JP2003500392A - Heterocyclic analgesic compounds and methods of use - Google Patents

Abstract

  (57) [Summary] 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 a variety of cellular receptors, including opioid receptors, other G-protein coupled receptors and ion channels. A further aspect of the present invention relates to the use of said novel heterocyclic compounds as analgesics.

Description

Detailed Description of the Invention

Related Application This application is related to US provisional patent application No. 60/195, filed April 11, 2000.
No. 809, U.S. Provisional Patent Application No. 60/168, filed December 3, 1999,
979 and US Provisional Patent Application No. 60/135, filed May 25, 1999.
, 721 claim the benefit of priority.

BACKGROUND OF THE INVENTION Pain is an unpleasant sensation of varying degrees of severity, either on a localized area of the body or on some part of the body, resulting from an injury, illness or affective disorder. Pain can be classified by its duration. Acute pain does not last for more than a month and usually has an easily identifiable cause and is a signal of tissue damage. Moreover, acute pain syndromes are interstitial, such as recurrent discomfort resulting from arthritis. Chronic pain is more than one month beyond the usual course of acute illness or injury, repeats at intervals of months or years, or as pain associated with chronic pathological processes. Can be defined. In contrast to acute pain, chronic pain loses its adaptive biological effect. Depression is common and abnormal pathological effects often exacerbate a patient's disability.

Millions of people suffer from chronic or difficult to cure pain. In some cases, symptoms and signs may appear within a few weeks to several months after the occurrence of injury or the onset of cancer or AIDS. As with many illnesses that were once poorly understood, pain and its symptoms have not been properly treated or have been grossly neglected. The inadequate treatment of pain has significantly impaired the quality of life of patients, causing emotional suffering, increasing the risk of losing their livelihoods and disrupting social life. Intense chronic pain affects both children and adults and often results in depression and, in rare cases, emotional disorders, including suicide.

During the last few years, health lawmakers, health professionals, supervisors and the general public have become increasingly interested in providing better pain treatment. The manifestation of this interest is manifested in part by the US Department of Health and Human Services' dissemination of "clinical guidelines" for treating acute and cancer pain. There is currently no nationally accepted consensus on the treatment of non-cancerous chronic pain, and the economic and social losses from chronic pain are still substantial, with estimates estimated at a few years each year. It amounts to 10 billion dollars.

Three general classes of drugs are currently available for pain management: non-steroidal anti-inflammatory drugs, opioids and adjuvant analgesics. This class of non-steroidal anti-inflammatory drugs includes aspirin, ibuprofen, diclofenac, acetaminophen, celecoxib and rofecoxib. In the opioid class,
There are morphine, oxycodone, fentanyl and pentazocine. Adjuvant analgesics include various antidepressants, anticonvulsants, neuroleptics and corticosteroids.

Opioids are the main class of analgesics used in the management of moderate to severe pain because of their effectiveness, ease of titration and good risk-of-benefits. Opioids cause analgesia by binding to specific receptors both inside and outside the CNS (Central Nervous System). Opioid analgesics are total agonists, according to the receptors they bind to and their unique activity at each receptor.
It is classified as a partial agonist or a mixed agonist / antagonist.

Three subclasses of opioid receptors have been identified in humans, namely δ
(Delta), kappa (kappa) and mu (mu) opioid receptors. Analgesia is believed to involve activation of the mu and / or kappa receptors. Morphine and morphine-like opioid agonists, despite their lower selectivity for the μ receptor over the kappa receptor, are probably the first choice for these opioid agonists.
It appears that analgesia occurs through interaction with receptors, and then selective agonists of human kappa receptors cause analgesia. This is because these compounds often cause discomfort and psychopathic effects rather than the euphoria associated with morphine and its congeners. What results when the human delta receptor is activated remains unclear.

Although opioids can be very effective in pain management, they do cause some side effects such as respiratory depression, constipation, physical dependence, tolerance, withdrawal.
These undesirable effects can severely limit their use.

Opioids are known to cause respiratory depression in proportion to their analgesia. Such respiratory depression can be life threatening. Therefore, there is a narrow gap between the effective dose and the dose that causes respiratory depression. Due to this low therapeutic index, patients receiving opioid therapy must be closely monitored for signs of respiratory failure.

Opioids also cause constipation in those who receive them. This side effect can be terrible and may require lengthy hospitalization and even surgical intervention.

All commonly used agonists include morphine, hydromorphone, meperidine, methadone, levorphanol and fentanyl. These opioids are classified as full agonists because they have unlimited analgesic potency and, when administered simultaneously, do not counteract or antagonize the effects of other opioids in this class. . Side effects include respiratory depression, constipation, nausea, urinary retention, confusion and sedation. Morphine is the most commonly used opioid for moderate to severe pain due to its versatile dosage form utility, its good pharmacokinetic and pharmacodynamic properties, and its relatively low cost. is there. Meperidine is a short-term course (eg, to treat the stiffness (quivering) caused by acute pain treatment and medications.
It may be useful for several days) but its duration of action is short (two and a half to three and a half hours)
Also, its metabolite, normeperidine, is harmful and should generally be avoided in cancer patients. Especially in the case of impaired renal function, such metabolites can accumulate and cause excitement of the CNS (central nervous system), which can lead to discomfort, agitation and seizures. Therefore,
Meperidine should not be used if opioids are expected to be used on a continuous basis.

The development of physical addiction by repeated use is a hallmark of these opioid drugs, and the potential for drug addiction is one of the major constraints on their clinical use. Almost all opioid users are lethargic, lose weight,
It develops drug addiction that can lead to loss of libido, anxiety and drug cravings.
Physical dependence is common, but poisoning and abuse are not commonly seen in pain patients who are properly prescribed opioid drugs.

Historically, the development of analgesic resistance was thought to limit the ability to use opioids for long periods of time without losing efficacy in pain treatment. Tolerance, i.e., less pain relief at the same dose over time, does not prove to be a general limitation of long-term opioid use. Experience with treating cancer pain revealed that what initially appeared to be resistant was, in most cases, the progression of the disease. Furthermore, for most opioids, there is no expected upper dose limit, as was once thought.

Withdrawal of opioid administration can result in withdrawal syndrome. Withdrawal syndrome is often the opposite of the effect obtained with this drug, but withdrawal symptoms with morphine result in complex symptoms that appear to be independent of its effect. Misconceptions about drug addiction and mislabeling patients with drug addicts result in unnecessary suppression of opioid dosing. Poisoning is an obsessive-compulsive disorder in which a person becomes obsessed with obtaining and using a substance, and continued use of it causes the quality of life to gradually deteriorate. Studies have pointed out that new onset of drug addiction is low when opioids are used to eliminate pain. Furthermore, for the treatment of pain from recurrent painful illnesses such as cancer, surgery or sickle cell disease, even opioid addicts benefit from the use of opioids with careful and appropriate judgment. Obtainable

Known opioids are very effective in treating pain. But they are
Its use has been limited due to some potentially serious side effects. Therefore, there is a need today for a drug that retains the known analgesic properties of opioids, but with reduced side-effect profile.

SUMMARY OF THE INVENTION One aspect of the present invention relates to novel heterocyclic compounds. A second aspect of the invention relates to the use of the novel heterocyclic compounds as ligands for various cellular receptors including morphine receptors, other G protein coupled receptors and ion channels. Another aspect of the invention relates to the use of these novel heterocyclic compounds as analgesics.

DETAILED DESCRIPTION OF THE INVENTION Pain is an unpleasant sensation of varying degrees of locality or some part of the body, resulting from an injury, illness or emotional disorder. Pain can be classified by its duration. Although acute pain does not last for more than a month, it usually has an easily identifiable cause (eg, hip fracture) and is a signal of tissue damage.
The associated effects are often anxiety and the associated physiological findings are due to sympathetic nerve stimulation (eg tachycardia, polypnea, sweating). Moreover, acute pain syndromes are interstitial, such as recurrent discomfort resulting from arthritis.

Chronic pain lasts for more than a month beyond the usual course of acute illness or injury, repeats at intervals of months or years, or is associated with chronic pathological processes. It can be defined as accompanying pain. In contrast to acute pain, chronic pain loses its adaptive biological effect. Depression is common and abnormal pathological effects often exacerbate a patient's disability. Chronic pain can be broadly divided into those that are presumed to be predominantly somatogenic and those that are predominantly psychogenic. By similar classification based on pathophysiological inference, nociceptive (corresponding to ongoing activation of pain-sensitive nerve fibers), neuropathic (abnormal somatosensory processing in afferent neuronal pathways) Caused) or psychogenic.

Nociceptive pain can be physical or organ. Most of the chronic pain in the elderly is nociceptive and physical, with arthritis, cancer pain and fascia pain being the most common. For analgesia, removal of peripheral causes (for example, suppression of inflammation around joints) is effective, and analgesics are often effective.

Common subtypes of neuropathic pain, collectively known as peripheral neuropathic pain, include:
It is thought to be caused by a mechanism involved in disease in peripheral nerves or nerve roots, and formation of neuromas and nerve compression after axonal injury are two major processes of the disease. . Another subtype of neuropathic pain is associated with reorganization of nociceptive information processing by the central nervous system, which persists stubbornly even if the activation state of pain-sensitive fibers does not persist . This type of pain, commonly known as deafferentation syndrome, includes postherpetic neuralgia, central pain (caused by any damage to the central nervous system), and phantom limb pain. There is. The third subtype of neuropathic pain, collectively referred to as sympathetic nerve maintenance pain, can be alleviated by interrupting the sympathetic nerve to the aching area. The prototypical disease is reflex sympathetic dystrophy syndrome. The precise mechanisms involved in these disorders are speculative but can cause pain that none of them have ever experienced, often described as burning, piercing, and so on. For now, these types of pain have little effect on analgesics.

[0021] Some patients have persistent pain who have no nociceptive lesions or evidence of neuropathic mechanisms of pain. Others often have nociceptive lesions, although the degree of pain and disability are poorly explained. Some people may explain these complaints by their psychopathological course. If no evidence of a psychological cause is found, the pain is called idiopathic. Many patients have an idiopathic pain syndrome that can be described as a chronic benign pain syndrome by common diagnosis, but this syndrome does not fit the identifiable physical cause and is more widespread. A term that refers to pain and disability most often associated with a set of abnormal effects. Some of these patients are described by a more formal psychological diagnosis of somatic pain disorder. Others have complaints that result in specific pain diagnoses, but the most common are paroxysmal back pain syndrome or atypical facial pain. In addition, some have significant organ involvement (eg, lumbar arachnoid), but apparently psychological contributions with excessive disability. Although difficult to diagnose, the relative contributions of both the organ and psychological components of pain can be defined.

Another clinically useful class of chronic pain is the widespread symptomatic. For example, chronic pain may be part of a medical condition (eg cancer or arthritis). A mixture of abnormal pathophysiological mechanisms may be involved, for example, tumors affecting nerves and bones may cause neuropathic and physical nociceptive pain, respectively, with psychological factors. It may be noticeable.

Three general classes of drugs are currently available for treating pain: non-steroidal anti-inflammatory agents, opioids and adjuvant analgesics. This class of non-steroidal anti-inflammatory agents includes aspirin, ibuprofen, diclofenac, acetaminophen, celecoxib and rofecoxib. In the opioid class,
There are morphine, oxycodone, fentanyl and pentazocine. Adjuvant analgesics include various antidepressants, anticonvulsants, neuroleptics and corticosteroids.

Of the three classes of drug substances used in pain management, opioids are usually the most effective for treating moderate to severe pain. Although opioids are highly effective in treating pain, they have been shown to cause several side effects including respiratory depression, constipation, physical addiction, tolerance and withdrawal. These undesirable effects can severely limit their use. Therefore, there is today a need for drug substances that retain the analgesic properties of known opioids, but with reduced side-effect aspects with respect to pain management.

Opioids, especially ligands for the μ-opioid receptor, are a major class of analgesics used in the management of moderate to severe pain because of their effectiveness, ease of titration, and favorable risk of benefit. is there. Unfortunately, currently available opioids have some undesirable side effects such as respiratory depression and constipation. Moreover, these agents can lead to resistance and addiction. Developmental studies of new selective ligands for opioid receptors hold promise for the production of potential analgesics without the side effects of morphine and its congeners. Applicants herein disclose novel analgesics, including selective ligands for opioid receptors. The individual compounds described herein have the potential to have agonistic, antagonistic and combined effects on opioids and other cellular receptors. Moreover, the novel compounds reported herein may have analgesic properties with no potential for respiratory depression and physical dependence associated with μ-opioid receptor-ligands such as morphine and fentanyl. The novel compounds reported herein may also retain properties for the treatment of neurological disorders such as physical or psychotoxicity, psychiatric disorders and tinnitus.

The μ opioid receptor is one of a group of cell surface protein systems that transduce extracellular signals into cells. For eukaryotic cells and prokaryotic cells, cell surface proteins detect such signals in a manner such that they detect extracellular signals and ultimately result in a cellular or concerted tissue or organ response. Gives the means to communicate within. By transmitting information about the extracellular environment into the cell via specific intracellular pathways, cell surface proteins elicit appropriate responses to individual stimuli. The reaction may be direct and transient, slow and persistent, or a mixture of several such reaction modes. Thanks to a number of different membrane surface proteins, eukaryotic cells are extremely sensitive to their environment.

Extracellular signal molecules such as growth hormones, vasodilators and neurotransmitters exert their effect, at least in part, through interaction with cell surface proteins. For example, some extracellular signaling molecules cause alterations in the transcriptional response of target genes through alterations in secondary messenger stages such as c-amphetamine. Other signals activate the expression of genes such as immediate-early genes that encode regulatory proteins, which in turn activate other genes that encode transcriptional regulatory proteins, resulting in expression of genes. Change indirectly. For example, expression of neuronal genes is regulated by numerous extracellular signals, including neurotransmitters and membrane electrical activity. Transsynaptic signals give rise to fast responses in neurons that occur over a time course ranging from milliseconds, such as the opening of ligand-gated channels, to seconds and minutes, such as events mediated by second messengers. Neuronal genes that are responsive to transsynaptic signals and membrane electrical activity, called immediate-early genes, whose transcription is rapid and transient within minutes (
Reference: For example, Sheng et al. (1990) Neuron 4: 477-485) There are genes that are activated, and genes that require protein synthesis for their expression and are induced or changed in the course of several hours.

Cell surface receptors and ion channels reside between cell surface proteins that respond to extracellular signals and initiate events leading to such various gene expressions and responses. Ion channels and cell surface localized receptors are ubiquitous and physiologically important cell surface membrane proteins. They play a central role in regulating the intracellular steps of various ions and chemicals, many of which are important for cell viability and function.

Receptors localized on the cell surface bind extracellularly signaling molecules or changes in the extracellular environment and transduce that signal via a signaling pathway to initiate a cellular response, It is a protein that exists across the membrane. Cell surface receptors bind circulating signal polypeptides such as neurotransmitters, growth factors and hormones during the initiation step in the induction of myriad intracellular pathways. Receptors are classified based on the distinct type of pathway that is induced. Included among these receptors are G-protein dependent receptors and G-proteins, which bind growth factors such as heparin-binding growth factor (HBGF) receptors and which have intrinsic tyrosine kinase activity, respectively. , And those that rely on agonist proteins through guanine nucleotide binding regulatory proteins.

This G protein transmembrane signal pathway is composed of three proteins, a receptor, a G protein and an agonist. The G protein, a mediator in the transmembrane signaling pathway, is a heterodimer and consists of alpha, beta and gamma subunits. Within the G-protein family, this alpha subunit is foreign. The function of the G protein is regulated by periodic binding of the GTP to the alpha subunit, which then causes hydrolysis of GTP to GDP and dissociation of GDP.

G protein-dependent receptors are a broad class of receptors that mediate signal transduction by binding to G proteins. Signal transduction is initiated via a ligand that binds to a cell membrane receptor, thereby stimulating this receptor to bind to a G protein. The interaction of the G protein with the receptor releases GDP, which is specifically bound to the G protein, and binds GTP, which activates the G protein. Activated G-proteins dissociate from this receptor and activate agonistic proteins that regulate the intracellular steps of specific second messengers. Examples of such agonist proteins include adenylate cyclase, guanylate cyclase, phospholipase C and the like.

G-protein dependent receptors, which are glycoproteins, are known to share certain structural similarities and homologies (see eg Gilman, AG, Ann.
Rev. Biochem. 56: 615-649 (1987), Strader, CD et al. The FASEB Journa
l 3: 1825-1832 (1989), Kobilka, BK, et al. Nature 329: 75-79 (1985) and
Young et al. Cell 45: 711-719 (1986)). Among the identified and cloned G-protein dependent receptors are the substance P receptor, the angiotensin receptor, alpha- and beta-adrenergic receptors and the serotonin receptor. G protein-dependent receptors share a conserved structural motif. A common and common structural feature of G-protein dependent receptors is the presence of seven moieties of about 20-25 amino acids each surrounded by eight hydrophilic regions of varying length. Each of these seven hydrophobic regions forms a transmembrane alpha helix,
The intervening hydrophilic regions alternately form loops facing inside and outside the cell. The third cytosol loop between transmembrane regions 5 and 6 is an intracellular region responsible for interaction with G proteins.

G protein-dependent receptors are known to be inducible. This inducibility was originally described in lower eukaryotes. For example, the c-amphetamine receptor of cell-like slime molds, namely cellular slime molds, is induced during differentiation (Klein et al., Sc
ience 241: 1467-1472 (1988)). During the differentiation of Dictyostelium discoideum, the pathway or c-amphetamine, induces high level expression of its G protein-dependent receptor. Such receptors drive signals to induce the expression of other genes involved in chemotaxis that sequence multicellular aggregates, provide organic structure, and form stalks. Introduce (Ref: Firtel, RA, et al. Cell 58: 235-239 (1989) and De
vreotes, P., Science 245: 1054-1058 (1989)).

Definitions For convenience, some terms used in the specification, examples, and appended claims are collected here.

[0035]   The abbreviation "CNS" refers to the central nervous system of an organism.

The term “cell surface protein” includes molecules that are present on the cell surface, interact with the extracellular milieu, and convey or convey information about the milieu into the cell.

The term “extracellular signal” includes a molecule or change in the environment that is transduced intracellularly via a cell surface protein that interacts directly or indirectly with that signal. An extracellular signal is any compound or substance that in some way specifically alters the activity of cell surface proteins. Examples of such signals include:
Acetylcholine, growth factors, hormones, and others such as phorbol mistric acetate (PMA), which bind to cell surface receptors and ion channels and regulate the activity of such receptors and channels. Molecules, such as, but not limited to. In addition, extracellular signals are expected to be used for the treatment of specific diseases by regulating the activity of cell surface proteins, thereby affecting the intracellular function, and regulating the activity of specific cell surface receptors. It also includes unidentified substances that are potential pharmacological agents.

The term “50% effective dose” is the dose of a drug that results in 50% of the drug's maximal response or effect, or for a given dose in 50% of subjects or tissue specimens. The dose that produces the reaction.

The term “50% lethal dose” refers to the dose of a drug that is lethal to 50% of subjects.

The term “therapeutic index” refers to the therapeutic index of a drug defined as 50% lethal dose / 50% effective dose.

The term “Structure Activity Relationship (SAR)” refers to a method by which a drug alters its molecular structure, thereby altering its interaction with receptors, enzymes and the like.

The term “agonist” mimics the action of a natural mediator, or when the natural mediator is unknown, changes in the receptor complex in the absence of other receptor ligands. Refers to the compound that causes it.

The terms “inverse agonist” and “negative antagonist” refer to compounds that are selective ligands for the inactive form of cellular receptors that exist as an equilibrium 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 change in the absence of other receptor-ligands.

The term “competitive antagonist” refers to a compound that binds to a receptor site but whose effect is counteracted by increasing concentrations of agonist.

The term “partial agonist” refers to a compound that binds to a receptor site but produces no maximal effect regardless of its concentration.

[0047]   The term "ligand" refers to a compound that binds at a receptor site.

“Heteroatom” as used herein refers to an atom of any element other than carbon or hydrogen. Suitable heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium.

The term “electron-withdrawing group” is known in the art of the invention and refers to the tendency of a substituent to attract a valence electron from an adjacent atom. That is, the substituent is electronegative with respect to the adjacent atom. The quantification of the electron withdrawing performance level is given by the Hammett sigma (σ) constant. This known constant is, for example, J. March, "Higher Organic Chemistry" (1977 edition), pages 251 to 259, published by McGraw-Hill, New York (J. March, Advanced Organic Chemistry, McGraw Hill Book Company,
New York, (1977 edition) pp. 251-259). Hammett's constant values are generally negative for electron-donating groups (σ [P] = − 0.66 for NH ₂ ) and positive for electron-withdrawing groups (for nitro groups). σ [P] = 0.78). Typical electron withdrawing groups include nitro, acyl, formyl, sulfonyl, trifluoromethyl, cyano, chloride and the like. Typical electron donating groups include amino, methoxy and the like.

The term “alkyl” refers to saturated aliphatic radicals including straight chain alkyl groups, side chain alkyl groups, cycloalkyl groups (alicyclic), alkyl-substituted cycloalkyl groups and cycloalkyl-substituted alkyl groups. . In a preferred embodiment, a straight chain or branched alkyl groups have 30 or fewer carbon atoms in its backbone (eg, C ₁ to C ₃₀ for straight _chain, C ₃ to C ₃₀ in the side chain) , More preferably 20
Have or less carbon atoms. Similarly, a suitable cycloalkyl is 3
To 10 carbon atoms in their ring structure, more preferably 5, 6 or 7 carbons in the ring structure.

Furthermore, the term “alkyl” (or “lower alkyl”) as used throughout the specification, examples and claims includes both “unsubstituted alkyl” and “substituted alkyl”, The latter of which refers to an alkyl moiety having a substituent that replaces a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, halogen, hydroxyl, carbonyl (
Carboxyl, alkoxycarbonyl, formyl or acyl etc.), thiocarbonyl (thioester, thioacetate or thioformate etc.), alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amide, amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio. , Sulfate, sulfonate, sulfamoyl (original: sulfamoyl), sulfonamide (original: sulfo
namido), sulfonyl, heterocyclyl (original: heterocyclyl), aralkyl,
Or it is part of an aromatic or heteroaromatic compound. It will be apparent to those skilled in the art that the moieties that are substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For example, substituted alkyl substituents can include substituted and unsubstituted forms of groups such as the ethers, alkylthio (original: al.
kylthio), carbonyl (including ketones, aldehydes, carboxylates and esters), —CF ₃ , —CN, etc., as well as amino, azide, imino, amide,
Phosphoryl (including phosphonate and phosphinate), sulfonyl (sulfate, sulfonamide (original: sulfonamido), sulfamoyl (original: sulfamoyl))
And sulfonates) and silyl groups. Typical substituted alkyls are described below. Cycloalkyl, alkyl, alkenyl, alkoxyl, alkylthio, aminoalkyl, carbonyl-substituted _alkyls, -CF 3, may be further substituted with -CN or the like.

The term “aralkyl” refers herein to an alkyl group substituted with an aryl group (eg, a group of aromatic or heteroaromatic compounds).

The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groups which are similar in length and displaceability with the alkyls described above, but which contain at least one double or triple bond, respectively. .

Unless otherwise specified, the “lower alkyl” used herein is
As defined above, means an alkyl group, but having 1 to 10 carbon atoms in its backbone structure, preferably 1 to 6 carbons.
Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths.
A preferred alkyl group is lower alkyl. In a preferred embodiment, the substituents referred to herein as alkyl are lower alkyl.

The term “aryl” as used herein includes, for example, benzene, pyrrole,
5-, 6- and 7-membered single ring aromatics that may contain from zero to four heteroatoms such as furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, * pyridazine and pyrimidine. including.
An aryl group having a heteroatom in the ring structure may also refer to “aryl heterocyclic compound” or “heteroaromatic compound”. The ring of the aromatic compound may be substituted at one or more ring positions with a substituent as described above. Examples of such substituents are halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl. , Silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl (original: he
terocyclyl), heteroaromatic or heterocyclic aromatic compound moieties, _-CF 3, -
There are CN etc. Similarly, the term "aryl" also includes polycyclic structures having two or more rings, wherein the two or more rings have two adjacent rings (these rings are "fused"). Two or more carbons are shared by a “ring”), but at least one of the rings is an aromatic compound, for example, the other cyclic ring structure is cycloalkyl, cycloalkenyl, It may be cycloalkynyl, aryl and / or heterocyclyl.

The terms “ortho”, “meta” and “para” refer to 1,2-, 1,3- and 1
, 4-disubstituted benzene. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

The term “heterocyclyl” or “heterocyclic group” refers to a 3- to 10-membered ring structure, more preferably a 3- to 10-membered ring structure in which the ring structure contains from 1 to 4 heteroatoms.
To 7-membered ring structure. Heterocyclic is also polycyclic. Heterocyclyl groups include, for example, azetidine, azepine (original: azepine), thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathine, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine. , Pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine (original: quinolizine
), Isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenalthazine, phenothiazine, furazan, phenoxazine, pyrrolidine, ocosolane (original: oxolane) ), Thiolane (original: thiolane), oxazole, piperidine,
There are lactams such as piperazine, morpholine, lactones, azetidinone (original: azedidinone) and pyrrolidinone (original: pyrrrolidinone), sultams, sultones, and the like. The ring of the heterocycle may be substituted at one or more positions, such as with the substituents described above. For example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl. (Original term: heterocyclyl), aromatic compound or heterocyclic aromatic compound moiety, —CF ₃ , —CN and the like.

The term “polycyclyl” or “polycyclic group” refers to two or more carbons that are common to two adjacent rings (eg, these rings are “fused rings”). Further rings (eg cycloalkyl, cycloalkynyl, aryl and / or
Or heterocyclyl). Rings that are joined through non-adjacent atoms are referred to as "bridged" rings. Each ring of the polycyclic group may be substituted with the substituents described above. Examples thereof are halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide,
Phosphonates, phosphinates, carbonyls, carboxyls, silyls, ethers, alkylthios, sulfonyls, ketones, aldehydes, esters, heterocyclyls, aromatic compounds or heterocyclic aromatic compound moieties,-
CF ₃ , -CN, etc.,

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 —NO ₂ .
The term "halogen" refers to -F, -Cl, -Br or -I. Also, the term "sulfhydryl" means -SH, terms "hydroxyl" means -OH, and "sulfonyl" -SO 2 _- means.

The terms "amine" and "amino" are known in the art of the present invention and refer to both unsubstituted and substituted amines, some of which may be represented by the general formula:

[0062]

[Chemical 1]

In the above formula, R ₉ , R ₁₀ and R ′ ₁₀ each independently represent hydrogen, alkyl, alkenyl, (CH ₂ ) _m —R ₈ , or R ₉ and R ₁₀ are When taken together with N to which they are attached, a heterocycle having 4 to 8 atoms in the ring structure is completed, and R ₈ represents aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle, m is zero or an integer in the range of 1 to 8.
In a preferred embodiment, only one of R ₉ or R ₁₀ can be a carbonyl, eg R ₉ , R ₁₀ and nitrogen do not form an imide. R ₉ and R ₁₀ (and optionally R ′ ₁₀ ) even in the more preferred embodiment
Are each hydrogen, alkyl, alkenyl, or - separately represents a _{(CH 2)} m -R _8. Thus, the term "alkylamine", as used herein, means an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto.
That is, at least one of R ₉ and R ₁₀ is an alkyl group.

The term “acylamino” is known in the art of the present invention and refers to a moiety that can be represented by the general formula:

[0065]

[Chemical 2]

In the above formula, R ₉ is as defined above and R ′ ₁₁ is hydrogen, alkyl, alkenyl or — (CH ₂ ) _m —R ₈ (m and R ₈ are as defined above). There is).

The term “amido” is known in the art as an amide-substituted carbonyl and includes a moiety that can be represented by the general formula:

[0068]

[Chemical 3]

In the above formula, R ₉ and R ₁₀ are as defined above. Preferred examples of amides would not include imides which could be unstable.

The term “alkylthio” refers to an alkyl group, as defined above,
It has sulfur radicals attached to it. The preferred embodiment, the "alkylthio" moiety is represented, -S- alkyl, -S- alkenyl, -S- alkynyl and _{-S- (CH 2) m -R 8} (m and _{R 8} are as defined above It is represented by one of Representative alkylthio groups include methylthio, ethylthio and the like.

The term “carbonyl” is known in the field of the invention and includes moieties such as can be represented by the general formula:

[0072]

[Chemical 4]

In the above formula, X is a chemical bond or oxygen or sulfur, R ₁₁ is hydrogen, alkyl, alkenyl, — (CH ₂ ) _m —R ₈ or a pharmaceutically acceptable salt,
R _'11 is hydrogen, alkyl, alkenyl or _{- (CH 2) m -R 8 (} m and _{R 8} are as defined above). When X is oxygen and R ₁₁ or R ′ ₁₁ is not hydrogen, this general formula is an “ester”. When X is oxygen and R ₁₁ is as defined above, this moiety is referred to herein as a carboxyl group, especially when R ₁₁ is hydrogen, this general formula is a “carboxylic acid”. X is oxygen, when R _{'1 1} is hydrogen, the formula is a "formate ester". Generally, when the oxygen atom of the above formula is replaced with sulfur, the formula is a "thiolcarbonyl" group. When X is sulfur and R ₁₁ and R ′ ₁₁ are not hydrogen, the formula is a “thiol ester”. If X is sulfur and R ₁₁ is hydrogen then the formula is a “thiolcarboxylic acid”. X is sulfur, if R _'11 is hydrogen, the formula is a "thiolformate ester". On the other hand, when X is a chemical bond and R ₁₁ is not hydrogen, the above formula is a “ketone” group. When X is a chemical bond and R ₁₁ is hydrogen, the above formula is an “aldehyde” group.

The term “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, t-butoxy and the like. An "ether" is two hydrocarbons covalently linked by one oxygen atom. Thus, the alkyl substituent that turns the alkyl into an ether is -O.
- alkyl, -O- alkenyl, -O- alkynyl, _{-O- (CH} 2) alkoxyl, such as can be represented by one of the m _-R 8 (m and _{R 8} are as defined above) Or similar to alkoxyl.

The term “sulfonate” is known in the art of the present invention and includes moieties as represented by the general formula:

[0076]

[Chemical 5]

In the above formula, R41 is an electron pair, hydrogen, alkyl, cycloalkyl or aryl.

The terms trifuryl, tosyl, mesyl and nonaflyl (original: nonaflyl) are known in the field of the invention, respectively trifluoromethanesulfonyl (original: trifluoromethanesulfonyl), p-toluenesulfonyl, fluoride,
Methanesulfonyl and nonafluorobutane sulfonyl (original: nonafluorobuta
nesulfonyl) group. Triflate (original: triflate), Tosylate (original:
The terms tosylate), mesylate and nonaflate (nonaflate) are known in the field of the present invention, respectively, trifluoromethanesulfonyl (trifluoromethanesulfonyl) ester, p-toluenesulfonate, methanesulfonate and nonarate, respectively. Fluorobutanesulfonyl (original: no
nafluorobutanesulfonyl) ester functional group and a molecule containing the above groups.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms are methyl, ethyl, phenyl, and trifluoromethanesulfonyl (original: trifluoromethanesulfon
yl), nonafluorobutanesulfonyl (original: nonafluorobutanesulfonyl),
p-toluenesulfonyl and methanesulfonyl (original language: methanesulfonyl)
Represents A more comprehensive list of abbreviations used by organic chemists of ordinary skill in the art in the present invention can be found in the first issue of each volume of the "Organic Chemistry Journal". This list is typically provided in the table entitled "List of Standard Abbreviations". The abbreviations included in the above list and all abbreviations used by organic chemists of ordinary skill in the art are incorporated herein by reference.

The term “sulfate” is known in the art of the present invention and includes a moiety that can be represented by the general formula:

[0081]

[Chemical 6]

In the above formula, R ₄₁ is as defined above.

The term “sulfonamide” is known in the art of the present invention and includes moieties that can be represented by the general formula:

[0084]

[Chemical 7]

In the above formula, R ₉ and R ′ ₁₁ are as defined above.

The term “sulfamoyl” is known in the art of the present invention and includes a moiety that can be represented by the general formula:

[0087]

[Chemical 8]

In the above formula, R ₉ and R ₁₀ are as defined above.

The term “sulfonyl” as used herein refers to a moiety that can be represented by the general formula:

[0090]

[Chemical 9]

In the above formula, R ₄₄ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

As used herein, the term “sulfoxido” refers to a moiety that can be represented by the general formula:

[0093]

[Chemical 10]

In the above formula, R ₄₄ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl or aryl.

[0095]   “Phosphoryl” can be represented by the general formula:

[0096]

[Chemical 11]

In the above formula, Q1 represents S or O, and R46 represents hydrogen, lower alkyl or aryl. When used, for example, to replace alkyl, the phosphoryl group of phosphorylalkyl can be represented by the general formula:

[0098]

[Chemical 12]

In the above formula, Q1 represents S or O, each R46 represents hydrogen, lower alkyl or aryl separately, and Q2 represents O, S or N. When Q1 is S, the phosphoryl moiety is a "phosphorothioate".

“Selenoalkyl” refers to an alkyl group having a substituted selenium group attached to the alkyl group. Typical "selenoethers" which may be substituted on alkyl are -Se-alkyl, -Se-alkenyl,
-Se- alkynyl and _{-Se- (CH 2) m -R 7} (m and _{R 7} are the defined in) is selected from one of the.

Analogous substitutions occur on alkenyl and alkynyl groups and include, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls.
ls), amidoalkynyls (original: amidoalkynyls), iminoalkenyl (original: i
minoalkenyl), iminoalkynyls (original: iminoalkynyls), thioalkenyl (
Produces thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.

As used herein, the definition of an expression such as, for example, alkyl, m, n, etc., when it occurs more than once in any structure, that in other places within the same structure. Is intended to be independent of the definition of.

“Substituted” or “substituted with” is such a substitution is subject to possible attachment of substituent atoms and substituents, the result of which is, for example, rearrangement, ring It will be understood that there is an implicit condition that a stable compound is formed, such as not spontaneously performing transformations such as modification and deletion.

The term “substituted” as used herein is intended to include permissible substituents of any organic compound. In a broad aspect, these permissible substituents include acyclic and cyclic substituents, branched and unbranched substituents, carbocyclic and heterocyclic substituents, aromatic and non-aromatic substituents of organic compounds. including. Exemplified substituents include, for example, those described herein above. These permissible substituents can be present one or more and can be the same or different for the appropriate organic compound. For purposes of this invention, a heteroatom such as nitrogen is
It is possible to have hydrogen substituents and / or any permissible substituents of the organic compounds described herein so as to meet the valency of these heteroatoms. The present invention in no way is limited by these permissible substituents of organic compounds.

The term “protecting group” as used herein means temporary substituents to protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups are acid esters of carvone, silyl esters of alcohols and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry is being investigated (Greene, TW; Wuts, PGM "Protecting Groups in Organic Synthesis", Second Edition .; Wiley: New York, 1991).

Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. All compounds, including cis or trans isomers, R and S optical isomers, diastereomers, (D) isomers, racemic mixtures thereof, and other mixtures thereof, are included in the invention. The present invention is intended to be included within the scope of.

For example, if a particular optical isomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis, isolated using chiral chromatography, or derivatized with a chiral adjuvant. It may be prepared and the resulting diastereomeric mixture is separated and the adjuvant cleaved to provide the pure desired optical isomer. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, the diastereomeric salt is formed with the appropriate optically active acid or base, then fractionated crystals or the field of the invention. The diastereoisomer thus formed is decomposed by known chromatographic means, followed by recovery of the pure optical isomer.

Possible equivalents of the above compounds include their corresponding compounds and compounds having the same general properties as them (eg, acting as an analgesic), in which case one of the substituents or It includes simpler changes, but does not act to inhibit the binding potency of this compound at opioid receptors. In general, the compounds of the present invention can be prepared, for example, by the methods shown in the general reaction schemes described below, or by using readily available starting materials, reagents and conventional synthetic methods. It may be prepared by improving. In these reactions, it is also possible to make use of variants which are known per se, but are not mentioned here.

For the purposes of the present invention, chemicals are identified in accordance with the Periodic Table of the Elements (CAS edition, “Guide to Chemistry and Physics” 67th edition, 1986-87, back cover). Similarly, for the purposes of the present invention, the term "hydrocarbon" is considered to include all permissible compounds having at least one hydrogen and one carbon atom. In a broad aspect, these acceptable hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic, substitutable or unsubstituted. Organic compounds are included.

[0110] Compounds of the invention   In certain embodiments, the compounds of the present invention are represented by formula A.

[0111]

[Chemical 13]

However, in the above formula, m is 1, 2, 3 or 4, n is 1 or 2, y is 1 or 2, R ₁ is alkyl, aryl or heteroaryl Or cycloalkyl, R ₂ is each independently H, alkyl, fluoroalkyl, aryl, heteroaryl or cycloalkyl, R ₁ and R ₂ may be bonded via a covalent bond, R _{1 3} are each independently H, alkyl, aryl, OR ₂ , OC (O) R ₂ , CH ₂ OR ₂ or CO ₂ R ₂ , where any two of R ₃ have their backbones It may also be a covalent bond consisting of 1, 2, 3 or 4 carbon atoms, each R ₄ independently being H, alkyl, aryl, heteroaryl, alkenyl or cycloalkyl, R 4 ₅ are each independently H, alkyl, CH ₂ Y, aryl, heteroaryl, F, OR ₂ or OC (O) R ₂ , and R ₆ are each independently H, alkyl, CH ₂ Y, Aryl, heteroaryl, F, OR ₂ or OC (O) R ₂ , and Y is each independently OR ₂ , N (R ₂ ) ₂ , SR ₂ , S (O) R ₂ , S (
O) ₂ R ₂ or P (O) (OR ₂ ) ₂ and R ₅ or R ₆ bonded to the carbon chain between R ₄ specified in formula A and the nitrogen on the ring is R ₄ , They may be connected by a covalent bond, R ₅ and R _{6 in the} case where two geminals or vicinals are aligned may be connected by a covalent bond, and X is C (R ₃ ) ₂ , O, S. , SO, SO ₂ , NR ₂ , NC (O) OR ₂ or C = 0, and the stereochemical configuration at the stereocenter of the compound represented by formula A is R-type, S-type, or It is mixed.

In certain examples, compounds of the present invention are represented by formula A and its attendant definitions, wherein X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, wherein X is C (R ₃ ) ₂ , O or NR ₂ .

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, wherein X is C (R ₃ ) ₂ .

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, wherein m is 2 or 3.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, wherein n is 1.

In certain examples, compounds of the present invention are represented by formula A and its attendant definitions, wherein y is 1.

In certain examples, compounds of the present invention are represented by formula A and its attendant definitions, wherein R ₁ is aryl or heteroaryl.

In certain examples, compounds of the present invention are represented by formula A and its attendant definitions, wherein each R ₂ is independently alkyl.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, R ₃ is each independently H or alkyl.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, R ₄ is cycloalkyl, aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, wherein R ₅ is each independently H, alkyl, aryl, heteroaryl or F.

In certain examples, compounds of the present invention are represented by formula A and its attendant definitions, wherein R ₆ is each independently H, alkyl, aryl, heteroaryl or F.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0 and n is 1 Is.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ and n is 1.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, X is C (R ₃ ) ₂ and n is 1.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0 and y is 1 Is.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ and y is 1.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, X is C (R ₃ ) ₂ and y is 1.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0 and R ₁ is , Aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ and R ₁ is aryl or hetero. Aryl.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, X is C (R ₃ ) ₂ and R ₁ is aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0 and R ₂ is , Each independently alkyl.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, wherein X is C (R ₃ ) ₂ , O, or NR ₂ and each R ₂ is independently alkyl. Is.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, X is C (R ₃ ) ₂ and R ₂ is each independently alkyl.

[0137]   In certain embodiments, the compounds of the invention are represented by Formula A and its attendant definitions.
And X is C (R_Three)_Two, O, NR_Two, Or C = 0, n is 1, and R ₁ Is aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, and R ₁ is aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. is there.

[0140]   In certain embodiments, the compounds of the invention are represented by Formula A and its attendant definitions.
And X is C (R_Three)_Two, O, NR_Two, Or C = 0, n is 1, and R ₁ Is aryl or heteroaryl, R_TwoAre each independently alkyl
.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, and R ₁ is aryl or heteroaryl and each R ₂ is independently alkyl.

In certain embodiments, compounds of the present invention are represented by formula A and the attendant definitions, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. And each R ₂ is independently alkyl.

[0143]   In certain embodiments, the compounds of the invention are represented by Formula A and its attendant definitions.
And X is C (R_Three)_Two, O, NR_Two, Or C = 0, n is 1, and R ₁ Is aryl or heteroaryl, R_TwoAre each independently alkyl
, R_ThreeAre each independently H or alkyl.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, and R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, and R ₃ is independently H or alkyl.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. And R ₂ is each independently alkyl and R ₃ is each independently H or alkyl.

[0146]   In certain embodiments, the compounds of the invention are represented by Formula A and its attendant definitions.
And X is C (R_Three)_Two, O, NR_Two, Or C = 0, n is 1, and R ₁ Is aryl or heteroaryl, R_TwoAre each independently alkyl
, R_ThreeAre each independently H or alkyl, and R_FourAre each a cyclo
Alkyl, aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ and n is 1 and R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, R ₃ is independently H or alkyl, and R ₄ is independently cycloalkyl, aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. Where R ₂ is independently alkyl, R ₃ is independently H or alkyl, and R ₄ is independently cycloalkyl, aryl or heteroaryl.

[0149]   In certain embodiments, the compounds of the invention are represented by Formula A and its attendant definitions.
And X is C (R_Three)_Two, O, NR_Two, Or C = 0, n is 1, and R ₁ Is aryl or heteroaryl, R_TwoAre each independently alkyl
, R_ThreeAre each independently H or alkyl, and R_FourIs cycloalkyl, ally
R or heteroaryl, R₅Are each independently H, alkyl, aryl
, Heteroaryl, or F.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ and n is 1 and R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, R ₃ is independently H or alkyl, R ₄ is cycloalkyl, aryl or heteroaryl, and R ₅ is independently , H, alkyl, aryl, heteroaryl, or F.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. R ₂ is each independently alkyl, R ₃ is each independently H or alkyl, R ₄ is cycloalkyl, aryl or heteroaryl, R ₅ is each independently H, alkyl, aryl, Heteroaryl, or F.

[0152]   In certain embodiments, the compounds of the invention are represented by Formula A and its attendant definitions.
And X is C (R_Three)_Two, O, NR_Two, Or C = 0, n is 1, and R ₁ Is aryl or heteroaryl, R_TwoAre each independently alkyl
, R_ThreeAre each independently H or alkyl, and R_FourHaso cycloalkyl, ant
Or heteroaryl, R₅Are each independently H, alkyl, aryl
R, heteroaryl, or F, and R₆Are each independently H, alkyl,
Aryl, heteroaryl, or F.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ , and n is 1 and R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, R ₃ is independently H or alkyl, R ₄ is cycloalkyl, aryl or heteroaryl, and R ₅ is independently , H, alkyl, aryl, heteroaryl, or F, and each R ₆ is independently H, alkyl, aryl,
Heteroaryl, or F.

In certain embodiments, compounds of the present invention are represented by formula A and its attendant definitions, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. R ₂ is each independently alkyl, R ₃ is each independently H or alkyl, R ₄ is cycloalkyl, aryl or heteroaryl, R ₅ is each independently H, alkyl, aryl, Heteroaryl, or F, and each R ₆ is independently H, alkyl, aryl, heteroaryl, or F.

In certain examples, compounds of the present invention are represented by formula A and its attendant definitions, wherein X is C (R ₃ ) ₂ , m is 2, n is 1, and R ₁ Is aryl, R ₂ is independently alkyl, R ₃ is independently H, R ₄ is aryl, R ₅ is independently H or alkyl, and R ₆ is independently Separately, it is H or alkyl.

In the assay based on opioid receptors from mammalian brain, the general structure A
The value of 50% inhibitory concentration (original: IC ₅₀ ) of a compound according to is less than 10 μMol, more preferably less than 5 μMol, most preferably for at least one subset of opioid receptors. It is less than 1 μMol.

[0157]   In certain examples, the compounds of the present invention are represented by formula B:

[0158]

[Chemical 14]

However, in the above formula, m is 1, 2, 3 or 4, n is 1 or 2, R ₁ is H, alkyl, aryl, heteroaryl or cycloalkyl; ₂ are each independently H, alkyl, fluoroalkyl, aryl, heteroaryl or cycloalkyl, R ₁ and R ₂ may be linked via a covalent bond, and R ₃ is independently each H, alkyl, _{aryl, oR 2, OC (O) R} 2, CH 2 oR 2 or _CO 2 _{R 2,} wherein any two of _{R 3} include its backbone 1, 2, 3 or 4 may be a covalent attachment consisting of carbon atoms, R ₄ are each independently, H, alkyl, aryl, heteroaryl, alkenyl or cycloalkyl, R ₅ are each independently , H, alkyl, _CH 2 Y, aryl, heteroaryl, F, an OR ₂ or _{OC (O) R 2, R} 6 are each independently, H, alkyl, _CH 2 Y, aryl, heteroaryl, F , OR ₂ or OC (O) R ₂ , and Y is each independently OR ₂ , N (R ₂ ) ₂ , SR ₂ , S (O) R ₂ , S (
O) ₂ R ₂ or P (O) (OR ₂ ) ₂ and R ₅ or R ₆ bonded to the carbon chain between R ₄ specified in formula B and the ring nitrogen is R ₄ and It may be connected by a covalent bond, R ₅ and R _{6 in the} case where two geminals or vicinals are aligned may be connected by a covalent bond, and X is C (R ₃ ) ₂ , O, S. , SO, SO ₂ , NR ₂ , NC (O) OR ₂ or C = 0, and the stereochemical configuration at the stereocenter of the compound represented by Formula B is R-type or S-type.

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, wherein X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0.

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, wherein X is C (R ₃ ) ₂ , O or NR ₂ .

In certain embodiments, compounds of the present invention are represented by formula B and the attendant definitions, wherein X is C (R ₃ ) ₂ .

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, wherein m is 2 or 3.

In certain embodiments, compounds of the present invention are represented by formula B and the attendant definitions, wherein n is 1.

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, wherein R ₁ is aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, wherein R ₂ is each independently alkyl.

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, R ₃ is each independently H or alkyl.

In certain embodiments, compounds of the present invention are represented by formula B and the attendant definitions, wherein R ₄ is cycloalkyl, aryl or heteroaryl.

In certain examples, compounds of the present invention are represented by formula B and its attendant definitions, wherein each R ₅ is independently H, alkyl, aryl, heteroaryl or F.

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, wherein R ₆ is each independently H, alkyl, aryl, heteroaryl or F.

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0 and n is 1 Is.

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ and n is 1.

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, X is C (R ₃ ) ₂ and n is 1.

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0 and R ₁ is , Aryl or heteroaryl.

In certain examples, compounds of the present invention are represented by formula B and the attendant definitions, wherein X is C (R ₃ ) ₂ , O, or NR ₂ , and R ₁ is aryl or hetero. Aryl.

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, X is C (R ₃ ) ₂ and R ₁ is aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula B and the attendant definitions, wherein X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, and R ₂ is , Each independently alkyl.

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ , and R ₂ is each independently alkyl. Is.

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, X is C (R ₃ ) ₂ and R ₂ is each independently alkyl.

[0180]   In certain examples, compounds of the present invention are represented by Formula B and its attendant definitions.
And X is C (R_Three)_Two, O, NR_Two, Or C = 0, n is 1, and R ₁ Is aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, and R ₁ is aryl or heteroaryl.

In certain examples, compounds of the present invention are represented by formula B and the attendant definitions, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. is there.

[0183]   In certain examples, compounds of the present invention are represented by Formula B and its attendant definitions.
And X is C (R_Three)_Two, O, NR_Two, Or C = 0, n is 1, and R ₁ Is aryl or heteroaryl, R_TwoAre each independently alkyl
.

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, and R ₁ is aryl or heteroaryl and each R ₂ is independently alkyl.

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. And each R ₂ is independently alkyl.

[0186]   In certain examples, compounds of the present invention are represented by Formula B and its attendant definitions.
And X is C (R_Three)_Two, O, NR_Two, Or C = 0, n is 1, and R ₁ Is aryl or heteroaryl, R_TwoAre each independently alkyl
, R_ThreeAre each independently H or alkyl.

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, and R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, and R ₃ is independently H or alkyl.

In certain embodiments, compounds of the present invention are represented by formula B and the attendant definitions, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. And R ₂ is each independently alkyl and R ₃ is each independently H or alkyl.

[0189]   In certain examples, compounds of the present invention are represented by Formula B and its attendant definitions.
And X is C (R_Three)_Two, O, NR_Two, Or C = 0, n is 1, and R ₁ Is aryl or heteroaryl, R_TwoAre each independently alkyl
, R_ThreeAre each independently H or alkyl, and R_FourAre each a cyclo
Alkyl, aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, and R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, R ₃ is independently H or alkyl, and R ₄ is independently cycloalkyl, aryl or heteroaryl.

In certain examples, compounds of the present invention are represented by formula B and the attendant definitions, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. Where R ₂ is independently alkyl, R ₃ is independently H or alkyl, and R ₄ is independently cycloalkyl, aryl or heteroaryl.

[0192]   In certain examples, compounds of the present invention are represented by Formula B and its attendant definitions.
And X is C (R_Three)_Two, O, NR_Two, Or C = 0, n is 1, and R ₁ Is aryl or heteroaryl, R_TwoAre each independently alkyl
, R_ThreeAre each independently H or alkyl, and R_FourAre each a cyclo
Alkyl, aryl or heteroaryl, R₅H and a
It is alkyl, aryl, heteroaryl, or F.

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, and R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, R ₃ is independently H or alkyl, R ₄ is independently cycloalkyl, aryl or heteroaryl, R ₅ Are each independently H, alkyl,
Aryl, heteroaryl, or F.

In certain examples, compounds of the present invention are represented by formula B and the attendant definitions, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. R ₂ are each independently alkyl, R ₃ are each independently H or alkyl, R ₄ are each independently cycloalkyl, aryl or heteroaryl, R ₅ are each independently H, Alkyl, aryl, heteroaryl, or F.

[0195]   In certain examples, compounds of the present invention are represented by Formula B and its attendant definitions.
And X is C (R_Three)_Two, O, NR_Two, Or C = 0, n is 1, and R ₁ Is aryl or heteroaryl, R_TwoAre each independently alkyl
, R_ThreeAre each independently H or alkyl, and R_FourAre each a cyclo
Alkyl, aryl or heteroaryl, R₅H and a
Rualkyl, aryl, heteroaryl, or F, R₆Respectively,
H, alkyl, aryl, heteroaryl, or F.

In certain embodiments, compounds of the present invention are represented by formula B and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, and R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, R ₃ is independently H or alkyl, R ₄ is independently cycloalkyl, aryl or heteroaryl, R ₅ Are each independently H, alkyl,
Aryl, heteroaryl, or F, and each R ₆ is independently H, alkyl, aryl, heteroaryl, or F.

In certain embodiments, compounds of the present invention are represented by formula B and the attendant definitions, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. R ₂ are each independently alkyl, R ₃ are each independently H or alkyl, R ₄ are each independently cycloalkyl, aryl or heteroaryl, R ₅ are each independently H, Alkyl, aryl, heteroaryl, or F, and each R ₆ is independently H, alkyl, aryl, heteroaryl, or F.

In an assay based on opioid receptors from mammalian brain, the general structure B
The value of 50% inhibitory concentration (original: IC ₅₀ ) of a compound according to is less than 10 μMol, more preferably less than 5 μMol, most preferably for at least one subset of opioid receptors. It is less than 1 μMol.

[0199]   In certain embodiments, the compounds of the present invention are represented by formula C.

[0200]

[Chemical 15]

However, in the above formula, m is 1, 2, 3 or 4, y is 0, 1 or 2, and R ₁ is H, alkyl, aryl, heteroaryl or cycloalkyl. , R ₂ are each independently H, alkyl, fluoroalkyl, aryl, heteroaryl or cycloalkyl, R ₁ and R ₂ may be bonded via a covalent bond, and R ₃ is each independently. to, H, alkyl, _{aryl, oR 2, OC (O) R} 2, CH 2 oR 2 or _{CO 2 R} 2, _{R 4} is, H, alkyl, aryl, heteroaryl, alkenyl or cycloalkyl, R ₅ is H, alkyl, CH ₂ Y, aryl, heteroaryl, F, OR ₂ or OC (O) R ₂ , and R ₆ is each independently H, alkyl, CH ₂ Y, aryl, heteroaryl, F, OR ₂ or OC (O) R ₂ , wherein Y is independently OR ₂ , N (R ₂ ) ₂ , SR ₂ , S (O) R ₂ , S (
O) ₂ R ₂ or P (O) (OR ₂ ) ₂ and R ₅ or R ₆ bonded to the carbon chain between R ₄ specified in Formula C and the ring nitrogen is R ₄ and R ₅ and R ₆ may be connected by a covalent bond, and R ₅ and R _{6 in the} case where two geminals or vicinals are aligned may be connected by a covalent bond, and stereochemistry at the stereocenter of the compound represented by the formula C The target configuration is R-type, S-type, or a mixture of these configurations.

In certain embodiments, compounds of the present invention are represented by formula C and its attendant definitions, wherein m is 2 or 3.

In certain embodiments, compounds of the present invention are represented by formula C and its attendant definitions, wherein y is 1.

In certain embodiments, compounds of the present invention are represented by formula C and its attendant definitions, R ₁ is aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula C and its attendant definitions, R ₂ is each independently alkyl.

In certain embodiments, compounds of the present invention are represented by formula C and its attendant definitions, R ₃ is each independently H or alkyl.

In certain embodiments, compounds of the present invention are represented by formula C and the attendant definitions, wherein R ₄ is cycloalkyl, aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula C and its attendant definitions, R ₅ is each independently H, alkyl, aryl, heteroaryl or F.

In certain embodiments, compounds of the present invention are represented by formula C and its attendant definitions, wherein R ₆ is each independently H, alkyl, aryl, heteroaryl or F.

In certain embodiments, compounds of the present invention are represented by formula C and its attendant definitions, R ₁ is aryl or heteroaryl, and R ₂ are each independently
It is alkyl.

In certain embodiments, compounds of the present invention are represented by formula C and its attendant definitions, R ₁ is aryl or heteroaryl, and R ₂ are each independently
Alkyl and R ₃ are each independently H or alkyl.

In certain embodiments, a compound of the present invention is represented by formula C and its attendant definitions, R ₁ is aryl or heteroaryl, and R ₂ are each independently
Alkyl, R ₃ is each independently H or alkyl, and R ₄ is cycloalkyl, aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula C and its attendant definitions, R ₁ is aryl or heteroaryl, and R ₂ are each independently
Alkyl, R ₃ is each independently H or alkyl, R ₄ is cycloalkyl, aryl or heteroaryl, and R ₅ is each independently
H, alkyl, aryl, heteroaryl or F.

In certain embodiments, a compound of the present invention is represented by formula C and its attendant definitions, R ₁ is aryl or heteroaryl, and R ₂ is each independently
Alkyl, R ₃ is each independently H or alkyl, R ₄ is cycloalkyl, aryl or heteroaryl, and R ₅ is each independently
H, alkyl, aryl, heteroaryl or F, and each R ₆ is independently H, alkyl, aryl, heteroaryl or F.

In the assay based on opioid receptors from mammalian brain, the general structure C
The value of 50% inhibitory concentration (original: IC ₅₀ ) of a compound according to is less than 10 μMol, more preferably less than 5 μMol, most preferably for at least one subset of opioid receptors. It is less than 1 μMol.

[0216]   In certain embodiments, the compounds of the present invention are represented by formula D.

[0217]

[Chemical 16]

However, in the above formula, m is 1, 2, 3 or 4, y is 0, 1 or 2, and R ₁ is H, alkyl, aryl, heteroaryl or cycloalkyl. , R ₂ are each independently H, alkyl, fluoroalkyl, aryl, heteroaryl or cycloalkyl, R ₁ and R ₂ may be bonded via a covalent bond, and R ₃ is each independently. to, H, alkyl, _{aryl, oR 2, OC (O) R} 2, CH 2 oR 2 or _{CO 2 R} 2, _{R 4} is, H, alkyl, aryl, heteroaryl, alkenyl or cycloalkyl, R ₅ are each independently, H, alkyl, _CH 2 Y, aryl, heteroaryl, F, an oR ₂ or _{OC (O) R 2, R} 6 are each independently, H, Alkyl, _CH 2 Y, aryl, heteroaryl, F, an OR ₂ or OC (O) _{R 2,} Y are each _{independently, OR 2, N (R 2} ) 2, SR 2, S (O) R ₂ , S (
O) ₂ R ₂ or P (O) (OR ₂ ) ₂ and R ₅ or R ₆ bonded to the carbon chain between R ₄ specified in formula D and the ring nitrogen is R ₄ and R ₅ and R ₆ may be connected by a covalent bond, and R ₅ and R _{6 in the} case where two geminals or vicinals are aligned may be connected by a covalent bond, and the stereochemistry at the stereocenter of the compound represented by formula D The physical arrangement is R-type or S-type.

In certain embodiments, compounds of the present invention are represented by formula D and its attendant definitions, wherein m is 2 or 3.

In certain embodiments, compounds of the present invention are represented by formula D and its attendant definitions, wherein y is 1.

In certain embodiments, compounds of the present invention are represented by formula D and its attendant definitions, wherein R ₁ is aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula D and its attendant definitions, R ₂ is each independently alkyl.

In certain embodiments, compounds of the present invention are represented by formula D and its attendant definitions, R ₃ is each independently H or alkyl.

In certain embodiments, compounds of the present invention are represented by formula D and its attendant definitions, wherein R ₄ is cycloalkyl, aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula D and the attendant definitions, wherein each R ₅ is independently H, alkyl, aryl, heteroaryl or F.

In certain embodiments, compounds of the present invention are represented by formula D and its attendant definitions, wherein R ₆ is each independently H, alkyl, aryl, heteroaryl or F.

In certain embodiments, compounds of the present invention are represented by formula D and its attendant definitions, R ₁ is aryl or heteroaryl, and R ₂ are each independently:
It is alkyl.

In certain embodiments, compounds of the present invention are represented by formula D and its attendant definitions, R ₁ is aryl or heteroaryl, and R ₂ are each independently:
Alkyl and R ₃ are each independently H or alkyl.

In certain embodiments, compounds of the present invention are represented by formula D and its attendant definitions, wherein R ₁ is aryl or heteroaryl and R ₂ is each independently
Alkyl, R ₃ is each independently H or alkyl, and R ₄ is cycloalkyl, aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula D and its attendant definitions, wherein R ₁ is aryl or heteroaryl and R ₂ is each independently:
Alkyl, R ₃ is each independently H or alkyl, R ₄ is cycloalkyl, aryl or heteroaryl, and R ₅ is each independently
H, alkyl, aryl, heteroaryl or F.

In certain embodiments, compounds of the present invention are represented by formula D and its attendant definitions, wherein R ₁ is aryl or heteroaryl and R ₂ is each independently
Alkyl, R ₃ is each independently H or alkyl, R ₄ is cycloalkyl, aryl or heteroaryl, and R ₅ is each independently
H, alkyl, aryl, heteroaryl or F, and each R ₆ is independently H, alkyl, aryl, heteroaryl or F.

In the assay based on opioid receptors from mammalian brain, the general structure D
The value of 50% inhibitory concentration (original: IC ₅₀ ) of a compound according to is less than 10 μMol, more preferably less than 5 μMol, most preferably for at least one subset of opioid receptors. It is less than 1 μMol.

[0233]   In certain embodiments, the compounds of the present invention are represented by formula E.

[0234]

[Chemical 17]

However, in the above formula, m is 1, 2, 3 or 4, n is 1 or 2, R ₁ is H, alkyl, aryl, heteroaryl or cycloalkyl, ₂ are each independently H, alkyl, fluoroalkyl, aryl, heteroaryl or cycloalkyl, R ₁ and R ₂ may be linked via a covalent bond, and R ₃ is independently each H, alkyl, _{aryl, oR 2, OC (O) R} 2, CH 2 oR 2 or _CO 2 _{R 2,} wherein any two of _{R 3} include its backbone 1, 2, 3 or 4 may be a covalent attachment consisting of carbon atoms, R ₄ is H, alkyl, aryl, heteroaryl, alkenyl or cycloalkyl, R ₅ are each independently, H, alkyl CH ₂ Y, aryl, heteroaryl, F, an OR ₂ or _{OC (O) R 2, R} 6 are each independently, H, alkyl, _CH 2 Y, aryl, heteroaryl, F, OR ₂ or OC (O) R ₂ and Y are each independently OR ₂ , N (R ₂ ) ₂ , SR ₂ , S (O) R ₂ , S (
O) ₂ R ₂ or P (O) (OR ₂ ) ₂ and R ₅ or R ₆ bonded to the carbon chain between R ₄ specified in formula E and the ring nitrogen is R ₄ and They may be connected by a covalent bond, R ₅ and R _{6 in the} case where two geminals or vicinals are aligned may be connected by a covalent bond, and X is C (R ₃ ) ₂ , O, S. , SO, SO ₂ , NR ₂ , NC (O) OR ₂ or C = 0, and the stereochemical configuration at the stereocenter of the compound represented by formula E is R-type, S-type, or It is mixed.

In certain examples, compounds of the present invention are represented by formula E and its attendant definitions, wherein X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, wherein X is C (R ₃ ) ₂ , O or NR ₂ .

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, wherein X is C (R ₃ ) ₂ .

In certain embodiments, compounds of the present invention are represented by formula E and the attendant definitions, wherein m is 2 or 3.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, wherein n is 1.

In certain embodiments, compounds of the present invention are represented by formula E and the attendant definitions, wherein R ₁ is aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, wherein each R ₂ is independently alkyl.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, R ₃ is each independently H or alkyl.

In certain embodiments, compounds of the present invention are represented by formula E and the attendant definitions, wherein R ₄ is cycloalkyl, aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, wherein R ₅ is each independently H, alkyl, aryl, heteroaryl or F.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, wherein R ₆ is each independently H, alkyl, aryl, heteroaryl or F.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0 and n is 1 Is.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ and n is 1.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, X is C (R ₃ ) ₂ and n is 1.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0 and R ₁ is , Aryl or heteroaryl.

In certain embodiments, a compound of the present invention is represented by formula E and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ and R ₁ is aryl or hetero. Aryl.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, X is C (R ₃ ) ₂ and R ₁ is aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0 and R ₂ is , Each independently alkyl.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, wherein X is C (R ₃ ) ₂ , O, or NR ₂ and each R ₂ is independently alkyl. Is.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, X is C (R ₃ ) ₂ and R ₂ is each independently alkyl.

[0256]   In certain embodiments, the compounds of the present invention are represented by formula E and its attendant definitions.
And X is C (R_Three)_Two, O, NR_Two, Or C = 0, n is 1, and R ₁ Is aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ and n is 1 and R ₁ is aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula E and the attendant definitions, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. is there.

[0259]   In certain embodiments, the compounds of the present invention are represented by formula E and its attendant definitions.
And X is C (R_Three)_Two, O, NR_Two, Or C = 0, n is 1, and R ₁ Is aryl or heteroaryl, R_TwoAre each independently alkyl
.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, and R ₁ is aryl or heteroaryl and each R ₂ is independently alkyl.

In certain embodiments, compounds of the present invention are represented by formula E and the attendant definitions, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. And each R ₂ is independently alkyl.

[0262]   In certain embodiments, the compounds of the present invention are represented by formula E and its attendant definitions.
And X is C (R_Three)_Two, O, NR_Two, Or C = 0, n is 1, and R ₁ Is aryl or heteroaryl, R_TwoAre each independently alkyl
, R_ThreeAre each independently H or alkyl.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, and R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, and R ₃ is independently H or alkyl.

In certain embodiments, a compound of the present invention is represented by formula E and its attendant definitions, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. And R ₂ is each independently alkyl and R ₃ is each independently H or alkyl.

[0265]   In certain embodiments, the compounds of the present invention are represented by formula E and its attendant definitions.
And X is C (R_Three)_Two, O, NR_Two, Or C = 0, n is 1, and R ₁ Is aryl or heteroaryl, R_TwoAre each independently alkyl
, R_ThreeAre each independently H or alkyl, and R_FourAre each a cyclo
Alkyl, aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ and n is 1 and R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, R ₃ is independently H or alkyl, and R ₄ is independently cycloalkyl, aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. Where R ₂ is independently alkyl, R ₃ is independently H or alkyl, and R ₄ is independently cycloalkyl, aryl or heteroaryl.

[0268]   In certain embodiments, the compounds of the present invention are represented by formula E and its attendant definitions.
And X is C (R_Three)_Two, O, NR_Two, Or C = 0, n is 1, and R ₁ Is aryl or heteroaryl, R_TwoAre each independently alkyl
, R_ThreeAre each independently H or alkyl, and R_FourAre each a cyclo
Alkyl, aryl or heteroaryl, R₅H and a
It is alkyl, aryl, heteroaryl, or F.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ and n is 1 and R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, R ₃ is independently H or alkyl, R ₄ is independently cycloalkyl, aryl or heteroaryl, R ₅ Are each independently H, alkyl,
Aryl, heteroaryl, or F.

In certain embodiments, compounds of the present invention are represented by formula E and the attendant definitions thereof, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. R ₂ are each independently alkyl, R ₃ are each independently H or alkyl, R ₄ are each independently cycloalkyl, aryl or heteroaryl, R ₅ are each independently H, Alkyl, aryl, heteroaryl, or F.

[0271]   In certain embodiments, the compounds of the present invention are represented by formula E and its attendant definitions.
And X is C (R_Three)_Two, O, NR_Two, Or C = 0, n is 1, and R ₁ Is aryl or heteroaryl, R_TwoAre each independently alkyl
, R_ThreeAre each independently H or alkyl, and R_FourAre each a cyclo
Alkyl, aryl or heteroaryl, R₅H and a
Rualkyl, aryl, heteroaryl, or F, R₆Respectively,
H, alkyl, aryl, heteroaryl, or F.

In certain embodiments, compounds of the present invention are represented by formula E and its attendant definitions, X is C (R ₃ ) ₂ , O, or NR ₂ and n is 1 and R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, R ₃ is independently H or alkyl, R ₄ is independently cycloalkyl, aryl or heteroaryl, R ₅ Are each independently H, alkyl,
Aryl, heteroaryl, or F, and each R ₆ is independently H, alkyl, aryl, heteroaryl, or F.

In certain embodiments, compounds of the present invention are represented by formula E and the attendant definitions, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. R ₂ are each independently alkyl, R ₃ are each independently H or alkyl, R ₄ are each independently cycloalkyl, aryl or heteroaryl, R ₅ are each independently H, Alkyl, aryl, heteroaryl, or F, and each R ₆ is independently H, alkyl, aryl, heteroaryl, or F.

In the assay based on opioid receptors from mammalian brain, the general structure E
The value of 50% inhibitory concentration (original: IC ₅₀ ) of a compound according to is less than 10 μMol, more preferably less than 5 μMol, most preferably for at least one subset of opioid receptors. It is less than 1 μMol.

[0275]   In certain embodiments, the compounds of the present invention are represented by formula F.

[0276]

[Chemical 18]

However, in the above formula, m is 1, 2, 3 or 4, y is 0, 1 or 2, and R ₁ is H, alkyl, aryl, heteroaryl or cycloalkyl. , R ₂ are each independently H, alkyl, fluoroalkyl, aryl, heteroaryl or cycloalkyl, R ₁ and R ₂ may be bonded via a covalent bond, and R ₃ is each independently. to, H, alkyl, _{aryl, oR 2, OC (O) R} 2, CH 2 oR 2 or _{CO 2 R} 2, _{R 4} are each independently, H, alkyl, aryl, heteroaryl, alkenyl or cycloalkyl alkyl, _{R 5} is H, alkyl, _CH 2 Y, aryl, heteroaryl, F, an oR ₂ or _{OC (O) R 2, R} 6 are each independently, H, Alkyl, _CH 2 Y, aryl, heteroaryl, F, an OR ₂ or OC (O) _{R 2,} Y are each _{independently, OR 2, N (R 2} ) 2, SR 2, S (O) R ₂ , S (
O) ₂ R ₂ or P (O) (OR ₂ ) ₂ and R ₅ or R ₆ bonded to the carbon chain between R ₄ specified in formula F and the ring nitrogen is R ₄ and They may be connected by a covalent bond, R ₅ and R _{6 in the} case where two geminals or vicinals are aligned may be connected by a covalent bond, and X is O, S, SO, SO ₂ , NR. ₂ , NC (O) OR ₂ or C = 0, and the stereochemical configuration at the stereocenter of the compound represented by Formula F is R-type, S-type, or a mixture of these configurations.

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, wherein X is O, NR ₂ , or C = 0.

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, wherein X is O or NR ₂ .

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, wherein X is NR ₂ .

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, wherein m is 2 or 3.

In certain examples, compounds of the present invention are represented by formula F and its attendant definitions, wherein y is 1.

In certain embodiments, compounds of the present invention are represented by formula F and the attendant definitions, wherein R ₁ is aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, wherein each R ₂ is independently alkyl.

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, R ₃ is each independently H or alkyl.

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, R ₄ is cycloalkyl, aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula F and the attendant definitions, wherein each R ₅ is independently H, alkyl, aryl, heteroaryl or F.

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, wherein R ₆ is each independently H, alkyl, aryl, heteroaryl or F.

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, X is O, NR ₂ , or C = 0 and y is 1.

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, X is O or NR ₂ and y is 1.

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, X is NR ₂ and y is 1.

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, X is O, NR ₂ , or C = 0 and R ₁ is aryl or heteroaryl. .

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, X is O or NR ₂ and R ₁ is aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, X is NR ₂ and R ₁ is aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, X is O, NR ₂ , or C = 0, and R ₂ is each independently alkyl. .

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, X is O or NR ₂ and R ₂ is each independently alkyl.

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, X is NR ₂ and R ₂ is each independently alkyl.

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, X is O, NR ₂ , or C = 0, R ₁ is aryl or heteroaryl, Each R ₂ is independently alkyl.

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, X is O or NR ₂ , R ₁ is aryl or heteroaryl,
Each R ₂ is independently alkyl.

In certain embodiments, a compound of the present invention is represented by formula F and its attendant definitions, X is NR ₂ , R ₁ is aryl or heteroaryl, and R ₂ is each independently alkyl. is there.

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, X is O, NR ₂ , or C = 0, R ₁ is aryl or heteroaryl, R ₂ is independently alkyl and R ₃ is independently H or alkyl.

In certain embodiments, compounds of the present invention are represented by formula F and the attendant definitions, wherein X is O or NR ₂ , R ₁ is aryl or heteroaryl,
R ₂ is independently alkyl and R ₃ is independently H or alkyl.

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, X is NR ₂ , R ₁ is aryl or heteroaryl, and R ₂ is each independently alkyl. And R ₃ is each independently H or alkyl.

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, X is O, NR ₂ , or C = 0, R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, R ₃ is independently H or alkyl, and R ₄ is independently cycloalkyl, aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula F and the attendant definitions, wherein X is O or NR ₂ , R ₁ is aryl or heteroaryl,
R ₂ is independently alkyl, R ₃ is independently H or alkyl, and R ₄ is cycloalkyl, aryl or heteroaryl.

[0306]   In certain embodiments, the compounds of the invention are represented by Formula F and its attendant definitions.
And X is NR_TwoAnd R₁Is aryl or heteroaryl, R_TwoHaso
Each independently alkyl, R_ThreeAre each independently H or alkyl, and R _Four Is cycloalkyl, aryl or heteroaryl.

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, X is O, NR ₂ , or C = 0, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, R ₃ is each independently H or alkyl, R ₄ is cycloalkyl, aryl or heteroaryl,
Each R ₅ is independently H, alkyl, aryl, heteroaryl, or F.

In certain embodiments, compounds of the present invention are represented by formula F and its attendant definitions, X is O or NR ₂ , R ₁ is aryl or heteroaryl,
R ₂ is independently alkyl, R ₃ is independently H or alkyl, R ₄ is cycloalkyl, aryl or heteroaryl, and R ₅ is independently H, alkyl, aryl, heteroaryl. , Or F.

[0309]   In certain embodiments, the compounds of the invention are represented by Formula F and its attendant definitions.
And X is NR_TwoAnd R₁Is aryl or heteroaryl, R_TwoHaso
Each independently alkyl, R_ThreeAre each independently H or alkyl, and R _Four Is cycloalkyl, aryl or heteroaryl, R₅Are separate
Are H, alkyl, aryl, heteroaryl, or F.

In certain embodiments, the compounds of the present invention are represented by formula F and its attendant definitions, X is O, NR ₂ , or C = 0, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, R ₃ is each independently H or alkyl, R ₄ is cycloalkyl, aryl or heteroaryl,
Each R ₅ is independently H, alkyl, aryl, heteroaryl, or F, and each R ₆ is independently H, alkyl, aryl, heteroaryl, or F.

In certain embodiments, the compounds of the present invention are represented by formula F and its attendant definitions, X is O or NR ₂ , R ₁ is aryl or heteroaryl,
R ₂ is independently alkyl, R ₃ is independently H or alkyl, R ₄ is cycloalkyl, aryl or heteroaryl, and R ₅ is independently H, alkyl, aryl, heteroaryl. , Or F, and each R ₆ is independently H, alkyl, aryl, heteroaryl, or F.

[0312]   In certain embodiments, the compounds of the invention are represented by Formula F and its attendant definitions.
And X is NR_TwoAnd R₁Is aryl or heteroaryl, R_TwoHaso
Each independently alkyl, R_ThreeAre each independently H or alkyl, and R _Four Is cycloalkyl, aryl or heteroaryl, R₅Are separate
Is H, alkyl, aryl, heteroaryl, or F, and R₆Is that
Independently, H, alkyl, aryl, heteroaryl, or F.

In the assay based on opioid receptors from mammalian brain, the general structure F
The value of 50% inhibitory concentration (original: IC ₅₀ ) of a compound according to is less than 10 μMol, more preferably less than 5 μMol, most preferably for at least one subset of opioid receptors. It is less than 1 μMol.

In certain embodiments, the present invention relates to compounds according to formula A, C, E or F and the attendant definitions, wherein the compound is a single stereoisomer.

In certain embodiments, the present invention provides a formulation comprising a compound of formula A, B, C, D, E or F and its corresponding supplementary definitions, and a pharmaceutically acceptable additive. Regarding things.

In certain embodiments, the present invention relates to pain, drug addiction or tinnitus in a mammal, comprising a compound represented by A, B, C, D, E or F and their corresponding supplementary definitions. And an effective amount of a pharmaceutically acceptable excipient to a mammal suffering from pain, drug addiction or tinnitus.

In certain embodiments of such methods, the mammal is a primate, horse, dog or cat. In some embodiments of such methods, the mammal is a human. In one embodiment of such method, the formulation is administered orally.
In one embodiment of such method, the formulation is administered intravenously. In certain embodiments of such methods, the formulation is administered sublingually. In certain embodiments of such methods, the formulation is administered to the eye.

In certain embodiments, the present invention relates to ligands for G protein-coupled or opioid receptors, which ligands include the generalized structures A, B,
Any of C, D, E, and F, and any of a set of supplementary definitions associated with one of these structures. Suitably, the ligands of the invention are antagonists, agonists, partial agonists or inverse agonists of one or more G protein coupled receptors or opioid receptors. In any event, preferably the ligands of the invention will be present at a concentration below about 10 micromolar, more preferably below 1 micromolar, and most preferably below 100 nanomolar. Effective against receptors. In another example, the ligands of the invention bind to G protein-coupled receptors of multiple families. In one embodiment, the ligand of the invention is
It selectively binds to a single family of G protein-coupled or opioid receptors. In another embodiment, the ligands of the invention selectively bind to a subtype of receptors belonging to a family of G protein-coupled or opioid receptors.

In certain embodiments, the selectivity of a ligand for a particular family or subtype of receptor makes the ligand an effective therapeutic agent for acute or chronic illnesses, diseases or disorders. In certain embodiments, the selectivity of a ligand for a particular family or subtype of receptor is greater than the binding affinity of that ligand for G protein-coupled or opioid receptors of other families or subtypes.
It has a binding affinity for receptors of those particular families or subtypes that is at least 10 times greater. In certain embodiments, the selectivity of a ligand for a receptor of a particular family or subtype is greater than the binding affinity of that ligand for G protein-coupled or opioid receptors of other families or subtypes. It has a binding affinity for receptors of those particular lineages or subtypes that is at least 100-fold greater. In certain embodiments, the selectivity of a ligand for a receptor of a particular family or subtype is greater than the binding affinity of that ligand for G protein-coupled or opioid receptors of other families or subtypes. It has a binding affinity for receptors of those particular lineages or subtypes that is at least 1000-fold greater. The intent of the present invention is a pharmaceutical formulation of a ligand according to the invention (see below). In certain embodiments, pharmaceutical formulations include ligands of the invention, which ligands are effective only at a particular family or subtype of G protein or opioid receptor, and thus Exert a therapeutic effect on an acute or chronic illness, disease or disorder that is at least in part due to biochemical or physiological processes associated with such receptors. In certain embodiments, pharmaceutical formulations include ligands of the invention, which ligands are effective at only one subtype of receptor, and, thus, at such particular subtype of receptor. It exerts a therapeutic effect on acute or chronic illnesses, diseases or disorders which are at least partly due to the associated biochemical or physiological processes. In the Background of the Invention (see above), an acute or chronic illness that is initiated or exacerbated by a biochemical or physiological process associated with a particular G protein-coupled or opioid receptor,
Examples of diseases or disorders are taught. One of ordinary skill in the art, by referring to the scientific literature, an acute or chronic illness, disease or disorder that is caused or exacerbated by a biochemical or physiological process associated with a particular G protein-coupled or opioid receptor. You could accumulate a more comprehensive list of. The present invention contemplates pharmaceutical formulations of the ligands according to the present invention having medical value against the acute or chronic illnesses, diseases or disorders mentioned above.

Biochemical Activities at Cellular Receptors and Assays for Detecting Such Activities Reagents are added to a sample, the sample and the reagent are measured, and the assay's procedure to identify sample attributes induced by the reagent. Are known to those skilled in the art. For example, one such assay process involves measuring the amount of enzyme present in a biological sample or solution in a chromogenic assay. Such assays are based on the generation of colored products in the reaction solution. Such reactions proceed as the colorless chromogenic substrate is converted to a colored product by the catalytic action of the enzyme.

Another assay useful in the present invention involves measuring the ability of a ligand to bind to a biological receptor using a technique known to those skilled in the art as a radioligand binding assay. Such an assay accurately measures the specific binding of the radioligand to the target receptor by expressing all and non-specific binding components thereof. Total binding is defined as the amount of residual radioligand in the receptor preparation (cell homogenate or recombinant receptor) after the bound radioligand is rapidly separated from the unbound radioligand. Non-specific binding component is defined as the amount of residual radioligand after the reaction mixture consisting of receptor, radioligand and excess unlabeled ligand is separated. Under such conditions, only the remaining radioligand represents those that bind to components other than the receptor. Radioligand binding is determined by subtracting non-specific binding from total radioactive binding. For a specific example of a radioligand assay for the μ receptor, see Wang, JB et al FEBS Lette.
See rs 1994, 338, 217.

Another assay useful in the present invention involves measuring the activity of a receptor, where activation of the receptor releases intracellularly stored calcium ions for use as a second messenger. Induce an intracellular event. Some G
Phospholipase C-mediated hydrolysis of phosphatidylinositol by activation of protein-coupled receptors (Berridge and Irvine (1984) Nature 312: 315-21.
) Induces the formation of inositol triphosphate (IP3, a G protein-coupled receptor second messenger), which in turn induces the release of intracellularly stored calcium ions.

Changes in calcium ion levels in the cytoplasm caused by the detachment of calcium ions from their intracellular accumulation are used to measure the action of G protein coupled receptors. This is another type of indirect assay. G protein-coupled receptors include muscarinic acetylcholine receptors (mAChRs), adrenergic receptors, sigma receptors, serotonin receptors, dopamine receptors, angiotensin receptors, adenosine receptors, bradykinin receptors, and metabolic excitability. Such as amino acid receptors. Cells expressing such G protein-coupled receptors show elevated cytosolic calcium levels, both as a result of intracellular accumulation contributions and as a result of ion channel activation, but in this case E
It is not necessary to perform such an assay with a calcium-free buffer optionally supplemented with a chelating agent such as GTA (ethylene glycol-diethylamine tetraacetic acid), but it is possible to discriminate the fluorescent response due to calcium released from internal accumulation. Would be desirable. Other types of indirect assays, when activated, result in altered levels of intracellular cyclic nucleotides such as, for example, cAMP (amphetamine), cGMP (guanosine-3 ′, 5′-cyclic phosphate). It relates to measuring the activity of a receptor. For example, activation of certain dopamine, serotonin, metabotropic glutamate and muscarinic acetylcholine receptors results in cytoplasmic cA activation.
It results in a decrease in MP or cGMP levels.

In addition, cyclic nucleotide-gated ion channels such as rod photoreceptor cell channels and olfactory nerve cell channels that are permeable to cations when activated by binding of cAMP or cGMP (see : Altenhofen, W. et al.
(1991) Proc. Natl. Acad. Sci USA 88: 9868-9872 and Dhallan et al. (19
90) Nature 347: 184-187). Changes in ion levels in the cytoplasm caused by changes in the activation amount of cyclic nucleotides of photoreceptors or olfactory nerve cell channels
It is used to measure the action of receptors that, when activated, result in changes in cAMP or cGMP. If activation of this receptor results in a decrease in the level of cyclic nucleotides, a receptor that increases the level of cyclic nucleotides in the cell before adding the receptor-active compound to the cell being measured. It may be preferable to expose the cells to (eg forskolin, etc.). Cells for these types of assays have DNA encoding cyclic nucleotide-gated ion channels, and certain DNA encoding receptors (when activated, levels of cyclic nucleotides in the cytoplasm Certain metabolic tropotropic glutamate receptors, muscarinic acetylcholine receptors, dopamine receptors that cause changes,
It can be prepared by co-transfecting host cells with a serotonin receptor or the like).

When activated by, for example, opening a dependent calcium channel, it has the ability to directly increase the intracellular concentration of calcium, or as a second messenger (eg, G protein-coupled receptor), Ca < The assay may be based on any cell that expresses a receptor protein that has the ability to indirectly influence intracellular calcium concentration, such as by inducing a reaction utilizing 2+>. Those cells that express endogenously such receptors or ion channels, and cells that can be transfected with suitable mediators that encode one or more such cell surface proteins are known to those of skill in the art. Are known to or can be identified by one of ordinary skill in the art. Essentially any cell that expresses an endogenous ion channel and / or receptor activity may be used, but an ion channel and / or an ion channel that favorably expresses a single type of ion channel or receptor Alternatively, it is preferred to use cells which have been transformed or transfected with heterologous DNA encoding the receptor. Many cells are known that can be genetically engineered to express heterologous cell surface proteins. Examples of such cells include hamster kidney (BHK) cells immediately after birth (ATCC No. CCL10), mouse L cells (ATCC No. CCLI.3), and DG44 cells (see Chasin (1986) Cell.
Molec. Genet. 12: 555), human embryonic kidney (HEK) (ATCC No. CRL157).
No. 3) Chinese Hamster Ovary (CHO) cells (ATCC No. CRL9618
No., CCL61, CRL9096), PC12 cells (ATCC No. CRL1)
721) and COS-7 cells (ATCC No. CRL1721), but are not limited thereto. Preferred cells for heterologous cell surface protein expression are those that can be easily and efficiently transfected. Preferred cells include, for example, HEK239 cells described in US Pat. No. 5,024,939.

Any compound known to activate the ion channel or receptor of interest may be used to initiate the assay. Selection of the active reagent for the appropriate ion channel or receptor depending on the ion channel or receptor of interest is within the skill of the art. Direct depolarization of the cell membrane to measure calcium channel activity has been demonstrated for potassium ion concentrations in the cell-containing wells containing cells in the range of about 50 to 150 millimolar (eg, 50 millimolar potassium chloride). It can be achieved by adding a potassium salt having an appropriate potassium ion concentration as in. With respect to ligand-gated receptors and ligand-gated ion channels, ligands that have an affinity for such receptors and that activate them are known. For example, nicotine-like acetylophorin receptors are known to be activated by nicotine or acetylophorin. Similarly, muscarinic and acetylophorin receptors can be activated by the addition of muscarinic or carbamylcholine.

[0327] If a compound has an effect on the activation or enhancement action of the target ion channel or receptor, the compound contains the ion channel or receptor in order to determine what effect it has. Agonist assays can be performed on cells known to be. Agonist assays are also known to possess the ability to activate ion channels or receptors in order to determine whether a cell expresses a working ion channel or receptor of interest, respectively. It can be carried out by using a reagent.

Contacting an agonistic receptor or ion channel with an agonist typically activates a transient response, and prolonged exposure to the agonist desensitizes the receptor or ion channel. And the subsequent activity is reduced. Therefore, generally speaking, assays for measuring the action of ion channels or receptors are performed by the addition of agonists (ie, in the reagent solution used to induce the reaction).
Should start. Agonists (whether the same cells or substantially the same cells)
That is, the potency of a compound having agonist activity compared to the level of observables in cells subjected to substantially the same treatment except that a reagent without (control agent) is added to the wells, It is measured by detecting a change in some observable within the cell, some of which are reduced by activation of a receptor, but typically increased. When conducting an agonist assay to test whether a cell expresses an agonistic receptor or ion channel of interest, a known agonist in wells containing test cells and wells containing control cells is used. Add pills and compare observable levels. According to such an assay, cells lacking the ion channel and / or receptor of interest should show substantially no observable increase in response to their known agonists. Cells for preparing recombinant cells, but substantially the same cells may be derived from the same cells that have not been modified by the introduction of heterologous DNA. Alternatively, it may be a cell in which a specific receptor or ion channel is removed. Whatever the statistical or otherwise significant difference in the level of observables is that the test compound in some way altered the activity of a particular receptor or ion channel, or Indicates either possessing a specific agonist or ion channel.

In an example of a drug screening assay for identifying compounds that have the ability to modulate an ion channel or receptor of interest, individual wells (or duplicate wells, etc.) can be of different cell types or of different types. Containing a recombinant cell line of another species expressing a homogeneous population of receptors or ion channels, and screening for compounds with unidentified activity to select one of the various active ion channels or receptors. For one or more ion channels or receptors it can be determined whether the compound has a modulatory activity. It is also possible to screen a large number of compounds (obtained from different reagent sources in the device or contained in different wells) and to compare for the presence or absence of regulatory activity on one particular receptor or ion channel. It is also contemplated that all individual wells may contain the same cell type, as possible.

Antagonist assays, including drug screening, can be performed as follows. That is, in the presence and absence of one or more compounds, sufficient time is allowed for the compounds to bind to the receptor and / or ion channel of interest (this compound is Culturing cells with working ion channels and / or receptors added to a solution in which the cells are soaked in each well of the microtiter plate until an affinity for the channels and / or receptors occurs),
This ion channel or receptor is then activated by the addition of a known agonist, and in the absence of the putative antagonist the same or substantially the same cells as the cultured cells. The levels of observables within these cultured cells are measured while being compared to the levels of observables within.

Thus, the assay is useful for rapidly screening compounds to identify those that modulate any receptor or ion channel within the cell. In particular, test the effector ligand-receptor or ligand-ion channel interaction on cellular receptors including ligand-gated ion channels, voltage-gated ion channels, G protein coupled receptors and growth factor receptors. Assays can be used to:

Compounds that can have a variety of characteristics can change their characteristics in response to a cellular event, but it is an assay to measure the detectable change in a solution that results from this cellular event. It will be apparent to those skilled in the art. When a cellular event occurs, different assays can be performed by selecting particular compounds that can have different characteristics. For example, an assay for measuring the ability of a compound to induce cell damage or cell death involves loading cells with a fluorescent indicator that is pH sensitive, such as BCECF (Molecular Probes Eugene, Oreg. 97402, Catalog No. B1150). However, it can be performed by measuring cell damage or cell death as a function of changes in fluorescence over time.

In another example of a useful assay, the action of a receptor, which results in a change in the level of cytoplasmic cyclic nucleotides upon activation, expresses such a receptor and c
It can be measured directly by an assay in cells injected with a fluorescent compound that changes fluorescence upon binding to AMP. Such fluorescent compounds include cAMP-dependent protein kinases whose catalytic and regulatory subunits are each labeled with various fluorescent dyes (Adams et al. (1991) Nature 349: 694-697). cAMP
Binding to this regulatory subunit changes the fluorescence emission spectrum,
Such changes can be used as an index of changes in cAMP concentration.

The action of certain neurotransmitter transporters located in the synaptic cleft at the junction between two neurons is described by the conjugate conjugate of an amine acid and a fluorescent indicator.
e), when the neurotransmitter is transported to the intracellular cytoplasm where the ester group is cleaved by esterase activity, and these conjugated conjugates start to fluoresce, fluorescence in the cytoplasm of such neuronal cells Can be measured by generation (fluorescent indicators of such conjugated conjugates include acetoxymethyl ester derivatives such as 5- (aminoacetamido) fluorescein (Molecular Probes, Inc.
There is catalog number A1363).

In carrying out these types of assays, reporter gene constructs are inserted into eukaryotic cells to produce recombinant cells having certain types of cell surface proteins on their surface. Even though this cell surface receptor is expressed endogenously,
Alternatively, it may be expressed by a heterologous gene introduced into the cell. Various methods for introducing heterologous DNA into eukaryotic cells are known to those skilled in the art, and any such method may be used. DNAs encoding various surface proteins are also known to those of skill in the art, or these DNAs may be cloned by any method known to those of skill in the art.

Recombinant cells are contacted with a test compound and the level of reporter gene expression is measured. Such contacting can be performed in any medium, and such testing is by any means using any protocol known to those of skill in the art, such as serial dilution to assess interactions of particular molecules. May be carried out in. The level of gene expression is measured after contacting the recombinant cells for sufficient time to allow any interaction to occur. The time for realizing such interaction can be empirically specified, and for example, the transition of time may be measured to measure the transcription level as a function of time. The amount of transcription may be measured using any suitable method known to those skilled in the art. For example, expression of a particular mRNA may be detected using the Northern method, or a particular protein product may be identified by a characteristic stain. The transcript is then compared to the transcript in the same cells without the test compound, or
Alternatively, it may be compared with the amount of transcription in substantially the same cells in which these specific receptors are not present. Substantially identical cells can be derived from the same cells from which recombinant cells were prepared but unaltered by the introduction of heterologous DNA. Alternatively,
The cell may be depleted of these particular receptors. Any statistically or otherwise significant difference in the amount of transcript indicates that such test compound in any way altered the specific receptor activity.

If the test compound does not potentiate, activate or induce the activity of cell surface proteins, the assay may be repeated, or a step may be introduced to modify this assay at which stage. , The recombinant cells are first tested for the ability of a known agonist or activator of a particular receptor to be transcriptionally active when transcribed, and then a test compound determines the activity of this agonist. Test compounds are assayed for their ability to inhibit, inhibit or otherwise affect.

Such transcription-based assays are useful for identifying compounds that interact with any cell surface protein whose activity ultimately alters gene expression. In particular, such an assay is for ligand-gated and voltage-gated ion channels, as well as for agonists between and / or ligands for numerous categories of cell surface-localized receptors, including G protein-coupled receptors. And can be used to test the interaction between ion channels.

Any transfectable cell capable of expressing the desired cell surface protein in such a way that the protein acts to transduce an extracellular signal into the cell may be used. Such cells may be selected to express cell surface proteins endogenously or may be genetically engineered to act in that way. Many such cells are known to those skilled in the art. Such cells include, but are not limited to, Ltk <−> cells, PC12 cells and COS-7 cells.

Preparations of cells useful for testing compounds to express receptors or ion channels and reporter gene expression constructs and to assess their activity are available in mammalian Ltk <−> cells and COS-7. Shown in the examples incorporated herein by reference to cell lines, such cell lines express the human type I muscarinic (HM1) receptor, and the c-fos enhancer-CAT reporter. Gene expression construct, or c-
Converted by any of the fos facilitator-luciferase reporter gene expression constructs.

Any cell surface protein known to or identifiable by one of skill in the art may be used in the assay. This cell surface protein can be expressed endogenously on the selected cell or can be expressed by cloned DNA. Representative cell surface proteins include, but are not limited to, cell surface receptors and ion channels. Cell surface receptors include, but are not limited to: That is, a muscarinic receptor (eg, human M2 (
Genbank permission number M16404), rat M3 (Genbank permission number M16407), human M4 (Genbank permission number M16405), human M5
(Bonner et al. (1988) "Neurons" 1: 403-410, etc.), neuronal nicotine-like acetylcholine receptors (for example, US Pat. No. 504,455 (filed on Apr. 3, 1990) alpha 2, alpha. 3 and beta 2 subtypes, which are expressly incorporated herein by reference in their entirety), rat alpha 2 subunit (Wada et al. (1988) "Science" 240: 330-334), rat.・ Alpha 3
Subunit (Boulter et al. (1986) Nature 319: 368-374), rat alpha 4 subunit (Goldman et al. (1987) cell 48: 965-973), rat alpha 5 subunit (Boulter et al. (1990) J. Biol. Chem. 265: 4472-4482)
, Rat beta 2 subunit (Deneris et al. (1988) "Neuron" 1: 45-
54), rat beta 3 subunit (Deneris et al. (1989) J. Biol. Chem.
264: 6268-6272), rat beta 4 subunit (Duvoisin et al. (1989)
"Neuron" 3: 487-496), rat alpha subunit, beta subunit and combinations of alpha and beta, GABA receptors (eg 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), gamma-subunit (Pritchett et al. (1989) Natur
e 338: 582-585), beta 2 and beta 3 subunits (Ymer et alo (1989) EM
BO J. 8: 1665-1670), delta subunit (Shivers, BD (1989) "neurons" 3: 327-337), and others), glutamine receptors (eg, receptors isolated from rat brain ( Hollmann et al. (1989) Nature 342: 643-648), and others), adrenergic receptors such as human beta 1 (Frielle et al.
1987) Proc. Natl. Acad. Sci. 84.:7920-7924)), human alpha 2 (Kobilk
a et al. (1987) "Science" 238: 650-656), Hamster Beta 2 (Dixon)
et al. (1986) Nature 321: 75-79), and others) dopamine receptors (eg,
Human D2 (Stormann et al. (1990) Molec. Pharm.37: 1-6), rat (Bunzow e
(1988) Nature 336: 783-787), and others), NGF receptors (eg,
Human NGF receptor (Johnson et al. (1986) Cell 47: 545-554, and others)
, Serotonin receptors (eg human 5HT1a (Kobilka et al. (1987) Natur
e 329: 75-79), rat 5HT2 (Julius et al. (1990) PNAS 87: 928-932),
Rat 5HT1c (Julius et al. (1988) "Science" 241: 558-564) and the like).

Reporter gene constructs can be prepared by operatively linking a reporter gene with at least one transcriptional regulatory element. If it contains only one transcriptional regulatory element, it is arguably a regulatable enhancer. At least one of the selected transcriptional regulatory elements can be indirectly or directly regulated by the activity of the selected cell surface receptor, and the activity of the receptor can be monitored via transcription of the reporter gene.

This construct may contain additional transcriptional regulatory elements, such as FIRE sequences or other sequences, although such sequences are not necessarily regulated by cell surface proteins, this construct has a background It is selected because it has the ability to reduce levels of transcription or amplify transduction signals to 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.

Reporter genes include 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 be included in the construct in the form of a fusion gene with a gene that contains the desired transcriptional regulatory sequences or exhibits other desired traits.

Examples of reporter genes include, but are not limited to:
That is, CAT (chloramphenicol acetyl transferase) (Alto
n 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 (Engeb
recht and Silverman (1984), PNAS 1: 4154-4158; Baldwin et al. (1984), Bi
ochemistry 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 regulatory elements include, but are not limited to, promoters, enhancers and binding sites for repressors and activators. Appropriate transcriptional regulatory elements are expressed rapidly, generally from the transcriptional regulatory region of a gene, the expression of which is derived from contact between a cell surface protein and an effector protein that regulates the activity of this cell surface protein. Can be induced within minutes. Examples of such genes include immediate early genes such as c-fos (see: Sheng et al. (1990) Neuron 4: 477-
485), but is not limited to this. An immediate early gene is a gene that is rapidly induced when a ligand binds to a cell surface protein. Transcriptional control elements preferred for use in genetic constructs include transcriptional control elements derived from immediate early genes,
Included are synthetic elements derived from other genes that exhibit some or all of the characteristics of the immediate-early gene, or elements in which the operably linked gene is constructed to exhibit such characteristics. Preferred gene features from which transcriptional regulatory elements are derived include low level or undetectable expression in quiescent cells, rapid induction within minutes of extracellular simulation at transcriptional levels, transient and new protein synthesis. There is, but is not limited to, induction unrelated to. Blocking transcription requires new protein synthesis and mRNA transcribed from these genes has a short lifespan. Not all of these attributes need to be implemented.

In Vivo Activity Assays Various experimental methods for assessing the analgesic effect of compounds, such as the “tailing” and “hot plate” tests, are known to those of skill in the art, but are useful in the present invention. Is. The “tail movement” test can be performed by applying an unpleasant thermal stimulus to the rat's tail and measuring the time until nociceptive tail movement occurs. Analgesia is evidenced by the increased time until the appearance of a tail swing response. The "hot plate" test is carried out in the same way, except that
An unpleasant thermal stimulus is applied to the rat's forepaws.

One experimental method known to those of skill in the art and useful in the present invention for evaluating compounds that cause respiratory depression is blood gas monitoring. This method utilizes the administration of the compound followed by measuring the partial pressures of oxygen and carbon dioxide in a blood sample taken from the animal. A decrease in the partial pressure of oxygen and an increase in the partial pressure of carbon dioxide
It can be an index of respiratory depression.

One experimental method known to those of skill in the art and useful in the present invention for evaluating compounds that cause inhibition of gastrointestinal motility is the “charcoal diet test”.
This method measures the migration of intestinal contents after administration of a test compound. Attenuated migration of intestinal contents can be an indicator of inhibition of gastrointestinal motility.

Various experimental methods for assessing the ability of a compound to elicit tolerance are known to those of skill in the art and are useful in the present invention. Tolerance can be defined as a condition characterized by a loss of reactivity or a diminished reactivity after long-term or abundant exposure to a compound compared to the reactivity upon initial exposure.

A variety of experimental methods for assessing the ability of compounds to cause physical addiction are known to those of skill in the art, but are useful in the present invention. In the present invention, the ability of test compounds to cause physical addiction is evaluated by giving test compounds to animals at increasing doses for 5 days. After the final administration, the animals were administered naloxone, an opioid antagonist, and observed for any behavioral signs of dependence such as vertical jumps.

Pharmaceutical Compositions In another aspect, one or more pharmaceutically acceptable carriers (additives) and / or diluents comprising a therapeutically effective amount of one or more of the above compounds. A pharmaceutically acceptable composition formulated therewith is provided by the present invention. As described in detail below, the pharmaceutical compositions of the present invention can be formulated for administration in solid or liquid phase forms, including those made as follows. That is, (1) oral administration, for example,
Tablets, boluses, powders, granules, sizing agents for application to the tongue, (2) drugs (watery or non-aqueous solvent or suspension), buccal agents, sublingual agents, and systemic absorption
) Parenteral administration, such as subcutaneous, intramuscular, intravenous or epidural injection as a sterile solvent or suspension, or sustained release administration, (3) topical application, emulsions, ointments or controlled release patches or, for example, skin, Spray applied to lungs or oral cavity, (4) vaginal or rectal use
For example, pessari, cream or foam, (5) sublingual, (6) eye drops, (7) transdermal or (8) nasal side.

The term “therapeutically effective amount” as used herein refers to cells in cells of at least one subpopulation of an animal, at any reasonable benefit / risk ratio applicable to any medical therapy. Refers to the amount of a compound, substance or composition which comprises a compound of this invention that is effective to produce the desired therapeutic effect.

As used herein, the phrase “pharmaceutically acceptable” is within the scope of sound medical judgment and does not involve excessive toxicity, irritation, allergic response, or other problems. , Refers to compounds, substances, compositions and dosage forms suitable for use in contact with human and animal tissues, with reasonable benefit / risk factors.

As used herein, the phrase "pharmaceutically acceptable carrier" refers to a liquid or solid phase excipient, diluent, additive, or solvent encapsulating a substance that is the compound of interest as an organ. Or, refers to a pharmaceutically acceptable substance, composition or vehicle involved in delivering or shipping from a body part to another organ or body part. Both carriers 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 substances that may be used as pharmaceutically acceptable carriers include: That is, (1) sugars such as lactose, glucose and sucrose, (2) starches such as corn starch and potato starch, (3) sodium, carboxymethyl cellulose and ethyl cellulose, celluloses such as cellulose acetate and derivatives thereof, and (4) tragacanth. Powder, (5) malt, (6) gelatin, (7) talc, (8) excipients such as cocoa butter and suppository wax, (9) peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and large Oil agents such as soybean oil, (10) glycols such as propylene glycol, (11) glycerol 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 buffer (21) Polyester, polycarbonate and / or polyanhydride and (22) other non-toxic compatible substances used in pharmaceutical formulations.

As mentioned above, certain embodiments of the compounds of this invention may contain basic functional groups such as amino or alkylamino, and thus may be combined with pharmaceutically acceptable acids and pharmaceutically acceptable acids. An acceptable salt can be formed. 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 may be prepared in-situ during the administration vehicle or dosage form manufacturing process or by reacting the pure compounds of the invention in the form of their free base separately with a suitable organic or inorganic acid, It may be prepared by separating the salt thus formed in a subsequent purification step. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate,
Palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,
There are succinate, tartrate, naphthylate (original: napthylate), mesylate, glucoheptonic acid, lactobionate (original: lactobionate), and lauryl sulfonate salts (reference: eg, Berge et a)
l. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).

Pharmaceutically acceptable salts of the compounds include, for example, conventional non-toxic salts or quaternary ammonium salts of compounds made from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts, including those derived from inorganic acids such as hydrochloride, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and acetic acid, propionic acid, succinic acid, glycolic acid. , Stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic (original: hydrox
ymaleic), phenylacetic acid, glutamic acid, benzoic acid, salicyclic, sulfanilic acid, 2-acetoxybenzoic (original: 2-acetoxybenzoic), fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid (original: ethane dis
ulfonic), oxalic acid, isothionic (original: isothionic).

In another embodiment, the compounds of the present invention may contain one or more acidic functional groups, thus forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. Can be formed. The term "pharmaceutically acceptable salt" in these cases refers to the relatively non-toxic, inorganic or organic base addition salts of the present invention. Similarly, these salts may be prepared in situ during the administration of the vehicle or dosage form, or in an appropriate form such as a cation hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation. It can be prepared by separately reacting a pure base, ammonia, or a pharmaceutically acceptable organic primary, secondary or tertiary amine with a pure compound in the form of its free acid. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like. Representative organic amines useful in the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see eg, Berge et al., Supra).

Wetting agents such as sodium laurate, magnesium stearate, emulsifiers and lubricants as well as colorants, strippers, coatings, sweetening, flavoring and fragrances, preservatives and antioxidants are also available. Present in the composition.

Examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride hydrate, sodium sulfite, isomeric sodium bisulfite, and sodium sulfate; (2) Oil-soluble antioxidants such as ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate (original: propyl gallate), alpha tocopherol, (3) citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and other metal chelating agents.

Some of the formulations of the present invention are suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. These formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will depend upon the recipient 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 speaking, the amount will be from about 1 percent to about 99 percent of the active ingredient, converted to 100 percent, and preferably from about 5 percent to about 70 percent.
Most preferably, it is in the range of about 10 percent to about 30 percent.

Methods of preparing these formulations or compositions include the step of bringing into association a compound of the invention with its carrier and, optionally, one or more accessory ingredients. In general, these formulations are prepared by uniformly and intimately bringing into association a compound of the invention with either the liquid phase carrier or the finely divided solid phase carrier, or both. If formed as a product.

Formulations of the invention suitable for oral administration include capsules, cachets, pills, tablets, troches (with a flavored base, usually sucrose and acacia or tragacanth), powders, granules. As a solvent or suspension in an agent or an aqueous or non-aqueous liquid, as an oil-in-water or water-in-oil emulsion, or as an elixir or syrup, or as a pastille (of gelatin and glycerin, or sucrose and acacia Such an inert base is used) and / or a gargle, etc., each containing a predetermined amount of the compound according to the present invention as an active ingredient. The compounds of the present invention may be administered as a bolus, electuary or paste.

In the solid phase dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is sodium citrate or dicalcium phosphate. , Mixed with one or more pharmaceutically acceptable carriers and / or any of the following: That is, (1) excipients or fillers such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid, (2) for example, carboxymethylcellulose, alginate, gelatin, polyvinyl, pyrrolidone, sucrose and or acacia. Binder of (
3) water retention agents such as glycerol, (4) disintegrating agents such as agar, calcium carbonate, potatoes or tapioca starch, alginic acid, certain silicates and sodium carbonate, (5) mild dyes such as paraffin solvents, ( 6) absorption enhancers such as quaternary ammonium compounds, (7) for example cetyl alcohol, glycerol monostearate and nonionic surfactant wetting agents, (8) absorbers such as kaolin and bentonite clay, (9) ) Lubricants such as talc, calcium stearate, magnesium stearate, solid phase polyethylene glycol, sodium lauryl sulphate and mixtures thereof, (10) colorants. Similarly, a similar type of solid phase composition,
It may be used as an excipient in soft and hard shell gelatin capsules using excipients such as lactose or lactose as well as high molecular weight polyethylene glycols.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may include binders (eg gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrating agents (eg sodium starch glycolate or crosslinked sodium carboxymethylcellulose), It can be prepared by using a surfactant or a dispersant. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Embodiments of tablets and other solid dosage forms of pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, include enteric coatings and other coatings known in the pharmaceutical industry. It can be optionally made or prepared with coatings and skins such as. Hydroxypropyl methylcellulose, in various proportions, to provide a slow or controlled release of the components contained therein, eg, to provide the desired release characteristics, other polymeric matrices, liposomes and / or microspheres. May be used to prepare these solid dosage forms. These are, for example:
It may be prepared for rapid release such as lyophilization. These tablets may be for example filtered through a bacterial retention filter, or in the form of a sterile solid phase composition which is soluble in sterile water or some other sterile injectable medium, mixed with a sterilant shortly before use. Can be sterilized by These compositions may also optionally contain opacifiers and may contain only or preferentially the active ingredient in any part of the gastrointestinal tract, optionally in such a manner as to delay them. It may be a composition that releases the components. Examples of embedding compositions which can be used are polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid phase 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, liquid phase dosage forms include, for example, water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, as commonly used by those skilled in the art. , Ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene Glycol, fatty acid esters of sorbitan and mixtures thereof.

In addition to inert diluents, oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preserving agents.

In addition to the active compounds, suspending agents are, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar. And tragacanth gum, and mixtures thereof.

Formulations of the pharmaceutical composition according to the invention for rectal or vaginal administration may suitably comprise one or more compounds according to the invention, eg cocoa butter, polyethylene glycol, suppository waxes or salicylates. It can be prepared by mixing with one or more non-irritating excipients or carriers, and is a solid phase at room temperature but a liquid phase at body temperature and thus a solution in the rectal or vaginal cavity. The active compound can be released.

Formulations of the present invention suitable for vaginal administration include pessaries, tampons, creams, gels, lotions, ointments, containing carriers as are known in the art to be appropriate.
Includes foam or spray formulations.

Dosage forms for systemic or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solvents, patches and inhalants. The active compound is sterile and, if necessary, a pharmaceutically acceptable carrier and preservative,
It may be mixed with a buffer or propellant.

In addition to the active compounds of the present invention, ointments, creams and gels have excipients such as animal and vegetable fats, oils, silicic acid, talc and zinc oxide, or mixtures thereof.

In addition to the compounds of the present invention, powders and sprays include excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Other common propellants are included in the propellant, for example, chlorofluorohydrocarbon and volatile non-substituted hydroxides such as butane and propane.

Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the human body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption synergists can likewise be used to enhance the flux of the compound across the skin. Such outflow can be controlled by either providing a quantity control membrane or by dispersing the compound in a polymer matrix or gel.

[0377]   Ophthalmic formulations, eye ointments, powders, solvents and the like are also considered to be within the scope of this invention.

Pharmaceutical compositions of the present invention suitable for parenteral administration include one or more pharmaceutically acceptable sterile and isotonic aqueous or non-aqueous solvents, dispersions, suspensions. Or an emulsion or a sterile powder, which can be reconstituted in a sterile injectable solvent or dispersion immediately before use, according to one or more of the present invention. Consisting of a compound and contained in these solvents or dispersants, sugars, alcohols, antioxidants, buffers, which make the formulation isotonic with the blood or anti-sedimentation agent or concentrate of the intended recipient There are drugs, bacteriostats, and solutes.

Suitable aqueous or non-aqueous carriers that can be used in the pharmaceutically acceptable compositions according to the present invention include water, ethanol, polyhydric alcohols such as glycerol, propylene glycol, polyethylene glycol and the like. Suitable mixtures are vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. To maintain proper fluidity, for example, a coating substance such as lecithin may be used, in the case of a dispersant, a required particle size may be maintained, or a surfactant may be used.

These compositions may contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. To prevent microorganisms from reacting to the compound of interest, for example,
It can be reliably prevented by containing various antibacterial and antifungal agents such as paraoxybenzoic acid esters, acetone chloroform, phenol sorbate and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride into these compositions. Alternatively, injectable pharmaceutical dosage forms may contain sustained absorption agents such as aluminum monostearate and gelatin to provide sustained absorption.

In some cases, it is desirable to delay absorption of the drug by subcutaneous or intravenous injection in order to prolong the effect of the drug. This can be achieved by using suspensions of crystalline or amorphous material with poor solubility in water. In that case, the absorption rate of the drug is
It depends on its dissolution rate, which depends on the size and shape of the crystals. Alternatively, in the form of a parenterally administered drug, delayed absorption is accomplished by dissolving or suspending the drug in olive oil vehicle.

Injectable depot forms are prepared by forming a microencapsulated matrix of the compound of interest in a biodegradable polymer such as the compound of polylactide and polyglycol (original: polylactide-polyglycolide). Is prepared. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations can be prepared by entrapping the drug in liposomes or microemulsions that are compatible with human tissues.

When the compound of the present invention is administered as a drug to humans and animals, it may be administered per se or, for example, from 0.1 to 99.5 in combination with a pharmaceutically acceptable carrier.
Pharmaceutical compositions containing 100% (more preferably 0.5-90%) of the active ingredient can be administered.

The preparations according to the invention can be administered orally, parenterally, topically or rectally. Of course, these are administered in the form appropriate for each route of administration. These administration methods include, for example, in the form of tablets or capsules, injections, inhalants, eye drops, ointments, suppositories, etc., administration by infusion or inhalation, lotion,
There are topical administration by application and rectal administration by suppository. Oral administration is preferred.

The terms “parenteral administration” and “administered parenterally” as used herein refer to
Refers to modes of administration other than enteric and rectal administration (usually by injection). For administration by injection, vein, muscle, artery, subarachnoid, intracapsular, orbit, heart, intracutaneous, peritoneal, transtracheal, subcutaneous, Subepidermal, joint, subcapsular, subarachnoid, intrathecal, intrasternal injections and infusions include, but are not limited to.

The terms “systemic administration”, “administered systemically”, “limbic administration” and “limbally administered” as used herein, enter the whole body of a patient and thus, for example, , Administration of compounds, drugs or other substances other than direct administration into the central nervous system that is affected by metabolism and similar processes such as subcutaneous administration.

These compounds may be administered by any suitable route of administration, eg buccal and sublingual, orally, nasally (eg by spray), rectally, vaginally, parenterally, intravesically, It may be administered to humans and other animals therapeutically, such as topically (as in powders, ointments or drops).

Regardless of the route of administration chosen, the compounds of the present invention can be used in their appropriately hydrated form, although the compounds of the present invention and / or the pharmaceutical compositions of the present invention can be used by those skilled in the art. It is prepared into a pharmaceutically acceptable dosage form by known conventional methods.

The actual dosage of the active ingredient in the pharmaceutical composition according to the present invention is not toxic to the patient, which ensures the amount of the active ingredient that effectively achieves the desired therapeutic response for the individual patient. As such, there may be various levels.

The dose level selected will depend on a variety of factors, including: These include the activity of the individual compound of the present invention to be applied (that is, ester, salt or amide thereof, etc.), route of administration, time of administration, excretion or metabolic rate of the specific compound applied, duration of treatment. , Other drugs, compounds and / or substances used in combination with the individual application compound, the age, sex, weight, condition, general health and medical history of the patient to be treated, and as is well known in the medical arts. There are factors.

A physician or veterinarian having ordinary skill in the art can easily determine and prescribe the effective amount of the pharmaceutical composition. For example, a physician or veterinarian may apply a compound of the present invention in a pharmaceutical composition from a level below the dosage required to achieve the desired therapeutic effect, until the desired effect is achieved. The dose may be titrated.

Generally speaking, a suitable daily dose of a compound according to the invention will be that which produces the lowest therapeutic effect. Such an effective dose generally depends on the factors mentioned above. Generally speaking, the indicated analgesic effect indica
When used for ted analgesic effects, the intravenous, intracerebroventricular intracerebroventricular and subcutaneous doses of the compounds according to the invention for patients will be in the range of about 0.0001 to about 100 mg per kilogram of body weight per day.

If desired, an effective daily dose of the active compound will be in unit dosage form at 2,3,4,5,6 doses at appropriate intervals throughout the day. , And smaller doses may be administered separately.

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 the treatment of one or more compounds according to the present invention formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents. There is provided a pharmaceutically acceptable composition comprising an effective amount. As described in detail below, the pharmaceutical compositions of the present invention may be specifically formulated for administration in a solid or liquid phase aspect, including modes of administration made as follows. That is, (1) oral administration, for example, tablets, boluses, powders, granules for ingestion (aqueous or non-aqueous solvent or suspension), buccal agent, sublingual agent, and systemic absorption, Glue for application to the tongue, (2) parenteral administration, eg subcutaneously as a sterile solvent or suspension,
Intramuscular, intravenous or epidural injection, or sustained release formulations, (3) topical application, eg emulsions, ointments or sprays applied to the skin, lungs or buccal cavity, (4) intravaginal or intrarectal,
For example, pessari, cream or foam, (5) sublingual (6) eye drops, (7) transdermal or (8) nasal side.

The compounds according to the invention may be formulated for administration in humans or veterinary medicine in any convenient manner, like other pharmaceutical agents.

The term “treatment” is intended to include prevention, treatment and cure.

Patients receiving such treatment include primates, especially humans, and mammals such as horses, cows, pigs and sheep, and broadly any animal in need of treatment, including poultry and pets. Is.

The compounds of the present invention can be administered per se or in admixture with a pharmaceutically acceptable carrier and are also combined with antibacterial agents such as, for example, penicillins, cephalosporins and glycopeptides. Can also be administered. Thus, conjoint therapy includes such modes as sequential, simultaneous and separate administration of the active compounds, such that the next is administered while the therapeutic effect of the first administered compound has not completely expired.

To add the active compounds of the present invention to animal feed, a pre-mix with a suitable feed containing an effective amount of the active compound is prepared and the mixture is mixed to form a complete feed. preferable.

Alternatively, an intermediate concentrate or bait supplement containing the active compound may be incorporated into the bait. Methods for preparing and administering premixes and complete diets with such diets are described in references (eg, "Applied Animal Nutrition" WH Freedman and CO., S
an Francisco, USA, 1969, or "Livestock Feeding and Feeding" O and B books, Corvall
is, Ore., USA, 1977)

Combinatorial Libraries The reaction methods described herein facilitate the creation of combinatorial libraries of compounds for screening for pharmaceutical, agrochemical or other biological or medically relevant activity or substance related properties. To be done. A combinatorial library for the purposes of the present invention is a mixture of chemically related compounds that can be screened for the presence or absence of desired properties, said library either existing in solvent form or in solid form. It may be covalently bound to the phase support. Preparing a large number of related compounds in a single reaction significantly reduces and simplifies the numerous steps of screening that must be performed. Screening for the proper biological, pharmaceutical or physical properties can be performed by conventional methods.

Diversity in a library can be created at a variety of different levels. For example, the aryl groups of the substrate used in the combinatorial method can vary in terms of the core aryl moiety, eg, variegated ring structures, and / or can vary with respect to other substituents.

Various techniques are available to those of skill in the art for generating combinatorial libraries of small organic molecules (see, eg, Trends Anal. Chem . 14:83; Affymax US Pat. No. 5,359,115). And 5,362,899, Ellman U.S. Patent No. 5,288,514, Still et al. PCT Publication No. WO 94/08051, C.
hen et al. (1994) JACS 116: 2661: Kerr et al. (1993) JACS 115: 252, PCT.
Publication Nos. WO92 / 10092, WO93 / 09668 and WO91 / 0708
7 and Lerner et al. PCT Publication No. WO 93/20242). Therefore, about 16 to 1,000,000 or more "Diversoma" ™ (original:
Diversity libraries on the order of diversomers) can be synthesized and screened for individual activities or properties.

In one exemplary embodiment, a library of substituted “diversoma” ™ is used using the reaction method described herein adapted to the technique described in Still et al PCT Publication No. WO 94/08051. , Can be linked to polymer beads using, for example, a hydrolyzable or photolyzable group and placed, for example, at one substrate position for synthesis. According to Still et al's technique, this library is synthesized on a set of beads, each bead being equipped with a set of labels that identify a particular "diversoma" on that bead. In one embodiment, which is particularly suitable for discovering enzyme inhibitors, these beads can be dispersed on the surface of a dialysis membrane, and "diversoma" is derived from these beads by dissolution of the bead linker. To be separated. Separated from each bead, the "Diversoma" ™ diffuses through the dialysis membrane into the assay zone where it interacts with the enzyme assay. A detailed description of a number of combinatorial methods follows.

A) Direct Characterization A trend that has become prominent in the field of combinatorial chemistry is to develop sensitivities of techniques such as mass spectrometry (MS), which, for example, are It can be used to characterize the amount of femtomolar (sub-femtomolar) and can be used to directly measure the chemical composition of selected compounds from a combinatorial library. For example, if the library is provided on an insoluble support matrix, discrete groups of compounds are first cleaved from this support and characterized by mass spectrometry. In another example, matrix-assisted laser desorption / ionization (
Mass spectrometric techniques such as MALDI) can be used to dissociate the compound from the matrix, especially in this method a labile bond is used from the beginning to bind the compound to the matrix. For example, beads selected from a library can be exposed to radiation in a matrix-assisted laser desorption / ionization (MALDI) step to detach the synthetic compound from the matrix and to ionize the synthetic compound for analysis by mass spectrometry. It can be irradiated.

B) Multi-Pin Synthesis The library of the methods described here can adopt the multi-pin library format. Briefly, Geysen and his colleagues (Geysen e
al. (1984) PNAS 81: 3998-4002) is a polyacrylic acid-grated array arranged in a microtiter plate format.
A method of preparing compounds has been introduced by parallel synthesis on polyethylene pins. Geisen's technique can be used to synthesize and screen thousands of compounds per week using this multi-pin method. The appropriate linker moieties are also attached to the pins and these compounds can be cleaved from the support after synthesis for purity evaluation and other measurements (see: 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) Split-Link-Recombinant Method In yet another example, a variegated library of compounds can be provided on a set of beads using a split-bond-recombinant strategy (see : For example, Houg
hten (1985) PNAS 82: 5131-5135; and US Pat. No. 4,631,211, 440.
, 0126, 5,480, 971). Briefly, as the name suggests, at each synthetic step where degeneracy is introduced into the library, these beads are loaded with various substituents added at specific positions in the library. , The various substituents are combined in separate reactions, and the beads are recombined into one pool for subsequent replication.

In one example, this split-join-recombination strategy is based on the Houg (Houg
It can be carried out using a method similar to the so-called “tea bag” method originally developed by Hten), the synthesis of the compound taking place on an inner resin-sealed porous polypropylene bag (Houghten et al. 1986) PNAS 82: 5131-5135). Substituents are attached to the compound-bearing resin by placing these bags in the proper reaction solvent, but such resin washing and deprotection are performed simultaneously in one reaction vessel. At the end of this synthesis, each bag will contain a single compound.

D) Combinatorial Library by Photoinduced Spatial Addressable Parallel Chemical Synthesis The scheme of combinatorial synthesis in which the identity of a compound is given by its position on the synthetic substrate is termed stereo-addressed synthesis. In one example, the combinatorial step is performed by controlling the addition of chemical reagents to specific locations on the solid support (Dower et al. (1991) Annu Rep Med Chem 26). : 271-280; Fodor, SPA (1991) Science 251: 767; Pirrung et al. (19
. 92) U.S. Pat. No. 5,143,854; Jacobs et al (1994) Trends Biotechn ol 12: 19-26). It can be miniaturized by the stereoscopic resolution of photolithography. Such techniques can be performed utilizing a protection / deprotection reaction with a photolabile protecting group.

Important points of this technique are shown in Gallop et al (1994) J Med Chem 37: 1233-1251. The synthetic substrate is a photosensitive nitroveratryloxycarbonyl nitroveratry.
It is prepared by covalent attachment of an amino linker or other photolabile linker protected by loxycarbonyl (NVOC). Light is used to selectively activate certain areas of the synthetic support for binding. Cleavage of the photolabile protecting group by light (deprotection) results in activation of selected areas. After activation, the first of a set of amino acid analogs, each carrying one photolabile protecting group on its amino terminus, is exposed to its entire surface. Coupling occurs only once in the region addressed by light in the previous step. The reaction is stopped, the plate is washed, and the substrate is again illuminated through the second mask, activating another area for reaction with the second protective building block. The pattern of masks and the array of reactants define the products and their locations. Since such a process utilizes photolithographic techniques, the number of compounds that can be synthesized is limited by the number of synthetic sites that can be addressed with the proper resolution. Since the position of each compound is precisely known, the interaction between the compound and other molecules can be evaluated directly.

In photoinduced chemical synthesis, the product depends on the pattern of illumination and the order of addition of the reactants. By varying the pattern of photolithography, many different combinations of test compounds can be synthesized simultaneously, and such features create many different masking strategies.

E) Combinatorial Library Encoding In yet another embodiment, the methods described herein utilize a compound library that includes an encoded labeling system. Recently improved methods for identifying active compounds from combinatorial libraries use the reaction steps that a given bead undergoes, the inferred structure carried by that bead, and a uniquely encoding label. Uses a chemical index system. Conceptually, such a method would mimic a phage display library,
In such libraries, the activity is derived from the expressed peptide, but the structure of this active peptide is deduced from its corresponding genomic DNA (deoxyribonucleic acid) sequence. Initially, DNA was used as a code for coding a synthetic combinatorial library. A variety of other encodings, including encoding with contiguous bio-oligomers (eg, oligonucleotides and peptides), and binary encoding with additional and different contiguous labels. Has been reported.

1) Labeling with Sequenceable Bio-Oligomers The principle of encoding combinatorial synthetic libraries with oligonucleotides was described in 1992 (Brenner et al. (1992) PNAS 89: 5381- Five
383), and the following year, examples of such libraries were published (Needles et al.
(1993) PNAS 90: 10700-10704). Arg (Arginine), Gln (Glutamine)
, Phe (phenylalanine), Lys (lysine), Val (valine), DV
It consists of all combinations of al (D-valine) and Thr (threonine) (three-letter amino acid code), which are specific dinucleotides (TA, TC, C respectively).
A combinatorial library of usually 7 ⁷ (= 823,543) peptides, each encoded by T, AT, TT, CA and AC), is a set of peptides and oligonucleotides on a solid support. Prepared by synthetic alternating circulation. In this work, the beads or peptides were simultaneously pre-incubated with a reagent that produces a protected OH group for oligonucleotide synthesis and a protected NH ₂ group for peptide synthesis (here in a ratio of 1 to 20), thereby allowing , The amino-bonding functionality on the beads was specifically differentiated.
Once prepared, each label consisted of 69-mers, 14 units of which were coded. The bead-bound library is incubated with fluorescently labeled antibodies, and the beads containing the strongly fluorescent bound antibodies are
Harvested by fluorescence activated cell sorting (FACS). The DNA label was expanded by polymerase chain reaction (PCR), sequenced, and peptides were synthesized as expected. Following such a technique, the compound can be derivatized for use in the methods described herein, wherein the nucleotide sequence of the label identifies the set of combinatorial reactions that a particular bead undergoes, thus The compound on the bead is identified.

The use of oligonucleotide labels allows for significantly sensitive label analysis. However, this method requires careful selection of the orthogonal protecting group combinations required to alternately co-synthesize the label and library constructs. In addition, the chemical reliability of the label (especially phosphate and sugar anomeric linkages) can place constraints on the reagents and conditions used to synthesize non-oligonucleotide libraries. In a preferred embodiment, the library uses a linker that can selectively cleave the test compound library construct for the assay.

Peptides have also been used as labeling molecules for combinatorial libraries. Two typical methods have been described in the field of the present invention, both of which employ a solid-phase branched linker on which the coding and ligand strands are alternately synthesized. In the first method (Kerr JM et al. (1993) J Am Chem Soc 115: 2529-2531), orthogonality in the synthesis uses acid labile protection on the coding strand and base labile protection on the compound strand. To be achieved.

In one alternative method (Nikolaiev et al. (1993) Pept Res 6: 161-170), both the coding unit and the test compound were separated such that they were attached to the same functional group on the resin. A branch linker is used. In one example, a cleavable linker is placed between the branch point and the bead, which can cleave the molecule containing both the code and the compound (Ptek et al. (1991) Tetrahedr ). on Lett 32: 3891-3894). In another example, the cleavable linker can be positioned so that the test compound is selectively separated from the beads, leaving the code behind. This last listed configuration is particularly valuable. Because in that configuration, test compounds can be screened without potential interference by the encoding group. In the example of the technique according to the invention in which the cleavage of the peptide library constructs and their corresponding labels and the sequence are carried out separately, the labels allow an accurate prediction of the structure of the peptides.

2) Nonsequenceable Labeling: Binary Encoding One alternative form of encoding a test compound library uses a set of labeled molecules with nonsequenceable electronic properties used as binary code (Ohlm
eyer et al. (1993) PNAS 90: 10922-10926). A typical label is a halogen aromatic alkyl ether, which, as trimethylsilyl ether, is detectable by electron capture gas chromatography (ECGC) at levels below femtomolar. Due to the nature and position of the aromatic halide substituents, as well as the diversity of alkyl chain lengths, at least 40 such labels can be synthesized, in principle 2 ⁴⁰ (eg from 10 ¹² Can encode many) different molecules. In the first report (Ohlmeyer et al., Supra), these labels were attached by photocleavable o-nitrobenzyl linkers to approximately 1% of the available amino groups of the peptide library. This method is convenient when preparing a combinatorial library of peptide-like or amino-containing molecules. However, more versatile systems have been developed that are basically capable of encoding arbitrary combinatorial libraries. Here, the compound was attached to the solid support via a photocleavable linker, whereas the label was attached via a catechol ether linker by inserting a carbene into the bead matrix (Nestler et al. al. (1994) J Org Chem 59: 4723-4724). Such an orthogonal attachment strategy allows for the selective cleavage of library constructs for solvent assays, followed by oxidative cleavage of the set of labels prior to encoding by ECGC.

Although some amide bond libraries in the field of the present invention use binary encoding with labels having electronic properties attached to amino groups, by attaching these labels directly to the bead matrix, , Provide much greater diversity in the structures that can be prepared in coded combinatorial libraries. When so attached, these labels and their linkers are almost unreactive, as are the bead matrices themselves. Two binary coded combinatorial libraries have been reported (Ohlmeyer et al.
(1995) PNAS 92: 6027-6031), in which a label with electronic properties is attached directly to a solid phase, providing guidance for generating a library of test compounds. Both libraries were constructed using an orthogonal attachment strategy, the library constructs were attached to a solid support by a photolabile linker, and the label was attached via a linker cleavable only by vigorous oxidation. The library construct can be utilized in multiple assays because the library construct can be repeatedly partially photoextracted from the solid support. Sequential light extraction allows for a much higher throughput iterative screening strategy as well. First, 9 beads
Placed in a 6-well microtiter plate, secondly, compounds are partially dissociated and transferred to the assay plate, thirdly, metal binding assay identifies active wells, and fourth, corresponding The beads are rearranged one by one into a new microtiter plate, fifthly only the active compounds are identified and sixthly their structure is deciphered.

Exemplary Embodiments Having generally described the invention, it should be understood more readily by reference to the following examples, which are intended to illustrate certain aspects and practice of the invention. The examples are provided solely for the purpose of illustration and are not intended to limit the invention.

[0421] Example 1 Synthesis of N-Boc-3-piperidinemethanol (2)

[0422]

[Chemical 19]

[0423] 30mL of THF and 30mL of in _{H 2} O of 3-piperidinemethanol (1) (
A solution of 15.20 g, 0.132 Mol) was chilled in an ice water bath to remove NEt ₃ (20
(mL) was added with stirring. Di-t-butyl-dicarbonate (34.56 g,
(1.2 eq) was introduced while stirring and cooling continued. The mixtures were warmed to room temperature and left stirring overnight. 100 mL ethyl acetate and 20 mL H ₂ O
Was added to the mixture. The aqueous layer was extracted with ethyl acetate (2 x 100 mL). Combine the extracts and wash with aqueous potassium carbonate (saturated, 2 × 50 mL), aqueous HCl (5%, 2 × 50 mL), brine (50 mL), dry over anhydrous sodium sulfate, filter and evaporate. It was 28.5 g (100%) of colorless oil
. TCL _Rf = 0.21 (ethyl acetate / hexane, 1: 2).

[0424] Example 2 Synthesis of N-Boc-piperidin-3-yl-formaldehyde (3)

[0425]

[Chemical 20]

Pyridinium Chromate Chromate (original: chloro) in 200 mL of dry CH ₂ Cl ₂
chromate) (98%, 34.0 g, 0.155 Mol) and Celite (24 g
To a stirred suspension of), N-Boc-3- piperidinemethanol (2 in _CH 2 Cl ₂ in 30 mL) (22.15 g, added 0.103 mol) in one portion, the mixture overnight at room temperature It was stirred. The mixture was filtered through a funnel filled with 20 g Celite. After removing the solvent, the remaining oily residue was purified by flash column (silica gel, hexane: ethyl acetate (4: 1)) to give 17.5 g colorless oil (80%). As 3.

Example 3 Synthesis of N- (1-Boc-piperidin-3-ylmethyl) -aniline (4)

[0428]

[Chemical 21]

N-Boc-3-piperidin-3-yl-formaldehyde 3 (5.20 g, 2 in 50 mL dry methanol and 50 mL trimethyl orthoformate).
Aniline (2.50 g, 1.1 eq) was added to the (4.4 mmol) solution and the mixture was stirred at room temperature for 30 minutes. _{NaBH 3 CN (95%, 1.84g} , 1.1
Eq.) Was introduced at once and the mixture was stirred at room temperature overnight. Mixture is 30m
Quenched with L potassium carbonate aqueous solution (saturated), then extracted with ethyl acetate (3 × 100 mL). The extracts were combined, washed with aqueous NaHCO ₃ (saturated, 2 × 50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was purified by flash column chromatography (silica gel, hexane: ethyl acetate (1: 1)) to give N- (1-Boc-3-piperidin-3-ylmethyl) -aniline. 4 was obtained as a white solid (5.60 g, 79%). IR (film, cm ^-1 ) 3
520, 3263, 3004, 2976, 2932, 2854, 1688, 15
89, 1521, 1482, 1422, 1365, 1267, 1243, 117
5, 1150, 794, 709; ¹ H NMR (CDCl ₃ , ppm) 7.20.
(T, 2H, J = 7.8Hz), 6.72 (t, 1H, J = 6.8Hz), 6.
63 (d, 2H, J = 8.3 Hz), 4.00-3.78 (m, 3H), 3.0
7-2.70 (m, 4H), 2.00-1.20 (m, 5H), 1.48 (s,
Overlap, 9H).

Example 4 Synthesis of N- (1-Boc-piperidin-3-ylmethyl) -N-phenyl-propionamide (5)

[0431]

[Chemical formula 22]

N- (1-Boc-piperidine-in dry methylene chloride in 25 mL methylene chloride
3-ylmethyl) -aniline 4 (4.60 g, 15.8 mmol) and N, N-
To a solution of diisopropylethylamine (1.40 mL, 15.8 mmol), propionyl chloride (1.40 mL, 15.8 mmol) was added dropwise at 0 ° C. After stirring overnight at room temperature, the reaction mixture was quenched with 30 mL H ₂ O,
Extracted with ethyl acetate (3 x 100 mL). The extracts were combined and aqueous HCl (5%, 20 mL), NaHCO ₃ (saturated, 2 × 30 mL), brine (50
(mL) and dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was purified by flash column chromatography (silica gel, hexane: ethyl acetate) to give N- (1-Boc-piperidin-3-ylmethyl).
-N-Propionamide 5 was obtained as a colorless oil (4.50 g, 82%).
IR (film, cm ^-1 ) 2975, 2934, 2854, 1690, 166
3,1591, 1496, 1422, 1402, 1365, 1265, 1242
, 1176, 1149, 1038, 962, 775, 702; ¹ H NMR (C
_{DCl 3, ppm) 7.44-7.22 (m} , 5H), 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, 5H), 1.48 (s, overlap, 9
H), 1.06 (t, 3H, J = 7.5 Hz).

Example 5 Synthesis of N- (1-phenethyl-piperidin-3-ylmethyl) -N-phenyl-propionamide (6)

[0434]

[Chemical formula 23]

Trifluoroacetic acid (5 mL) was added to N- (1-Boc-piperidin-3-ylmethyl) -N-phenyl-propionamide 5 (1..1) in 5 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water). 21 g, 3.49 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removing the solvent, the residue was dried under vacuum for 3 hours. DM the crude compound
Dissolve in phenylacetaldehyde (5.3 mL, 2M
(5.3 mmol in ol / DMF) was added. The mixture was stirred at room temperature for 30 minutes. 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 (saturated) and then extracted with ethyl acetate (3 x 60 mL). The extracts were combined and aqueous NaHCO ₃ solution (saturated, 2 × 10 mL),
Wash with brine (50 mL) and dry over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was purified by flash column chromatography to give 6. IR (film, cm ⁻¹ ) 3060, 3026, 2934, 2
854, 2800, 2765, 1662, 1495, 1452, 1401, 12
62,1203,1150,1106,966,1033,775,749; L
RMS351.

Example 6 Synthesis of N- (1-benzyl-piperidin-3-ylmethyl) -N-phenyl-propionamide (7)

[0437]

[Chemical formula 24]

[0438]   Trifluoroacetic acid (0.5 mL) was added to 0.5 mL of dry CH at 0 ° C. (ice water)._Two Cl_TwoN- (1-Boc-piperidin-3-ylmethyl) -N-phenyl-in
Propionamide 5 (1.21 g, 3.49 mmol) was added dropwise to the solution.
. The reaction mixture was stirred at room temperature for 30 minutes. TLC shows that this reaction is complete.
Was shown. After removing the solvent, the residue was dried under vacuum for 3 hours. Roughening
The product was dissolved in DMF (0.5 mL) and benzaldehyde (13.6 μL, 1
． 5 equivalents) was added. The mixture was stirred at room temperature for 30 minutes. NaB (OAc) _Three H (95%, 28.45 mg, 1.5 eq) was introduced at once and the mixture was
Shake overnight at room temperature. Quench the mixture with 5 mL of aqueous potassium carbonate (saturated).
And then extracted with ethyl acetate (3 × 10 mL). Mix the extracts of
NaHCO_ThreeWash with aqueous solution (saturated, 2 x 5 mL), brine (10 mL),
Dried over sodium sulfate. After removing the solvent, the remaining oily residue was collected.
Purify by thin layer chromatography (EtOAc / MeOH, 9: 1) to give N-
(1-Benzyl-piperidin-3-ylmethyl) -N-phenyl-propiona
The amide 7 was obtained as a colorless oil (26.6 mg, 88%). LRMS337.

Example 7 N- [1- (thiophen-2-ylmethyl) -piperidin-3-ylmethyl]-
N-phenyl-propionamide (8)

[0440]

[Chemical 25]

Trifluoroacetic acid (0.5 mL) was added to N- (1-Boc-piperidin-3-ylmethyl) -N-phenyl- in 0.5 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water).
It was added dropwise to a solution of propionamide 5 (31 mg, 0.090 mmol). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removing the solvent, the residue was dried under vacuum for 3 hours. The crude compound was dissolved in DMF (0.5 mL) and 2-thiophenecarboxaldehyde (original: carboxaldehyde) (12.5 μL, 1.5 eq) was added. The mixture was stirred at room temperature for 30 minutes. NaB (OAc) ₃ H (95%, 28.45 mg,
(1.5 eq) was introduced at once and the mixture was shaken overnight at room temperature. The mixture is
Quench with 5 mL of aqueous potassium carbonate (saturated), then ethyl acetate (3 x
10 mL). The extracts were mixed and the aqueous NaHCO ₃ solution (saturated, 2
X 5 mL), washed with brine (10 mL) and dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was subjected to preparative thin layer chromatography (EtO).
Purified by Ac / MeOH, 9: 1) and N- [1- (thiophen-2-ylmethyl) -piperidin-3-ylmethyl] -N-phenyl-propionamide 8
Was obtained as a colorless oil (25.2 mg, 82%). LRMS343.

Example 8 Synthesis of (N- [1- (4-pyridinyl-N-oxidemethyl) -piperidin-3-ylmethyl] -N-phenyl-propionamide (9)

[0443]

[Chemical formula 26]

Trifluoroacetic acid (0.5 mL) was added to N- (1-Boc-piperidin-3-ylmethyl) -N-phenyl- in 0.5 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water).
It was added dropwise to a solution of propionamide 5 (31 mg, 0.090 mmol). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removing the solvent, the residue was dried under vacuum for 3 hours. The crude compound was dissolved in DMF (0.5 mL) and 4-pyridinecarboxaldehyde (original: pyridinecarboxaldehyde) N-oxide (17 mg, 1.5 eq) was added. The mixture was stirred at room temperature for 30 minutes. NaB (OAc) ₃ H (95%, 28
． 45 mg, 1.5 eq) was introduced at once and the mixture was shaken overnight at room temperature. The mixture was quenched with 5 mL of aqueous potassium carbonate (saturated) and then extracted with ethyl acetate (3 x 10 mL). These extracts were combined, NaHCO ₃ solution (saturated, 2 × 5mL), washed with brine (10 mL), dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc / MeOH, 9: 1) to give 9 as a colorless oil (1
8.7 mg, 59%). LRMS354.

Example 9 (N- [1- (4-methoxybenzyl) -piperidin-3-ylmethyl] -N-
Synthesis of phenyl-propionamide (10)

[0446]

[Chemical 27]

Trifluoroacetic acid (0.5 mL) was added to N- (1-Boc-piperidin-3-ylmethyl) -N-phenyl- in 0.5 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water).
It was added dropwise to a solution of propionamide 5 (31 mg, 0.090 mmol). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removing the solvent, the residue was dried under vacuum for 3 hours. The crude compound was dissolved in DMF (0.5 mL) to give 4-anisaldehyde (16.7 μL).
, 1.5 equivalents) was added. The mixture was stirred at room temperature for 30 minutes. NaB (OA
c) ₃ H (95%, 28.45 mg, 1.5 eq) was introduced in one portion and the mixture was shaken overnight at room temperature. The mixture was quenched with 5 mL of aqueous potassium carbonate (saturated) and then extracted with ethyl acetate (3 x 10 mL). These extracts were combined, NaHCO ₃ solution (saturated, 2 × 5mL), washed with brine (10 mL), dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc / MeOH, 9: 1) to give (N- [1- (4-methoxybenzyl) -piperidin-3-ylmethyl]]. -N
-Phenyl-propionamide (10) as a colorless oil (18.7 mg, 59%)
) As. LRMS366.

Example 10 Synthesis of N- [1- (1H-imidazol-2-ylmethyl) -piperidin-3-ylmethyl] -N-phenyl-propionamide (11)

[0449]

[Chemical 28]

Trifluoroacetic acid (0.5 mL) was added to N- (1-Boc-piperidin-3-ylmethyl) -N-phenyl- in 0.5 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water).
Propionamide 5 (21 mg, 0.061 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removing the solvent, the residue was dried under vacuum for 3 hours. The crude compound was dissolved in DMF (0.5 mL) and 2-imidazole carboxaldehyde (original term: imidazole carboxaldehyde) (8.7 g, 1.5 eq) was added. The mixture was stirred at room temperature for 30 minutes. NaB (OAc) ₃ H (95%, 20.3 m
g, 1.5 eq) was introduced at once and the mixture was shaken overnight at room temperature. The mixture was quenched with 5 mL of aqueous potassium carbonate (saturated), then ethyl acetate (
3 × 10 mL). These extracts were combined, NaHCO ₃ solution (saturated, 2 × 5mL), washed with brine (10 mL), dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was subjected to preparative thin layer chromatography (E
tOAc / MeOH, 9: 1) and N- [1- (1H-imidazol-2-ylmethyl) -piperidin-3-ylmethyl] -N-phenyl-propionamide (11) as a colorless oil ( 10.7 mg, 54%). LR
MS327.

Example 11 (N- [1- (pyridin-3-ylmethyl) -piperidin-3-ylmethyl]-
Synthesis of N-phenyl-propionamide (12)

[0452]

[Chemical 29]

Trifluoroacetic acid (0.5 mL) was added to N- (1-Boc-piperidin-3-ylmethyl) -N-phenyl- in 0.5 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water).
Propionamide 5 (21 mg, 0.061 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removing the solvent, the residue was dried under vacuum for 3 hours. The crude compound was dissolved in DMF (0.5 mL) to give 3-piperidinecarboxaldehyde (
8.7 μL, 1.5 eq) was added. The mixture was stirred at room temperature for 30 minutes. N
aB (OAc) ₃ H (95%, 20.3 mg, 1.5 eq) was introduced at once,
The mixture was shaken overnight at room temperature. The mixture was quenched with 5 mL of aqueous potassium carbonate (saturated) and then extracted with ethyl acetate (3 x 10 mL). The extracts were combined, aqueous NaHCO ₃ solution (saturated, 2 × 5 mL), brine (10 mL
), And dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc / MeOH, 9: 1) to give (N- [1- (pyridin-3-ylmethyl) -piperidin-3-ylmethyl). ] -N-Phenyl-propionamide 12 was added as a colorless oil (15.6 mg
, 76%). LRMS338.

Example 12 Furan-2-carboxylic acid N- (1-Boc-piperidin-3-ylmethyl) -N
-Synthesis of phenylamide (13)

[0455]

[Chemical 30]

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 ₂ Cl ₂ . To the stirred suspension, room temperature 2-furoyl (original:
furoyl) chloride (95%, 35.1 mg, 1.2 eq) was added. After shaking the mixture at room temperature for 4 hours, the reaction mixture was passed through an aminopropyl NH ₂ cartridge and washed with CH ₂ Cl ₂ . CH ₂ Cl ₂ was removed to give furan-2-
Carboxylic acid N- (1-Boc-piperidin-3-ylmethyl) -N-phenylamide 13 (75 g, 93%) was obtained. LRMS285 (M-100) ^<+> .

Example 13 Furan-2-carboxylic acid N- (1-phenethylpiperidin-3-ylmethyl)-
Synthesis of N-phenylamide (14)

[0458]

[Chemical 31]

Trifluoroacetic acid (0.5 mL) was added to furan-2-carboxylate N- (1-Boc-piperidin-3-ylmethyl)-in 0.5 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water). It was added dropwise to a solution of N-phenylamide 13 (46 mg, 0.12 mmol). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removing the solvent, the residue was dried under vacuum for 3 hours (LRMS285). The crude compound was dissolved in DMF (0.5 mL) and phenylacetaldehyde (150 μL, in 2Mol / DMF) was added. The mixture was stirred at room temperature for 30 minutes. NaB (OAc) ₃ H (95%, 55 mg, 2
Equal volume) was introduced at once and the mixture was shaken overnight at room temperature. The mixture is 5 mL
Quenched with aqueous potassium carbonate solution (saturated), then ethyl acetate (3 x 10 m
L). These extracts were mixed and the NaHCO ₃ aqueous solution (saturated, 2 × 5 m
L), washed with brine (10 mL) and dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was subjected to preparative thin layer chromatography (EtOAc /
Purification with MeOH, 9: 1) furan-2-carboxylic acid N- (1-phenethylpiperidin-3-ylmethyl) -N-phenylamide 14 as a colorless oil (
20.3 mg, 44%). LRMS389.

Example 14 N- (1-Boc-piperidin-3-ylmethyl) thiophene-2-carboxylic acid
Synthesis of -N-phenylamide (15)

[0461]

[Chemical 32]

N- (1-Boc-piperidin-3-ylmethyl) -N-aniline 4 (60.9 g, 0.21 mmol) and piperidinomethyl polystyrene resin (60 mg) in 0.6 mL of dry CH ₂ Cl _2. ) To a stirred suspension of room temperature 2-thiophenecarbonyl chloride (97%, 39.2 mg, 1).
． 2 equivalents) was added. The reaction mixture was stirred for 4 hours at room temperature then passed through an aminopropyl NH ₂ cartridge and washed with CH ₂ Cl ₂ . CH ₂ Cl ₂ was removed to give thiophene-2-carboxylic acid N- (1-Boc-piperidin-3-ylmethyl) -N-phenylamide 15 (82.1 g, 98%). LRMS30
0 (M-100) ⁺ .

Example 15 Synthesis of thiophene-2-carboxylic acid N- (1-phenethylpiperidin-3-ylmethyl) -N-phenylamide (16)

[0464]

[Chemical 33]

Trifluoroacetic acid (0.5 mL) was added to N- (1-Boc-piperidin-3-ylmethyl) -N-phenylamide 15 (in 0.5 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water). 46.7 mg, 0.12 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removing the solvent, the residue was dried under vacuum for 3 hours (LRMS301).
). The crude compound was dissolved in DMF (0.5 mL) and phenylacetaldehyde (150 μL, in 2Mol / DMF) was added. The mixture was stirred at room temperature for 30 minutes. NaB (OAc) ₃ H (95%, 55 mg, 2 eq) was introduced in one portion and the mixture was shaken overnight at room temperature. The mixture was quenched with 5 mL of aqueous potassium carbonate (saturated) and then extracted with ethyl acetate (3 x 10 mL). The extracts were combined and aqueous NaHCO ₃ solution (saturated, 2 × 5 mL), brine (1
(0 mL) and dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was subjected to preparative thin layer chromatography (EtOAc / MeOH, 9: 1).
The thiophene-2-carboxylic acid N- (1-phenethylpiperidin-3-ylmethyl) -N-phenylamide 16 was purified as an oil (25.2 mg, 53%).
) As. LRMS405.

Example 16 Synthesis of N- (1-Boc-piperidin-3-ylmethyl) -N- (pyridin-3-yl) amine (17)

[0467]

[Chemical 34]

N- in 3 mL dry methanol and 3 mL trimethyl orthoformate
Boc-3-piperidin-3-yl-formaldehyde 3 (0.89 g, 4.1
To the 6 mmol) solution, 3-aminopyridine (0.39 g, 1 eq) was added and the mixture was stirred at room temperature for 1.5 hours. _{NaBH 3 CN (95%, 0.29g} , 1.
(05 eq.) Was introduced at once and the mixture was stirred overnight at room temperature. The mixture is 1
Quench with 0 mL of aqueous potassium carbonate (saturated), then ethyl acetate (3 x
3 mL). These extracts were mixed to form an aqueous NaHCO ₃ solution (saturated, 2
X 10 mL), washed with brine (20 mL), and dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was purified by flash column chromatography (silica gel, hexane / ethyl acetate) to give N- (1-Boc-
Piperidin-3-ylmethyl) -N- (pyridin-3-yl) amine 17 was obtained as a white solid (0.91 g, 75%). LRMS292.

Example 17 Synthesis of N- (1-Boc-piperidin-3-ylmethyl) -N- (pyridin-3-yl) propionamide (18)

[0470]

[Chemical 35]

[0471]   1 mL of dry CH_TwoCl_TwoN- (1-Boc-piperidin-3-ylmethyi in
Ru) -N- (pyridin-3-yl) amine 17 (10 m0 g, 0.34 mmol
) And piperidinomethyl polystyrene resin (100 mg) in a solution at room temperature.
Pionyl chloride (30 μL, 1 eq) was added. The mixture was stirred overnight at room temperature.
After stirring, the reaction mixture was treated with aminopropyl NH._TwoCH through the cartridge _Two Cl_TwoWashed with. CH_TwoCl_TwoTo remove N- (1-Boc-piperidine
-3-ylmethyl) -N- (pyridin-3-yl) propionamide 18 (85
mg, 71%). LRMS248 (M-100)⁺.

Example 18 N- (1-phenethyl-piperidin-3-ylmethyl) -N- (pyridin-3-
Synthesis of yl) propionamide (19)

[0473]

[Chemical 36]

Trifluoroacetic acid (0.5 mL) was added to N- (1-Boc-piperidin-3-ylmethyl) -N- (pyridin-3) in 0.5 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water). -Yl) propionamide 18 (42.5 mg, 0.12 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 30 minutes. After removing the solvent, the residue was dried under vacuum for 3 hours (LRMS 248). DM the crude compound
Dissolve in phenylacetaldehyde (122 μL, 2M, dissolved in F (0.5 mL).
in ol / DMF) was added. The mixture was stirred at room temperature for 30 minutes. NaB
(OAc) ₃ H (95%, 58 mg, 2 eq) was introduced in one portion and the mixture was shaken overnight at room temperature. The mixture was quenched with 5 mL of aqueous potassium carbonate (saturated) and then extracted with ethyl acetate (3 x 10 mL). Combine the extracts and wash with aqueous NaHCO ₃ (saturated, 2 × 5 mL), brine (10 mL),
It was dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc / MeOH, 9: 1) to give N
-(1-Phenethyl-piperidin-3-ylmethyl) -N- (pyridin-3-yl) propionamide 19 was obtained as an oil (9.2 mg, 28%). IR (
Film, cm ⁻¹ ) 3026, 2933, 2852, 2794, 2765, ¹
666, 1479, 1421, 1396, 1261, 1237, 1214, 11
88, 1159, 1114, 1078, 1026, 749, 719. LRMS3
52.

Example 19 Furan-2-carboxylic acid N- (1-Boc-piperidin-3-ylmethyl) -N
Synthesis of-(pyridin-3-yl) amide (20)

[0476]

[Chemical 37]

N- (1-Boc-piperidin-3-ylmethyl) -N- (pyridin-3-yl) amine 17 (99 mg, 0.34 mmol) in 1 mL of dry CH ₂ Cl _2.
To a solution of and piperidinomethyl polystyrene resin (100 mg) was added 2-furoyl chloride (95%, 56.0 mg, 1.2 eq) at room temperature. After stirring the mixture overnight at room temperature, the reaction mixture was passed through an aminopropyl NH ₂ cartridge and washed with CH ₂ Cl ₂ . CH ₂ Cl ₂ was removed to furan-2-carboxylic acid N- (1-Boc-piperidin-3-ylmethyl) -N- (pyridine-
3-yl) amide 20 (80 mg, 61%) was obtained. LRMS286 (M-10
0) ⁺ .

Example 20 Furan-2-carboxylic acid N- (1-phenethyl-piperidin-3-ylmethyl)
Synthesis of -N- (pyridin-3-yl) amide (21)

[0479]

[Chemical 38]

Trifluoroacetic acid (0.5 mL) was added to furan-2-carboxylate N- (1-Boc-piperidin-3-ylmethyl)-in 0.5 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water). N- (pyridin-3-yl) amide 20 (37 mg, 0.096 mmo
It was added dropwise to the solution of l). The reaction mixture was stirred at room temperature for 30 minutes. After removing the solvent, the residue was dried under vacuum for 3 hours (LRMS286). The crude compound was dissolved in DMF (0.5 mL) and phenylacetaldehyde (95 μm) was added.
L, in 2Mol / DMF) was added. The mixture was stirred at room temperature for 30 minutes. NaB (OAc) ₃ H (95%, 45 mg, 2 eq) was introduced in one portion and the mixture was shaken overnight at room temperature. The mixture is 5 mL of potassium carbonate aqueous solution (saturated)
Quenched with and then extracted with ethyl acetate (3 x 10 mL). These extracts were combined, NaHCO ₃ solution (saturated, 2 × 5mL), washed with brine (10 mL), dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc / MeOH, 9: 1) to furan-2-carboxylate N- (1-phenethyl-piperidin-3-ylmethyl). The -N- (pyridin-3-yl) amide 21 was converted into an oil (21.8 mg, 58).
%). IR (film, cm ⁻¹ ) 3024, 2932, 2854,
2801, 2767, 1647, 1574, 1478, 1424, 1397, 1
306, 1226, 1186, 1113, 1027, 1011, 752, 715
¹ H NMR (CDCl ₃ , ppm) 8.61 (d, 1 H), 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). LRMS390.

Example 21 Cyclopropanecarboxylic acid N- (1-Boc-piperidin-3-ylmethyl)-
N- (pyridin-3-yl) amide (22)

[0482]

[Chemical Formula 39]

N- (1-Boc-piperidin-3-ylmethyl) -N- (pyridin-3-yl) amine 17 (56 mg, 0.19 mmo in 0.6 mL dry CH ₂ Cl ₂
l) and piperidinomethyl polystyrene resin (3.5 mmol / g, 60 mg)
At room temperature, cyclopropane carbonyl chloride (98%, 21 μL, 1.2 eq) was added to the above solution. After shaking the mixture overnight at room temperature, the reaction mixture was passed through an aminopropyl NH ₂ cartridge and washed with CH ₂ Cl ₂ . To remove the CH ₂ Cl _2, to give cyclopropanecarboxylic acid N-(1-Boc-piperidin-3-ylmethyl) -N- (pyridin-3-yl) amide 22 (50mg, 73%). LRMS 260 (M-100) ⁺ .

Example 22 Synthesis of cyclopropanecarboxylic acid N- (1-phenethyl-piperidin-3-ylmethyl) -N- (pyridin-3-yl) amide (23)

[0485]

[Chemical 40]

Trifluoroacetic acid (0.5 mL) was added to cyclopropanecarboxylate N- (1-Boc-piperidin-3-ylmethyl) -N- in 0.5 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water). (Pyridin-3-yl) amide 22 (46 mg, 0.128 mm
ol) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes. After removing the solvent, the residue was dried under vacuum for 3 hours (LRMS 260). The crude compound was dissolved in DMF (0.5 mL) to give phenylacetaldehyde (13
0 μL) (in 2Mol / DMF) was added. The mixture was stirred at room temperature for 30 minutes. Introducing NaB (OAc) ₃ H (95%, 57 mg, 2 eq) at once,
The mixture was shaken overnight at room temperature. The mixture was quenched with 5 mL of aqueous potassium carbonate (saturated) and then extracted with ethyl acetate (3 x 10 mL). The extracts were combined, aqueous NaHCO ₃ solution (saturated, 2 × 5 mL), brine (10 mL
), And dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc / MeOH, 9: 1) to give cyclopropanecarboxylic acid N- (1-phenethyl-piperidine-3-.
Ylmethyl) -N- (pyridin-3-yl) amide 23 as an oil (23.5 mg
, 51%). IR (film, cm ⁻¹ ) 3026, 2931, 28
54, 2800, 2765, 1657, 1582, 1573, 1479, 144
5,1408,1263,1202,1188,1118,1025,748,
735; ¹ H NMR (CDCl ₃ , 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 (m, 1)
H), 1.87 (m, 2H), 1.70 (m, 2H), 1.56 (m, 1H),
1.26 (m, 2H), 1.09 (m, 3H), 0.69 (m, 1H); LRM
S364.

[0487] Example 23 Synthesis of N-Boc- (R) -nipecotic acid (original: nipecotic acid) (25)

[0488]

[Chemical 41]

Ethyl N-Boc- (R) -nipecotate-L-tartrate salt (24) (10.00 g, 32) in 50 mL dioxane and 50 mL H ₂ O.
． 5Mol) solution was cooled in an ice-water bath and NEt ₃ (9 mL) was added with stirring. Di-t-butyl-dicarbonate (7.44 g, 1.05 eq) was introduced while stirring and cooling continued. The mixtures were warmed to room temperature and kept stirring for 4 hours. 100mL of of _{H 2} O and ethyl acetate and 20mL was added to the mixture. The aqueous layer was extracted with ethyl acetate (2 x 100 mL). The extracts were mixed to form an aqueous potassium carbonate solution (saturated, 2 × 50 mL), an aqueous HCl solution (5%, 2 × 50
mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated to give ethyl-N- as a colorless oil 8.37 g (100%).
Boc- (R) -nipecotate was obtained.

Ethyl-N-Boc- (R) -nipecotate (7.
61 g, 29.6 mmol), LiOH (2.48 g, in 25 mL H ₂ O).
(2 eq) was added dropwise at 4 ° C. The reaction mixture was stirred at 4 ° C overnight. The pH of the mixture was adjusted to about 1 by adding aqueous HCl (10% w / w). The aqueous layer was extracted with ethyl acetate (3 x 100 mL). Mix these extracts to produce N
Wash with aqueous H ₄ Cl (saturated, 2 × 50 mL), brine (50 mL), dry over anhydrous Na ₂ SO ₄ , filter and evaporate to give N-Boc- (R) -nipecoic acid 25 as a white solid. As 6.25 g (92%) was obtained.

Example 24 Synthesis of (R) -1-Boc-piperidine-3-carboxylic acid phenylamide (26)

[0492]

[Chemical 42]

N-Boc- (R) -nipecoic acid 25 (4.00 g in 30 mL CH ₂ Cl ₂
, 17.5 mmol) and aniline (1.67 mL, 1.05 eq) with DCC
(4.88g, 1.05eq) was added in one portion at 0 ° C. The reaction mixture was stirred at room temperature overnight. The solvent was filtered and removed to give an oily crude product which was purified by flash column chromatography (silica gel, hexane: ethyl acetate) to give (R) -1-Boc-piperidine-3- Carboxylic acid phenylamide 2
6 was obtained as a colorless oil (5.26 g, 99%).

Example 25 Synthesis of (R) -1-phenethylpiperidine-3-carboxylic acid phenylamide (27)

[0495]

[Chemical 43]

Trifluoroacetic acid (0.5 mL) was added to (R) -1-Boc-piperidine-3-carboxylic acid phenylamide ₂ in 0.5 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water).
6 (46.7 mg, 0.154 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes. After removing the solvent, the residue was dried under vacuum for 3 hours (LRMS309). The crude compound was dissolved in DMF (0.5 mL) and phenylacetaldehyde (154 μL, in 2Mol / DMF) was added. The mixture was stirred at room temperature for 30 minutes. NaB (OAc) ₃ H (95%, 10
1 mg, 2 eq) was introduced at once and the mixture was shaken overnight at room temperature. The mixture was quenched with 5 mL of aqueous potassium carbonate (saturated), then ethyl acetate (
3 × 10 mL). These extracts were combined, NaHCO ₃ solution (saturated, 2 × 5mL), washed with brine (10 mL), dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was subjected to preparative thin layer chromatography (E
Purification by tOAc / MeOH, 9: 1) gave (R) -1-phenethylpiperidine-3-carboxylic acid phenylamide 27 as an oil (8.2 mg, 17%). LRMS309.

Example 26 (R) -N- (1-Boc-piperidin-3-ylmethyl) -aniline (28)
Synthesis of

[0498]

[Chemical 44]

(R) -1-Boc-piperidine-3-carboxylic acid phenylamide 26 (5.26 g, 17.28 mmol) in 20 mL dry THF was stirred in an ice bath with 34. Slowly added to 5 mL of 1.0 M borane. The mixture was refluxed for 2 hours then cooled in an ice bath and 20 mL of aqueous HCl (10
%) And further treated with NaOH (10%) to pH-10. The mixture was extracted with ethyl acetate (3 x 100 mL). The extracts were combined, washed with brine (2 x 50 mL) and dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was passed through a short column (silica gel, ethyl acetate) to give (R) -N- (1-Boc-piperidine-3).
-Ylmethyl) -aniline 28 was obtained as a colorless oil (4.59g, 91%).

Example 27 (R) N- (1-phenethyl-piperidin-3-ylmethyl) -N-phenyl-
Synthesis of propionamide (30)

[0501]

[Chemical formula 45]

By a procedure similar to that described in Examples 4 and 5, (R) -N- (1-Boc-piperidin-3-ylmethyl) -aniline 28 was added to (R) -N- (1-Boc- Piperidin-3-ylmethyl) -N-phenyl-propionamide 29, followed by (R) -N- (1-phenethyl-piperidin-3-ylmethyl) -N-phenyl-propionamide 30. (LRMS350).

Example 28 Synthesis of (S) -N- (1-Boc-piperidin-3-ylmethyl) -N-phenyl-propionamide (31)

[0504]

[Chemical formula 46]

(Racemic) -5 was resolved by HPLC on a Chiralpak AD semi-preparative column (hexane / isopropyl alcohol, 95: 5). The first compound isolated was (R) -29. The second was (S) -N- (1-Boc-piperidin-3-ylmethyl) -N-phenyl-propionamide 31.

Example 29 (S) N- (1-phenethyl-piperidin-3-ylmethyl) -N-phenyl-
Synthesis of propionamide (32)

[0507]

[Chemical 47]

Following the procedure described in Example 5, (S) -N- (1-Boc-piperidin-3-ylmethyl) -N-phenyl-propionamide 31 was treated with (S) N- (1-phenethyl-piperidine- 3-ylmethyl) -N-phenyl-propionamide 32. (LRMS350).

Example 30 Lack of Acute In Vivo Toxicity of 6 in Mice A 7 mg / mL solution of 6 in 50 mmol aqueous sodium acetate was prepared.
A dose of 1 mg / kg was administered to 4 male mice by intravenous injection in the tail. These mice did not show any adverse reaction to this compound. Furthermore,
A dose of 10 mg / kg was administered to 4 male mice by intraperitoneal injection. Similarly, at this concentration, these mice did not show any adverse reaction to this compound.

Example 31 In Vivo Analgesia in Mice The "tail-waving" analgesia model (D'Amour et al J) well known in the art of the present invention.
Pharmacol. Exp. Ther. 1941, 72, 74) was used. Four male mice weighing up to 22 g were treated with compound 6. Compound 6 for intraperitoneal and intravenous administration
Dissolved in the excipient of mmol aqueous sodium acetate solution. The control group received only the vehicle. Prior to treatment (0 min), radiant heat as a focused beam was applied to the medial dorsal surface of the mouse tail to elicit a tail-shaking response within 6-7.5 seconds and was preselected. Compound 6 was administered by intraperitoneal and intravenous injections for 30 minutes and 1 minute, respectively, followed by stimulation with the radiant heat of the focused beam used for preselection. The time required to elicit a tail-shaking response was recorded for each mouse and the maximum truncation time was set at 15 seconds. The time required to elicit a tail-shaking response was extended by 50% or more in treated mice, indicating that analgesia was occurring. The results of these experiments are recorded in Table 2. See also FIG.

[0511]

[Table 2]

Example 32 Agonism of the morphine receptor (original: Agonism) This example is based on the procedure shown by Maguire et al (Eur. J. Pharmacol. 1992, 213, 219).
) Was used to demonstrate significant agonism of morphine μ, κ, and δ receptors by (S) -32 and significant agonism of morphine μ and κ receptors by (R) -32. There is. The results are recorded in Table 3.

[0513]

[Table 3]

[0514] Example 33 1-phenethylpiperidine-3-carboxylic acid phenylamide 35

[0515]

[Chemical 48]

N-Boc-nipecoic acid 33 (102 mg, 0. ₂ %) in 2 mL of dry CH ₂ Cl ₂ .
445 mmol) and aniline (41 μL, 1.0 eq) with DCC resin (43
0 mg) was added. The reaction mixture was stirred at room temperature overnight. The solvent was filtered and removed to give an oily crude product which was purified by flash column chromatography (silica gel, hexane: ethyl acetate) to give 1-Boc-piperidine-
The 3-carboxylic acid phenylamide 34 was obtained as a colorless oil (120 mg, 89%).

Trifluoroacetic acid (0.5 mL) was added to 1-Boc-piperidine-3-carboxylic acid phenylamide 34 (62) in 0.5 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water).
mg, 0.20 mmol) was added dropwise. The reaction mixture is 3 at room temperature.
Stir for 0 minutes. After removing the solvent, the residue was dried under vacuum for 3 hours. This crude product was used in the next step without purification.

The crude composition from the previous step was dissolved in crude compound in DMF (0.5 mL) and phenylacetaldehyde (400 μL in 2 Mol / DMF) was added. The mixture was stirred at room temperature for 30 minutes. NaB (OAc) ₃ H (95%, 90 mg
(2 eq) was introduced at once and the mixture was shaken overnight at room temperature. The mixture is 5
Quench with mL of aqueous potassium carbonate (saturated), then ethyl acetate (3 x 1
0 mL). The extracts were mixed and the aqueous NaHCO ₃ solution (saturated, 2 ×
5 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was subjected to preparative thin layer chromatography (EtOA).
Purification by c / MeOH, 9: 1) gave 1-phenethylpiperidine-3-carboxylic acid phenylamide 35. LRMS309.

Example 34 1-Phenethylpiperidine-3-carboxylic acid N-phenyl-N-ethylamide 3
7

[0520]

[Chemical 49]

[0521] 2mL of dry in _CH 2 Cl ₂ N-Boc-Nipeko acid 33 (113mg, 0.
DCC resin (480 mg) was added to 493 mmol) and ethylaniline (62 μL, 1.0 eq). The reaction mixture was stirred at room temperature overnight. The solvent was filtered and removed to give an oily crude product which was purified by flash column chromatography (silica gel, hexane: ethyl acetate) to give 1-Boc-piperidine-3-carboxylic acid N-phenyl. -N-ethylamide 36 was added as a colorless oil (
150 mg, 92%).

Trifluoroacetic acid (0.5 mL) was added to 1-Boc-piperidine-3-carboxylic acid N-phenyl-N-ethylamide 36 (56 mg) in 0.5 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water). , 0.168 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes. After removing the solvent, the residue was vacuumed to 3
Allowed to dry for hours. This crude product was used in the next step without purification.

The crude composition from the previous step was dissolved the crude compound in DMF (0.5 mL) and phenylacetaldehyde (67 mg, 3 eq) was added. This mixture at room temperature for 3
Stir for 0 minutes. NaB (OAc) ₃ H (95%, 112 mg, 3 eq) was introduced in one portion and the mixture was shaken overnight at room temperature. The mixture was quenched with 5 mL of aqueous potassium carbonate (saturated) and then extracted with ethyl acetate (3 x 10 mL). These extracts were combined, NaHCO ₃ solution (saturated, 2 × 5mL), washed with brine (10 mL), dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was subjected to preparative thin layer chromatography (EtOAc / MeOH, 9
1) to give 1-phenethylpiperidine-3-carboxylic acid N-phenyl-N-ethylamide 37. LRMS336.

Example 35 Methoxyacetic acid N- (1-phenethylpiperidin-3-ylmethyl) -N-phenylamide 39

[0525]

[Chemical 50]

[0526]   2 mL dry CH_TwoCl_TwoN- (1-Boc-piperidin-3-ylmethyi in
) -Aniline 4 (101 mg, 0.348 mmol) and piperidinomethylpo
To a stirred suspension of styrene resin (110 mg) was added methoxyacetyl chloride (
Original language: methoxyacetyl chloride) (97%, 34 μL, 1.05 equivalent) was added.
. After the mixture was stirred for 4 hours at room temperature, the reaction mixture was treated with aminopropyl NH. _Two CH through the cartridge_TwoCl_TwoWashed with. CH_TwoCl_TwoRemove
Methoxyacetic acid N- (1-Boc-piperidin-3-ylmethyl) -N-phenyl
The amide 38 (70 mg, 56%) was obtained.

Trifluoroacetic acid (0.5 mL) was added to N- (1-Boc-piperidin-3-ylmethyl) -N-methoxyacetate in 0.5 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water).
-Phenylamide 38 (61.8 mg, 0.17 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 20 minutes. TLC showed the reaction was complete. After removing the solvent, the residue was dried under vacuum for 3 hours. This crude product was used in the next step without purification.

The crude composition from the previous step was dissolved the crude compound in DMF (1.0 mL) and phenylacetaldehyde (68.3 mg, 3 eq) was added. The mixture was stirred at room temperature for 30 minutes. NaB (OAc) ₃ H (95%, 108 mg, 3 eq) was introduced in one portion and the mixture was shaken overnight at room temperature. The mixture was quenched with 5 mL of aqueous potassium carbonate (saturated) and then extracted with ethyl acetate (3 x 10 mL). These extracts were combined, NaHCO ₃ solution (saturated, 2 × 5mL), washed with brine (10 mL), dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was subjected to preparative thin layer chromatography (EtOAc / MeOH
, 9: 1) and methoxyacetic acid N- (1-phenethylpiperidine-3
-Ylmethyl) -N-phenylamide 39 as a colorless oil (31 mg, 49%
) As. LRMS363.

Example 36 N- (1- (3′phenyl) propylpiperidin-3-ylmethyl) -N-phenylpropionamide 44

[0530]

[Chemical 51]

Trifluoroacetic acid (0.5 mL) was added to N- (1-Boc-piperidin-3-ylmethyl) -N-phenylpropionamide 5 in 0.5 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water). (58 mg, 0.167 mmol) was added dropwise to the solution.
The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removing the solvent, the residue was dried under vacuum for 3 hours. This crude product was used in the next step without purification.

The crude composition from the previous step was dissolved in DMF (0.5 mL) and benzaldehyde (46 μL, 2 eq) was added. The mixture was stirred at room temperature for 30 minutes. N
aB (OAc) ₃ H (95%, 75 mg, 2 eq) was introduced in one portion and the mixture was shaken overnight at room temperature. The mixture was quenched with 5 mL of aqueous potassium carbonate (saturated) and then extracted with ethyl acetate (3 x 10 mL). These extracts were combined, NaHCO ₃ solution (saturated, 2 × 5mL), washed with brine (10 mL), dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc / MeOH, 9: 1) to give N- (1- (3'phenyl) propylpiperidin-3-ylmethyl) -N. -Phenylpropionamide 44 was obtained as a colorless oil (49 mg, 80%). LRMS364.

[0533] Example 37 N-Boc-3-azetidinecarboxylic acid (46)

[0534]

[Chemical 52]

3-azetidinecarboxylic acid (45) (2) in 5 mL of THF and 5 mL of H ₂ O.
A solution of 50 mg, 2.47 mmol) was cooled in an ice-water bath and NEt ₃ (689 μm) was added.
L) was added with stirring. Di-t-butyl-dicarbonate (570 mg, 1.
(05 eq) was introduced while stirring and cooling continued. The mixtures were warmed to room temperature and left stirring overnight. 20mL of of _{H 2} O ethyl acetate and 10mL was added to the mixture. The aqueous layer was extracted with ethyl acetate (2 x 20 mL). These extracts were mixed to form an aqueous potassium carbonate solution (saturated, 2 × 10 mL), an aqueous HCl solution (
5%, 2x10 mL), washed with brine (10 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed to give 46 as a white solid 0.50 g (100%).

[0536] Example 38 N- (1-Boc-azetidin-3-ylmethyl) aniline 48

[0537]

[Chemical 53]

N-Boc-3-azetidinecarboxylic acid 46 (in 5 mL of dry CH ₂ Cl ₂
To a solution of 0.50 g, 2.48 mmol) and aniline (274 μL, 1.1 eq) was added DCC (730 mg, 1.1 eq) in one portion at 0 ° C. The mixture was stirred at room temperature for 3 hours. The solvent was filtered and removed to give an oily crude product which was flash column chromatographed (silica gel, hexane: ethyl acetate).
Purified by 1-Boc-azetidine-3-carboxylic acid phenylamide 47
Was obtained as a colorless oil (660 mg, 96%).

1-Boc-azetidine-3-carboxylic acid phenylamide 47 (650 mg, 2.35 mmol) in 5 mL dry THF was added to 5 mL 1.0 Mol borane in THF with stirring in an ice bath. I added it slowly. The mixture was refluxed for 3 hours, then cooled in an ice bath, quenched with 5 mL aq. HCl (10%), and further treated with NaOH (10%) to pH-10. The mixture was extracted with ethyl acetate (3 x 20 mL). Combine the extracts and wash with brine (2 x 10 mL).
), And dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was passed through a short column (silica gel, ethyl acetate) to give N- (1
-Boc-azetidin-3-ylmethyl) aniline 48 as a colorless oil (520
mg, 84%).

Example 39 N- (1-phenethylazetidin-3-ylmethyl) -N-phenylpropionamide 50

[0541]

[Chemical 54]

To a solution of N- (1-Boc-azetidin-3-ylmethyl) aniline 48 (218.6 mg, 0.791 mmol) and piperidinomethyl polystyrene resin (250 mg) in 2 mL of dry CH ₂ Cl _{2 was} added, Propionyl chloride (77 μL
, 1 eq) was added at room temperature. The reaction mixture was stirred at room temperature overnight then passed through an aminopropyl NH ₂ cartridge and washed with CH ₂ Cl ₂ . To remove the CH ₂ Cl _2, to give N- and (1-Boc-azetidin-3-ylmethyl) -N- phenylpropionamide 49 (241mg, 96%).

Trifluoroacetic acid (2 mL) was added to N- (1-Boc-azetidin-3-ylmethyl) -N-phenylpropionamide 49 (241 mg, 0) in 2 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water). .757 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 20 minutes. After removing the solvent, the residue was dried under vacuum for 2 hours. This crude product 6 was used without purification in the next step.

The crude composition from the previous step was dissolved the crude compound in DMF (3 mL) and phenylacetaldehyde (303 mg, 3 eq) was added. This mixture at room temperature for 30
Stir for minutes. NaB (OAc) ₃ H (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 (saturated) and then extracted with ethyl acetate (3 x 10 mL). These extracts were combined, NaHCO ₃ solution (saturated, 2 × 5mL), washed with brine (10 mL), dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was purified by flash column chromatography to give N-
(1-Phenethylazetidin-3-ylmethyl) -N-phenylpropionamide 50 (124 mg, 51%) was obtained. LRMS322.

Example 40 N- (1-phenethylpiperidin-3-ylmethyl) cyclopropanecarboxylic acid
-N-phenamide 52

[0546]

[Chemical 55]

To a solution of N- (1-Boc-azetidin-3-ylmethyl) aniline 48 (108.7 mg, 0.393 mmol) and piperidinomethyl polystyrene resin (130 mg) in 2 mL of dry CH ₂ Cl _{2 was} added, Cyclopropane carbonyl chloride (9
8%, 40 μL, 1.1 eq) was added at room temperature. The reaction mixture was stirred at room temperature overnight then passed through an aminopropyl NH ₂ cartridge and washed with CH ₂ Cl ₂ . To remove the CH ₂ Cl _2, to give cyclopropanecarboxylic acid N- (1-Boc- piperidin-3-ylmethyl) -N- Fen'amido 51 (120mg, 92%).

Trifluoroacetic acid (2 mL) was added to N- (1-Boc-piperidin-3-ylmethyl) -N-phenamide 51 (in ₂ mL dry CH ₂ Cl ₂ at 0 ° C. (ice water) (
87.5 mg, 0.265 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 20 minutes. After removing the solvent, the residue was dried under vacuum for 2 hours. This crude product was used in the next step without purification.

The crude composition from the previous step was dissolved the crude compound in DMF (3 mL) and phenylacetaldehyde (106 mg, 3 eq) was added. This mixture at room temperature for 30
Stir for minutes. NaB (OAc) ₃ H (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 (saturated) and then extracted with ethyl acetate (3 x 10 mL). These extracts were combined, NaHCO ₃ solution (saturated, 2 × 5mL), washed with brine (10 mL), dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was purified by flash column chromatography to give cyclopropanecarboxylic acid N- (1-phenethylpiperidin-3-ylmethyl) -N.
-Fenamide 52 (46 mg, 50%) was obtained. LRMS344.

[0550] Example 41 N- (1-Boc-morpholin-2-ylmethyl) aniline 55

[0551]

[Chemical 56]

N-Boc-3-carboxymorpholine 53 (20 g, 86.95 mmol) and aniline (8.71 mL, 95.58) in CH ₂ Cl ₂ (200 mL) at 0 ° C.
DCC (21.19 g, 102.69 mmol) was added to the solution (mmol) in several portions. The mixture was shaken at room temperature for 3 hours. The white precipitate was removed by filtration. The filtrate was washed with 5% HCl and saturated NaHCO ₃ , then Na ₂ S.
Dry over O ₄ , filter and evaporate. The residue was dried by azeotropic evaporation with benzene to give 54 as a white solid. C ₁₆
Was calculated LRMS regard H ₂₂ N ₂ O ₄ 306. 306 was found.

To a solution of N-Boc-morpholine-2-carboxylic acid phenylamide 54 obtained in the previous experiment in THF (100 mL) at 0 ° C. was added BH ₃ -THF solution (1.0
Mol, 180 mL) was added via addition funnel. After adding this solution, the mixture was refluxed for 7 hours. The reaction was quenched by the slow addition of aqueous NaHCO ₃ . THF was removed by evaporation. The residue was extracted with EtOAc (3 x 50 mL). The combined organic solution was dried over Na ₂ SO ₄ , filtered and evaporated. 55 was obtained as a white solid (17.15 g) from the residue which crystallized on standing at room temperature. Other solids (about 2 g) were also obtained from the mother liquor (76%).

Example 42 N- (2′-phenylethylmorpholin-2-yl-methyl) -N-phenylpropionamide 57

[0555]

[Chemical 57]

N- (1-Boc-morpholin-2-yl-methyl) -aniline 55 (7.49 g, 25.65 mmol) and pyridine (in CH ₂ Cl ₂ (50 mL) at 0 ° C.
To a solution of 3.1 mL, 34.48 mmol), propionyl chloride (2.4
5 mL, 28.20 mmol) was added. The mixture was stirred for 30 minutes then washed with sat. NaHCO ₃ , then dried over Na ₂ SO ₄ , filtered and evaporated to give a colorless oil. When this was left at room temperature, it crystallized and white solid 56 (5.
49 g, 60%) was obtained.

N- (1-Boc-morpholin-2-yl-methyl) -N-phenyl-propionamide 56 (5.40 g, 15.50) in CH ₂ Cl ₂ (10 mL) at 0 ° C.
To a solution of (mmol), TFA (10 mL) was added. After stirring for 2.5 hours, the solvent and excess TFA were removed by evaporation. The residue was dissolved in 20 mL CH ₂ Cl ₂ and neutralized with NaHCO ₃ . The organic layer was separated, washed with saturated NaHCO _3, and dried over _Na 2 SO _4. After evaporation of the solvent, a pale yellow oil is dissolved in _CH 3 CN (10mL), thereto _{H 2 O (10mL), K} 2 CO 3 (4.
80 g) and (2-bromoethyl) benzene (2.2 mL) were added. The mixture was stirred at 70 ° C. for 6 hours. After cooling to room temperature, the organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic solution was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by flash silica gel chromatography (4% MeOH in CH ₂ Cl ₂ ) to give a colorless oil 57 (5.00
, 92%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.5-7.
20 (m, 10H), 3.90-3.55 (m, 5H), 2.90-2.50 (
m, 6H), 2.20 (m, 1H), 2.00 (m, 3H), 1.0 (m, 3H)
), C ₂₂ H ₂₈ N ₂ O ₂ 352 and LRMS calculated. 352 was found.

[0558] Example 43 HPLC separation of the 57 enantiomers

[0559]

[Chemical 58]

The 57 enantiomers were separated using a preparative HPLC procedure. The conditions are as follows. Chiralpak AD column, 10% i-PrOH in hexane, μ = 5 mL /
Min, λ = 254 nm. The absolute configuration of the chiral center was not specified. The first peak (retention time = 10.45 min) is the arbitrarily assigned structure 152 and the second
The peak (retention time = 11.99 min) was the arbitrarily assigned structure 151.

Example 44 N- (2′-phenylethylmorpholin-2-yl-cyclopropanecarboxylic acid
Methyl) -N-phenylamide 59

[0562]

[Chemical 59]

A solution of N- (1-Boc-morpholin-2-yl-methyl) aniline 55 (91.5 mg, 0.313 mmol) and piperidinomethyl polystyrene resin (116 mg) in 1 mL of dry CH ₂ Cl _2. And cyclopropane carbonyl chloride (9
8%, 34 μL, 1.2 eq) was added at room temperature. The reaction mixture was shaken at room temperature for 1 hour, then passed through an aminopropyl NH ₂ cartridge and washed with CH ₂ Cl ₂ . To remove the CH ₂ Cl _2, cyclopropanecarboxylic acid N- (2'-Boc
-Morpholin-2-yl-methyl) -N-phenylamide 58 (91 mg, 81
%) Was obtained.

Trifluoroacetic acid (0.5 mL) was added to cyclopropanecarboxylate N- (2′-Boc-morpholin-2-yl-methyl) in 0.5 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water). -N-phenylamide 58 (63.2 mg, 0.175 mmol)
Was added dropwise to the above solution. The reaction mixture was stirred at room temperature for 20 minutes. After removing the solvent, the residue was dried under vacuum for 2 hours. This crude product was used in the next step without purification.

This crude product was dissolved in 2 mL of CH ₃ CN and treated with K ₂ CO ₃ (75 m
g) and (2-bromoethyl) benzene (47 μL, 2 eq) were added. The mixture was stirred at 50 ° C. for 4 hours. After cooling to room temperature, 2 mL NaHCO ₃ (saturated) and 10 mL EtOAc were added. The organic layer was separated. Water layer is EtOAc
Extracted with (2 x 5 mL). The combined organic solution was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by flash silica gel chromatography to give a colorless oil of cyclopropanecarboxylic acid N- (2'-phenylethylmorpholin-2-yl-methyl) -N-phenylamide 59 (55 mg, 86%. ) Got. LRMS364.

Example 45 N- (1-Boc-piperidin-3- (R) -ylcarboxyl) -N- (pyridin-3-yl) amide 64

[0567]

[Chemical 60]

R-Boc-nipecotic acid (6) in CH ₂ Cl ₂ at 0 ° C.
． 54 mmol, 1.50 g) and 3-aminopyridine (1.1 eq, 7.20).
mmol, 677 mg) of a solution of DCC (2.0 equiv.
It was treated with 3.08 mmol, 2.70 g). Warm the reaction mixture to 25 ° C and
Stir for 12 hours. The reaction mixture was then filtered to remove urea and the solvent removed in vacuo. Chromatography (SiO ₂ , 2.5 cm × 30.5 cm, hexane-EtOAc) gave 64 (1.26 g, theoretical 2.00 g, 63
%) Was obtained as a white solid. _{R f 0.33 (SiO 2, 3} : 1, hexane _{^{-EtOAc) LRMS m / z 305 (}} M +, C 16 H 23 N 3 O 3, 30
5 is required).

Example 46 N- (1-phenethyl-piperidin-3-R-ylmethyl) -N- (pyridine-
3-yl) cyclophenylpropionamide 66

[0570]

[Chemical formula 61]

A solution of 64 (0.33 mmol, 100 mg) in THF at 0 ° C. was added to 1 Mo in THF (2.0 eq, 0.655 mmol, 655 μL) under argon atmosphere.
Treated with 1 liter of LAH. The reaction mixture was warmed to 25 ° C. and stirred for 1 hour. Then the reaction mixture was cooled to 0 ° C. and quenched with 10% aqueous HCl. p
The H was adjusted to 10 with 10% aqueous NaOH and the reaction mixture was adjusted to 3 × EtOAc (2
5 mL). Organics were dried over NaCI _(sat) and MgSO4 _(sat) . The resulting amine was used directly in the next step.

The above solution in CH ₂ Cl ₂ at 0 ° C. was treated with cyclopropane carbonyl chloride (1.1 eq, 0.36 mmol, 33 μL and diisopropylethylamine (2.0 eq, 0. 652 mmol, 114 μL) The reaction mixture was warmed to 25 ° C. and stirred for 12 h.
Quenched with aqueous NaHCO ₃ % and extracted 3 × EtOAc (25 mL).
Chromatography (SiO ₂ , 1.3 cm x 30.5 cm, 3: 1, EtOAc
-Hexane) gave 65 (53 mg, theoretical 117 mg, 45%) as a golden oil. _{R f 0.32 (SiO 2, 3} : 1, EtOAc- _{^{hexane); LRMS m / z 359 (}} M +, requiring _{C 20 H 29 N 3 O 3} , 309).

Compound 65 (0.15 mmol, 33 mg) was treated with 20% under an argon atmosphere.
It was treated with _{TFA-CH 2} Cl 2. The reaction mixture was stirred for 12 hours. The solvent was removed in vacuo and the resulting oil was dried under vacuum for 3 hours. The crude amine salt obtained was used directly without purification.

[0574]   The above compound and phenylacetaldehyde (2.0 equivalents, 0.29 mmol
, 34 μL) was dissolved in DMF (500 μL) under an argon atmosphere.
The reaction mixture was stirred at 25 ° C. for 1 hour then treated with Na (OAc)._ThreeBH (2.0 etc.
Amount, 62 mg, 0.29 mmol) and stirred at 25 ° C. for 1 hour. this
The reaction mixture is 10% NaHCO._ThreeAfter quenching with aqueous solution, 3 × EtOAc (2
5 mL). Chromatography (PTLC, SiO_Two, 20 cm x 20
cm, 1 mm, 9: 1, EtOAc-CH_ThreeOH), 66 (19 mg,
Theoretically 53 mg, 36%) was obtained as a golden oil. R_f0.26
(SiO_Two, 3: 1, EtOAc-hexane); LRMS m / z 363 (M ⁺ , C₂₃H₂₉N_ThreeO, 363).

Example 47 N- (1-t-butyloxy-piperidin-3-S-ylcarboxy) -N- (
Pyridin-3-yl) amide 67

[0576]

[Chemical formula 62]

S-Boc-nipecoic acid (6.54 mmo in CH ₂ Cl ₂ (25 mL) at 0 ° C.
1, 1.50 g) and 3-aminopyridine (1.1 eq, 7.20 mmol, 6)
77 mg) of a solution of DCC (2.0 equiv., 13.08 mm) under an argon atmosphere.
ol, 2.70 g). The reaction mixture was warmed to 25 ° C. and stirred for 12 hours. The reaction mixture was then filtered to remove urea and the solvent removed in vacuo. Chromatography _(SiO 2, 2.5cm × 30.5cm, hexane -Et
OAc) gave 67 (1.08 g, theoretical 2.00 g, 54%) as a white solid. _{R f 0.33 (SiO 2, 3} : 1, hexane -EtOAc
_{^{) LRMS m / z 305 (M}} +, requiring _{C 16 H 23 N 3 O 3} , 305).

Example 48 N- (1-phenethyl-piperidin-3-S-ylmethyl) -N- (pyridine-
3-yl) cyclopropionamide 69

[0579]

[Chemical formula 63]

A solution of 67 (3.37 mmol, 1.03 mg) in THF (5 mL) at 0 ° C.
In an argon atmosphere under THF (2.0 equiv., 6.74 mmol, 6.74 mL).
1) LAH in 1). The reaction mixture was warmed to 25 ° C. and stirred for 1 hour. Then the reaction mixture was cooled to 0 ° C. and quenched with 10% aqueous HCl. The pH was adjusted to 10 with 10% aqueous NaOH and the reaction mixture was adjusted to 3xE.
Extracted with tOAc (25 mL). The organics were dried with NaCl _(sat.) And MgSO _4. The resulting amine was used directly in the next step.

The above solution in CH ₂ Cl ₂ at 0 ° C. was added under argon atmosphere to cyclopropane carbonyl chloride (1.5 eq, 3.66 mmol, 332 μL and diisopropylethylamine (1.1 eq, 2.eq). 68 mmol, 467 μL) The reaction mixture was warmed to 25 ° C. and stirred for 12 h.
Quenched with aqueous NaHCO ₃ and extracted with 3 × EtOAc (25 mL). Chromatography (SiO ₂ , 1.3 cm x 30.5 cm, 3: 1, EtOA
c-Hexane) gave 68 (263 mg, theoretical 877 mg, 30%) as a golden oil. R _f 0.32 (SiO ₂ , 3: 1, EtOA
c- _{^{hexane); LRMS m / z 359 (}} M +, C 20 H 29 N 3 O 3, 3
59).

Compound 68 (3.37 mmol, 1.21 g) was treated with 20 under argon atmosphere.
% Was treated with _{TFA-CH 2} Cl 2. The reaction mixture was stirred for 1 hour. The solvent was removed in vacuo and the resulting oil was dried under vacuum for 3 hours. The crude amine salt obtained was used directly without purification.

The above compound and phenylacetaldehyde (2.0 eq, 6.74 mmol
, 790 μL) was dissolved in DMF (10 mL) under argon atmosphere.
The reaction mixture was stirred at 25 ° C. for 1 hour, then treated with Na (OAc) ₃ BH (2.0 eq, 1.43 g, 6.74 mmol) and stirred at 25 ° C. for 12 hours.
The reaction mixture was quenched with 10% aq. NaHCO ₃ and then 3 x EtOAc.
It was extracted with (25 mL). Chromatography (PTLC, SiO ₂ , 20 cm x
20cm, 1mm, 9: by _{1, EtOAc-CH 3 OH)} , 69 (0.20
0 g, theoretically 1.22 g, 16%) was obtained as a golden oil. R _{f 0.26 (SiO 2, 3: 1} , EtOAc- hexane); LRMS m / z
363 ^(M _+, requiring _{C 23 H 29 N 3 O,} 363).

Example 49 (R) -Cyclopropanecarboxylic acid N- (1-phenethylpiperidin-3-ylmethyl) -N-phenamide 71

[0585]

[Chemical 64]

Following a procedure similar to that described in Example 48, from composition 28, N- (1-phenethylpiperidin-3-ylmethyl)-(R) -cyclopropanecarboxylic acid-N-
Fenamide 71 was obtained. LRMS362.

Example 50 (S) -Cyclopropanecarboxylic acid N- (1-phenethylpiperidin-3-ylmethyl) -N-phenamide 73

[0588]

[Chemical 65]

Following a procedure similar to that described in Example 48 from Composition 31 N- (1-phenethylpiperidin-3-ylmethyl) -N- (S) -cyclopropanecarboxylic acid.
Fenamide 73 was obtained. LRMS362.

Example 51 N- (1-phenethylpiperidin-3-ylmethyl) cyclopropanecarboxylic acid
-N- (pyridin-2-yl) amide 76

[0591]

[Chemical formula 66]

Cyclopropanecarboxylic acid N- (1-phenethylpiperidin-3-ylmethyl) -N- (pyridin-2-yl) amide 76 was prepared from composition 3 according to a procedure similar to that described in Examples 3-5. Obtained. LRMS359.

[0593] Example 52 N-benzyl propanolamine 77

[0594]

[Chemical formula 67]

3-Amino-1-propanol (60.5 mL, 792 mmol) was added to MeO.
Benzaldehyde (76.6 mL, 754) in H (1.51 L, 0.5 Mol)
mmol) and the solution was stirred and heated to 75 ° C. After 25 minutes, the reaction was cooled to room temperature and then cooled to 0 ° C. in an ice bath. Solid NaB
H ₄ (28.52 g, 754 mmol) was added over 20 minutes and stirred to warm the reaction to room temperature overnight. Water was added, the solvent was removed in vacuo and EtOAc was added. The organic layer was removed and treated with 5% aqueous HCl. A 10% aqueous NaOH solution was added dropwise to basify the solution. The aqueous layer was extracted with EtOAc (2x), combined organics were dried over _Na 2 SO _4, to give the pure N- benzyl propanolamine (77) and and concentrated in vacuo. The crude product 77 was used in the next step without purification. ¹ H NMR (CD ₃ OD) 7.4-7.2 (5H, m), 4.9
5 (2H, broads), 3.75 (2H, broads), 3.64 (
2H, t, J = 6.2 Hz), 2.70 (2H, t, J = 7.1 Hz), 1.7
7 (2H, q, J = 6.7 Hz). ¹³ C NMR (CD3OD) 140.79
, 129.61, 128.28, 61.78, 54.68, 47.56, 33.
10 ppm. LRMS: 165.91.

[0596] Example 53 4-benzyl-2-chloromethyl-1,4-oxazepan 79

[0597]

[Chemical 68]

N-benzylpropanolamine 77 (5.00 g, 30.3 mmol) was dissolved in epichlorohydrin (23.7 mL, 303 mmol) and heated to 40 ° C. Once the reaction was judged complete by TLC (3 h), epichlorohydrin was removed under high vacuum overnight (Intermediate 78: LRMS: 2).
57.58). H ₂ SO ₄ (9.2 mL, 3.3 Mol) was added with stirring at room temperature and the reaction was heated to 150 ° C. in a preheated oil bath until TLC judged complete (0.5 h). did. The reaction was removed from heat and cooled by adding ice. CH ₂ Cl ₂ was added, the organic layer was removed and discarded. EtOAc
Was added to this acidic aqueous layer, and further 10% KOH was added dropwise until the aqueous layer was basic. The organic layer was removed, the aqueous layer was extracted with EtOAc (2x), the combined organics were dried over sodium sulfate, filtered in vacuo and concentrated to 4-benzyl-2.
-Chloromethyl-1,4-oxazepane (79) was obtained. It was used in the next step without purification. ¹ H NMR (CD ₃ OD) 7.4-7.2 (5 H, m),
3.93-3.75 (3H, m), 3.67 (2H, broad d, J = 1.
3Hz), 3.44 (2H, dd, J = 5.9, 4.3Hz), 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. ¹³ C NMR (CD ₃ OD) 13
9.89, 130.33, 129.46, 128.39, 79.26, 68.3
1, 63.64, 59.59, 55.30, 46.57, 31.35 ppm. _{^{1 3 C NMR (CDCl 3)}} 139.10,128.82,128.32,12
7.11, 78.27, 67.43, 62.79, 58.55, 54.26, 4
5.80, 30.55 ppm. LRMS: 239.54.

Example 54 (4-benzyl-1,4-oxazepan-2-ylmethyl) -phenylamine (
80)

[0600]

[Chemical 69]

Aniline (2.59 mL, 28.4 mmol) and NaI (4.06 g, 27)
． 1 mmol) 4-benzyl-2-chloromethyl-1,4-oxazepane (79) (6.49 g, 27.1) in n-butanol (68 mL, 0.4 Mol).
mmol) and heated to 110 ° C. until the reaction was judged complete by TLC (4 h). The reaction was cooled to room temperature, water was added and _CH 2 Cl _2. The organic layer was removed and the aqueous layer was extracted with CH ₂ Cl ₂ (2x). The combined organics were dried over sodium sulfate, filtered in vacuo and concentrated to give (4-benzyl-1,4-oxazepan-2-ylmethyl) -phenylamine 80. It was used in the next step without purification. ¹ H NMR (partly, CDCl ₃ ) 4.0
8-3.86 (3H, m), 3.80 (1H, d, J = 13.3Hz), 3.7
3 (1H, d, J = 13.3 Hz), 3.22-3.05 (2H, m), 2.9
5-2.70 (3H, m), 2.64 (1H, dd, J = 13.6, 7.6Hz
), 2.1-1.9 (2H, m) ppm. ¹³ C NMR (CDCl ₃ ) 148
． 33, 139.38, 129.28, 129.11, 128.46, 127.
23, 117.44, 113.13, 76.70, 67.49, 62.92, 5
9.35, 54.76, 46.93, 30.75 ppm. LRMS: 296.6
8.

Example 55 4-Benzyl-1,4-oxazepan-2-ylmethyl) -N-phenylpropionamide (original: phenylpropionamide) (81)

[0603]

[Chemical 70]

IPr2EtN (4.72 mL, 27.1 mmol) in CH ₂ Cl ₂ (
4-benzyl-1,4-oxazepan-2-ylmethyl) -phenylamine (8
0) (27.1 Mol). 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 to room temperature with stirring overnight. CH ₂ Cl ₂ and 10% NaO
Aqueous H solution was added. The organic layer was removed and the aqueous layer was extracted with CH ₂ Cl ₂ (2x). The organic layer was dried over sodium sulfate, filtered in vacuo and concentrated. The resulting oily residue was chromatographed on silica gel (97: 1: 2 :: hexane: CH ₂ C).
l _2: Purification by 2N NH ³⁾ in EtOH, as a pale yellow oil, 4-benzyl-1,4-oxazepan-2-ylmethyl) -N- give phenylpropionamide (81). ¹ H NMR (CDCl ₃ , ppm) 7.36-7.19 (
8H, m), 6.94 (2H, broad d, J = 6.5Hz), 3.89-
3.38 (5H, m), 3.65 (1H, d, J = 13.3Hz), 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 (3
H, t, J = 7.5 Hz). ¹³ C NMR (CDCl ₃ ) 174.05, 14
3.19, 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 pp
m. LRMS: 352.72

Example 56 (4-phenethyl-1,4-oxazepan-2-ylmethyl) -N-phenylpropionamide (82)

[0606]

[Chemical 71]

Phenylacetaldehyde (0.17 mL, 1.42 Mol) was added to MeOH (
4-benzyl-1,4-oxazepan-2-ylmethyl) -N-phenylpropionamide (81) (0.115 g, 0.326 mm) dissolved in 9.5 mL).
ol). 10% Pd / C (0.101 g) was added and the mixture was shaken under 40 psi H ₂ until consumption of H ₂ was complete and the reaction was judged complete by TLC (4.25 h). . The crude reaction mixture was passed through a column of Celite,
Concentrate in vacuo and flash column chromatography (50: 48: 2:
: _Hexanes: CH ₂ Cl 2: Purification by 2N NH ₃₎ in EtOH, pure (4
-Phenethyl-1,4-oxazepan-2-ylmethyl) -N-phenylpropionamide (82) was obtained. ¹ H NMR (CDCl ₃ ) 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 (1H, 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 = 7.5Hz) ppm. ¹³ C NMR (CDCl ₃ ) 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: 36
6.98.

Example 57 (R)-& (S)-(4-phenethyl-1,4-oxazepan-2-ylmethyl) -N-phenylpropionamide 83 and 84

[0609]

[Chemical 72]

The enantiomer of (4-phenethyl-1,4-oxazepan-2-ylmethyl) -N-phenylpropionamide (82) was transferred to a chiral column (ChiralPak AD).
Column No. AD00CG-1F001) Hexane: iPrOH (λ =
235 nm; flow rate = 5 mL / min) (9: 1). Analytical chiral pack column, 90:10 hexane: isopropanol (λ = 220 nm; flow rate = 1 m)
L / min), the first compound eluting from the column (9.175 min), optionally assigned to 83 (R), and the second compound eluting from the column (13.909).
Min), 84 (S). The absolute configuration of 83 and 84 was not specified.

Example 58 4-Benzyl-1,4-ozazepan-2-ylmethyl) -N-phenylcyclopropanamide (original: phenylcyclopropanamide) 85

[0612]

[Chemical formula 73]

Pyridine (3.64 mL, 45.0 mmol) was added to the crude amine (80) (30.
0 mmol) in CH ₂ Cl ₂ solution. 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 judged complete by TLC (3.25
H), the reaction was slowly warmed to room temperature and stirred. CH ₂ Cl ₂ and saturated Na
HCO ₃ was added. The organic layer was removed and the aqueous layer was extracted with CH ₂ Cl ₂ (2x). The organic extract was dried over sodium sulfate, filtered in vacuo and concentrated. The oily residue obtained was subjected to alumina gel chromatography (96: 2: 2 :: hexane: C
H ₂ Cl ₂ : 2N NH _{3 in} EtOH) as a pale yellow oil, 4
-Benzyl-1,4-ozazepan-2-ylmethyl) -N-phenylcyclopropanamide (85) was obtained. ¹ H NMR (CD ₃ OD) 7.46-7.24 (
8H, m), 7.13 (2H, broad d, J = 7.2Hz), 3.90-
3.42 (5H, m), 2.92-2.76 (2H, m), 2.62-2.51
(1H, m), 2.30 (1H, dd, 13.7, 8.5Hz), 1.40-1
． 20 (2H, m), 0.96-0.82 (3H, m), 0.61 (2H, dd
, J = 7.9, 2.8 Hz) ppm. ¹³ C NMR (CD ₃ OD) 175.8
4,144.04,140.20,130.82,130.54,129.55
, 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-phenethyl-1,4-ozazepan-2-ylmethyl) -N-phenylcyclopropanamide 87

[0615]

[Chemical 74]

Phenylacetaldehyde (0.091 mL, 0.780 mmol) was added to Me.
N-benzylamine 86 (dissolved in OH (5.2 mL, 0.03 Mol)
0.055 g, 0.156 mmol). 10% Pd / C (0.0557
g) was added and the mixture was shaken under 40 psi H ₂ until the consumption of H ₂ was complete and the reaction was judged complete by TLC. The crude reaction mixture is passed through a celite column, concentrated in vacuo, further purified by flash column chromatography (50: 48: 2: _hexanes: CH ₂ Cl 2: 2N _NH 3 in EtOH)
Pure 4-phenethyl-1,4-ozazepan-2-ylmethyl) -N
-Phenylcyclopropanamide (87) was obtained. ¹ H NMR (CDCl ₃ )
7.47 (2H, m), 7.37-7.26 (5H, 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), 2.5
0 (1H, dd, J = 8.9, 6.7Hz) 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. ¹³ C NMR (C
DCl ₃₎ 173.79,143.39,140.46,129.52,128
． 82, 128.61, 128.44, 127.53, 126.05, 76.4
1, 67.15, 60.06, 59.53, 53.90, 52.09, 34.2
1,30.28, 12.92, 8.71, 8.50 ppm. LRMS: 378.
80.

Example 60 (R)-& (S) -4-phenethyl-1,4-ozazepan-2-ylmethyl)-
N-Phenylcyclopropanamide 88 & 89

[0618]

[Chemical 75]

The enantiomer of 4-phenethyl-1,4-ozazepan-2-ylmethyl) -N-phenylcyclopropanamide (87) was loaded onto a chiral column (Chiral Pack A
D column No. AD00CG-1F001) Hexane: iPrOH (λ
= 235 nm; flow rate = 5 mL / min) (9: 1). Analytical chiral pack column, 90:10 hexane: isopropanol (λ = 220 nm; flow rate = 1)
(mL / min), the first compound eluted from the column (9.017 min), optionally 88 (R), and the second compound eluted from the column (14.275 min).
, 89 (S). The absolute configuration of 88 and 89 has not been specified.

Example 61 1,4-Dioxa-aza-spiro [4,5] -decane-6-carboxylic acid methyl ester 91

[0621]

[Chemical 76]

PTSA (24.7, 130 mmol) and ethylene glycol (24.8 m)
L, 439 mmol) to methyl-4 in benzene (52 mL, 2.5 Mol).
-Oxo-3-piperidinecarboxylate hydrochloride (90) (25.1 g, 13
0 mmol). The solution was stirred and heated to reflux overnight. Of H 2 _O was removed using a Dean-Stark trap. When the reaction was judged complete by TLC, 5% aq. NaHCO ₃ and CH ₂ Cl ₂ were added and the organic layer was removed. The aqueous layer was extracted with CH ₂ Cl ₂ (5x), the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo, and silica gel chromatography was used to 20: 1, CH ₂ Cl ₂ : EtOH in EtOH. purification by 2N NH _3, to give the 91 (16.7g, 64%). ¹ H NMR (CDCl ₃ ) 3.82-3.70 (4
H, m), 3.48 (3H, s), 3.00-2.50 (4H, m), 2.43.
(1H, t), 1.76 (1H, m), 1.30 (1H, m) ppm. ¹³ C
NMR _(CDCl 3): 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 ether 92

[0624]

[Chemical 77]

Triethylamine (29.0,208 mmol) was added to CH ₂ Cl ₂ (156 m).
L, 0.5 Mol) in 1,4-dioxa-aza-spiro [4,5] -decane-
Added to 6-carboxylic acid methyl ether (91) (16.6 g, 82.5 mmol). The solution was cooled to 0 ° C. in an ice bath, then benzoylchloroformate (original: 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 filtered and concentrated in vacuo and purified using silica gel chromatography (10: 3, hexane: EtOAc) to give 8- Benzyloxycarbonyl-1,4-dioxa-8-aza-spiro [4,5] -decane-6-carboxylic acid methyl ether (92) was obtained (23.43 g, 85%).
. ¹ H NMR (CDCl ₃ ): 7.41-7.25 (5H, m), 5.10 (
2H, broads), 4.02-3.50 (11H, m), 2.80-2.
62 (1H, broads), 2.20-2.00 (1H, broads)
, 1.70-1.50 (1H, broads) ppm. ¹³ C NMR (CD
Cl ₃ ): 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.

Example 63 8-Benzyloxycarbonyl-1,4-dioxa-8-aza-spiro [4,5]
] -Decane-6-carboxylic acid 93

[0627]

[Chemical 78]

8-benzyloxycarbonyl-1,4-dioxa-8-aza-spiro [4,4
5] -Decan-6-carboxylic acid (92) (15.04 g, 44.8 mmol) was dissolved in 70% aqueous MeOH solution (136 mL, 0.33 Mol). K
OH (3.76 g, 89.7 mmol) was added and the solution was stirred at room temperature until the reaction was judged complete by TLC (6.75 h). The reaction is concentrated in vacuo, _CH 2 Cl ₂ was added and _{H 3} O. The organic layer was removed and discarded. The aqueous layer was carefully acidified with saturated NH ₄ Cl to pH = 6. The organic layer was removed in vacuo and concentrated. The crude product 93 was used in the next reaction without further purification (13.3 g, 93% yield). ¹ H NMR (CDCl ₃ ) 9.8-9.2 (1
H, broads), 7.45-7.22 (5H, broads), 5.1.
8-5.10 (2H, broads), 4.10-3.94 (4H, m), 3
． 92-3.78 (2H, m), 3.70-3.54 (2H, m), 2.82-
2.70 (1H, broads), 2.14-2.00 (1H, m), 1.7
0-1.54 (1H, m) ppm. ¹³ C NMR (CDCl ₃ ) 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.

Example 64 8-Benzyloxycarbonyl-1,4-dioxa-8-aza-spiro [4,5]
] -Decane-6-carboxylic acid anilide 94

[0630]

[Chemical 79]

1-Ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride (ED
CI, 2.13 g, 11.1 mmol) and aniline (1.29 mL, 14.2)
mmol) was added to a solution of acid 93 in CH ₂ Cl ₂ (66.7 mL, 0.14 Mol) with stirring. The solution was stirred until judged complete by TLC (3 hours). CH ₂ Cl ₂ was added and _{H 3} O. The organic layer was removed, dried over sodium sulfate, removed in vacuo and concentrated. The crude product is hexane: Et
Purification with 1: 1 OAc gave 8-benzyloxycarbonyl-1,4-dioxa-8-aza-spiro [4,5] -decane-6-carboxylic acid anilide (94) (2.26 g). , Yield 61%). ¹ H NMR (CDCl ₃ ): 8.20-8.
00 (1H, broads), 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), 5.1
1 (1H, d, 12.5Hz), 4.35 (1H, d, J = 12.9Hz), 4
． 16-3.94 (4H, m), 3.51 (1H, dd, J = 13.7, 11.
1Hz), 3.15 (1H, t, J = 11.8Hz), 2.75 (1H, dd,
J = 10.9, 4.5 Hz), 1.90-1.57 (3H, m) ppm. ¹³ C
NMR _(CDCl 3): 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, 5
0.24, 43.73, 41.87, 34.80 ppm. LRMS: 396.7
.

Example 65 8-benzyloxycarbonyl-1,4-dioxa-8-aza-spiro [4,5]
] -Decan-6-ylmethylphenylamide 95

[0633]

[Chemical 80]

Borane-THF (5.04 mL, 5.04 mmol) was added to THF (2.9 mL).
, 0.86 Mol) at 0 ° C. to a stirred solution at 0 ° C. The reaction was warmed to room temperature and then heated to reflux until TLC judged the reaction was complete (2.5 h). The reaction is cooled to room temperature and further cooled in an ice bath to give 5% HCl.
It was quenched at. CH ₂ Cl ₂ was added and 10% NaOH was added dropwise until the aqueous layer was basic. The organic layer was removed and the aqueous layer was extracted with CH ₂ Cl ₂ (2x). Organics were dried over sodium sulfate and chromatographed on silica gel (8:
1: 1 :: hexane: EtOAc: CH ₂ Cl ₂ ) and filtered,
8-benzyloxycarbonyl-1,4-dioxa-8-aza-spiro [4,5]
] -Decan-6-ylmethylphenylamide (95) was obtained (0.72 g, 73).
%). ¹ H NMR (CDCl ₃ ): 7.36 (5H, broads), 7.
16 (2H, t, J = 7.1Hz), 6.72-6.44 (3H, m), 5.2
2-5.00 (2H, broads), 4.05-3.95 (4H, m), 3
． 72 (1H, dd, J = 13.6, 3.9Hz), 3.66-3.30 (4H
, M), 2.97 (1H, dd, J = 13.3, 8.2 Hz), 2.20-1.
98 (1H, broads), 1.84-1.64 (1H, broads)
, 1.64-1.48 (1H, broads) ppm. ¹³ C NMR (partly CDCl ₃ ): 155, 148.15, 138, 129.41, 128.75.
, 128.3, 128.16, 117.28, 112.83, 108.64, 6
7.50, 65.04, 64.70, 44.92, 42.53, 42.19, 4
1.21, 33.16 ppm. LRMS: 382.88.

Example 66 (8-Benzyloxycarbonyl-1,4-dioxa-8-aza-spiro [4,4
5] -Decan-6-ylmethyl) -N-phenylpropionamide 96

[0636]

[Chemical 81]

IPr ₂ EtN (0.78 mL, 4.48 mmol) was added to CH ₂ Cl ₂ (4.
A solution of amine 95 (0.71 g, 1.86 Mol) in 6 mL, 0.4 Mol) was added. The solution was cooled to 0 ° C. and then propionyl chloride (0
． 19 mL, 2.33 mmol) was added dropwise with stirring. The reaction was warmed slowly to room temperature. When the reaction was judged complete by TLC (4.2
For 5 hours), CH ₂ Cl ₂ and saturated H ₂ O were added. The organic layer is separated and 5% HC
1 aqueous solution, then saturated NaHCO ₃ , and further brine. The organic extract was dried over Na ₂ SO ₄ and then purified by silica gel chromatography (6: 2: 2 :: hexane: EtOAc: CH ₂ Cl ₂ ) to give (8-benzyloxycarbonyl-1,4-dioxa-). 8-Aza-spiro [4,5] decane-6-ylmethyl) -N-phenylpropionamide (96) was obtained (0.7).
1 g, 87%). ¹ H NMR (CDCl ₃ ): 7.60-7.08 (8H, m
), 7.05-6.88 (2H, broads), 5.20 (1H, d, J =
13Hz), 5.05 (1H, d, J = 13Hz), 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. L
RMS: 438.84.

Example 67 (8-Phenethyl-1,4-dioxa-8-aza-spiro [4,5] -decane-
6-ylmethyl) -N-phenylpropionamide 97

[0639]

[Chemical formula 82]

In a hydrogenation flask, phenylacetaldehyde (0.87 mL, 7.
40 mmol) was dissolved in MeOH (49.4 mL, 0.03 Mol) (
8-benzyloxycarbonyl-1,4-dioxa-8-aza-spiro [4,5]
] -Decan-6-ylmethyl) -N-phenylpropionamide (96). 20% Pd / C (0.53 g) was added and the mixture was added to 40 p until the H ₂ consumption was complete and the reaction was judged complete by TLC (3.5 h).
Shake under H ₂ of si. The crude reaction mixture is passed through a celite column, concentrated in vacuo, further flash column chromatography and purified by (60: 38: 2: _hexanes:: CH ₂ Cl 2 2N NH ₃ in EtOH), pure ( 8-Phenethyl-1,4-dioxa-8-aza-spiro [4,5] decane-6-ylmethyl) -N-phenylpropionamide (97) (0.59 g, 92%) was obtained. ¹ H NMR (CDCl ₃ ): 7.42-7.12 ( ¹⁰ H, m), 4.08 (1
H, 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 (1
H, m), 2.80-2.64 (3H, m), 2.62-2.51 (2H, m)
, 2.33 (2H, broadt, 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.

Example 68 1-t-Butoxycarbonylpiperidin-3-ylmethylcarboxylic acid anilide 9
9

[0642]

[Chemical 83]

EDCI (4.23 g, 2.20 mmol) and aniline (2.56 mL, 2
The _{8.1mmol), CH 2 Cl 2 (} 132mL, 0.14Mol) N-B in
It was added to OC-3- (98) (4.5 g, 18.5 mmol). The solution was stirred at room temperature overnight. The reaction was judged complete by TLC. It was added CH ₂ Cl ₂ and _{H 2} O. The organic layer was removed and the water bath was extracted with CH ₂ Cl ₂ . The combined organics were dried over sodium sulfate, filtered in vacuo and concentrated. Silica gel purification (90: 5:
5 :: Hexane: EtOAc: running _{CH 2} Cl 2), to give pure 1-t-butoxycarbonyl-3-yl-carboxylate anilide (99) (4.10g, 70% ). ¹ H NMR (CDCl ₃ ): 9.03 (1 H, br
oad s), 7.62 (2H, broad s), 7.32 (2H, t, J =
8.0 Hz), 7.01 (1H, t, J = 7.4 Hz), 3.92-3.3.8
0 (1H, 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 (9
H, s) ppm. ¹³ C NMR (partly, CDCl ₃ ): 129.02,124
． 12, 119.95, 40.77, 33.23, 31.06, 28.59pp
m.

[0644] Example 69 1-t-butoxycarbonylpiperidin-3-ylethylphenylamine 100

[0645]

[Chemical 84]

1 Mol of borane-THF (6.28 mL, 6.26 mmol) was added to THF (
1-t-Butoxycarbonylpiperidin-3-ylethylcarboxylic acid anilide (99) (1 g, 3.14 mmol) in 3.7 mL) was added to a stirring solution at 0 ° C. The ice bath was removed and the reaction was judged to be complete by TLC (2.
Heated to reflux for 5 hours. The reaction is cooled to room temperature and further cooled in an ice bath,
Quench with 5% aq. HCl. The reaction was diluted with CH ₂ Cl ₂ and 10% N 2
Aqueous aOH solution was added dropwise until the aqueous layer was basic. The organic layer was removed and the aqueous layer was extracted with CH ₂ Cl ₂ (2x). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo, and flash column chromatography (90: 5).
: 5 :: hexane: EtOAc: CH ₂ Cl ₂ ) and purified by
-T-butoxycarbonylpiperidin-3-ylethylphenylamine (100
) Was obtained (0.90 g, 94%). ¹ H NMR (CDCl ₃ ): 7.24-7
． 15 (2H, m), 6.72 (1H, broad t, J = 7.3 Hz), 7
． 66-6.59 (2H, m), 4.0 (1H, breads), 3.93 (
2H, dt, J = 13.1, 4.0 Hz), 3.78-3.56 (1H, m),
3.18 (2H, t, J = 7.1Hz), 2.85 (1H, broad t, J
= 10.8 Hz), 2.58 (1H, broads), 1.94-1.82 (
1H, m), 1.74-1.38 (4H, m), 1.45 (9H, s), 1.2
4-1.08 (1H, m). ¹³ C NMR (CDCl ₃ ): 154.92,1
48.36, 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-Butoxycarbonylpiperidin-3-ylethyl) -N-phenylpropionamide 101

[0648]

[Chemical 85]

IPr ₂ EtN (0.60 mL, 3.47 mmol) was added to CH ₂ Cl ₂ (7.
22 mL, 0.4 Mol) was added to a solution of 100 (0.88 g, 2.89 Mol) at 0 ° C. Propionyl chloride (0.30 mL, 3.47 mmol) was added dropwise and the solution warmed to room temperature. When the reaction was judged complete by TLC (5 h), the reaction was diluted with CH ₂ Cl ₂ . H ₂ O was added and the organic layer was separated. The organic layer was washed with 5% aqueous HCl, then saturated aqueous NaHCO ₃ , and then brine. The crude product is dried over sodium sulphate, filtered and concentrated in vacuo and further subjected to silica gel chromatography (8: 1:
1 :: Hexane: EtOAc: obtained was purified by _{CH 2} Cl 2), pure (1-t-butoxycarbonyl-3-ylethyl) -N- phenylpropionamide (101) (0.81g, 78% ) of It was ¹ H NMR (CDCl ₃ ): 7.
46-7.29 (3H, m), 7.14 (2H, J = 7.6Hz), 3.90-
3.60 (4H, m), 2.74 (2H, broad t, J = 11.0Hz)
, 2.47 (1H, broads), 2.01 (2H, q, J = 7.3Hz)
, 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 = 7.4Hz) ppm. ¹³ C MR (CDCl ₃ ): 17
3.62, 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-phenethylpiperidin-3-ylethyl) -N-phenylpropionamide 102

[0651]

[Chemical 86]

Trifluoroacetic acid (0.38 mL, 4.9 mL) in CH ₂ Cl ₂ (0.38 mL).
9 mmol) was added dropwise to a stirred solution of 101 at 0 ° C. in CH ₂ Cl ₂ (0.40 mL). When the reaction was judged complete by TLC, this solution and excess trifluoroacetic acid were removed in vacuo. The crude compound was added to DMF (1.54 m
L, 0.18 mol) and dissolved in phenylacetaldehyde (0.10 mL
, 0.832 mmol), acetic acid (0.078 mL), and Na (OAc) ₃ BH
(0.118 g, 0.555 mmol) were added sequentially. When the reaction was judged complete by TLC, saturated K ₂ CO ₃ aqueous solution 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 NH 4 _CO. The organic layer was removed, dried over Na ₂ SO ₄ and further concentrated in vacuo. Silica gel chromatography (98: 2 :: CH ₂ Cl ₂ : 2N in EtOH
Purification by NH _3), (1- phenethyl-piperidin-3-ylethyl) -N-
Phenylpropionamide (102) was obtained. ¹³ C NMR: 173.64,
142.77, 140.45, 129.82, 128.84, 128.50, 1
28.45, 127.95, 126.13, 61.08, 60.03, 54.2
7, 47.06, 33.89, 33.46, 32.57, 30.86, 28.0
0, 25.31, 9.74 ppm.

Example 72 (1-Benzylpiperidin-3-ylethyl) -N-phenylpropionamide 103

[0654]

[Chemical 87]

Trifluoroacetic acid (0.38 mL, 4.9 mL) in CH ₂ Cl ₂ (0.38 mL).
9 mmol) was added dropwise to a stirred solution of 101 at 0 ° C. in CH ₂ Cl ₂ (0.40 mL). When the reaction was judged complete by TLC, this solution and excess trifluoroacetic acid were removed in vacuo. The crude compound was added to DMF (1.54 m
L, 0.18 mol) and dissolved in phenylacetaldehyde (0.10 mL
, 0.832 mmol), acetic acid (0.078 mL), and Na (OAc) ₃ BH
(0.118 g, 0.555 mmol) were added sequentially. When the reaction was judged complete by TLC, saturated K ₂ CO ₃ aqueous solution 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 NH 4 _CO aq. The organic layer was removed, dried over Na ₂ SO ₄ and further concentrated in vacuo. Purify by silica gel chromatography (99: 1 :: CH ₂ Cl ₂ : 2N NH _{3 in} EtOH) to give (1-benzylpiperidin-3-ylethyl)-
N-phenylpropionamide (103) was obtained. ¹³ C NMR: 7.46-
7.24 (8H, m), 7.15 (2H, broad d, J = 7.8Hz),
3.72 (2H, J = 7.8Hz), 3.52 (1H, J = 13.2Hz), 3
． 45 (1H, d, J = 13.2Hz), 2.79 (2H, broad d, J
= 8.2 Hz), 2.03 (2H, q, J = 7.3 Hz), 1.91 (1H, t
d, J = 11.0, 3.3 Hz), 1.84-1.30 (7H, m), 1.05
(3H, t, J = 7.4Hz), 0.98-0.84 (1H, m) ppm. Thirteen
C NMR (CDCl3): 173.65, 142.93, 138.4, 129
． 83, 129.35, 128.52, 128.31, 127.95, 127.
073.68,60.21,54.22,47.34,34.14,32.5
1,30.84, 28.04, 25.34, 9.78 ppm. LRMS: 350
． 95.

[0656] Example 73 5-Benzyl-oxa-5-azaspiro [2,5] octane 110

[0657]

[Chemical 88]

Triethylsulfonium iodide (2.13 g, 1 in DMSO (15 mL)
0.4 mmol) was added to NaH (0.4907 g, 20 mL) in DMSO (70 mL).
． 4 mmol). 1-Benzyl-piperidone (original: piperidone) -hydrochloride hydrate (109) was dissolved in DMSO (15 mL) and added to the reaction mixture at room temperature. In the dictionary where the reaction was judged complete by TLC (0.5 h), the reaction was poured onto ice and the product was extracted with CH ₂ Cl ₂ . Wash the organics with H ₂ O,
Dry over sodium sulfate, filter and concentrate in vacuo. Silica gel chromatography (900: 100: 3: CH ₂ Cl ₂ : hexane: 2N in EtOH.
NH ₃ ) to give pure (5-benzyl-oxa-5-azaspiro [2,5
] Octane 110) was obtained. ¹³ C NMR (CDCl ₃ ): 137.54,1
28.69, 127.83, 126.67, 62.55, 59.28, 53.3
2,52.96, 52.48, 30.90, 23.51 ppm.

Example 74 1-Benzylpiperidin-3-hydroxy-3-ylmethylphenylamine 11
1

[0660]

[Chemical 89]

[0661]   In a sealed tube device, 110 (0.89 g, 4.38 mmol) was added to aniline.
Dissolved in (2.0 mL, 21.9 mmol) and heated the reaction to 200 ° C.
. When the reaction was judged complete by TLC (2.5 hours), H_TwoO and E
tOAc was added. After adjusting the pH of the aqueous layer to 8, the organic layer is removed and sodium sulfate is added.
Dried above, filtered and concentrated in vacuo. Silica gel chromatography (60:
38: 0.2, hexane: CH_TwoCl_Two: 2N NH in EtOH_Three)
, 0.132 g (10% in two steps) of 1-benzylpiperidine-3
-Hydroxy-3-ylmethylphenylamine (111) was obtained.¹1 H NMR
(CDCl_Three): 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 (1H, d, J = 13.2Hz)
, 3.57 (1H, d, J = 13.2Hz), 3.45 (1H, broads
), 3.19 (2H, d, J = 5.5 Hz), 2.86 (2H, t, J = 11.
4Hz), 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. ^Thirteen C NMR (CDCl_Three): 148.94, 138.09, 129.31,
129.10, 128.44, 127.31, 117.41, 113.17, 7
0.15, 62.85, 62.11, 53.47, 51.48, 33.88, 2
1.76 ppm. LRMS: 297.08

Example 75 (1-Benzylpiperidin-3-hydroxy-3-ylethyl) -N-phenylpropionamide 112

[0663]

[Chemical 90]

[0664]   iPr_TwoEtN (0.078 mL, 0.45 mmol) in CH_TwoCl_Two(1
． Amine 111 (0.120 g, 0.405 Mol in 0 mL, 0.4 Mol)
) Was added to the solution at 0 ° C. Propionyl chloride (0.039 mL, 0.45
mmol) was added dropwise with stirring. The reaction allowed the solution to warm to room temperature. Anti
When the reaction was judged complete by TLC (overnight), the reaction was CH._TwoCl_Twoso
Diluted, H_TwoQuenched with O. The organic layer is separated, and this organic layer is 5% HCl aqueous solution.
Wash with liquid, then saturated NaHCO 3._ThreeWash with aqueous solution, then brine.
It was The crude product was dried over sodium sulfate, filtered and concentrated in vacuo, and
Silica gel chromatography (96: 4 :: hexane: 2N NH in EtOH _Three ) And pure (1-benzylpiperidin-3-hydroxy-3-yl ether)
Cyl) -N-phenylpropionamide (112) (0.117 g, 82%)
Obtained.¹1 H NMR (CDCl_Three): 7.44-7.05 (10H, m), 3.
99 (1H, 14.3Hz), 3.88 (1H, 14.2Hz), 3.51 (1
H, d, J = 13.2 Hz), 3.42 (1H, d, J = 13.2 Hz), 2.
28-2.30 (2H, m), 2.32-2.14 (1H, m), 2.08 (2
H, q, J = 7.4 Hz), 1.72-1.46 (3H, m), 1.46-1.
26 (2H, m), 1.03 (3H, t, J = 7.4Hz) ppm.^ThirteenC N
MR (CDCl_Three): 144.76, 129.59, 129.16, 128.3
2,128.16,127.71,127.16,72.17,62.78,6
1.97, 57.66, 53.34, 34.17, 28.02, 9.76 ppm
. LRMS: 352.76.

Example 76 (1-Phenethylpiperidin-3-hydroxy-3-ylethyl) -N-phenylpropionamide 113

[0666]

[Chemical Formula 91]

[0667]   In a hydrogenation flask, phenylacetaldehyde (0.17 mL, 1.
42 mmol) and Pd / C (0.101 g) in MeOH (9.45 mL).
Of 112 (0.0793 mg, 0.225 mmol). Furthermore, H _Two Until the reaction was judged complete by TLC and consumption of
40 psi H_TwoShaken under. The crude reaction mixture was passed through a column of Celite,
Concentrate in vacuo and then chromatograph on silica gel (80: 18: 2 :: hex).
Sun: CH_TwoCl_Two: 2N NH in EtOH_Three) And then (1-phenethyl)
Piperidin-3-hydroxy-3-ylethyl) -N-phenylpropionami
I got Do (113).¹1 H NMR (CDCl_Three): 176.66, 144.7
4,140.52,129.63,128.84,128.47,128.18
, 127.76, 126.11, 72.04, 62.27, 59.96, 58.
11, 53.51, 34.16, 33.58, 28.07, 22.10, 9.8
5 ppm.

[0668] Example 77 Synthesis of combinatorial libraries of compounds of the invention (See Figure 1) Reaction on solid support

[0669]

[Chemical Formula 92]

[0670]

[Chemical formula 93]

A library of 96 compounds was prepared with 12 anilines, 8 acid chlorides, and (2-
Synthesized from bromoethyl) benzene. The reductive amination and acylation reactions were synthesized using solid-phase chemistry, while the alkylation of piperidine with (2-bromoethyl) benzene was performed in solution.

A. Aldehyde-functionalized resin 115 One resin in a 250 mL peptide synthesis vessel (9.6 g, 0.70 mmol /
To g) was added 100 mL 0.4N CDI in anhydrous THF and shaken at room temperature for 17 hours. This resin was treated with CH ₂ Cl ₂ (3 × 100 mL) and THF (3 × 10 mL).
Excess CDI was removed by extensive washing with 0 mL) followed by treatment with 100 mL of 0.4 N 3-piperidinemethanol in THF at room temperature for 17 hours. The resulting resin (114) was DMF (3 x 100 mL), MeOH (4 x 100 mL), and C.
It was washed with H ₂ Cl ₂ (4 × 100 mL) and further dried in vacuum. Alcohol resin 114 contains sulfur trioxide complex (5.35 g, 33.6 mmol) in DMSO.
) And triethylamine (4.68 mL, 33.6 mmol) in 100 mL was added 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 ₂ Cl ₂ (4 x 100 mL) and further dried in vacuum. Resin 1
15 is aliquoted into 12 reactors in which the aldehyde is
Reacts with 2 anilines respectively.

B. Preparation of Resin 116 To 115 resin (about 0.8 g, 0.56 mmol) was added aniline (5.6 mmol) in 8 mL of methyl orthoformic acid ester (TMOF) and the mixture was shaken at room temperature for 1 hour. NaCNBH ₃ (700mg, 11.2mmol) was added to the mixture, followed by addition of AcOH 0.08 mL. After shaking at room temperature for 3 hours, the resulting resin 116 was DMF (3 × 10 mL), MeOH (4 × 10 mL).
, And CH ₂ Cl ₂ (4 × 10 mL), and further dried in vacuo. In this reductive amination, 12 resins 116 were obtained with 12 anilines.

C. Compound 118 Formulation 12 resin 116 was dispensed into a 96-well reaction block from column 1 to column 12 in an amount of 100 mg (0.07 mmol) per well (
(See FIG. 1). Eight acid chlorides in CH ₂ Cl ₂ were each dosed into each of the eight rows, row A to row H, in an amount of 1 mL per well (containing 0.7 mmol of acid chloride). After that, diisopropylethylamine was added to each well by 0.122 m.
An amount of L (0.7 mmol) was dosed into 96 wells. Reaction block 3 at room temperature
Shake for hours, then add these resins to DMF (3 x 1 mL / well), MeOH
(4 × 1 mL / well), and CH ₂ Cl ₂ (4 × 1 mL / well), and further dried in vacuum. The resulting resin 117 was treated with 50% TFA solution in CH ₂ Cl ₂ in an amount of 1 mL per well for 30 minutes at room temperature to release the polymer-bound piperidine 118 into 96 deep well plates. After washing the resins with CH ₂ Cl ₂ (2 × 0.5 mL / well), the volatiles were removed under high vacuum to give the crude compound.

D. Preparation of Compound 119 To piperidine 118 in a 96 deep well plate, 0.6 mL of acetonitrile was added per well to dissolve these compounds and the solution was transferred to a 96 well reaction block. (2-Bromoethyl) benzene was added to 96 wells at 0.010 mL (0.07 mmol) per well, followed by K ₂ CO ₃ at 50 mg per well. The mixture was stirred at 50 ° C. for 24 hours. After cooling the reaction block to room temperature, tris (2-aminoethyl) -amine polystyrene (2.45 mmol / g) was distributed to 96 wells at 50 mg per well. The mixture was shaken at 50 ° C. for 24 hours. The solution is 9% NH ₂ absorbent.
Filter into a 6-well format SPE plate and add CH ₂ Cl ₂ (2 × 0.6 mL /
Wells) and washed the resin in a 96 deep well plate. Volatiles were removed under high vacuum to give 96 final compositions 119 which were subjected to high performance liquid chromatography and mass spectrometry.

Example 78 Morphine Receptor Binding of Certain Compounds of the Invention (50% Inhibitory Concentration) The opioid (μ, κ, δ) receptor binding capacity of the compounds described herein is
ng et al. (FEBS Letters 1994, 338, 217), Maguire et al. (Eur. J. Pharmac
ol. 1992, 213, 219), and Simonin et al. (Mol. Pharmacol. 1994, 46, 1015).
Was measured according to the method shown by. The results of these assays are tabulated below.

[0677]

[Table 4]

Example 79 Analgesia in mice and rats (see Figure 2) This example demonstrates in vivo analgesia in mice and rats for compounds 6,30, 32, 66 and 69. An analgesia model (by the movement of the tail) known in the field of the present invention (D'Amour et al J. Pharmacol. Exp. Ther. 1941,
72, 74) was used. Four male mice or rats weighing up to 22 g were used for each dose. Three doses (1, 0.5, and 0.1 mg / kg) of compound 6
, 30, 32, 66, and 69 were dissolved in a 50 mM aqueous sodium acetate vehicle and administered intravenously. The control group received only the vehicle. Prior to treatment (time = 0 min), radiant heat as a focused beam was applied to the mid-dorsal surface of the mouse tail and 6
Tail shaking responses were elicited within ~ 7.5 seconds and preselected. Compound 6,30
, 32, 66, and 69 were administered intravenously for 1 minute and then stimulated with radiant heat of a focused beam. The time required to elicit a tail-shaking response was recorded for each mouse and the maximum truncation time was set at 15 seconds. The time required for inducing the tail-shaking response was extended by 50% or more as compared with the control group, and it was shown that the analgesic state occurred.

Example 80 N-Phenyl-N- [1- (4-phenylbutyl) piperidin-3-ylmethyl] propionamide (120)

[0680]

[Chemical 94]

Trifluoroacetic acid (1.0 mL) was added to the compound N- (1-Boc-piperidin-3-ylmethyl) -N-phenylpropionamide in 1.0 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water). (108 mg, 0.31 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removing the solvent, the crude product was used in the next step without purification.

The crude product from the previous step was dissolved in DMF (0.5 mL) and 4-phenylbutyraldehyde (49 μL, 1.1 eq) was added. This mixture at room temperature 60
Stir for minutes. NaB (OAc) ₃ H (95%, 340 mg, 5 eq) was introduced in one portion and the mixture was shaken overnight at room temperature. The mixture was mixed with 5 mL of NaOH (1
Quenched with 0%) and then extracted with ethyl acetate (3 x 10 mL). The extracts were combined, aqueous NaHCO ₃ solution (saturated, 2 × 5 mL), brine (10 m
It was washed with L) and dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was subjected to preparative thin layer chromatography (CH ₂ Cl ₂ / MeOH, 95: 5).
Was purified by to give N-phenyl-N- [1- (4-phenylbutyl) piperidin-3-ylmethyl] propionamide (120) as a colorless oil. L
RMS 379 (M + H ⁺ ).

Example 81 N- (2-Fluorophenyl) -N- (1-phenethylpiperidin-3-ylmethyl) propionamide (121)

[0684]

[Chemical 95]

Piperidine-1,3-dicarboxylic acid 1- in CH ₂ Cl ₂ (25 mL) at 0 ° C.
To a solution of t-butyl ester 1 (1.0 g, 4.4 mmol) and 2-fluoroaniline (463 μl, 4.8 mmol) was added DCC (0.99 g, 4.8 mmo).
l) was added in several portions. The mixture was stirred at room temperature overnight. The white precipitate was filtered off. After removing the solvent, the residue was purified by column chromatography (silica gel, hexane / ethyl acetate, 4: 1) to give 3- (2-fluorophenylcarbamyl) piperidine-1-carboxylic acid t-butyl ester (2). Was obtained as a colorless oil (1.13 g, 80%).

3- (2-Fluorophenylcarbamyl) piperidine-1-carboxylic acid t-butyl ester (2) (1.13 g, 3.5 mmol) in THF (4 mL) at 0 ° C.
BH ₃ -THF solution (1.0 M, 3.5 mL) was slowly added to the solution of (1). The mixture was refluxed for 2 hours. The reaction was quenched by the slow addition of 0 ° C. MeOH. The solvent was removed by evaporation. Column chromatography of the residue (
Purify with silica gel, hexane / ethyl acetate, 85:15) and add 3-[(2-fluorophenylamino) methyl] piperidine-1-carboxylic acid t-butyl ester (3) as a colorless oil (0.97 g, 90%).

[0687]

[Chemical 96]

3-[(2-Fluorophenylamino) methyl] piperidine-1-carboxylic acid t-butyl ester (3) in CH ₂ Cl ₂ (1 mL) at 0 ° C. (150 mg, 0
． 49 mmol) and N, N-diisopropylehilamine (original: diisopropy
lehylamine) (435 μL, 2.5 mmol) and propionyl chloride (1
30 μL, 1.5 mmol) was added. The reaction mixture was shaken overnight. The mixture is 1
Poured into 0% NaOH (5 mL) and extracted with ethyl acetate (3 x 10 mL). Extracts were mixed aqueous NaHCO ₃ (sat, 2 × 5 mL) and washed with, dried over _Na 2 SO _4, filtered and evaporated to give a slightly yellow oil. This oil was subjected to column chromatography (silica gel, hexane / ethyl acetate, 4: 1).
The product was purified with a solvent to give 3-{[(2-fluorophenyl) propionylamino] methyl} piperidine-1-carboxylic acid t-butyl ester (4) (162 mg, 92%).

3-{[(2-Fluorophenyl) propionylamino] methyl} piperidine-1-carboxylic acid t-butyl ester (4) in CH ₂ Cl ₂ (1 mL) at 0 ° C.
TFA (1 mL) was added to a solution of (162 mg, 0.45 mmol). Thirty
After stirring for a minute, the solvent and excess TFA were removed by evaporation. Residue is 1.5m
Dissolved in L CH ₃ CN (10 mL), to which was added K ₂ CO ₃ (1245 mg) and (2-bromoethyl) benzene (123 μL, 0.9 mmol). The mixture was stirred at 50 ° C. overnight. After cooling to room temperature, 5 mL of 10% NaOH was added. The organic layer was separated. The aquarium was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated.
The crude product was flash silica gel chromatography (5% M in CH ₂ Cl ₂
OH) to give colorless N- (2-fluorophenyl) -N- (1-phenethylpiperidin-3-ylmethyl) propionamide (121) (141m).
g, 85%). LRMS369 (M + H ⁺ ) was obtained.

Example 82 N- (1-phenethylpiperidin-3-ylmethyl) -N-phenylisobutyramide (123)

[0692]

[Chemical 97]

3-Phenylaminomethylpiperidine-1-dicarboxylic acid-t-butyl ester (1) (220 mg, 0.7) in 1.5 mL dry CH ₂ Cl ₂ (25 mL).
To a stirred solution of 6 mmol) and piperidinomethyl polystyrene resin (350 mg) was added room temperature isobutyryl chloride (122 μL, 1.5 eq). 3 at room temperature
After shaking for an hour, the reaction mixture was passed through an aminopropyl NH ₂ cartridge to remove C
Washed with H ₂ Cl ₂ . CH ₂ Cl ₂ was removed to give 3-[(isobutyrylphenylamino) methylpiperidine-1-carboxylic acid t-butyl ester (2) (25
9 g, 95%) was obtained.

Trifluoroacetic acid (0.5 mL) was added to t-butyl 3-[(isobutyrylphenylamino) methylpiperidine-1-carboxylate in 0.5 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water). It was added dropwise to a solution of ester (2) (106 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removing the solvent, the residue was dried under vacuum for 3 hours. The crude product was used in the next step without purification.

The crude compound obtained in the previous step was dissolved in CH ₃ CN (1.0 mL) and K ₂ CO ₃ (122 mg) and (2-bromoethyl) benzene (82 μl, 2 eq).
Was added. The mixture was stirred at 50 ° C. overnight. After cooling to room temperature, 5 mL
10% NaOH was added. The organic layer was separated. The aqueous layer was washed with EtOAc (2 x 10 m
L). The combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The oily residue that remained was separated by preparative thin layer chromatography (EtOAc / MeOH, 9: 1).
Was purified by to give N- (1-phenethylpiperidin-3-ylmethyl) -N-phenylisobutyramide (123) as a colorless oil (92 mg, 86%). LRMS345.

Example 83 N-phenyl-N- [1- (3-phenylpropylyl) piperidin-3-ylmethyl)] isobutyramide (124)

[0696]

[Chemical 98]

N-Phenyl-N- [1- (3-phenylpropylyl) piperidin-3-ylmethyl)] isobutyramide (124) was synthesized by the procedure shown in Example 84. L
RMS379.

Example 84 N- [1- (1-Methyl-2-phenethyl) piperidin-3-ylmethyl] -N
-Phenylpropionamide (125 and 126)

[0699]

[Chemical 99]

Trifluoroacetic acid (1.0 mL) was added to (R) -N- (1-Boc-peridin-3-ylmethyl) -N- in 1.0 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water). Phenylpropionamide (101 mg, 0.29 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removing the solvent, the crude product was used in the next step without purification.

The crude compound obtained in the previous step was dissolved in acetonitrile (1.0 mL) and
2-Bromo-1-phenylpropane (293 μL, 2 eq) and K ₂ CO ₃ (1
20 mg) was added. The mixture was stirred at 50 ° C overnight. 5 mL of this mixture
After quenching with 10% aqueous KOH solution, it was extracted with ethyl acetate (3 x 10 mL). The extracts were combined and aqueous NaHCO ₃ solution (saturated, 2 × 5 mL), brine (
10 mL) and dried over anhydrous sodium sulfate. After removing the solvent,
The oily residue that remained was subjected to preparative thin layer chromatography (EtOAc / MeOH, 95:
5) and N- [1- (1-methyl-2-phenethyl) piperidine-
3-ylmethyl] -N-phenylpropionamide was added as a colorless oil (66 mg,
62%). LRMS 365.

N- [1- (1-methyl-2-phenethyl) piperidin-3-ylmethyl]-
The diastereomer of N-phenylpropionamide was extracted with hexane (0.2) in a chiral column (Chiral Pack AD. Column No.
% Diethylamine): iPrOH (98: 2). The first compound eluted from the column is arbitrarily designated 125 and the second compound eluted from the column is 12
It was set to 6.

Example 85 N-Phenyl-N- [1- (2-phenylpropyl) piperidin-3-ylmethyl] propionamide (127 and 128)

[0704]

[Chemical 100]

Trifluoroacetic acid (1.0 mL) was added to (R) -N- (1-Boc-peridin-3-ylmethyl) -N- in 1.0 mL dry CH ₂ Cl ₂ at 0 ° C. (ice water). A phenylpropionamide compound (158 mg, 0.46 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removing the solvent, the crude product was used in the next step without purification.

This crude compound was dissolved in DMF (1.5 mL) and 2-phenylpropionaldehyde (93 μL, 1.5 eq) was added. The mixture was stirred at room temperature for 30 minutes. NaB (OAc) ₃ H (153 mg, 1.5 eq) was introduced in one shot,
The mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of 10% aqueous NaOH and then extracted with ethyl acetate (3 x 10 mL). The extracts were combined and washed with aqueous NaHCO ₃ (saturated, 2 × 5 mL), brine (10 mL),
It was dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc / MeOH, 95: 5),
N-phenyl-N- [1- (2-phenylpropyl) piperidin-3-ylmethyl] propionamide was obtained as a colorless oil (119 mg, 71%). LR
MS 365.

The diastereomer of N-phenyl-N- [1- (2-phenylpropyl) piperidin-3-ylmethyl] propionamide is a chiral column (Chiral Pack A
D. Column No. Separation with hexane (0.2% diethylamine): iPrOH (98: 2) in AD00CG-1F001). The first compound eluted from the column was arbitrarily designated 127 and the second compound eluted from the column was designated 128.

Example 86 N- [1- (1-phenethylpiperidin-3-yl) ethyl] -N-phenylpropionamide (129)

[0709]

[Chemical 101]

3- (1-Hydroxyethyl) piperidine-1 in 0.5 mL CH ₂ Cl _2.
To a stirred solution of dicarboxylic acid t-butyl ester (1) (31 mg, 0.135 mmol) and piperidinomethyl polystyrene resin (60 mg) was added methanesulfonyl chloride (15.7 μL, 1.5 eq). This mixture at room temperature for 6
Stir for 0 minutes. After removing the solvent, aniline (50 μL) was introduced. The mixture was heated at 95 ° C overnight. The crude product was purified by preparative thin layer chromatography (EtOAc
/ MeOH, 1: 2) to give 3- (1-phenylaminoethyl) piperidine-1-dicarboxylic acid t-butyl ester (2) (21 mg, 51%).
).

Composition 129 was made from 2 using the last multiple steps of the procedure described in Example 81. LRMS 365.

Example 87 1- (1-phenethylpiperidin-3-ylethyl) -3,4-dihydro-1H
-Quinolin-2-one (130)

[0713]

[Chemical 102]

3,4-Dihydro-1H-quinolin-2-one (96
mg, 0.65 mmol) was added NaH (26 mg, 1 eq). The mixture was stirred at room temperature for 45 minutes. 3-iodomethylpiperidine-carboxylic acid t-butyl ester (200 mg, 0.62 mmol) in 0.5 mL DMF was added to
It was slowly introduced into the reaction mixture. The reaction was continued for 1 hour at room temperature. The mixture was diluted with 10 mL EtOAc and aq. HCl (5%, 5 mL), NaHC
It was washed with O ₃ aqueous solution (saturated, 5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After removing the solvent, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc / MeOH, 3: 7) to give 3- (2-oxo-3,4-dihydro-2H-quinoline-1-). Ilmethyl) piperidine-1-carboxylic acid t-butyl ester (2) was obtained as a colorless oil (80 mg, 37%).

3- (2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl) piperidine-1-dicarboxylic acid t-butyl ester (2) was prepared according to the last multiple steps of the procedure described in Example 81. Using 1- (1-phenethylpiperidin-3-ylethyl) -3,4-dihydro-1H-quinolin-2-one (130) (68 mg, 8
5%). LRMS349.

Example 88 N-4-t-Butoxycarbonyl-1-carbobenzyloxy (2-anilinocarboxy) piperazine (131)

[0717]

[Chemical 103]

4-Boc-1-Cbz-piperazine- in CH ₂ Cl ₂ (15 mL) at 0 ° C.
2-carboxylic acid (2.66 mmol, 0.970 g and aniline (1.1 eq,
2.93 mmol, 270 μL) was treated with DCC (2.0 eq, 5.32 mmol, 1.10 g) under argon atmosphere. The reaction mixture was warmed to 25 ° C. and stirred for 12 hours. The reaction mixture was then filtered to remove urea and the solvent removed in vacuo. Chromatography (SiO ₂ , 2.5 cm x 30.5 cm,
With 1: 1 hexane-EtOAc, 131 (1.15 g, theoretical 1.1).
5 g, 98%) was obtained as a white foam. ^{_{LRMS m / z 439 (M +}} , requiring _{C 24 H 29 N 3 O 5} , 439).

Example 89 N-4-t-butoxycarbonyl-1-carbobenzyloxy (2-anilinomethyl) piperazine (132)

[0720]

[Chemical 104]

A solution of 131 (0.519 mmol, 228 mg) in THF (15 mL) at 0 ° C. was added under argon atmosphere to 1.0 Mol of BH ₃ -THF (2.5 eq, 1 eq.
． 30 mmol). The reaction mixture was warmed to 80 ° C. and stirred for 12 hours. Then the reaction mixture was cooled to 0 ° C. and quenched with 10% aqueous HCl. The reaction mixture was adjusted to pH 10 with 10% aqueous NaOH and adjusted to EtO.
Extracted with Ac (3 x 25 mL). The organics were washed with brine, dried over MgSO _4, to give the crude product 132.

Example 90 N- (4-t-Butyloxy-1-carbobenzyloxypiperazin-2-ylmethyl) -N- (anilino) cyclopropionamide (133)

[0723]

[Chemical 105]

[0724]   CH at 0 ℃_TwoCl_TwoCrude aniline intermediate (132) (0.519 mmol) in
Solution of cyclopropane carbonyl chloride (1.5 eq,
0.779 mmol, 77 μL) and diisopropylethylamine (2.0 eq.
, 1.04 mmol, 181 μL). Warm the reaction mixture to 25 ° C
It was stirred for 12 hours. Then the reaction mixture was washed with 10% NaHCO._ThreeAqueous solution
Enchi The reaction mixture was acidified with 10% aq. HCl and extracted with EtOAc (3 x
25 mL). Chromatography (PTLC, SiO_Two, 20 cm x 2
0 cm, 1 mm, 1: 2 EtOAc-Hexane) gave 133 (136 mg,
Theoretically 256 g, 53%) was obtained as a colorless oil: Rf 0.22 (
SiO_Two, 1: 2 EtOAc-hexane) LRMS m / z 493 (M⁺, C ₂₈ H₃₅N_ThreeO₅, 493).

[0725] Example 91 N-1-carbobenzyloxy (4-phenethyl - piperazin-2-ylmethyl) -N- (Aniri Roh) cycloalkyl propionamide (134)

[0726]

[Chemical formula 106]

A solution of 133 (0.079 mmol, 39 mg) in CH ₂ Cl ₂ (1 mL) at 25 ° C. was added to 50% TFA in CH ₂ Cl ₂ (
1 mL) solution. The reaction mixture was stirred for 2 hours. The solvent was removed in vacuo and the resulting oil was dried under high vacuum for 12 hours. The oil was then treated with phenethyl bromide (4.5 eq, 0.36 mmol, 49 mL) and K ₂ CO ₃ (5.0 eq, 0.39 mmol, 55 mg) in C.
Treated in H ₃ CN (250 mL) solution. The reaction mixture was stirred at 60 ° C. for 12 hours. The reaction mixture was directly purified by chromatography (PTLC, SiO ₂ , 20 cm × 20
cm, 1 mm, 1: 2 EtOAc? hexane) yielded 134 (29 mg, 38 mg theoretical yield, 76%) as a colorless oil. R _f 0.28 (SiO ₂ , 1: 2 EtOAc-hexane); LRMS m / z 497
(M +, C ₃₁ H ₃₅ N ₃ O ₃ requires 497).

[0728] Example 92 N-4-phenethyl - piperazin-2-ylmethyl) -N- (anilino) cycloalkyl propionamidine de (135)

[0729]

[Chemical formula 107]

A solution of 134 (0.048 mmol, 24 mg) in CH ₃ OH (1 mL) at 25 ° C. was treated with 10% Pd—C (20 mg) and then placed under a hydrogen atmosphere. After stirring the reaction mixture for 12 hours,
Filter through a pad of Celite. The solvent was removed in vacuum. The reaction mixture was directly purified by chromatography (PTLC, SiO ₂ , 20 cm × 20 cm, 1 mm, EtOAc? 10% CH ₃ O
H) gave 135 (12 mg, 18 mg theoretical yield, 67%) as a colorless oil: R _f 0.
22 (SiO ₂ , EtOAc? 10% CH ₃ OH); LRMS m / z 363 (M +, C ₂₃ H ₂₉ N ₃ O requires 363).

Example 93 N-1-Methyl (4-tert-butyloxypiperazin-2-ylmethyl) -N- (anilino) shik
Ropropionamide (136)

[0732]

[Chemical 108]

A solution of 133 (0.18 mmol, 90 mg) in CH ₃ OH (1.5 mL) at 25 ° C. was added to 10% Pd-C (20 mg).
After treatment with paraformaldehyde (11 mg), the mixture was placed under a hydrogen atmosphere. The reaction mixture was stirred for 12 hours and then filtered through a pad of Celite. The solvent was removed in vacuo and the resulting oil was purified by chromatography (PTLC, SiO ₂ , 20 cm × 20 c
m, 1 mm, EtOAc? 10% CH ₃ OH) yielded 136 (38 mg, 68 mg theoretical yield, 56%) as a colorless oil: R _f 0.40 (SiO ₂ , EtOAc? 10% CH ₃ OH); LRMS m / z 373 (M +,
C ₂₁ H ₃₁ N ₃ O ₃ requires 373).

Example 94 N-1-Methyl (4-phenethyl-piperazin-2-ylmethyl) -N- (anilino) cyclopro
Pionamide (137)

[0735]

[Chemical 109]

Compound 136 (0.091 mmol, 34 mg) was treated with a solution of 50% TFA in CH ₂ Cl ₂ (1 mL) at 25 ° C. The reaction mixture was stirred for 2 hours. The solvent was removed in vacuo and the resulting oil was dried under high vacuum for 12 hours. The oil thus produced was then combined with phenethyl bromide (2.0 eq, 0.18 mmol, 25 mL) and K ₂ CO ₃ (2.0 equiv, 0.18 mmol, 25 mg).
) In CH ₃ CN (300 mL). The reaction mixture was stirred at 60 ° C. for 12 hours. The reaction mixture was directly purified by chromatography (PTLC, SiO ₂ , 20 cm × 20
cm, 1 mm, EtOAc? 10% CH ₃ OH) yielded 137 (34 mg, 34 mg theoretical yield, 99%) as a colorless oil: R _f 0.33 (SiO ₂ , EtOAc? 10% CH ₃ OH). ); LRMS m / z 377 (M +
, C ₂₄ H ₃₁ N ₃ O requires 377).

Example 95 N- (1-cyclohexylethyl-piperidin-3-R-ylmethyl) -N- (anilino-3-yl) propionamide (139)

[0738]

[Chemical 110]

[0739]   138 (0.471 mmol, 116 mg) CH at 25 ℃₃OH (1 mL) solution with 10% Pd-C (20 mg)
After treatment, it was placed under a hydrogen atmosphere. After stirring the reaction mixture for 12 hours,
Filter through a pad of Celite. The solvent was removed in vacuo and the oil thus produced was washed with
1-bromo-2-cyclohexylethane (1.5 equivalents, 0.707 mmol, 111 mL) and K₂CO ₃  (1.5 eq, 0.707 mmol, 98 mg) CH₃Treated with CN (1 mL) solution. This reaction mixture
The combined solution was stirred for 12 hours at 60 ° C. This reaction mixture is then chromatographed
Direct purification (PTLC, SiO₂, 20 cm × 20 cm, 1 mm, EtOAc? 10% CH₃OH) Then, 13
9 (137 mg, 168 mg theoretical yield, 82%) occurred as a yellow oil: R_f0.29 (SiO₂,
EtOAc? 10% CH₃OH); LRMS m / z 356 (M +, C_{twenty three}H₃₆N₂O requires 356).

Example 96 N- (1- (3-ethylindole) piperidin-3-R-ylmethyl) -N- (anilino-3-yl)
Propionamide (140)

[0741]

[Chemical 111]

A solution of 138 (0.451 mmol, 172 mg) in CH ₃ OH (1 mL) at 25 ° C. was treated with 10% Pd—C (20 mg) and then placed under a hydrogen atmosphere. After stirring the reaction mixture for 12 hours,
Filter through a pad of Celite. After removing the solvent in vacuo, the resulting oil was 3- (2-
It was treated with a solution of bromoethyl) indole (1.5 eq, 0.677 mmol, 152 mg) and K ₂ CO ₃ (1.5 eq, 0.677 mmol, 94 mg) in CH ₃ CN (1 mL). This reaction mixture is
Stir at 60 ° C. for hours. The reaction mixture is then directly purified by chromatography (
PTLC, SiO ₂ , 20 cm × 20 cm, 1 mm, EtOAc? 10% CH ₃ OH) gives 140 (176 mg,
88 mg theoretical yield, 50%) occurred as a yellow oil: R _f 0.22 (SiO ₂ , EtOAc? 10% CH ₃ O
H); LRMS m / z 389 (M +, C ₂₅ H ₃₁ N ₃ O requires 389).

Example 97 N- (1- (1,1-difluoroethylbenzene) piperidin-3-R-ylmethyl) -N- (anili
No-3-yl) propionamide (141)

[0744]

[Chemical 112]

A solution of 138 (0.487 mmol, 185 mg) in CH ₃ OH (1 mL) at 25 ° C. was treated with 10% Pd—C (20 mg) and then placed under a hydrogen atmosphere. After stirring the reaction mixture for 12 hours,
Filter through a pad of Celite. After removing the solvent in vacuo, the resulting oil was converted to (2-bromo-1,1-difluoroethyl) benzene (1.5 eq, 0.731 mmol, 162 mg) and K ₂ CO ₃ (1.5 eq, 0.731 mmol, 101 mg). ) In CH ₃ CN (1 mL) solution. The reaction mixture was stirred for 12 hours at 60 ° C. The following reaction mixture was directly purified by chromatography (PTLC, SiO ₂ , 20 cm × 20 cm, 1 mm, 2: 1 hexane? EtOAc) to give 141 (20 mg, 188 mg theoretical yield, 11%) as yellow. Produced as an oil of: R _f 0.52 (Si
O _{2, 2:?} 1 hexanes EtOAc); LRMS m / z 386 (M +, C 23 H 28 F 2 N 2 O requires 386).

Example 98 1-Benzyl-azepan-2-one (142)

[0747]

[Chemical 113]

To a suspension of NaH (18.3 g, 763 mmol) in THF (195 mL) at 0 ° C. with stirring was added a solution of azepan-2-one (75.0 g, 667 mmol) in THF through an addition funnel. . An additional 2 L of solvent was added as the reaction proceeded to allow the stirring of this very viscous reaction suspension to be maintained. After the addition, the reaction solution was warmed to room temperature and stirred overnight, and when hydrogen gas was completely generated, benzyl bromide was added dropwise through an addition funnel, and the reaction solution was stirred overnight. The crude product was filtered through Celite and concentrated in vacuo. Recrystallization of hexane and ethyl acetate gave pure 1-benzyl-azepan-2-one (142) as a white fluffy solid. ¹ H NMR (CDCl ₃ ) 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. ¹³ C NMR (CDCl ₃ , 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-azepan-3-carboxylic acid methyl ester (143)

[0750]

[Chemical 114]

LDA was prepared as follows. Freshly distilled diisopropylamine (15.2 mL, 110 mmol) under N ₂ and CaH ₂ was added to 110 mL 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. Freshly prepared LDA was dissolved in anhydrous Et ₂ O (70 mL) at -70 ° C 1-benzyl-azepan-2-one (142) (10.
98 g, 544.0 mmol) was added dropwise to the solution. The reaction solution was stirred at 70 ° C. for 1 hour, and dimethyl carbonate (4.55 mL, 544 mmol) was added dropwise. The reaction was warmed to room temperature overnight. After the completion of the HPLC reaction was judged, the reaction solution was slowly poured into 5N HCl stirred in an ice bath. The organic layer was extracted. The aqueous layer CH ₂ C
washed twice with l _2, the compound organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by autoflash column with 80:20 hexane: EtOAc to give 10.85 g, (77%) of 1-benzyl-2-oxo-azepan-3-carboxylic acid methyl ester (143). Obtained as a pale yellow oil. ¹ H NMR (CDCl ₃ ) 7.42-7.10
(5H, wide 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. ¹³ C NMR (CDCl ₃ ,
75 MHz) 171.94, 171.04, 137.28, 128.55, 128.24, 127.43, 52.15 (2), 51.2
7, 48.31, 27.87, 27.41, 25.91 ppm. LRMS: 261.73.

Example 100 (1-Benzyl-azepan-3-yl) -methanol (144)

[0753]

[Chemical 115]

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 THF of LiAlH ₄ under stirring.
(1.5 mL) was added to the suspension over about 1.5 hours. The reaction mixture was stirred overnight. The reaction was judged complete by TLC and the reaction mixture was H ₂ O (0.4 mL) followed by 2N NaOH (1.
It was quenched by sequentially adding 0 mL) and H ₂ O (0.4 mL). The mixture was stirred at room temperature for 30 minutes then filtered, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by automated silica gel chromatography with EtOH in 15: 85: 5 CH ₂ Cl ₂ : hexane: 2N NH ₃ to give 0.1062 g (59%) of pure (1-benzyl-azepane). -3-yl) -methanol (144) was obtained. ¹ H NMR (CDCl ₃ ) 7.40-7.23 (5H, m), 3
.65 (2H, s), 3.54 (1H, dd, J = 10.4, 3.5 Hz), 3.43 (1H, dd, J = 10.4, 5.
4 Hz), 2.82 (1H, J = 13.3, 3.1Hz), 2.77 (2H, m), 2.44 (1H, ddd, J = 12.2
, 8.6, 3.3 Hz), 1.90 1.45 (6H, m) ppm. ¹³ C NMR (CDCl ₃ , 75 MHz) 139.14
, 128.97, 128.14, 126.91, 67.20, 63.85, 58.49, 56.87, 39.59, 29.68, 29.4
3, 25.23 ppm. LRMS: 219.64.

Example 101 Azepan -3-yl-methanol (145)

[0756]

[Chemical formula 116]

(1-benzyl-azepan-3-yl) -methanol (144) (0.0922g, 0.4192 mmol)
What was dissolved in MeOH (1 mL) was added to a stirring 5% MeOH suspension of 10% Pd / C (14.4 mg). The reaction mixture was purged with H _2, at room temperature overnight and the reaction solution was stirred. The completion of the reaction was judged by ¹ H-NMR analysis of one aliquot taken from the reaction solution. The reaction was filtered through a pad of Celite moistened with MeOH, rinsed with MeOH,
Concentrate in vacuo to give pure azepan-3-yl-methanol (145) in 60% yield (0.
0323g). Compound 145 was used in the next example without further purification. ¹ H
NMR (CDCl _3, a portion) 3.14-2.70 (4H, m), 1.92-1.73 (4H, m), 1.68-1.42 (3H,
m) ppm. ¹³ C NMR (CDCl ₃ , 75 MHz) 67.32, 52.01, 50.33, 41.31, 31.05, 29.
76, 25.44 ppm.

Example 102 3-Hydroxymethyl-azepan-1-carboxylic acid benzyl ester (146)

[0759]

[Chemical 117]

[0760]   Potassium carbonate was added to azepan-3-yl-methanol (145) (0.032g, 0.2485 mmol).
 THF / H₂O (2: 1, 0.31 mL) was added to the mixture. The suspension is cooled to 0 ° C., (
Benzyloxy) carbonyl chloride (0.071 mL, 0.497 mmol) was added dropwise.
. The reaction was warmed to room temperature overnight then concentrated in vacuo. CH₂Cl₂ And H ₂ O was added. Extract the organics, wash with brine and dry over sodium sulfate.
Filtered, concentrated in vacuo. Charge the crude material with 75:25 hexane: EtOAc.
Purified by automated silica gel chromatography, 3-hydroxymethyl-azepane
1-Carboxylic acid benzyl ester (146) was obtained in a yield of about 94%.

Since 146 has a cbz group, many of the peaks obtained in ¹ H and ¹³ C NMR spectra appear as two sets of peaks. The values in brackets listed are for the smaller of the two sets of peaks corresponding to the same proton or carbon. ¹ H NMR (CDCl ₃ ) 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. ¹³ C NMR (CDCl ₃ , 75 MHz) 157.02 (156.06), (
136.89) 136.74, 128.42, 127.91, 127.66, 67.16 (66.87), (65.27) 64.69, (4
8.12) 47.89, (42.13) 41.23, (30.05) 29.78, 28.78 (28.11), (24.87) 24.61,
14.13 ppm.

Example 103 3-Formyl-azepan-1-carboxylic acid benzyl ester (147)

[0763]

[Chemical 118]

Dess-Martin periodonazine (2.78 g, 6.56 mmol) was stirred at 0 ° C. with 3-hydroxymethyl-azepan-1-carboxylic acid benzyl ester (14
6) (1.2516 g, 5.02 mmol) in CH ₂ Cl ₂ (18.2 mL) was slowly added. The reaction was stirred for 1 hour until the reaction was judged to be complete by HPLC. The reaction was concentrated in vacuo, it was added a small amount of CH ₂ Cl _2. Et ₂ O was added to precipitate the by-product of periodonazine, the reaction was filtered, concentrated and immediately purified on an automated silica gel column with 1: 1 hexane: EtOAcuct to give pure 3-formyl-azepane- 1-Carboxylic acid benzyl ester (147) (0.3086 g) was obtained in a yield of 62%.

Since 147 has a Cbz group, most of the peaks obtained in ¹ H and ¹³ C NMR spectra appear as two sets of peaks. The numbers in parentheses listed are for the smaller of the two sets of peaks corresponding to the same proton or carbon. ¹ H NMR (C
DCl ₃ ) 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. ¹³ C NMR
(CDCl ₃ , 75 MHz) 202.52 (202.35), 155.98 (155.55), (136.59) 136.44, 128.3
1, 127.81, 127.61, 66.97, (51.57) 51.20, (48.68) 48.20, 46.02 (45.43), 2
8.67 (28.23), (26.27) 26.09, (24.37) 24.30 ppm.

Example 104 3- Phenylaminomethyl -azepan-1-carboxylic acid benzyl ester (148)

[0767]

[Chemical formula 119]

Aniline (0.126 mL, 1.38 mmol) was added to a solution of 3-formyl-azepan-1-carboxylic acid benzyl ester (147) (0.300 g, 1.15 mmol) in 5% HOAc in MeOH (11.5 mL). After stirring the reaction mixture for about 20 _{minutes, NaBH 3 CN (0.2164g, 3.44} mmol) was added slowly, at room temperature overnight and the reaction solution was stirred. The reaction was then concentrated in vacuo and EtOA and a few drops of 10% NaOH were added. The organics were washed with saturated NaCl (aq), dried over Na ₂ SO ₄ and concentrated in vacuo to give crude 3-phenylaminomethyl-azepan-1-carboxylic acid benzyl ester (148). Compound 148 was used in the next step without further purification.

Example 105 3-[(Phenyl-propionyl-amino) -methyl] -azepan-1-carboxylate benzyl
Ester (149)

[0770]

[Chemical 120]

Et (iPr) ₂ N (0.24 mL, 1.38 mmol) was added to a stirring solution of crude 3-phenylaminomethyl-azepan-1-carboxylic acid benzyl ester (148) in CH ₂ Cl ₂ (2.3 mL). Added under nitrogen gas. The reaction solution was cooled to 0 ° C in an ice bath, and then propionyl chloride (0.2
2 mL, 2.53 mmol) was added dropwise. The reaction was warmed to room temperature overnight.
The completion of the reaction was judged by TLC. Concentrate in vacuo and add EtOAc and 10% NaOH (aq). The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo 96: 2
: [2: Hexane: CH ₂ Cl ₂ : 2N NH ₃ dissolved in EtOH and purified by automated silica gel chromatography to give 3-[(phenyl-propionyl-amino) -methyl] -azepane.
-1-Carboxylic acid benzyl ester (149) (0.3266g) was obtained in two steps in 72% yield.

Because 149 has a Cbz group, many of the peaks generated in the ¹ H and ¹³ C NMR spectra appear as two sets of peaks. The numbers in parentheses listed are the smaller of the two sets of peaks corresponding to the same proton or carbon. ¹ H NMR (CDCl ₃ ) 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 (9
H, m) ppm. ¹³ C NMR (CDCl ₃ , 75 MHz) (174.1) 1743.98, 156.15 (156.03), 14
2.71, (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.

Example 106 N- (1-phenethylaminomethyl-azepan-3-ylmethyl) -N-phenylpropione
Amide (150)

[0774]

[Chemical 121]

3-[(Phenyl-propionyl-amino) -methyl] -azepan-1-carboxylic acid benzyl ester (149) and phenylacetaldehyde (0.148 mL, 1.27 mmol) 1.
A 5 mL MeOH solution was added to a 7.0 mL MeOH suspension of 10% Pd / C (0.0553g). The reaction mixture was shaken under 40 psi of hydrogen gas until the consumption of hydrogen gas ceased, and the completion of the reaction was judged by TLC. The crude reaction mixture was passed through a column of Celite moistened with MeOH, concentrated in vacuo, and subjected to flash column chromatography with 80: 18: 2 hexane: CH ₂ Cl ₂ : 2N NH ₃ in EtOH. Purified to N- (1-phenethylaminomethyl-azepan-3-ylmethyl) -N-phenylpropionamide (150) (0.0404g)
Was obtained in a yield of 43%. ¹ H NMR (CDCl ₃ ) 7.47-7.15 (10 H, m), 3.64 (2 H, wide
dd, J = 7.5, 1.8 Hz), 2.82-2.59 (4H, m), 2.74 (4H, wide 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. ¹³ C NMR (CDCl ₃ , 75 MHz) 174.
23, 143.08, 140.88, 129.85, 128.93, 128.46 (2), 127.91, 126.01, 61.22, 5
8.35, 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

[0777]

[Chemical formula 122]

A solution of dibromide 153 (30.0 g, 122 mmol) in 500 mL of isopropanol was cooled to 0 ° C. A solution of dibenzylethylenediamide (122 mmol, 28.8 mL) and triethylamine (TEA) (269 mmol, 2.2 eq, 37.5 mL) in 125 mL of isopropanol was added dropwise to this well stirred solution over 1 hour. (White precipitate TEA-H
Br is formed). Add all and add the addition funnel to isopropanol (3 x 10 mL).
After rinsing, the cooling bath was removed and the solution was heated to reflux slowly for 3 hours. The solution was placed in a 20 ° C. freezer overnight. The precipitated TEA-HBr was filtered off 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 THF. The solution was cooled to 20 ° C. and then filtered to remove further TEA-HBr. The filtrate was concentrated on a rotary evaporator and placed under 1 mm of mercury vacuum overnight to add acid 154 to a viscous brown foam (33 g).
Which was not purified further.

Example 108 Synthesis of diazepine 155

[0780]

[Chemical 123]

A solution of crude acid 154 (33 g) in 400 mL of THF was cooled to 0 ° C. 250 mL of 1 M LAH in THF was added dropwise over 45 minutes. The cooling bath was removed and the solution was heated to gentle reflux for 45 minutes and cooled to 0 ° C. The well-stirred cold solution was quenched by the dropwise addition of 10 mL of water, 10 mL of 1 M NaOH, and 30 mL of water. The suspension is stirred for 30 minutes, filtered and the filter cake is washed.
Wash with THF and methylene chloride. The filtrate was concentrated on a rotary evaporator and then placed under 1 mm mercury vacuum overnight to give a yellow viscous oil (155) (28 g, 74%, two-step crude yield). The product can be purified by gel chromatography using EtOAc with 0.5% ammonium hydroxide as eluent to give a colorless oil, but the crude material was often not purified.

Example 109 Synthesis of diazepine 156

[0783]

[Chemical formula 124]

A solution of crude alcohol 155 (28 g, 90.3 mmol) in 100 mL of methylene chloride was stirred at 25 ° C. TEA (1.1 eq, 99.3 mmol, 13.8 mL) was added, followed by 50 mL of TBDMSCl (1.05 eq, 94.8 mmol, 14.3 g) and DMAP (0.02 eq, 1.8 mmol, 220 mg).
Of methylene chloride solution was added. The solution was then cloudy, but the suspension was stirred overnight and then filtered. The filtrate was concentrated on a rotary evaporator. 1 residue
It was dissolved in 50 mL of chloroform, the solution was washed with water in a separating funnel, then dried over sodium sulphate and filtered. After concentrating the filtrate on a rotary evaporator, it was placed under 1 mm of mercury vacuum overnight to produce a yellow to brown viscous oil, which contained about 0.5% containing 80:20 hexane: EtOAc. The product was purified on silica gel using ammonium hydroxide. A colorless oil 156 (32 g, 83%) was obtained.

[0785] Example 110 Synthesis of diazepine 157

[0786]

[Chemical 125]

A solution of crude diamine 156 (16 g, 37.7 mmol) in 50 ml of methanol was placed in a dry Parr bottle, and 20% palladium hydroxide catalyst (about 3 g) was added. After vacuum pumping, the suspension was hydrogenated overnight on a par shaker with hydrogen pressure of 50 psi. The suspension was filtered and the filter cake washed with methylene chloride. The filtrate was concentrated on a rotary evaporator to give a colorless oil 157, some of which permanently solidified (9.1 g, 99%).

[0788] Example 111 Synthesis of diazepine 158

[0789]

[Chemical formula 126]

Diamine 157 (2.1 g, 8.6 mmol) was standardized at 0 ° C. using methylene chloride (80 mL) as a solvent, 2.2 equivalents of N-methylmorpholine and phenylacetyl chloride, water treatment, and silica gel chromatography. Used to convert to bisamide 158. Bisamide 158 separated as a colorless foam (3.9 g, 94%).

[0791] Example 112 Synthesis of diazepine 159

[0792]

[Chemical 127]

The silyl ether (3.9 g, 8.1 mmol) was added as a solvent in THF (80 m) according to a standard method at 25 ° C.
L), commercially available 1 M tetrabutylammonium fluoride in THF 1.1 eq, treated with water, and converted to alcohol 159 using silica gel chromatograph. Alcohol 159
Isolated as a colorless foam (2.2g, 73%).

[0794] Example 113 Synthesis of diazepine 160

[0795]

[Chemical 128]

Alcohol 159 (2.16 g, 5.9 mmol) was standardized at 25 ° C. using methylene chloride (50 mL) as solvent, 1.2 equivalents of commercially available Dess-Martin periodinane reagent, 1N NaOH 5
Aldehyde 160 using 0 mL treatment, water treatment and silica gel chromatograph
Converted to. Aldehyde 160 was isolated as a colorless solid (1.8g, 85%).

[0797] Example 114 Synthesis of diazepine 161

[0798]

[Chemical formula 129]

Aldehyde 160 (1.08 g, 3.0 mmol) was standardized at 25 ° C. using 99: 1 trimethylorthoformate: acetic acid (20 mL) as solvent, 1.1 eq aniline (3.3 mmol) and 1.5 hours later Add an equivalent amount of a commercially available 1M sodium cyanoborohydride THF solution (8.9 mmol),
Converted to amine 161. Water treatment and silica gel chromatograph (eluent: 90: 10: 1
Ethyl acetate: hexane: ammonium hydroxide) gave colorless amine foam 161.

[0800] Example 115 Synthesis of diazepine 162

[0801]

[Chemical 130]

Amine 161 (0.9 g, 2.0 mmol) was added by standard method using THF (15 mL) as a solvent, 6 equivalents (12 mmol) of commercially available 1M lithium ammonium hydride THF solution at 0 ° C., and then refluxed for 1 hour. Converted to amine 162. Quench by dripping water / 1N NaOH / water, dilute with methylene chloride, filter through slurry, and chromatograph on silica gel (eluent: 100:
1 ethyl acetate: ammonium hydroxide), the colorless oily amine 162 (0.
58g, 69%) was obtained. Physical data for Compound 162: ¹ H NMR (CDCl ₃ , free base): d 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.

[0803] Example 116 Synthesis of diazepine 163

[0804]

[Chemical 131]

Amine 162 (0.55 g, 1.3 mmol) was standardized at 0 ° C. using methylene chloride (5 m
L), N-methylmorpholine and propionyl chloride were both converted to amide 163 using 1.1 eq (1.5 mmol), water treatment, and silica gel chromatography. The amide 163 was isolated as a colorless foam (0.56g, 90%). The HCl salt was prepared by dissolving 163 in methanol (1.5 mL), adding 1.5 mL of a commercial 4N HCl dioxane solution and concentrating in vacuo. Physical data for Compound 163: ¹³ C NMR (CDCl ₃ , free base): d 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, 10.0. ¹ H NMR (CDCl ₃ , free base): d 7.1-7.4 (m, 15
H), 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.

[0806] Example 117 Synthesis of (1-benzyl-piperidin-3-yl) -phenyl-amine 164

[0807]

[Chemical 132]

1-Benzyl-piperidin-3-one hydrochloride (2.02 g, 8.95 mmol) and aniline (1
NaCNBH3 (1.8 g, 28.64 mmol) was added to a solution of .67 ml, 17.89 mmol) in methanol (20 mL) in several portions. The mixture was stirred overnight. The mixture was dissolved in 50 ml of water, the pH was brought to 12 with 2N KOH and extracted with CH ₂ Cl ₂ (3x50 ml). A standard treatment of the organic solution gave 164 as a dry residue, which was used in the next step without further purification. LRMS (calculated for C ₁₈ H ₂₂ N ₂ ) 266 was 266.

Example 118 Synthesis of N- (1-benzyl-piperidin-3-yl) -N-phenyl-propionamide (165)
CH ₂ C of crude (1-benzyl-piperidin-3-yl) phenyl-amine (164) (1.11 g) at 0 ° C.
To the l ₂ (5 ml) solution was added i-Pr ₂ NEt (1.45 ml) and propionyl chloride (0.54 ml). The mixture was stirred for 2 hours. The mixture was diluted with CH ₂ Cl ₂ (20 ml) and saturated NaHCO ₃ (2
x10 ml), brine (10 ml), and water (10 ml), and dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated under vacuum. Silica gel chromatography (0.5% to
Purification with 2% MeOH in CH ₂ Cl ₂ ) gave 165 as a colorless oil. LRMS (calculated for C ₂₁ H ₂₆ N ₂ O) 322 was 322; IR (film) 3059, 2937, 2863, 2797, 1
657, 1594, 1499, 1390, 1264, 1101, 1074, 739, 703 cm ^-1

[0810] Example 119 Synthesis of N-phenyl-N-piperidin-3-yl-propionamide (166)

[0811]

[Chemical 133]

N- (1-benzyl-piperidin-3-yl) -N-phenyl-propionamide (165) (150
a mixture of Pd-C (10%, 50 mg) and MeOH (50 ml) under H ₂ (1 atm) for 24 h. The catalyst was removed by filtration through Celite to give 166 as a colorless oil (105 mg, 97
%). ¹ H-NMR (300 MHz, CDCl ₃ ) d 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 ₁₄ H ₂₁ N ₂ On) (M + 1) ⁺ 233 was 233.

Example 120 Synthesis of 3- (phenyl-propionyl-amino) -piperidine-1-carboxylic acid tert-butyl ester (167)

[0814]

[Chemical 134]

[0815]   N-Phenyl-N-piperidin-3-yl-propionamide (166) (105mg, 0.45mmol)
And i-Pr₂Di-tert-butyl dicarbonate (THF) was added to a solution of NEt (0.26 ml, 1.5 mmol) in THF (2 ml).
Medium 1.0, 1.0 ml, 1.0 mmol) was added. The mixture was stirred overnight. After removing the solvent,
CH residue₂Cl₂(10 ml) and add saturated NaHCO 3.₃Wash with water, brine, and water, ₂ SO_FourDried. After filtration, the filtrate was concentrated under vacuum. Short silica residue
Filtration through a gel pad gave 167 as a pale yellow oil.¹H-NMR (300 MHz, CDCl₃)
 d 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 (CH₂₈N₂O₃-Calculate for BOC)⁺ 232 is 232
IR (Film) 2978, 2937, 2860, 1693, 1662, 1698, 1494, 1422,
1363, 1264, 1151, 1386, 1182 cm^-1.

Example 121 3- (S)-(Phenyl-propionyl-amido) -piperidine-1-carboxylic acid tert-butyl ester (168) and 3- (R)-(phenyl-propionyl-amino) -piperidine-1 -HPLC separation of carboxylic acid tert-butyl ester (169)

[0817]

[Chemical 135]

Chiral column (ChiralPak AD column; m = 5 ml / min; l =
Separation with (9: 1) hexane: iPrOH on 254 nm). The first compound to elute from the column (retention time = 4.956 minutes) was randomly designated as structure 168 (S) and the second compound to elute from the column (retention time = 4.956 minutes) was designated as structure 169 (R). did.

Example 122 Synthesis of (R) -N- (1-phenethyl-piperidin-3-yl) -N-phenylpropioamide (170)

[0820]

[Chemical 136]

3 (R)-(Phenyl-propionyl-amino) -piperidine-1-carboxylic acid tert-butyl ester (169) (100 mg) was dissolved in TFA-CH ₂ Cl ₂ (1 ml, 20%) mixture. Stir for 1 hour. After removal of the solvent, the residue was dried under vacuum for 30 minutes, dissolved in 5 ml of CH ₂ Cl ₂ ,
Washed with saturated K ₂ CO ₃ , dried (Na ₂ SO ₄ ) and filtered. The solvent was evaporated and the residue was dissolved in CH ₃ CN (1ml). Then K ₂ CO ₃ (125 mg, 3 eq), water (1 ml), and (2
-Bromoethyl) benzene (0.05 ml, 1.2 eq) was added. The mixture was heated at 70 ° C. for 12 hours. After cooling to room temperature, the mixture was diluted with saturated NaHCO ₃ (5 ml), C
Extracted with H ₂ Cl ₂ (2x10 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and evaporated. Silica gel chromatograph (100% CH ₂ Cl ₂ , 2% -4% MeOH CH ₂ Cl ₂ solution)
) To give 170 as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) d 7.40 (m
, 3H), 7.10 (m, 2H), 4.80 (m, 1H), .20 (m, 1H), 4.00 (m, 1H), 2.40 (m, 2
H), 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 C ₂₂ H ₂₈ N ₂ O ₂ ) ⁺ 336 was 336; IR
(Film) 2978, 2937, 2860, 1693, 1662, 1698, 1494, 1422, 1363, 1264, 1
151, 1386, 1182 cm ^-1 .

Example 123 (S) -N- (1-phenethyl-piperidin-3-yl) -N-phenylpropioamide (171)
Synthesis of

[0823]

[Chemical 137]

3 (S)-(Phenyl-propionyl-amino) -piperidine-1-carboxylic acid tert-butyl ester (168) (100 mg) was dissolved in a TFA-CH2Cl2 (1 ml, 20%) mixture and Stir for hours. After removing the solvent, the mixture was stirred for 1 hour. After removal of the solvent, the residue was dried 30 minutes under vacuum, then dissolved in CH ₂ Cl ₂ 5 ml, washed with saturated K ₂ CO _3, dried (Na ₂ SO _4), and filtered.
The solvent was evaporated and the residue was dissolved in CH ₃ CN (1ml). After that, K ₂ CO ₃ (125m
g, 3 eq), water (1 ml), and (2-bromoethyl) benzene (0.05 ml, 1.2 eq) were added. The mixture was heated at 70 ° C. for 12 hours. After cooling to room temperature, the mixture was diluted with saturated NaHCO ₃ (5 ml) and extracted with CH ₂ Cl ₂ (2x10 ml). Dry the combined organic layers (Na ₂ S
O ₄₎ were, filtered and evaporated. The residue was purified by silica gel chromatography (100% CH ₂ Cl ₂ , 2% -4% MeOH CH ₂ Cl ₂ solution) to give 171 as a colorless oil. ¹ H-NMR (
300 MHz, CDCl ₃ ) d 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 C ₂₂ H ₂₈ N ₂ O ₂ ) ⁺ 336 was 336; IR (film) 2978, 2937, 2860, 1693, 1662, 1698,
1494, 1422, 1363, 1264, 1151, 1386, 1182 cm ^-1 .

[0825] Example 124 Synthesis of (1-benzyl-1,2,5,6, tetrahydro-pyridin-3-yl) methanol (172)

[0826]

[Chemical 138]

Benzyl bromide (7.0 ml) was added to a solution of 3-hydroxymethylpyridine (5.0 g, 45.9 mmol) in acetone (50 ml). The mixture was refluxed for 24 hours. The mixture was cooled to room temperature. The solvent was removed. The residue was dissolved in MeOH (100 ml) and cooled in an ice bath. NaBH ₄ (1.5 eq) was added slowly. After the addition, the mixture was stirred at 0 ° C. for 2 hours. After removing MeOH, aqueous NaHCO ₃ solution (100 ml) was added. The mixture was added to EtOAc (3x100
ml). The combined organic solution was dried (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated under vacuum. Silica gel chromatography (2% -10% MeOH in CH ₂ Cl ₂ ) gave 172 (8.2 g, 88%) as a pale yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ) d 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 ₁₃ H ₁₇ NO) 203 was 203.

[0828] Example 125 Synthesis of (3-benzyl-3-aza-bicyclo [4.1.0] hept-1-yl) -methanol (173)

[0829]

[Chemical 139]

CH ₂ I ₂ (1.4 ml) was added to a solution of ZnEt ₂ (17.3 ml, 1.0 M) in CH ₂ Cl ₂ (20 ml) at 0 ° C. (
Note: Exothermic reaction! ). After stirring for 15 minutes, 172 (352 mg, 1.73 mmol) of CH ₂ Cl ₂ (2 ml
) The solution was added. The mixture was stirred overnight from 0 ° C to room temperature. 5% HCl was added until the mixture became a homogeneous solution (white solid dissolved). The two layers were separated. The aqueous layer was neutralized to pH = 10-12 by adding 2N KOH and extracted with CH ₂ Cl ₂ (twice). The combined organic solution was dried _{(K 2 CO 3 / Na 2} SO 4), filtered and concentrated. The LRMS of the crude mixture is
It was shown that the ratio of 173 and 172 was about 1: 1. The product was not separated from the starting material due to the similar polarities. LRMS (calculated for C ₁₄ H ₁₉ NO) 217 was 217.

[0831] Example 126 Synthesis of 3-benzyl-3-aza-bicyclo [4.1.0] heptane-1-carbaldehyde (174)

[0832]

[Chemical 140]

DMSO (0.3 ml) was added to a solution of oxalyl chloride (0.22 ml, 2.54 mmol) in CH ₂ Cl ₂ (2 ml) at -55 ° C.
A solution of 0 ml, 4.24 mmol) in CH ₂ Cl ₂ (1 ml) was added. The mixture was stirred for 2 minutes. Then, a CH ₂ Cl ₂ (1 ml) solution of the 173 solution (230 mg, 1.06 mmol) was added dropwise. -
After stirring at 55 ° C for 15 minutes, Et ₃ N (1.4 ml) was slowly added. The mixture was stirred for 5 minutes and then warmed to room temperature. Aqueous NaHCO ₃ solution (5 ml) was added. The two layers were separated and the aqueous layer was extracted with _{CH 2 Cl 2 (2x5 ml)} . The combined organics were dried (Na ₂ SO ₄ ), filtered and evaporated to give crude product. Chromatography gave 174 as a pale red liquid. ^{. 1 H-NMR (300 MHz} , CDCl 3) ( part) d 9.42 (s, 1H) , 7.30 (m, 5H); LRMS
(Calculated for C ₁₄ H ₁₇ NO) 215 was 215.

Example 127 (3-benzyl-3-aza-bicyclo [4.1.0] hept-1-ylmethyl) -phenyl-amine (
175) Synthesis

[0835]

[Chemical 141]

3-Benzyl-3-aza-bicyclo [4.1.0] heptane-1-carbaldehyde in 5% HOAc
(174) (300 mg, 1.39 mmol) in MeOH (2 ml) solution, aniline (0.38 ml, 4.18
mmol) and NaCNBH ₃ (250 mg, 3.97 mmol) were added. The mixture was stirred at room temperature for 2 hours. MeOH was removed by evaporation. Water (5 mL) was added to the residue. The mixture was neutralized with 2N KOH to pH = 10. After extraction with CH ₂ Cl ₂ (2 × 10 ml), standard treatment was performed, and silica gel chromatography (1% MeOH in CH ₂ Cl ₂ ) gave crude 175. LRM
Calculated for S (C ₂₀ H ₂₅ N ₂ , M + 1) 293 was 293.

Example 128 Synthesis of N- (3-benzyl-3-aza-bicyclo [4.1.0] hept-1-ylmethyl) -N-phenyl-propionamide (176)

[0838]

[Chemical 142]

[0839]   3-benzyl-3-aza-bicyclo [4.1.0] hept-1-ylmethyl) -phenyl-a at 0 ° C
CH of Min (175) (250 mg, 0.86 mmol)₂Cl₂ (2 ml) solution, add i-Pr₂NEt (0.30 ml,
 1.72 mmol) and propionyl chloride (0.11 ml, 1.29 mmol) were added. This mixture
Stir for 2 hours. CH the mixture₂Cl₂Diluted with (5 ml) and saturated NaHCO 3.₃ (2x5 ml),
Wash with line (5 ml) and water (5 ml) and wash with Na.₂SO_FourDried. Vacuum after filtration
The filtrate was concentrated below. The residue was chromatographed on silica gel (0.5% to 2% MeOH CH ₂ Cl₂The solution) to give 176 as a colorless oil.¹H-NMR (300 MHz, CDCl₃) d 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 (C_{twenty three}H₂₈N₂Calculated for O) 348 was 348; IR (Fi
Rum) 3308, 3105, 3064, 2978, 2937, 2874, 2811, 1689m 1666, 1598, 1540,
1499, 1445, 1314, 1246, 1196, 1074, 757 cm^-1 .

Example 129 Solid phase synthesis of N- [1- (4-fluorophenethyl) -piperidin-3-ylmethyl] -N-phenyl-propionamide (177)

[0841]

[Chemical 143]

2- (4-Formyl-3-methoxyphenoxy) ethyl polystyrene (100 mg, 0.46 mm
ol / g) was added to 1 m of DMF, and then 91 ml (0.46 mmol) of aniline was added. 3 at room temperature
After shaking for 0 min, 195 mg (0.92 mmol) Na (OAc) ₃ BH and 50 ml HOAc were added and the reaction mixture was stirred at room temperature overnight. The obtained resin (1) was added to DMF (3X1 ml), MeOH (4
It was washed thoroughly with X1 ml) and CH ₂ Cl ₂ (4 X 1 ml) and dried in vacuo. 1 to N-Fmo
A solution of c-nipecoic acid (81 mg, 0.23 mmol) and PyBroP (107 mg, 0.23 mmol) in DMF (1 ml) was added, and then 40 ml N, N-diisopropylethylamine (0.23 mmol) was added,
The resulting slurry was shaken at room temperature for 2 hours. The resin 2 obtained was added to DMF (3 X 1 ml), M
eOH (4 X 1 ml), and CH ₂ and washed with _{Cl 2 (4 X 1 ml)} , and dried in vacuo.

Resin 2 was treated with 1 ml of 25% piperidine for 30 minutes at room temperature and then treated with DMF (3 X 1 ml), MeO.
It was washed with H (4 x 1 ml) and CH ₂ Cl ₂ (4 x 1 ml) and dried in vacuo. 4-fluorophenylacetic acid (36 mg, 0.23 mmol) and PyBOP (120 mg, 0.23 mm) were added to the obtained resin.
ol) in 1 ml of DMF, and then 26 ml of N-methylmorpholine (0.23 mmol) was added. After infiltration at room temperature for 3 hours, the obtained resin (3) was added to DMF (3 X 1 ml) and MeOH (4 X 1
ml) and CH ₂ Cl ₂ (4 × 1 ml) and dried in vacuum. Resin 2 at room temperature 2
It was treated with 1 ml of 1 M BH ₃ -THF for 0 minutes. After washing with THF (3 x 1 ml) and MeOH (3 x 1 ml), the resin suspended in 1 ml of MeOH was heated at 60 ° C for 6 hours. The obtained resin (4) was added to DMF (3
X 1 ml), MeOH (4 x 1 ml), and CH ₂ Cl ₂ (4 x 1 ml) and dried in vacuo.

Propionyl chloride (28 ml, 0.322 mmol) was added to Resin 4 suspended in 1.5 ml CH ₂ Cl ₂ and the mixture was stirred at room temperature for 24 hours. The mixture was filtered and CH ₂ Cl ₂ (2 X 1
ml). Volatile substances were removed under aeration of nitrogen and freeze-dried with 50% CH ₃ CN to give colorless oily compound 177. LRMS 369.

Example 130 Solid phase synthesis of N- [1- (2-methylphenethyl) -piperidin-3-ylmethyl] -N-phenyl-propionamide (178)

[0846]

[Chemical 144]

Compound 178 was synthesized using a method similar to that described in Example 129. A colorless oily compound 178 was obtained (8.3 mg, 50%). LRMS 365.

Example 131 Chromatographic separation of (R)-and (S) -N- (1-phenethyl-azepan-3-ylmethyl) -N-phenethylpropionamide (179 and 180)

[0849]

[Chemical 145]

The enantiomer of N- (1-phenethyl-azepan-3-ylmethyl) -N-phenethylpropionamide (150) was applied at 92: 8 using a 2 cm ID Chiralpak AD column (column number ADOOCJ-AB009). : 0.1 Hexane: EtOH: Et ₂ NH (l = 235 nm, flow rate = 6 mL / min).
Chiral pack AD column for analysis (95: 5: 0.1 Hexane: EtOH: Et ₂ NH, flow rate = 1 mL / min,
(l = 230 nm, run time = 30 min), the first compound eluted from the column (9.871 min)
(S), and the compound (22.826 minutes) eluted from the second column was designated as 179 (S). Absolute placement has not been finalized.

Example 132 (R) -N- (1-tert-butyloxypiperidin-3-ylmethyl) -N-anilinotrifluoroacetamide (181)

[0852]

[Chemical 146]

A solution of aniline intermediate (1.72 mmol, 500 mg) in CH ₂ Cl ₂ (5 mL) at 0 ° C. was added to trifluoroacetic anhydride (TFAA) (1.2 eq, 2.06 mmol, 292 mL) and diisopropylethylamine (1.5 eq). , 2.58 mmol, 450 mL) under argon. After warming to 25 ° C. and stirring for 12 h, the reaction mixture was quenched with 10% aq. NaHCO ₃ . The reaction mixture was then acidified with 10% aq. HCl and extracted with 3X EtOAc (25 mL). Chromatography (PTLC, SiO ₂ , 20 cm X 20 cm, 1 mm, 1: 4 EtOAc-hexane) gave 181 (655 mg, theoretical 665 mg, 98%) as a colorless oil. R _f 0.22 (SiO ₂ , 1: 4 EtOAc-hexane); LRMS m / z 386 (M +, C ₁₉ H ₂₅ F ₃ N ₂ O ₃ , for 3
86 required).

Example 133 (R) -N-1- (phenethylpiperidin-3-ylmethyl) -N-anilinotrifluoroacetamide (182)

[0855]

[Chemical 147]

[0856]   181 (0.285 mmol, 110 mg) CH at 25 ° C₂Cl₂ (1 mL) solution in CH with 50% TFA₂Cl₂ 
(1 mL) solution. The reaction mixture was stirred for 2 hours. Remove the solvent in vacuo,
The resulting oil was dried under high vacuum for 12 hours. The oily substance obtained was treated with phenethyl bromide.
(2.0 eq, 0.57 mmol, 78 mL) and K₂CO₃ (2.5 eq, 0.71 mmol, 98 mg)
CH₃Treated with CN (1 mL) solution. The reaction mixture was stirred at 60 ° C. for 12 hours. The reaction
The mixture was directly chromatographed (PTLC, SiO 2₂, 20 cm X 20 cm, 1 mm, 9: 1 EtOAc-CH ₃ It was purified by OH) to obtain 182 (107 mg, theoretical value 111 mg, 96%) as a colorless oil. R_f0.3
0 (SiO₂, 9: 1 EtOAc-CH₃OH); LRMS m / z 390 (M +, C_{twenty two}H_{twenty five}F₃N₂(390 required for O)

[0857] Example 134 N-1-acetophenone-3-aniline carboxypiperidine (183)

[0858]

[Chemical 148]

A solution of aminoamide (5.91 mmol) in CH ₃ CN (20 ?? mL)? Was treated with bromoacetophenone (1.1 eq, 8.87 mmol, 1.23 g) and K ₂ CO ₃ (1.5 eq, 8.87 mmol, 1.23 g). Treated under Ar. Warm to 60 ° C. and stir for 12 h, then mix reaction mixture with 10% NaH
Quenched with aqueous CO ₃ and extracted with EtOAc (3 X 25 mL). Chromatograph (SiO ₂ , 2.5 cm X 30.5 cm, 1: 1 hexane-EtOAc followed by 9: 1 EtOAc-CH ₃ OH) gave 183 (1.08 g, theoretical 2.10 g, 51%) as a yellow foam. ) Got R _f 0.45 (SiO ₂ ,
_{9: 1 EtOAc -CH 3 OH)} ; LRMS m / z 322 (M +, C 20 H 22 N 2 O 2 322 required).

[0860] Example 135 N-1- (2'-oxo-phenethylpiperidin-3-ylmethyl) -N-aniline (184)

[0861]

[Chemical 149]

A solution of 183 (0.775 mmol, 250 mg) in THF (3 mL) at 0 ° C. was treated with 1.0 M BH ₃ -THF (2.0 eq, 1.55 mmol) under Ar. Then the reaction mixture is heated to 75 ° C.,
Stir for 12 hours. The reaction mixture was cooled to 0 ° C. and then quenched with 10% aqueous HCl solution. The pH was adjusted to 10 with 10% aqueous NaOH and the reaction mixture was extracted with EtOAc (3 X 25 mL). Organics were dried over NaCl _(sat) and MgSO _{4 (s)} . The reaction mixture was directly purified by chromatography (PTLC, SiO ₂ , 20 cm X 20 cm, 1 mm, 9: 1 EtOAc-CH ₃ OH) to give 184 (184 mg, theoretical 241 mg, 76%) as a colorless oil. Obtained. R _f 0.40 (SiO ₂ , 9: 1
_{EtOAc-CH 3 OH); LRMS} m / z 310 (M +, C 20 H 26 N 2 O is 310 required).

Example 136 N-1- (2′-acetoxy-phenethylpiperidin-3-ylmethyl) -N-anilinopropionamide (185)

[0864]

[Chemical 150]

A solution of 184 (0.58 mmol, 181 mg) in CH ₂ Cl ₂ (2 mL) at 0 ° C. was added under Ar to propionyl chloride (2.5 eq, 1.45 mmol, 126 mL) and diisopropylethylamine (2.5 eq, 1.45 mmol). , 253 mL). Warm up to 25 ° C. and stir for 12 hours, then chromatograph the reaction mixture (PTLC, SiO ₂ , 20 cm X 20 cm, 1 mm, 1: 1 EtOAc).
-Hexane) was directly purified to obtain 185 (193 mg, theoretical value 245 mg, 70%) as a colorless oil. R _f 0.36 (SiO ₂ , 1: 1 EtOAc-hexane); LRMS m / z 422 (M +, C ₂₆ H ₃₄ N ₂ O ₃
Requires 422).

Example 137 N-1- (2′-oxo-phenethylpiperidin-3-ylmethyl) -N-anilinopropionamide (186)

[0867]

[Chemical 151]

A solution of 185 (0.457 mmol, 193 mg) in THF-CH ₃ OH-H ₂ O 3: 1: 1 (1 mL) at 0 ° C. was added to 1 M Li.
It was treated with OH (2.0 eq, 0.914 mmol, 914 mL). After warming to 25 ° C. and stirring for 3 h, the reaction mixture was quenched with pH 7 buffer and extracted with EtOAc (3 × 10 mL). Organics were dried over NaCl _(sat) and MgSO _{4 (s)} . The resulting oil was purified by chromatography (PTLC, SiO ₂ , 20 cm X 20 cm, 1 mm, 9: 1 EtOAc-CH ₃ OH),
186 was obtained as a colorless oil. (114 mg, theoretical 167 mg, 68%): R _f 0.28 (SiO ₂ , 9: 1 Et
_{OAc -CH 3 OH); LRMS m} / z 366 (M +, C 23 H 30 N 2 O 2 366 required).

Example 138 N- [1- (1-phenethylpiperidin-3-yl) ethyl] -N-phenylpropionamide
And purification of four diastereomers (195, 196, 197, 198)

[0870]

[Chemical 152]

The starting material mono-Boc-diamine (see Example 86) was loaded onto a semi-prepared silica gel column.
Diastereomers 187 and 188 using HPLC with (hexane: ⁱ PrOH, 90:10)
Separated. The diastereomer 187 is the first compound (7
.72 min) (LRMS 305, 249, 205) and 188 is the second compound eluted from the column (8.43 min) (LRMS 305, 249, 205).

[0872]

[Chemical 153]

Following the standard procedure described in the examples, diastereomers 187 and 188 were converted to diastereomeric amides 189 and 190, respectively.

[0874]

[Chemical 154]

Chiral chromatograph was used to convert diastereomer 189 into its constituent enantiomers 191 and
Separated into 192. In particular, Semiprep Chiral Pack AD column (Hexane: ⁱ PrOH, 95: 5
) Using HPLC), 191 (first compound eluted from the column) and 192 (compound
The second eluting compound) was obtained from the column. When using a chiral pack AD column for analysis (hexane: ⁱ PrOH, 95: 5), the retention time of 191 was 8.35 minutes (LRMS 261, M-100).
, 192 had a retention time of 9.46 minutes (LRMS 261, M-100).

Similarly, diastereomer 190 was separated into two component enantiomers 193 and 194. In particular, HP using a semi-prep chiral pack AD column (Hexane: ⁱ PrOH, 95: 5)
LC was used to give 193 (first eluting compound from column) and 194 (second eluting compound from column). Chiral pack AD column for analysis (hexane: ⁱ PrOH,
(95: 5), the retention time of 193 is 7.78 minutes (LRMS 261, M-100) and the retention time of 194 is 11.90.
Minutes (LRMS 261, M-100).

[0877]

[Chemical 155]

Finally, the single enantiomers 191, 192, 193, 1 were followed according to the standard procedure described in this example.
94 is an enantiomerically pure tertiary amine-amide 195 (LRMS 365), 196 (LRMS
365), 197 (LRMS 365), 198 (LRMS 365).

[0879] Example 139 N- (1-indan-2-yl-piperidin-3-ylmethyl) -N-phenylpropionamide  (199)

[0880]

[Chemical 156]

Trifluoroacetic acid (1.0 mL) was dried over (R) -N- (1-Boc-piperidin-3-ylmethyl) -N-phenylpropionamide (200 mg, 0.58 mmol) at 0 ° C. (ice water). CH ₂ Cl ₂ 1.0 m
It was added dropwise to the L solution. The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of solvent, the crude product was used in the next step without purification.

The crude compound from the previous step was dissolved in CH ₃ CN (1.3 mL), and K ₂ CO ₃ (240 mg) and 2-iodoindane (283 mg, 1.16 mmol) were added. The reaction mixture was heated at 50 ° C. overnight. The reaction product was poured into 10 mL H ₂ O and then extracted with ethyl acetate (3 X 10 mL).
The extracts were mixed to form an aqueous NaOH solution (10%, 2 X 5 mL), an aqueous HCl solution (5%, 2 X 5 mL).
), Brine (10 mL), dried over anhydrous sodium sulfate and filtered.
The crude product was purified by preparative thin layer chromatography (CH ₂ Cl ₂ / MeOH, 95: 5) to give a colorless oil.
N- (1-indan-2-yl-piperidin-3-ylmethyl) -N-phenylpropionamide was obtained. LRMS 363.

Example 140 1- [1- (4-chloro-phenyl) -cyclobutanecarbonyl] -piperidine-3-carboxylic acid phenylamide (202)

[0884]

[Chemical 157]

200 (2.95 mmol, 603 mg), 1- (4-chlorophenyl) -1-cyclbutanecarboxylic acid (
201) (1.5 eq, 4.43 mmol, 932 mg) and iPr ₂ NEt (3.0 eq, 8.85 mmol, 1.5)
CH ₂ Cl ₂ (10 mL) solution 0 ℃ of mL), PyBroP under argon (1.5 eq, 4.43 mmol
, 2.07 g). Warm to 25 ° C. and stir for 12 h, then add 10% of the reaction mixture.
Quenched with aqueous HCl and extracted with EtOAc (3 X 25 mL). The organic layer was washed with NaHCO ₃ (saturated
), And dried with NaCl _(sat) and MgSO _{4 (s)} . Chromatograph (SiO ₂ ,
2.5 cm x 30.5 cm, 2: 1 hexane-EtOAc) gave a white foam 202 (0.851 g, theory 1.17 g, 73%). R _f 0.17 (SiO ₂ , 2: 1 hexane-EtOAc); LRMS m / z 396
(M +, C ₂₃ H ₂₅ ClN ₂ O ₂ requires 396)

Example 141 {1- [1- (4-chloro-phenyl) -cyclobutylmethyl] -piperidin-3-ylmethyl}-
Phenyl-amine (203)

[0887]

[Chemical 158]

A solution of 202 (0.504 mmol, 200 mg) in toluene (2 mL) at 0 ° C. was added to 3.0 M red Al under Ar.
It was treated with (3.5 eq, 1.76 mmol). The reaction mixture was stirred for 12 hours and returned to 25 ° C. Then the reaction mixture was cooled to 0 ° C, quenched with 10% aq.
It was extracted with Ac (3 X 25 mL). Organics were dried over NaCl _(sat) and Na ₂ SO _{4 (s)} .
The reaction mixture was chromatographed (PTLC, SiO ₂ , 20 cm X 20 cm, 1 mm, 2: 1 hexane.
-EtOAc) to give 203 (170 mg, theoretical 186 mg, 91%) as a colorless oil. R _f 0.6
1 (SiO ₂ , 2: 1 hexane-EtOAc); LRMS m / z 368 (M +, C ₂₃ H ₂₉ ClN ₂ requires 368)

Example 142 Cyclobutanecarboxylic acid {1- [1- (4-chloro-phenyl) -cyclobutylmethyl] -piperidin-3-ylmethyl} -phenyl-amide (204)

[0890]

[Chemical 159]

[0891]   203 (0.276 mmol, 102 mg) CH at 0 ° C₂Cl₂ (2 mL) solution, cyclobutane chloride
Rubonyl (1.5 equivalents, 0.414 mmol, 50 mL) and diisopropylethylamine (1.5
Eq., 0.414 mmol, 72 mL) under Ar. Warm to 25 ° C and stir for 12 hours
The reaction mixture was chromatographed (PTLC, SiO 2₂, 20 cm X 20 cm, 1 mm, 8: 1
Yellow oil 204 (100 mg, theoretical 124 mg, 81%).
Obtained. R_f0.27 (SiO₂, 8: 1 hexane-acetone); LRMS m / z 451 (M +, C₂₈H₃₅ClN ₂ (O requires 451)

Example 143 N- [1- (3-Methylbutane) -piperidin-3-R-ylmethyl] -N- (anilino-3-yl) propionamide (205)

[0983]

[Chemical 160]

[0894]   138 (0.170 mmol, 65 mg) CH at 25 ° C₃OH (1 mL) solution in 10% Pd-C (20 mg)
And then placed under a hydrogen atmosphere. The reaction mixture was stirred for 12 hours
Filtered through a Celite pad. The solvent was removed in vacuo and the resulting oil was
1-Bromo-3-methylbutane (1.5 eq, 0.255 mmol, 31 mL) and K₂CO₃ (1.5 equivalent
, 0.255 mmol, 35 mg) CH₃Treated with CN (0.5 mL) solution. Reaction mixture at 65 ° C for 1
It was stirred for 2 hours. Then, the reaction mixture was chromatographed (PTLC, SiO 2₂, 20 cm X 20
 cm, 1 mm, EtOAc-10% CH₃Directly purified by OH) to give 205 (36 mg, theory 54) as a colorless oil.
mg, 67%) was obtained. R_f0.60 (SiO₂, EtOAc-10% CH₃OH); LRMS m / z 316 (M +, C₂₀H ₃₂ N₂(O required 316)

Example 144 N-4-tert-butoxycarbonyl-1-carbobenzyloxy [2- (2′-fluoroanilinocarboxy)] piperazine (206)

[0896]

[Chemical 161]

4-Boc-1-Cbz-piperazine-2carboxylic acid (5.49 mmol, 2.00 g) and 2-fluoroaniline (1.5 eq, 8.24 mmol, 796 mL) in CH ₂ Cl ₂ (10 mL) at 0 ° C. Solution under Ar, D
Treated with CC (1.5 eq, 8.24 mmol, 1.70 g). The reaction mixture was warmed to 25 ° C. and stirred for 12 hours. The reaction mixture was filtered to remove urea and the solvent removed in vacuo. When chromatographed, (SiO ₂ , 2.5 cm X 30.5 cm, 3: 1 hexane
-EtOAc) 206 (1.83 g, theory 2.51 g, 73%) were obtained as a white foam. R _f 0.11 (SiO ₂ ,
3: 1 hexane-EtOAc); LRMS m / z 457 (M +, C ₂₄ H ₂₈ FN ₃ O ₅ requires 457)

Example 145 N-4-tert-Butoxycarbonyl-1-carbobenzyloxy [2- (2′-fluoroanilinomethyl)] piperazine (207)

[0899]

[Chemical 162]

A solution of 206 (2.19 mmol, 1.00 g) in THF (8.0 mL) at 0 ° C. was added to 1.0 M BH ₃ -THF (3.0 mL).
Equivalent, 6.57 mmol) and treated under Ar. The reaction mixture was heated to 75 ° C. and stirred for 12 hours. The reaction mixture was cooled to 0 ° C. and then quenched with 10% aqueous HCl solution. pH
Was adjusted to 10 with 10% aqueous NaOH and the reaction mixture was extracted with EtOAc (3 X 25 mL).
The organic was dried over NaCl _(sat) and MgSO _{4 (s)} . Chromatograph (SiO ₂ ,
2.5 cm X 30.5 cm, 3: 1 hexane-EtOAc), colorless oil 207 (0.744
g, theoretical 0.971 g, 77%). R _f 0.35 (SiO ₂ , 3: 1 hexane-EtOAc); LRMS
m / z 443 (443 required for M +, C ₂₄ H ₃₀ FN ₃ O ₄ )

Example 146 N- (4-tert-butyloxy-1-carbobenzyloxypiperazin-2-ylmethyl) -N-
(2'-Fluoroanilino) -cyclobutylcarboxamide (208)

[0902]

[Chemical formula 163]

A solution of 207 (0.248 mmol, 110 mg) in CH ₂ Cl ₂ (1 mL) at 0 ° C. was added under Ar to cyclobutanecarbonyl chloride (1.5 equivalents, 0.779 mmol, 77 mL) and diisopropylethylamine (2.0 equivalents, 1.04 mmol). , 181 mL). Warm up to 25 ℃ 1
After stirring for 2 hours, the reaction mixture was chromatographed (PTLC, SiO ₂ , 20 cm X 2
Direct purification with 0 cm, 1 mm, 1: 1 hexanes-EtOAc) gave 208 (130
mg, theoretical 130 mg, 99%). R _f 0.45 (SiO ₂ , 1: 1 hexane-EtOAc); LRMS m
/ z 525 (525 required for M +, C ₂₉ H ₃₆ FN ₃ O ₅ )

Example 147 N-1-Methyl (4-tert-butyloxypiperazin-2-ylmethyl 1) -N- (2′-fluoroanilino) -cyclobutylcarboxamide (209)

[0905]

[Chemical 164]

A solution of 208 (0.247 mmol, 130 mg) in CH ₃ OH (2.0 mL) at 25 ° C. was added to 30% Pd-C (20 mg).
And paraformaldehyde (74 mg) and then placed under a hydrogen atmosphere.
The reaction mixture was stirred for 12 hours and then filtered through a Celite pad. The solvent was removed in vacuo and the resulting oil was chromatographed (PTLC, SiO ₂ , 20 cm X 20
cm, 1 mm, EtOAc-20% CH ₃ OH) to give 209 as a colorless oil (74 mg, theoretical
100 mg, 74%) was obtained. R _f 0.58 (SiO ₂ , EtOAc-20% CH ₃ OH); LRMS m / z 405 (M +
, C ₂₂ H ₃₂ FN ₃ O ₃ requires 405)

Example 148 N-1-Methyl (4-phenethyl-piperazin-2-ylmethyl) -N- (2′-fluoroanilino)
-Cyclobutylcarboxamide (210)

[0908]

[Chemical 165]

Compound 209 (0.182 mmol, 74 mg) was treated with a solution of 50% TFA in CH ₂ Cl ₂ (1 mL) at 25 ° C. The reaction mixture was stirred for 2 hours. The solvent was removed in vacuo and the resulting oil was dried under high vacuum for 5 hours. Then, the obtained oily substance was treated with phenethyl bromide.
(2.0 eq, 0.364 mmol, 50 mL) and K ₂ CO ₃ (4.0 eq, 0.728 mmol, 100 mg)
In CH ₃ CN (1.0 mL) solution. The reaction mixture was stirred at 60 ° C. for 12 hours. The reaction mixture was chromatographed (PTLC, SiO ₂ , 20 cm X 20 cm, 1 mm, EtOAc-10%.
It was directly purified by CH ₃ OH) to obtain 210 (64 mg, theoretical value 75 mg, 85%) as a colorless oil. _{R f 0.46 (SiO 2, EtOAc} -10% CH 3 OH); LRMS m / z 409 (M +, C 25 H 32 FN 3 O 409 required).

Example 149 N-1-carbobenzyloxy [3- (2′-methylanilino) carboxy] piperazine (211
)

[0911]

[Chemical 166]

Cbz-nipecoic acid (3.80 mmol, 1.00 g), o-toluidine (2.0 equivalents, 7.60 mmo at 0 ° C.)
l, 811 mL) and diisopropylethylamine (2.0 eq, 7.60 mmol, 1.3 mL)
CH ₂ Cl ₂ (10 mL) solution of was treated with BOP (2.0 eq, 7.60 mmol, 3.36 g) under Ar. The reaction mixture was warmed to 25 ° C. and stirred for 12 hours. The reaction mixture was quenched with 10% aq. HCl and extracted with EtOAc (3 X 25 mL). The organic layer was washed with NaHCO ₃ (saturated)
Washed with and dried over NaCl _(sat) and MgSO _{4 (s)} . Chromatograph (SiO ₂ , 2
.5 cm X 30.5 cm, 2: 1 hexanes-EtOAc) gave a white foam 211 (1.16
g, theoretical 1.34 g, 87%). R _f 0.34 (SiO ₂ , 2: 1 hexane-EtOAc); LRMS m
/ z 352 (M +, C ₂₁ H ₂₄ N ₂ O ₃ requires 352)

[0913] Example 150 N-1-carbobenzyloxy [3- (2'-methylanilino) methyl] piperazine (212)

[0914]

[Chemical 167]

A solution of 211 (0.567 mmol, 0.200 g) in THF (1.0 mL) at 0 ° C. was added to 1.0 M BH ₃ -THF under Ar.
It was treated with (2.0 eq, 1.13 mmol). The reaction mixture was heated to 80 ° C. and stirred for 12 hours. The reaction mixture was cooled to 0 ° C. and quenched with 10% aq. HCl. p
H 2 was adjusted to 10 with 10% aqueous NaOH and the reaction mixture was extracted with 3 × EtOAc (25 mL). Organics were dried over NaCl _(sat) and MgSO _{4 (s)} . The reaction mixture was purified by chromatography (PTLC, SiO ₂ , 20 cm X 20 cm, 1 mm, 3: 1 hexane-EtOAc) to give 212 as a colorless oil (102 mg, theoretical 192 mg, 53%). . R _f 0.54 (SiO ₂ , 3: 1 hexane-E
tOAc); LRMS m / z 338 (M +, C ₂₁ H ₂₆ N ₂ O ₂ requires 338)

Example 151 N- (carbobenzyloxypiperazin-3-ylmethyl) -N- (2′-methylanilino) cyclobutylcarboxamide (213)

[0917]

[Chemical 168]

[0918]   212 (0.301 mmol, 102 mg) CH at 0 ° C₂Cl₂ (1 mL) solution under Ar, and
Tancarbonyl (1.5 eq, 0.452 mmol, 52 mL) and diisopropylethylamine
(1.5 eq, 0.452 mmol, 79 mL). Warm to 25 ° C and stir for 12 hours
The reaction mixture was chromatographed (PTLC, SiO 2₂, 20 cm X 20 cm, 1 mm, 2:
Direct purification with hexane-EtOAc) gave 213 (127 mg, theory 127 as a colorless oil.
mg, 99%) was obtained. R_f0.16 (SiO₂, 2: 1 hexane-EtOAc); LRMS m / z 420 (M +, C _{twenty one} H₃₂N₂O₃Need 420)

Example 152 N- (phenethyl-piperazin-3-ylmethyl) -N- (2'-methylanilino) cyclobutylcarboxamide (214)

[0920]

[Chemical 169]

A solution of 213 (0.302 mmol, 127 mg) in CH ₃ OH (1 mL) at 25 ° C. was treated with 30% Pd—C (25 mg) and placed under a hydrogen atmosphere. The reaction mixture was stirred for 12 hours and then filtered through a Celite pad. The solvent was removed in vacuo and the resulting oil was phenethyl bromide (1.5 eq, 0.453 mmol, 62 mL) and K ₂ CO ₃ (2.0 eq, 0.604 mmol, 83 mg).
) Was treated with CH ₃ CN (1.0 mL) solution of. The reaction mixture was stirred at 65 ° C. for 12 hours.
The reaction mixture was chromatographed (PTLC, SiO ₂ , 20 cm X 20 cm, 1 mm, EtOAc-10
% CH ₃ OH) to give 214 (51 mg, theoretical 118 mg, 43%) as a colorless oil. _{R f 0.45 (SiO 2, EtOAc} -10% CH 3 OH); LRMS m / z 390 (M +, C 26 H 34 N 2 O is 390 required).

[Brief description of drawings]

FIG. 1 is a schematic diagram showing the combinatorial library described in Example 77, reactants, reagents, and the conditions used to prepare it.

FIG. 2 shows 50% effective doses of some compounds of the present invention, morphine, and fentanyl when administered intravenously to mice and rats (see Example 79).

FIG. 3 shows changes in pO ₂ and pCO ₂ levels caused by intravenous administration of some compounds of the present invention, morphine, and fentanyl. These changes in blood gas can be used as an index of respiratory depression in rats.

[Procedure for Amendment] Submission for translation of Article 34 Amendment of Patent Cooperation Treaty

[Submission date] August 16, 2001 (2001.16)

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Contents of correction]

[Claims]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/4525 A61K 31/4525 4C086 31/4535 31/4535 31/454 31/454 31/4545 31/4545 31/4709 31/4709 31/495 31/495 31/5375 31/5375 31/55 31/55 31/551 31/551 31/553 31/553 A61P 25/04 A61P 25/04 25/30 25/30 27/16 27/16 43/00 105 43/00 105 111 111 111 C07D 205/04 C07D 205/04 211/42 211/42 211/56 211/56 211/60 211/60 221/04 221/04 223 / 04 223/04 223/10 223/10 241/04 241/04 243/08 506 243/08 506 265/30 265/30 267/10 267/10 401/06 401/06 401/12 401/12 405 / 12 405/12 405/14 405/14 409/06 409/06 409/12 409/12 491/113 491/113 (31) Priority claim number 60 / 195,809 (32) Priority date April 2000 11th (April 11, 2000) (33) Country claiming priority US US) (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF , BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ , TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR , BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, M A, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA , UG, UZ, VN, YU, ZA, ZW (72) Inventor Haus Quark James Earl USA Massachusetts 01742 Concorde Rowell Road 41 (72) Inventor Hefernan Michelle El Earl USA Massachusetts 01702 Framingham Sharp 303 E Worcester Road 1500 (72) Inventor Akira Brian M 01752 Marvallo Royal Crest Drive 36 Apartment 4 (72) Inventor Wushinhe United States Massachusetts 01752 Marvallo One Royal Crest Drive Apartment 1 (72) ONE Feng Jiang United States Massachusetts 01532 North Baro Edmunds Way 6 (72) Inventor Vanister Thomas Dee United States Massachusetts 01532 North Baro Green Street 112 F Term (Reference) 4C034 CB01 DB12 4C050 AA04 BB07 CC17 EE01 A01 FF01 FF02 GG02 FF02 FF02 GG02 EE28 EE38 FF01 4C056 EA06 EC02 4C063 AA01 AA03 BB03 BB09 CC12 CC75 CC92 DD10 EE01 4C086 AA01 AA02 AA03 BA03 BB02 BC02 BC17 BC21 BC27 BC28 BC31 BC38 BC50 BC41 MA35 MA52 NA35 MA52 NA52 MA35 MA52 MA52 MA41 MA52 MA52 MA54 MA52 MA52 MA54 MA52 MA52 MA52 MA52 MA52 MA52 MA52 MA52 MA52 MA52 MA52 MA52 MA52 MA05 MA52 MA54 MA07 MA01 MA05 MA01 MA05 MA05 MA52 MA52 MA04 MA07 MA52 MA14 MA07 MA01 MA05 MA01 MA05 MA52 MA54

Claims (204)

[Claims] 1. A compound represented by the following formula A: However, in the above formula, m is 1, 2, 3 or 4, n is 1 or 2, y is 1 or 2, R ₁ is alkyl, aryl, heteroaryl or cycloalkyl And R ₂ are each independently H, alkyl, fluoroalkyl, aryl, heteroaryl or cycloalkyl, R ₁ and R ₂ may be linked via a covalent bond, and R ₃ is each independently, H, alkyl, _{aryl, oR 2, OC (O) R} 2, CH 2 oR 2 or _CO 2 _{R 2,} wherein any two of _{R 3} include its backbone 1, 2 may be a covalent attachment of 3 or 4 carbon atoms, R ₄ are each independently, H, alkyl, aryl, heteroaryl, alkenyl or cycloalkyl, R _5, it Independently, H, alkyl, _CH 2 Y, aryl, heteroaryl, F, an OR ₂ or _{OC (O) R 2, R} 6 are each independently, H, alkyl, _CH 2 Y, aryl, heteroaryl , F, OR ₂ or OC (O) R ₂ , and Y is each independently OR ₂ , N (R ₂ ) ₂ , SR ₂ , S (O) R ₂ , S (
O) ₂ R ₂ or P (O) (OR ₂ ) ₂ and R ₅ or R ₆ bonded to the carbon chain between R ₄ specified in formula A and the nitrogen on the ring is R ₄ , They may be connected by a covalent bond, R ₅ and R _{6 in the} case where two geminals or vicinals are aligned may be connected by a covalent bond, and X is C (R ₃ ) ₂ , O, S. , SO, SO ₂ , NR ₂ , NC (O) OR ₂ or C = 0, and the stereochemical configuration at the stereocenter of the compound represented by formula A is R-type, S-type, or A compound that is a mixture. 2. X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0.
The compound according to. 3. The compound according to claim 1, wherein X is C (R ₃ ) ₂ , O or NR ₂ . 4. The compound of claim 1, wherein X is C (R ₃ ) ₂ . 5. The compound according to claim 1, wherein m is 2 or 3. 6. The compound according to claim 1, wherein n is 1. 7. The compound according to claim 1, wherein y is 1. 8. The compound according to claim 1, wherein R ₁ is aryl or heteroaryl. 9. The compound of claim 1, wherein each R ₂ is independently alkyl. 10. R ₁ is each independently H or alkyl.
The compound according to. 11. The compound according to claim 1, wherein R ₄ is cycloalkyl, aryl or heteroaryl. 12. The compound according to claim 1, wherein each R ₅ is independently H, alkyl, aryl, heteroaryl or F. 13. The compound according to claim 1, wherein each R ₆ is independently H, alkyl, aryl, heteroaryl or F. 14. The compound according to claim 1, wherein X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0 and n is 1. 15. The compound of claim 1, wherein X is C (R ₃ ) ₂ , O, or NR ₂ and n is 1. 16. The compound of claim 1, wherein X is C (R ₃ ) ₂ and n is 1. 17. The compound according to claim 1, wherein X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0 and y is 1. 18. The compound of claim 1, wherein X is C (R ₃ ) ₂ , O, or NR ₂ and y is 1. 19. The compound according to claim 1, wherein X is C (R ₃ ) ₂ and y is 1. 20. The compound of claim 1, wherein X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0 and R ₁ is aryl or heteroaryl. 21. The compound of claim 1, wherein X is C (R ₃ ) ₂ , O, or NR ₂ and R ₁ is aryl or heteroaryl. 22. The compound of claim 1, wherein X is C (R ₃ ) ₂ and R ₁ is aryl or heteroaryl. 23. The compound of claim 1, wherein X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, and each R ₂ is independently alkyl. 24. The compound of claim 1, wherein X is C (R ₃ ) ₂ , O, or NR ₂ and each R ₂ is independently alkyl. 25. The compound of claim 1, wherein X is C (R ₃ ) ₂ and each R ₂ is independently alkyl. 26. The compound of claim 1, wherein X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, n is 1 and R ₁ is aryl or heteroaryl. . 27. The compound of claim 1, wherein X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1 and R ₁ is aryl or heteroaryl. 28. The compound of claim 1, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. 29. X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, n is 1, R ₁ is aryl or heteroaryl, and R ₂ is independently alkyl. The compound of claim 1, which is 30. X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, R ₁ is aryl or heteroaryl, and R ₂ is each independently alkyl. The compound according to item 1. 31. The compound of claim 1, wherein X is C (R ₃ ) ₂ , n is 1, R ₁ is aryl or heteroaryl, and R ₂ is each independently alkyl. 32. X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, n is 1, R ₁ is aryl or heteroaryl, and R ₂ is independently alkyl. And R ₃ is each independently H or alkyl. 33. X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, R The compound of claim 1, wherein each ₃ is independently H or alkyl. 34. X is C (R ₃ ) ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is independently alkyl and R ₃ is independently H or The compound of claim 1, which is alkyl. 35. X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, n is 1, R ₁ is aryl or heteroaryl, and R ₂ is independently alkyl. And R ₃ is each independently H or alkyl and R ₄ is each independently cycloalkyl, aryl or heteroaryl. 36. X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, R The compound of claim 1, wherein each ₃ is independently H or alkyl, and each R ₄ is independently cycloalkyl, aryl or heteroaryl. 37. X is C (R ₃ ) ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is independently alkyl and R ₃ is independently H or A compound according to claim 1 which is alkyl and each R ₄ is independently cycloalkyl, aryl or heteroaryl. 38. X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, n is 1, R ₁ is aryl or heteroaryl, and R ₂ is independently alkyl. And R ₃ is independently H or alkyl, R ₄ is cycloalkyl, aryl or heteroaryl, and R ₅ is independently H, alkyl, aryl, heteroaryl, or F. The compound according to item 1. 39. X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, R _{3. The} compound according to claim 1, wherein ₃ is each independently H or alkyl, R ₄ is cycloalkyl, aryl or heteroaryl, and R ₅ is each independently H, alkyl, aryl, heteroaryl, or F. Compound of. 40. X is C (R ₃ ) ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl and R ₃ is independently H or The compound according to claim 1, wherein R ₅ is alkyl, R ₄ is cycloalkyl, aryl or heteroaryl, and R ₅ is independently H, alkyl, aryl, heteroaryl, or F. 41. X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, n is 1, R ₁ is aryl or heteroaryl, and R ₂ is independently alkyl. R ₃ is independently H or alkyl, R ₄ is cycloalkyl, aryl or heteroaryl, R ₅ is independently H, alkyl, aryl, heteroaryl, or F, R ₆ is independently H
The compound of claim 1, wherein the compound is alkyl, aryl, heteroaryl, or F. 42. X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, R ₃ is each independently H or alkyl, R ₄ is cycloalkyl, aryl or heteroaryl, R ₅ is each independently H, alkyl, aryl, heteroaryl, or F, and R ₆ is each The compound of claim 1, which is, separately, H, alkyl, aryl, heteroaryl, or F. 43. X is C (R ₃ ) ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, and R ₃ is each independently H or Alkyl, R ₄ is cycloalkyl, aryl or heteroaryl, R ₅ is independently H, alkyl, aryl, heteroaryl, or F, and R ₆ is independently H, alkyl, The compound of claim 1, which is aryl, heteroaryl, or F. 44. X is C (R_Three)_Two, M is 2, n is 1, and R is ₁ Is aryl and R_TwoAre each independently alkyl, R_ThreeAre different
H for each, R_FourIs aryl and R₅Are each independently H or alkyl
And R₆Wherein each is independently H or alkyl.
Compound 45. A compound represented by formula B below: However, in the above formula, m is 1, 2, 3 or 4, n is 1 or 2, R ₁ is H, alkyl, aryl, heteroaryl or cycloalkyl, and R ₂ is Each independently H, alkyl, fluoroalkyl, aryl, heteroaryl or cycloalkyl, R ₁ and R ₂ may be linked via a covalent bond, and R ₃ each independently H, alkyl. , Aryl, OR ₂ , OC (O) R ₂ , CH ₂ OR ₂ or CO ₂ R ₂ , wherein any two of R ₃ have a backbone of 1, 2, 3 or 4 carbons. may be a covalent attachment consisting of atoms, R ₄ are each independently, H, alkyl, aryl, heteroaryl, alkenyl or cycloalkyl, R ₅ are each independently, H, Al Le, _CH 2 Y, aryl, heteroaryl, F, an OR ₂ or _{OC (O) R 2, R} 6 are each independently, H, alkyl, _CH 2 Y, aryl, heteroaryl, F, OR ₂ Or OC (O) R ₂ and Y is independently OR ₂ , N (R ₂ ) ₂ , SR ₂ , S (O) R ₂ , S (
O) ₂ R ₂ or P (O) (OR ₂ ) ₂ and R ₅ or R ₆ bonded to the carbon chain between R ₄ specified in formula B and the ring nitrogen is R ₄ and It may be connected by a covalent bond, R ₅ and R _{6 in the} case where two geminals or vicinals are aligned may be connected by a covalent bond, and X is C (R ₃ ) ₂ , O, S. , SO, SO ₂ , NR ₂ , NC (O) OR ₂ or C = 0, and the stereochemical configuration at the stereocenter of the compound represented by formula B is R-type or S-type. 46. The compound of claim 45, wherein X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0. 47. The compound of claim 45, wherein X is C (R ₃ ) ₂ , O or NR ₂ . 48. The compound of claim 45, wherein X is C (R ₃ ) 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 R ₁ is aryl or heteroaryl. 52. The compound of claim 45, wherein each R ₂ is independently alkyl. 53. R ₃ is each independently H or alkyl.
The compound according to 5. 54. The compound of claim 45, wherein R ₄ is cycloalkyl, aryl or heteroaryl. 55. The compound of claim 45, wherein each R ₅ is independently H, alkyl, aryl, heteroaryl or F. 56. The compound of claim 45, wherein each R ₆ is independently H, alkyl, aryl, heteroaryl or F. 57. The compound of claim 45, wherein X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0 and n is 1. 58. The compound of claim 45, wherein X is C (R ₃ ) ₂ , O, or NR ₂ and n is 1. 59. The compound of claim 45, wherein X is C (R ₃ ) ₂ and n is 1. 60. The compound of claim 45, wherein X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0 and R ₁ is aryl or heteroaryl. 61. The compound of claim 45, wherein X is C (R ₃ ) ₂ , O, or NR ₂ and R ₁ is aryl or heteroaryl. 62. The compound of claim 45, wherein X is C (R ₃ ) ₂ and R ₁ is aryl or heteroaryl. 63. The compound of claim 45, wherein X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, and each R ₂ is independently alkyl. 64. The compound of claim 45, wherein X is C (R ₃ ) ₂ , O, or NR ₂ , and each R ₂ is independently alkyl. 65. The compound of claim 45, wherein X is C (R ₃ ) ₂ and each R ₂ is independently alkyl. 66. The compound of claim 45, wherein X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, n is 1 and R ₁ is aryl or heteroaryl. . 67. The compound of claim 45, wherein X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1 and R ₁ is aryl or heteroaryl. 68. The compound of claim 45, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. 69. X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, n is 1, R ₁ is aryl or heteroaryl, and R ₂ is independently alkyl. 46. The compound of claim 45, which is 70. X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, R ₁ is aryl or heteroaryl, and R ₂ is each independently alkyl. Item 45. The compound according to Item 45. 71. The compound of claim 45, wherein X is C (R ₃ ) ₂ , n is 1, R ₁ is aryl or heteroaryl, and R ₂ is each independently alkyl. 72. X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, n is 1, R ₁ is aryl or heteroaryl, and R ₂ is independently alkyl. 47. The compound of claim 45, wherein each R ₃ is independently H or alkyl. 73. X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, R 46. The compound of claim 45, wherein each ₃ is independently H or alkyl. 74. X is C (R ₃ ) ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is independently alkyl and R ₃ is independently H or 46. The compound of claim 45, which is alkyl. 75. X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, n is 1, R ₁ is aryl or heteroaryl, and R ₂ is each independently alkyl. 46. The compound of claim 45, wherein R ₃ is each independently H or alkyl and R ₄ is each independently cycloalkyl, aryl or heteroaryl. 76. X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, R ₃ are each independently H or alkyl, separately R ₄ each, cycloalkyl, aryl or heteroaryl, a compound according to claim 45. 77. X is C (R ₃ ) ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl and R ₃ is each independently H or 46. The compound of claim 45, which is alkyl and each R < ₄ > is independently cycloalkyl, aryl or heteroaryl. 78. X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, n is 1, R ₁ is aryl or heteroaryl, and R ₂ is each independently alkyl. R ₃ is independently H or alkyl, R ₄ is independently cycloalkyl, aryl or heteroaryl, R ₅ is independently H, alkyl, aryl, heteroaryl, or F 46. The compound of claim 45, which is 79. X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, R ₃ is each independently H or alkyl, R ₄ is each independently cycloalkyl, aryl or heteroaryl, R ₅ is each independently H or
46. The compound of claim 45, which is :, alkyl, aryl, heteroaryl, or F. 80. X is C (R ₃ ) ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is independently alkyl and R ₃ is independently H or alkyl, in each R ₄ is independently selected from cycloalkyl, aryl or heteroaryl, in each R ₅ is independently, H, alkyl, aryl, heteroaryl, or F, a compound according to claim 45. 81. X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, n is 1, R ₁ is aryl or heteroaryl, and R ₂ is each independently alkyl. R ₃ is independently H or alkyl, R ₄ is independently cycloalkyl, aryl or heteroaryl, R ₅ is independently H, alkyl, aryl, heteroaryl, or F 46. The compound of claim 45, wherein each R ₆ is independently H, alkyl, aryl, heteroaryl, or F. 82. X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, R ₃ is each independently H or alkyl, R ₄ is each independently cycloalkyl, aryl or heteroaryl, R ₅ is each independently H or
, Alkyl, aryl, heteroaryl, or F, R ₆ are each independently, H, alkyl, aryl, heteroaryl, or F, A compound according to claim 45. 83. X is C (R ₃ ) ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, and R ₃ is each independently H or Alkyl, R ₄ is each independently cycloalkyl, aryl or heteroaryl, R ₅ is independently H, alkyl, aryl, heteroaryl, or F, R ₆ is independently, H, alkyl,
46. The compound of claim 45, which is aryl, heteroaryl, or F. 84. A compound represented by formula C: However, in the above formula, m is 1, 2, 3 or 4, y is 0, 1 or 2, R ₁ is H, alkyl, aryl, heteroaryl or cycloalkyl, R ₂ Are each independently H, alkyl, fluoroalkyl, aryl, heteroaryl or cycloalkyl, R ₁ and R ₂ may be bonded via a covalent bond, and R ₃ is independently H , Alkyl, aryl, OR ₂ , OC (O) R ₂ , CH ₂ OR ₂ or CO ₂ R ₂ , R ₄ is H, alkyl, aryl, heteroaryl, alkenyl or cycloalkyl and R ₅ is , H, alkyl, _CH 2 Y, aryl, heteroaryl, F, an oR ₂ or _{OC (O) R 2, R} 6 are each independently, H, alkyl, _CH 2 Y, aryl Heteroaryl, F, OR ₂ or OC (O) _{R 2,} Y are each _{independently, OR 2, N (R 2} ) 2, SR 2, S (O) R 2, S (
O) ₂ R ₂ or P (O) (OR ₂ ) ₂ and R ₅ or R ₆ bonded to the carbon chain between R ₄ specified in Formula C and the ring nitrogen is R ₄ and R ₅ and R ₆ may be connected by a covalent bond, and R ₅ and R _{6 in the} case where two geminals or vicinals are juxtaposed may be connected by a covalent bond, and the stereochemistry at the stereocenter of the compound represented by the formula C A compound wherein the desired configuration is R-type, S-type, 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 paragraph 84, wherein R ₁ is aryl or heteroaryl. 88. The compound of claim 84, wherein each R ₂ is independently alkyl. 89. R ₃ is each independently H or alkyl.
The compound according to 4. 90. The compound of claim 84, wherein R ₄ is cycloalkyl, aryl or heteroaryl. 91. The compound of claim 84, wherein each R ₅ is independently H, alkyl, aryl, heteroaryl or F. 92. The compound of claim 84, wherein each R ₆ is independently H, alkyl, aryl, heteroaryl or F. 93. The compound of claim 84, wherein R ₁ is aryl or heteroaryl and R ₂ is each independently alkyl. 94. The compound of claim 84, wherein R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, and R ₃ is each independently H or alkyl. 95. R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, R ₃ is independently H or alkyl, and R ₄ is cycloalkyl, aryl. 85. The compound of claim 84, which is or heteroaryl. 96. R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, R ₃ is each independently H or alkyl, and R ₄ is cycloalkyl, aryl. Or heteroaryl and each R ₅ is independently H, alkyl, aryl, heteroaryl or F.
The compound according to 4. 97. R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, R ₃ is independently H or alkyl, and R ₄ is cycloalkyl, aryl. Or heteroaryl, R ₅ is each independently H, alkyl, aryl, heteroaryl or F, and R ₆ is
85. The compound of claim 84, each of which is independently H, alkyl, aryl, heteroaryl or F. 98. A compound represented by the following Formula D: However, in the above formula, m is 1, 2, 3 or 4, y is 0, 1 or 2, R ₁ is H, alkyl, aryl, heteroaryl or cycloalkyl, R ₂ Are each independently H, alkyl, fluoroalkyl, aryl, heteroaryl or cycloalkyl, R ₁ and R ₂ may be bonded via a covalent bond, and R ₃ is independently H , Alkyl, aryl, OR ₂ , OC (O) R ₂ , CH ₂ OR ₂ or CO ₂ R ₂ , R ₄ is H, alkyl, aryl, heteroaryl, alkenyl or cycloalkyl and R ₅ is , Each independently H, alkyl, CH ₂ Y, aryl, heteroaryl, F, OR ₂ or OC (O) R ₂ , and R ₆ is each independently H, alkyl, CH. ₂ Y, aryl, heteroaryl, F, OR ₂ or OC (O) R ₂ , Y is each independently OR ₂ , N (R ₂ ) ₂ , SR ₂ , S (O) R ₂ , S. (
O) ₂ R ₂ or P (O) (OR ₂ ) ₂ and R ₅ or R ₆ bonded to the carbon chain between R ₄ specified in formula D and the ring nitrogen is R ₄ and R ₅ and R ₆ may be connected by a covalent bond, and R ₅ and R _{6 in the} case where two geminals or vicinals are aligned may be connected by a covalent bond, and the stereochemistry at the stereocenter of the compound represented by formula D The compound having the R-configuration or the S-configuration is a compound. 99. The compound of claim 98, wherein m is 2 or 3. 100. The compound of claim 98, wherein y is 1. Wherein 101] R ₁ is aryl or heteroaryl, claim 98
The compound according to. 102. The compound of claim 98, wherein each R ₂ is independently alkyl. 103. The compound of paragraph 98, wherein each R ₃ is independently H or alkyl. 104. The compound of paragraph 98, wherein R ₄ is cycloalkyl, aryl or heteroaryl. 105. The compound of paragraph 98, wherein each R ₅ is independently H, alkyl, aryl, heteroaryl or F. 106. The compound of paragraph 98, wherein each R ₆ is independently H, alkyl, aryl, heteroaryl or F. 107. The compound of paragraph 98, wherein R ₁ is aryl or heteroaryl and R ₂ is each independently alkyl. 108. The compound of claim 98, wherein R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, and R ₃ is each independently H or alkyl. 109. R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, R ₃ is independently H or alkyl, and R ₄ is cycloalkyl, aryl 98. or heteroaryl.
The compound according to. 110. R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, R ₃ is independently H or alkyl, and R ₄ is cycloalkyl, aryl. 99. The compound of claim 98, which is or heteroaryl and each R < ₅ > is independently H, alkyl, aryl, heteroaryl, or F. 111. R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, R ₃ is independently H or alkyl, and R ₄ is cycloalkyl, aryl. Or heteroaryl, R ₅ is each independently H, alkyl, aryl, heteroaryl or F, and R ₆ is each independently H, alkyl, aryl, heteroaryl or F. The compound according to 98. 112. A compound of formula E: However, in the above formula, m is 1, 2, 3 or 4, n is 1 or 2, R ₁ is H, alkyl, aryl, heteroaryl or cycloalkyl, and R ₂ is Each independently H, alkyl, fluoroalkyl, aryl, heteroaryl or cycloalkyl, R ₁ and R ₂ may be linked via a covalent bond, and R ₃ each independently H, alkyl. , Aryl, OR ₂ , OC (O) R ₂ , CH ₂ OR ₂ or CO ₂ R ₂ , wherein any two of R ₃ have a backbone of 1, 2, 3 or 4 carbons. R ₄ may be H, alkyl, aryl, heteroaryl, alkenyl or cycloalkyl, and R ₅ may be each independently H, alkyl, CH ₂ Y, Aryl, heteroaryl, F, OR ₂ or OC (O) R ₂ , wherein each R ₆ is independently H, alkyl, CH ₂ Y, aryl, heteroaryl, F, OR ₂ or OC (O) R. ₂ and Y are each independently OR ₂ , N (R ₂ ) ₂ , SR ₂ , S (O) R ₂ , S (
O) ₂ R ₂ or P (O) (OR ₂ ) ₂ and R ₅ or R ₆ bonded to the carbon chain between R ₄ specified in formula E and the ring nitrogen is R ₄ and It may be connected by a covalent bond, R ₅ and R _{6 in the} case where two geminals or vicinals are aligned may be connected by a covalent bond, and X is C (R ₃ ) ₂ , O, S. , SO, SO ₂ , NR ₂ , NC (O) OR ₂ or C = 0, and the stereochemical configuration at the stereocenter of the compound represented by formula E is R-type, S-type, or A compound that is a mixture. 113. The compound of claim 112, wherein X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0. 114. The method of claim 112, wherein X is C (R ₃ ) ₂ , O or NR _2.
The compound according to. 115. The compound of claim 112, wherein X is C (R ₃ ) ₂ . 116. The compound of claim 112, wherein m is 2 or 3. 117. The compound of claim 112, wherein n is 1. 118. R ₁₁ is aryl or heteroaryl.
The compound according to 2. 119. 112. wherein each R ₂ is, independently, alkyl.
The compound according to. 120. The compound of claim 112, wherein each R ₃ is independently H or alkyl. 121. The compound of paragraph 112, wherein R ₄ is cycloalkyl, aryl or heteroaryl. Wherein 122] R ₅ are each independently, H, alkyl, aryl, heteroaryl, or F, A compound according to claim 112. Wherein 123] R ₆ are each independently, H, alkyl, aryl, heteroaryl, or F, A compound according to claim 112. 124. X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, and n
113. The compound of claim 112, wherein is 1. 125. The compound of claim 112, wherein X is C (R ₃ ) ₂ , O, or NR ₂ and n is 1. 126. The compound of claim 112, wherein X is C (R ₃ ) ₂ and n is 1. 127. X is C (R_Three)_Two, O, NR_Two, Or C = 0 and R ₁ 113. The compound of claim 112, wherein is aryl or heteroaryl. 128. The compound of claim 112, wherein X is C (R ₃ ) ₂ , O, or NR ₂ and R ₁ is aryl or heteroaryl. 129. The compound of claim 112, wherein X is C (R ₃ ) ₂ and R ₁ is aryl or heteroaryl. 130. X is C (R_Three)_Two, O, NR_Two, Or C = 0 and R _Two 113. The compound of claim 112, wherein each is independently alkyl. 131. The compound of claim 112, wherein X is C (R ₃ ) ₂ , O, or NR ₂ and each R ₂ is independently alkyl. 132. The compound of claim 112, wherein X is C (R ₃ ) ₂ and each R ₂ is independently alkyl. 133. X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, and n
113. The compound of claim 112, wherein is 1 and R ₁ is aryl or heteroaryl. 134. The compound of claim 112, wherein X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1 and R ₁ is aryl or heteroaryl. 135. The compound of clause 112, wherein X is C (R ₃ ) ₂ , n is 1 and R ₁ is aryl or heteroaryl. 136. X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, and n
113. The compound of claim 112, wherein is 1, R ₁ is aryl or heteroaryl, and R ₂ is each independently alkyl. 137. X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, R ₁ is aryl or heteroaryl, and R ₂ is each independently alkyl. Item 112. A compound according to Item 112. Wherein 138] X is _{C (R 3) 2,} n is 1, _{R 1} is aryl or heteroaryl, _{R 2} are each independently alkyl, claim 11
The compound according to 2. 139. X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, and n
113. The compound of claim 112, wherein R is 1, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, and R ₃ is each independently H or alkyl. 140. X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, R 113. The compound of claim 112, wherein each ₃ is independently H or alkyl. 141. X is C (R ₃ ) ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, and R ₃ is each independently H or 113. The compound of claim 112, which is alkyl. 142. X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, and n
Is 1, R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, R ₃ is independently H or alkyl, and R ₄ is independently cycloalkyl, aryl or hetero. 113. The compound of claim 112, which is aryl. 143. X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, R ₃ are each independently H or alkyl, and R ₄ is each independently
113. The compound of claim 112, which is cycloalkyl, aryl or heteroaryl. 144. X is C (R ₃ ) ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is independently alkyl and R ₃ is independently H or 113. The compound of claim 112, which is alkyl and each R < ₄ > is independently cycloalkyl, aryl or heteroaryl. 145. X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, and n
Is 1, R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, R ₃ is independently H or alkyl, and R ₄ is independently cycloalkyl, aryl or hetero. Aryl and each R ₅ is independently H, alkyl, aryl, heteroaryl, or F.
The compound according to 2. 146. X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, R ₃ are each independently H or alkyl, and R ₄ is each independently
Cycloalkyl, aryl or heteroaryl, each R ₅ is independently
113. The compound of claim 112, which is H, alkyl, aryl, heteroaryl, or F. 147. X is C (R ₃ ) ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, and R ₃ is each independently H or alkyl, in each R ₄ is independently selected from cycloalkyl, aryl or heteroaryl, in each R ₅ is independently, H, alkyl, aryl, heteroaryl, or F, a compound according to claim 112. 148. X is C (R ₃ ) ₂ , O, NR ₂ , or C = 0, and n
Is 1, R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, R ₃ is independently H or alkyl, and R ₄ is independently cycloalkyl, aryl or hetero. 113. Aryl, R ₅ is each independently H, alkyl, aryl, heteroaryl, or F, and R ₆ is each independently H, alkyl, aryl, heteroaryl, or F. 112. The compound according to. 149. X is C (R ₃ ) ₂ , O, or NR ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, R ₃ are each independently H or alkyl, and R ₄ is each independently
Cycloalkyl, aryl or heteroaryl, each R ₅ is independently
H, alkyl, aryl, heteroaryl, or F, _{R 6} are each independently, H, alkyl, aryl, heteroaryl, or F, claim 112
The compound according to. 150. X is C (R ₃ ) ₂ , n is 1, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, and R ₃ is each independently H or Alkyl, R ₄ is each independently cycloalkyl, aryl or heteroaryl, R ₅ is independently H, alkyl, aryl, heteroaryl, or F, R ₆ is independently, 113. The compound of claim 112, which is H, alkyl, aryl, heteroaryl, or F. 151. A compound of Formula F: However, in the above formula, m is 1, 2, 3 or 4, y is 0, 1 or 2, R ₁ is H, alkyl, aryl, heteroaryl or cycloalkyl, R ₂ Are each independently H, alkyl, fluoroalkyl, aryl, heteroaryl or cycloalkyl, R ₁ and R ₂ may be bonded via a covalent bond, and R ₃ is independently H , Alkyl, aryl, OR ₂ , OC (O) R ₂ , CH ₂ OR ₂ or CO ₂ R ₂ , each R ₄ is independently H, alkyl, aryl, heteroaryl, alkenyl or cycloalkyl. , R ₅ is H, alkyl, CH ₂ Y, aryl, heteroaryl, F, OR ₂ or OC (O) R ₂ , and R ₆ are each independently H, alkyl, CH. ₂ Y, aryl, heteroaryl, F, OR ₂ or OC (O) R ₂ , Y is each independently OR ₂ , N (R ₂ ) ₂ , SR ₂ , S (O) R ₂ , S. (
O) ₂ R ₂ or P (O) (OR ₂ ) ₂ and R ₅ or R ₆ bonded to the carbon chain between R ₄ specified in formula F and the ring nitrogen is R ₄ and They may be connected by a covalent bond, R ₅ and R _{6 in the} case where two geminals or vicinals are aligned may be connected by a covalent bond, and X is O, S, SO, SO ₂ , NR ₂ , NC (O) OR ₂ or C = 0, wherein the stereochemical configuration at the stereocenter of the compound of formula F is R-type, S-type, or a mixture of these configurations. Wherein 152] X is, O, NR _2, or C = 0, A compound according to claim 151. 153. The compound of clause 151, wherein X is O or NR ₂ . 154. The compound of claim 151, wherein X is NR ₂ . 155. The compound of claim 151, wherein m is 2 or 3. 156. The compound of paragraph 151, wherein y is 1. Wherein 157] R ₁ is aryl or heteroaryl, claim 15
The compound according to 1. 158. R 151 wherein R ₂ is each independently alkyl.
The compound according to. Wherein 159] R ₃ are each independently H or alkyl, A compound according to claim 151. 160. The compound of clause 151, wherein R ₄ is cycloalkyl, aryl or heteroaryl. 161. The compound of clause 151, wherein each R ₅ is independently H, alkyl, aryl, heteroaryl or F. 162. The compound of clause 151, wherein each R ₆ is independently H, alkyl, aryl, heteroaryl or F. 163. The compound of clause 151, wherein X is O, NR ₂ , or C = 0 and y is 1. 164. 151. X is O or NR ₂ , and y is 1, 151
The compound according to. 165. The compound of paragraph 151, wherein X is NR ₂ and y is 1. 166. The compound of clause 151, wherein X is O, NR ₂ , or C = 0 and R ₁ is aryl or heteroaryl. 167. The compound of clause 151, wherein X is O or NR ₂ and R ₁ is aryl or heteroaryl. 168. The compound of claim 151, wherein X is NR ₂ and R ₁ is aryl or heteroaryl. 169. The compound of clause 151, wherein X is O, NR ₂ , or C = 0 and each R ₂ is independently alkyl. 170. The compound of paragraph 151, wherein X is O or NR ₂ and each R ₂ is independently alkyl. 171. The compound of clause 151, wherein X is NR ₂ and R ₂ is each independently alkyl. 172. X 151, X is O, NR ₂ , or C = 0, R ₁ is aryl or heteroaryl, and R ₂ is each independently alkyl.
The compound according to. 173. The compound of clause 151, wherein X is O or NR ₂ , R ₁ is aryl or heteroaryl, and R ₂ is each independently alkyl. 174. The compound of claim 151, wherein X is NR ₂ , R ₁ is aryl or heteroaryl, and R ₂ is each independently alkyl. 175. X is O, NR ₂ , or C = 0, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, and R ₃ is each independently H or alkyl. 154. The compound of claim 151, wherein 176. X is O or NR ₂ , R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, and R ₃ is each independently H.
155. The compound of claim 151, which is or is alkyl. Wherein 177] X is NR _{2, R 1} is aryl or heteroaryl, _{R 2} are each independently alkyl, _{R 3} are each independently H or alkyl, as defined in claim 151 Compound. 178. X is O, NR ₂ , or C = 0, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, and R ₃ is each independently H or alkyl. The compound of claim 151, wherein R ₄ is each independently cycloalkyl, aryl or heteroaryl. 179. X is O or NR ₂ , R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, and R ₃ is each independently H.
Or alkyl, R ₄ is cycloalkyl, aryl or heteroaryl, A compound according to claim 151. 180. X is NR ₂ , R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, R ₃ is each independently H or alkyl, R ₄ is cycloalkyl, 155. The compound of claim 151, which is aryl or heteroaryl. 181. X is O, NR ₂ , or C = 0, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, and R ₃ is each independently H or alkyl. The compound of claim 151, wherein R ₄ is cycloalkyl, aryl or heteroaryl and R ₅ is each independently H, alkyl, aryl, heteroaryl, or F. 182. X is O or NR ₂ , R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, and R ₃ is each independently H.
Or alkyl, R ₄ is cycloalkyl, aryl or heteroaryl, and R ₅ is each independently H, alkyl, aryl, heteroaryl, or F
151. The compound of claim 151, which is 183. X is NR ₂ , R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, R ₃ is each independently H or alkyl, R ₄ is cycloalkyl, Aryl or heteroaryl, each R ₅ is independently H, alkyl, aryl, heteroaryl, or F,
155. The compound of claim 151. 184. X is O, NR ₂ , or C = 0, R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, and R ₃ is each independently H or alkyl. R ₄ is cycloalkyl, aryl or heteroaryl, R ₅ is independently H, alkyl, aryl, heteroaryl, or F, and R ₆ is independently H, alkyl, aryl, 157. The compound of claim 151, which is heteroaryl or F. 185. X is O or NR ₂ , R ₁ is aryl or heteroaryl, R ₂ is each independently alkyl, and R ₃ is each independently H.
Or alkyl, R ₄ is cycloalkyl, aryl or heteroaryl, and R ₅ is each independently H, alkyl, aryl, heteroaryl, or F
And each R ₆ independently represents H, alkyl, aryl, heteroaryl,
157. The compound of claim 151, which is or F. 186. X is NR ₂ , R ₁ is aryl or heteroaryl, R ₂ is independently alkyl, R ₃ is independently H or alkyl, R ₄ is cycloalkyl, Aryl or heteroaryl, each R ₅ is independently H, alkyl, aryl, heteroaryl, or F;
R ₆ are each independently, H, alkyl, aryl, heteroaryl, or F, A compound according to claim 151. 187. The compound of Claim 1, 84, wherein said compound is a single stereoisomer.
, 112, 151. 188. A formulation comprising the compound of claim 1, 45, 84, 98, 112 or 151 and a pharmaceutically acceptable additive. 189. The compound of claim 1, wherein the compound is a ligand for a cellular receptor.
45, 84, 98, 112, or 151. 190. The compound is a ligand for a G protein-coupled receptor,
The compound of claim 189. 191. The compound of paragraph 189, wherein said compound is a ligand for an opioid receptor. 192. The compound of paragraph 190, wherein said compound is a G protein-coupled receptor agonist. 193. The compound of paragraph 190, wherein said compound is a G protein-coupled receptor antagonist. 194. The compound of claim 1 wherein the compound is an opioid receptor agonist.
91. The compound according to 91. 195. The compound of claim 1, wherein the compound is an opioid receptor antagonist.
91. The compound according to 91. 196. The compound of paragraph 190, wherein said compound is a ligand selective for a subclass of G protein coupled receptors. 197. The compound of paragraph 191, wherein said compound is a ligand selective for a subclass of opioid receptors. 198. A method of treating pain, drug addiction, or tinnitus in a mammal, wherein an effective amount of the formulation of claim 188 is administered to a mammal suffering from pain, drug addiction, or tinnitus. A method of treatment comprising the steps of: 199. The method of treatment of claim 198, wherein said mammal is a primate, horse, dog, or feline animal. 200. The method of treatment of claim 198, wherein said mammal is a human. 201. The method of treatment of claim 198, wherein said formulation is administered orally. 202. The method of treatment of claim 198, wherein said formulation is administered intravenously. 203. The method of treatment of claim 198, wherein said formulation is administered sublingually. 204. The method of treatment of claim 198, wherein said formulation is administered ocularly.