Mitragynine analogs and uses thereof

Abstract

The present application includes mitragynine analogues of Formula la or lb, compositions comprising said compounds and uses thereof, for example for treating and managing pain, for treating neurological or psychiatric diseases and disorders, for example treating an opioid addiction or opioid withdrawal symptoms.

Description

TITLE: MITRAGYNINE ANALOGS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of priority from U.S. Provisional Patent Application No. 63 / 700992 filed on September 30, 2024, the contents of which are incorporated herein by reference in their entirety.FIELD

[0002] The present application relates to mitragynine analogs, compositions and uses thereof, for example for treating and managing pain, for treating neurological or psychiatric diseases and disorders, for example, for treating an opioid addiction or opioid withdrawal symptoms.BACKGROUND

[0003] Natural products and their metabolites have historically been an important source for discovering potential novel medications, and have been used as inspirations for novel drug design. Additionally, natural products used in traditional medicine provide important signals for potential clinical applications of novel analogs of natural products.

[0004] One such natural product of interest is Mitragyna Speciosa (or, “kratom”). Kratom is an evergreen tree from the Rubiacae family and is found in tropical climates, indigenous to South East Asia. The Rubicacae family is also known as the coffee family. Kratom is indigenous to Thailand, Indonesia, Malaysia, Myanmar and Papua New Guinea, where its leaves have historically been used in herbal medicine. Kratom leaves have traditionally been consumed via chewing, smoking, and tea. Kratom use has increased significantly in the USA since the 1960’s; estimates for the number of people using Kratom in the USA range from 2-3 million consumers up to 15 million consumers (“Kratom’s Emergence and Persistence Within the US Polydrug Epidemic”, in Current Addiction Reports. Kristin Elin Smith, Jeffrey M. Rogers, Jeffrey D Feldman). In the USA, Kratom is typically consumed via powders, capsules, or liquid tinctures.

[0005] Kratom users report a range of effects at differing doses. In general, small doses induce stimulating effects, while larger dosages cause opioid-like effects. Stimulant and euphoric effects are reported to be felt within 10 minutes and last forone to one and a half hours, and can include heightened work capacity, alertness, and sociability. Side effects for regular kratom users can include loss of weight, tiredness, and constipation, as well as withdrawal symptoms after suspension of regular use (Kratom (Mitragyna speciosa) drug profile, European Monitoring Centre for Drugs and Drug Addiction).

[0006] Kratom taken in larger doses can induce sweating, dizziness, nausea, leading to calmness and / or euphoria, lasting up to several hours (Kratom (Mitragyna speciosa) drug profile, European Monitoring Centre for Drugs and Drug Addiction). Kratom’s opioid-like effects include pain relief and possible opioid withdrawal symptoms after chronic frequent use in certain users. Side effects can include gastrointestinal upset and constipation. Kratom does not, however, seem to induce potentially lethal respiratory depression, a significant driver of fatalities in opioid misuse, or the highly addictive brain rewarding effects that drive opioid use disorder (The respiratory depressant effects of mitragynine are limited by its conversion to 7- OH mitragynine. British Journal of Pharmacology, 2022, Hill et al.; Evaluation of the rewarding effects of mitragynine and 7-hydroxymitragynine in an intracranial selfstimulation procedure in male and female rats, Drug and Alcohol Dependence, 2020, Behnood-Rod et al.).

[0007] Kratom contains multiple alkaloids, such as mitragynine, speciogynine, speciociliatine, paynantheine, corynantheidine and other indoles, with mitragynine being the most abundant. Mitragynine and related alkaloids have been found to have agonistic and / or antagonistic effects on opioid receptors. Mitragynine and 7- hydroxymitragynine are believed to be the two alkaloids mainly responsible for the effects of kratom. Of the two, 7-hydroxymitragynine, exhibits stronger opioid-like effects than mitragnynine in in-vitro testing. Per Obeng, Wilkerson, Leon, et al. (2021): “At human m-opioid receptor (MOR) in vitro, mitragynine has low affinity and is an antagonist, whereas 7-hydroxymitragynine has 9-fold higher affinity than mitragynine and is an MOR partial agonist. In rats, intraperitoneal mitragynine exhibits a complex pharmacology including MOR agonism; 7-hydroxymitragynine has higher MOR potency and efficacy than mitragynine. These results are consistent with 7- hydroxymitragynine being a highly selective MOR agonist and with mitragynine having a complex pharmacology that combines low efficacy MOR agonism with activity atnonopioid receptors. ’’(Journal of Pharmacology and Experimental Therapeutics. Obeng, Samuel et al. 2021 Mar; 376(3): 410-427).

[0008] Pharmacological studies fully articulating the interaction of mitragynine and other kratom alkaloids with adrenergic, serotonergic and dopaminergic receptors have not been definitively completed. Nevertheless, based on prevailing data, it is hypothesized that the traditional use of kratom as a mood enhancer is due in part to the interaction of its indole-based alkaloids (such as mitragynine, speciogynine, speciociliatine, and paynantheine) with the 5-HT1A and 5-HT2A (serotonin) receptors (“Kratom Alkaloids: Interactions With Enzymes, Receptors, and Cellular Barriers” Frontiers in Pharmacology. 2021 ; 12: 751656. Hanapi et al).

[0009] Although kratom has been used as a natural traditional medicine in southeast Asia for centuries, its use in the United States began to grow significantly from the early 2000s. While neither Kratom nor its alkaloids are approved by the FDA or other health regulators for therapeutic use, a variety of surveys from different geographies indicate that the reasons for use include energy I motivation (i.e. as a caffeine substitute), to self-treat depression and improve mood, pain management, as well as a lower harm alternative to other opioids for regular opioid users (“Understanding Kratom Use: A Guide for Healthcare Providers” Frontiers in Pharmacology, March 2022. Swogger et al.).

[0010] Kratom alkaloids have been found to have stimulating and analgesic effects, coupled with a lack of full opioid receptor agonism and consequential safety risks. Accordingly, there exists a need for further studies of these alkaloids to develop new therapeutic agents with improved pharmacological profiles for treating or managing pain, for treating neurological or psychiatric diseases and disorders, and other indications.SUMMARY

[0011] The present application discloses mitragynine analogues, which can be used, for example, for example fortreating and managing pain, fortreating neurological or psychiatric diseases and disorders, for example, for treating an opioid addiction or opioid withdrawal symptoms.

[0012] Accordingly, the present application includes a compound of Formula la or lb, or a pharmaceutically acceptable salt and / or solvate thereof:wX1is N, NR14, O or S;X2is NR15, O, S, S(O) or SO2;R1, R2, R8and R9are independently selected from H, halo, CN, OH, SH, C1-6alkyl, C2-6alkenyl, OC1-6alkyl, OC2-6alkenyl, aryl, C5-10heteroaryl, C3-10cycloalkyl, C3-10heterocycloalkyl, Oaryl, OC5-10heteroaryl, OC3-10cycloalkyl and OC3-10heterocycloalkyl, the latter 12 groups being optionally substituted with one or more of C1-salkyl, OC1-6alkyl and CN;R3is absent or is selected from H, OH, halo, CN, OP(O)(ORa)2, OC1-30alkyl, OC(O)C1-30alkyl, OC2-30alkenyl, OC(O)C2-30alkenyl, OC3-10cycloalkyl, OC3-10heterocycloalkyl, OC3-10heteroaryl and Oaryl, the latter 8 groups being optionally substituted with one or more of C1-6alkyl, OC1-6alkyl and CN;Rais selected from H and C1-6alkyl; each is a single or double bond, provided only one of — is a double bond and when X1is NR14, O or S, the adjacent to X1is a single bond and when the 22222 adjacent to R3is a double bond, R3is absent;R4and R10are independently selected from H, C1-6alkyl and C2-6alkenyl;R5and R11are independently selected from OH, OC1-6alkyl and OC2-6alkenyl;R6and R12are independently selected from C(O)C1-6alkyl, C(O)OC1-6alkyl, C(O)NHC1-6alkyl, C(O)N(C1-6alkyl)(C1-6alkyl), C(O)C2-6alkenyl, C(O)OC2-6alkenyl, C(O)NHC2-6alkenyl and C(O)N(C2-6alkenyl)(C2-6alkenyl);R7and R13are independently selected from H and C1-4alkyl;R14and R15are independently selected from H and C1-6alkyl; n and p are independently 1 or 2; and wherein all available hydrogen atoms are optionally and independently replaced with a halogen atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

[0013] The present application also includes a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier.

[0014] The present application also includes a method for treating pain, a method of managing pain and a method of inducing analgesic effect comprising administering an effective amount of one or more compounds of the application to a subject in need thereof.

[0015] The present application also includes a method of treating perioperative and postoperative pain in patients prone to opioid-induced respiratory depression comprising administering an effective amount of one or more compounds of the application to a subject in need thereof.

[0016] Also included in the present application is a method of treating an inflammatory condition comprising administering an effective amount of one or more compounds of the application to a subject in need thereof.

[0017] The present application also includes a method for treating a neurological disease or psychiatric disorder comprising administering an effective amount of one or more compounds of the application to a subject in need thereof. In some embodiments, the neurological disease is a mood disorder. In some embodiments, the mood disorder is a depression.

[0018] The present application also includes a method for treating an opioid addiction or opioid withdrawal symptoms comprising administering an effective amount of one or more compounds of the application to a subject in need thereof.

[0019] The present application also includes a method for enhancing cognitive and / or behavioral function comprising administering an effective amount of one or more compounds of the application to a subject in need thereof. In some embodiments,enhancing cognitive and / or behavioral function comprises enhancing one or more of memory, attention, language, work capacity, alertness, sociability, energy, motivation or mood.

[0020] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the application, are given by way of illustration only and the scope of the claims should not be limited by these embodiments but should be given the broadest interpretation consistent with the description as a whole.DESCRIPTION OF VARIOUS EMBODIMENTSI. Definitions

[0021] Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the present application herein described for which they are suitable as would be understood by a person skilled in the art.

[0022] The term “comprising” and its derivatives, as used herein, are intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and / or steps. The foregoing also applies to words having similar meanings such as the terms, “including”, “having” and their derivatives.

[0023] The term “consisting” and its derivatives, as used herein, are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, but exclude the presence of other unstated features, elements, components, groups, integers and / or steps.

[0024] The term “consisting essentially of’, as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps as well as those that do not materially affect the basic and novel characteristic(s) of features, elements, components, groups, integers, and / or steps.

[0025] Terms of degree such as “substantially”, “about” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that theend result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies.

[0026] As used in this application, the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise.

[0027] In embodiments comprising an “additional” or “second” component, the second component as used herein is chemically different from the other components or first component. A “third” component is different from the other, first, and second components, and further enumerated or “additional” components are similarly different.

[0028] The term “and / or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that “at least one of’ or “one or more” of the listed items is used or present.

[0029] The term “compound(s) of the application” or “compound(s) of the present application” and the like, as used herein refers to compound(s) of Formula la or lb, or a salt and / or solvate thereof.

[0030] The term “composition(s) of the application” or “composition(s) of the present application, and the like, as used herein refers to composition(s) comprising one or more compounds of the application and a carrier.

[0031] The term “suitable” as used herein means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, the identity of the molecule(s) to be transformed and / or the specific use for the compound, but the selection would be well within the skill of a person trained in the art.

[0032] The present description refers to a number of chemical terms and abbreviations used by those skilled in the art. Nevertheless, definitions of selected terms are provided for clarity and consistency.

[0033] The term “protecting group” or “PG” and the like as used herein refers to a chemical moiety which protects or masks a reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade ordecompose the remaining portions of the molecule. The selection of a suitable protecting group can be made by a person skilled in the art. Many conventional protecting groups are known in the art, for example as described in “Protective Groups in Organic Chemistry” McOmie, J.F.W. Ed., Plenum Press, 1973, in Greene, T.W. and Wuts, P.G.M., “Protective Groups in Organic Synthesis”, John Wiley & Sons, 3rd Edition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0034] The term “inert organic solvent” as used herein refers to a solvent that is generally considered as non-reactive with the functional groups that are present in the compounds to be combined together in any given reaction so that it does not interfere with or inhibit the desired synthetic transformation. Organic solvents are typically non-polar and dissolve compounds that are non soluble in aqueous solutions.

[0035] The term “alkyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “Cn1-n2”. For example, the term C1-10alkyl means an alkyl group having 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0036] The term “alkenyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkyl groups containing at least one double bond. The number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix “Cn1-n2”. For example, the term C2-6alkenyl means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms and at least one double bond.

[0037] The term “OMe" as used herein is equivalent to OCH3.

[0038] The term “OEt” as used herein is equivalent to OCH2CH3.

[0039] The term “alkynyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkynyl groups containing at least one triple bond. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “Cn1-n2”. For example, the term C2-6alkynyl means an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms.

[0040] The term “cycloalkyl,” as used herein, whether it is used alone or as part of another group, means a saturated carbocyclic group containing one or more rings. The number of carbon atoms that are possible in the referenced cycloalkyl group are indicated by the numerical prefix “Cn1-n2”. For example, the term Cs-10cycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0041] The term “aryl” as used herein, whether it is used alone or as part of another group, refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a one or more six-membered aromatic ring structures, wherein the ring atoms are all carbon. Aryl groups can comprise 6 or more carbon atoms.

[0042] The term “heterocycloalkyl” as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing at least one non-aromatic ring in which one or more of the atoms are a heteroatom selected from O, S and N and the remaining atoms are C. Heterocycloalkyl groups are either saturated or unsaturated (i.e. contain one or more double bonds). When a heterocycloalkyl group contains the prefix Cn1-n2this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteroatom as selected from O, S and N and the remaining atoms are C.

[0043] The term “heteroaryl” as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing at least one heteroaromatic ring in which one or more of the atoms are a heteroatom selected from O, S and N and the remaining atoms are C. When a heteroaryl group contains the prefix Cn1-n2this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteroatom as defined above.

[0044] The term “fluoro-substituted” refers to the substitution of one or more, including all, available hydrogens in a referenced group with fluoro.

[0045] The term “chloro-substituted” refers to the substitution of one or more, including all, available hydrogens in a referenced group with chloro.

[0046] The term “bromo-substituted” refers to the substitution of one or more, including all, available hydrogens in a referenced group with bromo.

[0047] The term “deutero-substituted” refers to the substitution of one or more, including all, available hydrogens in a referenced group with deuterium.

[0048] It is to be clear that all available hydrogen atoms in the compounds of the application, and all embodiments thereof, are optionally substituted with a fluorine, chlorine, bromine or deuterium atom unless otherwise indicated.

[0049] The terms “halo” or “halogen” as used herein, whether it is used alone or as part of another group, refers to a halogen atom and includes fluoro, chloro, bromo and iodo.

[0050] The term “available”, as in “available hydrogen atoms” or “available atoms” refers to atoms that would be known to a person skilled in the art to be capable of replacement by a substituent.

[0051] The term “subject” as used herein includes all members of the animal kingdom including mammals, such as a dog, a cat and a human. Thus, the methods and uses of the present application are applicable to both human therapy and veterinary applications.

[0052] The term “pharmaceutically acceptable” means compatible with the treatment of subjects, for example humans.

[0053] The term “pharmaceutically acceptable carrier” means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to a subject.

[0054] The term “pharmaceutically acceptable salt” means either an acid addition salt or a base addition salt which is suitable for, or compatible with the treatment of subjects.

[0055] The term “solvate” as used herein means a compound, or a salt and / or prodrug of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered.

[0056] The term “prodrug” as used herein means a compound, or salt and / or solvate of a compound, that, after administration, is converted into an active drug.

[0057] The term “treating” or “treatment” as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable. “Treating” and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. “Treating” and “treatment” as used herein also include prophylactic treatment. For example, a subject with early cancer can be treated to prevent progression, or alternatively a subject in remission can be treated with a compound or composition of the application to prevent recurrence. Treatment methods comprise administering to a subject a therapeutically effective amount of one or more of the compounds of the application and optionally consist of a single administration, or alternatively comprise a series of administrations.

[0058] “Palliating” a disease or disorder means that the extent and / or undesirable clinical manifestations of a disorder or a disease state are lessened and / or time course of the progression is slowed or lengthened, as compared to not treating the disorder.

[0059] The term “prevention” or “prophylaxis”, or synonym thereto, as used herein refers to a reduction in the risk or probability of a patient becoming afflicted with a disease, disorder or condition.

[0060] The term “neurological disease” refers to any disease of the nervous system, including diseases that involve the central nervous system, the peripheral nervous system and the autonomic nervous system (parts of which are located in both central and peripheral nervous system).

[0061] As used herein, the term “effective amount” or “therapeutically effective amount” means an amount of a compound, or one or more compounds of theapplication that is effective, at dosages and for periods of time necessary to achieve the desired result.

[0062] The term “administered” as used herein means administration of a therapeutically effective amount of a compound, or one or more compounds, or a composition of the application to a cell, a tissue or an organ in vivo or in vitro, or a subject.

[0063] The term “cell” as used herein refers to a single cell or a plurality of cells and includes a cell either in a cell culture or in a subject.II. Compounds and Compositions of the Application

[0064] The present application includes a compound of Formula la or lb, or a pharmaceutically acceptable salt and / or solvate thereof: wX1is N, NR14, O or S;X2is NR15, O, S, S(O) or SO2;R1, R2, R8and R9are independently selected from H, halo, CN, OH, SH, C1-6alkyl, C2-6alkenyl, OC1-6alkyl, OC2-6alkenyl, aryl, C5-10heteroaryl, C3-10cycloalkyl, C3-10heterocycloalkyl, Oaryl, OC5-10heteroaryl, OC3-10cycloalkyl and OC3-10heterocycloalkyl, the latter 12 groups being optionally substituted with one or more of C1-6alkyl, OC1-6alkyl and CN;R3is absent or is selected from H, OH, halo, CN, OP(O)(ORa)2, OC1-30alkyl, OC(O)C1-30alkyl, OC2-30alkenyl, OC(O)C2-30alkenyl, OC3-10cycloalkyl, OC3-10heterocycloalkyl,OC3-10heteroaryl and Oaryl, the latter 8 groups being optionally substituted with one or more of C1-6alkyl, OC1-6alkyl and CN;Rais selected from H and C1-6alkyl; each — is a single or double bond, provided only one of — is a double bond and when X1is NR14, O or S, the — adjacent to X1is a single bond and when the — adjacent to R3is a double bond, R3is absent;R4and R10are independently selected from H, C1-6alkyl and C2-6alkenyl;R5and R11are independently selected from OH, OC1-6alkyl and OC2-6alkenyl;R6and R12are independently selected from C(O)C1-6alkyl, C(O)OC1-6alkyl, C(O)NHC1-6alkyl, C(O)N(C1-6alkyl)(C1-6alkyl), C(O)C2-6alkenyl, C(O)OC2-6alkenyl, C(O)NHC2-6alkenyl and C(O)N(C2-6alkenyl)(C2-6alkenyl);R7and R13are independently selected from H and C1-4alkyl;R14and R15are independently selected from H and C1-6alkyl; n and p are independently 1 or 2; and wherein all available hydrogen atoms are optionally and independently replaced with a halogen atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

[0065] In some embodiments, the compound is of Formula la, — is a double bond adjacent to X1, and X1is N: or a pharmaceutically awherein R1, R2, R3, R4, R5, R6, R7and n are as defined for Formula la.0066] In some embodiments, the compound is of Formula la, is a double bond adjacent to X1, X1is N, and the relative stereochemistry is as follows: or a pharmaceutically a eof,wherein R1, R2, R3, R4, R5, R6, R7and n are as defined for Formula la.

[0067] In some embodiments, the compound is of Formula la, is a double bond adjacent to R3, and R3is absent:or a pharmaceutically a ,wherein X1, R1, R2, R4, R5, R6, R7and n are as defined for Formula la.

[0068] In some embodiments, the compound is of Formula la, is a double bond adjacent to R3, R3is absent, and the relative stereochemistry i follows:or a pharmaceutically acceptable salt and / or solvate thereof, wherein X1, R1, R2, R4, R5, R6, R7and n are as defined for Formula la.

[0069] In some embodiments, X1is NH, NC1-4alkyl, O or S, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof. In some embodiments, X1is NH, ND, O or S. In some embodiments, X1is NH.

[0070] In some embodiments, R1is selected from H, halo, aryl, OC1-4alkyl, OC2-4alkenyl, C5-8heteroaryl, C3-8cycloalkyl and C3-8heterocycloalkyl, the latter six groups being optionally substituted with one or more C1-4alkyl, OC1-4alkyl and CN, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

[0071] In some embodiments, R1is independently selected from H, Cl, Br, F, aryl, OCH3, OCF3, OCF2H, OCH2CH3, OCF2CF3, OCH2CF3, OCH2CH=CH2and furanyl, wherein all available hydrogen atoms are optionally and independently replaced with deuterium. In some embodiments, R1is selected from H and D. In some embodiments, R1is H.

[0072] In some embodiments, R2is selected from H, halo, CN, OH, SH, C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, aryl, C5-8heteroaryl, C3-8cycloalkyl, C3-8heterocycloalkyl, Oaryl, OC5-8heteroaryl, OC3-8cycloalkyl and OC3-8heterocycloalkyl, the latter 12 groups being optionally substituted with one or more of C1-4alkyl, OC1-4alkyl and CN, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

[0073] In some embodiments, R2is selected from H, Cl, Br, F, CN, OH, CH3, OCH3, CF3, OCF3, OCH3, OCH2CH3, OCH2CH=CH2, OCF2H, OCF2CF3, OCH2CF3, aryl, Oaryl and furanyl, wherein all available hydrogen atoms are optionally and independently replaced with deuterium. In some embodiments, R2is selected from H, D, OH, OD, OCH3, OCH2CH3, OCH2CH=CH2, OCF3, OCF2H, OCF2CF3, OCH2CF3and OCD3. In some embodiments, R2is OCH3.

[0074] In some embodiments, R1and R2are both H. In some embodiments, R1is H and R2is OCH3.

[0075] In some embodiment, R3is absent.

[0076] In some embodiments, R3is present and is selected from OH, halo, CN, OP(O)(OH)2, OP(O)(OC1-4alkyl)2, OC1-30alkyl, OC(O)C1-30alkyl, OC2-30alkenyl, OC(O)C2-30alkenyl, OC3-8cycloalkyl, OC3-8heterocycloalkyl, OC3-8heteroaryl and Oaryl, the latter 8 groups being optionally substituted with one or more of C1-4alkyl, OC1-4alkyl and CN, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

[0077] In some embodiments, R3is selected from OH, OD, Cl, F, CN, OCH3, OCF3, OCD3, OC(O)CH3and Oaryl. In some embodiments, R3is OH.

[0078] In some embodiments, R4is selected from H, C1-4alkyl and C2-4alkenyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof. In some embodiments, R4is selected from CH2CH3and CH2=CH2. In some embodiments, R4is CH2CH3.

[0079] In some embodiments, R5is selected from OH, OC1-4alkyl and OC2-4alkenyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof. In some embodiments, R5is selected from OH, OD, OCF3, OCF2H, OCH3and OCD3. In some embodiments, R5is OCH3.

[0080] In some embodiments, R6is selected from C(O)C1-4alkyl, C(O)OC1-4alkyl, C(O)NHC1-4alkyl, C(O)N(C1-4alkyl)(C1-4alkyl), C(O)C2-4alkenyl, C(O)OC2-4alkenyl, C(O)NHC2-4alkenyl and C(O)N(C2-4alkenyl)(C2-4alkenyl), wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof. In some embodiments, R6is selected from C(O)OCH3, C(O)OCF3, C(O)OCF2H and C(O)OCD3. In some embodiments, R6is C(O)OCH3.

[0081] In some embodiments, R7is selected from H and C1-2alkyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof. In some embodiments, R7is selected from H and D. In some embodiments, R7is H.

[0082] In some embodiments, n is 2. In some embodiments, n is 1.

[0083] In some embodiments, the compound is of Formula lb: or a pharmaceuticawherein X2, R8, R9, R10, R11, R12, R13and p are as defined for Formula lb.

[0084] In some embodiments, the compound is of Formula lb, and the relative stereochemistry is as follows: or a pharmaceutically acwherein X2, R8, R9, R10, R11, R12, R13and p are as defined for Formula lb.

[0085] In some embodiments, X2is NH, NC1-4alkyl, O, S, S(O) or SO2, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independentlyreplaced with an alternate isotope thereof. In some embodiments, X2is NH, ND, O S, S(O) or SO2. In some embodiments, X2is NH.

[0086] In some embodiments, R8is selected from H, halo, aryl, OC1-4alkyl, OC2-4alkenyl, C5-8heteroaryl, C3-8cycloalkyl and C3-8heterocycloalkyl, the latter six groups being optionally substituted with one or more of C1-4alkyl, OC1-4alkyl and CN, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

[0087] In some embodiments, R8is independently selected from H, Cl, Br, F, aryl, OCH3, OCF3, OCF2H, OCH2CH3, OCF2CF3, OCH2CF3, OCH2CH=CH2and furanyl, wherein all available hydrogen atoms are optionally and independently replaced with deuterium. In some embodiments, R8is selected from H and D. In some embodiments, R8is H.

[0088] In some embodiments, R9is selected from H, halo, CN, OH, SH, C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, aryl, C5-8heteroaryl, C3-8cycloalkyl, C3-8heterocycloalkyl, Oaryl, OC5-8heteroaryl, OC3-8cycloalkyl and OC3-8heterocycloalkyl, the latter 12 groups being optionally substituted with one or more of C1-4alkyl, OC1-4alkyl and CN, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

[0089] In some embodiments, R9is selected from H, Cl, Br, F, CN, OH, CH3, OCH3, CF3, OCF3, OCH3, OCH2CH3, OCH2CH=CH2, OCF2H, OCF2CF3, OCH2CF3aryl, Oaryl and furanyl, wherein all available hydrogen atoms are optionally and independently replaced with deuterium. In some embodiments, R9is selected from H, D, OH, OD, OCH3, OCH2CH3, OCH2CH=CH2, OCF3, OCF2H, OCF2CF3, OCH2CF3and OCD3. In some embodiments, R9is OCH3.

[0090] In some embodiments, R8and R9are both H. In some embodiments, R8is H and R9is OCH3.

[0091] In some embodiments, R10is selected from H, C1-4alkyl and C2-4alkenyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally andindependently replaced with an alternate isotope thereof. In some embodiments, R10is selected from CH2CH3and CH2=CH2. In some embodiments, R10is CH2CH3.

[0092] In some embodiments, R11is selected from OH, OC1-4alkyl and OC2-4alkenyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof. In some embodiments, R11is selected from OH, OD, OCF3, OCF2H, OCH3and OCD3. In some embodiments, R11is OCH3.

[0093] In some embodiments, R12is selected from C(O)C1-4alkyl, C(O)OC1-4alkyl, C(O)NHC1-4alkyl, C(O)N(C1-4alkyl)(C1-4alkyl), C(O)C2-4alkenyl, C(O)OC2-4alkenyl, C(O)NHC2-4alkenyl and C(O)N(C2-4alkenyl)(C2-4alkenyl), wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof. In some embodiments, R12is selected from C(O)OCH3, C(O)OCF3, C(O)OCF2H and C(O)OCD3. In some embodiments, R12is C(O)OCH3.

[0094] In some embodiments, R13is selected from H and C1-2alkyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof. In some embodiments, R13is selected from H and D. In some embodiments, R13is H.

[0095] In some embodiments, p is 2. In some embodiments, p is 1.

[0096] In some embodiments, the compounds of Formula la or lb are selected from the compounds listed in Table 1 below, or a pharmaceutically acceptable salt and / or solvate thereof:[ ] , p y p addition salt or a base addition salt. The selection of a suitable salt may be made by a person skilled in the art. Suitable salts include acid addition salts that may, for example, be formed by mixing a solution of a compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Additionally, acids that are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) and Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley VCH; S. Berge et al, Journal of Pharmaceutical Sciences 1977 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website).

[0098] An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound. Basic compounds that form an acid addition salt include, for example, compounds comprising an amine group. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include mono-,di- and tricarboxylic acids. Illustrative of such organic acids are, for example, acetic, trifluoroacetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2- hydroxyethanesulfonic acid. In some embodiments, exemplary acid addition salts also include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates (“mesylates”), naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like. In some embodiments, the mono- or di-acid salts are formed and such salts exist in either a hydrated, solvated or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts such as but not limited to oxalates may be used, for example in the isolation of compounds of the application for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0099] A base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound. Acidic compounds that form a basic addition salt include, for example, compounds comprising a carboxylic acid group. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxide as well as ammonia. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine,choline and caffeine. The selection of the appropriate salt may be useful, for example, so that an ester functionality, if any, elsewhere in a compound is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art. In some embodiments, exemplary basic salts also include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, abutyl amine, choline and salts with amino acids such as arginine, lysine and the like. Basic nitrogen containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl and dibutyl sulfates), long chain halides (e.g., decyl, lauryl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides) and others. Compounds carrying an acidic moiety can be mixed with suitable pharmaceutically acceptable salts to provide, for example, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts) and salts formed with suitable organic ligands such as quaternary ammonium salts. Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.

[0100] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the application and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the application. In addition, when a compound of the application contains both a basic moiety, such as, but not limited to an aliphatic primary, secondary, tertiary or cyclic amine, an aromatic or heteroaryl amine, pyridine or imidazole and an acidic moiety, such as, but not limited to tetrazole or carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the terms “salt(s)” as used herein. It is understood that certain compounds of the application may exist in zwitterionic form, having both anionic and cationic centers within the same compound and a net neutral charge. Such zwitterions are included within the application.

[0101] Solvates of compounds of the application include, for example, those made with solvents that are pharmaceutically acceptable. Examples of such solvents include water (resulting solvate is called a hydrate) and ethanol and the like. Suitable solvents are physiologically tolerable at the dosage administered.

[0102] It is understood and appreciated that in some embodiments, compounds of the present application may have at least one chiral center and therefore can exist as enantiomers and / or diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present application. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (for example, less than 20%, suitably less than 10%, more suitably less than 5%) of compounds of the present application having an alternate stereochemistry. It is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the present application.

[0103] The compounds of the present application may further exist in varying amorphous and polymorphic forms and it is contemplated that any amorphous forms, polymorphs, or mixtures thereof, which form are included within the scope of the present application.

[0104] The compounds of the present application are suitably formulated in a conventional manner into compositions using one or more carriers. Accordingly, the present application also includes a composition comprising one or more compounds of the application and a carrier. The compounds of the application are suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. Accordingly, the present application further includes a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier.

[0105] One or more compounds of the application are suitably used on their own but will generally be administered in the form of a composition in which the one or more compounds of the application (the active ingredient) are in association with an acceptable carrier.

[0106] The compounds of the application may be administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds of the application are administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and the pharmaceutical compositions formulatedaccordingly. Administration can be by means of a pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington’s Pharmaceutical Sciences (2000 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.

[0107] Parenteral administration includes intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (for example, by use of an aerosol), intrathecal, rectal and topical (including the use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0108] In some embodiments, topical administration includes liquid, ointment, cream, gel, hydrogel, cataplasm, pomade, liniment, milk, lotion, emulsion, spray, aerosol, collyrium, drops, powder forms of administration.

[0109] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.

[0110] In some embodiments, the one or more compounds of the application are orally administered, for example, with an inert diluent or with an assimilable edible carrier, or enclosed in hard or soft shell gelatin capsules, or compressed into tablets, or incorporated directly with the food of the diet. In some embodiments, for oral therapeutic administration, the one or more compounds are incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions, and the like. In the case of tablets, carriers that are used include lactose, corn starch, sodium citrate and salts of phosphoric acid. Pharmaceutically acceptable excipients include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets may be coated by methods well known in the art. In the case of tablets, capsules, caplets, pellets or granules fororal administration, pH sensitive enteric coatings, such as Eudragits™ designed to control the release of active ingredients are optionally used. Oral dosage forms also include modified release, for example immediate release and timed-release, formulations. Examples of modified-release formulations include, for example, sustained-release (SR), extended-release (ER, XR, or XL), time-release or timed- release, controlled-release (CR), or continuous-release (CR or Contin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet. Timed-release compositions can be formulated, e.g. liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. For oral administration in a capsule form, useful carriers or diluents include lactose and dried corn starch.

[0111] In some embodiments, liquid preparations for oral administration take the form of, for example, solutions, syrups or suspensions, or they are suitably presented as a dry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and / or emulsions are administered orally, one or more compounds of the application are suitably suspended or dissolved in an oily phase that is combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents are added. In some embodiments, such liquid preparations for oral administration are prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0112] It is also possible to freeze-dry the compounds of the application and use the lyophilizates obtained, for example, forthe preparation of products for injection.

[0113] In some embodiments, one or more compounds of the application are administered parenterally. In some embodiments, solutions of the one or more compounds of the application are prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. A person skilled in the art would know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compounds of the application are usually prepared, and the pH of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. In some embodiments, for ocular administration, ointments or droppable liquids are delivered by ocular delivery systems known to the art such as applicators or eye droppers. In some embodiments, such compositions include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzyl chromium chloride, and the usual quantities of diluents or carriers. For pulmonary administration, diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.

[0114] In some embodiments, the compounds of the application are formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. In some embodiments, formulations for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. In some embodiments, the compositions take such forms as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulating agents such as suspending, stabilizing and / or dispersing agents. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. Alternatively, the compounds of the application are suitably in a sterile powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0115] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, gels and powders.

[0116] In some embodiments, for intranasal administration or administration by inhalation, the compounds of the application are conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively, In some embodiments, the sealed container is a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. Suitable propellants include but are not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to deliver a metered amount. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the active compound. In some embodiments, capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator are formulated containing a powder mix of one or more compounds of the application and a suitable powder base such as lactose or starch. In some embodiments, the aerosol dosage forms take the form of a pump-atomizer.

[0117] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0118] Suppository forms of the compounds of the application are useful for vaginal, urethral and rectal administrations. Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature. The substances commonly used to create such vehicles include but are not limited to theobroma oil (also known as cocoa butter), glycerinated gelatin,other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. See, for example: Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533 for further discussion of suppository dosage forms.

[0119] In some embodiments, compounds of the application are coupled with soluble polymers as targetable drug carriers. In some embodiments, such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, in some embodiments, compounds of the application are coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.

[0120] In some embodiments, compounds of the application are coupled with viral, non-viral or other vectors. In some embodiments, viral vectors include retrovirus, lentivirus, adenovirus, herpesvirus, poxvirus, alphavirus, vaccinia virus or adeno- associated viruses. In some embodiments, non-viral vectors include nanoparticles, cationic lipids, cationic polymers, metallic nanoparticles, nanorods, liposomes, micelles, microbubbles, cell-penetrating peptides, or lipospheres. In some embodiments, nanoparticles include silica, lipid, carbohydrate, or other pharmaceutically acceptable polymers.

[0121] In some embodiments, depending on the mode of administration, the pharmaceutical composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of one or more compounds of the application, and from about 1 wt% to about 99.95 wt% or about 30 wt% to about 99.90 wt% of one or more pharmaceutically acceptable carriers, all percentages by weight being based on the total composition.

[0122] In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, one or more compounds of the application are administered in a dose of about 0.01 mg / kg body weight to about 250 mg / kg body weight, about 0.1 mg / kg to about 230 mg / kg, about 1 mg / kg to about 210mg / kg, about 30 mg / kg to about 200 mg / kg, about 50 mg / kg to about 180 mg / kg, about 60 mg / kg, to about 150 mg / kg, about 80 mg / kg to about 120 mg / kg once daily or twice daily.

[0123] In some embodiments, one or more compounds of the application are administered with another therapeutic agent concurrently with, prior to, or subsequent to, in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present application provides a single unit dosage form comprising one or more compounds of the application, an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0124] In certain embodiments, the additional therapeutically active agent is an analgesic, including neuropathic pain analgesics. In certain embodiments, the additional therapeutically active agent is an opioid analgesic. In certain embodiments, the additional therapeutically active agent is a non-opioid (e.g., nonsteroidal antiinflammatory drug (NSAID) or antidepressant). In certain embodiments, the additional therapeutically active agent is a NSAID. In certain embodiments, the additional therapeutically active agent is an antidepressant. In certain embodiments, the additional therapeutically active agent is a cannabinoid. In certain embodiments, the additional therapeutically active agent is a psychedelic including tryptamines, ergolines and phenethylamines or analogues therof. In certain embodiments, the additional therapeutically active agent is a toxin, such as botulinum toxin, resiniferatoxin, or capcaisin, or analogues thereof. In certain embodiments, the opioid analgesic is one or more agents selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol,properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, and pharmaceutically acceptable salts thereof. In some embodiments, the additional therapeutically active agent is a neuropathic pain analgesic selected from one or more of gabapentin, oxcarbazepine, pregabalin, and pharmaceutically acceptable salts thereof. In some embodiments, the NSAID is one or more agents selected from the group consisting of aceclofenac, acemetacin, actarit, alcofenac, alminoprofen, amfenac, aloxipirin, aminophenazone, antraphenine, aspirin, azapropazone, benorilate, benoxaprofen, benzydamine, butibufen, celecoxib, chlorthenoxacin, choline salicylate, clometacin, dexketoprofen, diclofenac, diflunisal, emorfazone, epirizole; etodolac, etoricoxib, feclobuzone, felbinac, fenbufen, fenclofenac, flurbiprofen, glafenine, hydroxylethyl salicylate, ibuprofen, indometacin, indoprofen, ketoprofen, ketorolac, lactyl phenetidin, loxoprofen, lumiracoxib, mefenamic acid, meloxicam, metamizole, metiazinic acid, mofebutazone, mofezolac, nabumetone, naproxen, nifenazone, niflumic acid, oxametacin, phenacetin, pipebuzone, pranoprofen, propyphenazone, proquazone, protizinic acid, rofecoxib, salicylamide, salsalate, sulindac, suprofen, tiaramide, tinoridine, tolfenamic acid, valdecoxib, and zomepirac.

[0125] In the above, the term “a compound” also includes embodiments wherein one or more compounds are referenced.III. Methods and Uses of the Application

[0126] In some embodiments, the present application includes a use of one or more compounds of the application as a medicament.

[0127] In some embodiments, the compounds of the application are useful in the treatment of pain or managing pain in a subject.

[0128] As such, the present application includes a method for treating pain comprising administering an effective amount of one or more compounds of the application to a subject in need thereof. The present application further includes a use of one or more compounds of the application for treating pain, a use of one or more compounds of the application for preparation of a medicament for treating pain, as well as one or more compounds of the application for use in treating pain.

[0129] The present application also includes a method for managing pain comprising administering an effective amount of one or more compounds of the application to a subject in need thereof. The present application further includes a use of one or more compounds of the application for managing pain, a use of one or more compounds of the application for preparation of a medicament for managing pain, as well as one or more compounds of the application for use in managing pain.

[0130] The present application further includes a method for inducing an analgestic effect comprising administering an effective amount of one or more compounds of the application to a subject in need thereof. The present application further includes a use of one or more compounds of the application for inducing analgestic effect, a use of one or more compounds of the application for preparation of a medicament for inducing analgestic effect, as well as one or more compounds of the application for use in inducing analgestic effect.

[0131] In some embodiments, the pain includes, but is not limited to, neuropathic pain (e.g., peripheral neuropathic pain), central pain, deafferentiation pain, fibromyalgia, chronic pain (e.g., chronic nociceptive pain, and other forms of chronic pain such as post-operative pain, e.g., pain arising after hip, knee, or other replacement surgery), peri-operative pain, pre-operative pain, stimulus of nociceptive receptors (nociceptive pain), acute pain (e.g., phantom and transient acute pain), noninflammatory pain, inflammatory pain, pain associated with cancer, wound pain, burn pain, postoperative pain, pain associated with medical procedures, pain resulting from pruritus, painful bladder syndrome, pain associated with premenstrual dysphoric disorder and / or premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with pre-term labor, pain associated with withdrawl symptoms from drug addiction, joint pain, arthritic pain (e.g., pain associated with crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis, or Reiter’s arthritis), lumbosacral pain, musculo-skeletal pain, headache, cluster headaches, migraine, muscle ache, lower back pain, neck pain, toothache, dental / maxillofacial pain, visceral pain, and the like, or combinations thereof.

[0132] In some embodiments, the pain comprises two or more types of pain described above. In some embodiments, one particular type of pain dominates. Insome embodiments, the painful comprises two or more types of pain without one dominating.

[0133] In some embodiments, the pain is neuropathic pain. In some embodiments, neuropathic pain is pain resulting from an injury to a nerve. In some embodiments, neuropathic pain develops resulting from a neuronal injury in one or more of the following: peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. In some embodiments, neuropathic pain results from conditions which include, but are not limited to diabetic neuropathy (e.g., peripheral diabetic neuropathy), sciatica, non-specific lower back pain, multiple sclerosis pain, carpal tunnel syndrome, fibromyalgia, HIV-related neuropathy, neuralgia (e.g., post-herpetic neuralgia or trigeminal neuralgia), physical trauma (e.g., amputation, surgery, invasive medical procedures, toxins, burns or infection), cancer or chemotherapy (e.g., chemotherapy-induced pain such as chemotherapy-induced peripheral neuropathy), or an inflammatory condition (e.g., a chronic inflammatory condition). In some embodiments, neuropathic pain results from a peripheral nerve disorder such as neuroma, nerve compression, nerve crush, nerve stretch or incomplete nerve transection, mononeuropathy or polyneuropathy, or combinations thereof. In some embodiments, neuropathic pain results from a disorder such as dorsal root ganglion compression, inflammation of the spinal cord, contusion, tumor or hemisection of the spinal cord, tumors of the brainstem, thalamus, or cortex, or trauma to the brainstem, thalamus, or cortex, or combinations thereof.

[0134] In some embodiments, the pain is non-inflammatory pain. The types of non-inflammatory pain include, without limitation, peripheral neuropathic pain (e.g., pain caused by a lesion or dysfunction in the peripheral nervous system), central pain (e.g., pain caused by a lesion or dysfunction of the central nervous system), deafferentation pain (e.g., pain due to loss of sensory input to the central nervous system), chronic nociceptive pain (e.g., certain types of cancer pain), noxious stimulus of nociceptive receptors (e.g., pain felt in response to tissue damage or impending tissue damage), phantom pain (e.g., pain felt in a part of the body that no longer exists, such as a limb that has been amputated), pain felt by psychiatric subjects (e.g., pain where no physical cause may exist), or wandering pain (e.g., wherein the pain repeatedly changes location in the body), or combinations thereof.

[0135] In some embodiments, the pain is an inflammatory pain. In some embodiments, the pain (e.g., inflammatory pain) is associated with an inflammatory condition and / or an immune disorder.

[0136] In some embodiments, the pain is acute. In some embodiments, the pain is chronic.

[0137] In some embodiments, the compounds of the application are useful in the treatment of peri-operative and postoperative pain.

[0138] In some embodiments, the compounds of the application are useful in the treatment of peri-operative and postoperative pain in patients prone to opioid- induced respiratory depression.

[0139] Accordingly, the present application also includes a method of treating peri-operative and postoperative pain in patients prone to opioid-induced respiratory depression comprising administering an effective amount of one or more compounds of the application to a subject in need thereof. The present application also includes a use of one or more compounds of the application for treating peri-operative and postoperative pain in patients prone to opioid-induced respiratory depression, a use of one or more compounds of the application for the preparation of a medicament for treating peri-operative and postoperative pain in patients prone to opioid-induced respiratory depression, as well as one or more compounds of the application for use in treating peri-operative and postoperative pain in patients prone to opioid-induced respiratory depression.

[0140] In some embodiments, the compounds of the application are useful in the treatment of an inflammatory condition.

[0141] Accordingly, the present application also includes a method of treating an inflammatory condition comprising administering an effective amount of one or more compounds of the application to a subject in need thereof. The present application also includes a use of one or more compounds of the application for treating an inflammatory condition, a use of one or more compounds of the application for the preparation of a medicament for treating an inflammatory condition, as well as one or more compounds of the application for use in treating an inflammatory condition.

[0142] Exemplary inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia or haemolytic autoimmune anaemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa or Takayasu's arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis or Reiter's arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies, allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes mellitus or type 2 diabetes mellitus), a skin condition (e.g., psoriasis, eczema, burns, dermatitis or pruritus (itch)), endometriosis, Guillain-Barre syndrome, infection, ischaemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraine headaches or tension headaches), ileus (e.g., postoperative ileus or ileus during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (e.g. painful bladder syndrome), gastrointestinal disorder (e.g., peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome or indeterminate colitis), inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myeasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious aneaemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g., Parkinson's disease, Huntington's disease, or Alzheimer's disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, schleroderma, scierodoma, sarcoidosis, spondyloarthopathies, Sjogren's syndrome, thyroiditis, transplantation rejection, tendonitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scarring, burns or physical injury), vasculitis, vitiligo or Wegener's granulomatosis. In certain embodiments, the inflammatory disorder is arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis or prostatistis, or combinations thereof In some embodiments, the inflammatorycondition is an acute inflammatory condition (e.g., inflammation resulting from infection), or combinations thereof. In some embodiments, the inflammatory condition is a chronic inflammatory condition (e.g., conditions resulting from asthma, arthritis or inflammatory bowel disease). In some embodiments, the inflammation is associated with trauma or non-inflammatory myalgia. In some embodiments, the inflammation is associated with cancer.

[0143] In some embodiments, the compounds of the application are useful in the treatment of a neurological disease or psychiatric disorder in a subject.

[0144] As such, the present application also includes a method for treating a neurological disease or psychiatric disorder comprising administering an effective amount of one or more compounds of the application to a subject in need thereof. The present application further includes a use of one or more compounds of the application for treating a neurological disease or psychiatric disorder, a use of one or more compounds of the application for preparation of a medicament for treating a neurological disease or psychiatric disorder, as well as one or more compounds of the application for use in treating a neurological disease or psychiatric disorder.

[0145] In some embodiments, the neurological disease is any type of neurological disease marked by the loss of nerve cells, including, but not limited to, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), or Huntington’s disease, or combinations thereof. Examples of neurological diseases include, but are not limited to, headache, stupor, coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuroophthalmology, movement disorders, demyelinating diseases, spinal cord disorders or disorders of peripheral nerves, muscle or neuromuscular junctions, or combinations thereof.

[0146] Neurological diseases also include addiction or a mental illness, including, but are not limited to, bipolar disorder or schizophrenia. Further examples of neurological diseases include acquired epileptiform aphasia, acute disseminated encephalomyelitis, adrenoleukodystrophy, agenesis of the corpus callosum, agnosia, Aicardi syndrome, Alexander disease, Alpers’ disease, alternating hemiplegia, Alzheimer’s disease, amyotrophic lateral sclerosis, anencephaly, Angelman syndrome, angiomatosis, anoxia, aphasia, apraxia, arachnoid cysts, arachnoiditis,Arnold-Chiari malformation, arteriovenous malformation, Asperger syndrome, ataxia telangiectasia, attention deficit hyperactivity disorder, autism, autonomic dysfunction, back pain, Batten disease, Behcet’s disease, Bell’s palsy, benign essential blepharospasm, benign focal, amyotrophy, benign intracranial hypertension, Binswanger’s disease, blepharospasm, Bloch Sulzberger syndrome, brachial plexus injury, brain abscess, brain injury, brain tumors (including glioblastoma multiforme), spinal tumor, Brown-Sequard syndrome, Canavan disease, carpal tunnel syndrome (CTS), causalgia, central pain syndrome, central pontine myelinolysis, cephalic disorder, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, Charcot-Marie-Tooth disease, chemotherapy-induced neuropathy and neuropathic pain, Chiari malformation, chorea, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, chronic regional pain syndrome, Coffin Lowry syndrome, coma, including persistent vegetative state, congenital facial diplegia, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt- Jakob disease, cumulative trauma disorders, Cushing’s syndrome, cytomegalic inclusion body disease (CIBD), cytomegalovirus infection, dancing eyes-dancing feet syndrome, Dandy-Walker syndrome, Dawson disease, De Morsier’s syndrome, Dejerine-Klumpke palsy, dementia, dermatomyositis, diabetic neuropathy, diffuse sclerosis, dysautonomia, dysgraphia, dyslexia, dystonias, early infantile epileptic encephalopathy, empty sella syndrome, encephalitis, encephaloceles, encephalotrigeminal angiomatosis, epilepsy, Erb’s palsy, essential tremor, Fabry’s disease, Fahr’s syndrome, fainting, familial spastic paralysis, febrile seizures, Fisher syndrome, Friedreich’s ataxia, frontotemporal dementia or other “tauopathies”, Gaucher’s disease, Gerstmann’s syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, Guillain-Barre syndrome, HTLV-1 associated myelopathy, Hallervorden-Spatz disease, head injury, headache, hemifacial spasm, hereditary spastic paraplegia, heredopathia atactica polyneuritiformis, herpes zoster oticus, herpes zoster, Hirayama syndrome, HIV-associated dementia and neuropathy (also neurological manifestations of AIDS), holoprosencephaly, Huntington’s disease or other polyglutamine repeat diseases, hydranencephaly, hydrocephalus, hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile, phytanic acid storage disease, Infantile Refsum disease, infantile spasms, inflammatory myopathy, intracranial cyst, intracranial hypertension Joubert syndrome Kearns-Sayre syndrome, Kennedydisease, Kinsbourne syndrome, Klippel Feil syndrome, Krabbe disease, Kugelberg- Welander disease, kuru, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral medullary (Wallenberg) syndrome, learning disabilities, Leigh’s disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Lewy body dementia, lissencephaly, locked-in syndrome, Lou Gehrig’s disease (aka motor neuron disease or amyotrophic lateral sclerosis), lumbar disc disease, lyme disease-neurological sequelae, Machado-Joseph disease, macrencephaly, megalencephaly, Melkersson-Rosenthal syndrome, Menieres disease, meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly, migraine, Miller Fisher syndrome, mini-strokes, mitochondrial myopathies, Mobius syndrome, monomelic amyotrophy, motor neurone disease, moyamoya disease, mucopolysaccharidoses, multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis and other demyelinating disorders, multiple system atrophy with postural hypotension, muscular dystrophy, myasthenia gravis, myelinoclastic diffuse sclerosis, myoclonic encephalopathy of infants, myoclonus, myopathy, myotonia congenital, narcolepsy, neurofibromatosis, neuroleptic malignant syndrome, neurological manifestations of AIDS, neurological sequelae of lupus, neuromyotonia, neuronal ceroid lipofuscinosis, neuronal migration disorders, Niemann-Pick disease, O’Sullivan- McLeod syndrome, occipital neuralgia, occult spinal dysraphism sequence, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus myoclonus, optic neuritis, orthostatic hypotension, overuse syndrome, paresthesia, Parkinson’s disease, paramyotonia congenita, paraneoplastic diseases, paroxysmal attacks, Parry Romberg syndrome, Pelizaeus-Merzbacher disease, periodic paralyses, peripheral neuropathy, painful neuropathy or neuropathic pain, persistent vegetative state, pervasive developmental disorders, photic sneeze reflex, phytanic acid storage disease, Pick’s disease, pinched nerve, pituitary tumors, polymyositis, porencephaly, Post-Polio syndrome, postherpetic neuralgia (PHN), postinfectious encephalomyelitis, postural hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion diseases, progressive, hemifacial atrophy, progressive multifocal leukoencephalopathy, progressive sclerosing poliodystrophy, progressive supranuclear palsy, pseudotumor cerebri, Ramsay-Hunt syndrome (Type I or Type II), Rasmussen’s Encephalitis, reflex sympathetic dystrophy syndrome, Refsum disease, repetitive motion disorders, repetitive stress injuries, restless legs syndrome, retrovirus- associated myelopathy, Rett syndrome, Reye’s syndrome Saint Vitus Dance, Sandhoff disease, Schilder’sdisease, schizencephaly, septo-optic dysplasia, shaken baby syndrome, shingles, Shy-Drager syndrome, Sjogren’s syndrome, sleep apnea, Soto’s syndrome, spasticity, spina bifida, spinal cord injury, spinal cord tumors, spinal muscular atrophy, stiffperson syndrome, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subarachnoid hemorrhage, subcortical arteriosclerotic encephalopathy, sydenham chorea, syncope, syringomyelia, tardive dyskinesia, Tay- Sachs disease, temporal arteritis, tethered spinal cord syndrome, Thomsen disease, thoracic outlet syndrome, tic douloureux, Todd’s paralysis, Tourette syndrome, transient ischemic attack, transmissible spongiform encephalopathies, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic paraparesis, tuberous sclerosis, vascular dementia (multi-infarct dementia), vasculitis including temporal arteritis, Von Hippel-Lindau Disease (VHL), Wallenberg’s syndrome, Werdnig-Hoffman disease, West syndrome, whiplash, Williams syndrome, Wilson’s disease, or Zellweger syndrome, or combinations thereof.

[0147] In some embodiments, psychiatric disorders include, but are not limited to, anxiety disorders (e.g., acute stress disorder agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, separation anxiety disorder, social phobia or specific phobia), attention- deficit / hyperactivity disorder, childhood disorders (e.g., attention-deficit / hyperactivity disorder, conduct disorder, or oppositional defiant disorder), eating disorders (e.g., anorexia nervosa or bulimia nervosa), mood disorders (e.g., depression, bipolar disorder, cyclothymic disorder, dysthymic disorder, or major depressive disorder), personality disorders (e.g., antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, narcissistic personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, schizoid personality disorder, or schizotypal personality disorder), psychotic disorders (e.g., brief psychotic disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, schizophrenia, or shared psychotic disorder), substance-related disorders (e.g., alcohol dependence, amphetamine dependence, cannabis dependence, cocaine dependence, food dependence, hallucinogen dependence, inhalant dependence, nicotine dependence, opioid dependence, phencyclidine dependence, ketamine dependence or sedative dependence), adjustment disorder, autism, delirium,dementia, multi-infarct dementia, learning or memory disorders (e.g., amnesia or age- related memory loss), or Tourette’s disorder, or combinations thereof.

[0148] In some embodiments, the neurological disease is a mood disorder. In some embodiments, mood disorder includes, but is not limited to, depressive disorders or conditions, such as, for example, major depressive disorders (e.g., unipolar depression), dysthymic disorders (e.g., chronic, mild depression), bipolar disorders (e.g., manic-depression), seasonal affective disorder, and / or depression associated with drug addiction (e.g., withdrawal). In some embodiments, the mood disorder is clinical or subclinical depression.

[0149] In some embodiments, the neurological disease is an addiction. In some embodiments, the neurological disease is a drug abuse. In some embodiments, the neurological disease is an addiction to one or more substances selected from the group consisting of opioids, nicotine, cocaine, psychostimulants, inhalants, dissociatives, sedatives, or alcohol, or combinations thereof.

[0150] In some embodiments, the compounds of the application are useful in treating a subject afflicted with the opioid addiction or opioid withdrawal symptoms.

[0151] As such, the present application also includes a method for treating a subject afflicted with the opioid addiction or opioid withdrawal symptoms comprising administering an effective amount of one or more compounds of the application to a subject in need thereof. The present application further includes a use of one or more compounds of the application for treating an opioid addiction or opioid withdrawal symptoms, a use of one or more compounds of the application for preparation of a medicament for treating an opioid addiction or opioid withdrawal symptoms, as well as one or more compounds of the application for use in treating an opioid addiction or opioid withdrawal symptoms.

[0152] In some embodiments, the compounds of the application are useful in enhancing cognitive and / or behavioral function of a subject.

[0153] As such, the present application also includes a method for enhancing cognitive and / or behavioral function comprising administering an effective amount of one or more compounds of the application to a subject in need thereof. The present application further includes a use of one or more compounds of the application forenhancing cognitive and / or behavioral function, a use of one or more compounds of the application for preparation of a medicament for enhancing cognitive and / or behavioral function, as well as one or more compounds of the application for use in enhancing cognitive and / or behavioral function.

[0154] In some embodiments, enhancing cognitive and / or behavioral function comprises enhancing one or more of memory, attention, language, work capacity, alertness, sociability, energy, motivation or mood. As such, in some embodiments, the compounds of the application act as stimulants.

[0155] In some embodiments, enhancing attention is used in treatment of attentional deficit endophenotype associated with neurological and neuropsychiatric disorders including attentional deficit disorder, attentional deficit hyperactivity disorder, depression, Alzheimer’s disease, frontotemporal dementia, Parkinson’s dementia, amyloidopathies, tauopathies, and / or synucleinopathies.

[0156] In some embodiments, enhancing motivation is used in treatment of attentional deficit endophenotype associated with neurological and neuropsychiatric disorders including depression, seasonal affective disorder, Alzheimer’s disease, frontotemporal dementia, Parkinson’s dementia, amyloidopathies, tauopathies, and / or synucleinopathies.

[0157] In some embodiments, the subject is a human. In some embodiments, the subject is a companion animal or pet. In some embodiments, the subject is a cat or a dog.

[0158] Effective amounts may vary according to factors such as the disease state, age, sex, species and / orweight of the subject. The amount of a given compound that will correspond to such an amount will vary depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art. The effective amount is one that following treatment therewith manifests as an improvement in or reduction of any disease symptom.

[0159] The dosage of the one or more compounds of the application can vary depending on many factors such as the pharmacodynamic properties of thecompound(s), the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate of the compound(s) in the subject to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. Compounds of the application may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. Dosages will generally be selected to maintain a serum level of compounds from about 0.01 pg / cc to about 1000 pg / cc, or about 0.1 pg / cc to about 100 pg / cc. As a representative example, oral dosages of a compound of the application will range between about 1 mg per day to about 1000 mg per day for an adult, suitably about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600mg or about 650 mg of per day. For parenteral administration, a representative amount is from about 0.001 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg or about 0.1 mg / kg to about 1 mg / kg will be administered. For oral administration, a representative amount is from about 0.001 mg / kg to about 10 mg / kg or about 0.1 mg / kg to about 10 mg / kg. For administration in suppository form, a representative amount is from about 0.1 mg / kg to about 10 mg / kg. In some embodiments, of the application, compositions are formulated for oral administration and the compounds are suitably in the form of tablets or suppositories containing 0.25, 0.5, 0.75, 1.0, 5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg of active ingredient per tablet. Compounds of the application may be administered in a single daily, weekly or monthly dose or the total daily dose may be divided into two, three, four, five or six daily doses.

[0160] In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for rectal administration. In some embodiments, the pharmaceutical composition is formulated for nasal administration. In some embodiments, the pharmaceutical composition is formulated for administration by injection.

[0161] In some embodiments, the one or more compounds of the application are administered in a dose of about 0.01 mg / kg body weight to about 250 mg / kg body weight, about 0.1 mg / kg to about 230 mg / kg, about 1 mg / kg to about 210 mg / kg, about30 mg / kg to about 200 mg / kg, about 50 mg / kg to about 180 mg / kg, about 60 mg / kg, to about 150 mg / kg, about 80 mg / kg to about 120 mg / kg and values therebetween in a single daily, weekly or monthly dose or the total daily dose may be divided into two, three, four, five or six daily doses.

[0162] In some embodiments, the one or more compounds of the application are administered at least once a week. However, in another embodiment, the one or more compounds are administered to the subject from about one time per two weeks, three weeks or one month. In another embodiment, the one or more compounds of the application are administered about one time per week to about once daily. In another embodiment, the one or more compounds of the application is administered 2, 3, 4, 5 or 6 times daily. The length of the treatment period depends on a variety of factors, such as the severity of the disease, disorder or condition, the age of the subject, the concentration and / or the activity of the one or more compounds of the application, and / or a combination thereof. It will also be appreciated that the effective dosage of the one or more compounds used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration is required. For example, the compounds are administered to the subject in an amount and for duration sufficient to treat the subject.

[0163] All references to “a compound” above, also include embodiments where one or more compounds are administered or used.IV. Methods of Preparing the Compounds of the Application

[0164] Compounds of the application can be prepared by various synthetic processes. The choice of particular structural features and / or substituents may influence the selection of one process over another. The selection of a particular process to prepare a given compound of the application is within the purview of the person of skill in the art. Some starting materials for preparing compounds of the application are available from commercial chemical sources. Other starting materials, for example as described below, are readily prepared from available precursors using straightforward transformations that are well known in the art.

[0165] In some embodiments, a compound of Formula la, wherein — is a double bond adjacent to X1, and X1is N, is prepared as shown in Schemes 1-6, whereR1, R2, R5and R6are as defined in Formula la, R3and R7are H, n is 1 and R4isCH2CH3.(DMF) and POCl3are mixed and kept at low temperature of for example below 5 °C. To said mixture a solution of compound 1 in a suitable solvent (such as DMF) is added, the pH is adjusted to about 9 with any suitable base (such as K2CO3) and resulting compound 2 is optionally purified. In step b, compound 2 reacts with nitroalkane such as CH3NO2in the presence of a base such as NH4OAc, heated is optionally purified. In step c, the nitro group of compound 3 is reduced to an amine in the presence of a suitable reducing agent (such as LiAIH4) in a suitable solvent (such as THF) to obtain compound 4, which is optionally purified.compound 4 in the presence of a suitable organic base (such as Et3N) in a suitable solvent (such as methylene chloride), and the resulting compound 5 is optionally purified. In step e, hydroxy-protected (E)-4-bromobut-2-en-1-ol [e.g. (E)-4-bromobut- 2-enyl] tert-butyl carbonate) is added to compound 5 in the presence of a suitable base (such as K2CO3), a suitable solvent (such as DMSO) and a nucleophile (such as pentane-1-thiol). The resulting compound 6 is optionally purified.

[0168] In step f in Scheme 3 added to compound 6 in the presence of a suitable acid (such d) in a suitable solvent (such as toluene). In step g, a further suitableprotecting group (Pg1) reagent (such as Boc2O) is added in excess to compound 7 in a suitable solvent (such as DMAP) to obtain compound 8, which is optionally purified.compound 8 in a suitable solvent (such as CH2CI2), and, with optional purification, provides keto compound 9. In step j, 2-diphenylphosphanylethyl(diphenyl)phosphane is added to compound 9 in the presence of a suitable catalyst (such as allyl(chloro)palladium) in a suitable solvent (such as THF). Then an organic amine base, such as diisopropylethylamine (DIPEA) is added in the presence of a suitable catalyst (such as Cs2CO3) and, with optional purification, provides cyclized compound 10.Wittig or Wittig-Horner reagent, suitable base (such as t-BuOK) and a suitable solvent (such as THF), and compound 1 1 is obtained and optionally purified. In step I, the protecting group is removed from compound 1 1 along with isomerization of the double bond, and the resulting compound 12 optionally purified.(such as Pd / C) in a suitable solvent (such as EtOAc) to obtain racemic mixture of compound la, which is optionally purified. In step n, racemic mixture is separated into compounds S-la and R-la.

[0172] In some embodiments, a compound of Formula la wherein — is a double bond adjacent to X1, and X1is N, R1, R2, R5and R6are as defined in Formula la, R7is H, n is 1 , R4is CH2CH3and R3is OC(O)CH3is prepared by reacting compound 12 as shown in Scheme 6 above with a suitable acetoxylating reagent (such as Pb(OAc)4) in a suitable solvent (such as methylene chloride) to obtain racemic mixtureof compound la, which is optionally purified and separated into R and S compound. To obtain compounds of Formula la with hydroxy group at the R3position, the acetoxy compound can be treated with, for example, sodium hydroxide to obtain racemic mixture of compound la, which is optionally purified and separated into R and S compound.

[0173] In some embodiments, a compound of Formula lb, wherein X2is N, p is 1 and R8to R13are as defined in Formula lb, is prepared as shown in Schemes 7-8 below.as halo) in a suitable solvent (such as methylene chloride) undergoes a cyclization with an amine group such as NH3(gas) in the presence of a suitable base (such as calcium chloride) and catalyst (such as anhydrous potassium carbonate) to form intermediate compound 14, which in step p is coupled with intermediate compound 15 in a suitable solvent (such as THF) with a suitable reagent (such as magnesium iodide) to form intermediate compound 16, which is optionally purified.reacts with a suitable electrophilic group in the presence of a base (such as lithium bis(trimethylsilyl)amide) to obtain intermediate compound 18 with a group -C=CH-R11, which reacts with a suitable catalyst (such as PtO2) in a suitable solvent (such as TFE) and in the presence of a suitable base (such as sodium bicarbonate) to obtain racemic mixture of compound lb, which is separated into compounds S-la and R-la.

[0176] Other compounds of Formula la and Formula lb can be prepared using similar synthetic pathways. These compounds can be synthesized by employing analogous procedures, starting from their respective and structurally appropriate starting materials. The modifications to the synthetic pathways are predictable to those skilled in the art, and the variations in reagents and conditions are within the scope of standard synthetic organic chemistry techniques. For example, the compounds can be synthesized by using procedures of Angyal P et al., Total synthesis and structural plasticity of kratom pseudoindoxyl metabolites, Angew. Chem, Ed. 2023, 62; or Varadi A. et al., Mitragynine / Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2, J. Med. Chem. 2016, 59, 8381-8397.

[0177] It is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants andintermediates in a manner that will be readily understood by one skilled in the art. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in “Protective Groups in Organic Synthesis", T.W. Green, P.G.M. Wuts, Wiley-lnterscience, New York, (1999). It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to one skilled in the art. Examples of transformations are given herein, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are given in “Comprehensive Organic Transformations - A Guide to Functional Group Preparations” R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, “Advanced Organic Chemistry, March, 4th ed. McGraw Hill (1992) or, “Organic Synthesis", Smith, McGraw Hill, (1994).

[0178] Techniques for purification of intermediates and final products include, for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily understood by one skilled in the art.

[0179] Salts of the compounds of the application are generally formed by dissolving a neutral compound in an inert organic solvent and adding eitherthe desired acid or base and isolating the resulting salt by either filtration or other known means.

[0180] The formation of solvates of the compounds of the application will vary depending on the compound and the solvate. In general, solvates are formed by dissolving a compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can bemade by a person skilled in the art. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a “hydrate”.

[0181] The following non-limiting examples are illustrative of the present application.ExamplesExample 1 : Synthesis of Exemplary Compounds la-2, (2S,3S,13bS)--la-2 and (2R,3R,13bR)-la-2Preparation of Intermediate Compound 2. L, 7 eq.) wascooled to 0 °C and POCI3(11 .4 g, 74.5 mmol, 6.94 mL, 1 .2 eq.) was added dropwise, maintaining the internal temperature below 5 °C. The mixture was stirred at 0 °C for 40 min and a solution of 1 (5H-[1 ,3]dioxolo[4,5-f]indole; 10 g, 62.05 mmol, 1 eq.) in DMF (50 mL) was added dropwise and stirred at 10 °C for 1 h. The mixture was allowed to warm to room temperature and stirred for additional 1 h. The reaction mixture was cooled to 0 °C and quenched by adding iced water in small portions. K2CO3was added in small portions until pH = 9. The solution was stirred for 30 min and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether (MTBE) and stirred for 10 min. The suspension was filtered, and the solid was dried under reduced pressure. Compound 2 (12.9 g) was obtained as solid and used in the following step without further purification.1H-NMR (400 MHz, DMSO-d6) δ = 11 .94 (s, 1 H), 9.84 (s, 1 H), 8.09 (s, 1 H), 7.47 (s, 1 H), 7.04 (s, 1 H), 6.02 (s, 1 H).Preparation of Intermediate Compound 3.

[0183] To a mixture of compound 2 (5H-[1 ,3]dioxolo[4,5-f]indole-7- carbaldehyde; 11.9 g, 62.9 mmol, 1 eq.) in MeNO2(136 mL) was added NH4OAc (1.21 g, 15.7 mmol, 0.25 eq.) at 20 °C. The reaction mixture was heated at 100 °C and stirred for 2 h to give a brown solution. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in CH2CI2(100 mL) and H2O (100 mL) and stirred for 10 min. The mixture was filtered, the solid was collected. The organic layer in the filtrate was separated, and the aqueous layer was extracted with CH2CI2(100 mL x 2). The combined organic layers were washed with aqueous saturated NaCI solution (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was combined with the solid collected by filtration, triturated with MTBE (10 mL). The solid was collected and dried under reduced pressure. Compound 3 (12.8 g, 55.1 mmol, 88% yield) was obtained as solid.1H-NMR (400 MHz, DMSO-d6) δ = 12.02 (br s, 1 H), 8.32 (d, J = 13.2 Hz, 1 H), 8.06 (s, 1 H), 7.99 (d, J = 13.2 Hz, 1 H), 7.53 (s, 1 H), 7.04 (s, 1 H), 6.03 (s, 2H).Preparation of Intermediate Compound 4. HF was added asolution of 3 (7-[(E)-2-nitrovinyl]-5H-[1 ,3]dioxolo[4,5-f]indole; 12.8 g, 55.13 mmol, 1 eq.) in tetra hydrofuran (THF) (150 mL) at 10 °C. The reaction mixture was warmed to room temperature and stirred for 3 h and heated at 50 °C for 1 h. The reaction mixture was cooled to 10 °C and quenched with water (14.6 g) carefully, followed by addition of NaOH (15% aqueous, 14.6 g) and water (30 g), stirred for 10 min, diluted with THF (20 mL), and filtered. The filtrate was dried over anhydrous Na2SO4and concentrated under reduced pressure. Compound 4 (10.1 g, 49.46 mmol, 89.71% yield) was obtained.1H-NMR (400 MHz, CDCI3) δ = 7.90 (br s, 1 H), 6.98 (s, 1 H), 6.93 (d, J = 0.2 Hz, 1 H), 6.83 (s, 1 H), 5.94 (s, 2H), 3.00 (d, J = 6.4 Hz, 2H), 2.83 (d, J = 6.4 Hz, 2H).Preparation of Intermediate Compound 5.[00 5-f]indol-7-yl)ethanamine; 10.1 g, 49.46 mmol, 1 eq.) and Et3N (6.01 g, 59.35 mmol, 8.26 mL, 1.2 eq.) in CH2CI2(180 mL) was added 4-nitrobenzenesulfonyl chloride (10.96 g, 49.46 mmol, 1 eq.) in small portions at room temperature and stirred for 2 h. The reaction mixture was diluted with H2O (30 mL) and CH2CI2(20 mL), filtered and the solid was collected. The CH2CI2layer of filtrate was separated and the aqueous layer was extracted with CH2CI2(20 mL x 2). The combined CH2CI2layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with CH2CI2(5 mL), filtered, combined with the previously collected solid, and dried under reduced pressure to give Compound 5 (13.4 g, 34.33 mmol, 69% yield) as red solid.1H-NMR (400 MHz, DMSO-d6) δ = 10.56 (br s, 1 H), 8.32 - 8.20 (m, 2H), 8.05 (t, J = 5.6 Hz, 1 H), 7.95 - 7.83 (m, 2H), 6.90 (d, J = 2.3 Hz, 1 H), 6.77 (d, J = 17.6 Hz, 2H), 5.88 (s, 2H), 3.18 - 3.00 (m, 2H), 2.69 (t, J = 7.2 Hz, 2H)Preparation of Intermediate Compound 6.butyl carbonate (4.74 g, 18.86 mmol, 1 .02 eq.) were added to the mixture of compound 5 (N-[2-(5H-[1 ,3]dioxolo[4,5-f]indol-7-yl)ethyl]-4-nitro-benzenesulfonamide, 7.2 g, 18.49 mmol, 1 eq.) in DMSO (72 mL) and stirred at room temperature for 16 h. Pentane-1-thiol (3.08 g, 29.59 mmol, 1.6 eq.) was then added and the reaction mixture was stirred at room temperature for additional 16 h. The reaction mixture was poured over iced water (500 mL) and extracted with CH2CI2(100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by flash silica gel chromatography (0~80% ethyl acetate in petroleum ether). Compound 6 (5.6 g, 14.96 mmol, 81% yield) was obtained. 1H-NMR (400 MHz, CDCI3) δ = 7.913 (br s, 1 H), 6.98 (s, 1 H), 6.92 (d, J = 2.4 Hz, 1 H),6.83 (s, 1 H), 5.93 (s, 2H), 5.88 - 5.81 (m, 1 H), 5.75 - 5.71 (m, 1 H), 4.51 (d, J = 6.0 Hz, 2H), 3.27 (d, J = 5.6 Hz, 3H), 2.93-2.87 (m, 4H), 1.48 (s, 9H).Preparation of Intermediate Compound 7.the solution of compound 6 (tert-butyl [(E)-4-[2-(5H-[1 ,3]dioxolo[4,5-f]indol-7- yl)ethylamino]but-2-enyl] carbonate, 7.1 g, 18.96 mmol, 1 eq.) in toluene (284 mL), followed by methyl 2,2-bis(ethylsulfanyl)-5-oxo-pentanoate (5.70 g, 22.75 mmol, 1.2 eq.) under anhydrous conditions. The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was used in the next step without work-up or purification.Preparation of Intermediate Compound 8.6 g, 75.87 mmol, 17.43 mL, 4 eq.) and 4-dimethylaminopyridine (DMAP) (2.32 g, 18.97 mmol, 1 eq.). The mixture was stirred at room temperature for 16 h. The mixture was diluted with water (100 mL), the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (0~10% ethyl acetate / petroleum ether) to yield Compound 8 (12.1 g, 17.03 mmol, 90% yield).1H-NMR (400 MHz, CDCI3) δ = 7.65 (s, 1 H), 6.78 (s, 1 H), 5.97 (d, J = 4.0 Hz, 1 H), 5.96 - 5.86 (m, 1 H), 5.76 - 5.69 (m, 1 H), 4.56 (d, J = 6.0 Hz, 2H), 4.12 - 4.08 (m, 1 H), 3.75 (s, 3H), 3.29 - 3.10 (m, 3H), 3.97-2.90 (m, 1 H), 2.75 - 2.61 (m, 5H), 2.45 - 2.27 (m, 2H), 2.13 - 2.03 (m, 1 H), 1.96 -1.85 (m, 1 H), 1.84 - 1.71 (m, 1 H), 1.66 (s, 9H), 1.50 (s, 9H), 1.25 - 1.21 (m, 6H). LCMS: m / z 707.2 [M+H]+, tR= 0.84 min.Preparation of Intermediate Compound 9.eq.) and CH2CI2(10.5 mL). AgOTf (354.33 mg, 1 .38 mmol, 1.6 eq.) was added under anhydrous conditions and the reaction mixture was stirred at room temperature for 3 h. The solid precipitate was removed by filtration, and the solvent was evaporated under reduced pressure to afford the crude intermediate, which was dissolved in a mixture of DMSO (10 mL) : H2O (2.5 mL) and the reaction mixture was stirred at 75 °C for 30 min. The reaction mixture was diluted with NaHCO3solution (50 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with aqueous saturated NaCI solution (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash silica gel chromatography (0~7% ethyl acetate / petroleum ether). Compound 9 (213 mg, 354.61 μmol, 41.15% yield, 100% purity) was obtained as light-yellow oil.1H- NMR (400 MHz, CDCI3) δ = 7.68 (s, 1 H), 6.79 (s, 1 H), 5.98 (s, 2H), 5.82 - 5.76 (m, 1 H), 5.71 - 5.67 (m, 1 H), 4.57- 4.52 (m, 2H), 4.03 - 3.99 (m, 1 H), 3.89 (s, 3H), 3.20 - 3.01 (m, 3H), 2.85 - 2.70 (m, 1 H), 2.68 - 2.55 (m, 3H), 2.39 - 2.27 (m, 3H), 1 .69 (s, 9H), 1 .50 (s, 9H). LCMS: m / z 601 .2 [M+H]+, tR= 0.77 min.Preparation of Intermediate Compound 10.μmol, 0.3 eq.) was added to the mixture of allyl(chloro)palladium (7.31 mg, 39.96 μmol, 0.15 eq.) in THF (0.4 mL) under anhydrous conditions, stirred for 15 min and the suspension formed was then added to the solution of compound 9 in THF (1.6 mL). N,N-diisopropylethylamine (DIEA) (68.85 mg, 532.75 μmol, 92.80 μL, 2 eq.) and CS2CO3(173.58 mg, 532 75 μmol 2 eq ) were then added and the reaction mixturewas stirred at 25 °C for 3 h. The reaction mixture was quenched with aqueous saturated NH4CI solution (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash silica gel chromatography (0~10% ethyl acetate / petroleum ether). Compound 10 (60 mg, 118.13 μmol, 44.35% yield, 95% purity) was obtained as light yellow solid.1H-NMR (400 MHz, CDCI3) δ = 7.58 (s, 1 H), 6.79 (s, 1 H), 6.12 - 6.07 (m, 1 H), 5.99 - 4.96 (m, 2H), 5.18 - 4.97 (m, 2H), 3.87 (s, 3H), 3.84 - 3.75 (m, 1 H), 3.58 - 3.52 (m, 1 H), 3.15 - 3.06 (m, 2H), 3.02 - 2.98 (m, 1 H), 2.90 - 2.85 (m, 1 H), 2.82 - 2.68 (m, 3H), 2.54 - 2.51 (m, 1 H), 2.29 - 2.25 (m, 1 H), 1 .74 (q, J = 11 .2 Hz, 1 H), 1 .65 (s, 9H). LCMS: m / z 483.2 [M+H]+, tR= 0.723 min.Preparation of Intermediate Compound 11 .g, 3.11 mmol, 3.0 eq.) in THF (3.5 mL) was added tBuOK (348.83 mg, 3.11 mmol, 3.0 eq.) under anhydrous conditions. The reaction mixture was stirred at room temperature for 2 h, then cooled to -78 °C, and a solution of compound 10 (500 mg, 1.04 mmol, 1 eq.) in THF (4.0 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred for additional 2 h. The mixture was quenched with aqueous saturated (sat.) NH4CI solution (3 mL) and stirred at room temperature for 16 h. The reaction mixture was extracted with EtOAc (10 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (0~10% ethyl acetate / petroleum ether). Compound 11 (370 mg, 724.67 μmol, 69.93% yield) was obtained as yellow oil. LCMS: m / z 511.2 [M+H]+, tR= 0.719 min.Preparation of Intermediate Compound 12.

[0192] Trifluoroacetic anhydride (TFAA, 32.91 mg, 156.7 μmol, 21.8 μL, 0.4 eq.) was added to trifluoroacetic acid (TFA, 38 g, 333 mmol, 24.7 mL) and stirred for 5 min and transferred to the mixture of compound 11 (200 mg, 391.71 μmol, 1 eq.) in CH2CI2(75 mL) under anhydrous conditions and stirred for 16 h at 25 °C. The reaction mixture was cooled to -30 °C and poured over cold saturated aqueous NaHCO3solution (400 mL) in small portions. The mixture was extracted with CH2CI2(150 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (0~13% ethyl acetate / petroleum ether). Compound 12 (74 mg, 174.88 μmol, 44.64% yield, 97% purity) was obtained as yellow oil.1H-NMR (400 MHz, CDCI3) δ = 7.61 (br s, 1 H), 7.37 (s, 1 H), 6.88 (s, H), 6.81 (s, 1 H), 6.38 - 6.28 (m, 1 H), 5.92 (s, 2H), 4.98 - 4.89 (m, 2H), 3.71 (m, 6H), 3.25 - 3.21 (d, J = 11.2 Hz, 1 H), 2.78 (dt, J = 13.33, 3.67 Hz, 1 H), 3.01-2.88 (m, 3H), 2.76-2.72 (dd, J = 11.19, 2.75 Hz, 1 H), 2.65 - 2.49 (m, 3H), 2.47 - 2.39 (m, 1 H), 1 .90-1.82 (m, 1 H). LCMS: m / z 411 .3 [M+H]+, tR= 4.99 min.Preparation of Intermediate Compound la-2.eq.), EtOAc (13 mL), and Pd / C (90.74 mg, 85.27 μmol, 10% purity, 0.5 eq.) and stirred under H2atmosphere at room temperature for 30 min. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0~18% ethyl acetate / petroleum ether). Compound la-2 (60 mg, 130.92 μmol, 76.77% yield, 90% purity) was obtained as yellow oil.1H-NMR (400 MHz, CDCI3) δ = 7.59 (br s, 1 H), 7.44 (s, 1 H), 6.86 (s, 1 H), 6.79 (s, 1 H), 5.92 - 5.89 (q, J = 1.26 Hz, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 3.20 - 3.11 (m, 1 H), 3.09 - 2.99 (m, 2H), 2.99 - 2.85 (m, 2H), 2.67 - 2.42 (m, 4H), 1.85 - 1.71 (m, 2H), 1.26 - 1.16 (m, 1 H), 0.87 (t, J = 7.34 Hz, 3H). LCMS: m / z 413.3 [M+H]+, tR= 5.24 min.Chiral separation of Compound la-2. Preparation of Compounds (2S,3S,13bS)-la-2 and (2R,3R,13bR)-la-2.separated by Chiral SFC (column: DAICEL CHIRALPAK AD (250mm x 30mm, 10um); mobile phase: CO2-EtOH (0.1%NH3H2O)]; B%: 50%%, isocratic elution mode) to give compound S-la-2 (20.5 mg, 48.44 μmol, 20% yield, 97.5% purity) and compound R- la-2 (22.9 mg, 53.46 μmol, 22% yield, 96% purity) as yellow solid. The absolute stereochemistry of Compounds (2S,3S,13bS)-la-2 and (2R,3R,13bR)-la-2 were tentatively assigned.

[0195] Compound (2S,3S,13bS)-la-2:1H-NMR (400 MHz, CDCI3) δ = 7.58 (br s, 1 H), 7.44 (s, 1 H), 6.86 (s, 1 H), 6.79 (s, 1 H), 5.91 (s, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 3.19 - 3.11 (m, 1 H), 3.08 - 2.99 (m, 2H), 2.99 - 2.86 (m, 2H), 2.67 - 2.43 (m, 4H), 1.85 - 1.70 (m, 2H), 1.81 - 1.65 (m, 2H), 1.68 - 1.62 (m, 1 H), 1.26 - 1.15 (m, 3H), 0.87 (t, J = 7.34, 3H). LCMS: m / z 413.2 [M+H]+, tR= 0.67 min. HPLC: tR= 4.64 min. Chiral SFC: tR= 1.595 min.

[0196] Compound (2R,3R,13bR)-la-2:1H-NMR (400 MHz, CDCI3) δ = 7.58 (br s, 1 H), 7.44 (s, 1 H), 6.86 (s, 1 H), 6.79 (s, 1 H), 5.91 (s, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 3.19 - 3.11 (m, 1 H), 3.08 - 2.99 (m, 2H), 2.99 - 2.86 (m, 2H), 2.67 - 2.43 (m, 4H), 1.85 - 1.70 (m, 2H), 1.81 - 1.65 (m, 2H), 1.68 - 1.62 (m, 1 H), 1.26 - 1.15 (m, 3H), 0.87 (t, J = 7.34, 3H). LCMS: m / z 413.2 [M+H]+, tR= 0.67 min. HPLC: tR= 4.64 min. Chiral SFC: tR= 2.118 min.Synthesis of Exemplary Compounds (2S,3S,7aS,13bS)-la-4 and (2R,3R,7aR,13bR)- la-4ethyl-1 ,2,3,4,6,7,7a, 13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)- 3-methoxyacrylate (16)

[0197] To a mixture of methyl (E)-2-((2S,3S,13bS)-3-ethyl-1 ,2,3,4,6,7,13,13b- octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate (13, 0.8 g, 1.94 mmol, 1 eq.) in methylene chloride (CH2CI2; 120 mL) was added lead (IV) acetate (Pb(OAc)4; 2.06 g, 4.27 mmol, 2.2 eq.) at 0 °C and stirred at 0 °C under anhydrous conditions for 1 .5 h. The suspension was transferred to iced water (150 mL) and aqueous saturated sodium bicarbonate (NaHCO3) solution (50 mL), stirred at 0- 5°C for 10 min, filtered, and the filtrate was extracted with methylene chloride (CH2CI2, 100 mLx2). The combined organic layers were washed with saturated sodium chloride solution (30 mL) and concentrated to afford methyl (E)-2-((2S,3S,7aS,13bS)-7a- acetoxy-3-ethyl-1 ,2,3,4,6,7,7a,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3- a]quinolizin-2-yl)-3-methoxyacrylate (16) as a racemate. LCMS: m / z 471.3 [M+H]+, tR= 2.345 min.Synthesis of intermediate compound methyl (E)-2-((2S,3S,7aS,13bS)-3-ethyl-7a- hydroxy-1 ,2,3,4,6,7,7a,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2- yl)-3-methoxyacrylate (17)

[0198] To a mixture of methyl (E)-2-((2S,3S,7aS,13bS)-7a-acetoxy-3-ethyl- 1 ,2,3,4,6,7,7a,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)-3- methoxyacrylate (16; 0.9 g, 1.91 mmol, 1 eq.) in methanol (MeOH, 30 mL) was addeda solution of sodium hydroxide (NaOH; 120.81 mg, 2.87 mmol, 1.5 eq.) in water (5 mL) at 0-5°C. It was stirred at 0-5°C under nitrogen atmosphere for 2h. The solution was transferred into iced water (300 mL) and extracted with methylene chloride (CH2CI2, 100 mLx2). The combined organic layers were washed with saturated sodium chloride solution (100 mL) and concentrated under reduced pressure. Purification by silica gel chromatography afforded methyl (E)-2-((2S,3S,7aS,13bS)-3-ethyl-7a-hydroxy- 1 ,2,3,4,6,7,7a,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)-3- methoxyacrylate (17) as a racemate. LCMS: m / z 429.2 [M+H]+, tR= 1.552 min.Synthesis of methyl (E)-2-((2S,3S,7aS,13bS)-3-ethyl-7a-hydroxy-1 ,2,3,4,6,7,7a,13b- octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate ((2S,3S,7aS,13bS)-la-4) and methyl (E)-2-((2R,3R,7aR,13bR)-3-ethyl-7a-hydroxy- 1 ,2,3,4,6,7,7a,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)-3- methoxyacrylate ((2R,3R,7aR,13bR)-la-4)

[0199] Racemic mixture of methyl (E)-2-((2S,3S,7aS,13bS)-3-ethyl-7a- hydroxy-1 ,2,3,4,6,7,7a,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2- yl)-3-methoxyacrylate (17; 158 mg) was separated by chiral SFC (column: Daicel ChiralPak IG (250*30mm, 10um); mobile phase: [CO2-EtOH(0.1%NH3'H2O)];B%:40%, isocratic elution mode) to give methyl (E)-2-((2S,3S,7aS,13bS)- 3-ethyl-7a-hydroxy-1 ,2,3,4,6,7,7a,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3- a]quinolizin-2-yl)-3-methoxyacrylate ((2S,3S,7aS,13bS)-la) and methyl (E)-2- ((2R,3R,7aR,13bR)-3-ethyl-7a-hydroxy-1 ,2,3,4,6,7,7a,13b-octahydro- [1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate((2R,3R,7aR,13bR)-la-). The absolute stereochemistry of Compounds (2S,3S,7aS,13bS)-la and (2R,3R,7aR,13bR)-la-were tentatively assigned.

[0200] Compound (2S,3S,7aS,13bS)-la:1H NMR (400 MHz, CDCI3) δ = 7.44 (s, 1 H), 7.07 (s, 1 H), 6.87 (s, 1 H), 5.98 (s, 2H), 3.81 (s, 3H), 3.69 (s, 3H), 3.14 - 2.94 (m, 3H), 2.87 - 2.57 (m, 3H), 2.46 (dd, J = 2.4, 11.6 Hz, 1 H), 2.39 - 2.30 (m, 1 H), 2.00 (br s, 1 H), 1.89 - 1.78 (m, 1 H), 1.74 - 1.65 (m, 1 H), 1.60 - 1.51 (m, 2H), 1.31 - 1.17 (m, 1 H), 0.82 (t, J = 7.2 Hz, 3H). LCMS: m / z 429.3 [M+H]+, tR= 1.504 min.

[0201] Compound (2R,3R,7aR,13bR)-la:1H NMR (400 MHz, CDCI3) δ = 7.44 (s, 1 H), 7.07 (s, 1 H), 6.87 (s, 1 H), 5.98 (s, 2H), 3.81 (s, 3H), 3.69 (s, 3H), 3.14 - 2.94 (m, 3H), 2.87 - 2.57 (m, 3H), 2.46 (dd, J = 2.4, 11.6 Hz, 1 H), 2.39 - 2.30 (m, 1 H), 2.00(br s, 1 H), 1.89 - 1.78 (m, 1 H), 1.74 - 1.65 (m, 1 H), 1.60 - 1.51 (m, 2H), 1.31 - 1.17 (m, 1 H), 0.82 (t, J = 7.2 Hz, 3H). LCMS: m / z 429.3 [M+H]+, tR= 1.550 min.Synthesis of Exemplary Compound (2S,3S,7aS,13bS)-la-3

[0202] To a solution of 3-methoxybenzene-1 ,2-diol (20, 50 g, 356.80 mmol, 1 eq) in dimethylformamide (DMF, 500 mL) was added copper(l) oxide (Cu2O, 3.12 g, 39.25 mmol, 0.11 eq), potassium carbonate ( K2CO3, 60.16 g, 435.29 mmol, 1.22 eq), and dibromomethane (CH2Br2, 75.67 g, 435.29 mmol, 30.55 mL, 1 .22 eq). The reaction mixture was stirred at 120 °C for 16 h. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (EtOAc, 3 x 300 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (6 x 300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel chromatography gave 4-methoxybenzo[d][1 ,3]dioxole (21).1H NMR (400MHz, DMS0-d6) δ = 6.85 - 6.74 (m, 1 H), 6.65 - 6.53 (m, 2H), 6.02 - 5.90 (m, 2H), 3.86- 3.71 (m, 3H)Synthesis of intermediate compound 4-methoxy-6-nitrobenzo[d][1 ,3]dioxole (22).

[0203] The reaction was performed using a continuous flow setup. Solution 1 : 4-methoxybenzo[d][1 ,3]dioxole (21 ; 45.0 g, 295.77 mmol, 1.0 eq) was dissolved in acetic anhydride (Ac2O, 220 mL). Solution 2: Fuming nitric acid (HNO3, 36.5 g, 591.54 mmol, 2.0 eq) was dissolved in acetic anhydride (Ac2O, 220 mL). Both solutions were pumped at a flow rate of 6 mL / min (Pump 1 for Solution 1 , Pump 2 for Solution 2) and mixed in a reactor coil maintained at 15 °C. The residence time was 6 min. After complete collection, the reaction mixture was quenched by transferring into iced water (200 mL), and the resulting precipitate was collected by filtration, washed with water (100 mL), and dried under reduced pressure to afford 4-methoxy-6- nitrobenzo[d][1 ,3]dioxole (22).1H NMR (400 MHz, DMSO-d6) δ = 7.61 (d, J = 2.2 Hz, 1 H), 7.52 (d, J = 2.1 Hz, 1 H), 6.23 (s, 2H), 3.93 (s, 3H).Synthesis of intermediate compound 7-methoxybenzo[d][1 ,3]dioxol-5-amine (23).

[0204] To a solution of 4-methoxy-6-nitrobenzo[d][1 ,3]dioxole (22; 55 g, 278.98 mmol, 1 eq) in methanol (1000 mL) was added palladium on activated charcoal (Pd / C, 10.19 g, 9.57 mmol, 10% purity) under anhydrous conditions. The suspension was degassed and purged with hydrogen gas. The mixture was stirred under hydrogen atmosphere (45 psi) at 20 °C for 40 h. The mixture was filtered, and the filtrate was concentrated to give 7-methoxybenzo[d][1 ,3]dioxol-5-amine (23). LCMS (ESI): m / z 168.1 [M+H]+, tR= 0.170 minSynthesis of intermediate compound 6-bromo-7-methoxybenzo[d][1 ,3]dioxol-5-amine (24).

[0205] 7-methoxybenzo[d][1 ,3]dioxol-5-amine (23; 58 g, 346.97 mmol, 1 eq) was dissolved in a solution of hydrogen bromide in acetic acid (HBr / AcOH, 2600 mL, 30 wt%). To the above solution was added dropwise a solution of bromine (Br2; 27.72 g, 173.48 mmol, 8.94 mL, 0.5 eq) in acetic acid (AcOH, 516 mL). The mixture was stirred at 15°C for 0.5 hour. The mixture was transferred to iced-water (5 L) and then adjusted to pH~12 with sodium hydroxide (NaOH). The resulting mixture was extracted with ethyl acetate (3x2 L). The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography gave 6-bromo-7-methoxybenzo[d][1 ,3]dioxol-5-amine (24).1H NMR (400 MHz, DMSO-d6) δ = 6.20 (s, 1 H), 5.93 - 5.81 (m, 2H), 5.03 (s, 2H), 3.97 - 3.88 (m, 3H). LCMS (ESI): m / z 248.0 [M+H]+, tR= 0.803 minSynthesis of intermediate compound tert-butyl (2-(8-methoxy-6-(trimethylsilyl)-5H- [1 ,3]dioxolo[4,5-f]indol-7-yl)ethyl)carbamate (25).

[0206] To a solution of 6-bromo-7-methoxybenzo[d][1 ,3]dioxol-5-amine (24; 7.2 g, 29.26 mmol, 1 eq) in dimethylformamide (DMF, 350 mL) was added lithium chloride (LiCI; 1.24 g, 29.26 mmol, 599.80 μL, 1 eq), 1 ,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (Pd(dppf)CI2; 6.42 g, 8.78 mmol, 0.3 eq), tert-butyl (4-(trimethylsilyl)but-3-yn-1-yl)carbamate (TBTMSBY; 10.60 g, 43.89 mmol, 1.5 eq) and sodium carbonate (Na2CO3; 6.20 g, 58.52 mmol, 2 eq). The mixture was stirred at 120 °C for 4 h. Ethyl acetate (EtOAc, 200 mL) was added and filtered. The filtrate was diluted with water (100 mL) and extracted with ethyl acetate (EtOAc, 3x100 mL). The combined organic layers were washed with brine (3x100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography gave tert-butyl (2-(8- methoxy-6-(trimethylsilyl)-5H-[1 ,3]dioxolo[4,5-f]indol-7-yl)ethyl)carbamate (25).1H NMR (400 MHz, DMSO-d6) δ = 10.23 (s, 1 H), 6.53 (s, 1 H), 5.87 (s, 2H), 4.01 - 3.99 (m, 3H), 3.14 - 3.03 (m, 2H), 2.87 - 2.80 (m, 2H), 1.40 - 1.38 (m, 9H), 0.31 (s, 8H). LCMS (ESI): m / z 407.2 [M+H]+, tR= 1 .083 minSynthesis of intermediate compound 2-(8-methoxy-5H-[1 ,3]dioxolo[4,5-f]indol-7- yl)ethan-1 -amine (26).

[0207] To a solution of tert-butyl (2-(8-methoxy-6-(trimethylsilyl)-5H- [1 ,3]dioxolo[4,5-f]indol-7-yl)ethyl)carbamate (25; 5 g, 12.30 mmol, 1 eq) in methylene chloride (CH2CI2, 100 mL) was added trifluoroacetic acid (TFA; 30.70 g, 269.25 mmol, 20 mL, 21.89 eq) and anisole (50 mL). The mixture was stirred at 20 °C for 3 h. The reaction mixture was diluted with water (30 mL) and the aqueous layer was extracted with methylene chloride (CH2CI2, 3x200 mL). The resulting aqueous layer was adjusted to pH~9 with sodium bicarbonate (NaHCO3), extracted with ethyl acetate (EtOAc, 3x200 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (3x100 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure to give 2-(8-methoxy-5H-[1 ,3]dioxolo[4,5-f]indol- 7-yl)ethan-1-amine (26). LCMS (ESI): m / z 235.1 [M+H]+, tR= 0.684 min.Synthesis of intermediate compound methyl 2-((2R,13bS,Z)-3-ethylidene-8-methoxy- 1 ,2,3,4,6,7,13,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)acetate (27).

[0208] To a solution of methyl (R,Z)-4-(chloromethyl)-3-(2-oxoethyl)hex-4- enoate (34; 1.40 g, 6.40 mmol, 1 eq) and 2-(8-methoxy-5H-[1 ,3]dioxolo[4,5-f]indol-7- yl)ethan-1-amine (26; 1.5 g, 6.40 mmol, 1 eq) in dimethylformamide (DMF, 230 mL) was added benzoic acid (PhCO2H, 234.59 mg, 1.92 mmol, 0.3 eq). The mixture was stirred under anhydrous conditions at 20 °C for 30 minutes. Additional methyl (R,Z)-4- (chloromethyl)-3-(2-oxoethyl)hex-4-enoate (34; 700 mg, 3.20 mmol, 0.5 eq) and benzoic acid (PhCO2H, 234.59 mg, 1.92 mmol, 0.3 eq) were introduced. The mixture was stirred under anhydrous conditions at 20 °C for 16 h. The mixture was diluted with water (200 mL), adjusted to pH~8 with sodium bicarbonate (NaHCO3), and then extracted with ethyl acetate (EtOAc, 3x300 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (3x200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by prep-HPLC (NH3H2O) gave methyl 2-((2R,13bS,Z)-3-ethylidene-8-methoxy- 1 ,2,3,4,6,7,13,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)acetate (27).1H NMR (400 MHz, DMSO-d6) δ = 10.55 (s, 1 H), 6.53 - 6.45 (m, 1 H), 5.85 (d, J = 0.7 Hz, 2H), 5.15 - 5.08 (m, 1 H), 3.95 - 3.89 (m, 3H), 3.77 (br d, J = 12.1 Hz, 1 H), 3.66 (s, 3H), 3.06 - 2.94 (m, 1 H), 2.90 - 2.79 (m, 1 H), 2.75 (br s, 1 H), 2.71 (br d, J = 5.7 Hz, 1 H), 2.69 - 2.65 (m, 1 H), 2.64 - 2.53 (m, 2H), 2.26 (br dd, J = 7.7, 15.2 Hz, 2H), 1 .63 (br d, J = 6.4 Hz, 4H), 1 .08 (br d, J = 11.7 Hz, 1 H). LCMS (ESI): m / z 399.2 [M+H]+, tR= 4.313 min.Synthesis of intermediate compound methyl (E)-2-((2S,13bS,Z)-3-ethylidene-8- methoxy-1 ,2,3,4,6,7,13,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2- yl)-3-hydroxyacrylate (28).

[0209] To a mixture of methyl 2-((2R,13bS,Z)-3-ethylidene-8-methoxy- 1 ,2,3,4,6,7,13,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)acetate (27; 0.4 g, 1.00 mmol, 1 eq) in anhydrous tetra hydrofuran (THF, 8 mL) was added lithium bis(trimethylsilyl)amide (LiHMDS, 1 M THF solution, 6.02 mL, 6.02 mmol, 6 eq)dropwise over 20 minutes, maintaining the temperature below -30°C. Then the mixture was stirred at -40 °C for 1 h. Anhydrous methyl formate (HCO2Me, 602.83 mg, 10.04 mmol, 608.92 μL, 10 eq) was added dropwise over 15 minutes while maintaining the temperature below -30°C. The mixture was stirred at -40 °C for 1 .5 h. The mixture was quenched with water (20 mL) and potassium hydroxide (KOH, 1 M, aqueous solution) to pH~12. The resulting mixture was extracted with methyl tert-butyl ether (MTBE, 3x20 mL). The aqueous layer was acidified with aqueous citric acid solution to pH~5, extracted with methylene chloride (CH2CI2, 3x20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl (E)-2-((2S,13bS,Z)-3-ethylidene-8-methoxy- 1 ,2,3,4,6,7,13,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)-3- hydroxyacrylate (28).1H NMR (400 MHz, DMSO-d6) δ = 10.52 (s, 1 H), 8.14 (s, 1 H), 7.80 (s, 1 H), 6.48 (s, 1 H), 5.86 (d, J = 1.8 Hz, 2H), 5.06 - 4.94 (m, 1 H), 3.96 - 3.93 (m, 3H), 3.91 - 3.84 (m, 1 H), 3.57 (s, 3H), 3.18 - 3.09 (m, 2H), 2.91 (br d, J = 12.3 Hz, 2H), 2.86 - 2.76 (m, 2H), 2.55 (s, 1 H), 2.16 - 2.11 (m, 1 H), 1.58 (br d, J = 6.6 Hz, 3H), 1.11 (s, 3H).LCMS (ESI): m / z 427.2 [M+H]+, tR= 2.11 min.Synthesis of intermediate compound methyl (S)-2-((2R,13bS,Z)-3-ethylidene-8- methoxy-1 ,2,3,4,6,7,13,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2- yl)-3,3-dimethoxypropanoate (29).

[0210] To a solution of methyl (E)-2-((2S,13bS,Z)-3-ethylidene-8-methoxy- 1 ,2,3,4,6,7,13,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)-3- hydroxyacrylate (28; 80 mg, 187.59 μmol, 1 eq) in methanol (MeOH, 10 mL) was added p-toluenesulfonic acid (TSOH.H2O, 160.00 mg, 841.15 μmol, 4.48 eq) and trimethoxymethane (HC(OMe)3, 19.91 mg, 187.59 μmol, 1 eq). The mixture was stirred at 65 °C for 19 h. The mixture was concentrated under reduced pressure; diluted with water (20 mL), adjusted to pH~8 with aqueous sodium bicarbonate solution, and extracted with methylene chloride (CH2CI2, 3x20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (3x20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl (S)-2-((2R, 13bS,Z)-3-ethylidene-8-methoxy- 1 ,2, 3, 4, 6, 7, 13,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)-3,3-dimethoxypropanoate (29).1H NMR (400 MHz, CDCI3) δ = 7.47 (br s, 1 H), 6.50 (s, 1 H), 5.86 (s, 2H), 5.51 (br d, J = 6.9 Hz, 1 H), 4.35 (d, J = 6.4 Hz, 1 H), 4.02 (s, 3H), 3.80 (s, 3H), 3.70 - 3.65 (m, 1 H),3.65 - 3.58 (m, 1 H), 3.41 (s, 3H), 3.32 (s, 3H), 3.25 (dd, J = 6.3, 10.8 Hz, 1 H), 3.17 - 3.05 (m, 2H), 2.98 - 2.86 (m, 3H), 2.68 (br d, J = 5.1 Hz, 1 H), 1.83 (br d, J = 3.9 Hz, 2H), 1.72 (d, J = 6.8 Hz, 3H). LCMS (ESI): m / z 473.2 [M+H]+, tR= 2.617 min.Synthesis of intermediate compound methyl (E)-2-((2S,13bS,Z)-3-ethylidene-8- methoxy-1 ,2,3,4,6,7,13,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2- yl)-3-methoxyacrylate (30).

[0211] To a solution of methyl (S)-2-((2R,13bS,Z)-3-ethylidene-8-methoxy- 1 ,2,3,4,6,7,13,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)-3,3- dimethoxypropanoate (29; 90 mg, 190.46 μmol, 1 eq) in dimethylformamide (DMF, 9 mL) was added potassium tert-butoxide (t-BuOK, 64.12 mg, 571.39 μmol, 3 eq) in glovebox. The mixture was stirred at 20 °C for 1 h. The mixture was adjusted to pH~5 with aqueous citric acid solution, extracted with methylene chloride (CH2CI2, 3x20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by prep-HPLC (NH3H2O) gave methyl (E)-2-((2S, 13bS,Z)-3-ethylidene-8-methoxy- 1 ,2, 3, 4, 6, 7, 13,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate (30).1H NMR (400 MHz, CDCI3) δ = 7.49 (s, 2H), 6.48 (s, 1 H), 5.86 (s, 2H), 5.27 - 5.09 (m, 1 H), 4.03 (s, 3H), 3.96 - 3.90 (m, 1 H), 3.79 (s, 3H), 3.70 (s, 3H), 3.63 - 3.55 (m, 2H), 3.15 (br d, J = 7.3 Hz, 2H), 3.03 - 2.84 (m, 2H), 2.74 - 2.59 (m, 1 H), 2.44 - 2.28 (m, 1 H), 2.08 - 1.94 (m, 1 H), 1.67 (br d, J = 6.5 Hz, 3H). LCMS (ESI): m / z 441.2 [M+H]+, tR= 2.751 min.Synthesis of intermediate compound methyl (E)-2-((2S,3S,13bS)-3-ethyl-8-methoxy- 1 ,2,3,4,6,7,13,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)-3- methoxyacrylate (31).

[0212] To a solution of methyl (E)-2-((2S,13bS,Z)-3-ethylidene-8-methoxy- 1 ,2,3,4,6,7,13,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)-3- methoxyacrylate (30; 10 mg, 22.70 μmol, 1 eq) in trifluoroethanol (TFE, 3 mL) were added sodium bicarbonate (NaHCO3, 15.07 mg, 179.35 μmol, 7.9 eq) and platinum dioxide (PtO3, 5.16 mg, 22.70 μmol, 1 eq) under anhydrous conditions. The mixture was stirred under hydrogen atmosphere (15 psi) at 20 °C for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by prep- HPLC (NH3H2O) gave methyl (E)-2-((2S,3S,13bS)-3-ethyl-8-methoxy-1 ,2, 3, 4, 6, 7, 13, 13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)-3- methoxyacrylate (31).1H NMR (400 MHz, CDCI3) 0 = 7.55 - 7.47 (m, 1 H), 7.44 (br s, 1 H), 6.50 (br s, 1 H), 5.86 (s, 2H), 4.04 (s, 3H), 3.73 (br d, J = 9.7 Hz, 6H), 3.14 - 2.99 (m, 4H), 2.95 - 2.85 (m, 2H), 2.58 - 2.40 (m, 3H), 1.86 - 1.71 (m, 2H), 1.66 - 1.63 (m, 1 H), 1.21 (dt, J = 2.0, 5.1 Hz, 1 H), 0.88 (br d, J = 7.1 Hz, 3H). LCMS (ESI): m / z 443.2 [M+H]+, tR= 3.141 min.Synthesis of intermediate compound methyl (E)-2-((2S,3S,7aS,13bS)-7a-acetoxy-3- ethyl-8-methoxy-1 ,2,3,4,6,7,7a,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3- a]quinolizin-2-yl)-3-methoxyacrylate (32).

[0213] To a stirred solution of ethyl (E)-2-((2S,3S,13bS)-3-ethyl-8-methoxy- 1 ,2,3,4,6,7,13,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)-3- methoxyacrylate (31; 38 mg, 85.88 μmol, 1 eq) in methylene chloride (CH2CI2, 8 ml.) was added lead(IV) acetate (Pb(OAc)4, 85 mg, 184.04 μmol, 2.14 eq) at 0 °C under anhydrous conditions. The resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was transferred to iced water (15 mL), extracted with methylene chloride (CH2CI2, 3x20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by aluminum oxide chromatography gave methyl (E)- 2-((2S,3S,7aS,13bS)-7a-acetoxy-3-ethyl-8-methoxy-1,2,3,4,6,7,7a,13b-octahydro- [1,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate (32). LCMS (ESI): m / z 459.2 [M+H]+, tR= 4.975 min.Synthesis of methyl (E)-2-((2S,3S,7aS,13bS)-3-ethyl-7a-hydroxy-8-methoxy- 1 ,2,3,4,6,7,7a,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)-3- methoxyacrylate ((2S,3S,7aS,13bS)-la-3).

[0214] To a solution of methyl (E)-2-((2S,3S,7aS,13bS)-7a-acetoxy-3-ethyl-8- methoxy-1 ,2,3,4,6,7,7a, 13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)-3- methoxyacrylate (32; 25 mg, 49.95 μmol, 1 eq) in methanol (MeOH, 4 mL) was added sodium hydroxide (NaOH; 1 M aqueous solution, 4 mL, 400.03 μmol, 8.01 eq) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (10 mL), extracted with methylene chloride (CH2CI2, 3x20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by prep-HPLC gave methyl (E)-2-((2S,3S,7aS, 13bS)-3-ethyl-7a-hydroxy-8-methoxy-1 ,2,3,4,6,7,7a,13b-octahydro-[1 ,3]dioxolo[4',5':5,6]indolo[2,3-a]quinolizin-2-yl)-3- methoxyacrylate ((2S,3S,7aS,13bS)-la-3).1H NMR (400 MHz, CDCI3) δ = 7.44 (br s, 1 H), 6.81 (s, 1 H), 5.95 (s, 2H), 4.07 (s, 3H), 3.81 (br s, 3H), 3.70 (s, 3H), 3.12 - 2.95 (m, 3H), 2.75 (br t, J = 12.3 Hz, 2H), 2.68 - 2.54 (m, 2H), 2.51 - 2.41 (m, 1H), 2.17 (br s, 1 H), 1 .89 - 1 .81 (m, 1 H), 1 .74 - 1.69 (m, 1 H), 1 .28 - 1 .21 (m, 1 H), 0.89 (br s, 3H). LCMS (ESI): m / z 459.3 [M+H]+, tR= 3.776 min. HPLC: tR= 3.763 min. Chiral SFC: tR= 1.054 min.Synthesis of Exemplary Compounds (1S,6S,7S)-lb-2 and (1S,6R,7S)-lb-2 3,4,5-tetrahydropyridin-4-yl)acetate (35)

[0215] To a solution of methyl (Z,3R)-4-(chloromethyl)-3-(2-oxoethyl)hex-4- enoate (34; 370 mg, 1.69 mmol, 1 eq) in anhydrous methylene chloride (CH2CI2, 40 ml.) was added calcium chloride (CaCI2, 1.50 g, 13.54 mmol, 8 eq) ) and anhydrous potassium carbonate (K2CO3, 1.87 g, 13.54 mmol, 8 eq) and stirred at 15- 20 °C for 3.5 h under NH3(gas, 15 psi). The reaction mixture was filtered and the filtrate was purged with nitrogen for 40 minutes to remove excess ammonia, during which additional methylene chloride was added to prevent complete solvent evaporation,affording methyl (R,Z)-2-(3-ethylidene-2,3,4,5-tetrahydropyridin-4-yl)acetate (35), which was used in next step without further purification.Synthesis of intermediate compound methyl 2-((1S,7R,Z)-6-ethylidene-7'-oxo- 2,3,5',6,7,7',8,8a-octahydro-5H-spiro[indolizine-1 ,6'-[1 ,3]dioxolo[4,5-f]indol]-7- y I) acetate (37)

[0216] To a methylene chloride solution of methyl 2-[(3Z,4R)-3-ethylidene-4,5- dihydro-2H-pyridin-4-yl]acetate (35; 50 mL, 4.31 mmol, 2.5 eq) was added a solution of spiro[cyclopropane-1 ,6'-[1 ,3]dioxolo[4,5-f]indol]-7'(5'H)-one (34; 350 mg, 1.72 mmol, 1 eq) in tetrahydrofuran (THF, 25 mL). Magnesium iodide (Mgl2, 526.95 mg, 1.89 mmol, 118.95 μL, 1.1 eq) was added and the reaction mixture was stirred at 20 °C for 16 h. The mixture was quenched with saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was extracted with methylene chloride (CH2CI2, 30 mLx2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography afforded 2- ((1 S,7R,Z)-6-ethylidene-7'-oxo-2,3,5',6,7,7',8,8a-octahydro-5H-spiro[indolizine-1 ,6'- [1 ,3]dioxolo[4,5-f]indol]-7-yl)acetate (37)1H NMR (400 MHz, CHLOROFORM-d) δ = 6.91 - 6.88 (m, 1 H), 6.31 - 6.27 (m, 1 H), 5.99 - 5.95 (m, 2H), 5.59 - 5.51 (m, 0.4H), 5.41 - 5.32 (m, 0.6H), 4.25 - 4.17 (m, 0.5H), 4.04 - 3.91 (m, 0.4H), 3.76 - 3.68 (m, 0.5H), 3.65 - 3.59 (m, 3H), 3.56 - 3.47 (m, 0.5H), 2.95 - 2.82 (m, 1 H), 2.74 - 2.54 (m, 3H), 2.53 - 2.44 (m, 1.6H), 2.41 - 2.21 (m, 1.4H), 2.19 - 2.08 (m, 1 H), 1.94 - 1.86 (m, 0.6H), 1.77 - 1.65 (m, 3H), 1.55 (br d, J = 12.6 Hz, 1 H), 1.45 - 1.32 (m, 1 H).Synthesis of intermediate compound methyl (E)-2-((1S,7S,Z)-6-ethylidene-7'-oxo- 2,3,5',6,7,7',8,8a-octahydro-5H-spiro[indolizine-1 ,6'-[1 ,3]dioxolo[4,5-f]indol]-7-yl)-3- hydroxyacrylate (38)

[0217] To a solution of 2-((1S,7R,Z)-6-ethylidene-7'-oxo-2,3,5',6,7,7',8,8a- octahydro-5H-spiro[indolizine-1 ,6'-[1 ,3]dioxolo[4,5-f]indol]-7-yl)acetate (37; 700 mg, 1.82 mmol, 1 eq) in tetrahydrofuran (THF, 8 mL) was added lithium bis(trimethylsilyl)amide (LiHMDS, 1 M THF solution, 10.93 mL, 10.93 mmol, 6 eq) dropwise, maintaining the internal temperature below -30 °C and stirred at -40 °C for 1 h. Methyl formate (HCO2Me, 1.09 g, 18.21 mmol, 1.10 mL, 10 eq) was added dropwise maintaining the temperature below -30 °C. The reaction mixture was stirred at -40 °C for 1.5 h, quenched with methanol (MeOH, 5 mL), warmed to 25 °C with awater bath, and stirred for 15 min. Water (40 mL) and methyl tert-butyl ether (MTBE, 120 mL) were added. The aqueous layer was separated, quenched with saturated aqueous sodium bicarbonate solution (40 mL) and extracted with methylene chloride (CH2CI2, 3x50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl (E)-2- ((1 S,7S,Z)-6-ethylidene-7'-oxo-2,3,5',6,7,7',8,8a-octahydro-5H-spiro[indolizine-1 ,6'-[1 .3]dioxolo[4,5-f]indol]-7-yl)-3-hydroxyacrylate (38). LCMS: m / z 413.1 [M+H]+, tR= 1.066 min.Synthesis of intermediate compound methyl (E)-2-((1S,7S,Z)-6-ethylidene-7'-oxo- 2,3,5',6,7,7',8,8a-octahydro-5H-spiro[indolizine-1 ,6'-[1 ,3]dioxolo[4,5-f]indol]-7-yl)-3- methoxyacrylate (39)

[0218] To a solution of methyl (E)-2-((1 S,7S,Z)-6-ethylidene-7'-oxo- 2,3,5',6,7,7',8,8a-octahydro-5H-spiro[indolizine-1 ,6'-[1 ,3]dioxolo[4,5-f]indol]-7-yl)-3- hydroxyacrylate (38; 450 mg, 1.09 mmol, 1 eq) in tetrahydrofuran (THF, 8 mL) was added methanol (MeOH, 69.92 mg, 2.18 mmol, 88.31 μL, 2 eq) and triphenylphosphine (PPh3, 429.26 mg, 1.64 mmol, 1.5 eq), cooled to 5 °C, and diisopropyl azodicarboxylate (DIAD, 330.94 mg, 1.64 mmol, 317.29 μL, 1 .5 eq) in tetrahydrofuran (THF, 2 mL) was added dropwise. The resulting mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure. Purification by silica gel chromatography gave methyl (E)-2-((1S,7S,Z)-6- ethylidene-7'-oxo-2,3,5',6,7,7',8,8a-octahydro-5H-spiro[indolizine-1 ,6'-[1 .3]dioxolo[4,5-f]indol]-7-yl)-3-methoxyacrylate (39).1H NMR (400 MHz, CD2CI2) δ = 7.36 (s, 1 H), 6.82 (s, 1 H), 6.30 (s, 1 H), 5.95 (d, J = 1.0 Hz, 2H), 5.40 (br s, 1 H), 5.06 - 4.99 (m, 1 H), 4.00 (d, J = 12.4 Hz, 1 H), 3.75 (s, 3H), 3.61 (s, 3H), 3.35 - 3.20 (m, 2H), 2.47 (br d, J = 12.3 Hz, 1 H), 2.44 - 2.36 (m, 2H), 2.36 - 2.27 (m, 1 H), 1.99 - 1.88 (m, 2H), 1.59 (br d, J = 6.3 Hz, 3H), 1.21 - 1.15 (m, 1 H). LCMS: m / z 427.3 [M+H]+, tR= 0.682 min.Synthesis of methyl (E)-2-((1S,6S,7S)-6-ethyl-7'-oxo-2,3,5',6,7,7',8,8a-octahydro-5H- spiro[i ndolizine- 1 ,6'-[1 ,3]dioxolo[4,5-f]indol]-7-yl)-3-methoxyacrylate ((1 S,6S,7S)-lb-2) and methyl (E)-2-((1 S,6R,7S)-6-ethyl-7'-oxo-2,3,5',6,7,7',8,8a-octahydro-5H- spiro[indolizine-1 ,6'-[1 ,3]dioxolo[4,5-f]indol]-7-yl)-3-methoxyacrylate ((1S,6R,7S)-lb-2)

[0219] To a solution of methyl methyl (E)-2-((1S,7S,Z)-6-ethylidene-7'-oxo- 2,3,5',6,7,7',8,8a-octahydro-5H-spiro[indolizine-1 ,6'-[1 ,3]dioxolo[4,5-f]indol]-7-yl)-3- methoxyacrylate (39; 90 mg, 211.04 μmol, 1 eq) in trifluoroethanol (TFE, 8 mL) was added platinum(IV) oxide (PtO2, 47.92 mg, 211.04 μmol, 1 eq) and sodium bicarbonate (NaHCO3,141.83 mg, 1.69 mmol, 65.69 μL, 8 eq) at 20 °C under anhydrous conditions and stirred under hydrogen atmosphere (15 psi) at 20 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. Purification by prep-HPLC (NH4HCO3) and chiral SFC separation afforded methyl (E)- 2-((1S,6S,7S)-6-ethyl-7'-oxo-2,3,5',6,7,7',8,8a-octahydro-5H-spiro[indolizine-1 ,6'- [1 ,3]dioxolo[4,5-f]indol]-7-yl)-3-methoxyacrylate ((1S,6S,7S)-lb-2) and methyl (E)-2- ((1 S,6R,7S)-6-ethyl-7'-oxo-2,3,5',6,7,7',8,8a-octahydro-5H-spiro[indolizine-1 ,6'- [1 ,3]dioxolo[4,5-f]indol]-7-yl)-3-methoxyacrylate ((1S,6R,7S)-lb-2).

[0220] (1S,6S,7S)-lb-2):1H NMR (400 MHz, (400 MHz, CD2CI2) δ = 7.30 (s,1 H), 6.84 (s, 1 H), 6.36 (s, 1 H), 5.96 (s, 2H), 5.06 (s, 1 H), 3.67 (s, 3H), 3.59 (s, 3H), 3.18 - 3.06 (m, 2H), 2.76 (td, J = 3.5, 12.7 Hz, 1 H), 2.35 - 2.18 (m, 3H), 2.17 - 2.06 (m, 2H), 1.96 - 1.81 (m, 1 H), 1.72 - 1.59 (m, 1 H), 1.53 - 1.43 (m, 1 H), 1.26 - 1.14 (m, 1 H), 1.02 (br d, J = 12.6 Hz, 1 H), 0.84 (t, J = 7.4 Hz, 3H). LCMS: m / z 429.3 [M+H]+, tR= 4.061 min. HPLC: tR= 4.031 min. Chiral SFC: tR= 2.882 min.

[0221] (1S,6R,7S)-lb-2:1H NMR (400 MHz, CD2CI2) δ = 7.25 (s, 1 H), 6.82 (s,1 H), 6.32 (s, 1 H), 5.95 (d, J = 2.4 Hz, 2H), 5.13 - 5.10 (m, 1 H), 5.20 - 5.06 (m, 1 H), 3.73 (br s, 3H), 3.60 (s, 3H), 3.29 - 3.11 (m, 2H), 2.42 - 2.23 (m, 3H), 2.18 (br d, J = 9.4 Hz, 1 H), 2.07 - 1.95 (m, 1 H), 1.95 - 1.86 (m, 1H), 1.84 - 1.67 (m, 2H), 1.42 - 1.28 (m, 1 H), 1 .11 - 0.90 (m, 2H), 0.84 - 0.76 (m, 3H). LCMS: m / z 429.3 [M+H]+, tR= 3.943 min. HPLC: tR= 3.971 min. Chiral SFC: tR= 2.186 min.Synthesis of Exemplary Compoundsmethoxy-7'-oxo-2,3,5',6,7,7',8,8a-octahydro-5H-spiro[indolizine-1 ,6'-[1 ,3]dioxolo[4,5- f]indol]-7-yl)acetate (43).

[0222] To a solution of methyl 2-[(3Z,4R)-3-ethylidene-4,5-dihydro-2H-pyridin- 4-yl]acetate (35; 401.25 mg, 2.21 mmol, 3.44 eq) in methylene chloride (CH2CI2, 25 ml.) was added a solution of 8-methoxyspiro[5H-[1 ,3]dioxolo[4,5-f]indole-6,1'- cyclopropane]-7-one (42; 150 mg, 643.17 μmol, 1 eq) in tetrahydrofuran (THF, 10 mL). Magnesium iodide (Mgl2178.87 mg, 643.17 μmol, 1 eq) was then introduced under anhydrous conditions and stirred at 20 °C for 12 h, quenched by adding saturated aqueous sodium bicarbonate solution (10 mL). The aqueous layer was extracted with methylene chloride (CH2CI2, 3x20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography gave methyl 2-[(1S,6Z,7R,8aS)-6-ethylidene-8'-methoxy-7'-oxo- spiro[2,3,5,7,8,8a-hexahydroindolizine-1 ,6'-5H-[1 ,3]dioxolo[4,5-f]indole]-7-yl]acetate (43). LCMS (ESI): m / z 415.2 [M+H]+, tR= 3.347 min.Synthesis of intermediate compound methyl (E)-2-((1S,7S,8aS,Z)-6-ethylidene-8'- methoxy-7'-oxo-2,3,5',6,7,7',8,8a-octahydro-5H-spiro[indolizine-1 ,6'-[1 ,3]dioxolo[4,5- f]indol]-7-yl)-3-hydroxyacrylate (44).

[0223] To a solution of methyl 2-[(1S,6Z,7R,8aS)-6-ethylidene-8'-methoxy-7'- oxo-spiro[2,3,5,7,8,8a-hexahydroindolizine-1 ,6'-5H-[1 ,3]dioxolo[4,5-f]indole]-7-yl]acetate (43; 290 mg, 699.72 μmol, 1 eq) in tetra hydrofuran (THF, 5 mL) was added lithium bis(trimethylsilyl)amide (LiHMDS, 1 M in THF, 4.2 mL, 4.20 mmol, 6 eq), maintaining the internal temperature below -30 °C and stirred at -40 °C for 1 h. Methyl formate (HCO2Me, 420.20 mg, 7.00 mmol, 10 eq) was introduced dropwise, maintaining the internal temperature below -30 °C, stirred at -40 °C for additional 1.5 h. The reaction mixture was quenched with methanol (MeOH, 4 mL), and warmed up to 25 °C with a water bath and stirred at this temperature for 15 min. Water (10 mL) and methyl tert-butyl ether (MTBE, 30 mL) were added. The aqueous phase was diluted with saturated aqueous sodium bicarbonate solution (40 mL) and extracted with methylene chloride (CH2CI2, 3x20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl (E)-2-[(1S,6Z,7S,8aS)-6-ethylidene-8'-methoxy-7'-oxo-spiro[2,3,5,7,8,8a- hexahydroindolizine-1 ,6'-5H-[1 ,3]dioxolo[4,5-f]indole]-7-yl]-3-hydroxy-prop-2-enoate (44). LCMS (ESI): m / z 443.1 [M+H]+, tR= 1.09 min.Synthesis of intermediate compound methyl (E)-2-((1S,7S,8aS,Z)-6-ethylidene-8'- methoxy-7'-oxo-2,3,5',6,7,7',8,8a-octahydro-5H-spiro[indolizine-1 ,6'-[1 ,3]dioxolo[4,5- f]indol]-7-yl)-3-methoxyacrylate (45).

[0224] To a solution of methyl (E)-2-[(1S,6Z,7S,8aS)-6-ethylidene-8'-methoxy- 7'-oxo-spiro[2,3,5,7,8,8a-hexahydroindolizine-1 ,6'-5H-[1 ,3]dioxolo[4,5-f]indole]-7-yl]- 3- hydroxy- pro p-2- enoate (44; 70 mg, 158.21 μmol, 1 eq), methanol (MeOH, 50.69 mg, 1.58 mmol, 64.02 μL, 10 eq) and triphenylphosphine (PPh2; 82.99 mg, 316.41 μmol, 2 eq) in tetrahydrofuran (THF, 1 mL) was added a solution of diisopropyl azodicarboxylate (DIAD; 57.58 mg, 284.77 μmol, 1.8 eq) in tetrahydrofuran (THF, 1 mL) dropwise at 15 °C. The resulting mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure. Purification by silica gel chromatography gave methyl (E)-2-[(1S,6Z,7S,8aS)-6-ethylidene-8'-methoxy-7'-oxo- spiro[2,3,5,7,8,8a-hexahydroindolizine-1 ,6'-5H-[1 ,3]dioxolo[4,5-f]indole]-7-yl]-3- methoxy-prop-2-enoate (45).1H NMR (400 MHz, CDCI3) δ = 7.37 (s, 1 H), 5.92 (s, 1 H), 5.87 (s, 2H), 5.14 - 5.04 (m, 1 H), 4.15 (s, 3H), 4.06 (br d, J = 12.2 Hz, 1 H), 3.77 (s, 3H), 3.66 (s, 3H), 3.34 (br t, J = 9.5 Hz, 2H), 2.59 - 2.48 (m, 2H), 2.46 - 2.36 (m, 1 H), 2.00 - 1.91 (m, 1 H), 1.64 (br d, J = 6.6 Hz, 3H), 1.34 (br d, J = 12.0 Hz, 1 H). LCMS (ESI): m / z 457.1 [M+H]+, tR= 0.649 min.Synthesis of methyl (E)-2-((1S,6S,7S,8aS)-6-ethyl-8'-methoxy-7'-oxo- 2,3,5',6,7,7',8,8a-octahydro-5H-spiro[indolizine-1 ,6'-[1 ,3]dioxolo[4,5-f]indol]-7-yl)-3- methoxyacrylate ((1S,6S,7S,8aS)-lb-1) and methyl (E)-2-((1S,6R,7S)-6-ethyl-8'- methoxy-7'-oxo-2,3,5',6,7,7',8,8a-octahydro-5H-spiro[indolizine-1 ,6'-[1,3]dioxolo[4,5- f]indol]-7-yl)-3-methoxyacrylate ((2S,3S,7aS,13bS)-lb-1).

[0225] To a solution of methyl (E)-2-[(1S,6Z,7S,8aS)-6-ethylidene-8'-methoxy- 7'-oxo-spiro[2,3,5,7,8,8a-hexahydroindolizine-1 ,6'-5H-[1 ,3]dioxolo[4,5-f]indole]-7-yl]- 3-methoxy-prop-2-enoate (45; 35 mg, 76.67 μmol, 1 eq) in trifluoroethanol (TFE, 20 ml.) was added platinum dioxide (PtO2; 34.82 mg, 153.34 μmol, 2 eq) and sodium bicarbonate (NaHCO3; 51.53 mg, 613.38 μmol, 8 eq). The mixture was stirred under hydrogen (15 psi) at 20 °C for 3h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by prep-HPLC (NH3H2O) and SFC gave methyl (E)-2-[(1 S,6S,7S)-6-ethyl-8'-methoxy-7'-oxo-spiro[3,5,6,7,8,8a- hexahydro-2H-indolizine-1 ,6'-5H-[1 ,3]dioxolo[4,5-f]indole]-7-yl]-3-methoxy-prop-2- enoate ((1S,6S,7S,8aS)-lb-1) andnd methyl (E)-2-((1S,6R,7S)-6-ethyl-8'-methoxy-7'- oxo-2,3,5',6,7,7',8,8a-octahydro-5H-spiro[indolizine-1 ,6'-[1 ,3]dioxolo[4,5-f]indol]-7-yl)- 3-methoxyacrylate ((2S,3S,7aS,13bS)-lb-1).

[0226] (1S,6S,7S,8aS)-lb-1 :1H NMR (400 MHz, CD2CI2) δ = 7.31 (s, 1 H), 6.03(s, 1 H), 5.90 - 5.86 (m, 2H), 5.18 - 5.01 (m, 1 H), 4.08 (s, 3H), 3.68 (s, 3H), 3.60 (s, 3H), 3.17 - 3.07 (m, 2H), 2.81 - 2.72 (m, 1 H), 2.29 - 2.16 (m, 3H), 2.14 - 1.99 (m, 2H), 1.90 - 1.80 (m, 1 H), 1.68 - 1.65 (m, 1 H), 1.50 (br d, J = 7.1 Hz, 1 H), 1.23 - 1.16 (m, 1 H), 1.08 (br d, J = 11.9 Hz, 1 H), 0.84 (t, J = 7.3 Hz, 3H). LCMS (ESI): m / z 459.3 [M+H]+, tR= 0.685 min. HPLC: tR= 4.041 min. Chiral SFC: tR= 3.068 min.

[0227] (2S,3S,7aS,13bS)-lb-1 :1H NMR (400 MHz, CD2CI2) δ = 7.26 (s, 1 H),5.98 (s, 1 H), 5.92 - 5.79 (m, 2H), 5.25 - 5.12 (m, 1 H), 4.08 (s, 3H), 3.74 (br s, 3H), 3.60 (s, 3H), 3.24 - 3.15 (m, 2H), 2.41 - 2.22 (m, 3H), 2.20 - 2.12 (m, 1 H), 2.07 - 1.95 (m, 1 H), 1.91 - 1.82 (m, 1 H), 1.72 (br t, J = 10.9 Hz, 2H), 1.31 (br s, 1 H), 1.16 - 1.08 (m, 1 H), 1.00 - 0.91 (m, 1 H), 0.83 - 0.76 (m, 3H). LCMS (ESI): m / z 459.1 [M+H]+, tR= 0.444 min. HPLC: tR= 3.929 min. Chiral SFC: tR= 1 .106 min.Example 2: Receptor Binding AssayGeneral Protocol

[0228] 1) Prepare the test or reference compounds on the dilution source plate starting at 0.2mM or 2mM, using 4-fold serial dilution, for a total of 8 doses.2) Transfer 1 ul of test compounds or controls from the source plate to the assay plate according to the plate map.3) Following the plate map, dispense 100pl of diluted membrane stocks into the plate.4) Add 10OpI of the appropriate diluted radio ligand to the plate.5) Seal the plate and then shake at 300 rpm at room temperature for 1 hour.6) Soak the Unifilter-96 GF / C filter plates with 50 pl of 0.3% PEI (polyethylenimine) per well for at least 0.5 hour at room temperature.7) When the incubation is finished, filter the reaction mixture through GF / C plates using Perkin Elmer Filtermate Harvester, and then wash each plate 4 times with cold wash buffer.8) Dry the filter plates for 1 hour at 50 degrees Celsius.9) After drying, seal the bottom of the filter plate wells using Perkin Elmer Unifilter-96 backing seal tape.10) Add 50 pl of PerkinElmer Microscint 20 cocktail and seal top of filter plates with Perkin Elmer TopSeal-A sealing film.11) Count3H trapped on filter using Perkin Elmer MicroBeta2 Reader.12) Analyze the data with GraphPad Prism 5 to calculate the "Inhibition [% Control]" using the equation: %lnh = (1 -Background subtracted Assay value / Background subtracted HC value)*100.Example 3: GPCR Receptor cAMP AssayGeneral Protocol

[0229] 1) Recover the cells using HBSS (hank's balanced salt solution) to resuspend the cells respectively and count cell number by Cell Counter.2) Dilute the cells with assay buffer at appropriate cell density.3) Dilute testing sample or reference and transfer 100 nL WOxserial diluted solutions of each sample to the assay plate by ECHO The testing sample and referencesare 4-fold serial dilutions, 10 concentrations in total. The high control is 100 nl of 100X top concentration of reference and low control is equal volume of DMSO.4) Add 10 μL of cell suspension to the assay plate, incubate at room temperature.5) cAMP standard curve preparation: prepare the cAMP standard curve starting from 800 nM, following 4-fold serial dilution, 10 concentrations in total. Add the serial diluted cAMP standard solution to the assay plate, 10 μL / well.6) Add 10 μL of cAMP detection solution to the assay plate, incubate at room temperature for 1 h, avoiding direct light.7) Read the assay plate using Envision.Example 4: Mouse PK ExperimentMethods

[0230] The pharmacokinetic properties of the test compounds are evaluated in male C57BL / j6 mice. A single dose is administered PO or IV as per Table 3 below. Blood samples are collected at 8 time-points from N=3 mice per time-point and are snap frozen prior to analysis. The concentration of the test articles in plasma are evaluated using an LC-MS / MS (liquid chromatography with tandem mass spectrometry) method and the pharmacokinetics properties are calculated using a noncompartmental analysis.Example 5: Mouse hot plate experimentsMethodsThermal assessment is conducted using the hot plate method. Briefly, a heat conductive surface is heated to 52°C. The animal is then placed onto the surface and prevented from leaving the platform by blockades. The latency to response is measured by recording first sign of lifting or licking the hind paws. Post-dose hot plate assessments in the treatment groups occurs at the following post-dose time-points: 30 min, 1 h and 2 h. 10 Male C57BL6J mice are used per treatment group.Example 6: DOR Fluorescence Imaging Plate Reader (FLIPR) Assay Protocol Materials

[0231] Cell line information:

[0234] EquipmentList of equipmentCell preparation1) 1 vial of DOR cell was thawed rapidly in 37 °C water bath. The suspension was watched and the tube was removed from water bath just before the last bit of ice melted.2) Cell suspension was transferred into 15mL centrifuge tube with 10mL medium.3) The cells were centrifuged at 1000 rpm for 5 min.4) The supernatant was removed and the cells re-suspended with medium.5) Cell viability and cell density was determined with cell counter.6) Cell density was adjusted to 1.0 x 106cells / mL with medium, and 20 μL / well cell suspensions were added into 384-well plate (20,000 cells per well).7) Cells were incubated in CO2incubator (37°C with 5% CO2) for20-22 hours.

[0236] Compounds and reagent preparation1) Assay buffer: HBSS with 20 mM HEPES.2) Fluo-4 DirectTM Loading Buffer: one vial of thawed Fluo-4 Direct™ solutions (10 ml / vial) with additional 10 ml Assay Buffer (freshly prepared).

[0237] EC80 testing1) The agonist reference compound was serially diluted by Echo to 5* test concentration in the test plate.2) The medium was gently removed, and 20 μL of assay buffer and 20 μL Fluo-4DirectTM Loading Buffer were added into each well of the 384-well -plate.3) The cell-plate was incubated for 50 min in a CO2incubator (37°C with 5% CO2), followed with 10 min cooling at room temperature.4) The cell plate and compound plate were placed into FLIPR.5) The FLIPR program to transfer 10 μL / well compound solutions into the cell plate with the fluorescence signal acquired in real-time was executed (interval = 1 sec). Data were exported by the method of “Max-Min”, “Read 1 to Maximum allowed” in FLPR software, and EC80 was calculated.

[0238] Sample testing with FLIPR assay1) Compounds were serially diluted by Echo.2) The medium was gently removed, and the cells were washed once with the assay buffer. 20 μL assay buffer and 20 μL Fluo-4 DirectTM Loading Buffer were added into each well of the 384-well cell plate by pipetting.3) The cell-plate was incubated for 50 min in a CO2incubator (37°C with 5% CO2), followed with 10 min cooling at room temperature.4) For the agonist assay, the cell-plate was placed into FLIPR and the FLIPR program to transfer 10 μL / well compound solutions into the cell-plate with the fluorescence signal acquired in real-time was executed (interval = 1 sec).5) For the antagonist assay, the FLIPR program to transfer 10 μL / well agonist compound at 6* EC80 concentration into the cell-plate with the fluorescence signalacquired in real-time was executed (interval = 1 sec). Data were exported by the method of “Max-Min”, “Read 1 to Maximum allowed” in FLPR software.Example 7: Protocol of op-Kappa and Op-Mu cAMP AssayMaterials

[0239] Reagents cAMP HiRange Detection Kit, VKEY-Bio1X HBSS (Hanks' Balanced Salt Solution), Invitrogen3-lsobutyl-1 -methylxanthine (IBMX), SigmaU69593 ((+)-(5α,7α,8β)-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]- benzeneacetamide), Sigma nor-BIND (Norbinaltorphimine dihydrochloride / nor-Binaltorphimine), AbeamDAMGO (D-Ala2, N-MePhe4, Gly-ol]-enkephalin), AbeamCTOP ({D-Phe}-CY-{D-Trp}-{Orn}T{Pen}T-NH2), MCE

[0240] Culture MediumThe following cell lines were used:• op-kappa HEK293• op-mu HEK293

[0241] ApparatusOptiPlate-384, White, PerkinElmer384 well plate for Echo, Labcyte

[0242] EquipmentEnVision (PerkinElmer);Vi-cell counter, Beckman (Cat# Vi-CELLTM XR Cell Viability Analyzer)

[0243] Methods1) Assay buffer preparation: 5x stimulation buffer was diluted by ddH2O.2) Compounds dilution:For agonist testing: Compounds were diluted by Echo following plate maps and 50nL compounds along with 25nL forskolin were transferred to opti-plate. The final concentration of forskolin was 3μM. For antagonist testing: Compounds were diluted by Echo following plate maps and 50nL compounds along with 25nL forskolin and 25nL reference agoinst were transferred to opti-plate. The final concentration of forskolin was 3μM for Op-Kappa target and 1μM for Op-Mu. The final concentration of U69593 (op-Kappa) and DAMGO (Op-Mu) was 20nM and 10nM respectively.3) The cells were thawed and then washed twice with HBSS buffer. The cells were resuspended with 1X stimulate buffer.4) 10 uL / well (3000 cells per well for op-Kappa and 5000 cells per well for op-Mu) of cell suspension were added to opti-plate, centrifuged at 1000 rpm for 10sand incubated at 23 °C for 1 h.5) 10 uL of Eu labeled antibody+cAMP tracer Solution (500 uL Eu2 labeled + 500 uL cAMP tracer in 20 mL Detection buffer) was added to each well of assay plate, centrifuged at 1000 rpm for 10 s and incubated at 23 °C for 1 h.6) HTRF signal was acquired by Envision.Results:- 81 -9178482

[0244] The results demonstrate affinity and indications of agonist and antagonist activity for the opioid receptors.Hot plate test

[0245] In the hot plate test, oral administration of (2S,3S,7aS,13bS)-la-3, (1S,6S,7S)-lb-2 , (1S,6S,7S,8aS)-lb-1 (10, 20 or 40 mg / kg) or (2S,3S,7aS,13bS)-la-4 (40 mg / kg) did not result in a significant increase in response times when compared to vehicle treated animals. By contrast, significant increases in response latency relative to negative controls were seen for (2S,3S,7aS,13bS)-la-4 at 10 and 20 mg / kg at 30 and 60 min following administration and at 120 min following administration of 20 mg / kg of 18.Pharmacokinetics

[0246] Plasma samples of Male C57BL / 6J Mouse, Fasted were analyzed following intravenous (IV, 1 mg / kg) and oral (PO, 10 mg / kg) administrations of exemplary compound (2S,3S,7aS,13bS)-la-4. The concentration of test compound in plasma was determined by LC-MS / MS. Pharmacokinetic parameters were monitored for 4 hours for IV and for 24 hours for PO administrations and were calculated using Phoenix WinNonlin version 8.3.5 software. Results are shown in the two tables below.Pharmacokinetic Profile in Intravenous Administration- 82 -9178482Pharmacokinetic Profile in Oral Administration- 83 -9178482

Claims

CLAIMS:

1. A compound of Formula la or lb, or a pharmaceutically acceptable salt and / or solvate thereof:whereinX1is N, NR14, O or S;X2is NR15, O, S, S(O) or SO2;R1, R2, R8and R9are independently selected from H, halo, ON, OH, SH, C1-6alkyl, C2-6alkenyl, OC1-6alkyl, OC2-6alkenyl, aryl, C5-10heteroaryl, C3-10cycloalkyl, C3-ioheterocycloalkyl, Oaryl, OC5-10heteroaryl, OC3-10cycloalkyl aanndd OC3-wheterocycloalkyl, the latter 12 groups being optionally substituted with one or more C1-6alkyl, OC1-6alkyl and ON;R3is absent or is selected from H, OH, halo, ON, OP(O)(ORa)2, OC1-30alkyl, OC(O)C1-30alkyl, OC2-30alkenyl, OC(O)C2-30alkenyl, OC3-10cycloalkyl, OC3-10heterocycloalkyl, OC3-10heteroaryl and Oaryl, the latter 8 groups being optionally substituted with one or more C1-6alkyl, OC1-6alkyl and ON;Rais selected from H and C1-6alkyl; each is a single or double bond, provided only one of is a double bond andwhen X1is NR14, O or S, thedjacent to X1is a single bond and when th adjacent to R3is a double bond, R3is absent;R4and R10are independently selected from H, C1-6alkyl and C2-6alkenyl;R5and R11are independently selected from OH, OC1-6alkyl and OC2-6alkenyl;R6and R12are independently selected from C(O)C1-6alkyl, C(O)OC1-6alkyl, C(O)NHC1-6alkyl, C(O)N(C1-6alkyl)(C1-6alkyl), C(O)C2-6alkenyl, C(O)OC2-6alkenyl, C(O)NHC2-6alkenyl and C(O)N(C2-6alkenyl)(C2-6alkenyl);R7and R13are independently selected from H and C1-4alkyl;R14and R15are independently selected from H and C1-6alkyl; n and p are independently 1 or 2; and wherein all available hydrogen atoms are optionally and independently replaced with a halogen atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

2. The compound of claim 1 , wherein the compound is of Formula la is adouble bond adjacent to X1, and X1is N:or a pharmaceutically acceptable salt and / or solvate thereof.

3. The compound of claim 3, having the following relative stereochemistry:

4. The compound of claim 1 , wherein the compound is of Formula la is adouble bond adjacent to R3, and R3is absent:or a pharmaceutically acceptable salt and / or solvate thereof.

5. The compound of claim 4, having the following relative stereochemistry:

6. The compound of any one of claims 1 and 4-5, wherein X1is NH, NC1-4alkyl, O or S, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

7. The compound of claim 6, wherein X1is NH.

8. The compound of any one of claims 1 to 7, wherein R1is selected from H, halo, aryl, OC1-4alkyl, OC2-4alkenyl, C5-8heteroaryl, C3-8cycloalkyl and C3-8heterocycloalkyl, the latter six groups being optionally substituted with one or more of C1-4alkyl, OC1-4alkyl and CN, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

9. The compound of claim 8, wherein R1is independently selected from H, Cl, Br, F, aryl, OCH3, OCF3, OCF2H, OCH2CH3, OCF2CF3, OCH2CF3, OCH2CH=CH2and furanyl, wherein all available hydrogen atoms are optionally and independently replaced deuterium.

10. The compound of claim 9, wherein R1is H.

11. The compound of any one of claims 1 to 10, wherein R2is selected from H, halo, ON, OH, SH, C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, aryl, C5-8heteroaryl, C3-8cycloalkyl, C3-8heterocycloalkyl, Oaryl, OC5-8heteroaryl, OC3-8cycloalkyl and OC3-8heterocycloalkyl, the latter 12 groups being optionally substituted with one or more of C1-4alkyl, OC1-4alkyl and ON, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

12. The compound of claim 11 , wherein R2is selected from H, Cl, Br, F, CN, OH, CH3, CF3, OCF3, OCH3, OCH2CH3, OCH2CH=CH2, OCF2H, OCF2CF3, OCH2CF3, aryl, Oaryl and furanyl, wherein all available hydrogen atoms are optionally and independently replaced with deuterium.

13. The compound of claim 12, wherein R2is OCH3.

14. The compound of any one of claims 1 to 7, wherein R1and R2are both H.

15. The compound of any one of claims 1 to 7, wherein R1is H and R2is OCH3.

16. The compound of any one of claims 1 to 3, wherein R3is absent.

17. The compound of any one of claims 1 to 3, wherein R3is present and is selected from OH, halo, ON, OP(O)(OH)2, OP(O)(OC1-4alkyl)2, OC1-30alkyl, OC(O)C1-30alkyl, OC2-30alkenyl, OC(O)C2-30alkenyl, OC3-8cycloalkyl, OC3-8heterocycloalkyl, OC3-8heteroaryl and Oaryl, the latter 8 groups being optionally substituted with one or more of C1-4alkyI, OC1-4alkyl and ON, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

18. The compound of claim 17, wherein R3is OH.

19. The compound of any one of claims 1 to 18, wherein R4is selected from H, C1-4alkyl and C2-4alkenyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

20. The compound of claim 19, wherein R4is CH2CH3.

21. The compound of any one of claims 1 to 20, wherein R5is selected from OH, OC1-4alkyl and OC2-4alkenyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

22. The compound of claim 21 , wherein R5is OCH3.

23. The compound of any one of claims 1 to 22, wherein R6is selected from C(O)C1-4alkyl, C(O)OC1-4alkyl, C(O)NHC1-4alkyl, C(O)N(C1-4alkyl)(C1-4alkyl), C(O)C2-4alkenyl, C(O)OC2-4alkenyl, C(O)NHC2-4alkenyl and C(O)N(C2-4alkenyl)(C2-4alkenyl), wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

24. The compound of claim 23, wherein R6is C(O)OCH3.

25. The compound of any one of claims 1 to 22, wherein R7is selected from H and C1-2alkyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

26. The compound of claim 25, wherein R7is H.

27. The compound of any one of claims 1 to 26, wherein n is 1 .

28. The compound of claim 1 , wherein the compound is of Formula lb:or a pharmaceutically acceptable salt and / or solvate thereof.

29. The compound of claim 28, having the following relative stereochemistry:

30. The compound of any one of claims 1 and 28-29, wherein X2is NH, NC1-4alkyl, O or S, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

31. The compound of claim 30, wherein X2is NH.

32. The compound of any one of claims 1 and 28-31, wherein R8is independently selected from H, halo, aryl, OC1-4alkyl, OC2-4alkenyl, C5-8heteroaryl, C3-8cycloalkyl and C3-8heterocycloalkyl, the latter six groups being optionally substituted with one or more of C1-4alkyl, OC1-4alkyl and CN, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

33. The compound of claim 32, wherein R8is independently selected from H, Cl, Br, F, aryl, OCH3, OCF3, OCF2H, OCH2CH3, OCF2CF3, OCH2CF3, OCH2CH=CH2and furanyl, wherein all available hydrogen atoms are optionally and independently replaced with deuterium.

34. The compound of claim 33, wherein R8is H.

35. The compound of any one of claims 1 and 28-34, wherein R9is selected from H, halo, CN, OH, SH, C1-4alkyl, C2-4alkenyl, OC1-4alkyl, OC2-4alkenyl, aryl, C5-8heteroaryl, C3-8cycloalkyl, C3-8heterocycloalkyl, Oaryl, OC5-8heteroaryl, OC3-8cycloalkyl and OC3-8heterocycloalkyl, the latter 12 groups being optionally substituted with one or more of C1-4alkyl, OC1-4alkyl and CN, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine or a bromine atom, a chlorine and all available atoms are optionally and independently replaced with an alternate isotope thereof.

36. The compound of claim 35, wherein R9is selected from H, Cl, Br, F, CN, OH, CH3, OCH3, CF3, OCF3, OCH3, OCH2CH3, OCH2CH=CH2, OCF2H, OCF2CF3, OCH2CF3aryl, Oaryl and furanyl, wherein all available hydrogen atoms are optionally and independently replaced with deuterium.

37. The compound of claim 36, wherein R9is OCH3.

38. The compound of any one of claims 1 and 28-31 , wherein R8and R9are bothH.

39. The compound of any one of claims 1 and 28-31 , wherein R8is H and R9isOCHs.

40. The compound of any one of claims 1 and 28-39, wherein R10is selected from H, C1-4alkyl and C2-4alkenyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

41. The compound of claim 40, wherein R10is CH2CH3.

42. The compound of any one of claims 1 and 28-41 , wherein R11is selected from OH, OC1-4alkyl and OC2-4alkenyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

43. The compound of claim 42, wherein R11is OCH3.

44. The compound of any one of claims 1 and 28-43, wherein R12is selected from C(O)C1-4alkyl, C(O)OC1-4alkyl, C(O)NHC1-4alkyl, C(O)N(C1-4alkyl)(C1-4alkyl), C(O)C2-4alkenyl, C(O)OC2-4alkenyl, C(O)NHC2-4alkenyl and C(O)N(C2-4alkenyl)(C2-4alkenyl), wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

45. The compound of claim 44, wherein R12is C(O)OCH3.

46. The compound of any one of claims 1 and 28-45, wherein R13is selected from H and C1-2alkyl, wherein all available hydrogen atoms are optionally and independently replaced with a fluorine, a chlorine or a bromine atom and all available atoms are optionally and independently replaced with an alternate isotope thereof.

47. The compound of claim 46, wherein R13is H.

48. The compound of any one of claims 1 and 28-47, wherein p is 1 .

49. The compound of claim 1 , wherein the compound of Formula la or lb is selected from the compounds listed in Table 1 , or a pharmaceutically acceptable salt and / or solvate thereof.

50. A pharmaceutical composition comprising one or more compounds of any one of claims 1 to 49 and a pharmaceutically acceptable carrier.

51. A method for treating pain comprising administering an effective amount of one or more compounds of any one of claims 1 to 49 to a subject in need thereof.

52. A method for managing pain comprising administering an effective amount of one or more compounds of any one of claims 1 to 49 to a subject in need thereof.

53. A method of treating peri-operative and postoperative pain in patients prone to opioid-induced respiratory depression comprising administering an effective amount of one or more compounds of any one of claims 1 to 49 to a subject in need thereof.

54. A method for inducing analgestic effect comprising administering an effective amount of one or more compounds of any one of claims 1 to 49 to a subject in need thereof.

55. A method of treating an inflammatory condition comprising administering an effective amount of one or more compounds of any one of claims 1 to 49 to a subject in need thereof.

56. A method for treating a neurological disease or psychiatric disorder comprising administering an effective amount of one or more compounds any one of claims 1 to 49 to a subject in need thereof.

57. The method of claim 56, wherein the neurological disease or psychiatric disorder is a mood disorder.

58. The method of claim 57, wherein the mood disorder is a depression.

59. A method for treating an opioid addiction or opioid withdrawal symptoms comprising administering an effective amount of one or more compounds of any one of claims 1 to 49 to a subject in need thereof.

60. A method for enhancing cognitive and / or behavioral function comprising administering an effective amount of one or more compounds of any one of claims 1 to 49 to a subject in need thereof.

61. The method of claim 60, wherein enhancing cognitive and / or behavioral function comprises enhancing one or more of memory, attention, language, work capacity, alertness, sociability, energy, motivation or mood.

62. The method of any one of claims 51 to 61 , wherein the subject is a human.

63. The method of any one of claims 51 to 61 , wherein the subject is a dog.

64. The method of any one of claims 51 to 61 , wherein the subject is a cat.

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