Ergoline derivatives and uses thereof

Abstract

Provided herein are ergoline derivatives which modulate 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. (I)

Description

Attorney Docket No.: CYBP-004WO 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 / 643,999, filed May 8, 2024, which is incorporated herein by reference in its entirety. 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

[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 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.

[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

[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 and Table 2; 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 / 137605700.1Attorney Docket No.: CYBP-004WOor a pharmaceutically wherein R1Ais H, C1-C6 alkyl, or C1-C6 hydroxyalkyl; R2Ais C2-C6alkyl, C1-C6hydroxyalkyl, or phenyl; R3Ais C1-C6alkyl-R4Aor ; or C1-C6 alkyl-phenyl, and R6Ais H, C1-C6 alkyl, or C1-C6 alkyl-phenyl; or R5Aand R6A, together with the atom to which each is attached, combine to form 3- 8 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from O, S, and N.

[0007] In some embodiments, when R3Ais , R5Ais –Et, and R6Ais –Et, then R2Ais not –nPr.

[0008] Disclosed herein, in some embodiments, is a compound of Formula B:or a pharmaceutically acceptable salt thereof, wherein R1Bis H, C1-C6 alkyl, or C1-C6 hydroxyalkyl; 2 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO R2Bis –Me; ; phenyl, and R6Bis H, C1-C6alkyl, or C1-C6alkyl-atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from O, S, and N.

[0009] In some embodiments, when R1Bis H, R3Bis , and R5Bis –Et, then R6Bis not –Et. In some embodiments, when R3Bis , R5Bis H, and R6Bis H, then R1Bis not H or –Me. In some embodiments, when R1Bis H, R3Bis , and R5Bis H, then R6Bis not – nBu or –iPr.

[0010] Disclosed herein, in some embodiments, is a compound of Formula C:or a pharmaceutically acceptable salt thereof, wherein R1Cis H, C1-C6alkyl, or C1-C6hydroxyalkyl; R2Cis C1-C6alkyl, C1-C6hydroxyalkyl, or phenyl; R3Cis C1-C6 alkyl- ;3 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO or C1-C6 alkyl-phenyl, and R6Cis C1-C6 alkyl-phenyl, or R5Cand R6C,to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0011] 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.

[0012] Disclosed herein, in some embodiments, is a process for providing a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0013] 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0014] 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

[0015] 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 and Table 2; 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 present disclosure also features methods for synthesizing compounds and compositions useful for treating a disease or disorder (e.g., pain). Definitions

[0016] 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 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. 4 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO

[0017] 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.

[0018] 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”.

[0019] The terms “disease,” “disorder,” and “condition” are used interchangeably herein.

[0020] 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, 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 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 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 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 “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. 5 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO

[0021] 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.

[0022] 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 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. 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. 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.

[0023] 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 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 “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 receptor and the natural binding partner depending on the concentration of the compound 6 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO exposed to the serotonin receptor, and or may decrease the probability that a complex forms between the serotonin receptor and the natural binding partner.

[0024] 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. 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 serotonin receptor-mediated disease is characterized by abnormal serotonin receptor activity.

[0025] 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 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 crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0026] 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 (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.

[0027] 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 sample is the compound of interest. Purity can be measured by any appropriate method, e.g., chromatography, gel electrophoresis or HPLC analysis. 7 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO Selected Chemical Definitions

[0028] 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 to the standard rules of chemical valency known in the chemical arts.

[0029] 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 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, Cambridge University Press, Cambridge, 1987.

[0030] 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 “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 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., 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 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 8 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0031] As used herein, a pure enantiomeric compound is substantially free from other 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, 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 are based upon total weight of all enantiomers or stereoisomers of the compound.

[0032] 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 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% 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.

[0033] 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 is the aci– and nitro– forms of phenylnitromethane, that are likewise formed by treatment with acid 9 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0034] 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, 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.

[0035] 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.

[0036] “Alkyl” refers to a radical of a straight–chain or branched saturated hydrocarbon group 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– C9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–C8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–C7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–C6 alkyl”, 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, an alkyl group has 1 carbon atom (“C1 alkyl”). 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 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 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).

[0037] “Hydroxyalkyl” refers to an alkyl group, as defined above, wherein one or more (e.g., one, two, three, four, or five) of the hydrogen atoms are independently replaced with a hydroxyl 10 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO group (–OH). Exemplary hydroxyalkyl groups include –CH2OH, –CH2CH2OH, –C(CH3)2OH and the like

[0038] “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 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 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

[0039] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. Formula A

[0040] Disclosed herein, in some embodiments, is a compound of Formula A:or a pharmaceutically acceptable salt thereof, wherein R1Ais H, C1-C6 alkyl, or C1-C6 hydroxyalkyl; R2Ais C2-C6alkyl, C1-C6hydroxyalkyl, or phenyl; R3Ais C1-C6alkyl-R4Aor ; 11 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO R4Ais ; and R5Ais H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Ais H, C1-C6 alkyl, or C1-C6 alkyl- phenyl; or R5Aand R6A, together with the atom to which each is attached, combine to form 3- 8 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from O, S, and N.

[0041] In some embodiments, when R3Ais , R5Ais –Et, and R6Ais –Et, then R2Ais not –nPr.

[0042] In some embodiments, the compound is a compound of Formula A, or a pharmaceutically acceptable salt thereof, wherein: R1Ais H, C1-C6alkyl, or C1-C6hydroxyalkyl; R2Ais C2-C6 alkyl, C1-C6 hydroxyalkyl, or phenyl; R3Ais C1-C6 alkyl-R4Aor ; R4Ais ; and R5Ais H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Ais C1-C6 alkyl-phenyl, or R5Aand R6A, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0043] In some embodiments, the compound is a compound of Formula A, or a pharmaceutically acceptable salt thereof, wherein: R1Ais H or C1-C6 alkyl; R2Ais C2-C6 alkyl, C1-C6 hydroxyalkyl, or phenyl; R3Ais C1-C6 alkyl-R4Aor ; R4Ais ; and R5Ais H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Ais C1-C6 alkyl-phenyl, or R5Aand R6A, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N. 12 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO

[0044] In some embodiments, the compound is a compound of Formula A, or a pharmaceutically acceptable salt thereof, wherein: R1Ais H; R2Ais C2-C6alkyl, C1-C6hydroxyalkyl, or phenyl; R3Ais C1-C6alkyl-R4Aor ; R4Ais ; and R5Ais H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Ais C1-C6 alkyl-phenyl, or R5Aand R6A, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0045] In some embodiments, the compound is a compound of Formula A, or a pharmaceutically acceptable salt thereof, wherein: R1Ais H, C1-C6 alkyl, or C1-C6 hydroxyalkyl; R2Ais C2-C6alkyl, C1-C6hydroxyalkyl, or phenyl; R3Ais ; and R5Ais H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Ais C1-C6 alkyl-phenyl, or R5Aand R6A, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0046] In some embodiments, the compound is a compound of Formula A, or a pharmaceutically acceptable salt thereof, wherein: R1Ais H or C1-C6alkyl; R2Ais C2-C6 alkyl, C1-C6 hydroxyalkyl, or phenyl; R3Ais ; and R5Ais H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Ais C1-C6 alkyl-phenyl, or R5Aand R6A, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0047] In some embodiments, the compound is a compound of Formula A, or a pharmaceutically acceptable salt thereof, wherein: R1Ais H; 13 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO R2Ais C2-C6alkyl, C1-C6hydroxyalkyl, or phenyl; R3Ais ; and R5Ais H, C1-C6alkyl, or C1-C6alkyl-phenyl, and R6Ais C1-C6alkyl-phenyl, or R5Aand R6A, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0048] In some embodiments, the compound is a compound of Formula A, or a pharmaceutically acceptable salt thereof, wherein: R1Ais H, C1-C6 alkyl, or C1-C6 hydroxyalkyl; R2Ais C2-C6alkyl, C1-C6hydroxyalkyl, or phenyl; R3Ais ; and R5Ais H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Ais C1-C6 alkyl-phenyl.

[0049] In some embodiments, the compound is a compound of Formula A, or a pharmaceutically acceptable salt thereof, wherein: R1Ais H or C1-C6 alkyl; R2Ais C2-C6alkyl, C1-C6hydroxyalkyl, or phenyl;or C1-C6 alkyl-phenyl, and R6Ais C1-C6 alkyl-phenyl.

[0050] In some embodiments, the compound is a compound of Formula A, or a pharmaceutically acceptable salt thereof, wherein: R1Ais H; R2Ais C2-C6 alkyl, C1-C6 hydroxyalkyl, or phenyl; R3Ais ; and R5Ais H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Ais C1-C6 alkyl-phenyl.

[0051] In some embodiments, R1Ais H or C1-C6alkyl. In some embodiments, R1Ais H. In some embodiments, R1Ais C1-C6 alkyl. In some embodiments, R1Ais C1-C6 hydroxyalkyl. In some embodiments, R1Ais C1-C3hydroxyalkyl.

[0052] In some embodiments, R1Ais –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, –(CH2)4CH3, or –(CH2)5CH3. In some embodiments, R1Ais –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some 14 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO embodiments, R1Ais –Me. In some embodiments, R1Ais –Et. In some embodiments, R1Ais – nPr. In some embodiments, R1Ais –iPr. In some embodiments, R1Ais –nBu. In some embodiments, R1Ais –sBu. In some embodiments, R1Ais –tBu. In some embodiments, R1Ais .

[0053] In some embodiments, R2Ais C2-C6 alkyl or C1-C6 hydroxyalkyl. In some embodiments, R2Ais C2-C6alkyl. In some embodiments, R2Ais C1-C6hydroxyalkyl. In some embodiments, R2Ais phenyl.

[0054] In some embodiments, R2Ais –Et, –nPr, –iPr, –nBu, –sBu, –tBu, –(CH2)4CH3, or – (CH2)5CH3. In some embodiments, R2Ais –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, R2Ais –Et. In some embodiments, R2Ais –nPr. In some embodiments, R2Ais – iPr. In some embodiments, R2Ais –nBu. In some embodiments, R2Ais –sBu. In some embodiments, R2Ais –tBu. In some embodiments, R2A.

[0055] In some embodiments, R3Ais C1-C6alkyl-3Aembodiments, R is C1-C3alkyl-R4A. In some embodiments, R3Ais .

[0056] In some embodiments, R5Ais H or C1-C6 alkyl. In some embodiments, R5Ais H or C1- C6alkyl-phenyl. In some embodiments, R5Ais H. In some embodiments, R5Ais C1-C6alkyl. In some embodiments, R5Ais C1-C6alkyl-phenyl. In some embodiments, R5Ais C1-C3-phenyl.

[0057] In some embodiments, R5Ais –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, –(CH2)4CH3, or –(CH2)5CH3. In some embodiments, R5Ais –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, R5Ais –Me. In some embodiments, R5Ais –Et. In some embodiments, R5Ais – nPr. In some embodiments, R5Ais –iPr. In some embodiments, R5Ais –nBu. In some embodiments, R5Ais –sBu. In some embodiments, R5Ais –tBu. In some embodiments, R5Ais CH3CH3is orAttorney Docket No.: CYBP-004WO CH3. In some embodiments, R5AisisC6 alkyl-phenyl. In some embodiments, R6Ais H. In some embodiments, R6Ais C1-C6 alkyl. In some embodiments, R6Ais C1-C6 alkyl-phenyl. In some embodiments, R6Ais C1-C3-phenyl.

[0059] 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. In some embodiments, R6Ais –Me. In some embodiments, R6Ais –Et. In some embodiments, R6Ais – nPr. In some embodiments, R6Ais –iPr. In some embodiments, R6Ais –nBu. In some embodiments, R6Ais –sBu. In some embodiments, R6Ais –tBu. In some embodiments, R6Ais CH3CH3is or is iscombine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N. 16 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO

[0061] In some embodiments, R5Aand R6A, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O and N. In some embodiments, R5Aand R6A, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N. In some embodiments, R5Aand R6A, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O and N. In some embodiments, R5Aand R6A, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1-2 N atoms. In some embodiments, R5Aand R6A, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1 N atom.

[0062] In some embodiments, R5Aand R6A, together with the atom to which each is attached, combine to form .

[0063] In some R5Ais H, C -C alkyl, or C -C alkyl-ph6A1 6 1 6 enyl, and R is C1-C6 alkyl-phenyl.

[0064] In some embodiments, R5Ais H or C1-C6 alkyl, and R6Ais C1-C6 alkyl-phenyl.

[0065] In some embodiments, R5Ais H, and R6Ais C1-C6alkyl-phenyl.

[0066] In some embodiments, R5Ais C1-C6 alkyl, and R6Ais C1-C6 alkyl-phenyl.

[0067] In some embodiments, R5Ais H or C1-C6alkyl, and R6Ais C1-C3alkyl-phenyl.

[0068] In some embodiments, R5Ais H, and R6Ais C1-C3alkyl-phenyl.

[0069] In some embodiments, R5Ais C1-C6 alkyl, and R6Ais C1-C3 alkyl-phenyl. CH3CH3

[0070] In some .

[0071] In some .

[0072] In some .17 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO CH3

[0073] In some .

[0074] In some a compound of Formula A-I:or a pharmaceutically wherein the variables are as described herein.

[0075] In some embodiments, the compound of Formula A is a compound of Formula A-II:or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein.

[0076] In some embodiments, the compound has the structure of any one of the following, or a pharmaceutically acceptable salt thereof: Formula B

[0077] Disclosed herein, in some embodiments, is a compound of Formula B: 18 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WOor a pharmaceutically wherein R1Bis H, C1-C6 alkyl, or C1-C6 hydroxyalkyl; R2Bis –Me; R3Bis C1-C6alkyl- ;R4Bis ; and R5Bis H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Bis H, C1-C6 alkyl, or C1-C6 alkyl- phenyl; or R5Band R6B, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from O, S, and N.

[0078] In some embodiments, when R1Bis H, R3Bis , and R5Bis –Et, then R6Bis not –Et. In some embodiments, when R3Bis , R5Bis H, and R6Bis H, then R1Bis not H or –Me. In some embodiments, when R1Bis H, R3B, and R5Bis H, then R6Bis not – nBu or –iPr. In some embodiments, (i) when R1Bis H, R3Bis , and R5Bis –Et, then 19 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO R6Bis not –Et; (ii) when R3Bis , R5Bis H, and R6Bis H, then R1Bis not H or –Me; and (iii) then R6Bis not –nBu or –iPr.

[0079] In is a compound of Formula B, or aR1Bis H, C1-C6 alkyl, or C1-C6 hydroxyalkyl; R2Bis –Me; R3Bis C1-C6alkyl-R4Bor ; R4Bis ; and R5Bis H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Bis C1-C6 alkyl-phenyl, or R5Band R6B, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0080] In some embodiments, the compound is a compound of Formula B, or a pharmaceutically acceptable salt thereof, wherein: R1Bis H or C1-C6 alkyl; R2Bis –Me; R3Bis C1-C6alkyl- ;R4Bis ; and R5Bis H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Bis C1-C6 alkyl-phenyl, or R5Band R6B, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0081] In some embodiments, the compound is a compound of Formula B, or a pharmaceutically acceptable salt thereof, wherein: R1Bis H; R2Bis –Me; 20 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO R3Bis C1-C6 alkyl-R4Bor ; R4Bis ; and R5Bis H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Bis C1-C6 alkyl-phenyl, or R5Band R6B, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0082] In some embodiments, the compound is a compound of Formula B, or a pharmaceutically acceptable salt thereof, wherein: R1Bis H, C1-C6alkyl, or C1-C6hydroxyalkyl; R2Bis –Me; R3Bis ; and R5Bis H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Bis C1-C6 alkyl-phenyl, or R5Band R6B, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0083] In some embodiments, the compound is a compound of Formula B, or a pharmaceutically acceptable salt thereof, wherein: R1Bis H or C1-C6alkyl; R2Bis –Me; R3Bis ; and R5Bis H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Bis C1-C6 alkyl-phenyl, or R5Band R6B, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0084] In some embodiments, the compound is a compound of Formula B, or a pharmaceutically acceptable salt thereof, wherein: R1Bis H; R2Bis –Me; R3Bis ; and 21 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO R5Bis H, C1-C6alkyl, or C1-C6alkyl-phenyl, and R6Bis C1-C6alkyl-phenyl, or R5Band R6B, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0085] In some embodiments, the compound is a compound of Formula B, or a pharmaceutically acceptable salt thereof, wherein: R1Bis H, C1-C6alkyl, or C1-C6hydroxyalkyl; R2Bis –Me; R3Bis ; and R5Bis H, C1-C6alkyl, or C1-C6alkyl-phenyl, and R6Bis C1-C6alkyl-phenyl.

[0086] In some embodiments, the compound is a compound of Formula B, or a pharmaceutically acceptable salt thereof, wherein: R1Bis H or C1-C6 alkyl; R2Bis –Me; or C1-C6alkyl-phenyl,6Band R is C1-C6alkyl-phenyl.

[0087] In some embodiments, the compound is a compound of Formula B, or a pharmaceutically acceptable salt thereof, wherein: R1Bis H; R2Bis –Me; R3Bis ; and R5Bis H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Bis C1-C6 alkyl-phenyl.

[0088] In some embodiments, R1Bis H or C1-C6 alkyl. In some embodiments, R1Bis H. In some embodiments, R1Bis C1-C6alkyl. In some embodiments, R1Bis C1-C6hydroxyalkyl. In some embodiments, R1Bis C1-C3 hydroxyalkyl.

[0089] In some embodiments, R1Bis –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, –(CH2)4CH3, or –(CH2)5CH3. In some embodiments, R1Bis –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, R1Bis –Me. In some embodiments, R1Bis –Et. In some embodiments, R1Bis – nPr. In some embodiments, R1Bis –iPr. In some embodiments, R1Bis –nBu. In some 22 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO embodiments, R1Bis –sBu. In some embodiments, R1Bis –tBu. In some embodiments, R1Bis . some embodiments, R2Bis C2-C6 alkyl or C1-C6 hydroxyalkyl. In some embodiments,C6alkyl. In some embodiments, R2Bis C1-C6hydroxyalkyl. In some embodiments, R2Bis phenyl.

[0091] In some embodiments, R2Bis –Et, –nPr, –iPr, –nBu, –sBu, –tBu, –(CH2)4CH3, or – (CH2)5CH3. In some embodiments, R2Bis –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, R2Bis –Et. In some embodiments, R2Bis –nPr. In some embodiments, R2Bis – iPr. In some embodiments, R2Bis –nBu. In some embodiments, R2Bis –sBu. In some embodiments, R2Bis –tBu. In some embodiments, R2B.

[0092] In some embodiments, R3Bis C1-C6alkyl-embodiments, R3Bis C1-C3alkyl-R4B. In some embodiments, R3Bis .

[0093] In some embodiments, R5Bis H or C1-C6 alkyl. In some embodiments, R5Bis H or C1- C6alkyl-phenyl. In some embodiments, R5Bis H. In some embodiments, R5Bis C1-C6alkyl. In some embodiments, R5Bis C1-C6 alkyl-phenyl. In some embodiments, R5Bis C1-C3-phenyl.

[0094] 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 –Me. In some embodiments, R5Bis –Et. In some embodiments, R5Bis – nPr. In some embodiments, R5Bis –iPr. In some embodiments, R5Bis –nBu. In some embodiments, R5Bis –sBu. In some embodiments, R5Bis –tBu. In some embodiments, R5Bis CH3CH3is or isAttorney Docket No.: CYBP-004WO CH3CH3issome some In some embodiments, R6Bis C1-C6 alkyl-phenyl. In some embodiments, R6Bis C1-C3-phenyl.

[0096] 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 –Me. In some embodiments, R6Bis –Et. In some embodiments, R6Bis – nPr. In some embodiments, R6Bis –iPr. In some embodiments, R6Bis –nBu. In some embodiments, R6Bis –sBu. In some embodiments, R6Bis –tBu. In some embodiments, R6Bis CH3CH3is or is iscombine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0098] In some embodiments, R5Band R6B, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O and N. In some embodiments, R5Band R6B, together with the 24 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N. In some embodiments, R5Band R6B, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O and N. In some embodiments, R5Band R6B, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1-2 N atoms. In some embodiments, R5Band R6B, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1 N atom.

[0099] In some embodiments, R5Band R6B, together with the atom to which each is attached, combine to form .

[0100] In some R5Bis H, C1-C6alkyl, or C16B-C6alkyl-phenyl, and R is C1-C6alkyl-phenyl, or R5Band R6B, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0101] In some embodiments, R5Bis H, C1-C6alkyl, or C1-C6alkyl-phenyl, and R6Bis C1-C6alkyl-phenyl, or R5Band R6B, together with the atom to which each is attached, combine to form 3-7 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0102] In some embodiments, R5Bis H, C1-C6alkyl, or C1-C6alkyl-phenyl, and R6Bis C1-C6alkyl-phenyl, or R5Band R6B, together with the atom to which each is attached, combine to form 5-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0103] In some embodiments, R5Bis H or C1-C6 alkyl, and R6Bis C1-C6 alkyl-phenyl, or R5Band R6B, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0104] In some embodiments, R5Bis H, and R6Bis C1-C6alkyl-phenyl, or R5Band R6B, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0105] In some embodiments, R5Bis C1-C6 alkyl, and R6Bis C1-C6 alkyl-phenyl, or R5Band R6B, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N. 25 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO

[0106] In some embodiments, R5Bis H or C1-C6alkyl, and R6Bis C1-C6alkyl-phenyl, or R5Band R6B, together with the atom to which each is attached, combine to form 3-7 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0107] In some embodiments, R5Bis H, and R6Bis C1-C6alkyl-phenyl, or R5Band R6B, together with the atom to which each is attached, combine to form 3-7 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0108] In some embodiments, R5Bis C1-C6 alkyl, and R6Bis C1-C6 alkyl-phenyl, or R5Band R6B, together with the atom to which each is attached, combine to form 3-7 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0109] In some embodiments, R5Bis H or C1-C6alkyl, and R6Bis C1-C6alkyl-phenyl, or R5Band R6B, together with the atom to which each is attached, combine to form 5-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0110] In some embodiments, R5Bis H, and R6Bis C1-C6 alkyl-phenyl, or R5Band R6B, together with the atom to which each is attached, combine to form 5-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0111] In some embodiments, R5Bis C1-C6 alkyl, and R6Bis C1-C6 alkyl-phenyl, or R5Band R6B, together with the atom to which each is attached, combine to form 5-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0112] In some embodiments, R5Bis H, C1-C6alkyl, or C1-C6alkyl-phenyl, and R6Bis C1-C6alkyl-phenyl.

[0113] In some embodiments, R5Bis H or C1-C6alkyl, and R6Bis C1-C6alkyl-phenyl.

[0114] In some embodiments, R5Bis H, and R6Bis C1-C6 alkyl-phenyl.

[0115] In some embodiments, R5Bis C1-C6alkyl, and R6Bis C1-C6alkyl-phenyl.

[0116] In some embodiments, R5Bis H or C1-C6 alkyl, and R6Bis C1-C3 alkyl-phenyl.

[0117] In some embodiments, R5Bis H, and R6Bis C1-C3alkyl-phenyl.

[0118] In some embodiments, R5Bis C1-C6 alkyl, and R6Bis C1-C3 alkyl-phenyl. CH3CH3

[0119] In some .

[0120] In some .26 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO CH3

[0121] In some .

[0122] In some .

[0123] In some a compound of Formula B-I:or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein.

[0124] In some embodiments, the compound of Formula B is a compound of Formula B-II: or a pharmaceuticallywherein the variables are as described herein.

[0125] In some embodiments, the compound has the structure of any one of the following, or a pharmaceutically acceptable salt thereof:27 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO

[0126] In some embodiments, e compoun as e srucure of any one of the following, or a pharmaceutically acceptable salt thereof:29 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO

[0127] In some embodiments, the a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the a pharmaceutically acceptable salt thereof.

[0129] In some embodiments, the a pharmaceutically acceptable salt thereof.

[0130] In some embodiments, the a pharmaceutically acceptable salt thereof.31 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO

[0131] In some embodiments, the a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, the a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, the a pharmaceutically acceptable salt thereof.Formula C

[0134] Disclosed herein, in some embodiments, is a compound of Formula C: ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO or a pharmaceutically acceptable salt thereof, wherein R1Cis H, C1-C6 alkyl, or C1-C6 hydroxyalkyl; R2Cis C1-C6alkyl, C1-C6hydroxyalkyl, or phenyl; ; phenyl, and R6Cis C1-C6 alkyl-phenyl, or R5Cand 6RC, each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0135] In some embodiments, when R1Cis H, R3C, and R5Cis –Et, then R6Cis not–Et. In some embodiments, when R3Cis , R5Cis H, and R6Cis H, then R1Cis not H or –Me. In some embodiments, when R1Cis H, R3Cis , and R5Cis H, then R6Cis not – nBu or –iPr. In some embodiments, (i) when R1Cis H, R3C 5C, and R is –Et, then R6Cis not –Et; (ii) when R3Cis , R5Cis H, and R6Cis H, then R1Cis not H or –Me; and (iii) then R6Cis not –nBu or –iPr.

[0136] Inis a compound of Formula C, or a pharmaceutically acceptable salt thereof, wherein: R1Cis H or C1-C6alkyl; R2Cis C1-C6 alkyl, C1-C6 hydroxyalkyl, or phenyl; R3Cis C1-C6 alkyl-R4Cor ; 33 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO R4Cis ; and R5Cis H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Cis C1-C6 alkyl-phenyl, or R5Cand R6C, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0137] In some embodiments, the compound is a compound of Formula C, or a pharmaceutically acceptable salt thereof, wherein: R1Cis H; R2Cis C1-C6 alkyl, C1-C6 hydroxyalkyl, or phenyl; R3Cis C1-C6 alkyl- ;R4Cis ; and R5Cis H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Cis C1-C6 alkyl-phenyl, or R5Cand R6C, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0138] In some embodiments, the compound is a compound of Formula C, or a pharmaceutically acceptable salt thereof, wherein: R1Cis H, C1-C6alkyl, or C1-C6hydroxyalkyl; R2Cis C1-C6 alkyl, C1-C6 hydroxyalkyl, or phenyl; R3Cis ; and R5Cis H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Cis C1-C6 alkyl-phenyl, or R5Cand R6C, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0139] In some embodiments, the compound is a compound of Formula C, or a pharmaceutically acceptable salt thereof, wherein: R1Cis H or C1-C6alkyl; R2Cis C1-C6 alkyl, C1-C6 hydroxyalkyl, or phenyl;Attorney Docket No.: CYBP-004WO R5Cis H, C1-C6alkyl, or C1-C6alkyl-phenyl, and R6Cis C1-C6alkyl-phenyl, or R5Cand R6C, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0140] In some embodiments, the compound is a compound of Formula C, or a pharmaceutically acceptable salt thereof, wherein: R1Cis H; R2Cis C1-C6 alkyl, C1-C6 hydroxyalkyl, or phenyl; or C1-C6alkyl-phenyl, and R6Cis C1-C6alkyl-phenyl, or R5CandR6C, to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0141] In some embodiments, the compound is a compound of Formula C, or a pharmaceutically acceptable salt thereof, wherein: R1Cis H, C1-C6alkyl, or C1-C6hydroxyalkyl; R2Cis C1-C6 alkyl, C1-C6 hydroxyalkyl, or phenyl;or C1-C6alkyl-phenyl, and R6Cis C1-C6alkyl-phenyl.

[0142] In some embodiments, the compound is a compound of Formula C, or a pharmaceutically acceptable salt thereof, wherein: R1Cis H or C1-C6 alkyl; R2Cis C1-C6alkyl, C1-C6hydroxyalkyl, or phenyl;or C1-C6alkyl-phenyl, and R6Cis C1-C6alkyl-phenyl.

[0143] In some embodiments, the compound is a compound of Formula C, or a pharmaceutically acceptable salt thereof, wherein: R1Cis H; R2Cis C1-C6alkyl, C1-C6hydroxyalkyl, or phenyl; R3Cis ; and 35 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO R5Cis H, C1-C6alkyl, or C1-C6alkyl-phenyl, and R6Cis C1-C6alkyl-phenyl.

[0144] In some embodiments, R1Cis H or C1-C6alkyl. In some embodiments, R1Cis H. In some embodiments, R1Cis C1-C6 alkyl. In some embodiments, R1Cis C1-C6 hydroxyalkyl. In some embodiments, R1Cis C1-C3hydroxyalkyl.

[0145] In some embodiments, R1Cis –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, –(CH2)4CH3, or –(CH2)5CH3. In some embodiments, R1Cis –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, R1Cis –Me. In some embodiments, R1Cis –Et. In some embodiments, R1Cis – nPr. In some embodiments, R1Cis –iPr. In some embodiments, R1Cis –nBu. In some embodiments, R1Cis –sBu. In some embodiments, R1Cis –tBu. In some embodiments, R1Cis .some embodiments, R2Cis C2-C6alkyl or C1-C6hydroxyalkyl. In some embodiments, R2Cis C2-C6 alkyl. In some embodiments, R2Cis C1-C6 hydroxyalkyl. In some embodiments, R2Cis phenyl.

[0147] In some embodiments, R2Cis –Et, –nPr, –iPr, –nBu, –sBu, –tBu, –(CH2)4CH3, or – (CH2)5CH3. In some embodiments, R2Cis –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, R2Cis –Et. In some embodiments, R2Cis –nPr. In some embodiments, R2Cis – iPr. In some embodiments, R2Cis –nBu. In some embodiments, R2Cis –sBu. In some embodiments, R2Cis –tBu. In some embodiments, R2C.

[0148] In some embodiments, R3Cis C1-C6 alkyl-embodiments, R3Cis C1-C3 alkyl-R4C. In some embodiments, R3C.

[0149] In some embodiments, R5Cis H or C1-C6alkyl. In some embodiments, R5Cis H or C1- C6 alkyl-phenyl. In some embodiments, R5Cis H. In some embodiments, R5Cis C1-C6 alkyl. In some embodiments, R5Cis C1-C6alkyl-phenyl. In some embodiments, R5Cis C1-C3-phenyl.

[0150] In some embodiments, R5Cis –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, –(CH2)4CH3, or –(CH2)5CH3. In some embodiments, R5Cis –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, R5Cis –Me. In some embodiments, R5Cis –Et. In some embodiments, R5Cis – nPr. In some embodiments, R5Cis –iPr. In some embodiments, R5Cis –nBu. In some embodiments, R5Cis –sBu. In some embodiments, R5Cis –tBu. In some embodiments, R5Cis 36 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO CH3CH3is or is is .In some embodiments, R6C. In some embodiments, R6Cis CH3combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0153] In some embodiments, R5Cand R6C, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms 37 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO independently selected from O and N. In some embodiments, R5Cand R6C, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N. In some embodiments, R5Cand R6C, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O and N. In some embodiments, R5Cand R6C, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1-2 N atoms. In some embodiments, R5Cand R6C, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1 N atom.

[0154] In some embodiments, R5Cand R6C, together with the atom to which each is attached, combine to form .

[0155] In some R5Cis H, C -C alkyl, or C -C alkyl-phenyl6C1 6 1 6 , and R is C1-C6 alkyl-phenyl, or R5Cand R6C, together with the atom to which each is attached, combine to form 3-7 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0156] In some embodiments, R5Cis H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Cis C1-C6 alkyl-phenyl, or R5Cand R6C, together with the atom to which each is attached, combine to form 5-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0157] In some embodiments, R5Cis H or C1-C6alkyl, and R6Cis C1-C6alkyl-phenyl, or R5Cand R6C, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0158] In some embodiments, R5Cis H, and R6Cis C1-C6 alkyl-phenyl, or R5Cand R6C, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0159] In some embodiments, R5Cis C1-C6alkyl, and R6Cis C1-C6alkyl-phenyl, or R5Cand R6C, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0160] In some embodiments, R5Cis H or C1-C6 alkyl, and R6Cis C1-C6 alkyl-phenyl, or R5Cand R6C, together with the atom to which each is attached, combine to form 3-7 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N. 38 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO

[0161] In some embodiments, R5Cis H, and R6Cis C1-C6alkyl-phenyl, or R5Cand R6C, together with the atom to which each is attached, combine to form 3-7 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0162] In some embodiments, R5Cis C1-C6alkyl, and R6Cis C1-C6alkyl-phenyl, or R5Cand R6C, together with the atom to which each is attached, combine to form 3-7 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0163] In some embodiments, R5Cis H or C1-C6 alkyl, and R6Cis C1-C6 alkyl-phenyl, or R5Cand R6C, together with the atom to which each is attached, combine to form 5-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0164] In some embodiments, R5Cis H, and R6Cis C1-C6alkyl-phenyl, or R5Cand R6C, together with the atom to which each is attached, combine to form 5-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0165] In some embodiments, R5Cis C1-C6 alkyl, and R6Cis C1-C6 alkyl-phenyl, or R5Cand R6C, together with the atom to which each is attached, combine to form 5-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

[0166] In some embodiments, R5Cis H or C1-C6 alkyl, and R6Cis C1-C6 alkyl-phenyl.

[0167] In some embodiments, R5Cis H, and R6Cis C1-C6alkyl-phenyl.

[0168] In some embodiments, R5Cis C1-C6 alkyl, and R6Cis C1-C6 alkyl-phenyl.

[0169] In some embodiments, R5Cis H or C1-C6alkyl, and R6Cis C1-C3alkyl-phenyl.

[0170] In some embodiments, R5Cis H, and R6Cis C1-C3 alkyl-phenyl.

[0171] In some embodiments, R5Cis C1-C6alkyl, and R6Cis C1-C3alkyl-phenyl. CH3CH3

[0172] In some .

[0173] In some .

[0174] In some .

[0175] In some .

[0176] In someis a compound of Formula C-I: 39 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO or a pharmaceuticallywherein the variables are as

[0177] In some embodiments, the compound of Formula C is a compound of Formula C-II: or a pharmaceuticallywherein the variables are as described herein.

[0178] In some embodiments, the compound has the structure of any one of the following, or a pharmaceutically acceptable salt thereof:40 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO

[0179] In some embodiments, the compound has the structure of any one of the following, or a pharmaceutically acceptable salt thereof:41 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO

[0180] In some , or a pharmaceutically acceptable salt thereof.42 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO

[0181] In some embodiments, the a pharmaceutically acceptable salt thereof.

[0182] In some embodiments, the a pharmaceutically acceptable salt thereof.

[0183] In some embodiments, the a pharmaceutically acceptable salt thereof.

[0184] In some embodiments, the a pharmaceutically acceptable salt thereof.43 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO Exemplary Compounds

[0185] Disclosed herein, in some embodiments, is a compound described in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

[0186] Disclosed herein, in some embodiments, is a compound described in Table 1, or a pharmaceutically acceptable salt thereof. Table 1. Exemplary compounds of the disclosure Compound Name Structure No. The y metho s s m ar o ose ncu e n e xamp es sec on.

[0187] Disclosed herein, in some embodiments, is a compound described in Table 2, or a pharmaceutically acceptable salt thereof. Table 2. Exemplary compounds of the disclosure Compound Name Structure44 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO The ymethods similar to those included in the Examples section. Pharmaceutical Compositions

[0188] 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 or Table 2; or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier.

[0189] 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, the 45 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO compound is provided in a prophylactically effective amount in the pharmaceutical composition.

[0190] 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 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.

[0191] 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 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.

[0192] 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) 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 sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0193] 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 46 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO 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).

[0194] Although the descriptions of pharmaceutical compositions provided herein are 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 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

[0195] 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 of serotonin receptors are implicated in many diseases and disorders. Modulating Serotonin Receptors

[0196] 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 Formula A, Formula B, or Formula C, or a subformula thereof; a compound of Table 1 or Table 2; or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein.

[0197] Upon having contacted the serotonin receptor, the compound may activate the serotonin receptor or inhibit the serotonin receptor.

[0198] 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. 47 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO In some embodiments, the serotonin receptor is 5-HT1Areceptor, 5-HT2Areceptor, 5-HT2Breceptor, 5-HT2Creceptor, 5-HT6receptor, or 5-HT7receptor.

[0199] In some embodiments, the serotonin receptor is 5-HT2A receptor, 5-HT2C receptor, or 5-HT7receptor, or a combination thereof. In some embodiments, the serotonin receptor is 5- HT2A receptor, 5-HT2C receptor, or 5-HT7 receptor.

[0200] 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 embodiments, the serotonin receptor is 5-HT6 receptor. In some embodiments, the serotonin receptor is 5-HT7receptor.

[0201] 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

[0202] 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 or Table 2; or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein.

[0203] In some embodiments, the disease or disorder is a serotonin receptor-mediated disease or disorder.

[0204] 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 compulsive disorder.

[0205] 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 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, 48 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO post-stroke convulsions, brain ischemia, migraine, stroke, spinal cord injury, peripheral neuropathy, acute neuropathic pain, or chronic neuropathic pain.

[0206] 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.

[0207] 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, the pain existential pain.

[0208] In some embodiments, the pain is acute. In some embodiments, the pain is chronic.

[0209] 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 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.

[0210] 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 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., neuropathic back pain).

[0211] 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 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. 49 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO

[0212] 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. 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.

[0213] 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 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 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.

[0214] In some embodiments, the depression is moderate depression, major depression, treatment resistant depression, complicated grief disorder, prolonged grief disorder (PGD), social anxiety, post-surgical depression, depression from chronic pain, or depression in Alzheimer’s disease.

[0215] 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 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.

[0216] 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 50 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO 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 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 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 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).

[0217] In some embodiments, the disease is obsessive-compulsive spectrum disorder (OCSD). In some embodiments, the disease comprises body dysmorphic disorder (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 Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections.

[0218] Compounds of the disclosure may be used to treat an autoimmune disease, wherein the autoimmune disease comprises 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, 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, vitiligo, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, ankylosing spondilitis, scleroderma, Type I diabetes, 51 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO psoriatic arthritis, osteoarthritis, inflammatory bowel disease, atopic dermatitis and asthma, or Wegener's granulomatosis. EXAMPLES

[0219] 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 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) 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) IC5050% inhibitory concentration IC75 75% inhibitory concentration IC9090% inhibitory concentration 52 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO 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 THF tetrahydrofuran TLC thin layer chromatography Tos p-toluenesulfonyl vol volume(s) WB washing buffer Example 1. General Scheme for Preparing Ergoline Analogs 53 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WOExample 2. Synthesis of (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg]quinoline-9-carboxamide (nor-LSD) NH

[0221] refluxing solution in a nitrogen environment. Reaction mixture was refluxed for an additional 6 h. 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. Recrystallization from IPA or EtOAc gave 6-cyano-nor-LSD (71%) with mp of 190–191 °C. 54 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO

[0222] 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 ammonia vapor, yielded tan crystals. Recrystallized from EtOAc / hexanes, yielding nor-LSD (61%) with mp of 196–198 °C (dec).

[0223] Nor-LSD (66 mg) was added to DMF. Then added K2CO3 and ethyl iodide. Volatiles were removed when TLC indicated completion. Then CHCl3was added, dried, and separated by centrifugal chromatography. Major product was dissolved in hot benzene, filtered, and 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-methyl-4,5,5a,6,6a,7,8,9- octahydroindolo[4,3-fg]quinoline-9-carboxamide (dihydro-LSD)

[0224] (6aR,9R)-N,N-diethyl-7-methyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3-fg]quinoline- 9-carboxamide (dihydro-LSD) is prepared as described in WO 2022 / 226408. Accordingly, LSD is dissolved in trifluoroacetic acid followed by the addition of triethyl silane. The resulting mixture is stirred at 40 °C for 72 hours. After cooling down to room temperature, silica gel is added and the mixture concentrated in vacuo. The resulting powder is added to the top of a flash chromatography column previously filled with silica gel and the product is eluted with dichloromethane / methanol 98:2 to give (6aR,9R)-N,N-diethyl-7-methyl-4,5,5a,6,6a,7,8,9- octahydroindolo[4,3-fg]quinoline-9-carboxamide (mixture of diastereomers; epimers at position 5a) as a dark-tinted amorphous solid. Example 4. Synthesis of (6aR,9R)-N,N-diethyl-7-phenyl-4,5,5a,6,6a,7,8,9- octahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound I-1) 55 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO9-carboxamide (Intermediate a)

[0225] Intermediate a is synthesized by reacting nor-LSD with an appropriate phenylating reagent to introduce the phenyl 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 a phenylating agent as e.g. phenylbromide or iodide or another suitable phenylating agent under 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. 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 Intermediate a. (6aR,9R)-N,N-diethyl-7-phenyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3-fg]quinoline-9- carboxamide (Compound I-1)

[0226] Compound I-1 is synthesized in analogy to the procedure of (6aR,9R)-N,N-diethyl-7- methyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3-fg]quinoline-9-carboxamide (dihydro-LSD) as described above. Accordingly, Intermediate a is dissolved in trifluoroacetic acid are a similar, appropriate solvent, followed by the addition of triethylsilane. The resulting mixture is stirred at an appropriate temperature, e.g.40 °C, until intermediate a in consumed, e.g., 72 hours. After cooling down to room temperature, silica gel is added and the mixture concentrated in vacuo. The resulting powder is added to the top of a flash chromatography column previously filled with silica gel and the product is eluted with an appropriate eluent, e.g. dichloromethane / methanol 98:2, to give (6aR,9R)-N,N-diethyl-7-phenyl-4,5,5a,6,6a,7,8,9- octahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound I-1). Compound I-1 is characterized through spectroscopic methods like NMR, IR, and mass spectrometry. 56 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO Example 5. Synthesis of 1-((6aR,9R)-7-methyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3- fg]quinolin-9-yl)-2-(piperidin-1-yl)ethan-1-one (Compound II-1) N Nyl)-2- (piperidin-1-yl)ethan-1-one (Intermediate b)

[0227] Intermediate b is synthesized starting with lysergic acid converting it to an appropriate precursor, e.g., the corresponding bromomethylketone or a similar analog suitable for introduction of the piperidine moiety. Protect any sensitive functional groups if necessary. Purify the final product using standard purification techniques such as column chromatography or recrystallization. Confirm the structure of the synthesized compound through spectroscopic methods like NMR, IR, and mass spectrometry. Synthesis of 1-((6aR,9R)-7-methyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3-fg]quinolin-9-yl)-2- (piperidin-1-yl)ethan-1-one (Compound II-1)

[0228] Compound II-1 is synthesized in analogy to the procedure of (6aR,9R)-N,N-diethyl-7- methyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3-fg]quinoline-9-carboxamide (dihydro-LSD) as described above. Accordingly, Intermediate b is dissolved in trifluoroacetic acid or a similar, appropriate solvent, followed by the addition of triethylsilane. The resulting mixture is stirred at an appropriate temperature, e.g.40 °C, until Intermediate b in consumed, e.g., after 72 hours. After cooling down to room temperature, silica gel is added and the mixture and concentrated in vacuo. The resulting powder is added to the top of a flash chromatography column previously filled with silica gel and the product is eluted with an appropriate eluent, e.g. dichloromethane / methanol 98:2, to give 1-((6aR,9R)-7-methyl-4,5,5a,6,6a,7,8,9- octahydroindolo[4,3-fg]quinolin-9-yl)-2-(piperidin-1-yl)ethan-1-one (Compound II-1). Example 6. Synthesis of (6aR,9R)-N-(hexan-2-yl)-7-methyl-4,5,5a,6,6a,7,8,9- octahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound II-2) 57 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WOfg]quinoline-9-carboxamide (Intermediate c)

[0229] Intermediate c 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 N-hexan-2-yl carboxamide use an appropriate reagent (e.g., hexan-2-amine) 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 NMR, IR, and mass spectrometry. Verify the purity and identity of Intermediate c. Synthesis of (6aR,9R)-N-(hexan-2-yl)-7-methyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3- fg]quinoline-9-carboxamide (Compound II-2)

[0230] Compound II-2 is synthesized in analogy to the procedure of (6aR,9R)-N,N-diethyl-7- methyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3-fg]quinoline-9-carboxamide (dihydro-LSD) as described above. Accordingly, intermediate c is dissolved in trifluoroacetic acid or a similar, appropriate solvent, followed by the addition of triethyl silane. The resulting mixture is stirred at an appropriate temperature, e.g., at 40 °C, until intermediate c in consumed, e.g., after 72 hours. After cooling down to room temperature, silica gel is added and the mixture and concentrated in vacuo. The resulting powder is added to the top of a flash chromatography column previously filled with silica gel and the product is eluted with an appropriate eluent, e.g. dichloromethane / methanol 98:2, to give (6aR,9R)-N-(hexan-2-yl)-7-methyl- 4,5,5a,6,6a,7,8,9-octahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound II-2). Compound II-2 is characterized through spectroscopic methods like NMR, IR, and mass spectrometry. 58 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO Example 7. Synthesis of (6aR,9R)-7-methyl-N-(1-phenylethyl)-4,5,5a,6,6a,7,8,9- octahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound II-3)fg]quinoline-9-carboxamide (Intermediate d)

[0231] Intermediate d 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 1-phenethyl carboxamide use an appropriate reagent (e.g., 1-phenylethan-1-amine) 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 NMR, IR and mass spectrometry. Verify the purity and identity of Intermediate d. Synthesis of (6aR,9R)-7-methyl-N-(1-phenylethyl)-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3- fg]quinoline-9-carboxamide (Compound II-3)

[0232] Compound II-3 is synthesized in analogy to the procedure of (6aR,9R)-N,N-diethyl-7- methyl-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3-fg]quinoline-9-carboxamide (dihydro-LSD) as described above. Accordingly, Intermediate d is dissolved in trifluoroacetic acid or a similar, appropriate solvent, followed by the addition of triethyl silane. The resulting mixture is stirred at an appropriate temperature, e.g.40 °C, until Intermediate c in consumed, e.g.72 hours. After cooling down to room temperature, silica gel is added and the mixture and concentrated in vacuo. The resulting powder is added to the top of a flash chromatography column previously filled with with silica gel and the product is eluted with an appropriate eluent, e.g. dichloromethane / methanol 98:2, to give (6aR,9R)-7-methyl-N-(1-phenylethyl)- 4,5,5a,6,6a,7,8,9-octahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound II-3). 59 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO Compound II-3 is characterized through spectroscopic methods like NMR, IR, and mass spectrometry. Example 8. Synthesis of (6aR,9R)-N,N-diethyl-4-(1-hydroxyethyl)-7-methyl- 4,5,5a,6,6a,7,8,9-octahydroindolo[4,3-fg]quinoline-9-carboxamide (Compound II-4)

[0233] Compound II-4 is synthesized from (6aR,9R)-N,N-diethyl-7-methyl-4,5,5a,6,6a,7,8,9- octahydroindolo[4,3-fg]quinoline-9-carboxamide (dihydro-LSD, see above) by employing an appropriate alkylating reagent in the presence of an appropriate catalyst (e.g., K2CO3), under nitrogen atmosphere to introduce the hydroxyethyl moiety at the desired position. After completion of the reaction, remove volatiles under vacuum. Purify the residue using a chromatographic technique, similar to the one described in previous examples, employing a suitable elution solvent. Recrystallize the product from a suitable solvent to obtain a pure compound.

[0234] Analyze the obtained compound using various spectroscopic techniques (IR, NMR, mass spectrometry) to confirm its structure. Confirm the presence of the hydroxyethyl group at the desired position. Example 9. Synthesis of Intermediates and Analytical Methods Synthesis of Intermediates

[0235] 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 NMR 60 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO

[0236] NMR spectra were recorded using a Bruker 500MHz Avance III HD spectrometer 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. Mass Spectrometry

[0237] Mass spectra were acquired using a Waters HClass; Binary Solvent Pump, SM-FTN, CMA, PDA, QDa using the methods described below. Method 1 – UPLC Acidic Method

[0238] Column: ACQUITY UPLC® CSH C18, 130A, 1.7 µm, 2.1 x 30 mm at 40 °C

[0239] Detection: UV at 210-400 nm unless otherwise indicated, MS by electrospray ionisation

[0240] Solvents: A: 0.1% Formic in water, B: MeCN

[0241] Gradient: Time %A %B Flow rate (mL / min)Time %A %B Flow rate (ml / min)

[0242] Column: ACQUITY UPLC® BEH C18, 130A, 1.7 µm, 2.1 x 30 mm at 40 °C

[0243] Detection: UV at 210-400 nm unless otherwise indicated, MS by electrospray ionisation

[0244] Solvents: A: 0.1% Ammonia in water, B: MeCN

[0245] Gradient: Time %A %B Flow rate61 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO Time %A %B Flow rate (ml / min) -3: (5aS,6aR,9R)-7-methyl-N-(1-phenylethyl)-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3-fg]quinoline-9-carboxamide- carboxylic acid

[0246] 2M sodium hydroxide solution (4.5 mL, 8.85 mmol) was added to a stirred solution of methyl (6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxylate (500 mg, 1.77 mmol) in ethanol (4 mL). The mixture was stirred at ambient temperature for 1 h. The pH was adjusted to 6 with 1M hydrochloric acid and the mixture stirred for an additional 10 min. The resulting precipitate was collected by filtration, washed with ice-cold ethanol (5 mL) and dried under vacuum to give (6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg]quinoline-9-carboxylic acid (372 mg, 1.4 mmol, 77 %, 98% Purity).

[0247] MS (ESI) m / z 269.5 (M+H)+ Step 2: (6aR,9R)-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg]quinoline-9-carboxamide

[0248] Propylphosphonic anhydride (1.22 mL, 50% Wt in EtOAc, 2.08 mmol) was added to a stirred suspension of (6aR,9R)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9- 62 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO carboxylic acid (372 mg, 1.39 mmol), diethylamine (287 μL, 2.77 mmol) and triethylamine (386 μL, 2.77 mmol) in anhydrous DCM (4 mL). The mixture was stirred at ambient temperature for 18 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 flash column chromatography to give (6aR,9R)-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3- fg]quinoline-9-carboxamide (423 mg, 1.31 mmol, 94.3 %)

[0249] MS (ESI) m / z 324.4 (M+H)+ Step 3: (6aR,9R)-7-methyl-N-(1-phenylethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3- fg]quinoline-9-carboxamide

[0250] DIPEA (200 μL, 1.15 mmol) was added to a stirred solution of (6aR,9R)-7-methyl- 4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxylic acid (95.0 mg, 354 μmol), 1- phenylethan-1-amine (50 μL, 389 μmol) and ((3H-[1,2,3]triazolo[4,5-b]pyridin-3- yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (231 mg, 443 μmol) in anhydrous DMF (1 mL). The reaction mixture was stirred at ambient temperature for 30 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 give (6aR,9R)-7-methyl-N-(1-phenylethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9- carboxamide (97 mg, 0.26 mmol, 77%). The product was a 1:1 mixture of diastereoisomers.

[0251] MS (ES+): m / z 372.4 (M+H)+ Step 4: (5aS,6aR,9R)-7-methyl-N-(1-phenylethyl)-4,5,5a,6,6a,7,8,9- octahydroindolo[4,3-fg]quinoline-9-carboxamide

[0252] Triethylsilane (800 μL, 5.01 mmol) was added to a stirred solution of (9R)-7-methyl- N-(1-phenylethyl)-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (77.0 mg, 207 μmol) in trifluoroacetic acid (8.00 mL, 104 mmol). The mixture was stirred at ambient temperature for 1 h. The volatiles were removed under reduced pressure and the residue partitioned between saturated aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL). The layers were separated and the aqueous layer extracted with ethyl acetate 63 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO (2 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 reversed-phase column chromatography (5.5 g RediSepRf C18 Gold, 10-30% acetontrile / water (0.1% formic acid). The fractions containing product were lyophilized to give (5aS,6aR,9R)-7-methyl-N-(1-phenylethyl)-4,5,5a,6,6a,7,8,9-octahydroindolo[4,3- fg]quinoline-9-carboxamide (19.5 mg, 52 μmol, 25 %, 99% Purity).

[0253] 1H NMR (500 MHz, DMSO-d6) δ 1.18 (q, J = 11.6 Hz, 1H), 1.37 (dd, J = 10.3, 7.0 Hz, 3H), 2.36 (d, J = 5.7 Hz, 3H), 2.89 (d, J = 12.0 Hz, 1H), 2.93 – 3.13 (m, 3H), 3.55 (t, J = 7.9 Hz, 1H), 4.93 (h, J = 7.1 Hz, 1H), 5.39 (s, 1H), 6.22 (s, 0.5H), 6.29 (s, 0.5H), 6.34 (dd, J = 7.5, 4.5 Hz, 1H), 6.76 (d, J = 8.0 Hz, 0.5H), 6.83 (d, J = 8.0 Hz, 0.5H), 6.89 (q, J = 7.6 Hz, 1H), 7.17 – 7.27 (m, 1H), 7.28 – 7.35 (m, 4H), 8.41 (d, J = 8.5 Hz, 1H).

[0254] MS (ES+): m / z 374.2 (M+H)+ Example 11. Potency of Exemplary Compounds Across 5-HT Receptor Subtypes

[0255] HEK 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.

[0256] 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.

[0257] 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).

[0258] 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.

[0259] Results are shown in the tables below. Table 3. 5HT1A 5HT2A 5HT2B 064 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO ND = not determined Table 4. 5HT2C 5HT6 5HT7 Compound Emax (%) pEC50 Emax (%) pEC50 Emax (%) pEC50EQUIVALENTS

[0260] 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 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 present in, employed in, or otherwise relevant to a given product or process.

[0261] 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 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 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 65 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO otherwise indicated or otherwise evident from the context and understanding of one of ordinary 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.

[0262] 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 there is a conflict between any of the incorporated references and the instant specification, the specification shall control.

[0263] 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 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. 66 ACTIVE / 137605700.1

Claims

Attorney Docket No.: CYBP-004WO CLAIMS What is claimed:

1. A compound of Formula A:or a pharmaceutically wherein R1Ais H, C1-C6alkyl, or C1-C6hydroxyalkyl; R2Ais C2-C6 alkyl, C1-C6 hydroxyalkyl, or phenyl; R3Ais C1-C6 alkyl-R4Aor ; R4Ais ; and R5Ais H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Ais H, C1-C6 alkyl, or C1-C6 alkyl- phenyl; or R5Aand R6A, together with the atom to which each is attached, combine to form 3- 8 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from O, S, and N, provided that when R3Ais , R5Ais –Et, and R6Ais –Et, then R2Ais not –nPr.

2. The compound of claim 1, wherein R1Ais H.

3. The compound of claim 1, wherein R1Ais C1-C6alkyl.

4. The compound of claim 3, wherein R1Ais –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, – (CH2)4CH3, or –(CH2)5CH3. 67 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO 5. The compound of claim 3, wherein R1Ais –Me, –Et, –nPr, –iPr, –nBu, or –tBu.

6. The compound of claim 1, wherein R1Ais C1-C6 hydroxyalkyl.

7. The compound of claim 6, wherein R1Ais C1-C3 hydroxyalkyl.

8. The compound of claim 6, wherein R1A.

9. The compound of any one of claims 1-8,R2Ais C2-C6 alkyl.

10. The compound of claim 9, wherein R2Ais –Et, –nPr, –iPr, –nBu, –sBu, –tBu, – (CH2)4CH3, or –(CH2)5CH3.

11. The compound of claim 9, wherein R2Ais –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

12. The compound of any one of claims 1 to 8, wherein R2Ais C1-C6 hydroxyalkyl.

13. The compound of claim 12, wherein R2Ais C1-C3hydroxyalkyl.

14. The compound of claim 12, wherein R2A.

15. The compound of any one of claims 1-8, is phenyl.

16. The compound of any one of claims 1-15, wherein R3Ais C1-C6alkyl-R4A.

17. The compound of any one of claims 1-15, wherein R3Ais C1-C3alkyl-R4A.

18. The compound of any one of claims 1-15, wherein R3Ais .

19. The compound of any one of claims 1-18, wherein R5Ais H.

20. The compound of any one of claims 1-18, wherein R5Ais H or C1-C6 alkyl.

21. The compound of any one of claims 1-18, wherein R5Ais C1-C6 alkyl.

22. The compound of claim 20, wherein R5Ais –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, – (CH2)4CH3, or –(CH2)5CH3. 68 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO 23. The compound of claim 20, wherein R5Ais –Me, –Et, –nPr, –iPr, –nBu, –sBu, or – tBu.

24. The compound of any one of claims 1-18, wherein R5Ais C1-C6alkyl-phenyl.

25. The compound of claim 24, wherein R5Ais C1-C3-phenyl.

26. The compound of claim 24, wherein R5A.

27. The compound of claim 24, wherein R5A.

28. The compound of any one of claims 1-is H.

29. The compound of any one of claims 1-27, wherein R6Ais H or C1-C6 alkyl.

30. The compound of any one of claims 1-27, wherein R6Ais C1-C6 alkyl.

31. The compound of claim 30, wherein R6Ais –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, – (CH2)4CH3, or –(CH2)5CH3.

32. The compound of claim 30, wherein R6Ais –Me, –Et, –nPr, –iPr, –nBu, –sBu, or – tBu.

33. The compound of any one of claims 1-27, wherein R6Ais C1-C6 alkyl-phenyl.

34. The compound of claim 33, wherein R6Ais C1-C3-phenyl.

35. The compound of claim 33, wherein R6A.

36. The compound of claim 33, wherein R6A.69 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO 37. The compound of any one of claims 1-18, wherein R5Aand R6A, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

38. The compound of any one of claims 1-18, wherein R5Aand R6A, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O and N.

39. The compound of any one of claims 1-18, wherein R5Aand R6A, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

40. The compound of any one of claims 1-18, wherein R5Aand R6A, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O and N.

41. The compound of any one of claims 1-18, wherein R5Aand R6A, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1-2 N atoms.

42. The compound of any one of claims 1-18, wherein R5Aand R6A, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1 N atom.

43. The compound of any one of claims 1-18, wherein R5Aand R6A, together with the atom to which each is attached, combine to .

44. The compound of any one of claims 1-43, wherein the compound has the structure of any one of the following, or a pharmaceutically acceptable salt thereof: ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO 45. A compound of Formula B:or a pharmaceutically wherein R1Bis H, C1-C6alkyl, or C1-C6hydroxyalkyl; R2Bis –Me; R3Bis C1-C6 alkyl-R4Bor ; R4Bis ; and R5Bis H, C1-C6 alkyl, or C1-C6 alkyl-phenyl, and R6Bis H, C1-C6 alkyl, or C1-C6 alkyl- phenyl; or R5Band R6B, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from O, S, and N, provided that: (i) then(ii) then R1Bis(iii) when R1Bis H, R3Bis , and R5Bis H, then R6Bis not –nBu or –iPr.

46. The compound of claim 45, wherein R1Bis H. 71 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO 47. The compound of claim 45, wherein R1Bis C1-C6alkyl.

48. The compound of claim 47, wherein R1Bis –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, – (CH2)4CH3, or –(CH2)5CH3.

49. The compound of claim 47, wherein R1Bis –Me, –Et, –nPr, –iPr, –nBu, or –tBu.

50. The compound of claim 45, wherein R1Bis C1-C6 hydroxyalkyl.

51. The compound of claim 50, wherein R1Bis C1-C3hydroxyalkyl.

52. The compound of claim 50, wherein R1B.

53. The compound of any one of claims 45-R3Bis C1-C6 alkyl-R4A.

54. The compound of any one of claims 45-52, wherein R3Bis C1-C3 alkyl-R4A.

55. The compound of any one of claims 45-52, wherein R3B.

56. The compound of any one of claims 45-55, wherein R5Bis H.

57. The compound of any one of claims 45-55, wherein R5Bis H or C1-C6alkyl.

58. The compound of any one of claims 45-55, wherein R5Bis C1-C6 alkyl.

59. The compound of claim 58, wherein R5Bis –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, – (CH2)4CH3, or –(CH2)5CH3.

60. The compound of claim 58, wherein R5Bis –Me, –Et, –nPr, –iPr, –nBu, –sBu, or – tBu.

61. The compound of any one of claims 45-55, wherein R5Bis C1-C6alkyl-phenyl.

62. The compound of claim 61, wherein R5Bis C1-C3-phenyl.

63. The compound of claim 61, wherein R5B. 72ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO 64. The compound of claim 61, wherein R5B.

65. The compound of any one of claims 45-is H.

66. The compound of any one of claims 45-64, wherein R6Bis H or C1-C6 alkyl.

67. The compound of any one of claims 45-64, wherein R6Bis C1-C6alkyl.

68. The compound of claim 67, wherein R6Bis –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, – (CH2)4CH3, or –(CH2)5CH3.

69. The compound of claim 67, wherein R6Bis –Me, –Et, –nPr, –iPr, –nBu, –sBu, or – tBu.

70. The compound of any one of claims 45-64, wherein R6Bis C1-C6alkyl-phenyl.

71. The compound of claim 70, wherein R6Bis C1-C3-phenyl.

72. The compound of claim 70, wherein R6B.

73. The compound of claim 3703, wherein R6B.

74. The compound of any one of claims 45-55, wherein R5Band R6B, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

75. The compound of any one of claims 45-55, wherein R5Band R6B, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O and N.

76. The compound of any one of claims 45-55, wherein R5Band R6B, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N. 73 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO 77. The compound of any one of claims 45-55, wherein R5Band R6B, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O and N.

78. The compound of any one of claims 45-55, wherein R5Band R6B, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1-2 N atoms.

79. The compound of any one of claims 45-55, wherein R5Band R6B, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1 N atom.

80. The compound of any one of claims 45-55, wherein R5Band R6B, together with the atom to which each is attached, combine to .

81. The compound of any one of claimsthe compound has the structure of any one of the following, or a pharmaceutically acceptable salt thereof:74 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO82. A compound of Formula C:or a pharmaceutically acceptable salt thereof, wherein R1Cis H, C1-C6 alkyl, or C1-C6 hydroxyalkyl; R2Cis C1-C6alkyl, C1-C6hydroxyalkyl, or phenyl; R3Cis C1-C6alkyl- ;R4Cis ; and 75 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO R5Cis H, C1-C6alkyl, or C1-C6alkyl-phenyl, and R6Cis C1-C6alkyl-phenyl, or R5Cand R6C, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

83. The compound of claim 82, wherein R1Cis H.

84. The compound of claim 82, wherein R1Cis C1-C6alkyl.

85. The compound of claim 84, wherein R1Cis –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, – (CH2)4CH3, or –(CH2)5CH3.

86. The compound of claim 85, wherein R1Cis –Me, –Et, –nPr, –iPr, –nBu, or –tBu.

87. The compound of claim 82, wherein R1Cis C1-C6hydroxyalkyl.

88. The compound of claim 82, wherein R1Cis C1-C3 hydroxyalkyl.

89. The compound of claim 88, wherein R1C.

90. The compound of any one of claims 82- R3Cis C1-C6alkyl-R4C.

91. The compound of any one of claims 82-89, wherein R3Cis C1-C3 alkyl-R4C.

92. The compound of any one of claims 82-89, wherein R3C.

93. The compound of any one of claims 82-92, wherein R5Cis H or C1-C6 alkyl.

94. The compound of any one of claims 82-92, wherein R5Cis H.

95. The compound of any one of claims 82-92, wherein R5Cis C1-C6alkyl.

96. The compound of claim 95, wherein R5Cis –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, – (CH2)4CH3, or –(CH2)5CH3.

97. The compound of claim 95, wherein R5Cis –Me, –Et, –nPr, –iPr, –nBu, –sBu, or – tBu. 76 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO 98. The compound of any one of claims 82-92, wherein R5Cis C1-C6alkyl-phenyl.

99. The compound of claim 98, wherein R5Cis C1-C3-phenyl.

100. The compound of claim 98, wherein .

101. The compound of claim 98, wherein .

102. The compound of any one of claims 82-R6Cis C1-C3-phenyl.

103. The compound of claim 102, wherein R6C.

104. The compound of claim 103, wherein R6C.

105. The compound of any one of claims 82-92, and R6C, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

106. The compound of any one of claims 82-92, wherein R5Cand R6C,, together with the atom to which each is attached, combine to form 3-8 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O and N.

107. The compound of any one of claims 82-92, wherein R5Cand R6C,, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, S, and N.

108. The compound of any one of claims 82-92, wherein R5Cand R6C,, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O and N. 77 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO 109. The compound of any one of claims 82-92, wherein R5Cand R6C,, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1-2 N atoms.

110. The compound of any one of claims 82-92, wherein R5Cand R6C,, together with the atom to which each is attached, combine to form 3-6 membered monocyclic heterocyclyl having 1 N atom.

111. The compound of any one of claims 82-92, wherein R5Cand R6C,, together with the atom to which each is attached, combine to .

112. A compound, or a pharmaceuticallythereof, selected from: ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO113. A compound, or a pharmaceutically acceptable salt thereof, selected from: ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO 114. A compound, or a phahereof, selected from:

115. A pharmaceutical comnd of any one of claims 1-114, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

116. 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 1-114, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 115.

117. The method of claim 116, wherein the serotonin receptor is 5-HT2Areceptor, 5-HT2Creceptor, or 5-HT7 receptor. 80 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO 118. 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 1-114, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 115.

119. The method of claim 118, wherein the disease is pain.

120. The method of claim 118 or 119, wherein the pain is treatment resistant pain.

121. The method of claim 118 or 119, wherein the pain is opioid resistant pain.

122. The method of claim 118 or 119, wherein the pain is opioid resistant refractory pain.

123. The method of claim 118 or 119, wherein the pain is neuropathic pain.

124. The method of claim 118 or 119, wherein the pain is nociceptive pain.

125. The method of claim 118 or 119, wherein the pain is inflammatory pain.

126. The method of claim 118 or 119, wherein the pain is nociplastic pain.

127. The method of any one of claims 118-126, wherein the pain is acute.

128. The method of any one of claims 118-126, wherein the pain is chronic.

129. The method of claim 118, 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 (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.

130. The method of claim 118, wherein the disease is depression, anxiety, pain, inflammation, addiction, an autoimmune disease, an eating disorder, or an obsessive compulsive disorder. 81 ACTIVE / 137605700.1Attorney Docket No.: CYBP-004WO 131. The method of claim 118, wherein the disease is social anxiety disorder, avoidant personality disorder, or schizotypal personality disorder.

132. The method of claim 118, 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.

133. The method of claim 118, wherein the disease is depression caused by cancer, chronic pain, chemotherapy, chronic stress, or post traumatic stress disorder.

134. The method of claim 118, wherein the disease is obsessive-compulsive spectrum disorder (OCSD).

135. The method of claim 118, wherein the disease is body dysmorphic disorder (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 Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections.

136. The method of claim 118, 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, 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, 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. 82 ACTIVE / 137605700.1

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