
n is 1 or 2;
R1 represents H, alkyl, aryl, heteroaryl, or cycloalkyl;

R2 represents independently for each occurrence H, alkyl, fluoroalkyl, aryl, heteroaryl, or cycloalkyl;
R1 and R2 may be connected through a covalent bond;
R3 represents independently for each occurrence H, alkyl, aryl, OR2, OC(O)R2, CH2OR2, or CO2R2; wherein any two instances of R3 may be connected by a covalent tether whose backbone consists of 1, 2, 3, or 4 carbon atoms;
R4 represents independently for each occurrence aryl, heteroaryl, alkenyl, or cycloalkyl;
R5 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
R6 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
Y represents independently for each occurrence OR2, N(R2)2, SR2, S(O)R2, S(O)2R2, or P(O)(OR2)2;
a covalent bond may connect R4 and an instance of R5 or R4 that is attached to the carbon chain between R4 and the ring nitrogen explicitly shown in B;
any two geminal or vicinal instances of R5 and R6 may be connected through a covalent bond;
X represents C(R3)2, O, S, SO, SO2, NR2, NC(O)OR2, or C=O; and the stereochemical configuration at any stereocenter of a compound represented by B
is R or S.
46. The compound of claim 45, wherein X is C(R3)2, O, NR2, or C=O.
47. The compound of claim 45, wherein X is C(R3)2, O, or NR2.
48. The compound of claim 45, wherein X is C(R3)2.
49. The compound of claim 45, wherein m is 2 or 3.
50. The compound of claim 45, wherein n is 1.
51. The compound of claim 45, wherein R1 represents aryl or heteroaryl.
52. The compound of claim 45, wherein R2 represents independently for each occurrence alkyl.
53. The compound of claim 45, wherein R3 represents independently for each occurrence H or alkyl.
54. The compound of claim 45, wherein R4 represents cycloalkyl, aryl, or heteroaryl.
55. The compound of claim 45, wherein R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
56. The compound of claim 45, wherein R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
57. The compound of claim 45, wherein X is C(R3)2, O. NR2, or C=O; and n is 1.
58. The compound of claim 45, wherein X is C(R1)2, O, or NR2, and n is 1.
59. The compound of claim 45, wherein X is C(R3)2, and n is 1.
60. The compound of claim 45, wherein X is C(R3)2, O, NR2, or C=O; and R1 represents aryl or heteroaryl.
61. The compound of claim 45, wherein X is C(R3)2, O, or NR2; and R1 represents aryl or heteroaryl.
62. The compound of claim 45. wherein X is C(R3)2; and R1 represents aryl or heteroaryl.
63. The compound of claim 45, wherein X is C(R3)2, O, NR2, or C=O; and R2 represents independently for each occurrence alkyl.
64. The compound of claim 45, wherein X is C(R3)2, O, or NR2; and R2 represents independently for each occurrence alkyl.
65. The compound of claim 45, wherein X is C(R3)2; and R2 represents independently for each occurrence alkyl.
66. The compound of claim 45, wherein X is C(R3)2, O, NR2, or C=O; n is 1; and represents aryl or heteroaryl.
67. The compound of claim 45, wherein X is C(R3)2, O, or NR2; n is 1; and R1 represents aryl or heteroaryl.
68. The compound of claim 45, wherein X is C(R3)2; n is 1; and R4 represents aryl or heteroaryl.
69. The compound of claim 45, wherein X is C(R3)2, O, NR2, or C=O; n is 1; R1 represents aryl or heteroaryl; and R2 represents independently for each occurrence alkyl.
70. The compound of claim 45, wherein X is C(R3)2, O, or NR2; n is 1; R1 represents aryl or heteroaryl; and R2 represents independently for each occurrence alkyl.
71. The compound of claim 45, wherein X is C(R3)2; n is 1; R1 represents aryl or heteroaryl; and R2 represents independently for each occurrence alkyl.
72. The compound of claim 45, wherein X is C(R3)2, O, NR2, or C=O; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; and represents independently for each occurrence H or alkyl.
73. The compound of claim 45, wherein X is C(R3)2, O, or NR2; n is 1; R1 represents aryl or heteroaryl, R2 represents independently for each occurrence alky; and R3 represents independently for each occurrence H or alkyl.
74. The compound of claim 45, wherein X is C(R3)2; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
75. The compound of claim 45, wherein X is C(R3)2, O, NR2, or C=O; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
76. The compound of claim 45, wherein X is C(R3)2, O, or NR2; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
77. The compound of claim 45, wherein X is C(R3)2; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
78. The compound of claim 45, wherein X is C(R3)2, O, NR2, or C=O; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; and R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, of F.
79. The compound of claim 45, wherein X is C(R3)2, O, or NR2; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; and R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
80. The compound of claim 45, wherein X is C(R3)2; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; and R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
81. The compound of claim 45, wherein X is C(R3)2, O, NR2, or C=O; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
82. The compound of claim 45, wherein X is C(R3)2, O, or NR2; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
83. The compound of claim 45, wherein X is C(R3)2; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
84. A compound represented by C:

wherein m is 1, 2, 3 or 4;
y is 0, 1 or 2;
R1 represents H, alkyl, aryl, heteroaryl, or cycloalkyl;
R2 represents independently for each occurrence H, alkyl, fluoroalkyl, aryl, heteroaryl, or cycloalkyl;
R1 and R2 may be connected through a covalent bond;
R3 represents independently for each occurrence H, alkyl, aryl, OR2, OC(O)R2, CH2OR2, or CO2R2;
R4 represents H, alkyl, aryl, heteroaryl, alkenyl, or cycloalkyl;
R5 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
R6 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
Y represents independently for each occurrence OR2, N(R2)2, SR2, S(O)R2, S(O)2R2, or P(O)(OR2)2;
a covalent bond may connect R4 and an instance of R5 or R6 that is attached to the carbon chain between R4 and the ring nitrogen explicitly shown in C;
any two geminal or vicinal instances of R5 and R6 may be connected through a covalent bond; and the stereochemical configuration at any stereocenter of a compound represented by C
is R, S, or a mixture of these configurations.
85. The compound of claim 84, wherein m is 2 or 3.
86. The compound of claim 84, wherein y is 1.
87. The compound of claim 84, wherein R1 represents aryl or heteroaryl.
88. The compound of claim 84, wherein R2 represents independently for each occurrence alkyl.
89. The compound of claim 84, wherein R3 represents independently for each occurrence H or alkyl.
90. The compound of claim 84, wherein R4 represents cycloalkyl, aryl, or heteroaryl.
91. The compound of claim 84, wherein R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
92. The compound of claim 84, wherein R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
93. The compound of claim 84, wherein R1 represents aryl or heteroaryl; and R2 represents independently for each occurrence alkyl.
94. The compound of claim 84, wherein R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
95. The compound of claim 84, wherein R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
96. The compound of claim 84, wherein R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; and R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
97. The compound of claim 84, wherein R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
98. A compound represented by D:

wherein m is 1, 2, 3 or 4;
y is 0, 1 or 2;
R1 represents H, alkyl, aryl, heteroaryl, or cycloalkyl;
R2 represents independently for each occurrence H, alkyl, fluoroalkyl, aryl, heteroaryl, or cycloalkyl;
R1 and R2 may be connected through a covalent bond;
R3 represents independently for each occurrence H, alkyl, aryl, OR2, OC(O)R2, CH2OR2, or CO2R2;
R4 represents H, alkyl, aryl, heteroaryl, alkenyl, or cycloalkyl;
R5 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
R6 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
Y represents independently for each occurrence OR2, N(R2)2, SR2, S(O)R2 S(O)2R2, or P(O)(OR2)2;
a covalent bond may connect R4 and an instance of R5 or R6 that is attached to the carbon chain between R4 and the ring nitrogen explicitly shown in D;
any two geminal or vicinal instances of R5 and R6 may be connected through a covalent bond; and the stereochemical configuration at any stereocenter of a compound represented by D
is R or S.
99. The compound of claim 98, wherein m is 2 or 3.
100. The compound of claim 98, wherein y is 1.
101. The compound of claim 98, wherein R1 represents aryl or heteroaryl.
102. The compound of claim 98, wherein R2 represents independently for each occurrence alkyl.
103. The compound of claim 98, wherein R3 represents independently for each occurrence H or alkyl.
104. The compound of claim 98, wherein R4 represents cycloalkyl, aryl, or heteroaryl.
105. The compound of claim 98, wherein R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
106. The compound of claim 98, wherein R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
107. The compound of claim 98, wherein R1 represents aryl or heteroaryl; and R2 represents independently for each occurrence alkyl.
108. The compound of claim 98, wherein R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
109. The compound of claim 98, wherein R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
110. The compound of claim 98, wherein R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; and R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
111. The compound of claim 98, wherein R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
112. A compound represented by E:

wherein m is 1, 2, 3 or 4;
n is 1 or 2;
R1 represents H, alkyl, aryl, heteroaryl, or cycloalkyl;
R2 represents independently for each occurrence H, alkyl, fluoroalkyl, aryl, heteroaryl, or cycloalkyl;
R1 and R2 may be connected through a covalent bond;
R3 represents independently for each occurrence H, alkyl, aryl, OR2, OC(O)R2, CH2OR2, or CO2R2; wherein any two instances of R3 may be connected by a covalent tether whose backbone consists of 1, 2, 3, or 4 carbon atoms;
R4 represents H, alkyl, aryl, heteroaryl, alkenyl, or cycloalkyl;
R5 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
R6 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
Y represents independently for each occurrence OR2, N(R2)2, SR2, S(O)R2, S(O)2R2, or P(O)(OR2)2;
a covalent bond may connect R4 and an instance of R5 or R6 that is attached to the carbon chain between R4 and the ring nitrogen explicitly shown in E;
any two geminal or vicinal instances of R5 and R6 may be connected through a covalent bond;
X represents C(R3)2, O, S, SO, SO2, NR2, NC(O)OR2, or C=O; and the stereochemical configuration at any stereocenter of a compound represented by E
is R, S, or a mixture of these configurations.
113. The compound of claim 112, wherein X is C(R3)2, O, NR2, or C=O.
114. The compound of claim 112, wherein X is C(R3)2, O, or NR2.
115. The compound of claim 112, wherein X is C(R3)2.
116. The compound of claim 112, wherein m is 2 or 3.
117. The compound of claim 112, wherein n is 1.
118. The compound of claim 112, wherein R1 represents aryl or heteroaryl.
119. The compound of claim 112, wherein R2 represents independently for each occurrence alkyl.
120. The compound of claim 112, wherein R3 represents independently for each occurrence H or alkyl.
121. The compound of claim 112, wherein R4 represents cycloalkyl, aryl, or heteroaryl.
122. The compound of claim 112, wherein R3 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
123. The compound of claim 112, wherein R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
124. The compound of claim 112, wherein X is C(R3)2, O, NR2, or C=O; and n is 1.
125. The compound of claim 112, wherein X is C(R3)2, O, or NR2; and n is 1.
126. The compound of claim 112, wherein X is C(R3)2; and n is 1.
127. The compound of claim 112, wherein X is C(R3)2. O, NR2, or C=O; and R1 represents aryl or heteroaryl.
128. The compound of claim 112, wherein X is C(R3)2, O, or NR2; and R1 represents aryl or heteroaryl.
129. The compound of claim 112, wherein X is C(R3)2; and R1 represents aryl or heteroaryl.
130. The compound of claim 112, wherein X is C(R3)2, O, NR2, or C=O; and R2 represents independently for each occurrence alkyl.
131. The compound of claim 112, wherein X is C(R3)2, O, or NR2; and R2 represents independently for each occurrence alkyl.
132. The compound of claim 112, wherein X is C(R3)2; and R2 represents independently for each occurrence alkyl.
133. The compound of claim 112, wherein X is C(R3)2, O, NR2, or C=O; n is 1;
and R1 represents aryl or heteroaryl.
134. The compound of claim 112, wherein X is C(R3)2, O, or NR2; n is 1; and R1 represents aryl or heteroaryl.
135. The compound of claim 112, wherein X is C(R3)2, n is 1; and R1 represents aryl of heteroaryl.
136. The compound of claim 112, wherein X is C(R3)2, O, NR2, or Cue; n is 1;

represents aryl or heteroaryl; and R2 represents independently for each occurrence alkyl.
137. The compound of claim 112, wherein X is C(R3)2, O, or NR2; n is 1; R1, represents aryl or heteroaryl; and R2 represents independently for each occurrence alkyl.
138. The compound of claim 112, wherein X is C(R3)2; n is 1; R1 represents aryl or heteroaryl; and R2 represents independently for each occurrence alkyl.
139. The compound of claim 112, wherein X is C(R3)2, O; NR2, or C=O; n is 1;

represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl;
and R3 represents independently for each occurrence H or alkyl.
140. The compound of claim 112, wherein X is C(R3)2, O, or NR2; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
141. The compound of claim 112, wherein X is C(R3)2; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
142. The compound of claim 112, wherein X is C(R3)2, O, NR2, or C=O; n is 1;

represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
143. The compound of claim 112, wherein X is C(R3)2, O, or NR2; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
144. The compound of claim 112, wherein X is C(R3)2; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
145. The compound of claim 112, wherein X is C(R1)2, O, NR2, or C=O; n is 1;

represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl, R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; and R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
146. The compound of claim 112, wherein X is C(R3)2, O, or NR2; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; and R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
147. The compound of claim 112, wherein X is C(R3)2; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; and R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
148. The compound of claim 112, wherein X is C(R3)2, O, NR2, or C=O; n is 1;

represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
149. The compound of claim 112, wherein X is C(R3)2, O, or NR2; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
150. The compound of claim 112, wherein X is C(R3)2; n is 1; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
151. A compound represented by F:

wherein m is 1, 2, 3 or 4;
y is 0, 1, or 2;
R1 represents H, alkyl, aryl, heteroaryl, or cycloalkyl;
R2 represents independently for each occurrence H, alkyl, fluoroalkyl, aryl, heteroaryl, or cycloalkyl;
R1 and R2 may be connected through a covalent bond;
R3 represents independently for each occurrence H, alkyl, aryl, OR2, OC(O)R2, CH2OR2, or CO2R2;
R4 represents independently for each occurrence H, alkyl, aryl, heteroaryl, alkenyl, or cycloalkyl;
R5 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;

R6 represents independently for each occurrence H, alkyl, CH2Y, aryl, heteroaryl, F, OR2, or OC(O)R2;
Y represents independently for each occurrence OR2, N(R2)2, SR2, S(O)R2, S(O)2R2, or P(O)(OR2)2;
a covalent bond may connect R4 and an instance of R5 or R6 that is attached to the carbon chain between R4 and the ring nitrogen explicitly shown in F;
any two geminal or vicinal instances of R5 and R6 may be connected through a covalent bond;
X represents O, S, SO, SO2, NR2, NC(O)OR2, or C=O; and the stereochemical configuration at any stereocenter of a compound represented by F
is R, S, or a mixture of these configurations.
152. The compound of claim 151, wherein X is O, NR2, or C=O.
153. The compound of claim 151, wherein X is O or NR2.
154. The compound of claim 151, wherein X is NR2.
155. The compound of claim 151, wherein m is 2 or 3.
156. The compound of claim 151, wherein y is 1.
157. The compound of claim 151, wherein R1 represents aryl or heteroaryl.
158. The compound of claim 151, wherein R2 represents independently for each occurrence alkyl.
159. The compound of claim 151, wherein R3 represents independently for each occurrence H or alkyl.
160. The compound of claim 151, wherein R4 represents cycloalkyl, aryl, or heteroaryl.
161. The compound of claim 151, wherein R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
162. The compound of claim 151, wherein R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
163. The compound of claim 151, wherein X is O, NR2, or C=O; and y is 1.
164. The compound of claim 151, wherein X is O or NR2; and y is 1.
165. The compound of claim 151, wherein X is NR2; and y is 1.
166. The compound of claim 151, wherein X is O, NR2, or C=O; and R1 represents aryl or heteroaryl.
167: The compound of claim 151, wherein X is O or NR2; and R1 represents aryl or heteroaryl.
168. The compound of claim 151, wherein X is NR2; and R1 represents aryl or heteroaryl.
169. The compound of claim 151, wherein X is O, NR2, or C=O; and R2 represents independently for each occurrence alkyl.
170. The compound of claim 151, wherein X is O or NR2; and R2 represents independently for each occurrence alkyl.
171. The compound of claim 151, wherein X is NR2; and R2 represents independently for each occurrence alkyl.
172. The compound of claim 151, wherein X is O, NR2, or C=O; R1 represents aryl or heteroaryl; and R2 represents independently for each occurrence alkyl.
173. The compound of claim 151, wherein X is O or NR2; R1 represents aryl or heteroaryl;
and R2 represents independently for each occurrence alkyl.
174. The compound of claim 151, wherein X is NR2; R1 represents aryl or heteroaryl; and R2 represents independently for each occurrence alkyl.
175. The compound of claim 151, wherein X is O, NR2, or C=O; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
176. The compound of claim 151, wherein X is O or NR2; R1 represents aryl or heteroaryl;
R2 represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
177. The compound of claim 151, wherein X is NR2; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; and R3 represents independently for each occurrence H or alkyl.
178. The compound of claim 151, wherein X is O, NR2, or C=O; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
179. The compound of claim 151, wherein X is O or NR2, R1 represents aryl or heteroaryl;
R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
180. The compound of claim 151, wherein X is NR2; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R2 represents independently for each occurrence H or alkyl; and R4 represents cycloalkyl, aryl, or heteroaryl.
181. The compound of claim 151, wherein X is O, NR2, or C=O; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; and R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
182. The compound of claim 151, wherein X is O or NR2; R1 represents aryl or heteroaryl;
R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl; or heteroaryl;
and R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
183. The compound of claim 151, wherein X is NR2; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents, independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; and represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
184. The compound of claim 151, wherein X is O, NR2, or C=O; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
185. The compound of claim 151, wherein X is O or NR2; R1 represents aryl or heteroaryl;
R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; R5, represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
186. The compound of claim 151, wherein X is NR2; R1 represents aryl or heteroaryl; R2 represents independently for each occurrence alkyl; R3 represents independently for each occurrence H or alkyl; R4 represents cycloalkyl, aryl, or heteroaryl; R5 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F; and R6 represents independently for each occurrence H, alkyl, aryl, heteroaryl, or F.
187. The compound of claim 1, 84, 112, or 151, wherein said compound is a single stereoisomer.
188.A formulation, comprising a compound of claim 1, 45, 84, 98, 112, or 151, and a pharmaceutically acceptable excipient.
189. The compound of claim 1, 45, 84, 98, 112, or 151, wherein said compound is a ligand for a cellular receptor.
190. The compound of claim 189, wherein said compound is a ligand for a G-protein-coupled receptor.
191. The compound of claim 189, wherein said compound is a ligand for an opioid receptor.
192. The compound of claim 190, wherein said compound is an agonist of a G-protein-coupled receptor.
193. The compound of claim 190, wherein said compound is an antagonist of a G-protein-coupled receptor.
194. The compound of claim 191, wherein said compound is an agonist of an opioid receptor.
195. The compound of claim 191, wherein said compound is an antagonist of an opioid receptor.
196. The compound of claim 190, wherein said compound is a ligand which is selective for a subclass of G-protein-coupled receptor.
197. The compound of claim 191, wherein said compound is a ligand which is selective for a subclass of opioid receptor.
198. A method of treating pain, drug addiction, or tinnitus in a mammal, comprising the step of:

administering to a mammal with pain, drug addiction, or tinnitus an effective amount of a formulation of claim 188.
199. The method of claim 198, wherein said mammal is a primate, equine, canine or feline.
200. The method of claim 198, wherein said mammal is a human.
201. The method of claim 198, wherein said formulation is administered orally.
202. The method of claim 198, wherein said formulation is administered intravenously.
203. The method of claim 198, wherein said formulation is administered sublingually.
204. The method of claim 198, wherein said formulation is administered ocularly.
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