Design, synthesis, and biological evaluation of nitrogen-walk derivatives of nan as mu opioid receptor selective modulators

Abstract

A series of non-peptide mu opioid receptor (MOR) selective modulators is provided. The compounds have the general formula (I) where R is (II) and where one of a, b, c, d, e or f is the point of attachment of indole ring R to the epoxymorphinan skeleton; at least one of the atoms at positions a, b, c, d, e and f is N; the remaining atoms at positions at a, b, c, d, e and f are CH; and * is a chiral carbon. The compounds are generally MOR antagonists and are used to treat disorders related to opioid receptor functions such as opioid addiction and opioid overdose, for the treatment of neurological diseases and for the treatment of pain, without causing constipation.

Description

[0001] DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF NITROGEN- WALK DERIVATIVES OF NAN AS MU OPIOID RECEPTOR SELECTIVE MODULATORS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims benefit of United States provisional patent application 63 / 532,172, filed August 11, 2023. STATEMENT OF FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT This invention was made with government support under grant numbers UG3DA054785 and UG3 / UH3DA050311 awarded by the National Institutes of Health, National Institute on Drug Abuse. The United States government has certain rights in the invention. BACKGROUND OF THE INVENTION Technical Field The invention generally relates to mu opioid receptor selective modulators. In particular, the invention provides derivatives of 17-cyclopropylmethyl-3,14β-dihydroxy- 4,5α-epoxy-6α-(indole-7-carboxamido)morphinan (NAN) with enhanced mu opioid receptor selective modulation abilities. Description of Related Art Opioid receptors belong to the G-protein coupled receptors (GPCRs) super family. There are four opioid receptors viz. MOR, KOR, DOR and the nociception / orphanin FQ receptor (NOP). MOR is the primary pharmacological target of most known opioids. The overall effect of MOR activation results in lowering of postsynaptic neuronal excitability or inhibition of presynaptic neurotransmitter release. The vast array of pharmacological effects as a result of MOR activation include analgesia, euphoria, sedation, respiratory depression, cough suppression and constipation. Along with the analgesia produced by opioids, their ability to cause euphoria, due to activation of the MOR in several regions of the brain, often leads to opioid misuse. Opioid use disorder (OUD) affects approximately 2.7 million people in the United States. Currently, detoxification and maintenance therapy are the two most commonly used approaches to treat opioid use disorders. Methadone, buprenorphine, and naltrexone are first- line opioid medicines approved by the US Food and Drug Administration (FDA) for opioid use disorders. Methadone and buprenorphine, mu opioid receptor (MOR) full and partial agonists, respectively, show good efficacy for opioid addiction maintenance therapy. However, about 50% of patients relapse after being treated for opioid use disorders with methadone and buprenorphine. While opioid antagonists naltrexone and naloxone are used to manage opioid misuse, overdose and reduce relapse, they carry side effects such as dysphoria, depression and, even suicide. One of the most concerning side effects are the withdrawal symptoms precipitated by naltrexone and naloxone, including abdominal cramps, nausea / vomiting, diarrhea, muscle aches, anxiety, confusion, and extreme sleepiness. High doses of these drugs are also reported to show hepatotoxicity, cardiovascular and pulmonary problems. Other side effects of currently used OUD drugs, such as methylnaltrexone (MNTX), naloxegol, and naldemedine, include abdominal pain, diarrhea, nausea, headache, vomiting, severe constipation, life-threatening arrhythmia, etc. Further, some of these drugs are very expensive. The severity of opioid-induced constipation (OIC), is typically underestimated. This opioid-associated bowel dysfunction occurs in 40-80% of MOR agonist-treated patients and contributes to a considerable percentage of treatment cessation, causing a substantial burden to the patients and health systems. As neither dietary changes nor laxative products are effective in preventing or treating OIC, peripherally acting μ opioid receptor antagonists (PAMORAs) have become the major research of interest due to their targeting the underlying mechanisms of OIC, i.e., MOR receptor activation in the gastrointestinal (GI) tract. As opioid pain relievers promote analgesia mainly in supraspinal sites and the spinal cord, the peripheral selectivity is essential for potential OIC therapeutic agents to avoid compromising the analgesic effects of opioid pain relievers. In other words, PAMORAs are designed to be taken with an opioid to reverse opioid-induced constipation (OIC) without compromising the opioid’s analgesic effects. The compound 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(indole-7- carboxamido)morphinan also known as NAN, likely acts as a bitopic ligand. This indicates that the epoxymorphinan (“message”) acts at the MOR orthosteric site, whereas the indole ring (“address”) acts at the MOR allosteric site. NAN has many favorable pharmacological properties such as high binding affinity at MOR, moderately selective for MOR over KOR and DOR, and does not produce any significant withdrawal symptoms in morphine pelleted mice. However, after evaluating the absorption, distribution, metabolism, excretion and toxicity properties, it was discovered that NAN has high inhibition of the human ether-a-go- go related gene (hERG) channel with an IC50 of 0.021 µM. The hERG channel is responsible for cardiac repolarization and any disruption to this process can result in sudden cardiac death. Therefore, NAN is not an ideal drug candidate. Therefore, it is critical to develop novel, affordable therapeutics that are selective, potent, and reversible antagonists for the mu opioid receptor (MOR) for the treatment of OUD, with fewer and / or less severe side effects than presently available treatments. SUMMARY OF THE INVENTION Other features and advantages of the present invention will be set forth in the description of invention that follows, and in part will be apparent from the description or may be learned by practice of the invention. The invention will be realized and attained by the compositions and methods particularly pointed out in the written description and claims hereof. Disclosed herein is a series of 17-cyclopropylmethyl-3,14β-dihydroxy- 4,5α-epoxy-6α-(indole-7-carboxamido)morphinan (NAN) derivative compounds that are mu opioid receptor (MOR) modulators. The derivatives retain or increase MOR potency but overcome the hERG liability issue. The pharmacological characteristics of the compounds are described herein as is their use for preventing and / or treating substance use disorders (e.g. to treat disorders such as opioid abuse and addiction, opioid overdose, alcoholism, opioid induced constipation, etc.) and / or for pain management (i.e., as an analgesic), and / or to treat neurological and other disorders such as irritable bowel movement disorders. It is an object of the disclosure to provide a compound having the general Formula I or a pharmaceutically acceptable salt or stereoisomer thereof: Formula I where R is , and where: one of a, b, c, d, e or f is a position of attachment of R to the carbonyl carbon of the epoxymorphinan skeleton; at least one of a, b, c, d, e and f is N; positions at a, b, c, d, e and f that are not N are CH; and* is a chiral carbon. In some aspects, R is

[0002] . In some aspects, the pharmaceutically acceptable salt is a hydrochloride salt. Also provided is a composition comprising at least one compound of any of the compounds disclosed herein and a physiologically acceptable carrier. In some aspects, the composition further comprises at least one addictive narcotic drug and / or methadone. In further aspects, the addictive narcotic drug is oxycodone, hydrocodone, morphine and / or fentanyl, or a mixture thereof. Also provided herein is a method of preventing or treating opioid addiction in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one compound disclosed herein, wherein the at least one compound is administered to the subject with or instead of an opioid. In some aspects, the at least one compound is administered orally. In further aspects, the at least one compound is administered with an addictive narcotic drug in a tapered regimen. Also provided is a method of treating an opioid overdose in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one compound disclosed herein. There is further provided a method of treating acute and / or chronic pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one compound disclosed herein. In some aspects, the acute and / or chronic pain is visceral pain, cancer pain, neuropathic pain, allodynia, hyperalgesia, pain due to inflammation, arthritis pain, pain due to migraines or pain resulting from accident and / or injury. Also provided is a method of treating a neurological disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one compound disclosed herein. In certain aspects, the neurological disease or condition is or is caused by: a bacterial or viral infection, Alzheimer’s disease, Parkinson’s disease, dementia, depression and / or anxiety, aberrant behavioral changes, a decline in cognitive function, progressive slowing of motor function and loss of dexterity and coordination, central nervous system (CNS) lymphomas, nerve damage, encephalitis, traumatic head injury, sports related head injury or chemotherapy. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. Structure of NAN (left) and the 36 designed analogs (right) which include introducing an additional nitrogen on the indole ring along with changing the location of the amide bond to the indole ring. Figure 2A and B. A and B collectively show the results of warm-water tail immersion assays of nitrogen-walk analogs (n = 6) as agonists at a single dose of 10 mg / kg s.c. Saline and morphine were used as the negative and positive controls, respectively. Data are presented as mean values ± SD. *P < 0.05, **P < 0.01, and ***P < 0.0005, ****P < 0.0001, compared to 10 mg / kg morphine (s.c.). A, odd numbered compounds; B, even numbered compounds. Figure 3A and B. A and B collectively show the results of warm-water tail immersion assay results of nitrogen-walk analogs (n = 6) as antagonists at a single dose of 10 mg / kg s.c. Saline and morphine were used as the negative and positive controls, respectively. Data are presented as mean values ± SD. *P < 0.05, **P < 0.01, and ***P < 0.0005, ****P < 0.0001, compared to 10 mg / kg morphine (s.c.). A, odd numbered compounds; B, even numbered compounds. Figure 4A and B. A, Dose response study of the most potent NAN analogs (n = 6) as antagonists in presence of morphine (10 mg / kg) in the warm-water tail immersion assays along with B, the corresponding AD50values. Doses are in mg / kg and data are presented as mean values ± SD. Figure 5. In Vivo withdrawal assays of compound 7 in morphine-pelleted mice (n = 6), including wet dog shakes, jumps and paw tremors. All doses of compound 7 were administered s.c. *P < 0.05, **P < 0.01, and ***P < 0.0005, ****P < 0.0001, compared to 1 mg / kg naloxone (NLX; s.c.). DETAILED DESCRIPTION Opioid use disorder (OUD) affects approximately 2.7 million people in the United States alone. Currently, the therapeutic options for individuals who suffer from OUD are limited and have significant drawbacks. Therefore, it is critical to develop novel therapeutics that are selective, potent, and reversible antagonists for the mu opioid receptor (MOR) for the treatment of OUD. The present disclosure describes the design and biological evaluation of analogues based upon 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(indole-7- carboxamido)morphinan (NAN). Compared to NAN, the analogues exhibit enhanced physiochemical properties. These novel compounds are potent and selective modulators (ligands) for MOR and are used to treat neurological disorders and associated conditions as described herein. For example, the compounds are used to treat one or more of substance use disorders, e.g., opioid addiction, opioid overdose, alcoholism, as well as other neurological disorders related to opioid receptor functions; or it targets principally the PNS MOR and is used to prevent or treat opioid-induced constipation, irritable bowel movement disorders, etc. The analogues were designed using molecular design technique called “nitrogen- walk”, in which the CH groups around of indole ring were consecutively replaced with a nitrogen atom. In addition, the position of attachment of the indole ring to the epoxymorphinan skeleton was varied. The compounds were tested for their agonism and antagonism in a mouse antinociception model. Following this single-dose assessment, in vivo dose response studies were conducted. The compounds showed subnanomolar binding affinity at MOR, which is comparable to the parent compound, NAN and except for compounds 11 and 12, were selective for MOR over KOR. All compounds showed higher selectivity over MOR than DOR. The compounds are thus selective MOR antagonists. Significantly, the compounds exhibit little or no inhibition of the human ether-a-go-go related gene (hERG) and are thus safer for use than NAN. The present compounds do not disrupt cardiac repolarization, which can otherwise result in sudden cardiac death. The compounds described herein are advantageously non-toxic (are of low toxicity) to mammals when administered in vivo. The compounds are thus useful to combat drug (opioid) abuse (including opioid overdose) and / or addiction, opioid use and / or addiction in those being treated for pain; for the treatment of pain (e.g., taken instead of an opioid as an opioid substitute), advantageously without causing constipation, or taken with an opioid; for the treatment of various neurological diseases associated with the MOR (and, optionally, KOR and DOR) receptors; etc. “Binding selectivity” describes how a ligand may bind more preferentially to one receptor than another. A selectivity coefficient is the equilibrium constant for the reaction of displacement by one ligand of another ligand in a complex with the substrate. An antagonist is a substance that acts against and blocks an action or effect of another substance. The disclosure provides compounds having general Formula I Formula I where R is and where one of a, b, c, d, e or f is the point of attachment of indole ring R to the epoxymorphinan skeleton and the point of attachment varies independently from compound to compound; at least one of the atoms at positions a, b, c, d, e and f is independently N (i.e. at least one C of the indole ring is substituted or replaced by N), and the position of N varies independently from compound to compound, but N and the point of attachment cannot be at the same position; and the remaining atoms at positions at a, b, c, d, e and f are CH, i.e. the atoms that are not N are CH. In other words, substituted indole ring R is attached to the epoxymorphinan skeleton at one of a, b, c, d, e or f; and one of a, b, c, d, e and f is N, whereas the other positions are CH, as shown below: In Formula 1, * indicates a chiral carbon that is in either the α or β configuration. An alternative but equivalent representation of the compounds disclosed herein is depicted below: As used herein, “substituted” generally refers to i) the replacement of a carbon atom by a non-carbon atom such as N. However, in some aspects, one or more (e.g. 1, 2, 3, 4 or 5) of the C atoms are replaced by N. In further aspects, one or more (e.g. 1, 2, 3, 4 or 5) of a, b, c, d, e and f are independently replaced (substituted) by an atom or atomic group that is not N, examples of which include a halogen (e.g. Cl, Br, etc.), O, S, P, CO, NO, etc. These substitutions are allowed if the antagonist activity of the compound is not decreased (by more than e.g. 10%), or stays the same, or increases. Generally, in the present compounds, only one C is replaced by N. In some aspects, R is selected from the following list, where compound numbers reflect those of Tables 1 and 2 presented in the Examples section below, with some compounds (R groups) being the same in both tables but numbered differently for the α and β isomers (Table 1 and Table 2, respectively). For example, the first R group is (1) in Table 1 and (2) in Table 2, the second listed R group is (3) in Table 1 and (4) in Table 2, and so on. In yet further aspects, R = (compound 7 / 8 herein). Pharmaceutically acceptable salts and stereoisomers (enantiomers and diastereomers) of the compounds are also encompassed. "Pharmaceutically acceptable salts" of the compounds refers to the relatively non-toxic, inorganic and organic acid addition salts and base addition salts of compounds of the present disclosure. In some aspects, these salts are prepared in situ during the final isolation and purification of the compounds. In some aspects, acid addition salts can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Exemplary acid addition salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, sulfamates, malonates, salicylates, propionates, methylene-bis-β-hydroxynaphthoates, gentisates, isethionates, di-p- toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p- toluenesulfonates, cyclohexylsulfamates and laurylsulfonate salts, and the like. See, for example S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 66, 1-19 (1977) which is incorporated herein by reference. Base addition salts can also be prepared by separately reacting the purified compound in its acid form with a suitable organic or inorganic base and isolating the salt thus formed. Base addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include the sodium, potassium, calcium, barium, zinc, magnesium, and aluminum salts. Suitable inorganic base addition salts are prepared from metal bases which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide and the like. Suitable amine base addition salts are prepared from amines which have sufficient basicity to form a stable salt, and preferably include those amines which are frequently used in medicinal chemistry because of their low toxicity and acceptability for medical use. ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, e.g., lysine and arginine, and dicyclohexylamine, and the like. In some aspects, the salt is an HCl (hydrochloride) salt. METHODS Diseases and conditions that can be treated using the pharmacological agents described herein include but are not limited to those associated with opioid receptors MOR, and also KOR and DOR. Encompassed herein are methods of using the disclosed compounds, for example, to treat and / or prevent opioid dependence, to facilitate drug withdrawal, and / or to treat pain without causing opioid dependence. The methods generally involve administering to a subject in need thereof a therapeutically efficacious amount of at least one compound disclosed herein. A therapeutically efficacious or effective amount is generally an amount that lessens or eliminates at least one symptom of a disease or condition, such as a symptom of withdrawal or pain. In some aspects, the compounds are used for the treatment of substance use and / or abuse disorders, e.g. opioid addiction and overdose, alcoholism, as well as other neurological disorders related to opioid receptor functions, opioid induced constipation, irritable bowel movement disorders, etc. The compounds are thus useful to combat drug (opioid) abuse (including opioid overdose) and / or addiction, opioid use and / or addiction in those being treated for pain; constipation in those being treated for pain by taking opioids; for the treatment of pain (e.g., taken instead of an opioid as an opioid substitute), or taken with an opioid, etc. With respect to substance use and / or abuse disorders such as opioid addiction, the compounds may be used as non- or less addictive substitutes for those who are at risk of becoming addicted, or who are already addicted due to opioid use and are trying to stop or decrease opioid intake, or who experience an opioid overdose, etc. The present invention thus provides compositions and method for the treatment of drug addiction, e.g., to narcotic drugs. In some aspects, the compositions comprise a therapeutically effective amount of, for example, an addictive narcotic drug and / or methadone and at least one compound disclosed herein. The at least one compound disclosed herein is present in an amount of from about 1 to 100% by weight of the solution / composition. The dosage amount of the addictive narcotic drug / methadone is preferably from about 10 to 80 mg per kg of body weight. An individual who should withdraw from a narcotic drug or is undergoing withdrawal from a narcotic drug may be treated by administering to the individual a therapeutically effective amount of the aforesaid solution. Administration of this solution enables the individual to withdraw from the narcotic drug and eliminate dependency on the narcotic drug without the drug withdrawal symptoms and the pain associated with those symptoms. A gradual decrease of the amount of e.g. addictive narcotic drug / methadone and an increase in the amount of the present compound “weans” the user from the drug or methadone in a tapered regime, reducing dependency gradually. For example, the amount of a narcotic or methadone in the composition may initially be 95% for a few days or a week, then 90% for a few days or a week, then 85, 80, 75, 57, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5 and then 0%, with a compound disclosed herein making up the remainder of the composition (e.g. 5, 10, 15, 20, 25…etc.%) until the compound makes up 100% of the composition. At that point, the composition can be discontinued, or maintained, as deemed medically expedient for the patient. Since the present compounds are not addictive, long-term dependency as a replacement for a narcotic drug is avoided. The benefit of a gradual, stepwise method of treatment is that dependency on the narcotic drug and / or the subsequent dependency on the replacement drug, methadone, is eliminated without the pain and other symptoms associated with withdrawal from these drugs. For drug treatment, administration may be either voluntarily or involuntary, e.g., in a setting in which a subject is required to undergo administration. The addiction that is treated may be due to the overuse of prescription opiates or to addiction resulting from the purely recreational (usually illegal) use of opiates. In some embodiments, the methods of the invention treat symptoms of opioid withdrawal. The symptoms of opioid withdrawal include psychological, physical and / or somatic symptoms. Physical and physical symptoms of opioid withdrawal include tremors, hot or cold flashes, chicken skin nodules, sweating, shortness of breath, increased heart rate, elevated blood pressure, physical pain, vomiting, diarrhea, and fever. In some embodiments, the methods treat physical and / or somatic symptoms of opioid withdrawal. In some embodiments, the physical and / or somatic symptom is selected from tremor and shaking. Psychological symptoms of opioid withdrawal include dysphoria, anxiety, restlessness, irritability, insomnia, yawning, hallucinations, hyperalgesia, hypersensitivity (hyperkatifitia), and anorexia. It is generally believed that although these symptoms are not physical / somatic, they are symptoms of opioid withdrawal and result from cessation or reduction of opioid dosage and / or physiological changes caused by administration of opioid antagonists. In some embodiments, the method treats dysphoria. Symptoms of opioid withdrawal include irritability, anxiety, restlessness, irritability, insomnia, yawning, hallucinations, tremors, hot or cold flashes, chicken keloids, sneezing, sweating, shortness of breath, elevated heart rate, elevated blood pressure, pupil dilation, piloerection, headache, body pain, muscle cramps, muscle soreness, bone pain, joint soreness, hyperalgesia, hypersensitivity (hyperkatifitia), watery secretions of the eyes and nose (tearing and watery nasal discharge), nausea, vomiting, diarrhea, abdominal pain, anorexia, and fever. As noted above, one diagnostic tool developed for opioid withdrawal is DSM-5. DSM-5 specifies that, for a subject diagnosed with opioid withdrawal, 3 of the following 9 symptoms must occur within minutes to days after cessation (or reduction) of opioid exposure or administration of an opioid antagonist or partial agonist. The DSM-5 symptoms are (1) dysphoria, (2) nausea, (3) muscle soreness, (4) lacrimation or watery nasal discharge, (5) pupil dilation, piloerection or sweating, (6) diarrhea, (7) yawning, (8) fever and (9) insomnia. Thus, in some embodiments, the subject experiences at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 of the above DSM-5 symptoms, and preferably, administration of the compound of formula (I) treats at least one of the symptoms experienced by the subject. The severity of withdrawal symptoms will depend on the opioid causing the dependency, the dose and time of treatment or abuse, the rate at which the opioid ceases to be used, and the characteristics of the subject, including age, sex, body weight, and the like. Thus, in some embodiments, the method treats opioid withdrawal symptoms selected from the group consisting of: tremor, hot or cold flashes, chicken keloids, sweating, tachypnea, elevated heart rate, elevated blood pressure, physical pain, vomiting, diarrhea, fever, irritability, anxiety, restlessness, irritability, insomnia, yawning, hallucinations, hyperalgesia, hypersensitivity (hyperkatifitia), and anorexia, or a combination thereof. Alternatively, or in addition, the compounds are used as safe alternatives to (instead of) opiates, or in addition to opiates, to treat pain and prevent addiction. The compounds are used for the treatment of acute and / or chronic pain for example, visceral pain, chronic pain, cancer pain, acute pain, breakthrough pain or neuropathic pain, allodynia or hyperalgesia, pain due to inflammation, arthritis pain, migraines, pain resulting from accident and / or injury, pain from a disease other than cancer, etc. Any type of pain that can be lessened or completely eradicated may be treated by the compounds and methods disclosed herein. In general, when opioids are used to treat acute pain, or especially when they are used to treat chronic pain, uncomfortable and even severe constipation can result, adding significantly to the well-being of the patient. The compounds disclosed herein are given to prevent or treat such opioid induced constipation and are typically, but not always, administered with an opioid. Exemplary opioids with which the compounds are administered include but are not limited to: oxycodone (OxyContin), hydrocodone (Vicodin), morphine, methadone and the artificial opioid fentanyl. Patient populations for whom opiates are frequently prescribed and who are at risk of developing constipation include but are not limited to: those with terminal illnesses or conditions such as cancer or severe injuries; those with short term pain such as subjects who have had surgery; those will long-term but non-terminal illnesses such as those with pain-inducing progressive skeletal or nerve disorders, etc. With respect to neurological disorders or conditions which are prevented or treated, such diseases / disorders include but are not limited to: neurodegeneration of any type e.g. those caused by bacterial or viral infections (e.g. neuro-AIDS); Alzheimer’s disease; Parkinson’s disease; dementia; depression and / or anxiety; aberrant behavioral changes; a gradual decline in cognitive function, including trouble with concentration, memory, and attention; progressive slowing of motor function and loss of dexterity and coordination; central nervous system (CNS) lymphomas; neurological symptoms of herpes virus infections; nerve damage and pain; encephalitis; traumatic head injury; sports related head injury; etc. In some embodiments, the neurological diseases or conditions are associated with individuals whose immune systems are compromised, e.g. as a result of medical treatments (e.g. chemotherapy, etc.), as a result of disease such as human immunodeficiency virus infection / acquired immunodeficiency syndrome (HIV / AIDS), as a result of one or more genetic disorders or mutations, as a result of environmental insult or challenges (e.g. poor nutrition, excessive stress, pollutants, etc.), or due to advancing age. With respect to irritable bowel movement disorders that are prevented or treated, examples include irritable bowel syndrome (IBS, e.g., characterized by mostly diarrhea and abdominal discomfort (IBS-D; mostly constipation and abdominal discomfort (IBS-C); alternating loose stools and constipation with abdominal discomfort (IBS-mixed); and undefined subtype (IBS-U) in which symptoms vary); inflammatory bowel disease (IBD) characterized by destructive inflammation and permanent harm to the intestines; etc. In general, the individuals who are treated as described herein already exhibit gross, observable and usually measurable symptoms of such as neurological damage, pain and / or constipation. In such instances, the methods may include a step of identifying individuals suitable for receiving treatment using known examination techniques and other tests such as blood tests, viral and / or bacterial culture, self-reported discomfort, etc. Patients identified as positive for symptoms are deemed candidates for treatment. In some aspects, the individuals who can benefit from receiving the agents described herein do not yet display overt symptoms of the disease or condition to be treated but are known to be at risk of developing the disease or condition. For example, a person would be a candidate for prophylactic (or simultaneous) treatment even prior to the emergence of overt symptoms might include one who is: known to abuse or be addicted to opiates, suffering from alcoholism, is going to undergo chemotherapy other immuno-compromising or painful procedure, a person known to have any other disease or condition (e.g. a genetic predisposition) toward developing a compromised immune system and / or neurological damage or neurodegeneration, or a person who is undergoing treatment with opiates (e.g. for pain management) and is likely to develop constipation, etc. In such cases, at least one symptom of the disease or condition may be prevented or at least lessened (ameliorated). In some cases, complete prevention or eradication of symptoms is achieved, i.e., the patient never develops any symptoms or is cured of all symptoms. The individuals who are treated using the agents and methods of the invention are generally mammals, and are usually, but not always, humans. However, veterinary applications of this technology are also contemplated. The individuals (subjects, patients, etc.) that are treated may be adults or juveniles (e.g., children). All methods disclosed herein may be carried out in vitro (e.g., in a laboratory setting using cell culture, isolated opioid receptors, etc.) or in vivo, also in a laboratory setting (e.g., in an animal model) or in a subject or patient in need thereof for the purpose of medical treatment. All such methods are encompassed herein. COMPOSITIONS AND ADMINISTRATION The present invention also provides compositions for use in preventing and / or treating dysfunction and / or bodily dysfunction caused using opioids or various diseases or conditions described herein which are associated with opioid receptors, in particular the MOR. The compositions include one or more substantially purified compounds as described herein, and a pharmacologically (physiologically) suitable (compatible) carrier. The preparation of such compositions is well known to those of skill in the art. Typically, such compositions are prepared either as liquid solutions or suspensions, however solid forms such as tablets, pills, powders and the like are also contemplated. Solid forms suitable for solution in, or suspension in, liquids prior to administration may also be prepared. The preparation may also be emulsified. The active ingredients may be mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredients. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol and the like, or combinations thereof. In addition, the composition may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and the like. If it is desired to administer an oral form of the composition, various thickeners, flavorings, diluents, emulsifiers, dispersing aids or binders and the like may be added. The composition of the present invention may contain any such additional ingredients to provide the composition in a form suitable for administration. Other suitable medications may also be administered together with the compounds, either separately in different preparations, or together in the same preparation. The final amount of compound in the formulations may vary. However, in general, the amount in the formulations will be from about 1-99%. The compositions may be pills, capsules, etc. designed for long-term or slow (extended) release. The compounds may be incorporated into a patch or implantable insert for long term release. In addition, administration may be via needles or by a needle-free device. Other suitable types of compositions are described, for example, in published United States patent application US10532030B2, the complete contents of which is hereby incorporated by reference in entirety. The compositions (preparations) of the present invention may be administered by any of the many suitable means which are well known to those of skill in the art, including but not limited to by injection (e.g. intravenous, intraperitoneal, intramuscular, subcutaneous, intra-aural, intraarticular, into the spinal column, intracranial, and the like); by inhalation; orally; intravaginally, intranasally, topically (by absorption through epithelial or mucocutaneous linings e.g., nasal, oral, vaginal, rectal, gastrointestinal mucosa, and the like); as eye drops; via sprays, by a patch that is attachable to the skin of a patient; or via an implantable delivery device; etc. In preferred embodiments, the mode of administration is by injection. In addition, the compositions may be administered in conjunction with other treatment modalities such as substances that boost the immune system, various chemotherapeutic agents, antibiotic agents, and the like. The methods generally involve administering to a subject (patient) in need thereof a therapeutically effective amount of one or more of the compounds described herein. The exact dosage that will be administered, as well as the mode and frequency of administration, will vary from subject to subject, with guidance being provided by clinical trials data. However, in general, it is believed that a dose in the range of from about from 1 mg to about 600 mg per day, more specifically from about 10 mg to about 100 mg range, is administered, for example, about 1, 2, 3, or 4 times per day, unless administered intravenously in which case the dosage is adjusted accordingly to achieve suitable biologically active and effective levels of the agent(s) in the subject’s bloodstream. In some embodiments, the compounds are administered in combination with another analgesic agent such as an opioid analgesic or triptan (non-opioid) analgesic. Non-limiting examples of non-opioid analgesics useful in such combinations include aspirin; acetaminophen; a non-steroidal anti-inflammatory drug (NSAID), an arylalkanoic acid, a profen, a fenamic acid, an oxicam, a pyrazolidine derivative; a Cox-2 inhibitor, a local analgesic; an atypical analgesic, an NMDA receptor antagonist, an α2-adrenoreceptor agonists and / or a synthetic drug having narcotic properties. In various embodiments disclosed herein the non-opioid analgesic agent is acetaminophen, naproxen or a pharmaceutically acceptable salt thereof. In other aspects, methods of agonizing, partially agonizing or antagonizing one or more opioid receptors are provided. The methods comprise contacting at least one opioid receptor (typically MOR, but alternatively KOR and / or DOR) with a compound of the disclosure. These methods may be carried out in vitro or in vivo for any purpose. KITS There is also provided a kit comprising a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof; instructions for its use in any of the methods of the invention; and optionally, opioids and / or opiates. In some embodiments, the opioid and / or opiate containing fraction comprises a plurality of unit dose forms of the opioid and / or opiate, such as those suitable for use in a tapering regimen. In the kits, a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof and / or an opioid and / or an opiate and / or an opioid antagonist and / or a partial agonist may be formulated as a pharmaceutical composition with a pharmaceutically acceptable carrier, diluent and / or vehicle. The pharmaceutical compositions may be formulated for administration by any of the routes described herein, including oral, rectal, nasal, topical (including buccal and sublingual), parenteral (including intramuscular, intraperitoneal, subcutaneous and intravenous) or in a form suitable for administration by inhalation or insufflation. It is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Representative illustrative methods and materials are herein described; methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention. All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual dates of public availability and may need to be independently confirmed. It is noted that, as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as support for the recitation in the claims of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitations, such as "wherein [a particular feature or element] is absent", or "except for [a particular feature or element]", or "wherein [a particular feature or element] is not present (included, etc.)...". As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible. The invention is further described by the following non-limiting examples which further illustrate the invention, and are not intended, nor should they be interpreted to, limit the scope of the invention. EXAMPLES EXAMPLE 1. A total of 36 NAN analogues were designed, synthesized and biologically characterized. First, competitive radioligand binding assays utilizing monocloned opioid receptor-expressed Chinese hamster ovary (CHO) cells were used to determine binding affinity and selectivity for the MOR, kappa (KOR) and delta opioid receptors (DOR). Then, [35S]GTPγS binding assays were utilized to assess the functional activity at the MOR. Third, the compounds were tested for their agonism and antagonism in a mouse antinociception model, which identified eight suitable antagonists. Following this, single- dose assessment in vivo dose response studies with the eight identified antagonists were completed in which compound 7, depicted below, was identified as the most potent. Chemical Synthesis. All 36 newly designed nitrogen-walk compounds were synthesized based upon previous methods. The starting material for all compounds was naltrexone (NTX). Reductive amination utilizing benzylamine followed by sodium borohydride (NaBH4) yielded the α-monobenzyl intermediate, whereas using the dibenzylamine (DBA) and sodium cyanoborohydride (NaCNBH3) yielded the β-dibenzyl intermediate (Scheme 1). The reduced intermediate underwent catalytic hydrogenation under acidic conditions to yield the salt form of alpha (α) or beta (β) naltrexamine. Naltrexamine (α or β) was coupled with the appropriate acid using EDCI, HOBt and TEA under anhydrous conditions, followed by dealkylation using K2CO3. These final compounds were transformed to their hydrochloric acid salt forms, fully characterized, and applied for in vitro and in vivo pharmacological characterization. Scheme 1. Synthetic route for nitrogen-walk derivatives. In Vitro Pharmacological Studies. All newly synthesized compounds were subjected to competitive radioligand binding assay to obtain the binding affinity and selectivity at MOR, KOR, and DOR. The [35S]-GTPγS binding was completed at MOR to determine agonist potency and efficacy of each ligand by measuring its efficacy relative to the full agonist DAMGO for MOR activation. The in vitro data for the 6α-derivatives are shown in Table 1 and the data for 6β-derivatives are shown in Table 2. Overall, all 36 compounds showed sub nanomolar binding affinity at MOR, which is comparable to the parent compound, NAN. Also, all compounds are more selective for MOR over KOR, except for compounds 11 and 12. Interestingly, both of these compounds possess the additional nitrogen at position 4 and the amide bond at position 6 on the indole ring. All compounds showed higher selectivity over MOR than DOR. Compounds 1-8, the most structurally identical to NAN, in which the amide bond is retained at position 7 and an additional nitrogen is walked around the ring, shows similar MOR binding affinity to the parent compound. Compound 7 is the most potent at MOR with a binding affinity of 0.18 nanomolar and is also the most selective over KOR. When the amide bond is at position 6, all compounds have similar MOR binding affinity with compounds 10, 14, and 16 being the most potent, but they are not as selective for MOR when compared with NAN. Compounds 10, 14, and 16 are all in the beta conformation. When the amide bond is at position 5, no compounds had a higher MOR binding affinity compared to the parent compound. When the amide bond is at position 4, compounds 32 and 36 had a higher binding affinity when compared to NAN. In most cases, when the additional nitrogen is at position 2 or 3, the binding affinity for MOR increases. Table 1. Opioid Receptor Binding Affinity and MOR [35S]-GTPγS Functional Assay Results for Even- Numbered 6α-Analogs Compds. -R Ki (nM) Selectivity MOR [35S]-GTPγS binding MOR KOR DOR K / U D / U EC50% Emax (nM) of DAMGO NAN 0.23 ±0.02 1.69 13.69 7.3 59.5 3.85 19.11 ±0.35 ±1.39 ±2.32 ±3.31 1 0.25 ±0.02 3.63 8.05 ±0.77 14.28 31.67 1.59 24.24 ±0.59 ±0.30 ±1.64 3 0.37 ±0.06 1.42 10.31 3.88 28.20 4.26 15.73 ±0.18 ±1.80 ±0.19 ±0.90 5 0.34 ±0.06 1.33 27.38 3.97 81.77 1.99 26.71 ±0.04 ±4.97 ±0.22 ±0.41 7 0.18±0.006 2.93 30.44 16.28 168.95 4.25 9.76 ±0.41 ±4.84 ±1.22 ±0.88 9 0.72 ±0.09 6.87 26.14 9.55 36.34 8.61 27.07 ±0.93 ±3.39 ±1.06 ±2.14 11 0.36 ±0.06 0.29 3.10 ±0.43 0.82 8.67 4.28 41.42 ±0.06 ±0.70 ±2.75 13 0.32 ±0.05 1.79 41.25 5.57 128.35 1.37 11.20 ±0.03 ±3.53 ±0.27 ±0.46 15 0.29 ±0.05 2.13 73.21 7.33 251.66 3.86 36.52 ±0.25 ±6.93 ±0.69 ±2.73 17 0.66 ±0.06 14.34 17.29 21.76 26.23 5.73 22.31 ±1.30 ±2.82 ±0.85 ±2.18 19 0.86 ±0.12 2.87 6.17 ±0.21 3.33 7.15 3.94 48.17 ±0.26 ±0.12 ±3.69 21 0.34 ±0.05 1.65 41.97 4.92 125.32 1.33 35.83 ±0.23 ±5.24 ±0.15 ±0.55 23 0.50 ±0.02 4.70 12.12 9.34 24.08 2.66 19.70 ±0.19 ±1.00 ±0.34 ±1.43 25 0.36 ±0.05 1.32 16.04 3.64 44.38 3.14 30.25 ±0.24 ±1.44 ±0.37 ±2.22 27 0.62 ±0.05 1.52 3.14 ±0.39 2.43 5.04 1.96 28.4 ±0.05 ±0.38 ±2.17 29 0.85 ±0.16 9.61 13.91 11.38 16.46 4.17 45.63 ±1.26 ±0.42 ±0.70 ±2.88 31 0.23 ±0.04 4.87 71.50 21.61 317.11 1.41 15.41 ±0.51 ±11.04 ±0.29 ±0.52 33 0.35 ±0.03 3.09 8.52 ±1.53 8.86 24.42 3.99 25.50 ±0.51 ±0.75 ±1.14 35 0.44 ±0.07 7.49 20.60 16.94 46.60 6.51 14.00 ±1.55 ±2.13 ±1.19 ±0.88 Table 2. Opioid Receptor Binding Affinity and MOR [35S]-GTPγS Functional Assay Results for Even- Numbered 6β-Analogs

[0003] Compds. -R Ki (nM) Selectivity MOR [35S]-GTPγS binding MOR KOR DOR K / U D / U EC50% Emax (nM) of DAMGO NAN 0.23 ±0.02 1.69 ±0.35 13.69 7.3 59.5 3.85 19.11 ±1.39 ±2.32 ±3.31 2 0.33 ±0.04 0.95 ±0.11 23.71 2.90 72.17 2.09 21.75 ±1.81 ±0.44 ±1.75 4 0.25 ±0.03 2.92 ±0.22 91.97 11.93 375.64 2.05 38.52 ±10.18 ±0.22 ±0.72 6 0.44 ±0.10 1.00 ±0.10 42.11 2.29 96.38 2.99 25.00 ±8.78 ±0.56 ±1.60 8 0.44 ±0.03 6.01 ±1.09 146.99 13.70 334.93 3.99 18.77 ±8.55 ±0.49 ±1.33 10 0.18 ±0.02 0.43 ±0.05 8.22 2.44 46.69 0.52 53.83 ±1.03 ±0.08 ±2.15 12 0.36 ±0.05 0.32 ±0.04 10.22 0.89 28.48 1.91 34.39 ±1.55 ±0.27 ±1.56 14 0.15 ±0.02 0.43 ±0.04 8.74 2.84 58.27 0.60 29.03 ±1.33 ±0.03 ±1.08 16 0.16 ±0.03 0.18 ±0.03 3.40 1.15 21.96 2.98 23.99 ±0.35 ±0.37 ±1.88 18 0.42 ±0.04 1.66 ±0.16 85.83 4.00 206.6 1.47 21.70 ±2.39 ±0.20 ±1.85 20 0.35 ±0.04 4.04 ±0.45 77.23 11.55 220.97 5.31 37.66 ±8.25 ±0.91 ±2.36 22 0.27 ±0.03 2.15 ±0.13 100.19 7.89 368.54 0.52 13.95 ±2.37 ±0.07 ±1.31 24 0.26 ±0.03 0.86 ±0.11 51.27 3.26 194.96 7.03 6.44 ±8.40 ±1.73 ±0.48 26 0.27 ±0.05 0.78 ±0.15 55.92 2.87 206.15 1.57 14.00 ±8.09 ±0.20 ±1.16 28 0.64 ±0.03 3.75 ±0.59 15.7 5.84 24.4 2.23 17.2 ±2.45 ±0.38 ±1.09 30 0.37 ±0.03 4.70 ±0.48 82.87 12.82 226.05 1.36 22.24 ±13.14 ±0.10 ±2.06 32 0.19±0.01 4.35 ±0.47 13.17 22.81 69.08 3.62 13.54 ±1.30 ±0.68 ±1.13 34 0.32 ±0.03 0.671 ND 2.09 ND 2.98 23.99 ±0.13 ±0.37 ±1.88 36 0.21 ±0.04 6.24 ±0.62 34.35 29.31 161.44 2.34 19.39 ±7.06 ±0.40 ±0.98 ND: not determined. In Vivo Warm-Water Tail Immersion Assay. The warm-water immersion assay tests whether the synthesized compounds pertain antinociceptive properties and to test the ability of the compound to antagonize morphine’s antinociceptive properties. The mice’s tail is dipped in warm water and recorded. The longer the tail is kept in water, the higher the MPE%, the higher the antinociceptive effects of the compound. All newly synthesized compounds were tested for single dose agonism to exclude any agonists from further studies. The test compound (10mg / kg) was injected subcutaneously, and the assay was conducted 20 minutes later. However, no compounds showed significant antinociceptive properties that were similar to morphine. Compounds 10, 13, 17, 19, 20, 21, 28, 29 and 32 showing the least antinociceptive effects at 10 mg / kg. (Figure 2A and B). All newly synthesized compounds were tested in the tail immersion assay for antagonism shown in Figure 3A and B. Compounds 1, 4, 6, 7, 14, 15, 21, 31 had an MPE of less than 25% showing the least antinociceptive effects at 10 mg / kg. Following this single-dose assessment, in vivo dose response studies with the eight identified antagonists were completed and shown in Figure 4. The potencies of the eight compounds were studied and the resulting AD50 values ranged from 0.09-5.07 mg / kg. Six out of eight compounds showed comparable AD50 values with NAN. Compound 7 has the most potent AD50value of 0.09 mg / kg. In Vivo Opioid Withdrawal Studies. When comparing compound 7 to naloxone (NLX), 7 has less withdrawal effects even at doses 5 times higher (Figure 5). At 1 mg / kg, 7 produced less wet dog shakes, jumps and paw tremoring than NLX at 1 mg / kg. Even at 5 mg / kg, 7 produced less wet dog shakes and paw tremoring than NLX at 1 mg / kg. CONCLUSIONS ^ The 36 proposed compounds were designed utilizing the potent MOR modulator, NAN, and then synthesized using a multistep synthetic route. ^ Radioligand binding assay was completed at MOR for all 36 compounds. ^ The 36 compounds were then tested for single dose agonism and single dose antagonism, which resulted in a total of 8 compounds being the most potent for antagonism. ^ Dose response was completed for all 8 compounds, which resulted in compd. 7 showing excellent antagonism. ^ Withdrawal studies on compd.7 were completed and compared with naloxone, which indicates compd. 7 has less withdrawal symptoms than NLX. EXPERIMENTAL SECTION Chemistry. All nonaqueous reactions were carried out under a pre-dried nitrogen gas atmosphere. All solvents and reagents were purchased from Sigma-Aldrich, Alfa Aesar, and Fisher Scientific and were used as received without further purification. Analytical thin-layer chromatography (TLC) analyses were carried out on Analtech Uniplate F254 plates, and flash column chromatography (FCC) was performed over silica gel (230-400 mesh, Merck). The1H (400 MHz) and13C (100 MHz) nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Ultrashield 400 Plus spectrometer, and chemical shifts were expressed in parts per million. The high-resolution mass spectra were obtained on an Applied BioSystems 3200 Q trap with a turbo V source for TurbolonSpray. Analytical reversed-phase high-performance liquid chromatography (HLPC) was performed on a Waters Arc HPLC using an XBridgeTMC183.5 µm column (4.6 x 50 mm). All analyses were conducted at ambient temperature with a flow rate of 0.2 mL / min. The mobile phase is acetonitrile / water (70:30) with 0.1% trifluoroacetic acid (TFA). The UV detector was set up at 210 nm. Compound purities were calculated as the percentage peak area of the analyzed compound, and the retention times (Rt) were presented in minutes. The purity of all newly synthesized compounds was identified as ≥95%. General Procedure for the Amide Coupling / Hydrolysis Reaction. A solution of carboxylic acid (2.5 equiv) in dry DMF (1.5 mL) was added with hydrobenzotriazole (HOBt, 3 equiv), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide (EDCI, 3 equiv), 4 Å molecular sieves, and triethylamine (5 equiv) on an ice-water bath. After 1 hour, a solution of 6α-naltrexamine or 6β-naltrexamine (1 equiv) in pre-dried DMF (1.5 mL) was added dropwise. The resulting mixture was stirred at room temperature. Once TLC indicated complete consumption of the starting material, the reaction mixture was filtered through Celite. The filtrate was evaporated to dryness and dissolved in anhydrous methanol (3 mL) and then K2CO3 (2.5 equiv) was added. The resulting mixture was stirred overnight at room temperature and filtered again over Celite. After being concentrated, the residue was purified by flash column chromatography with CH2Cl2 / MeOH (1% NH3∙H2O) as the eluent to give the free base. After structural confirmation by1H NMR, the corresponding free base was then converted into a hydrochloride salt, which was then fully characterized by1H NMR,13C NMR, HRMS, and HPLC. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6α-[1H-indazole-7- carboxamide]morphinan Hydrochloride (1). Compound 1 was synthesized as shown in the general procedure with 62% yield.1H NMR (400 MHz, DMSO-d6) δ: 13.04 (s, 1H), 8.90 (s, 1H), 8.36 (s, 1H), 8.19 (s, 1H), 7.99 (t, J = 7.0 Hz, 2H), 7.24 (t, J = 7.4 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.38 (s, 1H), 4.86 (d, J = 3.8 Hz, 1H), 4.71 (m, 1H), 3.96 (d, J = 6.8 Hz, 1H), 3.35 (m, 1H), 3.29 (m, 1H), 3.10 (m, 1H), 3.05 (m, 1H), 2.97 (m, 1H), 2.74 (m, 1H), 2.54 (m, 1H), 1.97 (m, 1H), 1.67 (m, 1H), 1.58 (m, 1H), 1.49 (m, 1H), 1.22 (m, 1H), 1.08 (m, 1H), 0.70 (m, 1H), 0.62 (m, 1H), 0.50 (m, 1H), 0.41 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 165.45, 146.34, 146.08, 138.84, 128.72, 125.50, 125.46, 124.53, 124.52, 124.14, 122.11, 119.66, 119.18, 118.28, 87.25, 69.44, 61.07, 57.06, 45.90, 45.28, 30.30, 29.27, 23.53, 19.38, 5.71, 5.20, 2.59. HRMS m / z: calc. 487.2345 for C28H31N4O4 [M + H]+; obs.: 487.2344 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.518 min) and was found to be 99.33% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6β-[1H-indazole-7- carboxamide]morphinan Hydrochloride (2). Compound 2 was synthesized as shown in the general procedure with 58% yield.1H NMR (400 MHz, DMSO-d6) δ: 12.98 (s, 1H), 9.32 (s, 1H), 8.87 (s, 1H), 8.85 (s, 1H), 8.14 (d, J = 1.4 Hz, 1H), 7.99 (t, J = 7.1 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 6.18 (s, 1H), 4.89 (d, J = 7.9 Hz, 1H), 3.87 (d, J = 5.1 Hz, 1H), 3.87 (m, 1H), 3.81–3.76 (m, 1H), 3.43–3.39 (m, 2H), 3.14– 3.03 (m, 2H), 2.86 (m, 1H), 2.46–2.41 (m, 2H), 1.95 (m, 1H), 1.79 (m, 1H), 1.66 (m, 1H), 1.50 (m, 1H), 1.39 (m, 1H), 1.08 (m, 1H), 0.68 (m, 1H), 0.60 (m, 1H), 0.51 (m, 1H), 0.42 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 165.41, 142.14, 141.32, 137.78, 133.55, 129.68, 124.52, 124.51, 124.39, 120.57, 119.58, 119.31, 117.91, 116.82, 89.81, 69.77, 61.74, 56.71, 51.04, 46.52, 45.66, 29.46, 27.35, 23.84, 23.04, 5.72, 5.12, 2.63. HRMS m / z calc. 487.2345 for C28H31N4O4[M + H]+; obs.: 487.2356 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.482 min) and was found to be 100.00% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6α-[1H-pyrrolo[3,2-b]pyridine-7- carboxamide]morphinan Hydrochloride (3). Compound 3 was synthesized as shown in the general procedure with 75% yield.1H NMR (400 MHz, DMSO-d6) δ: 12.48 (s, 1H), 9.23 (s, 1H), 9.02 (d, J = 7.5 Hz, 1H), 8.92 (s, 1H), 8.78 (d, J = 5.8 Hz, 1H), 8.11 (t, J = 3.0 Hz, 1H), 8.00 (d, J = 5.8 Hz, 1H), 6.90 (dd, J = 3.0, 1.8 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.46 (s, 1H), 4.87 (d, J = 3.9 Hz, 1H), 4.78–4.70 (m, 1H), 3.98 (d, J = 6.7 Hz, 1H), 3.30–3.28 (m, 2H), 3.12–3.04 (m, 2H), 3.00–2.95 (m, 1H), 2.78–2.70 (m, 1H), 2.55–2.53 (m, 1H), 2.02–1.95 (m, 1H), 1.71–1.60 (m, 2H), 1.53–1.47 (m, 1H), 1.30–1.21 (m, 1H), 1.12– 1.05 (m, 1H), 0.71–0.67 (m, 1H), 0.65–0.60 (m, 1H), 0.52–0.48 (m, 1H), 0.43–0.39 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 163.68, 146.51, 139.37, 129.33, 129.10, 128.16, 122.59, 122.34, 119.71, 118.82, 116.50, 115.92, 114.71, 100.00, 87.22, 69.93, 61.49, 57.54, 50.45, 46.97, 45.77, 30.73, 29.54, 24.00, 19.49, 6.18, 5.66, 3.08. HRMS m / z: calc. 487.2345 for C28H31N4O4 [M + H]+; obs. 487.2335 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.295 min) and was found to be 98.30% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6β-[1H-pyrrolo[3,2-b]pyridine-7- carboxamide]morphinan Hydrochloride (4). Compound 4 was synthesized as shown in the general procedure with 76% yield.1H NMR (400 MHz, DMSO-d6) δ: 12.43 (s, 1H), 9.59 (d, J = 8.0 Hz, 1H), 9.37 (s, 1H), 8.91 (s, 1H), 8.81 (d, J = 5.8 Hz, 1H), 8.08 (dd, J = 6.2, 4.5 Hz, 2H), 6.88 (dd, J = 3.0, 1.8 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 6.30 (s, 1H), 4.93 (d, J = 7.7 Hz, 1H), 3.92 (d, J = 5.1 Hz, 1H), 3.83–3.77 (m, 1H), 3.28–3.24 (m, 2H), 3.14–3.03 (m, 3H), 2.92–2.86 (m, 1H), 2.46–2.43 (m, 1H), 2.09–2.00 (m, 1H), 1.85 (d, J = 13.7 Hz, 1H), 1.70–1.64 (m, 1H), 1.50–1.40 (m, 2H), 1.11–1.07 (m, 1H), 0.71–0.67 (m, 1H), 0.63–0.57 (m, 1H), 0.54–0.51 (m, 1H), 0.46–0.39 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 163.38, 142.47, 141.88, 136.33, 130.05, 129.57, 125.15, 121.08, 120.59, 119.94, 118.41, 116.25, 114.00, 99.99, 89.95, 70.18, 62.14, 57.21, 52.12, 46.96, 46.17, 29.88, 27.80, 23.99, 23.54, 6.21, 5.61, 3.13. HRMS m / z: calc. 487.2345 for C28H31N4O4 [M + H]+; obs.: 487.2316 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.297 min) and was found to be 99.06% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6α-[1H-pyrrolo[3,2-c]pyridine-7- carboxamide]morphinan Hydrochloride (5). Compound 5 was synthesized as shown in the general procedure with 89% yield.1H NMR (400 MHz, DMSO-d6) δ: 12.76 (s, 1H), 9.40 (s, 1H), 9.26 (s, 1H), 9.08 (s, 1H), 9.02 (d, J = 7.4 Hz, 1H), 8.92 (s, 1H), 7.88 (dd, J = 5.5, 2.7 Hz, 1H), 7.11 (dd, J = 3.1, 1.5 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 6.46 (s, 1H), 4.84 (d, J = 3.8 Hz, 1H), 4.79 – 4.70 (m, 1H), 3.98 (d, J = 6.8 Hz, 1H), 3.29–3.26 (m, 2H), 3.13–3.05 (m, 2H), 3.00–2.95 (m, 1H), 2.78–2.71 (m, 1H), 2.56–2.53 (m, 1H), 2.03–1.94 (m, 1H), 1.69–1.59 (m, 2H), 1.50 (dd, J = 14.7, 9.9 Hz, 1H), 1.31–1.22 (m, 1H), 1.13–1.06 (m, 1H), 0.74–0.67 (m, 1H), 0.65–0.60 (m, 1H), 0.53–0.47 (m, 1H), 0.45–0.38 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 162.94, 146.58, 139.97, 139.33, 137.85, 133.80, 130.74, 129.10, 126.07, 122.63, 119.71, 118.88, 115.66, 104.90, 87.30, 69.93, 61.45, 57.50, 52.73, 46.82, 45.74, 30.72, 29.54, 23.99, 19.49, 6.18, 5.67, 3.07. HRMS m / z: calc. 487.2345 for C28H31N4O4[M + H]+; obs.: 487.2360 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.302 min) and was found to be 99.46% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6β-[1H-pyrrolo[3,2-c]pyridine-7- carboxamide]morphinan Hydrochloride (6). Compound 6 was synthesized as shown in the general procedure with 85% yield.1H NMR (400 MHz, DMSO-d6) δ: 12.69 (s, 1H), 9.59 (d, J = 7.9 Hz, 1H), 9.40 (s, 2H), 9.16 (s, 1H), 8.92 (s, 1H), 7.85 (d, J = 2.9 Hz, 1H), 7.09 (dd, J = 2.9, 1.3 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 6.32 (s, 1H), 4.92 (d, J = 7.8 Hz, 1H), 3.93 (d, J = 5.3 Hz, 1H), 3.84–3.79 (m, 1H), 3.38–3.32 (m, 3H), 3.13–3.06 (m, 2H), 2.92–2.87 (m, 1H), 2.45–2.43 (m, 1H), 2.06–1.96 (m, 1H), 1.86 (d, J = 13.7 Hz, 1H), 1.71–1.64 (m, 1H), 1.52–1.39 (m, 2H), 1.13–1.05 (m, 1H), 0.72–0.66 (m, 1H), 0.64–0.58 (m, 1H), 0.56–0.50 (m, 1H), 0.45–0.40 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 162.86, 142.46, 141.89, 139.93, 137.95, 133.85, 130.34, 130.06, 126.25, 121.08, 119.92, 118.37, 115.41, 104.82, 90.01, 70.16, 62.09, 57.16, 51.90, 46.97, 46.15, 29.86, 27.78, 24.08, 23.51, 6.22, 5.62, 3.11. HRMS m / z: calc. 487.2345 for C28H31N4O4 [M + H]+; obs.: 487.2351 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.300 min) and was found to be 99.01% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6α-[1H-pyrrolo[2,3-c]pyridine-7- carboxamide]morphinan Hydrochloride (7). Compound 7 was synthesized as shown in the general procedure with 80% yield.1H NMR (400 MHz, DMSO-d6) δ: 11.91 (s, 1H), 8.93 (s, 1H), 8.69 (d, J = 7.7 Hz, 1H), 8.24 (d, J = 5.5 Hz, 1H), 7.93 (d, J = 5.5 Hz, 1H), 7.82 (s, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.73 (s, 1H), 6.60 (d, J = 8.1 Hz, 1H), 4.82 (d, J = 3.8 Hz, 1H), 4.79– 4.71 (m, 1H), 3.98 (d, J = 6.6 Hz, 1H), 3.40–3.27 (m, 2H), 3.12–2.96 (m, 3H), 2.78–2.69 (m, 1H), 2.57–2.53 (m, 1H), 2.04–1.95 (m, 1H), 1.70–1.67 (m, 2H), 1.49 (dd, J = 15.1, 9.7 Hz, 1H), 1.15–1.05 (m, 2H), 0.75–0.67 (m, 1H), 0.67–0.61 (m, 1H), 0.52–0.48 (m, 1H), 0.43–0.39 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 163.75, 146.24, 139.44, 136.60, 134.74, 134.48, 131.08, 129.20, 122.59, 119.90, 118.99, 118.76, 101.98, 87.99, 69.88, 61.38, 57.50, 45.83, 45.67, 30.66, 29.69, 23.99, 20.37, 6.19, 5.68, 3.06. HRMS m / z: calc.487.2345 for C28H31N4O4 [M + H]+; obs.: 487.2363 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.482 min) and was found to be 99.69% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6β-[1H-pyrrolo[2,3-c]pyridine-7- carboxamide]morphinan Hydrochloride (8). Compound 8 was synthesized as shown in the general procedure with 62% yield.1H NMR (400 MHz, DMSO-d6) δ: 11.98 (s, 1H), 9.45 (s, 1H), 8.90 (s, 1H), 8.24 (d, J = 5.6 Hz, 1H), 7.96 (d, J = 5.6 Hz, 1H), 7.82 (s, 1H), 6.76 (d, J = 8.2 Hz, 1H), 6.74 (s, 1H), 6.67 (d, J = 8.2 Hz, 1H), 5.04 (d, J = 7.7 Hz, 1H), 3.90 (d, J = 5.2 Hz, 1H), 3.84–3.76 (m, 1H), 3.40–3.30 (m, 2H), 3.14–3.02 (m, 2H), 2.92–2.85 (m, 1H), 2.48– 2.45 (m, 2H), 2.13–2.03 (m, 1H), 1.81 (d, J = 13.8 Hz, 1H), 1.67–1.60 (m, 1H), 1.50–1.40 (m, 2H), 1.11–1.07 (m, 1H), 0.72–0.66 (m, 1H), 0.63–0.60 (m, 1H), 0.54–0.51 (m, 1H), 0.46–0.43 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 161.80, 142.59, 141.86, 132.92, 131.04, 130.18, 121.07, 119.82, 118.98, 118.36, 117.45, 102.08, 90.26, 70.21, 66.93, 62.07, 57.15, 51.55, 46.97, 46.17, 30.06, 27.81, 24.10, 23.49, 6.23, 5.61, 3.11. HRMS m / z: calc. 487.2345 for C28H31N4O4 [M + H]+; obs.: 487.2346 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.452 min) and was found to be 99.88% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6α-[1H-indazole-6- carboxamide]morphinan Hydrochloride (9). Compound 9 was synthesized as shown in the general procedure with 78% yield.1H NMR (400 MHz, DMSO-d6) δ: 8.88 (s, 1H), 8.20 (d, J = 7.6 Hz, 1H), 8.15 (d, J = 0.9 Hz, 1H), 8.09 (s, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 4.81 (d, J = 3.9 Hz, 1H), 4.63 (m, 1H), 3.94 (d, J = 6.7 Hz, 1H), 3.36 (m, 1H), 3.29 (m, 1H), 3.10 (m, 1H), 3.05 (m, 1H), 2.97 (m, 1H), 2.73 (m, 1H), 2.54 (m, 1H), 1.94 (m, 1H), 1.65 (m, 1H), 1.54 (m, 1H), 1.46 (m, 1H), 1.19 (m, 1H), 1.08 (m, 1H), 0.69 (m, 1H), 0.62 (m, 1H), 0.49 (m, 1H), 0.41 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 166.46, 146.10, 139.37, 138.82, 133.40, 132.20, 128.74, 124.23, 122.10, 120.24, 119.53, 119.10, 118.31, 109.96, 87.18, 69.39, 61.05, 57.02, 52.45, 46.12, 45.23, 30.25, 29.24, 23.50, 19.37, 5.70, 5.18, 2.56. HRMS m / z: calc.487.2345 for C28H31N4O4 [M + H]+; obs.: 487.2400 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.453 min) and was found to be 99.95% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6β-[1H-indazole-6- carboxamide]morphinan Hydrochloride (10). Compound 10 was synthesized as shown in the general procedure with 70% yield.1H NMR (400 MHz, DMSO-d6) δ: 13.41 (s, 1H), 9.33 (s, 1H), 8.85 (s, 1H), 8.78 (d, J = 8.0 Hz, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 6.15 (s, 1H), 4.87 (d, J = 7.8 Hz, 1H), 3.86 (d, J = 5.1 Hz, 1H), 3.73 (m, 1H), 3.44–3.38 (m, 2H), 3.11 (m, 1H), 3.04 (m, 1H), 2.86 (m, 1H), 2.46–2.41 (m, 2H), 1.90 (m, 1H), 1.77 (m, 1H), 1.63 (m, 1H), 1.47 (m, 1H), 1.42 (m, 1H), 1.05 (m, 1H), 0.68 (m, 1H), 0.59 (m, 1H), 0.51 (m, 1H), 0.42 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 165.99, 142.17, 141.30, 139.40, 133.46, 131.98, 129.68, 124.25, 120.58, 120.23, 119.20, 117.92, 109.62, 89.84, 69.75, 61.75, 56.71, 51.32, 48.55, 46.50, 45.62, 29.41, 27.35, 23.76, 23.03, 5.70, 5.09, 2.61. HRMS m / z: calc. 487.2345 for C28H31N4O4 [M + H]+; obs.: 487.2323 [M + H]+. The purity of the compound was checked by HPLC (Rt=2.452 min) and was found to be 99.92% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6α-[1H-pyrrolo[3,2-b]pyridine-6- carboxamide]morphinan Hydrochloride (11). Compound 11 was synthesized as shown in the general procedure with 82% yield.1H NMR (400 MHz, DMSO-d6) δ: 12.82 (s, 1H), 9.21 (s, 1H), 9.11 (s, 1H), 8.84 (s, 1H), 8.84 (s, 1H), 8.66 (d, J = 7.2 Hz, 1H), 8.26 (s, 1H), 6.88 (s, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.34 (s, 1H), 4.80 (d, J = 3.8 Hz, 1H), 4.71–4.64 (m, 1H), 3.94 (d, J = 6.8 Hz, 1H), 3.27–3.23 (m, 2H), 3.11–3.05 (m, 2H), 2.98–2.93 (m, 1H), 2.77–2.68 (m, 1H), 2.56–2.54 (m, 1H), 1.98–1.89 (m, 1H), 1.67–1.47 (m, 3H), 1.29– 1.19 (m, 1H), 1.11–1.09 (m, 1H), 0.74–0.67 (m, 1H), 0.65–0.61 (m, 1H), 0.52–0.47 (m, 1H), 0.44–0.37 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 163.58, 146.64, 139.33, 138.91, 131.29, 129.17, 125.82, 123.45, 122.62, 119.64, 118.95, 118.62, 87.45, 69.89, 61.53, 57.52, 50.27, 46.94, 45.74, 30.68, 29.62, 24.00, 19.73, 6.18, 5.66, 3.05. HRMS m / z: calc. 487.2345 for C28H31N4O4[M + H]+; obs.: 487.2347 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.290 min) and was found to be 99.81% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6β-[1H-pyrrolo[3,2-b]pyridine-6- carboxamide] morphinan Hydrochloride (12). Compound 12 was synthesized as shown in the general procedure with 79% yield.1H NMR (400 MHz, DMSO-d6) δ: 13.12 (s, 1H), 9.33 (d, J = 7.8 Hz, 2H), 9.18 (s, 1H), 8.96 (s, 1H), 8.89 (s, 1H), 8.33 (t, J = 2.9 Hz, 1H), 6.91 (s, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 6.27 (s, 1H), 4.90 (d, J = 7.8 Hz, 1H), 3.91 (d, J = 5.1 Hz, 1H), 3.79–3.73 (m, 1H), 3.30–3.28 (m, 2H), 3.13–3.05 (m, 2H), 2.92–2.86 (m, 1H), 2.47–2.44 (m, 1H), 2.01–1.92 (m, 1H), 1.82 (d, J = 13.7 Hz, 1H), 1.68–1.62 (m, 1H), 1.49–1.41 (m, 2H), 1.12–1.06 (m, 1H), 0.68 (dd, J = 8.5, 4.9 Hz, 1H), 0.71–0.66 (m, 1H), 0.56–0.49 (m, 1H), 0.44–0.41 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 163.18, 142.57, 141.86, 139.02, 131.50, 130.10, 127.63, 125.49, 123.31, 121.12, 119.89, 118.45, 90.13, 70.19, 62.18, 57.20, 52.13, 46.99, 46.14, 29.85, 27.82, 24.18, 23.53, 6.22, 5.60, 3.13. HRMS m / z: calc. 487.2345 for C28H31N4O4[M + H]+; obs.: 487.2343 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.295 min) and was found to be 99.16% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6α-[1H-pyrrolo[3,2-c]pyridine-6- carboxamide]morphinan Hydrochloride (13). Compound 13 was synthesized as shown in the general procedure with 55% yield.1H NMR (400 MHz, DMSO-d6) δ: 13.24 (s, 1H), 9.18 (s, 1H), 9.10 (s, 1H), 8.93 (s, 1H), 8.69 (s, 1H), 7.99 (s, 1H), 7.04 (s, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 6.48 (s, 1H), 4.79 (d, J = 3.8 Hz, 1H), 4.72–4.69 (m, 1H), 3.99 (d, J = 6.7 Hz, 1H), 3.31–3.27 (m, 2H), 3.11–2.98 (m, 3H), 2.76–2.70 (m, 1H), 2.57–2.51 (m, 1H), 2.02–1.93 (m, 1H), 1.67–1.60 (m, 2H), 1.49 (dd, J = 14.9, 9.7 Hz, 1H), 1.25–1.19 (m, 1H), 1.12–1.08 (m, 1H), 0.72–0.68 (m, 1H), 0.65–0.59 (m, 1H), 0.52–0.48 (m, 1H), 0.42–0.39 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 146.03, 140.55, 138.90, 134.43, 128.67, 125.46, 122.15, 119.28, 118.50, 107.93, 87.05, 69.40, 60.94, 57.02, 46.37, 45.31, 45.22, 30.19, 29.10, 23.53, 19.41, 5.71, 5.19, 2.59. ] HRMS m / z: calc. 487.2345 for C28H31N4O4 [M + H]+; obs.: 487.2319 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.305 min) and was found to be 99.33% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6β-[1H-pyrrolo[3,2-c]pyridine-6- carboxamide]morphinan Hydrochloride (14). Compound 14 was synthesized as shown in the general procedure with 67% yield.1H NMR (400 MHz, DMSO-d6) δ: 13.50 (s, 1H), 9.80 (s, 1H), 9.39 (s, 1H), 9.20 (s, 1H), 8.91 (s, 1H), 8.76 (s, 1H), 8.04 (s, 1H), 7.08 (s, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 6.32 (s, 1H), 4.96 (d, J = 7.7 Hz, 1H), 3.93 (d, J = 4.7 Hz, 1H), 3.83–3.76 (m, 1H), 3.28–3.26 (m, 2H), 3.15–3.03 (m, 3H), 2.93–2.87 (m, 1H), 2.44–2.41 (m, 1H), 2.06–1.97 (m, 1H), 1.84 (d, J = 13.6 Hz, 1H), 1.69–1.61 (m, 1H), 1.50– 1.42 (m, 2H), 1.10–1.08 (m, 1H), 0.72–0.69 (m, 1H), 0.64–0.58 (m, 1H), 0.55–0.52 (m, 1H), 0.46–0.39 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 142.49, 141.92, 141.34, 137.15, 130.07, 127.93, 125.86, 121.13, 119.93, 118.45, 108.12, 90.03, 70.16, 62.10, 57.18, 55.37, 52.25, 46.97, 46.16, 29.88, 27.78, 24.04, 23.51, 6.22, 5.62, 3.11. HRMS m / z: calc. 487.2345 for C28H31N4O4[M + H]+; obs.: 487.2318 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.308 min) and was found to be 99.29% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6α-[1H-pyrrolo[2,3-b]pyridine-6- carboxamide]morphinan Hydrochloride (15). Compound 15 was synthesized as shown in the general procedure with 77% yield.1H NMR (400 MHz, DMSO-d6) δ: 12.10 (s, 1H), 8.94 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 7.3 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.71–7.68 (m, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 6.58 (dd, J = 3.4, 1.8 Hz, 1H), 4.76 (d, J = 3.9 Hz, 1H), 4.75–4.69 (m, 1H), 3.99 (d, J = 6.8 Hz, 1H), 3.41–3.24 (m, 2H), 3.11– 2.99 (m, 3H), 2.78–2.68 (m, 1H), 2.58–2.52 (m, 1H), 2.02–1.99 (m, 1H), 1.67–1.60 (m, 2H), 1.46 (dd, J = 15.1, 9.8 Hz, 1H), 1.13–0.98 (m, 2H), 0.74–0.67 (m, 1H), 0.65–0.60 (m, 1H), 0.54–0.48 (m, 1H), 0.44–0.41 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 164.54, 147.19, 146.12, 142.93, 139.46, 130.01, 129.42, 129.27, 123.01, 122.53, 119.87, 118.60, 114.25, 100.83, 88.45, 69.88, 61.35, 57.50, 45.85, 45.63, 45.52, 30.72, 29.74, 23.98, 20.62, 6.20, 5.68, 3.06. HRMS m / z calc. 487.2345 for C28H31N4O4[M + H]+; obs.: 487.2337 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.560 min) and was found to be 99.39% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6β-[1H-pyrrolo[2,3-b]pyridine-6- carboxamide]morphinan Hydrochloride (16). Compound 16 was synthesized as shown in the general procedure with 69% yield.1H NMR (400 MHz, DMSO-d6) δ: 11.80 (s, 1H), 8.88 (s, 1H), 8.64 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.71–7.67 (m, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 6.57 (dd, J = 3.4, 1.8 Hz, 1H), 5.03 (d, J = 7.8 Hz, 1H), 3.89 (d, J = 5.2 Hz, 1H), 3.70–3.67 (m, 2H), 3.37–3.30 (m, 2H), 3.09– 3.04 (m, 2H), 2.90–2.85 (m, 1H), 2.48–2.40 (m, 1H), 2.08–1.99 (m, 1H), 1.75 (d, J = 13.7 Hz, 1H), 1.66–1.58 (m, 1H), 1.49–1.39 (m, 2H), 1.12–1.06 (m, 1H), 0.72–0.65 (m, 1H), 0.62–0.57 (m, 1H), 0.54–0.50 (m, 1H), 0.43–0.40 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 165.19, 147.07, 143.64, 142.66, 141.81, 130.29, 129.83, 129.23, 122.71, 121.09, 119.73, 118.37, 114.32, 100.80, 90.61, 70.26, 62.01, 57.13, 51.46, 46.98, 46.20, 30.19, 27.79, 24.27, 23.46, 6.22, 5.61, 3.10. HRMS m / z: calc. 487.2345 for C28H31N4O4 [M + H]+: 487.2340; obs.: 487.2327 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.543 min) and was found to be 99.37% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6α-[1H-indazole-5- carboxamide]morphinan Hydrochloride (17). Compound 17 was synthesized as shown in the general procedure with 64% yield.1H NMR (400 MHz, DMSO-d6) δ: 8.89 (s, 1H), 8.39 (s, 1H), 8.22 (d, J = 0.8 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 4.80 (d, J = 3.8 Hz, 1H), 4.64 (m, 1H), 3.95 (d, J = 6.7 Hz, 1H), 3.36 (m, 1H), 3.25 (m, 1H), 3.09 (m, 1H), 3.04 (m, 1H), 2.98 (m, 1H), 2.73 (m, 1H), 2.54 (m, 1H), 1.94 (m, 1H), 1.64 (m, 1H), 1.53 (m, 1H), 1.45 (m, 1H), 1.20 (m, 1H), 1.08 (m, 1H), 0.69 (m, 1H), 0.61 (m, 1H), 0.50 (m, 1H), 0.40 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 166.32, 146.10, 140.95, 138.81, 134.68, 128.76, 126.84, 125.50, 122.25, 122.10, 120.85, 119.10, 118.31, 109.77, 87.32, 69.40, 61.04, 57.01, 45.98, 45.22, 30.24, 29.25, 23.51, 19.45, 5.70, 5.18, 2.56. HRMS m / z: calc.487.2345 for C28H31N4O4 [M + H]+; obs.: 487.2340 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.437 min) and was found to be 99.89% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6β-[1H-indazole-5- carboxamide]morphinan Hydrochloride (18). Compound 18 was synthesized as shown in the general procedure with 59% yield.1H NMR (400 MHz, DMSO-d6) δ: 8.87 (s, 1H), 8.68 (d, J = 8.0 Hz, 1H), 8.39 (s, 1H), 8.22 (d, J = 0.9 Hz, 1H), 7.90 (dd, J = 8.8 Hz, 1.5 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 6.20 (s, 1H), 4.87 (d, J = 7.8 Hz, 1H), 3.88 (d, J = 5.2 Hz, 1H), 3.72 (m, 1H), 3.33 (m, 1H), 3.30 (m, 1H), 3.10 (m, 1H), 3.04 (m, 1H), 2.87 (m, 1H), 2.47 (m, 1H), 2.45 (m, 1H), 1.91 (m, 1H), 1.78 (m, 1H), 1.62 (m, 1H), 1.48 (m, 1H), 1.40 (m, 1H), 1.07 (m, 1H), 0.68 (m, 1H), 0.59 (m, 1H), 0.52 (m, 1H), 0.42 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 165.96, 142.20, 141.29, 140.93, 134.69, 129.70, 126.70, 125.20, 123.83, 122.33, 120.58, 119.23, 117.90, 109.75, 89.95, 69.76, 61.76, 56.70, 51.21, 46.50, 45.60, 29.40, 27.36, 23.85, 23.04, 5.71, 5.10, 2.62. HRMS m / z: calc. 487.2345 for C28H31N4O4[M + H]+; obs.: 487.2338 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.435 min) and was found to be 99.75% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6α-[1H-benzo[d]imidazole-5- carboxamide]morphinan Hydrochloride (19). Compound 19 was synthesized as shown in the general procedure with 40% yield.1H NMR (400 MHz, DMSO-d6) δ: 9.42 (s, 1H), 9.23 (s, 1H), 8.86 (s, 1H), 8.38 (d, J = 7.6 Hz, 1H), 8.35 (s, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.34 (s, 1H), 4.80 (d, J = 3.8 Hz, 1H), 4.68–4.60 (m, 1H), 3.94 (d, J = 6.6 Hz, 1H), 3.20–3.17 (m, 2H), 3.11–3.05 (m, 2H), 2.98–2.94 (m, 1H), 2.77–2.67 (m, 1H), 2.55–2.52 (m, 1H), 1.97–1.90 (m, 1H), 1.67–1.62 (m, 1H), 1.57–1.51 (m, 1H), 1.49–1.44 (m, 1H), 1.26–1.18 (m, 1H), 1.10–1.06 (m, 1H), 0.74– 0.67 (m, 1H), 0.66–0.59 (m, 1H), 0.52–0.47 (m, 1H), 0.43–0.37 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 165.39, 146.15, 142.35, 138.83, 133.31, 131.70, 131.37, 128.74, 125.01, 122.14, 119.12, 118.39, 114.38, 114.19, 87.09, 69.41, 64.89, 61.02, 57.02, 46.31, 45.24, 30.26, 29.21, 23.53, 19.29, 5.72, 5.20, 2.58. HRMS m / z: calc. 487.2345 for C28H31N4O4[M + H]+; obs.: 487.2360 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.287 min) and was found to be 99.77% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6β-[1H-benzo[d]imidazole-5- carboxamide]morphinan Hydrochloride (20). Compound 20 was synthesized as shown in the general procedure with 25% yield.1H NMR (400 MHz, DMSO-d6) δ: 9.34 (s, 1H), 9.27 (s, 1H), 8.90 (d, J = 8.1 Hz, 1H), 8.85 (s, 1H), 8.33 (s, 1H), 8.02 (dd, J = 8.6, 1.3 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 6.19 (s, 1H), 4.88 (d, J = 7.8 Hz, 1H), 3.88 (d, J = 5.0 Hz, 1H), 3.77–3.70 (m, 1H), 3.34–3.29 (m, 2H), 3.13– 3.04 (m, 2H), 2.89–2.84 (m, 1H), 2.47–2.42 (m, 2H), 1.95–1.87 (m, 1H), 1.80–1.76 (m, 1H), 1.65–1.60 (m, 1H), 1.49–1.40 (m, 2H), 1.10–1.04 (s, 1H), 0.71–0.66 (m, 1H), 0.63–0.58 (m, 1H), 0.55–0.49 (m, 1H), 0.44–0.38 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 165.13, 142.62, 142.17, 141.37, 134.67, 134.07, 131.18, 129.72, 124.39, 120.68, 119.37, 117.97, 114.36, 114.19, 89.83, 69.79, 61.75, 56.74, 51.48, 46.55, 45.69, 29.46, 27.38, 23.81, 23.08, 5.77, 5.18, 2.66. HRMS m / z: calc. 487.2345 for C28H31N4O4[M + H]+; obs.: 487.2317 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.287 min) and was found to be 99.05% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6α-[1H-pyrrolo[3,2-b]pyridine-5- carboxamide]morphinan Hydrochloride (21). Compound 21 was synthesized as shown in the general procedure with 83% yield.1H NMR (400 MHz, DMSO-d6) δ: 11.80 (s, 1H), 8.88 (s, 1H), 8.39 (d, J = 8.7 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.86 (t, J = 2.9 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.73 (s, 1H), 6.61 (d, J = 8.1 Hz, 1H), 6.37 (s, 1H), 4.77 (d, J = 3.7 Hz, 1H), 4.74–4.67 (m, 1H), 3.94 (d, J = 6.6 Hz, 1H), 3.39–3.32 (m, 2H), 3.31–3.26 (m, 1H), 3.12–3.04 (m, 2H), 3.00–2.94 (m, 1H), 2.78–2.69 (m, 1H), 2.5 –2.51 (m, 1H), 1.99–1.90 (m, 1H), 1.69–1.59 (m, 2H), 1.48 (dd, J = 15.2, 9.8 Hz, 1H), 1.10–1.04 (m, 2H), 0.74–0.67 (m, 1H), 0.65–0.59 (m, 1H), 0.51–0.46 (m, 1H), 0.43–0.38 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 164.36, 146.18, 142.65, 139.43, 132.59, 130.87, 129.24, 122.51, 120.16, 119.87, 118.71, 115.27, 102.08, 88.31, 69.86, 61.50, 57.52, 49.05, 45.82, 45.66, 30.69, 29.72, 23.95, 20.61, 6.17, 5.65, 3.04. HRMS m / z: calc. 487.2345 for C28H31N4O4 [M + H]+; obs.: 487.2363 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.392 min) and was found to be 99.94% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6β-[1H-pyrrolo[3,2-b]pyridine-5- carboxamide]morphinan Hydrochloride (22). Compound 22 was synthesized as shown in the general procedure with 69% yield.1H NMR (400 MHz, DMSO-d6) δ: 12.01 (s, 1H), 9.08 (d, J = 6.9 Hz, 1H), 8.85 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.94 (s, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.72–6.70 (m, 1H), 6.66 (d, J = 8.2 Hz, 1H), 6.21 (s, 1H), 5.02 (d, J = 7.7 Hz, 1H), 3.87 (d, J = 4.9 Hz, 1H), 3.77–3.70 (m, 2H), 3.37–3.32 (m, 2H), 3.13– 3.01 (m, 3H), 2.89–2.84 (m, 1H), 2.47–2.44 (m, 1H), 2.05–1.96 (m, 1H), 1.76 (d, J = 13.6 Hz, 1H), 1.64–1.58 (m, 1H), 1.48–1.40 (m, 2H), 1.12–1.07 (m, 1H), 0.71–0.68 (m, 1H), 0.63–0.58 (m, 1H), 0.53–0.49 (m, 1H), 0.46–0.44 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 161.39, 142.65, 141.82, 130.21, 121.08, 119.77, 118.38, 115.29, 90.46, 70.24, 62.13, 57.16, 51.60, 46.97, 46.13, 30.03, 27.83, 24.21, 23.46, 6.20, 5.59, 3.09. HRMS m / z: calc. 487.2345 for C28H31N4O4[M + H]+; obs.: 487.2338 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.372 min) and was found to be 99.88% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6α-[1H-pyrrolo[2,3-c]pyridine-5- carboxamide]morphinan Hydrochloride (23). Compound 23 was synthesized as shown in the general procedure with 58% yield.1H NMR (400 MHz, DMSO-d6) δ: 12.91 (s, 1H), 9.32 (s, 1H), 9.00 (s, 1H), 8.93 (s, 1H), 8.84 (s, 1H), 8.77 (s, 1H), 8.15 (s, 1H), 6.96 (s, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 6.47 (s, 1H), 4.78 (d, J = 3.6 Hz, 1H), 4.70–4.68 (m, 1H), 3.99 (d, J = 4.8 Hz, 1H), 3.37–3.21 (m, 2H), 3.12–3.01 (m, 3H), 2.77–2.69 (m, 1H), 2.56–2.54 (m, 1H), 1.99–1.93 (m, 1H), 1.67–1.58 (m, 2H), 1.54–1.44 (m, 1H), 1.18–1.10 (m, 2H), 0.72–0.68 (m, 1H), 0.65–0.61 (m, 1H), 0.53–0.48 (m, 1H), 0.44–0.41 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 159.75, 146.42, 139.40, 129.18, 125.33, 122.60, 119.78, 118.89, 116.10, 109.20, 87.71, 69.88, 61.40, 57.49, 45.79, 30.67, 29.61, 24.00, 6.20, 5.68, 3.07. HRMS m / z: calc. 487.2345 for C28H31N4O4[M + H]+; obs.: 487.2362 [M+H]+. The purity of the compound was checked by HPLC (Rt= 2.310 min) and was found to be 99.86% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6β-[1H-pyrrolo[2,3-c]pyridine-5- carboxamide]morphinan Hydrochloride (24). Compound 24 was synthesized as shown in the general procedure with 80% yield.1H NMR (400 MHz, DMSO-d6) δ: 13.11 (s, 1H), 9.60 (s, 1H), 9.38 (s, 1H), 9.01 (s, 1H), 8.89 (s, 1H), 8.86 (s, 1H), 8.25 (s, 1H), 7.04 (s, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 6.34 (s, 1H), 4.96 (d, J = 7.8 Hz, 1H), 3.93 (d, J = 5.0 Hz, 1H), 3.81–3.76 (m, 1H), 3.32–3.30 (m, 2H), 3.12–3.03 (m, 3H), 2.93–2.86 (m, 1H), 2.47–2.38 (m, 1H), 2.01 (dd, J = 25.7, 13.0 Hz, 1H), 1.87–1.79 (m, 1H), 1.67–1.61 (m, 1H), 1.48–1.42 (m, 2H), 1.12–1.06 (m, 1H), 0.72–0.64 (m, 1H), 0.62–0.59 (m, 1H), 0.55–0.53 (m, 1H), 0.44–0.38 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 161.69, 142.53, 141.91, 140.01, 135.28, 132.65, 130.11, 121.13, 119.88, 118.95, 118.43, 115.87, 108.24, 90.17, 70.17, 62.06, 57.16, 52.13, 46.97, 46.15, 29.90, 27.79, 24.11, 23.51, 6.23, 5.63, 3.12. HRMS m / z: calc. 487.2345 for C28H31N4O4[M + H]+; obs.: 487.2319 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.300 min) and was found to be 99.19% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6α-[1H-pyrrolo[2,3-b]pyridine-5- carboxamide]morphinan Hydrochloride (25). Compound 25 was synthesized as shown in the general procedure with 78% yield.1H NMR (400 MHz, DMSO-d6) δ: 12.12 (s, 1H), 8.91 (s, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.21 (d, J = 7.6 Hz, 1H), 7.62–7.59 (m, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.63 (dd, J = 3.4, 1.7 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 4.80 (d, J = 3.9 Hz, 1H), 4.69–4.61 (m, 1H), 3.97 (d, J = 6.7 Hz, 1H), 3.41–3.26 (m, 2H), 3.13– 2.97 (m, 3H), 2.77–2.69 (m, 1H), 2.59–2.51 (m, 1H), 1.99–1.91 (m, 1H), 1.65 (d, J = 10.8 Hz, 1H), 1.58–1.43 (m, 2H), 1.28–1.17 (m, 1H), 1.13–1.06 (m, 1H), 0.72–0.67 (m, 1H), 0.65–0.62 (m, 1H), 0.52–0.49 (m, 1H), 0.42–0.40 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 165.95, 148.77, 146.59, 142.16, 139.30, 129.23, 128.48, 122.69, 122.59, 119.80, 119.57, 118.79, 101.66, 87.73, 69.89, 61.49, 57.48, 57.12, 46.46, 45.70, 30.72, 29.70, 24.00, 19.88, 6.20, 5.68, 3.05. HRMS m / z: calc. 487.2345 for C28H31N4O4[M + H]+; obs.: 487.2326 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.417 min) and was found to be 99.84% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6β-[1H-pyrrolo[2,3-b]pyridine-5- carboxamide]morphinan Hydrochloride (26). Compound 26 was synthesized as shown in the general procedure with 72% yield.1H NMR (400 MHz, DMSO-d6) δ: 12.15 (s, 1H), 8.91 (s, 1H), 8.82 (d, J = 5.4 Hz, 1H), 8.81 (s, 1H), 8.60 (d, J = 1.8 Hz, 1H), 7.61 (dd, J = 3.4, 5.4 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 6.63 (dd, J = 3.4, 1.7 Hz, 1H), 4.88 (d, J = 7.8 Hz, 1H), 3.89 (d, J = 5.0 Hz, 1H), 3.75–3.71 (m, 1H), 3.38–3.29 (m, 2H), 3.12– 3.03 (m, 2H), 2.90–2.86 (m, 1H), 2.47–2.43 (m, 2H), 1.97–1.88 (m, 1H), 1.81 (d, J = 13.8 Hz, 1H), 1.6 –1.60 (m, 1H), 1.50–1.39 (m, 2H), 1.11–1.08 (m, 1H), 0.72–0.65 (m, 1H), 0.64–0.58 (m, 1H), 0.54–0.51 (m, 1H), 0.44–0.41 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 165.59, 148.57, 142.65, 141.80, 141.78, 130.19, 129.11, 128.57, 122.49, 121.11, 120.01, 119.75, 118.99, 118.39, 101.74, 90.40, 70.23, 62.13, 57.15, 51.68, 46.99, 46.10, 29.87, 27.84, 24.36, 23.52, 6.23, 5.62, 3.12. HRMS m / z: calc. 487.2345 for C28H31N4O4 [M + H]+; obs.: 487.2317 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.415 min) and was found to be 99.67% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6α-[1H-indazole-4- carboxamide]morphinan Hydrochloride (27). Compound 27 was synthesized as shown in the general procedure with 64% yield.1H NMR (400 MHz, DMSO-d6) δ: 8.90 (s, 1H), 8.39 (d, J = 0.8 Hz, 1H), 8.10 (d, J = 7.7 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.62 (d, J = 6.9 Hz, 1H), 7.43 (dd, J = 8.3, 6.9 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 4.85 (d, J = 3.8 Hz, 1H), 4.67 (m, 1H), 3.96 (d, J = 6.7 Hz, 1H), 3.35 (m, 1H), 3.26 (m, 1H), 3.10 (m, 1H), 3.05 (m, 1H), 2.98 (m, 1H), 2.73 (m, 1H), 2.54 (m, 1H), 1.96 (m, 1H), 1.67 (m, 1H), 1.56 (m, 1H), 1.47 (m, 1H), 1.17 (m, 1H), 1.07 (m, 1H), 0.69 (m, 1H), 0.62 (m, 1H), 0.50 (m, 1H), 0.41 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 166.05, 146.09, 140.35, 138.87, 133.55, 128.77, 127.38, 125.25, 122.12, 120.68, 120.06, 119.14, 118.30, 113.30, 87.24, 69.37, 61.03, 57.03, 48.56, 45.88, 45.25, 30.22, 29.29, 23.52, 19.46, 5.69, 5.17, 2.56. HRMS m / z: calc. 487.2345 for C28H31N4O4 [M + H]+; obs.: 487.2345. The purity of the compound was checked by HPLC (Rt= 2.462 min) and was found to be 99.63% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6β-[1H-indazole-4- carboxamide]morphinan Hydrochloride (28). Compound 28 was synthesized as shown in the general procedure with 64% yield.1H NMR (400 MHz, DMSO-d6) δ: 8.89 (s, 1H), 8.73 (d, J = 8.1 Hz, 1H), 8.38 (d, J = 0.9 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 7.1 Hz, 1H), 7.44 (dd, J = 8.2 Hz, 7.1 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 4.90 (d, J = 7.8 Hz, 1H), 3.90 (d, J = 5.1 Hz, 1H), 3.76 (m, 1H), 3.37 (m, 1H), 3.31 (m, 1H), 3.11 (m, 1H), 3.04 (m, 1H), 2.87 (m, 1H), 2.48–2.44 (m, 2H), 1.95 (m, 1H), 1.80 (m, 1H), 1.65 (m, 1H), 1.48 (m, 1H), 1.41 (m, 1H), 1.06 (m, 1H), 0.67 (m, 1H), 0.60 (m, 1H), 0.52 (m, 1H), 0.41 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 165.92, 142.22, 141.33, 140.42, 133.81, 129.73, 127.18, 125.24, 120.75, 120.61, 119.58, 119.25, 117.94, 113.39, 89.91, 69.78, 61.69, 56.70, 51.13, 46.51, 45.65, 29.47, 27.36, 23.79, 23.05, 5.73, 5.11, 2.63. HRMS m / z: calc. 487.2345 for C28H31N4O4[M + H]+; obs.: 487.2331 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.455 min) and was found to be 99.81% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6α-[1H-benzo[d]imidazole-4- carboxamide]morphinan Hydrochloride (29). Compound 29 was synthesized as shown in the general procedure with 69% yield.1H NMR (400 MHz, DMSO-d6) δ: 9.20 (s, 2H), 8.92 (s, 1H), 8.15 (d, J = 7.5 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.46 (s, 1H), 4.83 (d, J = 3.7 Hz, 1H), 4.79–4.71 (m, 1H), 3.98 (d, J = 6.7 Hz, 1H), 3.32–3.24 (m, 2H), 3.12–3.10 (m, 1H), 3.07–3.04 (m, 1H), 3.01–2.95 (m, 1H), 2.78–2.64 (m, 1H), 2.56–2.51 (m, 1H), 2.04–1.96 (m, 1H), 1.68–1.63 (m, 1H), 1.62–1.58 (m, 1H), 1.52–1.45 (m, 1H), 1.27–1.17 (m, 1H), 1.14–1.06 (m, 1H), 0.73–0.66 (m, 1H), 0.66–0.59 (m, 1H), 0.53–0.48 (m, 1H), 0.43–0.38 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 164.11, 146.05, 142.12, 138.93, 132.59, 128.72, 124.28, 123.96, 122.07, 121.25, 119.16, 118.29, 117.23, 117.12, 87.16, 69.49, 61.01, 57.04, 46.00, 45.28, 30.30, 29.16, 23.54, 19.47, 5.73, 5.21, 2.61. HRMS m / z: calc. 487.2345 for C28H31N4O4 [M + H]+; obs.: 487.2360 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.313 min) and was found to be 99.88% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6β-[1H-benzo[d]imidazole-4- carboxamide]morphinan Hydrochloride (30). Compound 30 was synthesized as shown in the general procedure with 35% yield.1H NMR (400 MHz, DMSO-d6) δ: 9.51 (s, 1H, exchangeable), 9.31 (s, 1H), 8.92 (s, 1H), 8.15 (d, J = 7.3 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 6.36 (s, 1H, exchangeable), 4.89 (d, J = 7.8 Hz, 1H), 3.93 (d, J = 4.7 Hz, 1H), 3.83–3.79 (m, 1H), 3.35– 3.29 (m, 2H), 3.12–3.06 (m, 2H), 2.91–2.85 (m, 1H), 2.47–2.44 (m, 2H), 2.07–1.95 (m, 1H), 1.85–1.81 (m, 1H), 1.70–1.63 (m, 1H), 1.49–1.47 (m, 1H), 1.46–1.39 (m, 1H), 1.11–1.06 (m, 1H), 0.72–0.65 (m, 1H), 0.64–0.57 (m, 1H), 0.56–0.49 (m, 1H), 0.44–0.39 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 163.98, 142.08, 142.05, 141.37, 133.14, 132.72, 129.65, 124.68, 123.62, 120.90, 120.58, 119.36, 117.89, 117.58, 89.95, 69.75, 61.54, 56.70, 51.17, 46.48, 45.72, 29.51, 27.31, 23.78, 23.02, 5.73, 5.11, 2.64. HRMS m / z: calc.487.2345 for C28H31N4O4 [M + H]+; obs.: 487.2334 [M + H]+.The purity of the compound was checked by HPLC (Rt= 2.305 min) and was found to be 99.54% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6α-[1H-pyrrolo[3,2-c]pyridine-4- carboxamide]morphinan Hydrochloride (31). Compound 31 was synthesized as shown in the general procedure with 77% yield.1H NMR (400 MHz, DMSO-d6) δ: 12.57 (s, 1H), 9.32 (s, 1H), 8.92 (s, 1H), 8.82 (s, 1H), 8.35 (d, J = 6.0 Hz, 1H), 7.87 (s, 2H), 7.24 (s, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 6.43 (s, 1H), 4.82 (d, J = 3.7 Hz, 1H), 4.75–4.68 (m, 1H), 3.98 (d, J = 6.6 Hz, 1H), 3.33–3.22 (m, 3H), 3.12–2.98 (m, 3H), 2.77–2.69 (m, 1H), 2.59–2.52 (m, 1H), 2.01–1.93 (m, 1H), 1.65 (dd, J = 20.3, 12.0 Hz, 2H), 1.48 (dd, J = 15.2, 9.8 Hz, 1H), 1.12–1.05 (m, 1H), 0.74–0.67 (m, 1H), 0.64–0.59 (m, 1H), 0.51–0.48 (m, 1H), 0.43–0.39 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 159.58, 145.83, 142.50, 138.97, 132.33, 128.73, 125.70, 122.79, 122.12, 119.38, 118.30, 110.04, 103.21, 87.31, 69.35, 64.89, 60.93, 57.05, 45.81, 45.36, 45.20, 30.19, 29.26, 23.51, 19.72, 5.70, 5.18, 2.58. HRMS m / z: calc. 487.2345 for C28H31N4O4 [M + H]+; obs.: 487.2345 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.302 min) and was found to be 98.84% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6β-[1H-pyrrolo[3,2-c]pyridine-4- carboxamide]morphinan Hydrochloride (32). Compound 32 was synthesized as shown in the general procedure with 75% yield.1H NMR (400 MHz, DMSO-d6) δ: 12.71 (s, 1H), 9.35 (s, 1H), 8.89 (s, 1H), 8.36 (d, J = 6.1 Hz, 1H), 7.93 (s, 2H), 7.25 (s, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 6.31 (s, 1H), 4.98 (d, J = 7.7 Hz, 1H), 3.90 (d, J = 5.1 Hz, 1H), 3.82–3.77 (m, 1H), 3.30–3.28 (m, 3H), 3.13–3.05 (m, 2H), 2.88–2.81 (m, 1H), 2.53–2.51 (m, 1H), 2.11–2.02 (m, 1H), 1.82–1.79 (m, 1H), 1.68–1.64 (m, 1H), 1.49–1.40 (m, 2H), 1.09–1.07 (m, 1H), 0.73–0.66 (m, 1H), 0.62–0.58 (m, 1H), 0.53–0.50 (m, 1H), 0.43–0.40 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 158.65, 142.11, 141.40, 129.65, 122.75, 122.48, 121.45, 120.65, 119.43, 119.39, 117.96, 110.23, 103.48, 89.74, 69.71, 61.59, 56.69, 51.57, 46.48, 45.70, 29.51, 27.31, 23.56, 23.00, 5.73, 5.11, 2.63. HRMS m / z: calc.487.2345 for C28H31N4O4[M + H]+; obs.: 487.2333 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.308 min) and was found to be 98.57% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6α-[1H-pyrrolo[2,3-c]pyridine-4- carboxamide]morphinan Hydrochloride (33). Compound 33 was synthesized as shown in the general procedure with 74% yield.1H NMR (400 MHz, DMSO-d6) δ: 13.31 (s, 1H), 9.26 (s, 1H), 9.24 (s, 1H), 8.92 (s, 1H), 8.74 (s, 1H), 8.72 (d, J = 7.8 Hz, 1H), 8.39 (s, 1H), 7.24 (s, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.43 (s, 1H), 4.83 (d, J = 3.6 Hz, 1H), 4.71–4.66 (m, 1H), 3.98 (d, J = 6.6 Hz, 1H), 3.28–3.22 (m, 2H), 3.12–3.06 (m, 2H), 3.01–2.96 (m, 1H), 2.78–2.69 (t, J = 12.4 Hz, 1H), 2.57–2.53 (m, 1H), 2.01–1.94 (m, 1H), 1.67 (d, J = 11.8 Hz, 1H), 1.61–1.56 (m, 1H), 1.52–1.46 (m, 1H), 1.25–1.16 (m, 1H), 1.11–1.07 (m, 1H), 0.71–0.69 (m, 1H), 0.64–0.60 (m, 1H), 0.52–0.46 (m, 1H), 0.42–0.39 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 163.71, 146.60, 140.46, 139.36, 135.27, 132.34, 129.19, 128.72, 123.49, 122.64, 119.66, 118.90, 104.33, 87.41, 69.86, 61.44, 57.49, 46.68, 45.76, 30.68, 29.68, 24.00, 19.75, 6.19, 5.67, 3.06. HRMS m / z: calc. 487.2345 for C28H31N4O4 [M + H]+; obs.: 487.2320 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.287 min) and was found to be 99.40% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6β-[1H-pyrrolo[2,3-c]pyridine-4- carboxamide]morphinan Hydrochloride (34). Compound 34 was synthesized as shown in the general procedure with 68% yield.1H NMR (400 MHz, DMSO-d6) δ: 12.72 (s, 1H), 9.63 (d, J = 8.0 Hz, 1H), 9.42 (s, 2H), 9.19 (s, 1H), 8.94 (s, 1H), 7.85 (m, 1H), 7.10 (m, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 6.35 (s, 1H), 4.93 (d, J = 8.0 Hz, 1H), 3.94 (d, J = 5.3 Hz, 1H), 3.80–3.72 (m, 1H), 3.12-3.07 (m, 2H), 2.90–2.89 (m, 1H), 2.04-2.01 (m, 1H), 1.89–1.85 (m, 1H), 1.68–1.65 (m, 1H), 1.50–1.40 (m, 2H), 1.09–1.07 (m, 1H), 0.68–0.62 (m, 1H), 0.61–0.54 (m, 1H), 0.53–0.51 (m, 1H), 0.43–0.40 (m, 1H).13C NMR (100 MHz, DMSO- d6) δ: 165.39, 146.15, 142.35, 138.83, 133.31, 131.70, 131.37, 128.74, 125.01, 122.14, 119.12, 118.39, 114.38, 114.19, 87.09, 69.41, 64.89, 61.02, 57.02, 46.31, 45.24, 30.26, 29.21, 23.53, 19.29, 5.72, 5.20, 2.58. HRMS m / z: calc. 487.2345 for C28H31N4O4 [M + H]+; obs.: 487.2333 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.310 min) and was found to be 99.88% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6α-[1H-pyrrolo[2,3-b]pyridine-4- carboxamide]morphinan Hydrochloride (35). Compound 35 was synthesized as shown in the general procedure with 85% yield.1H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 8.90 (s, 1H), 8.36 (d, J = 5.0 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 3.1 Hz, 1H), 7.45 (d, J = 5.0 Hz, 1H), 6.83 (dd, J = 3.1, 1.8 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 4.84 (d, J = 3.9 Hz, 1H), 4.68–4.63 (m, 1H), 3.96 (d, J = 6.7 Hz, 1H), 3.38–3.25 (m, 2H), 3.10–3.04 (m, 2H), 2.99–2.95 (m, 1H), 2.78–2.68 (m, 1H), 2.58–2.53 (m, 1H), 2.02–1.91 (m, 1H), 1.67 (d, J = 11.0 Hz, 1H), 1.59–1.54 (m, 1H), 1.47 (dd, J = 15.2, 9.8 Hz, 1H), 1.18–1.11 (m, 2H), 0.73–0.66 (m, 1H), 0.65–0.58 (m, 1H), 0.53–0.50 (m, 1H), 0.43–0.41 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 166.18, 149.07, 146.51, 141.87, 139.38, 134.77, 129.24, 128.47, 122.61, 119.68, 118.79, 118.19, 114.08, 100.81, 87.60, 69.83, 61.47, 57.48, 49.05, 46.40, 45.75, 30.67, 29.75, 23.99, 19.93, 6.18, 5.66, 3.05. HRMS m / z: calc. 487.2345 for C28H31N4O4 [M + H]+; obs.: 487.2316 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.397 min) and was found to be 99.69% pure. 17-Cyclopropylmethyl-3,14β-dihydro-4,5α-epoxy-6β-[1H-pyrrolo[2,3-b]pyridine-4- carboxamide]morphinan Hydrochloride (36). Compound 36 was synthesized as shown in the general procedure with 69% yield.1H NMR (400 MHz, DMSO-d6) δ: 11.98 (s, 1H), 8.89 (s, 1H), 8.79 (d, J = 8.1 Hz, 1H), 8.35 (d, J = 5.0 Hz, 1H), 7.65–7.58 (m, 1H), 7.48 (d, J = 5.0 Hz, 1H), 6.84 (dd, J = 3.2, 1.9 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 4.88 (d, J = 7.8 Hz, 1H), 3.89 (d, J = 5.0 Hz, 1H), 3.80–3.72 (m, 1H), 3.38–3.30 (m, 2H), 3.12– 3.05 (m, 2H), 2.91–2.84 (m, 1H), 2.47–2.43 (m, 2H), 1.96 (dd, J = 24.8, 12.9 Hz, 1H), 1.80 (d, J = 13.6 Hz, 1H), 1.69–1.60 (m, 1H), 1.50–1.39 (m, 2H), 1.09–1.04 (m, 1H), 0.72–0.62 (m, 1H), 0.62–0.58 (m, 1H), 0.55–0.49 (m, 1H), 0.44–0.40 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ: 166.42, 149.65, 142.61, 142.31, 141.76, 134.04, 130.13, 128.28, 121.11, 119.86, 118.44, 118.03, 113.58, 101.09, 90.23, 70.21, 62.20, 57.18, 51.65, 46.95, 46.14, 29.95, 27.79, 24.12, 23.45, 6.16, 5.62, 3.04. HRMS m / z: calc. 487.2345 for C28H31N4O4 [M + H]+; obs.: 487.2354 [M + H]+. The purity of the compound was checked by HPLC (Rt= 2.393 min) and was found to be 99.79% pure. Biological Evaluation of Drugs. Morphine (morphine sulfate pentahydrate salt) was purchased from Mallinckrodt (St. Louis, MO) or provided by the National Institute of Drug Abuse (NIDA). Naltrexone and naloxone were purchased as their hydrochloride salts from Sigma-Aldrich (St. Louis, MO). All drugs and test compounds were dissolved in pyrogen-free isotonic saline (Baxter Healthcare, Deerfield, IL) or sterile-filtered distilled / deionized water. All other reagents and radioligands were purchased from either Sigma-Aldrich or Thermo Fisher. Animals. Male Swiss Webster mice (25−35 g, 6−8 weeks, Harlan Laboratories, Indianapolis, IN) were housed in a temperature-controlled (20−22 °C) AAALAC-accredited facility in which they had ad libitum access to food and water. The mice were maintained on a 12 h / 12 h light−dark cycle (0600−1800 lights on) for the duration of the experiment and were tested during the light segment of this cycle. Mice arrived at the vivarium housed 4 / cage and, following 1 week habituation, were separated into individual cages. Mice were allowed to acclimate to individual caging for at least 24 h and then were randomly assigned to the various treatment conditions before the start of studies. Experimenters were blinded to these treatment conditions during the duration of the experiment and data analysis. No adverse events occurred during the experiment, and no mice were excluded from data analysis. Protocols and procedures (Animal Welfare Assurance Number D16-00180) were approved by the Institutional Animal Care and Use Committee (IACUC) at the Virginia Commonwealth University Medical Center and complied with the recommendations of the IASP (International Association for the Study of Pain). In Vitro Competitive Radioligand Binding Assay. The competition binding assay was conducted using the monoclonal mouse opioid receptors expressed in Chinese hamster ovary (CHO) cell lines (the monoclonal human δ opioid receptor was used in the DOR assay). In this assay, 20−30 μg of membrane protein was incubated with the corresponding radioligand in the presence of different concentrations of test compounds in TME buffer (50 mM Tris, 3 mM MgCl2, and 0.2 mM EGTA, pH 7.7) for 1.5 h at 30 °C. The bound radioligand was separated by filtration using the Brandel harvester. Specific (i.e., opioid receptor-related) binding at the MOR, KOR, and DOR was determined as the difference in binding obtained in the absence and presence of 5 μM naltrexone, U50,488, and SNC80, respectively. All competition binding data were transformed to % bound = specific binding in the presence of competing ligand / specific binding in the absence of competing ligand × 100%. In Vitro [35S]GTPγS Functional Assay. The [35S]GTPγS functional assay was conducted to determine the efficacy of the compounds at the MOR. In this assay, 10 μg of MOR-CHO membrane protein was incubated in a final volume of 500 μL containing TME with 100 mM NaCl, 20 μM GDP, 0.1 nM [35S]GTPγS, and varying concentrations of the compound under investigation for 1.5 h in a 30 °C water bath. The Bradford protein assay was utilized to determine and adjust the concentration of protein required for the assay. Nonspecific binding was determined with 20 μM unlabeled GTPγS. Furthermore, 3 μM DAMGO was included in the assay as the maximally effective concentration of a full agonist for the MOR. After incubation, the bound radioactive ligand was separated from the free radioligand by filtration through a GF / B glass fiber filter paper and rinsed three times with ice-cold wash buffer (50 mM Tris−HCl, pH 7.2) using the Brandel harvester. Bound radioactivity was determined by liquid scintillation counting. All assays were determined in duplicate and repeated at least three times. Net stimulated [35S]GTPγS binding was defined as agonist-stimulated minus basal binding in the absence of the agonist. Percent of DAMGO-stimulated [35S]GTPγS binding was defined as (net-stimulated binding by ligand / net-stimulated binding by 3 μM DAMGO) × 100%. Data Analysis of Receptor Binding and [35S]GTPyS Functional Assay. The assays of all samples were conducted in duplicate and repeated at least three times for a total of ≥3 independent determinations. Results were reported as mean values ± SEM. Concentration−effect curves were fitted by nonlinear regression to a four parameter model with the minimum constrained to 0, using GraphPad Prism software, to determine Hill deficient, EC50, and Emaxvalues. IC50values were obtained from nonlinear regression fitting to the four parameter model with the maximum (absence of competitor) constrained 100% and the minimum constrained to 0 using GraphPad Prism software. By using the Cheng−Prusoff equation Ki= IC50 / [1 + ([L] / KD)], where [L] is the concentration of the competitor and KD is the KD of the radioligand; binding Ki values were determined from IC50 values. Warm-Water Tail Immersion Assay. The antinociceptive effect of synthesized compounds was determined using the warm-water tail immersion assay. Swiss Webster mice (six male mice for each group, 25−35 g, 6−8 weeks old) were used in this assay. Antinociception for all compounds was examined in male Swiss Webster mice. The water bath temperature was set as 56 ± 0.1 °C. The baseline latency (control) was determined before administration of the compounds to the mice, and only mice with a baseline latency of 2 to 4 s were used. In the agonism study, the tail immersion was done 20 min (time that the morphine effect starts to peak) after injecting the test compounds subcutaneously (s.c.). To prevent tissue damage, a 10 s maximum cutoff time was imposed. Antinociceptive response was calculated as the percentage of the maximum possible effect (%MPE), where % MPE = [(test − control latency) / (10 − control latency)] × 100. When being studied for their antagonist effects to morphine, the test compounds were given (s.c.) 5 min before morphine. The tail immersion test was then conducted 20 min after giving morphine (s.c.). %MPE was calculated for each mouse. AD50values were calculated using the least-squares linear regression analysis followed by calculation of 95% confidence interval by the Bliss method. Opioid-Withdrawal Studies. Swiss Webster mice (six male mice for each group, 25−35 g, 6−8 weeks old) were used for opioid withdrawal studies. Following a previously reported protocol, a 75 mg morphine pellet was implanted into the back of the mice, and the mice were allowed to recover in their home cages. Before being tested, a 30 min period was allowed for habituation to an open-topped, square, clear Plexiglas observation chamber (26 × 26 × 26 cm3) with lines partitioning the bottom into quadrants. All drugs and test compounds were administered (s.c.). The withdrawal was precipitated 72 h from pellet implantation with naloxone (1 mg / kg, s.c.) or the test compounds at varying doses. Withdrawal commenced within 3 min after antagonist administration. Escape jumps, paw tremors, and wet dog shakes were quantified by counting their occurrences over 20 min for each mouse. The data are presented as the mean ± SEM. Statistical Analysis. One-way ANOVA followed by the post-hoc Dunnett test were performed to assess the significance using GraphPad Prism software (GraphPad Software, San Diego, CA). EXAMPLE 2. A subject suffers from addiction to an opioid. One or more compounds disclosed herein is administered to the subject in a tapered regimen as disclosed herein. In other words, a composition comprising the opioid and / or methadone and the one or more compounds is administered in which the amount of opioid / methadone is gradually decreased and the amount of the one or more compounds is gradually increased until the composition contains no opioid / methadone but is 100% composed of the one or more compounds disclosed herein. The subject is cured of his / her dependency on the opioid, without experiencing the typical side effects of opioid withdrawal and without causing constipation. EXAMPLE 3. A subject suffers from pain, either acute or chronic. One or more compounds disclosed herein is administered to the subject in an amount sufficient to lessen or eliminate the pain. The pain is lessened or eliminated without causing the subject to become constipated or addicted. While the invention has been described in terms of its several exemplary embodiments, those skilled in the art will recognize that the invention can be practiced with modification within the spirit and scope of the appended claims. Accordingly, the present invention should not be limited to the embodiments as described above but should further include all modifications and equivalents thereof within the spirit and scope of the description provided herein.

Claims

CLAIMS We claim:

1. A compound having the general Formula I or a pharmaceutically acceptable salt or stereoisomer thereof:Formula I where R is, and where one of a, b, c, d, e or f is a position of attachment of R to the carbonyl carbon of the epoxymorphinan skeleton; at least one of a, b, c, d, e and f is N; positions at a, b, c, d, e and f that are not N are CH; and* is a chiral carbon.

2. The compound of claim 1, wherein R is3. The compound of claim 1, wherein R is4. The compound of claim 1, wherein.

5. The compound of claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

6. A composition comprising at least one compound of any of claims 1-5 and a physiologically acceptable carrier.

7. The composition of claim 6, further comprising at least one addictive narcotic drug and / or methadone.

8. The composition of claim 7, wherein the addictive narcotic drug is oxycodone, hydrocodone, morphine and / or fentanyl, or a mixture thereof.

9. A method of preventing or treating opioid addiction in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one compound of claim 1-5, wherein the at least one compound is administered to the subject with or instead of an opioid.

10. The method of claim 9, wherein the at least one compound is administered orally.

11. The method of claim 9, wherein the at least one compound is administered with an addictive narcotic drug in a tapered regimen.

12. A method of treating an opioid overdose in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one compound of claims 1-5.

13. A method of treating acute and / or chronic pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one compound of claims 1-5.

14. The method of claim 13, wherein the acute and / or chronic pain is visceral pain, cancer pain, neuropathic pain, allodynia, hyperalgesia, pain due to inflammation, arthritis pain, pain due to migraines or pain resulting from accident and / or injury.

15. A method of treating a neurological disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least onecompound of claims 1-5.

16. The method of claim 15, wherein the neurological disease or condition is or is caused by: a bacterial or viral infection, Alzheimer’s disease, Parkinson’s disease, dementia, depression and / or anxiety, aberrant behavioral changes, a decline in cognitive function, progressive slowing of motor function and loss of dexterity and coordination, central nervous system (CNS) lymphomas, nerve damage, encephalitis, traumatic head injury, sports related head injury or chemotherapy.

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