Ergoline derivatives and uses thereof

Abstract

Provided herein are compounds which are modulators of serotonin receptors and compositions thereof. Also provided herein are methods of modulating serotonin receptors and methods of treating diseases and disorders (e.g., pain) in a subject in need thereof.

Description

Attorney Docket No.: CYBP-003WO ERGOLINE DERIVATIVES AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 643,995, filed May 8, 2024, which is incorporated herein by reference in its entirety. 5 FIELD

[0002] The present disclosure relates to compounds, compositions, and methods useful for the treatment of diseases and disorders, including pain. Also provided are compounds, compositions, and methods useful for modulating serotonin receptors. BACKGROUND 10

[0003] Serotonin receptors, also known as 5-HT receptors or 5-hydroxytryptamine receptors, are classified into seven types: 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7. Serotonin receptors influence behavioral, neuronal, and physiological processes, and regulation of serotonin receptors are implicated in many diseases and disorders. A number of ergoline compounds are known to modulate serotonin receptors, e.g., function as agonists or antagonists 15 for neurotransmitters, such as dopamine, noradrenaline, and serotonin, at these receptors. Many ergoline compounds, including naturally occurring, synthetic, and semi-synthetic structures, bind nonspecifically to serotonin receptors. Additionally, ergoline compounds such as lysergic acid diethylamide (LSD) are known to have psychoactive effects (e.g., hallucinations), in addition to physiological effects. 20

[0004] Accordingly, there is a need for developing safe and effective ergoline compounds and / or ergoline derivatives that modulate serotonin receptors (e.g., selectively modulate serotonin receptors) for the treatment of diseases and disorders (e.g., pain), and that have minimal or no side effects (e.g., hallucinations). SUMMARY 25

[0005] Provided herein are compounds and pharmaceutically acceptable salts thereof (e.g., compounds of Formula A, Formula B, and Formula C, and subformulas thereof; compounds of Table 1, Table 2, and Table 3; and pharmaceutically acceptable salts thereof), compositions, and methods useful for treating diseases and disorders (e.g., pain).

[0006] Disclosed herein, in some embodiments, is a compound of Formula A: 1 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO or a pharmaceutically accepwherein 5 R1Ais H, C2-C6 alkenyl, C2-C6 alkynyl, –C(O)-R4A, or –O-R4A; R2Ais C2-C6 alkyl, 3-8 membered monocyclic carbocyclyl, phenyl, –C1-C6 alkyl-phenyl, or –O-C1-C6 alkyl-phenyl, ; kyl, 3-8 membered monocyclic carbocyclyl, or –C1-C6 alkyl-R7A;10 R5Ais H, C1-C6alkyl, C1-C6hydroxyalkyl, or C2-C6alkynyl; R6Ais H, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C2-C6 alkynyl; and R7Ais –C1-C6alkyl-O- C1-C6alkyl or 3-8 membered monocyclic carbocyclyl,

[0007] In some embodiments, when R3Ai , R5Ai6A 2As –Et, and R is –Et, then R is not . 15 [00ound of Formula B: or a pharmaceutically accep, wherein 20 R1Bis C2-C6 alkenyl, C2-C6 alkynyl, –C(O)-R4A, or –O-R4A; R2Bis –Me; 2 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO R3Bis ; R4Bis C1-C6 alkyl, 3-8 membered monocyclic carbocyclyl, or –C1-C6 alkyl-R7B; R5Bis H, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C2-C6 alkynyl; R6Bis H, C1-C6alkyl, C1-C6hydroxyalkyl, or C2-C6alkynyl; and 5 R7Bis –C1-C6 alkyl-O- C1-C6 alkyl or 3-8 membered monocyclic carbocyclyl.

[0009] Disclosed herein, in some embodiments, is a compound of Formula C:or a pharmaceutically acceptable salt thereof, 10 wherein R1Cis H; R2Cis –Me; ; 15droxyalkyl or C2-C6alkynyl

[0010] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] Disclosed herein, in some embodiments, is a process for providing a compound 20 disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0012] Disclosed herein, in some embodiments, is a method of treating a disease or disorder (e.g., a serotonin receptor-mediated disease or disorder) in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a 25 pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. 3 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO

[0013] Disclosed herein, in some embodiments, is a compound disclosed herein or a composition disclosed herein, in the manufacture of a medicament for the treatment of a disease or disorder (e.g., a serotonin receptor-mediated disease or disorder). DETAILED DESCRIPTION 5

[0014] As generally described herein, the present disclosure provides compounds (e.g., compounds of Formula A, Formula B, and Formula C, and subformulas thereof; compounds of Table 1, Table 2, and Table 3; and pharmaceutically acceptable salts thereof) and compositions designed, for example, to act as serotonin receptor modulators. The compounds and compositions disclosed herein are useful for treating a disease or disorder (e.g., pain). The 10 present disclosure also features methods for synthesizing compounds and compositions useful for treating a disease or disorder (e.g., pain). Definitions

[0015] As used herein, the following terms are generally intended to have the meanings as described below, unless expressly indicated otherwise or the context in which they are used 15 indicates otherwise. Unless defined otherwise, the terms used herein have meanings as commonly understood by one of ordinary skill in the areas related to the present disclosure.

[0016] As used herein, the terms “a,” “an,” and “the” refer to one or to more than one, unless context indicates otherwise. Similarly, the term “or” is intended to include “and”, unless context indicates otherwise. 20

[0017] As used herein, the term “about”, unless specifically mentioned otherwise, or unless a person skilled in the art would have understood otherwise, is considered to cover a range of ±10% of the listed value(s). It is further noted that any value provided may also be considered to cover a range of ±10% of that value, even without the use of the term “about”.

[0018] The terms “disease,” “disorder,” and “condition” are used interchangeably herein. 25

[0019] As used herein, the term “effective amount” refers to an amount sufficient to elicit the desired biological response, e.g., to treat a disease or disorder (e.g., a serotonin receptor- mediated disease or disorder). As will be appreciated by those of ordinary skill in this art, the effective amount of a compound disclosed herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, 30 the mode of administration, and the age, weight, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment. As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount 4 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or symptoms thereof or to delay or minimize one or more symptoms associated with the disease, disorder, or condition, or symptoms thereof. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which 5 provides a therapeutic benefit in the treatment of the disease, disorder, or condition, or symptoms thereof. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount 10 sufficient to prevent a disease, disorder, or condition, or symptoms thereof (e.g., one or more symptoms associated with the disease, disorder, or condition), or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition, or symptoms thereof. The term 15 “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0020] As used herein, the term “modulation” refers to the inhibition or potentiation of serotonin receptor function. A “modulator” (e.g., a modulator compound) may be, for example, an agonist, partial agonist, antagonist, or partial antagonist of the serotonin receptor. 20

[0021] As used herein, the term “pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans. The term “pharmaceutically acceptable salt” refers to a salt of a compound disclosed herein that is 25 pharmaceutically acceptable. In particular, such salts include salts of the compounds disclosed herein that are prepared with relatively nontoxic acids or bases (e.g., inorganic or organic acid addition salts and base addition salts). When compounds contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. 30 When compounds contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Some compounds contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Exemplary pharmaceutically acceptable salts are found, e.g., in Berge, et al. (J. Pharm. Sci. 5 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO 1977, 66(1), 1; and Gould, P.L., Int. J. Pharmaceutics 1986, 33, 201-217, each of which is hereby incorporated by reference in its entirety.

[0022] The term “modulating serotonin receptor”, as used herein, refers to the ability of a compound disclosed herein to alter the function of serotonin receptor(s). A serotonin receptor 5 modulator may activate the activity of a serotonin receptor, may activate or inhibit the activity of a serotonin receptor depending on the concentration of the compound exposed to the serotonin receptor, or may inhibit the activity of a serotonin receptor. Such activation or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway, and / or maybe manifest only in particular cell types. The term 10 “modulating serotonin receptor,” also refers to altering the function of a serotonin receptor by increasing or decreasing the probability that a complex forms between a serotonin receptor and a natural binding partner to form a multimer. A serotonin receptor modulator may increase the probability that such a complex forms between the serotonin receptor and the natural binding partner, may increase or decrease the probability that a complex forms between the serotonin 15 receptor and the natural binding partner depending on the concentration of the compound exposed to the serotonin receptor, and or may decrease the probability that a complex forms between the serotonin receptor and the natural binding partner.

[0023] As used herein, the term “serotonin receptor-mediated disease” or “serotonin receptor- mediated disorder” refers to a disease or disorder in which serotonin receptor(s) plays a role. 20 A serotonin receptor-mediated disease or disorder may be completely or partially mediated by modulating serotonin receptor(s). In particular, a serotonin receptor-mediated disease or disorder is one in which modulation of serotonin receptor(s) results in some effect on the underlying disease or disorder (e.g., administration of a serotonin receptor modulator results in improvement in the disease or disorder, or symptoms thereof). In some embodiments, a 25 serotonin receptor-mediated disease is characterized by abnormal serotonin receptor activity.

[0024] As used herein, the term “solvate” refers to forms of the compound that are associated with a solvent or water (also referred to as “hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid, and the like. The compounds disclosed herein may be prepared, e.g., in crystalline 30 form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non- stoichiometric solvates. In some embodiments, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the 6 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0025] As used herein, the term “subject”, to which administration is contemplated, includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject 5 (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein. 10

[0026] The terms “substantially pure” and “isolated”, as may be used interchangeably herein describe a compound, which has been separated from components that naturally accompany it. Typically, a compound is substantially pure when at least 60%, more preferably at least 75%, more preferably at least 90%, 95%, 96%, 97%, or 98%, and most preferably at least 99% of the total material (by volume, by wet or dry weight, or by mole percent or mole fraction) in a 15 sample is the compound of interest. Purity can be measured by any appropriate method, e.g., chromatography, gel electrophoresis or HPLC analysis. Selected Chemical Definitions

[0027] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according 20 to the standard rules of chemical valency known in the chemical arts.

[0028] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general 25 principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, 30 Cambridge University Press, Cambridge, 1987.

[0029] As used herein, the term “isomers” refers to compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed 7 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non–superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the 5 absolute configuration of its asymmetric center and is described by the R– and S–sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (–)–isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. Isomers, e.g., 10 stereoisomers, can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon 15 Compounds (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0030] As used herein, a pure enantiomeric compound is substantially free from other 20 enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, 25 more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In some embodiments, the weights 30 are based upon total weight of all enantiomers or stereoisomers of the compound.

[0031] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R–position / center / carbon compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R–compound. In some 8 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO embodiments, the enantiomerically pure R–compound in such compositions can, for example, comprise, at least about 95% by weight R–compound and at most about 5% by weight S– compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S–compound can comprise, for example, about 90% 5 excipient and about 10% enantiomerically pure S–compound. In some embodiments, the enantiomerically pure S–compound in such compositions can, for example, comprise, at least about 95% by weight S–compound and at most about 5% by weight R–compound, by total weight of the compound. In some embodiments, the active ingredient can be formulated with little or no excipient or carrier. 10

[0032] As used herein, the term “tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism 15 is the aci– and nitro– forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0033] When a range of values is listed, it is intended to encompass each value and sub–range within the range. For example “C1–C6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6,20 C1–C6, C1–C5, C1–C4, C1–C3, C1–C2, C2–C6, C2–C5, C2–C4, C2–C3, C3–C6, C3–C5, C3–C4, C4– C6, C4–C5, and C5–C6alkyl.

[0034] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present disclosure.

[0035] “Alkyl” refers to a radical of a straight–chain or branched saturated hydrocarbon group 25 having from 1 to 20 carbon atoms (“C1–C20alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1–C12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–C10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–C9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–C8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–C7 alkyl”). In some 30 embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–C6alkyl”, also referred to herein as “lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–C5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–C4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–C3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–C2alkyl”). In some embodiments, 9 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2–C6alkyl”). Examples of C1–C6alkyl groups include methyl (C1), ethyl (C2), n–propyl (C3), isopropyl (C3), n–butyl (C4), tert–butyl (C4), sec–butyl (C4), iso–butyl (C4), n–pentyl (C5), 3–pentanyl (C5), amyl (C5), neopentyl (C5), 3–methyl–2–butanyl (C5), tertiary 5 amyl (C5), and n–hexyl (C6). Additional examples of alkyl groups include n–heptyl (C7), n– octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkyl group is 10 unsubstituted C1–C10alkyl (e.g., –CH3). In some embodiments, the alkyl group is substituted C1–C10 alkyl. Common alkyl abbreviations include –Me (–CH3), –Et (–CH2CH3), –iPr (– CH(CH3)2), –nPr (–CH2CH2CH3), –nBu (–CH2CH2CH2CH3), –iBu (–CH2CH(CH3)2), –sBu (– CH(CH3)(CH2CH3)), and –tBu (–C(CH3)3).

[0036] “Hydroxyalkyl” refers to an alkyl group, as defined above, wherein one or more (e.g., 15 one, two, three, four, or five) of the hydrogen atoms are independently replaced with a hydroxyl group (–OH). Exemplary hydroxyalkyl groups include –CH2OH, –CH2CH2OH, –C(CH3)2OH and the like.

[0037] “Heterocyclyl” refers to a radical of a non–aromatic ring system having ring carbon atoms and one or more (e.g., 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) ring heteroatoms, wherein 20 each heteroatom is independently selected from nitrogen (N), oxygen (O), and sulfur (S). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a bicyclic system (“bicyclic heterocyclyl”), e.g., a fused, bridged, or spiro ring system, and can be saturated or can be partially unsaturated. Heterocyclyl 25 bicyclic ring systems can include one or more heteroatoms in one or both rings. A heterocyclyl group may be described as, e.g., a 3-10 membered heterocyclyl, wherein the term “membered” refers to the non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, and sulfur, within the moiety. Compounds 30

[0038] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. 10 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO Formula A

[0039] Disclosed herein, in some embodiments, is a compound of Formula A: 5 or a pharmaceutically accepwherein R1Ais H, C2-C6 alkenyl, C2-C6 alkynyl, –C(O)-R4A, or –O-R4A; R2Ais C2-C6alkyl, 3-8 membered monocyclic carbocyclyl, phenyl, –C1-C6alkyl-phenyl, or –O-C1-C6 alkyl-phenyl, 10 ; kyl, 3-8 membered monocyclic carbocyclyl, or –C1-C6 alkyl-R7A;R5Ais H, C1-C6alkyl, C1-C6hydroxyalkyl, or C2-C6alkynyl; R6Ais H, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C2-C6 alkynyl; and R7Ais –C1-C6alkyl-O- C1-C6alkyl or 3-8 membered monocyclic carbocyclyl. 15

[0040] In some embodiments, when R3Ais , R5Ais –Et, and R6Ais –Et, then R2Ais not . [00ompound of Formula A, or a pharmaceutically acceptable salt thereof, wherein: R1Ais H, C2-C6alkenyl, C2-C6alkynyl, –C(O)-R4A, or –O-R4A; 20 R2Ais , 3-8 membered monocyclic carbocyclyl, phenyl, or –O-C1-C6 alkyl- phenyl;;kyl, 3-8 membered monocyclic carbocyclyl, or –C1-C6alkyl-R7A; 11 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO R5Ais H, C1-C6alkyl, C1-C6hydroxyalkyl, or C2-C6alkynyl; R6Ais H, C1-C6alkyl, C1-C6hydroxyalkyl, or C2-C6alkynyl; and R7Ais –C1-C6 alkyl-O- C1-C6 alkyl or 3-8 membered monocyclic carbocyclyl.

[0042] In some embodiments, the compound is a compound of Formula A, or a 5 pharmaceutically acceptable salt thereof, wherein: R1Ais H, C2-C6alkenyl, C2-C6alkynyl, –C(O)-R4A, or –O-R4A; R2Ais , 3-8 membered monocyclic carbocyclyl, or phenyl;R3Ais ; R4Ais C1-C6 alkyl, 3-8 membered monocyclic carbocyclyl, or –C1-C6 alkyl-R7A; 10 R5Ais H, C1-C6alkyl, C1-C6hydroxyalkyl, or C2-C6alkynyl; R6Ais H, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C2-C6 alkynyl; and R7Ais –C1-C6 alkyl-O- C1-C6 alkyl or 3-8 membered monocyclic carbocyclyl.

[0043] In some embodiments, R1Ais H. In some embodiments, R1Ais C2-C6 alkenyl. In some embodiments, R1Ais C2-C6 alkynyl. In some embodiments, R1Ais –C(O)-R4Aor –O-R4A. In 15 some embodiments, R1Ais –C(O)-R4A. In some embodiments, R1Ais–O-R4A.

[0044] In some embodiments, R1Ai . In some embodiment . 4A

[0045] In some embodiments, R is C1-C6 alkyl. In some embod–Et, –nPr, – iPr, –nBu, –sBu, –tBu, –(CH2)4CH3, or –(CH2)5CH3. In some embodiments, R4Ais –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. 20

[0046] In some embodiments, R4Ais 3-8 membered monocyclic carbocyclyl. In some embodiments, R4Ais 3-6 membered monocyclic carbocyclyl. In some embodiments, R4Ais 3- 6 membered monocyclic carbocyclyl. In some embodiments, R4Ai ,.diments, 7-9, wherein R4Ais –C1-C6 alkyl-R7A. In some embodiments, 25 R7Ais –O-C1-C6alkyl. In some embodiments, R7Ais –OMe, –OEt, –OiPr, or –OtBu. In some embodiments, R7Ais –OMe. In some embodiments, R7Ais 3-8 membered monocyclic 12 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO carbocyclyl. In some embodiments, R7Ais 3-6 membered monocyclic carbocyclyl. In some 7A 7Ais[ ] n some em o men s, s or . 5

[0049] In some embodiments mbodiments, R2Ais –Et, –nPr, –iPr, –nBu, –sBu, –tBu, –(CH2)4CH3, or –(CH2)5CH3. In some embodiments, R2Ais –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

[0050] In some embodiments, R2Ais 3-8 membered monocyclic carbocyclyl. In some embodiments, R2Ais 3-6 membered monocyclic carbocyclyl. In some embodiments, R2Ais 10 . nyl.

[0052] In some embodiments, R2Ais –C1-C6alkyl-phenyl. In some embodiments, R2Ais .ome embodiments, R2Ais –O-C1-C6 alkyl-phenyl. In some embodiments, R2Ais 15 .e embodiments, R5Ais H. In some embodiments, R5Ais H or C1-C6 alkyl. In some embodiments, R5Ais C1-C6alkyl. In some embodiments, R5Ais C1-C6hydroxyalkyl. In some embodiments, R5Ais C2-C6 alkynyl.

[0055] In some embodiments, R5Ais –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, –(CH2)4CH3, or 20 –(CH2)5CH3. In some embodiments, R5Ais –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, R5Ais . In some embodiments, R5Ai .

[0056] In some embodimen s, R6Ais H. In some embodiments, s or C1-C6alkyl. In some embodiments, R6Ais C1-C6 alkyl. In some embodiments, R6Ais C1-C6 hydroxyalkyl. In some embodiments, R6Ais C2-C6alkynyl. 13 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO

[0057] In some embodiments, R6Ais –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, –(CH2)4CH3, or –(CH2)5CH3. In some embodiments, R6Ais –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. The compound of claim 51, wherein R6Ais . The compound of claim 53, wherein R6Ais. 5 e embodiments, the compound is a compound of Formula A-I:or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein. 10

[0059] In some embodiments, the compound has the structure of any one of the following, or a pharmaceutically acceptable salt thereof: ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO

[0060] In some embodiments, the compound has the structure of any one of the following, or a pharmaceutically acceptable salt thereof: 15 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO

[0061] In some embodiments re of any one of the following, ora pharmaceutically acceptable salt thereof: ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO

[0062] In some embodiments re of any one of the following, ora pharmaceutically acceptable salt thereof: ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO a pharmaceutically

[0064] In some embodiments, the compoun ally acceptable salt thereof.O 5

[0065] In some embodiments, the compound , or a pharmaceutically acceptable salt thereof.18 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO

[0066] In some embodiments, the compound , or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the compoun ally acceptable salt thereof.O N N 5

[0068] In some embodiments, the compound is , or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, the compoun ally acceptable salt thereof.

[0070] In some embodiments, the compoun a pharmaceutically 10 acceptable salt thereof.Formula B

[0071] Disclosed herein, in some embodiments, is a compound of Formula B: 19 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO or a pharmaceutically accewherein 5 R1Bis C2-C6 alkenyl, C2-C6 alkynyl, –C(O)-R4A, or –O-R4A; R2Bis –Me; ; kyl, 3-8 membered monocyclic carbocyclyl, or –C1-C6alkyl-R7B;R5Bis H, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C2-C6 alkynyl; 10 R6Bis H, C1-C6alkyl, C1-C6hydroxyalkyl, or C2-C6alkynyl; and R7Bis –C1-C6 alkyl-O- C1-C6 alkyl or 3-8 membered monocyclic carbocyclyl.

[0072] n some embodiments, the compound is a compound of Formula B, or a pharmaceutically acceptable salt thereof, wherein: R1Bis C2-C6alkenyl, C2-C6alkynyl, or –O-R4B; 15 R2Bis –Me; R3Bis ; R4Bis C1-C6 alkyl, 3-8 membered monocyclic carbocyclyl, or –C1-C6 alkyl-R7B; R5Bis H, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C2-C6 alkynyl; R6Bis H, C1-C6alkyl, C1-C6hydroxyalkyl, or C2-C6alkynyl; and 20 R7Bis –C1-C6 alkyl-O- C1-C6 alkyl or 3-8 membered monocyclic carbocyclyl.

[0073] n some embodiments, the compound is a compound of Formula B, or a pharmaceutically acceptable salt thereof, wherein: R1Bis C2-C6alkenyl or C2-C6alkynyl; R2Bis –Me; 25 R3Bis ; 20 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO R4Bis C1-C6alkyl, 3-8 membered monocyclic carbocyclyl, or –C1-C6alkyl-R7B; R5Bis H, C1-C6alkyl, C1-C6hydroxyalkyl, or C2-C6alkynyl; R6Bis H, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C2-C6 alkynyl; and R7Bis –C1-C6alkyl-O- C1-C6alkyl or 3-8 membered monocyclic carbocyclyl. 5

[0074] In some embodiments, R1Bis C2-C6 alkenyl or C2-C6 alkynyl. In some embodiments, R1Bis C2-C6alkenyl. In some embodiments, R1Bis C2-C6alkynyl. In some embodiments, R1Bis –C(O)-R4Bor –O-R4B. In some embodiments, R1Bis –C(O)-R4B. In some embodiments, R1Bis–O-R4B.

[0075] In some embodiments, R1Bi . In some embodiment . 10

[0076] In some embodiments, R4Bis 1-C6 alkyl. In some embod –Et, –nPr, –iPr, –nBu, –sBu, –tBu, –(CH2)4CH3, or –(CH2)5CH3. In some embodiments, R4Bis –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

[0077] In some embodiments, R4Bis 3-8 membered monocyclic carbocyclyl. In some embodiments, R4Bis 3-6 membered monocyclic carbocyclyl. In some embodiments, R4Bis 3- 15 6 membered monocyclic carbocyclyl. In some embodiments, R4Bi ,. iments, R4B 7B 7Bis –C1-C6alkyl-R . In some embodiments, R is –O-C1- C6 alkyl. In some embodiments, R7Bis –OMe, –OEt, –OiPr, or –OtBu. In some embodiments, R7Bis –OMe. 20

[0079] In some embodiments, R7Bis 3-8 membered monocyclic carbocyclyl. In some embodiments, R7Bis 3-6 membered monocyclic carbocyclyl. In some embodiments, R7Bis .

[0080] In some embodiments R4Bi .

[0081] In some embodiments, . ents, R5Bis H or C1-C6alkyl. In 25 some embodiments, R5Bis C1-C6 alkyl. In some embodiments, R5Bis C1-C6 hydroxyalkyl. In some embodiments, R5Bis C2-C6alkynyl. 21 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO

[0082] In some embodiments, R5Bis –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, –(CH2)4CH3, or –(CH2)5CH3. In some embodiments, R5Bis –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, R5Bis . In some embodiments, R5Bis .

[0083] In some embodim6Bis H. In some embodiment C1-C6alkyl. In iments, R65 some embodBis C1-C6 alkyl. In some embodiments, R6Bis C1-C6 hydroxyalkyl. The compound of any one of claims 1-45, wherein R6Bis C2-C6alkynyl.

[0084] In some embodiments, R6Bis –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, –(CH2)4CH3, or –(CH2)5CH3. In some embodiments, R6Bis –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, R6Bis . In some embodiments, R6Bis . 10

[0085] In some embodime compound is a compound ofor a pharmaceutically accepwherein the variables are as described herein. 15

[0086] In some embodiments, the compound has the structure of any one of the following, or a pharmaceutically acceptable salt thereof:22 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO

[0087] In some embodiments, re of any one of the following, or a pharmaceutically acceptable salt thereof:24 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO

[0088] In some embodiments, the compound has the structure of any one of the following, or a pharmaceutically acceptable salt thereof:a pharmaceutically 525 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO

[0090] In some embodiments, the compoun a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the compound ally acceptable salt thereof.5

[0092] In some embodiments, the compoun a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the compoun a pharmaceutically acceptable salt thereof.26 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO N

[0094] In some embodiments, the compoun a pharmaceutically acceptable salt thereof.Formula C

[0095] Disclosed herein, in some embodiments, is a compound of Formula C: 5 or a pharmaceutically accepwherein R1Cis H; 10 R2Cis –Me; ;ydroxyalkyl or C2-C6alkynyl.

[0096] In some embodiments, the compound is a compound of Formula C, or a 15 pharmaceutically acceptable salt thereof, wherein: R1Cis H; R2Cis –Me; ;20 R6Cis C2-C6 alkynyl. 27 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO

[0097] In some embodiments, R6Cis C1-C6hydroxyalkyl. In some embodiments, R6Cis C2-C6alkynyl.

[0098] In some embodiments, R6Cis . In some embodiments, R6Cis .

[0099] In some embodiments, the c nd is a compound of Formula5 or a pharmaceutically accepwherein the variables are as described herein.

[0100] In some embodiments, the compound has the structure of any one of the following, or 10 a pharmaceutically acceptable salt thereof:28 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO

[0101] In some embodiments, the compound has the structure of any one of the following, or a pharmaceutically acceptable salt thereof: lly 5

[0103] In some embodiments, the compound , or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the compoun a pharmaceutically acceptable salt thereof.29 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO Exemplary Compounds

[0105] Disclosed herein, in some embodiments, is a compound described in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt thereof.

[0106] Disclosed herein, in some embodiments, is a compound described in Table 1, or a 5 pharmaceutically acceptable salt thereof. Table 1. Exemplary compounds of the disclosure Compound No.Name Structure30 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO (6aR,9R)-7-butyl-N,N-diethyl- The y methods sm ar to tosencuded n te Exampes secton.

[0107] Disclosed herein, in some embodiments, is a compound described in Table 2, or a 5 pharmaceutically acceptable salt thereof. Table 2. Exemplary compounds of the disclosure Compound Name Structure31 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO32 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO 6R9R NNdi hl7 hl4 The by meth.

[0108] Disclosed herein, in some embodiments, is a compound described in Table 2, or a 5 pharmaceutically acceptable salt thereof. Table 3. Exemplary compounds of the disclosure Compound No. Name Structure The ymethods similar to those included in the Examples section. 33 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO Pharmaceutical Compositions

[0109] Disclosed herein, in some embodiments, are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula A, Formula B, or Formula C, or a subformula thereof; a compound of Table 1, 5 Table 2, or Table 3; or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier.

[0110] In some embodiments, the compound is provided in an effective amount in the pharmaceutical composition. In some embodiments, the compound is provided in a therapeutically effective amount in the pharmaceutical composition. In some embodiments, 10 the compound is provided in a prophylactically effective amount in the pharmaceutical composition.

[0111] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route 15 of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. 20

[0112] While it is possible for a compound disclosed herein to be administered alone, it is preferable to administer the compound as a pharmaceutical composition, where the compound is combined with one or more pharmaceutically acceptable carriers. The compounds disclosed herein may be formulated for administration in any convenient way for use in human or veterinary medicine. In some embodiments, the compound included in the pharmaceutical 25 composition may be active itself, or may be a prodrug, e.g., capable of being converted to an active compound in a physiological setting. Regardless of the route of administration selected, the compounds disclosed herein and / or the pharmaceutical compositions disclosed herein are formulated into pharmaceutically acceptable dosage forms such as described below or by other conventional methods known to those of skill in the art. 30

[0113] As described below, the pharmaceutical compositions disclosed herein may be formulated for administration in solid or liquid form, including those adapted for inhalation, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) 34 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO administration, and intranasal administration. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference. The compounds disclosed herein can also be administered in sustained release forms or from 5 sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0114] Pharmaceutically acceptable carriers include any and all diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, preservatives, lubricants and the like, as suited to the particular dosage form desired, e.g., injection. General 10 considerations in the formulation and / or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21stEdition (Lippincott Williams & Wilkins, 2005).

[0115] Although the descriptions of pharmaceutical compositions provided herein are 15 principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary 20 pharmacologist can design and / or perform such modification with ordinary experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21sted., Lippincott Williams & Wilkins, 2005. Methods of Use and Treatment 25

[0116] Serotonin receptors, also known as 5-HT receptors or 5-hydroxytryptamine receptors, are classified into seven types: 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7. Some serotonin receptors are coupled to G proteins (e.g., 5-HT1, 5-HT2, 5-HT4, and 5-HT7), and other serotonin receptors are receptor channels, i.e., ligand-gated ion channels, (e.g., 5-HT3). Serotonin receptors influence behavioral, neuronal, and physiological processes, and regulation 30 of serotonin receptors are implicated in many diseases and disorders. 35 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO Modulating Serotonin Receptors

[0117] Disclosed herein, in some embodiments, are methods of modulating a serotonin receptor in a subject in need thereof, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of 5 Formula A, Formula B, or Formula C, or a subformula thereof; a compound of Table 1, Table 2, or Table 3; or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein.

[0118] Upon having contacted the serotonin receptor, the compound may activate the serotonin receptor or inhibit the serotonin receptor. 10

[0119] In some embodiments, the serotonin receptor is 5-HT1Areceptor, 5-HT2Areceptor, 5- HT2B receptor, 5-HT2C receptor, 5-HT6 receptor, or 5-HT7 receptor, or a combination thereof. In some embodiments, the serotonin receptor is 5-HT1A receptor, 5-HT2A receptor, 5-HT2B receptor, 5-HT2C receptor, 5-HT6 receptor, or 5-HT7 receptor.

[0120] In some embodiments, the serotonin receptor is 5-HT2A receptor, 5-HT2C receptor, or15 5-HT7 receptor, or a combination thereof. In some embodiments, the serotonin receptor is 5- HT2A receptor, 5-HT2C receptor, or 5-HT7 receptor.

[0121] In some embodiments, the serotonin receptor is 5-HT1Areceptor. In some embodiments, the serotonin receptor is 5-HT2A receptor. In some embodiments, the serotonin receptor is 5- HT2Breceptor. In some embodiments, the serotonin receptor is 5-HT2Creceptor. In some 20 embodiments, the serotonin receptor is 5-HT6 receptor. In some embodiments, the serotonin receptor is 5-HT7receptor.

[0122] Thus, in a further aspect, the condition that may be treated in accordance herewith can be any serotonin receptor mediated disorder. Treatment of Diseases and Disorders 25

[0123] Disclosed herein, in some embodiments, are methods of treating a disease in a subject in need thereof, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula A, Formula B, or Formula C, or a subformula thereof; a compound of Table 1, Table 2, or Table 3; or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed 30 herein.

[0124] In some embodiments, the disease or disorder is a serotonin receptor-mediated disease or disorder. 36 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO

[0125] In some embodiments, the disease is depression, anxiety, pain, inflammation, addiction, an autoimmune disease, an eating disorder, or an obsessive compulsive disorder. In some embodiments, the disease is depression, anxiety, pain, inflammation, or addiction. In some embodiments, the disease is an autoimmune disease, an eating disorder, or an obsessive 5 compulsive disorder.

[0126] In some embodiments, the disease is autism, anxiety, depression, bipolar disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, a psychotic disorder, a psychotic symptom, social withdrawal, obsessive-compulsive disorder (OCD), phobia, post-traumatic stress syndrome, post-traumatic stress disorder (PTSD), a 10 behavior disorder, an impulse control disorder, a substance abuse disorder (e.g., a withdrawal symptom, opiate addiction, nicotine addiction, and ethanol addition), a sleep disorder, a memory disorder (e.g., a deficit, loss, or reduced ability to make new memories), a learning disorder, Tourette's syndrome, epilepsy, cerebral ischemia, special learning disorders, seizures, post-stroke convulsions, brain ischemia, migraine, stroke, spinal cord injury, peripheral 15 neuropathy, acute neuropathic pain, or chronic neuropathic pain.

[0127] Also provided are methods for treating social withdrawal in conditions including, but not limited to, social anxiety disorder, avoidant personality disorder, and schizotypal personality disorder. In some embodiments, the disease is apathy. In some embodiments, the disease is attention, or lack thereof. 20

[0128] In some embodiments, the disease is pain. In some embodiments, the pain is treatment resistant pain. In some embodiments, the pain is opioid resistant pain. In some embodiments, the pain is opioid resistant refractory pain. In some embodiments, the pain is neuropathic pain. In some embodiments, the pain is nociceptive pain. In some embodiments, the pain is inflammatory pain. In some embodiments, the pain is nociplastic pain. In some embodiments, 25 the pain existential pain.

[0129] In some embodiments, the pain is acute. In some embodiments, the pain is chronic.

[0130] In some embodiments, the pain is neuropathic pain. The neuropathic pain may be acute or chronic. In some cases, the neuropathic pain may be associated with a condition such as herpes, HIV, traumatic nerve injury, stroke, post-ischemia, fibromyalgia, reflex sympathetic 30 dystrophy, complex regional pain syndrome, spinal cord injury, sciatica, phantom limb pain, diabetic neuropathy, and cancer chemotherapeutic-induced neuropathic pain. Methods for enhancing pain relief and for providing analgesia to a patient are also contemplated.

[0131] Neuropathic pain or neuropathy is caused by injury to nerves (e.g., autonomic nerves, motor nerves, or sensory nerves). In some embodiments, neuropathic pain is caused by 37 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO metabolic nerve damage. Metabolic neuropathies include, but are not limited to, diabetic neuropathy, drug-induced neuropathy, and post herpetic neuropathy. In some embodiments, neuropathic pain is caused by a discrete nerve injury. Discrete nerve injuries include, but are not limited to, post-amputation pain, post-surgical pain, and nerve entrapment injuries (e.g., 5 neuropathic back pain).

[0132] In some embodiments, the subject has cancer. In some embodiments, the subject has been treated with an anti-cancer therapy. In some embodiments, the disease is anti-cancer therapy-induced neuropathic pain. In some embodiments, the anti-cancer therapy is selected from: administration of an immunotherapeutic agent, a chemotherapeutic agent, a growth 10 inhibitory agent, a cytotoxic agent, or a combination thereof; radiation therapy; surgery; and combinations thereof. In some embodiments, the disease is chemotherapeutic-induced pain. In some embodiments, the disease is cancer chemotherapy-induced pain.

[0133] In some embodiments, the pain is treatment resistant pain. In some embodiments, the pain is refractory pain. In some embodiments, the pain is treatment resistant refractory pain. 15 In some embodiments, the pain is opioid resistant pain. In some embodiments, the pain is opioid resistant refractory pain. In some embodiments, the opioid is codeine, fentanyl, hydromorphone, methadone, morphine, or oxycodone, or a pharmaceutically acceptable salt thereof. In some embodiments, the opioid is hydromorphone, morphine, or oxycodone, or a pharmaceutically acceptable salt thereof. 20

[0134] In some embodiments, compounds disclosed herein relieve depression or a symptom of depression without affecting behavior or motor coordination and without inducing or promoting seizure activity. Exemplary depression conditions that are expected to be treated according to this aspect of the invention include, but are not limited to, major depressive disorder, dysthymic disorder, psychotic depression, postpartum depression, premenstrual 25 syndrome, premenstrual dysphoric disorder, seasonal affective disorder (SAD), bipolar disorder (or manic depressive disorder), mood disorder, and depressions caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress, and post traumatic stress disorders. In addition, patients suffering from any form of depression often experience anxiety. Various symptoms associated with anxiety include fear, panic, heart 30 palpitations, shortness of breath, fatigue, nausea, and headaches (e.g., migraine headaches or cluster headaches) among others. Anxiety or any of the symptoms thereof may be treated by administering a compound as described herein.

[0135] In some embodiments, the depression is moderate depression, major depression, treatment resistant depression, complicated grief disorder, prolonged grief disorder (PGD), 38 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO social anxiety, post-surgical depression, depression from chronic pain, or depression in Alzheimer’s disease.

[0136] Compounds of the disclosure may be useful to control food intake in a patient and thus used to treat eating disorders in such patients. Eating disorders can include but not be limited 5 to overeating resulting in obesity, bulimia, compulsive eating, pica, insufficient eating leading to anorexia, improper eating resultant of diabetes, and abnormalities in the perception of taste (ageusia / dysgeusia) that lead to abnormal eating patterns. It is also understood to one of skill in the art that eating disorders may also involve disorders of taste and smell and thus the invention also encompasses methods of treating taste and smell disorders. 10

[0137] Compounds of the disclosure may be used to treat binge eating disorder. Binge eating disorder is a form of Eating Disorder Not Otherwise Specified. As defined by the DSM-IV-TR, it is characterized by recurrent binge eating episodes. Such episodes include eating larger amounts of food than normal during a short period of time (for instance, within a two hour period) and a lack of control over eating during the binge episode (for instance, one cannot stop 15 eating). According to the DSM-IV-TR, binge eating disorders are associated with three or more of the following symptoms: eating until uncomfortably full; eating large amounts of food when not physically hungry; eating much more rapidly than normal; eating alone on account of embarrassment over how much one is eating; and feeling disgusted, depressed or guilty after overeating. Additionally, individuals with binge eating disorder feel distress about their 20 binging behavior. The DSM-IV-TR also characterizes binge eating to occur, on average, at least 2 days a week for six months, while not being associated with the regular use of inappropriate compensatory behaviors such as purging or excessive exercise and not occurring exclusively during the course of bulimia nervosa or anorexia nervosa. As used herein “depression” includes major depressive disorder, dysthymic disorder, depressive disorder not 25 otherwise specified (for instance, premenstrual dysphoric disorder), and depressive episodes that may be present in another disorder (e.g. as in other mood disorders such as bipolar disorder or a mood disorder due to a general medical condition).

[0138] In some embodiments, the disease is obsessive-compulsive spectrum disorder (OCSD). In some embodiments, the disease comprises body dysmorphic disorder (BDD), compulsive 30 skin picking, Tourette syndrome, Attention Deficit / Hyperactivity Disorder, anorexia nervosa, antisocial personality disorder (ASPD), autism, basal ganglia disorder, borderline personality disorder (BPD), bulimia, depersonalization disorder, epilepsy, Huntington’s disease, hypochondriasis, kelptomania, personality disorder, pathologic gambling, sexual compulsions, 39 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO Sydenham's chorea, torticollis, trichotillomania, or Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections.

[0139] Compounds of the disclosure may be used to treat an autoimmune disease, wherein the autoimmune disease comprises Ankylosing Spondylitis, Chagas disease, chronic obstructive 5 pulmonary disease, Crohns Disease, Dermatomyositis, Endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, Hidradenitis suppurativa, Kawasaki disease, IgA nephropathy, idiopathic thrombocytopenic purpura, interstitial cystitis, lupus erythematosus, mixed connective tissue disease, morphea, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anaemia, psoriasis, 10 psoriatic Arthritis, polymyositis, primary biliary cirrhosis, relapsing polychondritis, rheumatoid arthritis, schizophrenia, scleroderma, Sjögren's syndrome, stiff person syndrome, temporal arteritis, ulcerative colitis, vasculitis, vitiligo, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, ankylosing spondilitis, scleroderma, Type I diabetes, psoriatic arthritis, osteoarthritis, inflammatory bowel disease, atopic dermatitis and asthma, or 15 Wegener's granulomatosis. EXAMPLES

[0140] In order that present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in the present disclosure are offered to illustrate the compounds, pharmaceutical compositions, and methods provided 20 herein and are not to be construed in any way as limiting their scope. Abbreviations AcOH glacial acetic acid aq aqueous Boc tert-butyloxycarbonyl br broad Cbz carboxybenzyl CDI 1,1-carbonyl-diimidazole conc concentrated d doublet DAB 3,3'-diaminobenzidine DCM dichloromethane DIPEA N,N-diisopropylethylamine (aka Hünig’s base) 40 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO DMEM Dulbecco’s Modified Eagle Medium DMF N,N-dimethylformamide DMSO dimethyl sulfoxide (ES+) electrospray ionization, positive mode Et ethyl EtOAc ethyl acetate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium HATU 3-oxid hexafluorophosphate HPLC high performance liquid chromatography (reverse phase) hr hour(s) IC50 50% inhibitory concentration IC75 75% inhibitory concentration IC90 90% inhibitory concentration m multiplet (M+H)+protonated molecular ion Me methyl MeCN acetonitrile MeOH methanol MHz megahertz min minute(s) m / z mass-to-charge ratio NMR nuclear magnetic resonance (spectroscopy) nt not tested Ph phenyl prep HPLC preparative high performance liquid chromatography PG protective group Ph phenyl q quartet RT room temperature RP HPLC reverse phase high performance liquid chromatography s singlet sat saturated t triplet 41 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO THF tetrahydrofuran TLC thin layer chromatography Tos p-toluenesulfonyl vol volume(s) WB washing buffer Example 1. General Scheme for Preparing Ergoline Analogs

[0141] A general scheme for synthesizing compounds disclosed herein is shown above. 5 Example 2. Synthesis of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg]quinoline-9-carboxamide (nor-LSD)

[0142] . g 3 . g to refluxing solution in a nitrogen environment. Reaction mixture was refluxed for an additional 6 h. 42 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO Reaction mixture was then cooled, washed with tartaric acid, and solvents were removed. The resulting residue was dissolved in CH2Cl2, washed with tartaric acid, dried with Na2SO4. The product was plugged through alumina column (CH2Cl2 / MeOH). Centrifugal chromatography with alumina and CH2Cl2, under nitrogen and ammonia, yielded solid product. 5 Recrystallization from IPA or EtOAc gave 6-cyano-nor-LSD (71%) with mp of 190–191 °C.

[0143] Then 6-cyano-nor-LSD (0.33 g) was added to acetic acid and H2O. Added powdered zinc, and reaction mixture was heated for 4 h at 130 °C. Reaction mixture was then cooled, diluted with H2O, brought to alkaline pH with NH4OH, extracted with CH2Cl2, and dried. The solvent was then removed. Centrifugal chromatography (alumina, CHCl3 / MeOH), under 10 ammonia vapor, yielded tan crystals. Recrystallized from EtOAc / hexanes, yielding nor-LSD (61%) with mp of 196–198 °C (dec).

[0144] Nor-LSD (66 mg) was added to DMF. Then added K2CO3 and ethyl iodide. Volatiles were removed when TLC indicated completion. Then CHCl3 was added, dried, and separated by centrifugal chromatography. Major product was dissolved in hot benzene, filtered, and 15 cooled. Crystallization yielded N-ethyl-nor-LSD (61%) with mp of 108–110 °C and [α]D +40.5° (c 0.46, EtOH). Example 3. Synthesis of (6aR,9R)-N,N-diethyl-7-isopropyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound I-1) 20

[0145] Compound I-1 is synthesized by reacting nor-LSD with an appropriate alkylating agent to introduce the isopropyl group at 7-position. This step may involve the use of an alkylating agent (e.g., an alkyl bromide or alkyl iodide) along with a suitable base in a controlled environment. Ensure the protection of sensitive functional groups and control the reaction 25 conditions to achieve the desired regioselectivity.

[0146] Purify the final product through techniques like chromatography, crystallization, or a combination of both. Isolate the desired compound. Confirm the structure of the synthesized compound using spectroscopic techniques such as NMR, IR, and mass spectrometry. Verify the purity and identity of the compound. 43 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO Example 4. Synthesis of (6aR,9R)-7-cyclohexyl-N,N-diethyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound I-2)5

[0147] Compound I-2 is synthesized by reacting nor-LSD with an appropriate alkylating agent to introduce the cyclohexyl group at 7-position. This step may involve the use of an alkylating agent (e.g., cyclohexyl halide or derivative) along with a suitable base in a controlled environment. Ensure the protection of sensitive functional groups and control the reaction conditions to achieve the desired regioselectivity. 10

[0148] Purify the final product through techniques like chromatography, crystallization, or a combination of both. Isolate the desired compound. Confirm the structure of the synthesized compound using spectroscopic techniques such as NMR, IR, and mass spectrometry. Verify the purity and identity of the compound. Example 5. Synthesis of (6aR,9R)-7-benzyl-N,N-diethyl-4,6,6a,7,8,9- 15 hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound I-3)

[0149] Compound I-3 is syntheswith an appropriate alkylating agent as e.g. benzyl bromide or a similar reagent to introduce the benzyl group at 7-position. This 20 step may involve the use of an alkylating agent (e.g., benzyl bromide or benzyl iodide) along with a suitable base in a controlled environment. Ensure the protection of sensitive functional groups and control the reaction conditions to achieve the desired regioselectivity.

[0150] Purify the final product through techniques like chromatography, crystallization, or a combination of both. Isolate the desired compound. Confirm the structure of the synthesized 44 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO compound using spectroscopic techniques such as NMR, IR, and mass spectrometry. Verify the purity and identity of the compound. Example 6. Synthesis of (6aR,9R)-7-(benzyloxy)-N,N-diethyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound I-4) 5

[0151] Compound I-4 is synthesized by reacting nor-LSD with an appropriate reagent to introduce the benzyloxy group at 7-position. Utilize phenylmethanol as the starting material for the benzyloxy group. Employ suitable reagents and conditions to attach the benzyloxy 10 group to the nor-LSD intermediate. Ensure the protection of sensitive functional groups and control the reaction conditions to achieve the desired regioselectivity.

[0152] Purify the final product through techniques like chromatography, crystallization, or a combination of both. Isolate the desired compound. Confirm the structure of the synthesized compound using spectroscopic techniques such as NMR, IR, and mass spectrometry. Verify 15 the purity and identity of the compound. Example 7. Synthesis of (6aR,9R)-N,N-diethyl-7-isobutyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound I-5) 20

[0153] Compound I-5 is synthesizD with an appropriate alkylbromide or a similar reagent to introduce the isobutyl group at 7-position. This step may involve the use of an alkylating agent (e.g., isobutyl bromide) under suitable reaction conditions with a suitable base in a controlled environment. Ensure the protection of sensitive functional groups and control the reaction conditions to achieve the desired regioselectivity. 45 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO

[0154] Purify the final product through techniques like chromatography, crystallization, or a combination of both. Isolate the desired compound. Confirm the structure of the synthesized compound using spectroscopic techniques such as NMR, IR, and mass spectrometry. Verify the purity and identity of the compound. 5 Example 8. Synthesis of (6aR,9R)-7-butyl-N,N-diethyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound I-6)

[0155] Compound I-6 is synthesized by reacting nor-LSD with an appropriate alkylbromide or 10 a similar reagent to introduce the n-butyl group at 7-position. Ensure the reaction is carried out under conditions favoring substitution at the 7-position. This step may involve the use of an alkylating agent (e.g., n-butyl bromide or iodide or another suitable butylating agent) under suitable reaction conditions with a suitable base in a controlled environment. Ensure the protection of sensitive functional groups and control the reaction conditions to achieve the 15 desired regioselectivity.

[0156] Purify the final product through techniques like chromatography, crystallization, or a combination of both. Isolate the desired compound. Confirm the structure of the synthesized compound using spectroscopic techniques such as NMR, IR, and mass spectrometry. Verify the purity and identity of the compound. 20 Example 9. Synthesis of (6aR,9R)-7-cyclopentyl-N,N-diethyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound I-7) ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO

[0157] Compound I-7 is synthesized by reacting nor-LSD with an appropriate alkylbromide or a similar reagent to introduce the cyclopentyl moiety at 7-position. Ensure the reaction is carried out under conditions favoring substitution at the 7-position. This step may involve the use of an alkylating agent (e.g., cyclopentyl bromide or iodide or another suitable 5 cyclopentylating agent) under suitable reaction conditions with a suitable base in a controlled environment. Ensure the protection of sensitive functional groups and control the reaction conditions to achieve the desired regioselectivity.

[0158] Purify the final product through techniques like chromatography, crystallization, or a combination of both. Isolate the desired compound. Confirm the structure of the synthesized 10 compound using spectroscopic techniques such as NMR, IR, and mass spectrometry. Verify the purity and identity of the compound. Example 10. Synthesis of (6aR,9R)-N,N-diethyl-7-phenyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound I-8) 15

[0159] Compound I-8 is synthesiz-LSD with an appropriate phenylating reagent to introduce the phynyl group at 7-position. Ensure the reaction is carried out under conditions favoring substitution at the 7-position. This step may involve the use of an phenylating agent (e.g., phenylbromide or iodide or another suitable phenylating agent) under 20 suitable reaction conditions with a suitable catalyst and base in a controlled environment. Ensure the protection of sensitive functional groups and control the reaction conditions to achieve the desired regioselectivity.

[0160] Purify the final product through techniques like chromatography, crystallization, or a combination of both. Isolate the desired compound. Confirm the structure of the synthesized 25 compound using spectroscopic techniques such as NMR, IR, and mass spectrometry. Verify the purity and identity of the compound. Example 11. Synthesis of (6aR,9R)-4-(but-2-yn-1-yl)-N,N-diethyl-7-methyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound II-1) 47 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO

[0161] Compound II-1 is synthesized by employing LSD in an appropriate solvent (e.g., chloroform or dichloromethane). Introduce the desired alkyl group by adding but-2-yn-1-yl 5 magnesium bromide or a similar reactive alkynyl compound. Allow the reaction to proceed under controlled conditions, maintaining an inert atmosphere and proper temperature. Ensure the protection of sensitive functional groups and control the reaction conditions to achieve the desired regioselectivity.

[0162] Work up the reaction mixture, perhaps by washing with an appropriate acidic or basic 10 solution to remove impurities. Isolate the crude product and purify it through column chromatography or another suitable method. Confirm the structure of the synthesized compound using spectroscopic techniques such as NMR, IR, and mass spectrometry. Verify the purity and identity of the compound. Example 12. Synthesis of (6aR,9R)-4-(cyclopropylmethoxy)-N,N-diethyl-7-methyl- 15 4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound II-2)

[0163] Compound II-2 is synthesize y e p oy g LSD in an appropriate solvent (e.g., chloroform or dichloromethane). For the introduction of the cyclopropylmethoxy group at the 48 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO 4-position, use a cyclopropylmethanol precursor in the presence of appropriate activating agents or catalysts. Ensure the protection of sensitive functional groups and control the reaction conditions to achieve the desired regioselectivity. Purify the final product through techniques like chromatography, crystallization, or a combination of both. Isolate the desired compound. 5 Confirm the structure of the synthesized compound using spectroscopic techniques such as NMR, IR, and mass spectrometry. Verify the purity and identity of the compound. Example 13. Synthesis of (6aR,9R)-N,N-diethyl-4-(2-methoxyacetyl)-7-methyl- 4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound II-3) 10

[0164] Compound II-3 is synthesized by employing LSD in an appropriate solvent (e.g., chloroform or dichloromethane). For the introduction of the methoxyacetyl group in the 4- position use a suitable acylation reagent (e.g., methoxyacetyl chloride) under appropriate conditions in the presence of an appropriate base and activating agents or catalysts. Ensure the 15 protection of sensitive functional groups and control the reaction conditions to achieve the desired regioselectivity. Purify the final product through techniques like chromatography, crystallization, or a combination of both. Isolate the desired compound. Confirm the structure of the synthesized compound using spectroscopic techniques such as NMR, IR, and mass spectrometry. The methoxyacetyl group should show up in the appropriate region in the IR 20 spectrum. Verify the purity and identity of the compound. Example 14. Synthesis of (6aR,9R)-4-(cyclopentanecarbonyl)-N,N-diethyl-7-methyl- 4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound II-4) 49 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO

[0165] Compound II-4 is synthesized by employing LSD in an appropriate solvent (e.g., chloroform or dichloromethane). For the introduction of the cyclopentanecarbonyl group in the 5 4-position use a suitable acylation reagent (e.g., cyclopentylmethanoyl chloride) under appropriate conditions in the presence of an appropriate base and activating agents or catalysts. Purify the final product through techniques like chromatography, crystallization, or a combination of both. Isolate the desired compound. Confirm the structure of the synthesized compound using spectroscopic techniques such as NMR, IR, and mass spectrometry. The 10 cyclopentanecarbonyl group should show up in the appropriate region in the IR spectrum. Verify the purity and identity of the compound. Example 15. Synthesis of (6aR,9R)-4-acetyl-N,N-diethyl-7-methyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound II-5) 15

[0166] Compound II-5 is synthesiLSD in an appropriate solvent (e.g., chloroform or dichloromethane). For the introduction of the acetyl group in the 4-position use a suitable acylation reagent (e.g., acetyl chloride) under appropriate conditions in the presence of an appropriate base and activating agents or catalysts. Purify the final product through 20 techniques like chromatography, crystallization, or a combination of both. Isolate the desired 50 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO compound. Confirm the structure of the synthesized compound using spectroscopic techniques such as NMR, IR, and mass spectrometry. The acetyl group should show up in the appropriate region in the IR spectrum. Verify the purity and identity of the compound. Example 16. Synthesis of (6aR,9R)-N,N-diethyl-7-methyl-4-(prop-1-en-2-yl)- 5 4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (II-6) N

[0167] Compound II-6 is synthesi LSD in an appropriate solvent (e.g.,chloroform or dichloromethane). For the introduction of the prop-1-en-2-yl group in the 4- 10 position use a suitable alkenyl iodide (e.g., propenyl iodide), or similar reagent and carry out the reaction under nitrogen and appropriate conditions in the presence of an appropriate base and activating agents or catalysts. Purify the final product through techniques like chromatography, crystallization, or a combination of both. Isolate the desired compound. Confirm the structure of the synthesized compound using spectroscopic techniques such as 15 NMR, IR, and mass spectrometry. Verify the purity and identity of the compound. Example 17. Synthesis of (6aR,9R)-N-(1-hydroxyethyl)-7-methyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound III-1) 20

[0168] Compound III-1 is synthesy p y g commercial lysergic acid or a suitable derivative in an appropriate solvent (e.g., chloroform or dichloromethane). For the introduction of the hydroxyethyl amide moiety use an appropriate reagent and carry out the reaction under nitrogen and appropriate conditions in the presence of an appropriate base and activating agents 51 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO or catalysts. Ensure the reaction conditions favor the introduction of the hydroxyethyl group at the desired position. Purify the final product through techniques like chromatography, crystallization, or a combination of both. Isolate the desired compound. Confirm the structure of the synthesized compound using spectroscopic techniques such as NMR, IR, and mass 5 spectrometry. Verify the purity and identity of the compound. Example 18. Synthesis of (6aR,9R)-N-(but-2-yn-1-yl)-7-methyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound III-2)10

[0169] Compound III-2 is synthesized by employing commercial lysergic acid or a suitable derivative in an appropriate solvent (e.g., chloroform or dichloromethane). For the introduction of the but-2-yn-1-yl amide use an appropriate reagent, e.g. but-2-yn-1-amine or similar and carry out the reaction under nitrogen and appropriate conditions in the presence of an appropriate base and activating agents or catalysts. Ensure the reaction conditions favor the 15 introduction of the but-2-yn-1-yl amide at the desired position. Purify the final product through techniques like chromatography, crystallization, or a combination of both. Isolate the desired compound. Confirm the structure of the synthesized compound using spectroscopic techniques such as NMR, IR, and mass spectrometry. Verify the purity and identity of the compound. Example 19. Synthesis of (6aR,9R)-N,N-diethyl-5-methoxy-7-methyl-4,6,6a,7,8,9- 20 hexahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound III-3)

[0170] Compound III-3 is synthese y e p oy g LSD or a suitable derivative in an appropriate solvent (e.g., chloroform or dichloromethane). For the introduction of the methoxy 52 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO moiety in 5-position use an appropriate methoxylation reagent and carry out the reaction under nitrogen and appropriate conditions in the presence of appropriate activating agents or catalysts. Ensure the reaction conditions favor the introduction of the methoxy group at the 5-position. Purify the final product through techniques like chromatography, crystallization, or a 5 combination of both. Isolate the desired compound. Confirm the structure of the synthesized compound using spectroscopic techniques such as NMR, IR, and mass spectrometry. Verify the purity and identity of the compound. Example 20. Synthesis of Intermediates and Analytical Methods Synthesis of Intermediates 10

[0171] Known synthetic intermediates were procured from commercial sources or were obtained using published literature procedures. Additional intermediates were prepared by the representative synthetic processes described herein. Analytical methods

[0172] NMR spectra were recorded using a Bruker 500MHz Avance III HD spectrometer 15 equipped with a Bruker 5mm SmartProbeTM. Spectra were measured at 298 K, unless indicated otherwise, and were referenced relative to the solvent resonance. The chemical shifts are reported in parts per million. Data were acquired using Bruker TopSpin software and processed using MestreNova software.

[0173] Mass spectra were acquired using a Waters HClass; Binary Solvent Pump, SM-FTN, 20 CMA, PDA, QDa using the methods described below. Method 1 – UPLC Acidic Method

[0174] Column: ACQUITY UPLC® CSH C18, 130A, 1.7 µm, 2.1 x 30 mm at 40 °C

[0175] Detection: UV at 210-400 nm unless otherwise indicated, MS by electrospray ionisation

[0176] Solvents: A: 0.1% Formic in water, B: MeCN 25

[0177] Gradient: Time %A %B Flow rateTime %A %B Flow rate53 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO 0.00 98 2 0.77 2.50 0 100 0.77

[0178] Column: ACQUITY UPLC® BEH C18, 130A, 1.7 µm, 2.1 x 30 mm at 40 °C

[0179] Detection: UV at 210-400 nm unless otherwise indicated, MS by electrospray ionisation

[0180] Solvents: A: 0.1% Ammonia in water, B: MeCN 5

[0181] Gradient: Time %A %B Flow rate (ml / min)me ow ra e (ml / min)I-2: (6aR,9R)-N-(but-2-yn-1-yl)-7-methyl- 4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide 10

[0182] DR)-7-methyl- 4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxylic acid (40.0 mg, 149 μmol), but-2- yn-1-amine hydrochloride (17.3 mg, 164 μmol) and ((3H-[1,2,3]triazolo[4,5-b]pyridin-3- yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (97.2 mg, 186 μmol) in anhydrous DCM (1 mL). The reaction mixture was stirred at ambient temperature for 30 15 minutes. The reaction was quenched with saturated aqueous sodium hydrogen carbonate solution (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The crude product was purified by flash column chromatography (4 g RediSepRf Si, 0-100% (ethyl acetate / ethanol (3:1) / iso-hexane) to 54 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO give (6aR,9R)-N-(but-2-yn-1-yl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9- carboxamide (14.0 mg, 43.8 μmol, 29.4 %, 100% purity).

[0183] 1H NMR (500 MHz, DMSO) δ 1.73 (t, J = 2.4 Hz, 3H), 2.46 (s, 3H), 2.51 – 2.63 (m, 2H), 2.99 – 3.13 (m, 3H), 3.44 (dd, J = 14.7, 5.4 Hz, 1H), 3.73 – 3.91 (m, 2H), 6.47 (d, J = 5.0 5 Hz, 1H), 7.00 – 7.09 (m, 3H), 7.19 (dt, J = 7.5, 3.6 Hz, 1H), 8.18 (t, J = 5.1 Hz, 1H), 10.70 (s, 1H).

[0184] MS (ES+): m / z 320.3 (M+H)+ Example 22. Synthesis of Compound I-5: (6aR,9R)-N,N-diethyl-7-isobutyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide 10Step 1: (6aR,9R)-7-cyano-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg]quinoline-9-carboxamide

[0185] To stirred mixture of (6aR,9R)-N,N-diethyl-7-methyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (20.0 mg, 61.8 μmol) in chloroform (0.50 15 mL), was added cyanogen bromide (33.0 mg, 311.6 μmol). The reaction mixture was stirred at 60 °C for 3 h. An additional portion of cyanogen bromide (20.0 mg, 189 μmol) was added and reaction mixture was stirred at 60 °C for a further 1 h. The reaction mixture was cooled down to ambient temperature, diluted with DCM (5 mL) and quenched with 0.1 M citric acid (5 mL). The mixture was transferred to phase separator, the organic layer was collected, and the 20 aqueous layer was washed with DCM (2 x 5 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by flash column chromatography (4 g RediSepRf Si, 20-60% ethyl acetate in iso-hexane) to afford (6aR,9R)-7- 55 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO cyano-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (10.8 mg, 31 μmol, 50 %, 96% Purity).

[0186] MS (ES+): m / z 335.4 (M+H)+ Step 2: (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9- 5 carboxamide (nor-LSD)

[0187] Zinc powder (10.1 mg, 155 μmol) was added to a stirred solution of (6aR,9R)-7-cyano- N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (10.8 mg, 31.0 μmol) in mixture of acetic acid (0.50 mL) and water (0.10 mL). The mixture was heated to 100 °C and stirred for 2 h. After cooling to room temperature, the mixture was diluted with 10 DCM (5 mL) and quenched by dropwise addition of saturated aqueous sodium hydrogen carbonate solution until pH ~10. The mixture was transferred to phase separator, organic layer was collected, the aqueous layer was washed with DCM (2 x 5 mL) and the combined organic layers were concentrated under reduced pressure to give (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (8.40 mg, 25 μmol, 81 %). 15

[0188] MS (ES+): m / z 310.3 (M+H)+ Step 3: (6aR,9R)-N,N-diethyl-7-isobutyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg]quinoline-9-carboxamide

[0189] Titanium(IV) isopropoxide (15.0 μL, 49.5 μmol) was added to a stirred solution of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (8.40 20 mg, 27.1 μmol) and isobutyraldehyde (5.00 μL, 55 μmol) in anhydrous DCM (0.50 mL). The mixture was stirred at ambient temperature for 20 min before sodium triacetoxyborohydride (9.00 mg, 42.5 μmol) was added. The reaction mixture was stirred at ambient temperature for a further 20 h. The reaction mixture was concentrated onto silica and directly purified by flash column chromatography (4 g cartridge, 30-80% (3:1 ethyl acetate / ethanol + 2%25 NH4OH) in iso-hexane) to give (6aR,9R)-N,N-diethyl-7-isobutyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (4.00 mg, 11 μmol, 40 %, 99% purity).

[0190] 1H NMR (500 MHz, CDCl3) δ 0.95 (d, J = 6.6 Hz, 3H), 1.02 (d, J = 6.5 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.88 (td, J = 13.1, 6.4 Hz, 1H), 2.26 (dd, J = 13.0, 4.7 Hz, 1H), 2.63 (td, J = 14.0, 10.7 Hz, 2H), 2.75 (t, J = 10.7 Hz, 1H), 3.13 (dd, J = 11.3, 4.6 30 Hz, 1H), 3.36 (d, J = 11.2 Hz, 1H), 3.40 – 3.54 (m, 5H), 3.72 – 3.79 (m, 1H), 6.33 (s, 1H), 6.89 (d, J = 1.9 Hz, 1H), 7.12 – 7.22 (m, 3H), 7.88 (s, 1H).

[0191] MS (ES+): m / z 366.4^(M+H)+ 56 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO Example 23. Synthesis of Compound I-2: (6aR,9R)-7-cyclohexyl-N,N-diethyl- 4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide

[0192] 2- irred solution5 of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (16.0 mg, 51.7 μmol) and cyclohexanone (53.5 μL, 517 μmol) in a mixture of MeOH (0.50 mL) and Acetic Acid (0.10 mL). The mixture was heated to 60 °C and stirred for 16 h. The reaction was quenched with saturated aqueous sodium hydrogen carbonate solution (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (20 mL), 10 dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The crude product was purified by flash column chromatography (4 g RediSepRf Si, 0-10% methanol (0.7M NH3) / DCM) to give (6aR,9R)-7-cyclohexyl-N,N-diethyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (5.90 mg, 15 μmol, 29 %, 99% purity).

[0193] 1H NMR (500 MHz, MeOD-d4) δ 1.19 (t, J = 7.1 Hz, 4H), 1.24 (dd, J = 12.2, 3.1 Hz, 15 1H), 1.32 – 1.37 (m, 0H), 1.47 (qt, J = 12.7, 3.5 Hz, 1H), 1.64 (qd, J = 12.2, 3.5 Hz, 1H), 1.75 (dd, J = 45.0, 12.7 Hz, 2H), 1.83 – 2.00 (m, 1H), 2.64 (ddd, J = 14.6, 11.3, 1.8 Hz, 1H), 2.71 (t, J = 10.8 Hz, 1H), 3.12 – 3.19 (m, 0H), 3.21 – 3.25 (m, 1H), 3.45 (qd, J = 7.1, 2.8 Hz, 2H), 3.51 – 3.63 (m, 3H), 3.76 – 3.86 (m, 2H), 6.32 (s, 1H), 6.97 (d, J = 1.7 Hz, 1H), 7.03 – 7.14 (m, 2H), 7.18 (dd, J = 7.6, 1.0 Hz, 1H). 20

[0194] MS (ES+): m / z 392.3 Example 24. Synthesis of Compound I-7: (6aR,9R)-7-cyclopentyl-N,N-diethyl- 4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide

[0195] 2-y py p . g, μ irred solution 25 of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (20.0 57 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO mg, 64.6 μmol) and cyclopentanone (28.6 μL, 323 μmol) in a mixture of MeOH (0.50 mL) and Acetic Acid (0.10 mL). The mixture was heated to 60 °C and stirred for 1 h. The reaction was quenched with saturated aqueous sodium hydrogen carbonate solution (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (20 mL), 5 dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The crude product was purified by reversed-phase column chromatography (5.5 g RediSepRf C18 Gold, 10-80% acetonitrile / water (10 mM ammonium bicarbonate). The fractions containing the product were lyophilized to give (6aR,9R)-7-cyclopentyl-N,N-diethyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide (4.90 mg, 12 μmol, 19 %). 10

[0196] 1H NMR (500 MHz, MeOD-d4) δ 1.19 (t, J = 7.1 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.52 – 1.75 (m, 5H), 1.90 – 1.98 (m, 1H), 2.68 (ddd, J = 13.5, 11.2, 2.0 Hz, 1H), 2.76 (t, J = 10.6 Hz, 1H), 3.13 (dd, J = 11.4, 4.6 Hz, 1H), 3.45 (q, J = 7.1 Hz, 2H), 3.49 – 3.59 (m, 2H), 3.59 – 3.70 (m, 2H), 3.79 – 3.86 (m, 1H), 3.95 (p, J = 7.8 Hz, 1H), 6.31 (s, 0H), 6.96 (d, J = 1.6 Hz, 1H), 7.05 – 7.11 (m, 2H), 7.18 (dd, J = 7.4, 1.2 Hz, 1H). 15

[0197] MS (ES+): m / z 378.5 Example 25. Synthesis of Compound II-6: (6aR,9R)-N,N-diethyl-7-methyl-4-(prop-1- en-2-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamideStep 1: (6aR,9R)-4-acetyl-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- 20 fg]quinoline-9-carboxamide

[0198] Acetic anhydride ( 142 μL, 1.5 mmol) was added to a stirred mixture of (6aR,9R)-N,N- diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (97.0 mg, 300 μmol), DMAP (5 mg, 41 μmol) and DIPEA (157 μL, 3 Eq, 900 μmol) in MeCN (2.00 mL). 58 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO The mixture was heated to 60 °C and stirred for 16 h. The reaction was quenched with saturated aqueous sodium hydrogen carbonate solution (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The crude product was purified by 5 flash column chromatography (4 g RediSepRf Si, 0-10% methanol (0.7M NH3) / DCM) to give (6aR,9R)-4-acetyl-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9- carboxamide (101 mg, 0.26 mmol, 87 %).

[0199] MS (ES+): m / z 366.4 Step 2: (6aR,9R)-N,N-diethyl-7-methyl-4-(prop-1-en-2-yl)-4,6,6a,7,8,9- 10 hexahydroindolo[4,3-fg]quinoline-9-carboxamide

[0200] Tebbe reagent in toluene (0.5 M) (520 μL, 260 μmol) was added dropwise to stirred mixture of (6aR,9R)-4-acetyl-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg]quinoline-9-carboxamide (101.0 mg, 260 μmol) in anhydrous THF (2.00 mL) under inert atmosphere and at 0 °C. The mixture was stirred for 10 min at 0 °C and for further 90 min at 15 ambient temperature. Then mixture was cooled down to 0 °C, Tebbe reagent in toluene (0.5 M) (520 μL, 0.50 molar, 260 μmol) was added dropwise and mixture was stirred for further 60 min at ambient temperature. The reaction was diluted with MTBE (20 mL), cooled down to 0 °C, quenched with sodium sulfate decahydrate, suspension was stirred for 10 min at ambient temperature. Crude product was filtered through celite, washed with ethyl acetate (3 x 10 mL) 20 and filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (12 g RediSepRf Si, 0-10% methanol (0.7M NH3) / DCM) to give (6aR,9R)-N,N-diethyl-7-methyl-4-(prop-1-en-2-yl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg]quinoline-9-carboxamide (26.0 mg, 68 μmol, 26 %).

[0201] 1H NMR (500 MHz, CDCl3) δ 1.18 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 2.30 25 (d, J = 1.2 Hz, 3H), 2.66 (s, 3H), 2.91 – 3.02 (m, 1H), 3.08 – 3.18 (m, 1H), 3.26 – 3.36 (m, 1H), 3.40 – 3.65 (m, 6H), 3.90 – 4.10 (m, 1H), 4.90 (d, J = 1.4 Hz, 1H), 5.11 (s, 1H), 6.28 – 6.43 (m, 1H), 6.99 (d, J = 1.7 Hz, 1H), 7.16 – 7.25 (m, 2H), 7.37 – 7.51 (m, 1H).

[0202] MS (ES+): m / z 364.0 Example 26. Synthesis of Compound I-8: (6aR,9S)-N,N-diethyl-7-phenyl-4,6,6a,7,8,9- 30 hexahydroindolo[4,3-fg]quinoline-9-carboxamide 59 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WOp y , y y y , , , tetrahydroindolo[4,3-fg] quinoline-4(6H)-carboxylate

[0203] DMAP (5 mg, 41 μmol) was added to a stirred mixture of (6aR,9R)-N,N-diethyl-7- 5 methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (177 mg, 547 μmol) and Boc Anhydride (143 mg, 657 μmol) in DCM (2.00 mL). The reaction mixture was stirred 2 h at ambient temperature and then it was concentrated under reduced pressure.

[0204] The crude product was purified by chromatography on silica gel (12 g cartridge, 0-10% (0.7 M NH3 / MeOH) in DCM) to afford tert-butyl (6aR,9R)-9-(diethylcarbamoyl)-7-methyl- 10 6a,7,8,9-tetrahydroindolo[4,3-fg]quinoline-4(6H)-carboxylate (223 mg, 526 μmol, 96.2 %).

[0205] MS (ES+): m / z 424.5 Step 2: tert-Butyl (6aR,9R)-9-(diethylcarbamoyl)-6a,7,8,9-tetrahydroindolo[4,3- fg]quinoline-4(6H)-carboxylate

[0206] mCPBA (142 mg, 77% Wt, 632 μmol) was added in one portion to a stirred mixture of15 tert-butyl (6aR,9R)-9-(diethylcarbamoyl)-7-methyl-6a,7,8,9-tetrahydroindolo[4,3- fg]quinoline-4(6H)-carboxylate (223 mg, 527 μmol) in DCM (3.00 mL) under inert atmosphere and at 0 °C. The reaction was stirred at 0 °C for 20 min. Then iron(II) sulfate heptahydrate (73 mg, 263 μmol) in Methanol (1.00 mL) was added. Then reaction was stirred for 3 h at ambient temperature. The reaction was quenched with 0.1 M pH 9 EDTA aqueous 20 solution (10 mL) and stirred for 10 min. The mixture was then transferred into a separating funnel and crude product was extracted with DCM + 10% MeOH (3 x 15 mL). The combined organic layer was washed with Brine (20 mL), collected, dried over Magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 60 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO g cartridge, 0-10% (0.7 M NH3 / MeOH) in DCM) to afford tert-butyl (6aR,9R)-9- (diethylcarbamoyl)-6a,7,8,9-tetrahydroindolo[4,3-fg]quinoline-4 (6H)-carboxylate (71 mg, 173 μmol, 32.9 %).

[0207] MS (ES+): m / z 410.0 5 Step 3: (6aR,9R)-9-(diethylcarbamoyl)-7-phenyl-6a,7,8,9-tetrahydroindolo[4,3- fg]quinoline-4(6H)-carboxylate

[0208] BippyPhos Pd G6 Br (20.0 mg, 24 μmol) was added to a stirred mixture of tert-butyl (6aR,9R)-9-(diethylcarbamoyl)-6a,7,8,9-tetrahydroindolo[4,3-fg]quinoline-4(6H)- carboxylate (100.0 mg, 232 μmol), bromobenzene (50.0 μL, 475 μmol), Cs2CO3 (226.7 mg, 10 696 μmol) and 4Å Molecular sieves (200 mg) in 1,4-Dioxane (2.00 mL) under inert atmosphere. The reaction was stirred at 60 °C for 5 h under inert atmosphere. The reaction was cooled down to ambient temperature and diluted with ethyl acetate (10 mL). The mixture was filtered through celite, washed with ethyl acetate (3 x 10 mL) and filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (12 g15 cartridge, 0-50% EtOAc in isohexane) to afford tert-butyl (6aR,9R)-9-(diethylcarbamoyl)-7- phenyl-6a,7,8,9-tetrahydroindolo[4,3-fg]quinoline-4(6H)-carboxylate (81.0 mg, 160 μmol, 68 %).

[0209] MS (ES+): m / z 486.5 Step 4: (6aR,9R)-N,N-diethyl-7-phenyl-4,6,6a,7,8,9-hexahydroindolo[4,3- 20 fg]quinoline-9-carboxamide

[0210] A mixture of tert-butyl (6aR,9R)-9-(diethylcarbamoyl)-7-phenyl-6a,7,8,9- tetrahydroindolo[4,3-fg]quinoline-4(6H)-carboxylate (40.0 mg, 77 μmol) in TFA ( 1.00 mL, 13.0 mmol) was stirred for 90 min. The reaction was diluted with DCM (10 mL), quenched with sat. sodium bicarbonate solution (10 mL) and transferred into a separating funnel. The 25 crude product was extracted with DCM (3 x 10 mL). The combined organic layer was collected, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (4 g cartridge, 20-80%, (1:3 EtOH / EtOAc) in isohexane), fractions containing product were combined and concentrated. The product was recrystalised from 1:1 MTBE and iso-hexane solution to afford (6aR,9S)-N,N-diethyl-7-phenyl- 30 4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (18.0 mg, 44 μmol, 57 %).

[0211] 1H NMR (500 MHz, CDCl3) δ 1.14 (t, J = 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 2.72 (ddd, J = 14.9, 11.6, 1.8 Hz, 1H), 3.23 (dd, J = 14.9, 5.2 Hz, 1H), 3.32 – 3.45 (m, 2H), 3.50 61 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO (ddd, J = 16.1, 11.3, 7.0 Hz, 3H), 3.70 (dd, J = 11.9, 7.9 Hz, 1H), 3.92 (tt, J = 7.7, 3.0 Hz, 1H), 4.37 (ddt, J = 11.4, 5.1, 2.4 Hz, 1H), 6.46 (t, J = 2.6 Hz, 1H), 6.81 (t, J = 1.9 Hz, 1H), 7.01 – 7.07 (m, 1H), 7.15 – 7.24 (m, 5H), 7.33 (dd, J = 8.6, 7.3 Hz, 2H), 7.87 – 7.91 (m, 1H).

[0212] MS (ES+): m / z 386.5 5 Example 27. Synthesis of Compound II-1: (6aR,9R)-4-(but-2-yn-1-yl)-N,N-diethyl-7- methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamideStep 1: Methyl (6aR)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxylate

[0213] mCPBA (476 mg, 77% Wt, 2.125 mmol) was added to a stirred solution of methyl 10 (6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxylate (500.0 mg, 1.771 mmol) in DCM (10.00 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min. A solution of iron(II) sulfate heptahydrate (246 mg, 0.885 mmol) in degassed methanol (10 mL) was added and the mixture allowed to warm to ambient temperature and stirred for 1 h. The reaction was quenched with aqueous 0.1M EDTA solution (50 mL, adjusted to pH 9 15 with NH4OH) and stirred vigorously for 10 min. The mixture was extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by flash column chromatography (12 g RediSepRf Si, 0-10% methanol (0.7M NH3) / DCM) to give 62 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO methyl (6aR)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxylate (217 mg, 0.80 mmol, 45 %, 99% Purity) as a 3:2 mixture of epimers.

[0214] MS (ES+): m / z 269.3 (M+H)+ Step 2: 7-(tert-Butyl) 9-methyl (6aR,9R)-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline- 5 7,9(4H)-dicarboxylate

[0215] di-tert-Butyl dicarbonate (89.5 mg, 410 μmol) was added to a stirred solution of methyl (9R)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxylate (100 mg, 373 μmol) in DCM (2 mL). The mixture was stirred at ambient temperature for 1 h. The reaction was quenched with saturated aqueous sodium hydrogen carbonate solution (20 mL) and extracted 10 with DCM (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by flash column chromatography (24 g RediSepRf Si, 0-100% ethyl acetate / iso- hexane) to give 7-(tert-butyl) 9-methyl (9R)-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline- 7,9(4H)-dicarboxylate (50.0 mg, 0.13 mmol, 34 %, 94% Purity). 15

[0216] MS (ES+): m / z 269.3 (M+H-Boc)+ Step 3: 7-(tert-Butyl) 9-methyl (6aR)-4-(but-2-yn-1-yl)-6,6a,8,9- tetrahydroindolo[4,3-fg]quinoline-7,9(4H)-dicarboxylate

[0217] Sodium hydride (10.9 mg, 60% Wt in mineral oil, 271 μmol) was added to a stirred solution of 7-(tert-butyl) 9-methyl (9R)-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-7,9(4H)- 20 dicarboxylate (50.0 mg, 136 μmol) in anhydrous THF (1.00 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 minutes before 1-bromobut-2-yne (27.3 mg, 18.0 μL, 206 μmol) was added. The mixture was allowed to warm to ambient temperature and stirred for a further 30 minutes. The reaction was quenched with saturated aqueous sodium hydrogen carbonate solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic 25 layers were washed with brine (30 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. Teh residue was purified by flash column chromatography (4 g RediSepRf Si, 0-100% ethyl acetate / iso-hexane) to give 7-(tert-butyl) 9-methyl (9R)-4- (but-2-yn-1-yl)-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-7,9(4H)-dicarboxylate (27.8 mg, 65 μmol, 48 %, 99% Purity) as a mixture of epimers. 30

[0218] MS (ES+): m / z 321.0 (M+H-Boc)+ Step 4: (6aR)-4-(but-2-yn-1-yl)-7-(tert-butoxycarbonyl)-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxylic acid 63 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO

[0219] Lithium hydroxide monohydrate (15.00 mg, 357.5 μmol) was added to a stirred solution of 7-(tert-butyl) 9-methyl (9R)-4-(but-2-yn-1-yl)-6,6a,8,9-tetrahydroindolo[4,3- fg]quinoline-7,9(4H)-dicarboxylate (27.8 mg, 66.1 μmol) in a mixture of MeOH (1.00 mL) and water (0.5 mL). The mixture was stirred at ambient temperature for 2.5 h. The mixture was 5 diluted with additional methanol (10 mL) and evaporated to dryness under reduced pressure to give lithium (9R)-4-(but-2-yn-1-yl)-7-(tert-butoxycarbonyl)-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxylate (27.8 mg, 67 μmol, 100 %, 99% Purity). The crude product was used directly in next step without further purification.

[0220] MS (ES+): m / z 307.6 (M+H-Boc)+ 10 Step 5: tert-Butyl (6aR)-4-(but-2-yn-1-yl)-9-(diethylcarbamoyl)-6,6a,8,9- tetrahydroindolo[4,3-fg]quinoline-7(4H)-carboxylate

[0221] Propylphosphonic anhydride (80.0 μL, 50% Wt in ethyl acetate, 136 μmol) was added to a stirred solution of lithium (9R)-4-(but-2-yn-1-yl)-7-(tert-butoxycarbonyl)-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxylate (27.3 mg, 66.1 μmol) and diethylamine (70.0 15 μL, 677 μmol) in DCM (1 mL). The mixture was stirred at ambient temperature for 1.5 h. The reaction was quenched with saturated aqueous sodium hydrogen carbonate solution (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was purfied by flash column chromatography (4 g RediSepRf Si, 0-100%20 ethyl acetate / isohexane) to give tert-butyl (9R)-4-(but-2-yn-1-yl)-9-(diethylcarbamoyl)- 6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-7(4H)-carboxylate (15.2 mg, 23 μmol, 35 %, 70% Purity).

[0222] MS (ES+): m / z 462.2 (M+H)+ Step 6: (6aR,9R)-4-(but-2-yn-1-yl)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- 25 fg]quinoline-9-carboxamide hydrochloride

[0223] HCl (4M in dioxane) (146 mg, 1.00 mL, 4.00 molar, 174 Eq, 4.00 mmol) was added to a vial containing tert-butyl (6aR,9R)-4-(but-2-yn-1-yl)-9-(diethylcarbamoyl)-6,6a,8,9- tetrahydroindolo[4,3-fg]quinoline-7(4H)-carboxylate (15.2 mg, 70% Wt, 1 Eq, 23.0 μmol). The mixture was stirred at ambient temperature for 30 min. The volatiles were removed under30 reduced pressure to give (6aR,9R)-4-(but-2-yn-1-yl)-N,N-diethyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide hydrochloride (13.0 mg, 23 μmol, 99 %, 70% Purity), which was used directly in the next step without further purification. 64 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO

[0224] MS (ES+): m / z 362.4 Step 7: (6aR,9R)-4-(but-2-yn-1-yl)-N,N-diethyl-7-methyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide

[0225] Formaldehyde (37% solution) (328.0 μL, 37% Wt, 376 μmol), triethylamine (15.0 μL, 5 108 μmol) and sodium triacetoxyborohydride (11.0 mg, 51.9 μmol) were added sequentially to a stirred suspension of (6aR,9R)-4-(but-2-yn-1-yl)-N,N-diethyl-4,6,6a,7,8,9- hexahydroindolo[4,3-fg]quinoline-9-carboxamide hydrochloride (8.31 mg, 14.6 μmol) in DCM (0.5 mL). The mixture was stirred at ambient temperature for 30 minutes. The reaction was quenched with saturated aqueous sodium hydrogen carbonate solution (5 mL) and 10 extracted with DCM (3 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by reversed-phase chromatography (5.5 g RediSepRF C18 Gold, 10-80% acetonitrile / water (10 mM ammonium bicarbonate)). The fractions containing product were lyophilized to give (6aR,9R)-4-(but-2-yn-1-yl)-N,N-diethyl-7-methyl-4,6,6a,7,8,9- 15 hexahydroindolo[4,3-fg]quinoline-9-carboxamide (1.20 mg, 2.7 μmol, 19 %).

[0226] 1H NMR (500 MHz, MeOD) δ 0.81 – 1.46 (m, 6H), 1.79 (s, 3H), 2.48 (s, 3H), 2.55 – 2.74 (m, 2H), 2.96 – 3.07 (m, 1H), 3.08 – 3.19 (m, 1H), 6.73 (d, J = 10.5 Hz, 1H), 6.95 (d, J = 4.7 Hz, 1H), 7.06 – 7.16 (m, 2H), 7.20 (d, J = 7.0 Hz, 1H). 3H occluded by residual solvent peaks. 20

[0227] MS (ES+): m / z 376.5 Example 28. Potency of Exemplary Compounds Across 5-HT Receptor Subtypes

[0228] HHEK cells overexpressing 5-HT1A(plus Gqi chimeric G-protein), 5-HT2A, 5HT2B, 5- HT2C, 5-HT6 (plus Gqs chimeric G-protein), and 5-HT7 (plus Gqs chimeric G-protein) were counted and seeded in black, clear-bottomed 384 well plates. 25

[0229] Next day, media was removed from the cell plates and 30 µl assay buffer (20 mM HEPES: HBSS, pH 7.4) was added. 10 µl Calcium 5 dye solution (prepared in assay buffer) was added to the wells and the plates incubated at 37^C for 40 minutes.

[0230] Compound dilutions (including serial dilutions) were performed in 100% DMSO then transferred to intermediate dilutions in assay buffer for a limited amount of time (<10 minutes). 30

[0231] The plates were placed in the FLIPR, and fluorescence monitored every 1 second. After 20 seconds 10 µl test compounds and controls were added to the wells and the fluorescence monitored for 5 minutes at ex / emm: 488nm / 510-570nm to monitor compounds as agonists. 65 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO

[0232] Results are shown in the tables below. Table 4. 5HT1A 5HT2A 5HT2B Compound Emax (%) pEC50 Emax (%) pEC50 Emax (%) pEC50Table 5. 5HT2C 5HT6 5HT7 0 566 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO EQUIVALENTS

[0233] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more 5 than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the group members are 10 present in, employed in, or otherwise relevant to a given product or process.

[0234] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any 15 other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the present disclosure refers to as comprising particular elements and / or features, some embodiments of the present disclosure or aspects of the present disclosure consist, or consist 20 essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary 25 skill in the art, values that are expressed as ranges can assume any specific value or sub–range within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0235] The present disclosure refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If 30 there is a conflict between any of the incorporated references and the instant specification, the specification shall control.

[0236] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope 67 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims. 68 ACTIVE / 137605080.1

Claims

Attorney Docket No.: CYBP-003WO CLAIMS What is claimed:

1. A compound of Formula A: 5 or a pharmaceutically accepwherein R1Ais H, C2-C6 alkenyl, C2-C6 alkynyl, –C(O)-R4A, or –O-R4A; R2Ais C2-C6 alkyl, 3-8 membered monocyclic carbocyclyl, phenyl, –C1-C6 alkyl-phenyl, 10 or –O-C1-C6 alkyl-phenyl, ; kyl, 3-8 membered monocyclic carbocyclyl, or –C1-C67Aalkyl-R ; R5Ais H, C1-C6alkyl, C1-C6hydroxyalkyl, or C2-C6alkynyl; R6Ais H, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C2-C6 alkynyl; and 15 R7Ais –C1-C6alkyl-O- C1-C6alkyl or 3-8 membered monocyclic carbocyclyl, provided that when R3A 5Ais –Et, and R6Ais –Et,then R2Ais no .

2. The compoun o c am , w ere n s .

3. The compound of claim 1, wherein R1Ais C2-C6 alkenyl. 20 4. The compound of claim 3, wherein R1Ai.

5. The compound of claim 1, wherein R1Ais C2-C6alkynyl. 69 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO 6. The compound of claim 5, wherei .

7. The compound of claim 1, wherei )4A 4A-R or –O-R .

8. The compound of claim 1, wherein R1Ais –C(O)-R4A.

9. The compound of claim 1, wherein R1Ais–O-R4A. 5 10. The compound of any one of claims 7-9, wherein R4Ais C1-C6 alkyl.

11. The compound of claim 10, wherein R4Ais –Et, –nPr, –iPr, –nBu, –sBu, –tBu, –(CH2)4CH3, or –(CH2)5CH3.

12. The compound of claim 10, wherein R4Ais –Et, –nPr, –iPr, –nBu, –sBu, or – tBu. 10 13. The compound of any one of claims 7-9, wherein R4Ais 3-8 membered monocyclic carbocyclyl.

14. The compound of claim 13, wherein R4Ais 3-6 membered monocyclic carbocyclyl.

15. The compound of claim 13, wherein R4Ais 3-6 membered monocyclic 15 carbocyclyl.

16. The compound of claim 13, wherein R4Aor.

17. The compound of any one of claims 7-9, wherein R4Ais –C1-C6alkyl-R7A.

18. The compound of claim 17, wherein R7Ais –O-C1-C6alkyl 20 19. The compound of claim 18, wherein R7Ais –OMe, –OEt, –OiPr, or –OtBu.

20. The compound of claim 18, wherein R7Ais –OMe.

21. The compound of claim 17, wherein R7Ais 3-8 membered monocyclic carbocyclyl. 70 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO 22. The compound of claim 20, wherein R7Ais 3-6 membered monocyclic carbocyclyl.

23. The compound of claim 20, wherein R7Ais , or.5 24. The compound of claim 20, wherein R7Ais .

25. The compound of claim 17, wherein R4Ais or .

26. The compound of any one of claims 1-25kyl.

27. The compound of claim 26, wherein R2Ais –Et, –nPr, –iPr, –nBu, –sBu, –tBu, –(CH2)4CH3, or –(CH2)5CH3. 10 28. The compound of claim 26, wherein R2Ais –Et, –nPr, –iPr, –nBu, –sBu, or – tBu.

29. The compound of any one of claims 1 to 25, wherein R2Ais 3-8 membered monocyclic carbocyclyl.

30. The compound of claim 29, wherein R2Ais 3-6 membered monocyclic 15 carbocyclyl.

31. The compound of claim 29, wherein R2Ai or.

32. The compound of any one of claims 1 to 25, wherein R2Ais phenyl.

33. The compound of any one of claims 1 to 25, wherein R2Ais –C1-C6 alkyl- 20 phenyl.

34. The compound of claim 33, wherein R2A.71 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO 35. The compound of any one of claims 1 to 25, wherein R2Ais –O-C1-C6alkyl- phenyl.

36. The compound of claim 35, wherein R2Ai .

37. The compound of any one of claims 1-36is H. 5 38. The compound of any one of claims 1-36, wherein R5Ais H or C1-C6 alkyl.

39. The compound of any one of claims 1-36, wherein R5Ais C1-C6 alkyl.

40. The compound of claim 39, wherein R5Ais –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, –(CH2)4CH3, or –(CH2)5CH3.

41. The compound of claim 39, wherein R5Ais –Me, –Et, –nPr, –iPr, –nBu, –sBu, 10 or –tBu.

42. The compound of any one of claims 1-36, wherein R5Ais C1-C6hydroxyalkyl.

43. The compound of claim 42, wherein R5Ais .

44. The compound of any one of claims 1-36, ein R5Ais C2-C6alkynyl.

45. The compound of claim 44, wherein R5Ais . 15 46. The compound of any one of claims 1-45,w ere n s H.

47. The compound of any one of claims 1-45, wherein R6Ais H or C1-C6alkyl.

48. The compound of any one of claims 1-45, wherein R6Ais C1-C6 alkyl.

49. The compound of claim 48, wherein R6Ais –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, –(CH2)4CH3, or –(CH2)5CH3. 20 50. The compound of claim 48, wherein R6Ais –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

51. The compound of any one of claims 1-45, wherein R6Ais C1-C6 hydroxyalkyl.

52. The compound of claim 51, wherein R6A.72 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO 53. The compound of any one of claims 1-45, wherein R6Ais C2-C6alkynyl.

54. The compound of claim 53, wherein R6Ais .

55. The compound of any one of claims 1-54,ompound has the structure of any one of the following, or a pharmaceutically acceptable salt thereof: ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO 56. A compound oor a pharmaceutically acceptable salt thereof, 5 wherein R1Bis C2-C6alkenyl, C2-C6alkynyl, –C(O)-R4A, or –O-R4A; R2Bis –Me; ;kyl, 3-8 membered monocyclic carbocyclyl, or –C1-C6 alkyl-R7B; 10 R5Bis H, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C2-C6 alkynyl; R6Bis H, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C2-C6 alkynyl; and R7Bis –C1-C6 alkyl-O- C1-C6 alkyl or 3-8 membered monocyclic carbocyclyl. 74 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO 57. The compound of claim 56, wherein R1Bis C2-C6alkenyl.

58. The compound of claim 57, wherein R1Bi .

59. The compound of claim 56, wherein R1Bis C2-C6 alkynyl.

60. The compound of claim 59, wherei . 5 61. The compound of claim 56, wherei )-R4Bor –4BO-R .

62. The compound of claim 56, wherein R1Bis –C(O)-R4B.

63. The compound of claim 56, wherein R1Bis–O-R4B.

64. The compound of any one of claims 61-63, wherein R4Bis C1-C6 alkyl.

65. The compound of claim 64, wherein R4Bis –Et, –nPr, –iPr, –nBu, –sBu, –tBu, 10 –(CH2)4CH3, or –(CH2)5CH3.

66. The compound of claim 64, wherein R4Bis –Et, –nPr, –iPr, –nBu, –sBu, or – tBu.

67. The compound of any one of claims 61-63, wherein R4Bis 3-8 membered monocyclic carbocyclyl. 15 68. The compound of claim 67, wherein R4Bis 3-6 membered monocyclic carbocyclyl.

69. The compound of claim 67, wherein R4Bis 3-6 membered monocyclic carbocyclyl.

70. The compound of claim 67, wherein R4B, or20 .

71. The compound of any one of claims 61-63, wherein R4Bis –C1-C6 alkyl-R7B.

72. The compound of claim 71, wherein R7Bis –O-C1-C6alkyl 75 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO 73. The compound of claim 72, wherein R7Bis –OMe, –OEt, –OiPr, or –OtBu.

74. The compound of claim 72, wherein R7Bis –OMe.

75. The compound of claim 71, wherein R7Bis 3-8 membered monocyclic carbocyclyl. 5 76. The compound of claim 71, wherein R7Bis 3-6 membered monocyclic carbocyclyl.

77. The compound of claim 76, wherein R7Bi , or.

78. The compound of claim 76, wherein R7Bi r .10 79. The compound of claim 76, wherein R7Bi .

80. The compound of any one of claims 56-7, rein R5Bis H.

81. The compound of any one of claims 56-79, wherein R5Bis H or C1-C6alkyl.

82. The compound of any one of claims 56-79, wherein R5Bis C1-C6alkyl.

83. The compound of claim 82, wherein R5Bis –Me, –Et, –nPr, –iPr, –nBu, –sBu, 15 –tBu, –(CH2)4CH3, or –(CH2)5CH3.

84. The compound of claim 82, wherein R5Bis –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

85. The compound of any one of claims 56-79, wherein R5Bis C1-C6hydroxyalkyl. 20 86. The compound of claim 85, wherein R5B.

87. The compound of any one of claims 56-79, wherein R5Bis C2-C6 alkynyl.

88. The compound of claim 87, wherein R5Bis .76 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO 89. The compound of any one of claims 56-88, wherein R6Bis H.

90. The compound of any one of claims 56-88, wherein R6Bis H or C1-C6alkyl.

91. The compound of any one of claims 56-88, wherein R6Bis C1-C6alkyl.

92. The compound of claim 91, wherein R6Bis –Me, –Et, –nPr, –iPr, –nBu, –sBu, 5 –tBu, –(CH2)4CH3, or –(CH2)5CH3.

93. The compound of claim 91, wherein R6Bis –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

94. The compound of any one of claims 56-88, wherein R6Bis C1-C6hydroxyalkyl. 10 95. The compound of claim 94, wherein R6Bis .

96. The compound of any one of claims 56-8, rein R6Bis C2-C6 alkynyl.

97. The compound of claim 96, wherein R6Bi .

98. The compound of any one of claims 56-97, compound has the structure of any one of the following, or a pharmaceutically acceptable salt thereof:77 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO N 99. A compound of Formula C: 5 or a pharmaceutically accepwherein R1Cis H; R2Cis –Me; ; 10ydroxyalkyl or C2-C6 alkynyl.

100. The compound of claim 99, wherein R6Cis C1-C6 hydroxyalkyl.

101. The compound of claim 100, wherein R6Cis . compound of claim 99, wherein R6102. TheCis C2-C6 alkynyl. 15 103. The compound of claim 102, wherein R6Ci .

104. The compound of any one of claims 99-103, wherein the compound has the structure of any one of the following, or a pharmaceutically acceptable salt thereof: 79 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO105. A compound, or a pharmaceutically acceptable salt thereof, selected from:80 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO81 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO106. A pharmaceutical composition comprising a compound of any one of claims 1-105, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 83 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO 107. A method of modulating a serotonin receptor in a subject in need thereof, the method comprising administering to the subject a compound of any one of claims 1-105, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 106.

108. The method of claim 107, wherein the serotonin receptor is 5-HT2A receptor, 5 5-HT2C receptor, or 5-HT7 receptor.

109. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a compound of any one of claims 1-105, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 106.

110. The method of claim 109, wherein the disease is pain. 10 111. The method of claim 109 or 110, wherein the pain is treatment resistant pain.

112. The method of claim 109 or 110, wherein the pain is opioid resistant pain.

113. The method of claim 109 or 110, wherein the pain is opioid resistant refractory pain.

114. The method of claim 109 or 110, wherein the pain is neuropathic pain. 15 115. The method of claim 109 or 110, wherein the pain is nociceptive pain.

116. The method of claim 109 or 110, wherein the pain is inflammatory pain.

117. The method of claim 109 or 110, wherein the pain is nociplastic pain.

118. The method of any one of claims 110-117, wherein the pain is acute.

119. The method of any one of claims 110-117, wherein the pain is chronic. 20 120. The method of claim 109, wherein the disease is autism, anxiety, depression, bipolar disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, a psychotic disorder, a psychotic symptom, social withdrawal, obsessive- compulsive disorder (OCD), phobia, post-traumatic stress syndrome, post-traumatic stress disorder (PTSD), a behavior disorder, an impulse control disorder, a substance abuse disorder 25 (e.g., a withdrawal symptom, opiate addiction, nicotine addiction, and ethanol addition), a sleep disorder, a memory disorder (e.g., a deficit, loss, or reduced ability to make new memories), a learning disorder, Tourette's syndrome, epilepsy, cerebral ischemia, special learning disorders, seizures, post-stroke convulsions, brain ischemia, migraine, stroke, spinal cord injury, peripheral neuropathy, acute neuropathic pain, or chronic neuropathic pain. 84 ACTIVE / 137605080.1Attorney Docket No.: CYBP-003WO 121. The method of claim 109, wherein the disease is depression, anxiety, pain, inflammation, addiction, an autoimmune disease, an eating disorder, or an obsessive compulsive disorder.

122. The method of claim 109, wherein the disease is social anxiety disorder, 5 avoidant personality disorder, or schizotypal personality disorder.

123. The method of claim 109, wherein the disease is major depressive disorder, dysthymic disorder, psychotic depression, postpartum depression, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder (SAD), bipolar disorder (or manic depressive disorder), or a mood disorder. 10 124. The method of claim 109, wherein the disease is depression caused by cancer, chronic pain, chemotherapy, chronic stress, or post traumatic stress disorder.

125. The method of claim 109, wherein the disease is obsessive-compulsive spectrum disorder (OCSD).

126. The method of claim 109, wherein the disease is body dysmorphic disorder 15 (BDD), compulsive skin picking, Tourette syndrome, Attention Deficit / Hyperactivity Disorder, anorexia nervosa, antisocial personality disorder (ASPD), autism, basal ganglia disorder, borderline personality disorder (BPD), bulimia, depersonalization disorder, epilepsy, Huntington’s disease, hypochondriasis, kelptomania, personality disorder, pathologic gambling, sexual compulsions, Sydenham's chorea, torticollis, trichotillomania, or 20 Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections.

127. The method of claim 109, wherein the disease is Ankylosing Spondylitis, Chagas disease, chronic obstructive pulmonary disease, Crohns Disease, Dermatomyositis, Endometriosis, Goodpasture’s syndrome, Graves’ disease, Guillain-Barré syndrome, Hashimoto's disease, Hidradenitis suppurativa, Kawasaki disease, IgA nephropathy, 25 idiopathic thrombocytopenic purpura, interstitial cystitis, lupus erythematosus, mixed connective tissue disease, morphea, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anaemia, psoriasis, psoriatic Arthritis, polymyositis, primary biliary cirrhosis, relapsing polychondritis, rheumatoid arthritis, schizophrenia, scleroderma, Sjögren’s syndrome, stiff person syndrome, temporal arteritis, ulcerative colitis, vasculitis, 30 vitiligo, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, ankylosing spondilitis, scleroderma, Type I diabetes, psoriatic arthritis, osteoarthritis, inflammatory bowel disease, atopic dermatitis and asthma, or Wegener's granulomatosis. 85 ACTIVE / 137605080.1

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